David K. Stevenson, M.D.

All Publications

• Outcome of pregnancy oral glucose tolerance test and preterm birth. Epidemiology (Cambridge, Mass.) Liang, R., Panelli, D. M., Stevenson, D. K., Rehkopf, D. H., Shaw, G. M., Sørensen, H. T., Pedersen, L. 2024

  Abstract

  Gestational diabetes is associated with adverse outcomes such as preterm birth (<37 weeks). However, there is no international consensus on screening criteria or diagnostic levels for gestational diabetes, and it is unknown whether body mass index (BMI) or obesity modifies the relation between glucose level and preterm birth.We studied a pregnancy cohort restricted to two Danish regions from the linked Danish Medical Birth Register to study associations between glucose measurements from the 2-hour post-load 75-gram oral glucose tolerance test (one-step approach) and preterm birth from 2004-2018. In Denmark, gestational diabetes screening is a targeted strategy for mothers with identified risk factors. We used Poisson regression to estimate rate ratios (RR) of preterm birth with z-standardized glucose measurements. We assessed effect measure modification by stratifying analyses and testing for heterogeneity.Among 11,337 pregnancies (6.2% delivered preterm), we observed an adjusted preterm birth RR of 1.2 (95% CI: 1.1-1.3) for a 1 standard deviation glucose increase of 1.4 mmol/L from the mean 6.7 mmol/L. There was evidence for effect measure modification by obesity, e.g., adjusted RR for non-obese (BMI <30): 1.2 (95%CI: 1.1-1.3) vs. obese (BMI ≥30): 1.3 (95%CI: 1.2-1.5), P=0.05 for heterogeneity.Among mothers screened for gestational diabetes, increased glucose levels, even those below the diagnostic level for gestational diabetes in Denmark, were associated with increased preterm birth risk. Obesity (BMI ≥30) may be an effect measure modifier, not just a confounder, of the relation between blood glucose and preterm birth risk.

  View details for DOI 10.1097/EDE.0000000000001752

  View details for PubMedID 38771706

• Microbiome preterm birth DREAM challenge: Crowdsourcing machine learning approaches to advance preterm birth research. Cell reports. Medicine Golob, J. L., Oskotsky, T. T., Tang, A. S., Roldan, A., Chung, V., Ha, C. W., Wong, R. J., Flynn, K. J., Parraga-Leo, A., Wibrand, C., Minot, S. S., Oskotsky, B., Andreoletti, G., Kosti, I., Bletz, J., Nelson, A., Gao, J., Wei, Z., Chen, G., Tang, Z. Z., Novielli, P., Romano, D., Pantaleo, E., Amoroso, N., Monaco, A., Vacca, M., De Angelis, M., Bellotti, R., Tangaro, S., Kuntzleman, A., Bigcraft, I., Techtmann, S., Bae, D., Kim, E., Jeon, J., Joe, S., Theis, K. R., Ng, S., Lee, Y. S., Diaz-Gimeno, P., Bennett, P. R., MacIntyre, D. A., Stolovitzky, G., Lynch, S. V., Albrecht, J., Gomez-Lopez, N., Romero, R., Stevenson, D. K., Aghaeepour, N., Tarca, A. L., Costello, J. C., Sirota, M. 2023: 101350

  Abstract

  Every year, 11% of infants are born preterm with significant health consequences, with the vaginal microbiome a risk factor for preterm birth. We crowdsource models to predict (1) preterm birth (PTB; <37 weeks) or (2) early preterm birth (ePTB; <32 weeks) from 9 vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from public raw data via phylogenetic harmonization. The predictive models are validated on two independent unpublished datasets representing 331 samples from 148 pregnant individuals. The top-performing models (among 148 and 121 submissions from 318 teams) achieve area under the receiver operator characteristic (AUROC) curve scores of 0.69 and 0.87 predicting PTB and ePTB, respectively. Alpha diversity, VALENCIA community state types, and composition are important features in the top-performing models, most of which are tree-based methods. This work is a model for translation of microbiome data into clinically relevant predictive models and to better understand preterm birth.

  View details for DOI 10.1016/j.xcrm.2023.101350

  View details for PubMedID 38134931

• Comparative predictive power of serum vs plasma proteomic signatures in feto-maternal medicine. AJOG global reports Espinosa, C., Ali, S. M., Khan, W., Khanam, R., Pervin, J., Price, J. T., Rahman, S., Hasan, T., Ahmed, S., Raqib, R., Rahman, M., Aktar, S., Nisar, M. I., Khalid, J., Dhingra, U., Dutta, A., Deb, S., Stringer, J. S., Wong, R. J., Shaw, G. M., Stevenson, D. K., Darmstadt, G. L., Gaudilliere, B., Baqui, A. H., Jehan, F., Rahman, A., Sazawal, S., Vwalika, B., Aghaeepour, N., Angst, M. S. 2023; 3 (3): 100244

  Abstract

  Blood proteins are frequently measured in serum or plasma, because they provide a wealth of information. Differences in the ex vivo processing of serum and plasma raise concerns that proteomic health and disease signatures derived from serum or plasma differ in content and quality. However, little is known about their respective power to predict feto-maternal health outcomes. Predictive power is a sentinel characteristic to determine the clinical use of biosignatures.This study aimed to compare the power of serum and plasma proteomic signatures to predict a physiological pregnancy outcome.Paired serum and plasma samples from 73 women were obtained from biorepositories of a multinational prospective cohort study on pregnancy outcomes. Gestational age at the time of sampling was the predicted outcome, because the proteomic signatures have been validated for such a prediction. Multivariate and cross-validated models were independently derived for serum and plasma proteins.A total of 1116 proteins were measured in 88 paired samples from 73 women with a highly multiplexed platform using proximity extension technology (Olink Proteomics Inc, Watertown, MA). The plasma proteomic signature showed a higher predictive power (R=0.64; confidence interval, 0.42-0.79; P=3.5×10-6) than the serum signature (R=0.45; confidence interval, 0.18-0.66; P=2.2×10-3). The serum signature was validated in plasma with a similar predictive power (R=0.58; confidence interval, 0.34-0.75; P=4.8×10-5), whereas the plasma signature was validated in serum with reduced predictive power (R=0.53; confidence interval, 0.27-0.72; P=2.6×10-4). Signature proteins largely overlapped in the serum and plasma, but the strength of association with gestational age was weaker for serum proteins.Findings suggest that serum proteomics are less informative than plasma proteomics. They are compatible with the view that the partial ex-vivo degradation and modification of serum proteins during sample processing are an underlying reason. The rationale for collecting and analyzing serum and plasma samples should be carefully considered when deriving proteomic biosignatures to ascertain that specimens of the highest scientific and clinical yield are processed. Findings suggest that plasma is the preferred matrix.

  View details for DOI 10.1016/j.xagr.2023.100244

  View details for PubMedID 37456144

  View details for PubMedCentralID PMC10339042

• Data-driven longitudinal characterization of neonatal health and morbidity. Science translational medicine De Francesco, D., Reiss, J. D., Roger, J., Tang, A. S., Chang, A. L., Becker, M., Phongpreecha, T., Espinosa, C., Morin, S., Berson, E., Thuraiappah, M., Le, B. L., Ravindra, N. G., Payrovnaziri, S. N., Mataraso, S., Kim, Y., Xue, L., Rosenstein, M. G., Oskotsky, T., Marić, I., Gaudilliere, B., Carvalho, B., Bateman, B. T., Angst, M. S., Prince, L. S., Blumenfeld, Y. J., Benitz, W. E., Fuerch, J. H., Shaw, G. M., Sylvester, K. G., Stevenson, D. K., Sirota, M., Aghaeepour, N. 2023; 15 (683): eadc9854

  Abstract

  Although prematurity is the single largest cause of death in children under 5 years of age, the current definition of prematurity, based on gestational age, lacks the precision needed for guiding care decisions. Here, we propose a longitudinal risk assessment for adverse neonatal outcomes in newborns based on a deep learning model that uses electronic health records (EHRs) to predict a wide range of outcomes over a period starting shortly before conception and ending months after birth. By linking the EHRs of the Lucile Packard Children's Hospital and the Stanford Healthcare Adult Hospital, we developed a cohort of 22,104 mother-newborn dyads delivered between 2014 and 2018. Maternal and newborn EHRs were extracted and used to train a multi-input multitask deep learning model, featuring a long short-term memory neural network, to predict 24 different neonatal outcomes. An additional cohort of 10,250 mother-newborn dyads delivered at the same Stanford Hospitals from 2019 to September 2020 was used to validate the model. Areas under the receiver operating characteristic curve at delivery exceeded 0.9 for 10 of the 24 neonatal outcomes considered and were between 0.8 and 0.9 for 7 additional outcomes. Moreover, comprehensive association analysis identified multiple known associations between various maternal and neonatal features and specific neonatal outcomes. This study used linked EHRs from more than 30,000 mother-newborn dyads and would serve as a resource for the investigation and prediction of neonatal outcomes. An interactive website is available for independent investigators to leverage this unique dataset: https://maternal-child-health-associations.shinyapps.io/shiny_app/.

  View details for DOI 10.1126/scitranslmed.adc9854

  View details for PubMedID 36791208

• Omics approaches: interactions at the maternal-fetal interface and origins of child health and disease. Pediatric research Ozen, M., Aghaeepour, N., Maric, I., Wong, R. J., Stevenson, D. K., Jantzie, L. L. 2022

  Abstract

  Immunoperinatology is an emerging field. Transdisciplinary efforts by physicians, physician-scientists, basic science researchers, and computational biologists have made substantial advancements by identifying unique immunologic signatures of specific diseases, discovering innovative preventative or treatment strategies, and establishing foundations for individualized neonatal intensive care of the most vulnerable neonates. In this review, we summarize the immunobiology and immunopathology of pregnancy, highlight omics approaches to study the maternal-fetal interface, and their contributions to pregnancy health. We examined the importance of transdisciplinary, multiomic (such as genomics, transcriptomics, proteomics, metabolomics, and immunomics) and machine-learning strategies in unraveling the mechanisms of adverse pregnancy, neonatal, and childhood outcomes and how they can guide the development of novel therapies to improve maternal and neonatal health. IMPACT: Discuss immunoperinatology research from the lens of omics and machine-learning approaches. Identify opportunities for omics-based approaches to delineate infection/inflammation-associated maternal, neonatal, and later life adverse outcomes (e.g., histologic chorioamnionitis [HCA]).

  View details for DOI 10.1038/s41390-022-02335-x

  View details for PubMedID 36216868

• Progressive Metabolic Abnormalities Associated with the Development of Neonatal Bronchopulmonary Dysplasia. Nutrients Ye, C., Wu, J., Reiss, J. D., Sinclair, T. J., Stevenson, D. K., Shaw, G. M., Chace, D. H., Clark, R. H., Prince, L. S., Ling, X. B., Sylvester, K. G. 2022; 14 (17)

  Abstract

  Objective: To assess the longitudinal metabolic patterns during the evolution of bronchopulmonary dysplasia (BPD) development. Methods: A case-control dataset of preterm infants (<32-week gestation) was obtained from a multicenter database, including 355 BPD cases and 395 controls. A total of 72 amino acid (AA) and acylcarnitine (AC) variables, along with infants' calorie intake and growth outcomes, were measured on day of life 1, 7, 28, and 42. Logistic regression, clustering methods, and random forest statistical modeling were utilized to identify metabolic variables significantly associated with BPD development and to investigate their longitudinal patterns that are associated with BPD development. Results: A panel of 27 metabolic variables were observed to be longitudinally associated with BPD development. The involved metabolites increased from 1 predominant different AC by day 7 to 19 associated AA and AC compounds by day 28 and 16 metabolic features by day 42. Citrulline, alanine, glutamate, tyrosine, propionylcarnitine, free carnitine, acetylcarnitine, hydroxybutyrylcarnitine, and most median-chain ACs (C5:C10) were the most associated metabolites down-regulated in BPD babies over the early days of life, whereas phenylalanine, methionine, and hydroxypalmitoylcarnitine were observed to be up-regulated in BPD babies. Most calorie intake and growth outcomes revealed similar longitudinal patterns between BPD cases and controls over the first 6 weeks of life, after gestational adjustment. When combining with birth weight, the derived metabolic-based discriminative model observed some differences between those with and without BPD development, with c-statistics of 0.869 and 0.841 at day 7 and 28 of life on the test data. Conclusions: The metabolic panel we describe identified some metabolic differences in the blood associated with BPD pathogenesis. Further work is needed to determine whether these compounds could facilitate the monitoring and/or investigation of early-life metabolic status in the lung and other tissues for the prevention and management of BPD.

  View details for DOI 10.3390/nu14173547

  View details for PubMedID 36079804

• HMOX1 Genetic Polymorphisms Display Ancestral Diversity and May Be Linked to Hypertensive Disorders in Pregnancy. Reproductive sciences (Thousand Oaks, Calif.) Sun, T., Cruz, G. I., Mousavi, N., Maric, I., Brewer, A., Wong, R. J., Aghaeepour, N., Sayed, N., Wu, J. C., Stevenson, D. K., Leonard, S. A., Gymrek, M., Winn, V. D. 2022

  Abstract

  Racial disparity exists for hypertensive disorders in pregnancy (HDP), which leads to disparate morbidity and mortality worldwide. The enzyme heme oxygenase-1 (HO-1) is encoded by HMOX1, which has genetic polymorphisms in its regulatory region that impact its expression and activity and have been associated with various diseases. However, studies of these genetic variants in HDP have been limited. The objective of this study was to examine HMOX1 as a potential genetic contributor of ancestral disparity seen in HDP. First, the 1000 Genomes Project (1KG) phase 3 was utilized to compare the frequencies of alleles, genotypes, and estimated haplotypes of guanidine thymidine repeats (GTn; containing rs3074372) and A/T SNP (rs2071746) among females from five ancestral populations (Africa, theAmericas, Europe, East Asia, and South Asia, N=1271). Then, using genomic DNA from women with a history of HDP, we explored the possibility of HMOX1 variants predisposing women to HDP (N=178) compared with an equivalent ancestral group from 1KG (N=263). Both HMOX1 variants were distributed differently across ancestries, with African women having a distinct distribution and an overall higher prevalence of the variants previously associated with lower HO-1 expression. The two HMOX1 variants display linkage disequilibrium in all but the African group, and within EUR cohort, LL and AA individuals have a higher prevalence in HDP. HMOX1 variants demonstrate ancestral differences that may contribute to racial disparity in HDP. Understanding maternal genetic contribution to HDP will help improve prediction and facilitate personalized approaches to care for HDP.

  View details for DOI 10.1007/s43032-022-01001-1

  View details for PubMedID 35697922

• Population-based associations between maternal pre-pregnancy body mass index and spontaneous and medically indicated preterm birth using restricted cubic splines in California. Annals of epidemiology Mayo, J. A., Stevenson, D. K., Shaw, G. M. 2022

  Abstract

  The literature pertaining to risk of spontaneous preterm birth (sPTB) as related to body mass index (BMI), specifically high BMI, is conflicting.To assess the relationships between maternal pre-pregnancy BMI and sPTB separately for Non-Hispanic Whites, Non-Hispanic Blacks, Hispanics, and Asians.Population-based cohort study of mothers who delivered a singleton livebirth in California from 2007-2012. Associations between BMI and sPTB were estimated from Cox proportional hazard models. BMI was modelled with restricted cubic splines to account for non-linear relationships.A total of 2,645,950 births were included in the analysis, 135,357 (5.12%) in which the mother had a sPTB. Compared to mothers within the same race/ethnicity and a BMI of 26 kg/m2, all mothers with a BMI 28 kg/m2 or higher had significantly elevated adjusted hazard ratios sPTB. Asian mothers with a BMI between 16 to 25 kg/m2 had significantly decreased hazard ratios for sPTB while a of BMI 20 kg/m2 or less among Non-Hispanic White, Non-Hispanic Black, and Hispanic mothers showed increased hazard ratios.This study observed that mothers with high pre-pregnancy BMIs were more likely to experience sPTB across all race/ethnicities.

  View details for DOI 10.1016/j.annepidem.2022.05.009

  View details for PubMedID 35667536

• A data-driven health index for neonatal morbidities. iScience De Francesco, D., Blumenfeld, Y. J., Maric, I., Mayo, J. A., Chang, A. L., Fallahzadeh, R., Phongpreecha, T., Butwick, A. J., Xenochristou, M., Phibbs, C. S., Bidoki, N. H., Becker, M., Culos, A., Espinosa, C., Liu, Q., Sylvester, K. G., Gaudilliere, B., Angst, M. S., Stevenson, D. K., Shaw, G. M., Aghaeepour, N. 2022; 25 (4): 104143

  Abstract

  Whereas prematurity is a major cause of neonatal mortality, morbidity, and lifelong impairment, the degree of prematurity is usually defined by the gestational age (GA) at delivery rather than by neonatal morbidity. Here we propose a multi-task deep neural network model that simultaneously predicts twelve neonatal morbidities, as the basis for a new data-driven approach to define prematurity. Maternal demographics, medical history, obstetrical complications, and prenatal fetal findings were obtained from linked birth certificates and maternal/infant hospitalization records for 11,594,786 livebirths in California from 1991 to 2012. Overall, our model outperformed traditional models to assess prematurity which are based on GA and/or birthweight (area under the precision-recall curve was 0.326 for our model, 0.229 for GA, and 0.156 for small for GA). These findings highlight the potential of using machine learning techniques to predict multiple prematurity phenotypes and inform clinical decisions to prevent, diagnose and treat neonatal morbidities.

  View details for DOI 10.1016/j.isci.2022.104143

  View details for PubMedID 35402862

• Perinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations. Experimental neurology Reiss, J. D., Peterson, L. S., Nesamoney, S. N., Chang, A. L., Pasca, A. M., Marić, I., Shaw, G. M., Gaudilliere, B., Wong, R. J., Sylvester, K. G., Bonifacio, S. L., Aghaeepour, N., Gibbs, R. S., Stevenson, D. K. 2022: 113988

  Abstract

  Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.

  View details for DOI 10.1016/j.expneurol.2022.113988

  View details for PubMedID 35081400

• Newborn screen metabolic panels reflect the impact of common disorders of pregnancy. Pediatric research Reiss, J. D., Chang, A. L., Mayo, J. A., Bianco, K., Lee, H. C., Stevenson, D. K., Shaw, G. M., Aghaeepour, N., Sylvester, K. G. 2021

  Abstract

  BACKGROUND: Hypertensive disorders of pregnancy and maternal diabetes profoundly affect fetal and newborn growth, yet disturbances in intermediate metabolism and relevant mediators of fetal growth alterations remain poorly defined. We sought to determine whether there are distinct newborn screen metabolic patterns among newborns affected by maternal hypertensive disorders or diabetes in utero.METHODS: A retrospective observational study investigating distinct newborn screen metabolites in conjunction with data linked to birth and hospitalization records in the state of California between 2005 and 2010.RESULTS: A total of 41,333 maternal-infant dyads were included. Infants of diabetic mothers demonstrated associations with short-chain acylcarnitines and free carnitine. Infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia had alterations in acetylcarnitine, free carnitine, and ornithine levels. These results were further accentuated by size for gestational age designations.CONCLUSIONS: Infants of diabetic mothers demonstrate metabolic signs of incomplete beta oxidation and altered lipid metabolism. Infants of mothers with hypertensive disorders of pregnancy carry analyte signals that may reflect oxidative stress via altered nitric oxide signaling. The newborn screen analyte composition is influenced by the presence of these maternal conditions and is further associated with the newborn size designation at birth.IMPACT: Substantial differences in newborn screen analyte profiles were present based on the presence or absence of maternal diabetes or hypertensive disorder of pregnancy and this finding was further influenced by the newborn size designation at birth. The metabolic health of the newborn can be examined using the newborn screen and is heavily impacted by the condition of the mother during pregnancy. Utilizing the newborn screen to identify newborns affected by common conditions of pregnancy may help relate an infant's underlying biological disposition with their clinical phenotype allowing for greater risk stratification and intervention.

  View details for DOI 10.1038/s41390-021-01753-7

  View details for PubMedID 34671094

• Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset. Science translational medicine Stelzer, I. A., Ghaemi, M. S., Han, X., Ando, K., Hedou, J. J., Feyaerts, D., Peterson, L. S., Rumer, K. K., Tsai, E. S., Ganio, E. A., Gaudilliere, D. K., Tsai, A. S., Choisy, B., Gaigne, L. P., Verdonk, F., Jacobsen, D., Gavasso, S., Traber, G. M., Ellenberger, M., Stanley, N., Becker, M., Culos, A., Fallahzadeh, R., Wong, R. J., Darmstadt, G. L., Druzin, M. L., Winn, V. D., Gibbs, R. S., Ling, X. B., Sylvester, K., Carvalho, B., Snyder, M. P., Shaw, G. M., Stevenson, D. K., Contrepois, K., Angst, M. S., Aghaeepour, N., Gaudilliere, B. 2021; 13 (592)

  Abstract

  Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 * 10-40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 * 10-7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.

  View details for DOI 10.1126/scitranslmed.abd9898

  View details for PubMedID 33952678

• Understanding how biologic and social determinants affect disparities in preterm birth and outcomes of preterm infants in the NICU. Seminars in perinatology Stevenson, D. K., Aghaeepour, N., Maric, I., Angst, M. S., Darmstadt, G. L., Druzin, M. L., Gaudilliere, B., Ling, X. B., Moufarrej, M. N., Peterson, L. S., Quake, S. R., Relman, D. A., Snyder, M. P., Sylvester, K. G., Shaw, G. M., Wong, R. J. 2021: 151408

  Abstract

  To understand the disparities in spontaneous preterm birth (sPTB) and/or its outcomes, biologic and social determinants as well as healthcare practice (such as those in neonatal intensive care units) should be considered. They have been largely intractable and remain obscure in most cases, despite a myriad of identified risk factors for and causes of sPTB. We still do not know how they might actually affect and lead to the different outcomes at different gestational ages and if they are independent of NICU practices. Here we describe an integrated approach to study the interplay between the genome and exposome, which may drive biochemistry and physiology, with health disparities.

  View details for DOI 10.1016/j.semperi.2021.151408

  View details for PubMedID 33875265

• A Peripheral Immune Signature of Labor Induction. Frontiers in immunology Ando, K., Hédou, J. J., Feyaerts, D., Han, X., Ganio, E. A., Tsai, E. S., Peterson, L. S., Verdonk, F., Tsai, A. S., Marić, I., Wong, R. J., Angst, M. S., Aghaeepour, N., Stevenson, D. K., Blumenfeld, Y. J., Sultan, P., Carvalho, B., Stelzer, I. A., Gaudillière, B. 2021; 12: 725989

  Abstract

  Approximately 1 in 4 pregnant women in the United States undergo labor induction. The onset and establishment of labor, particularly induced labor, is a complex and dynamic process influenced by multiple endocrine, inflammatory, and mechanical factors as well as obstetric and pharmacological interventions. The duration from labor induction to the onset of active labor remains unpredictable. Moreover, prolonged labor is associated with severe complications for the mother and her offspring, most importantly chorioamnionitis, uterine atony, and postpartum hemorrhage. While maternal immune system adaptations that are critical for the maintenance of a healthy pregnancy have been previously characterized, the role of the immune system during the establishment of labor is poorly understood. Understanding maternal immune adaptations during labor initiation can have important ramifications for predicting successful labor induction and labor complications in both induced and spontaneous types of labor. The aim of this study was to characterize labor-associated maternal immune system dynamics from labor induction to the start of active labor. Serial blood samples from fifteen participants were collected immediately prior to labor induction (baseline) and during the latent phase until the start of active labor. Using high-dimensional mass cytometry, a total of 1,059 single-cell immune features were extracted from each sample. A multivariate machine-learning method was employed to characterize the dynamic changes of the maternal immune system after labor induction until the establishment of active labor. A cross-validated linear sparse regression model (least absolute shrinkage and selection operator, LASSO) predicted the minutes since induction of labor with high accuracy (R = 0.86, p = 6.7e-15, RMSE = 277 min). Immune features most informative for the model included STAT5 signaling in central memory CD8+ T cells and pro-inflammatory STAT3 signaling responses across multiple adaptive and innate immune cell subsets. Our study reports a peripheral immune signature of labor induction, and provides important insights into biological mechanisms that may ultimately predict labor induction success as well as complications, thereby facilitating clinical decision-making to improve maternal and fetal well-being.

  View details for DOI 10.3389/fimmu.2021.725989

  View details for PubMedID 34566984

  View details for PubMedCentralID PMC8458888

• Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants. JAMA network open Oskotsky, T., Maric, I., Tang, A., Oskotsky, B., Wong, R. J., Aghaeepour, N., Sirota, M., Stevenson, D. K. 2021; 4 (11): e2133090

  Abstract

  Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)-specifically fluoxetine hydrochloride and fluvoxamine maleate-with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size.To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs).This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US.Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine).Death.A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, relative risk (RR) of mortality was reduced among patients prescribed any SSRI (497 of 3401 [14.6%] vs 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03); fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). The association between receiving any SSRI that is not fluoxetine or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06).These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.

  View details for DOI 10.1001/jamanetworkopen.2021.33090

  View details for PubMedID 34779847

• Single-Cell Analysis of the Neonatal Immune System Across the Gestational Age Continuum. Frontiers in immunology Peterson, L. S., Hedou, J., Ganio, E. A., Stelzer, I. A., Feyaerts, D., Harbert, E., Adusumelli, Y., Ando, K., Tsai, E. S., Tsai, A. S., Han, X., Ringle, M., Houghteling, P., Reiss, J. D., Lewis, D. B., Winn, V. D., Angst, M. S., Aghaeepour, N., Stevenson, D. K., Gaudilliere, B. 2021; 12: 714090

  Abstract

  Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8+CD161+ T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections.

  View details for DOI 10.3389/fimmu.2021.714090

  View details for PubMedID 34497610

  View details for PubMedCentralID PMC8420969

• The Impact of Hypoxia in Early Pregnancy on Placental Cells. International journal of molecular sciences Zhao, H., Wong, R. J., Stevenson, D. K. 2021; 22 (18)

  Abstract

  Oxygen levels in the placental microenvironment throughout gestation are not constant, with severe hypoxic conditions present during the first trimester. This hypoxic phase overlaps with the most critical stages of placental development, i.e., blastocyst implantation, cytotrophoblast invasion, and spiral artery remodeling initiation. Dysregulation of any of these steps in early gestation can result in pregnancy loss and/or adverse pregnancy outcomes. Hypoxia has been shown to regulate not only the self-renewal, proliferation, and differentiation of trophoblast stem cells and progenitor cells, but also the recruitment, phenotype, and function of maternal immune cells. In this review, we will summarize how oxygen levels in early placental development determine the survival, fate, and function of several important cell types, e.g., trophoblast stem cells, extravillous trophoblasts, syncytiotrophoblasts, uterine natural killer cells, Hofbauer cells, and decidual macrophages. We will also discuss the cellular mechanisms used to cope with low oxygen tensions, such as the induction of hypoxia-inducible factor (HIF) or mammalian target of rapamycin (mTOR) signals, regulation of the metabolic pathway, and adaptation to autophagy. Understanding the beneficial roles of hypoxia in early placental development will provide insights into the root cause(s) of some pregnancy disorders, such as spontaneous abortion, preeclampsia, and intrauterine growth restriction.

  View details for DOI 10.3390/ijms22189675

  View details for PubMedID 34575844

• Parental age and preterm birth: a population-based cohort of nearly 3 million California livebirths from 2007 to 2012. Journal of perinatology : official journal of the California Perinatal Association Mayo, J. A., Lu, Y., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2020

  Abstract

  PURPOSE: To assess the relationships between parental ages and preterm birth subtypes.METHODS: A population-based cohort analysis of California livebirths 2007-2012. Associations between maternal and paternal age with spontaneous and medically indicated preterm birth were estimated from Cox proportional hazard models. Parental age was modeled with restricted cubic splines to account for nonlinear relationships.RESULTS: Young paternal age was associated with increased hazard ratios for spontaneous and medically indicated preterm birth. Older fathers showed elevated hazards for preterm birth in crude analysis but after adjustment the relationship was generally not observed. Aging mothers showed increased hazard ratios for both preterm birth phenotypes.CONCLUSIONS: After adjusting for parental demographics, births to younger fathers and older mothers had the highest risks for spontaneous preterm birth. The paternal influence on preterm birth was observed to be independent of maternal factors.

  View details for DOI 10.1038/s41372-020-00894-7

  View details for PubMedID 33293667

• A novel point-of-care device for measuring glucose-6-phosphate dehydrogenase enzyme deficiency. Seminars in perinatology Wong, R. J., Montiel, C., Kunda, M., Stevenson, D. K., Bhutani, V. K. 2020: 151356

  Abstract

  Extreme hyperbilirubinemia can cause bilirubin neurotoxicity. Infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency can develop hemolysis and thus are at high risk. We evaluated a device that quantitatively measures G6PD activity kinetically using digital microfluidics (DMF). Intra- and inter-instrument and -day imprecision (CVs) were first assessed. G6PD activity in 86 samples was then measured and compared between DMF and 2 reference methods. Overall DMF reproducibility was 3.8% over 5 days by 2 operators on 2 instruments. Mean intra- and inter-instrument variabilities were 3.6% and 3.9%, respectively (n=28), with a user variability of 4.3%. Mean G6PD activity was 6.40±4.62 and 6.37±4.62U/g hemoglobin for DMF and Reference Methods 1 (n=46) and 12.15±3.86 and 11.48±1.55 for DMF and 2 (n=40), respectively, and strongly correlated (r=0.95 and 0.95) with mean biases of +0.04±2.90 and +0.67±1.55 for methods 1 and 2, respectively. The novel device could be used for early newborn G6PD screening.

  View details for DOI 10.1016/j.semperi.2020.151356

  View details for PubMedID 33293060

• Integration of mechanistic immunological knowledge into a machine learning pipeline improves predictions. Nature machine intelligence Culos, A., Tsai, A. S., Stanley, N., Becker, M., Ghaemi, M. S., McIlwain, D. R., Fallahzadeh, R., Tanada, A., Nassar, H., Espinosa, C., Xenochristou, M., Ganio, E., Peterson, L., Han, X., Stelzer, I. A., Ando, K., Gaudilliere, D., Phongpreecha, T., Marić, I., Chang, A. L., Shaw, G. M., Stevenson, D. K., Bendall, S., Davis, K. L., Fantl, W., Nolan, G. P., Hastie, T., Tibshirani, R., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2020; 2 (10): 619-628

  Abstract

  The dense network of interconnected cellular signalling responses that are quantifiable in peripheral immune cells provides a wealth of actionable immunological insights. Although high-throughput single-cell profiling techniques, including polychromatic flow and mass cytometry, have matured to a point that enables detailed immune profiling of patients in numerous clinical settings, the limited cohort size and high dimensionality of data increase the possibility of false-positive discoveries and model overfitting. We introduce a generalizable machine learning platform, the immunological Elastic-Net (iEN), which incorporates immunological knowledge directly into the predictive models. Importantly, the algorithm maintains the exploratory nature of the high-dimensional dataset, allowing for the inclusion of immune features with strong predictive capabilities even if not consistent with prior knowledge. In three independent studies our method demonstrates improved predictions for clinically relevant outcomes from mass cytometry data generated from whole blood, as well as a large simulated dataset. The iEN is available under an open-source licence.

  View details for DOI 10.1038/s42256-020-00232-8

  View details for PubMedID 33294774

  View details for PubMedCentralID PMC7720904

• Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn. Physiological reviews Hansen, T. W., Wong, R. J., Stevenson, D. K. 2020; 100 (3): 1291–1346

  Abstract

  Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.

  View details for DOI 10.1152/physrev.00004.2019

  View details for PubMedID 32401177

• Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia. PloS one Hao, S. n., You, J. n., Chen, L. n., Zhao, H. n., Huang, Y. n., Zheng, L. n., Tian, L. n., Maric, I. n., Liu, X. n., Li, T. n., Bianco, Y. K., Winn, V. D., Aghaeepour, N. n., Gaudilliere, B. n., Angst, M. S., Zhou, X. n., Li, Y. M., Mo, L. n., Wong, R. J., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Mcelhinney, D. B., Sylvester, K. G., Ling, X. B. 2020; 15 (3): e0230000

  Abstract

  Placental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms.Serum levels of placenta-related proteins-leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)-were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice.An elastic net-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R2 = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R2 = 0.27) and mouse HO-1 Het (R2 = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs.Serum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.

  View details for DOI 10.1371/journal.pone.0230000

  View details for PubMedID 32126118

• Computational discovery of therapeutic candidates for preventing preterm birth. JCI insight Le, B. L., Iwatani, S. n., Wong, R. J., Stevenson, D. K., Sirota, M. n. 2020; 5 (3)

  Abstract

  Few therapeutic methods exist for preventing preterm birth (PTB), or delivery before completing 37 weeks of gestation. In the US, progesterone (P4) supplementation is the only FDA-approved drug for use in preventing recurrent spontaneous PTB. However, P4 has limited effectiveness, working in only approximately one-third of cases. Computational drug repositioning leverages data on existing drugs to discover novel therapeutic uses. We used a rank-based pattern-matching strategy to compare the differential gene expression signature for PTB to differential gene expression drug profiles in the Connectivity Map database and assigned a reversal score to each PTB-drug pair. Eighty-three drugs, including P4, had significantly reversed differential gene expression compared with that found for PTB. Many of these compounds have been evaluated in the context of pregnancy, with 13 belonging to pregnancy category A or B - indicating no known risk in human pregnancy. We focused our validation efforts on lansoprazole, a proton-pump inhibitor, which has a strong reversal score and a good safety profile. We tested lansoprazole in an animal inflammation model using LPS, which showed a significant increase in fetal viability compared with LPS treatment alone. These promising results demonstrate the effectiveness of the computational drug repositioning pipeline to identify compounds that could be effective in preventing PTB.

  View details for DOI 10.1172/jci.insight.133761

  View details for PubMedID 32051340

• Residential proximity to green space and preeclampsia in California. Environmental epidemiology (Philadelphia, Pa.) Weber, K. A., Lyons, E. n., Yang, W. n., Stevenson, C. n., Stevenson, D. K., Shaw, G. M. 2020; 4 (6): e120

  Abstract

  We investigated whether residing near more green space might reduce the risk of preeclampsia.Participants were women who delivered a live, singleton birth between 1998 and 2011 in eight counties of the San Joaquin Valley in California. There were 7276 cases of preeclampsia divided into mild, severe, or superimposed on preexisting hypertension. Controls were 197,345 women who did not have a hypertensive disorder and delivered between 37 and 41 weeks. Green space was estimated from satellite data using Normalized Difference Vegetation Index (NDVI), an index calculated from surface reflectance at the visible and near-infrared wavelengths. Values closer to 1 denote a higher density of green vegetation. Average NDVI was calculated within a 50 m, 100 m, and 500 m buffer around each woman's residence. Odds ratios and 95% confidence intervals were estimated comparing the lowest and highest quartiles of mean NDVI to the interquartile range comparing each preeclampsia phenotype, divided into early (20-31 weeks) and late (32-36 weeks) preterm birth, to full-term controls.We observed an inverse association in the 500 m buffer for women in the top quartile of NDVI and a positive association for women in the lowest quartile of NDVI for women with superimposed preeclampsia. There were no associations in the 50 and 100 m buffers.Within a 500 m buffer, more green space was inversely associated with superimposed preeclampsia. Future work should explore the mechanism by which green space may protect against preeclampsia.

  View details for DOI 10.1097/EE9.0000000000000120

  View details for PubMedID 33336135

  View details for PubMedCentralID PMC7727466

• Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries. JAMA network open Jehan, F. n., Sazawal, S. n., Baqui, A. H., Nisar, M. I., Dhingra, U. n., Khanam, R. n., Ilyas, M. n., Dutta, A. n., Mitra, D. K., Mehmood, U. n., Deb, S. n., Mahmud, A. n., Hotwani, A. n., Ali, S. M., Rahman, S. n., Nizar, A. n., Ame, S. M., Moin, M. I., Muhammad, S. n., Chauhan, A. n., Begum, N. n., Khan, W. n., Das, S. n., Ahmed, S. n., Hasan, T. n., Khalid, J. n., Rizvi, S. J., Juma, M. H., Chowdhury, N. H., Kabir, F. n., Aftab, F. n., Quaiyum, A. n., Manu, A. n., Yoshida, S. n., Bahl, R. n., Rahman, A. n., Pervin, J. n., Winston, J. n., Musonda, P. n., Stringer, J. S., Litch, J. A., Ghaemi, M. S., Moufarrej, M. N., Contrepois, K. n., Chen, S. n., Stelzer, I. A., Stanley, N. n., Chang, A. L., Hammad, G. B., Wong, R. J., Liu, C. n., Quaintance, C. C., Culos, A. n., Espinosa, C. n., Xenochristou, M. n., Becker, M. n., Fallahzadeh, R. n., Ganio, E. n., Tsai, A. S., Gaudilliere, D. n., Tsai, E. S., Han, X. n., Ando, K. n., Tingle, M. n., Maric, I. n., Wise, P. H., Winn, V. D., Druzin, M. L., Gibbs, R. S., Darmstadt, G. L., Murray, J. C., Shaw, G. M., Stevenson, D. K., Snyder, M. P., Quake, S. R., Angst, M. S., Gaudilliere, B. n., Aghaeepour, N. n. 2020; 3 (12): e2029655

  Abstract

  Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies.To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB.This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019.Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites.The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation.Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways.This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.

  View details for DOI 10.1001/jamanetworkopen.2020.29655

  View details for PubMedID 33337494

• Association between preconception paternal health and pregnancy loss in the USA: an analysis of US claims data. Human reproduction (Oxford, England) Kasman, A. M., Zhang, C. A., Li, S. n., Lu, Y. n., Lathi, R. B., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2020

  Abstract

  Is preconception paternal health associated with pregnancy loss?Poor preconception paternal health is associated with a higher risk of pregnancy loss as confirmed in sensitivity analyses accounting for maternal age and health.Preconception paternal health can negatively impact perinatal outcomes.Retrospective cohort study of US insurance claims database from 2009 to 2016 covering 958 804 pregnancies.US insurance claims database including women, men and pregnancies within the USA between 2007 and 2016. Paternal preconception health status (e.g. metabolic syndrome diagnoses (MetS), Charlson comorbidity index (CCI) and individual chronic disease diagnoses) was examined in relation to pregnancy loss (e.g. ectopic pregnancy, miscarriage and stillbirth).In all, 958 804 pregnancies were analyzed. The average paternal age was 35.3 years (SD 5.3) and maternal age was 33.1 years (SD 4.4). Twenty-two percent of all pregnancies ended in a loss. After adjusting for maternal factors, the risk of pregnancy loss increased with increasing paternal comorbidity. For example, compared to men with no components of MetS, the risk of pregnancy loss increased for men with one (relative risk (RR) 1.10, 95% CI 1.09-1.12), two (RR 1.15, 95% CI 1.13-1.17) or three or more (RR 1.19, 95% CI 1.14-1.24) components. Specifically, less healthy men had a higher risk of siring a pregnancy ending in spontaneous abortion, stillbirth and ectopic pregnancies. Similar patterns remained with other measures of paternal health (e.g. CCI, chronic diseases, etc.). When stratifying by maternal age as well as maternal health, a similar pattern of increasing pregnancy loss risk for men with 1, 2 or 3+ MetS was observed. A statistically significant but weak association between timing of pregnancy loss and paternal health was found.Retrospective study design covering only employer insured individuals may limit generalizability.Optimization of a father's health may improve pregnancy outcomes.National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085). M.L.E. is an advisor for Sandstone Diagnostics, Dadi, Hannah and Underdog. No other competing interests were declared.N/A.

  View details for DOI 10.1093/humrep/deaa332

  View details for PubMedID 33336240

• Comments on the 20th Anniversary of NeoReviews. NeoReviews Stevenson, D. K., Wong, R. J., Hay, W. W. 2020; 21 (10): e643–e648

  View details for DOI 10.1542/neo.21-10-e643

  View details for PubMedID 33004557

• A Genome-Wide Analysis of Clinical Chorioamnionitis among Preterm Infants AMERICAN JOURNAL OF PERINATOLOGY Spiegel, A. M., Li, J., Oehlert, J. W., Mayo, J. A., Quaintance, C. C., Girsen, A. I., Druzin, M. L., El-Sayed, Y. Y., Shaw, G. M., Stevenson, D. K., Gibbs, R. S. 2019; 36 (14): 1453–58

  View details for DOI 10.1055/s-0038-1677503

  View details for Web of Science ID 000499481500005

• Male-to-Female Ratios, Race/Ethnicity, and Spontaneous Preterm Birth among 11 Million California Infants. American journal of perinatology Shaw, G. M., Mayo, J. A., Eisenberg, M. L., Catalano, R., Stevenson, D. K. 2019

  Abstract

  OBJECTIVE: An observed disparity in population-scale data are a larger number of males among preterm births (PTBs). We investigated spontaneous PTB risk among women of various race/ethnic groups in combination with infants' sex.STUDY DESIGN: This observational study was conducted in>10 million California births (1991-2012) using birth certificates linked with maternal and infant hospital discharge data.RESULTS: Male-to-female ratios among term (37-42 weeks) infants exhibited the narrow ratio range 1.02 to 1.06 across race/ethnic groups. Such ratios among spontaneous PTBs were generally larger for all race/ethnic groups except non-Hispanic blacks. For blacks, ratios tended to be lower and similar to their term birth counterpart, 1.03. Hazard ratios adjusted for maternal age and education for non-Hispanic blacks were 0.99 (95% confidence interval [CI] 0.90-1.09), 1.01 (95% CI 0.95-1.08), 0.98 (95% CI 0.94-1.03), and 1.03 (95% CI 1.01-1.05), respectively, for gestational week groupings of 20 to 23, 24 to 27, 28 to 321, and 32 to 36. Hazard ratios for non-Hispanic whites for the same groupings were 1.08 (95% CI 0.98-1.18), 1.13 (95% CI 1.07-1.19), 1.21 (95% CI 1.17-1.25), and 1.18 (95% CI 1.17-1.19).CONCLUSION: Why male-to-female ratios are similar across gestational ages in blacks but substantially higher in other race/ethnic groups is theoretically considered relative to inflammation, stress, and other influences.

  View details for DOI 10.1055/s-0039-3400449

  View details for PubMedID 31756757

• Disease burden in offspring is associated with changing paternal demographics in the United States. Andrology Greenberg, D. R., Khandwala, Y. S., Lu, Y., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2019

  Abstract

  BACKGROUND: Average paternal age in the United States has increased substantially in the last few decades. Children of advanced age fathers have a higher incidence of early onset cancer and neuropsychiatric disease.OBJECTIVES: To quantify the number of population adjusted cases of early-onset cancer and neuropsychiatric disease in children attributable to increasing paternal age in the United States.METHODS: Paternal age in the United States from 1972 to 2015 was collected using the National Vital Statistics System (NVSS). Population attributable fraction and paternal age-specific cumulative incidence rates of several cancers and neuropsychiatric disorders were obtained from peer-reviewed publications. Paternal age-specific birth rates were correlated with paternal age-specific cumulative incidence rates to determine the number of attributable cases of disease caused by advancing age of fathers in the United States.RESULTS: The 2015 birth cohort in the United States is estimated to expect 9.2% more cases of acute lymphoblastic leukemia (ALL) diagnosed before 16years of age (157 additional cases), 13.2% more cases of embryonal tumors in children <5years of age (209 additional cases), and 13.0% more cases of breast cancer in females younger than 40years old (424 additional cases) compared to the 1972 birth cohort. We can estimate to expect 10.5% more cases of schizophrenia diagnosed before 21years of age (2864 additional cases), 6.3% more cases of autism spectrum disorder (ASD) in adolescents <17years of age (2934 additional cases), 4.5% more cases of anorexia nervosa (AN) in females 8-30years old (620 additional cases), and 9.2% more cases of bipolar disorder in young patients 16-25years old (252 additional cases) in the 2015 birth cohort compared to the 1972 birth cohort.CONCLUSION: Increasing paternal age in the United States is associated with a substantial increase in the number of cases of early-onset cancer and neuropsychiatric disease in offspring.

  View details for DOI 10.1111/andr.12700

  View details for PubMedID 31478609

• Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia FRONTIERS IN IMMUNOLOGY Han, X., Ghaemi, M. S., Ando, K., Peterson, L. S., Ganio, E. A., Tsai, A. S., Gaudilliere, D. K., Stelzer, I. A., Einhaus, J., Bertrand, B., Stanley, N., Culos, A., Tanada, A., Hedou, J., Tsai, E. S., Fallahzadeh, R., Wong, R. J., Judy, A. E., Winn, V. D., Druzins, M. L., Blumenfeld, Y. J., Hlatky, M. A., Quaintance, C. C., Gibbs, R. S., Carvalho, B., Shaw, G. M., Stevenson, D. K., Angst, M. S., Aghaeepour, N., Gaudilliere, B. 2019; 10

  View details for DOI 10.3389/fimmu.2019.01305

  View details for Web of Science ID 000470999000001

• A Genome-Wide Analysis of Clinical Chorioamnionitis among Preterm Infants. American journal of perinatology Spiegel, A. M., Li, J., Oehlert, J. W., Mayo, J. A., Quaintance, C. C., Girsen, A. I., Druzin, M. L., El-Sayed, Y. Y., Shaw, G. M., Stevenson, D. K., Gibbs, R. S. 2019

  Abstract

  OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with clinical chorioamnionitis among preterm infants.STUDY DESIGN: We reanalyzed a genome-wide association study (GWAS) from preterm newborns at less than 30 weeks' gestation. Cases and control definitions were determined using administrative records. There were 213 clinical chorioamnionitis cases and 707 clinically uninfected controls. We compared demographic and clinical outcomes of cases and controls. We performed a GWAS and compared the distribution of SNPs from the background genes and from the immunome genes. We used a Wilcoxon's rank-sum test to compare the SNPs normalized odds ratio and used odds ratios and p-values to determine candidate genes.RESULTS: Infants affected by clinical chorioamnionitis were more likely to have periventricular leukomalacia, high-grade retinopathy, and high-grade intraventricular hemorrhage (IVH). Although a GWAS did not identify SNPs associated with clinical chorioamnionitis at the genome-wide significance level, a direct test on the exonic variants in the human immunome revealed their significant increase of risk in clinical chorioamnionitis.CONCLUSION: Among very preterm infants, clinical chorioamnionitis was associated with periventricular leukomalacia, high-grade retinopathy, and IVH. Our analysis of variants in the human immunome indicates an association with clinical chorioamnionitis in very preterm pregnancies.

  View details for PubMedID 30674050

• APS Presidential Plenary 2019: the way of science: serendipity and the illusion of linearity. Pediatric research Stevenson, D. K. 2019

  View details for DOI 10.1038/s41390-019-0456-y

  View details for PubMedID 31195402

• Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy. Bioinformatics (Oxford, England) Ghaemi, M. S., DiGiulio, D. B., Contrepois, K., Callahan, B., Ngo, T. T., Lee-McMullen, B., Lehallier, B., Robaczewska, A., Mcilwain, D., Rosenberg-Hasson, Y., Wong, R. J., Quaintance, C., Culos, A., Stanley, N., Tanada, A., Tsai, A., Gaudilliere, D., Ganio, E., Han, X., Ando, K., McNeil, L., Tingle, M., Wise, P., Maric, I., Sirota, M., Wyss-Coray, T., Winn, V. D., Druzin, M. L., Gibbs, R., Darmstadt, G. L., Lewis, D. B., Partovi Nia, V., Agard, B., Tibshirani, R., Nolan, G., Snyder, M. P., Relman, D. A., Quake, S. R., Shaw, G. M., Stevenson, D. K., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2019; 35 (1): 95–103

  Abstract

  Motivation: Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.Results: We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementation: Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary information: Supplementary data are available at Bioinformatics online.

  View details for PubMedID 30561547

• Short interpregnancy interval as a risk factor for preterm birth in non-Hispanic Black and White women in California. Journal of perinatology : official journal of the California Perinatal Association Lonhart, J. A., Mayo, J. A., Padula, A. M., Wise, P. H., Stevenson, D. K., Shaw, G. M. 2019

  Abstract

  Short interpregnancy interval (IPI) is associated with adverse pregnancy outcomes, including preterm birth (PTB < 37 weeks GA). We investigated whether short IPI (< 6 months) contributes to the higher PTB frequency among non-Hispanic Blacks (NHB).Using a linked birth cohort > 1.5 million California live births, we examined frequencies of short IPI between racial/ethnic groups and estimated risks by multivariable logistic regression for spontaneous PTB. We expanded the study to births 1991-2012 and utilized a "within-mother" approach to permit methodologic inquiry about residual confounding.NHB women had higher frequency (7.6%) of short IPI than non-Hispanic White (NHW) women (4.4%). Adjusted odds ratios for PTB and short IPI were 1.64 (95% CI 1.54, 1.76) for NHW and 1.49 (1.34, 1.65) for NHB. Using within-mother analysis did not produce substantially different results.Short IPI is associated with PTB but does not explain risk disparity between NHWs and NHBs.

  View details for DOI 10.1038/s41372-019-0402-1

  View details for PubMedID 31209276

• Understanding health disparities. Journal of perinatology : official journal of the California Perinatal Association Stevenson, D. K., Wong, R. J., Aghaeepour, N., Angst, M. S., Darmstadt, G. L., DiGiulio, D. B., Druzin, M. L., Gaudilliere, B., Gibbs, R. S., B Gould, J., Katz, M., Li, J., Moufarrej, M. N., Quaintance, C. C., Quake, S. R., Relman, D. A., Shaw, G. M., Snyder, M. P., Wang, X., Wise, P. H. 2018

  Abstract

  Based upon our recent insights into the determinants of preterm birth, which is the leading cause of death in children under five years of age worldwide, we describe potential analytic frameworks that provides both a common understanding and, ultimately the basis for effective, ameliorative action. Our research on preterm birth serves as an example that the framing of any human health condition is a result of complex interactions between the genome and the exposome. New discoveries of the basic biology of pregnancy, such as the complex immunological and signaling processes that dictate the health and length of gestation, have revealed a complexity in the interactions (current and ancestral) between genetic and environmental forces. Understanding of these relationships may help reduce disparities in preterm birth and guide productive research endeavors and ultimately, effective clinical and public health interventions.

  View details for PubMedID 30560947

• Filtered sunlight versus intensive electric powered phototherapy in moderate-to-severe neonatal hyperbilirubinaemia: a randomised controlled non-inferiority trial LANCET GLOBAL HEALTH Slusher, T. M., Vreman, H. J., Brearley, A. M., Vaucher, Y. E., Wong, R. J., Stevenson, D. K., Adeleke, O. T., Ojo, I. P., Edowhorhu, G., Lund, T. C., Gbadero, D. A. 2018; 6 (10): E1122–E1131

  Abstract

  Kernicterus resulting from severe neonatal hyperbilirubinaemia is a leading cause of preventable deaths and disabilities in low-income and middle-income countries, partly because high-quality intensive phototherapy is unavailable. Previously, we showed that filtered-sunlight phototherapy (FSPT) was efficacious and safe for treatment of mild-to-moderate neonatal hyperbilirubinaemia. We aimed to extend these studies to infants with moderate-to-severe hyperbilirubinaemia.We did a prospective, randomised controlled non-inferiority trial in Ogbomoso, Nigeria-a simulated rural setting. Near-term or term infants aged 14 days or younger who were of 35 weeks or more gestational age and with total serum bilirubin concentrations at or above the recommended age-dependent treatment levels for high-risk neonates were randomly assigned (1:1) to either FSPT or intensive electric phototherapy (IEPT). Randomisation was computer-generated, and neither clinicians nor the parents or guardians of participants were masked to group allocation. FSPT was delivered in a transparent polycarbonate room lined with commercial tinting films that transmitted effective phototherapeutic light, blocked ultraviolet light, and reduced infrared radiation. The primary outcome was efficacy, which was based on assessable treatment days only (ie, those on which at least 4 h of phototherapy was delivered) and defined as a rate of increase in total serum bilirubin concentrations of less than 3·4 μmol/L/h in infants aged 72 h or younger, or a decrease in total serum bilirubin concentrations in those older than 72 h. Safety was defined as no sustained hypothermia, hyperthermia, dehydration, or sunburn and was based on all treatment days. Analysis was by intention to treat with a non-inferiority margin of 10%.Between July 31, 2015, and April 30, 2017, 174 neonates were enrolled and randomly assigned: 87 to FSPT and 87 to IEPT. Neonates in the FSPT group received 215 days of phototherapy, 82 (38%) of which were not assessable. Neonates in the IEPT group received 219 treatment days of phototherapy, 67 (31%) of which were not assessable. Median irradiance was 37·3 μW/cm2/nm (IQR 21·4-56·4) in the FSPT group and 50·4 μW/cm2/nm (44·5-66·2) in the IEPT group. FSPT was efficacious on 116 (87·2%) of 133 treatment days; IEPT was efficacious on 135 (88·8%) of 152 treatment days (mean difference -1·6%, 95% CI -9·9 to 6·7; p=0·8165). Because the CI did not extend below -10%, we concluded that FSPT was not inferior to IEPT. Treatment was safe for all neonates.FSPT is safe and no less efficacious than IEPT for treatment of moderate-to-severe neonatal hyperbilirubinaemia in near-term and term infants.Thrasher Research Fund and National Center for Advancing Translational Sciences.

  View details for PubMedID 30170894

• Stillbirth and Live Birth at Periviable Gestational Age: A Comparison of Prevalence and Risk Factors. American journal of perinatology Carmichael, S. L., Blumenfeld, Y. J., Mayo, J. A., Profit, J., Shaw, G. M., Hintz, S. R., Stevenson, D. K. 2018

  Abstract

  OBJECTIVE: We compared the prevalence of and risk factors for stillbirth and live birth at periviable gestational age (20-25 weeks).STUDY DESIGN: This is a cohort study of 2.5 million singleton births in California from 2007 to 2011. We estimated racial-ethnic prevalence ratios and used multivariable logistic regression for risk factor comparisons.RESULTS: In this study, 42% of deliveries at 20 to 25 weeks' gestation were stillbirths, and 22% were live births who died within 24 hours. The prevalence of delivery at periviable gestation was 3.4 per 1,000 deliveries among whites, 10.9 for blacks, 3.5 for Asians, and 4.4 for Hispanics. Nonwhite race-ethnicity, lower education, uninsured status, being U.S. born, older age, obesity, smoking, pre-pregnancy hypertension, nulliparity, interpregnancy interval, and prior preterm birth or stillbirth were all associated with increased risk of both stillbirth and live birth at 20 to 25 weeks' gestation, compared with delivery of a live birth at 37 to 41 weeks.CONCLUSION: Inclusion of stillbirths and live births in studies of deliveries at periviable gestations is important.

  View details for PubMedID 30208499

• Epigenetic immune cell counting in human blood samples for immunodiagnostics SCIENCE TRANSLATIONAL MEDICINE Baron, U., Werner, J., Schildknecht, K., Schulze, J. J., Mulu, A., Liebert, U., Sack, U., Speckmann, C., Gossen, M., Wong, R. J., Stevenson, D. K., Babel, N., Schuermann, D., Baldinger, T., Bacchetta, R., Gruetzkau, A., Borte, S., Olek, S. 2018; 10 (452)

  Abstract

  Immune cell profiles provide valuable diagnostic information for hematologic and immunologic diseases. Although it is the most widely applied analytical approach, flow cytometry is limited to liquid blood. Moreover, either analysis must be performed with fresh samples or cell integrity needs to be guaranteed during storage and transport. We developed epigenetic real-time quantitative polymerase chain reaction (qPCR) assays for analysis of human leukocyte subpopulations. After method establishment, whole blood from 25 healthy donors and 97 HIV+ patients as well as dried spots from 250 healthy newborns and 24 newborns with primary immunodeficiencies were analyzed. Concordance between flow cytometric and epigenetic data for neutrophils and B, natural killer, CD3+ T, CD8+ T, CD4+ T, and FOXP3+ regulatory T cells was evaluated, demonstrating substantial equivalence between epigenetic qPCR analysis and flow cytometry. Epigenetic qPCR achieves both relative and absolute quantifications. Applied to dried blood spots, epigenetic immune cell quantification was shown to identify newborns suffering from various primary immunodeficiencies. Using epigenetic qPCR not only provides a precise means for immune cell counting in fresh-frozen blood but also extends applicability to dried blood spots. This method could expand the ability for screening immune defects and facilitates diagnostics of unobservantly collected samples, for example, in underdeveloped areas, where logistics are major barriers to screening.

  View details for PubMedID 30068569

• Prethreshold retinopathy of prematurity: VEGF inhibition without VEGF inhibitors. Journal of perinatology : official journal of the California Perinatal Association Gaynon, M. W., Wong, R. J., Stevenson, D. K., Sunshine, P. 2018

  Abstract

  The risk of developing treatment-warranted Type 1 retinopathy of prematurity (ROP) might be reduced in preterm infants by modifying certain systemic factors. There are steps that can be taken both early and late in the course of retinal vascular maturation that may potentially reduce an infant's risk of developing Type 1 ROP. In prethreshold stage 2-3 ROP without plus disease, a combination of supplemental oxygen, correction of severe anemia, and light adaptation to reduce rod photoreceptor oxygen consumption helped us to reduce ROP severity, and encouraged a return to a more physiologic retinal vascular maturation pattern. Thus, it may be possible to reduce the risk of developing Type 1 ROP by making adjustments in certain systemic parameters aimed at reducing retinal hypoxia, thereby gently lowering pathologically elevated levels of vascular endothelial growth factor (VEGF) within the eye.

  View details for PubMedID 30046180

• Bilirubin binding in jaundiced newborns: from bench to bedside? Pediatric research Ahlfors, C. E., Bhutani, V. K., Wong, R. J., Stevenson, D. K. 2018

  Abstract

  BACKGROUND: Bilirubin-induced neurologic dysfunction (BIND) is a spectrum of preventable neurological sequelae in jaundiced newborns. Current total plasma bilirubin (BT) concentration thresholds for phototherapy and/or exchange transfusion poorly predict BIND.METHODS: The unbound (free) bilirubin (Bf) measured at these BT thresholds provides additional information about the risk for BIND. Bf can be readily adapted to clinical use by determining Bf population parameters at current BT thresholds. These parameters can be established using a plasma bilirubin binding panel (BBP) consisting of BT, Bf, and two empiric constants, the maximum BT (BTmax) and the corresponding equilibrium association bilirubin constant (K).RESULTS: BTmax and K provide the variables needed to accurately estimate Bf at BT

  View details for PubMedID 29967530

• Residential agricultural pesticide exposures and risks of preeclampsia. Environmental research Shaw, G. M., Yang, W., Roberts, E. M., Aghaeepour, N., Mayo, J. A., Weber, K. A., Maric, I., Carmichael, S. L., Winn, V. D., Stevenson, D. K., English, P. B. 2018; 164: 546–55

  Abstract

  We investigated risks of preeclampsia phenotypes from potential residential pesticide exposures, including 543 individual chemicals and 69 physicochemical groupings that were applied in the San Joaquin Valley of California during the study period, 1998-2011. The study population was derived from birth certificate data linked with Office of Statewide Health Planning and Development maternal and infant hospital discharge data. The following numbers of women with preeclampsia phenotypes were identified: 1045 with superimposed (pre-existing hypertension with preeclampsia) preeclampsia (265 with gestational weeks 20-31 and 780 with gestational weeks 32-36); 3471 with severe preeclampsia (824 with gestational weeks 20-31 and 2647 with gestational weeks 32-36); and 2780 with mild preeclampsia (207 with gestational weeks 20-31 and 2573 with gestational weeks 32-36). The reference population for these groups was 197,461 women who did not have diabetes (gestational or pre-existing), did not have any hypertensive disorder, and who delivered at 37 weeks or later. The frequency of any exposure was lower or about the same in each preeclampsia case group (further delineated by gestational age), and month time period, relative to the frequency in reference population controls. Nearly all odds ratios were below 1.0 for these any vs no exposure comparisons. This study showed a general lack of increased risks between a range of agriculture pesticide exposures near women's residences and various preeclampsia phenotypes.

  View details for PubMedID 29614386

• Hypoxia regulates placental angiogenesis via alternatively activated macrophages. American journal of reproductive immunology (New York, N.Y. : 1989) Zhao, H., Kalish, F. S., Wong, R. J., Stevenson, D. K. 2018: e12989

  Abstract

  PROBLEM: Uterine and placental macrophages play critical roles in maintaining a normal pregnancy. The majority of these macrophages are believed to be alternatively activated macrophages (M2).METHOD OF STUDY: Mouse bone marrow cells were differentiated into macrophages and polarized to M2 in vitro by treatment with IL-4 [M2a] or IL-10 [M2c] and M1 with LPS/IFN-gamma as controls. Macrophage subtypes were confirmed by surface markers and characterized by gene expression profiles.RESULTS: Compared to M1, M2 showed strong pro-angiogenic activity by expressing higher mRNA for angiogenic-associated factors (Cxcl12, Vegfa, PlGF, Mmp2). M2c produced the highest levels of PlGF, Mmp2, and Cxcr4. To mimic the normal placental microenvironment, M2 were exposed to hypoxia and sex hormones (progesterone, estrogen). In both M2c and M2a, severe hypoxic (1%-3% O2 ) exposure significantly suppressed PlGF, Cxcl12, and Mmp2 mRNA, but not Vegfa, compared to normoxia (21% O2 ) or physiological hypoxia (5% O2 ). mRNA expression returned to normal when hypoxic cells were returned to normoxia. Hypoxia (1%) reduced antioxidant levels in M2 and re-exposure to normoxia significantly increased superoxide dismutase (Sod1, Sod2) and heme oxygenase-1 (HO-1) levels in M2a, and only glutathione peroxidase (Gpx1, Gpx3, Gpx4) in M2c. However, progesterone and estrogen treatment had minimal effects on angiogenic factor expression in M2.CONCLUSION: M2, particularly M2c, displayed strong pro-angiogenic potential, which decreased under severe hypoxia such as in early pregnancy. Thus, conditions that alter the placental oxygen microenvironment or macrophage response in early pregnancy might cause aberrant angiogenesis and vascular remodeling, and lead to abnormal placental vascular development.

  View details for PubMedID 29932269

• Natural Selection Has Differentiated the Progesterone Receptor among Human Populations. American journal of human genetics Li, J., Hong, X., Mesiano, S., Muglia, L. J., Wang, X., Snyder, M., Stevenson, D. K., Shaw, G. M. 2018

  Abstract

  The progesterone receptor (PGR) plays a central role in maintaining pregnancy and is significantly associated with medical conditions such as preterm birth that affects 12.6% of all the births in U.S. PGR has been evolving rapidly since the common ancestor of human and chimpanzee, and we herein investigated evolutionary dynamics of PGR during recent human migration and population differentiation. Our study revealed substantial population differentiation at the PGR locus driven by natural selection, where very recent positive selection in East Asians has substantially decreased its genetic diversity by nearly fixing evolutionarily novel alleles. On the contrary, in European populations, the PGR locus has been promoted to a highly polymorphic state likely due to balancing selection. Integrating transcriptome data across multiple tissue types together with large-scale genome-wide association data for preterm birth, our study demonstrated the consequence of the selection event in East Asians on remodeling PGR expression specifically in the ovary and determined a significant association of early spontaneous preterm birth with the evolutionarily selected variants. To reconstruct its evolutionary trajectory on the human lineage, we observed substantial differentiation between modern and archaic humans at the PGR locus, including fixation of a deleterious missense allele in the Neanderthal genome that was later introgressed in modern human populations. Taken together, our study revealed substantial evolutionary innovation in PGR even during very recent human evolution, and its different forms among human populations likely result in differential susceptibility to progesterone-associated disease conditions including preterm birth.

  View details for PubMedID 29937092

• Noninvasive blood tests for fetal development predict gestational age and preterm delivery SCIENCE Ngo, T. M., Moufarrej, M. N., Rasmussen, M. H., Camunas-Soler, J., Pan, W., Okamoto, J., Neff, N. F., Liu, K., Wong, R. J., Downes, K., Tibshirani, R., Shaw, G. M., Skotte, L., Stevenson, D. K., Biggio, J. R., Elovitz, M. A., Melbye, M., Quake, S. R. 2018; 360 (6393): 1133–36

  Abstract

  Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.

  View details for PubMedID 29880692

• Heme oxygenase-1 deficiency promotes severity of sepsis in a non-surgical preterm mouse model. Pediatric research Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. 2018

  Abstract

  BACKGROUND: Sepsis in preterm infants is associated with systemic inflammatory responses. The stress-response protein heme oxygenase-1 (HO-1) has protective anti-inflammatory properties. Recently, we reported a protective role of HO-1 using our non-surgical cecal slurry (CS) model in wild-type (WT) mouse pups. Here, we extend these findings to investigate the association of HO-1 deficiency with sepsis severity.METHODS: Adapting the Wynn model, we induced sepsis in 4-day-old HO-1-deficient (HO-1+/-, Het) pups to determine if HO-1 deficiency affected survival rates at the LD40 (2.0mg/g) of WT pups. To see if HO-1 induction affected sepsis severity, we gave 30-mumol heme/kg subcutaneously to 3-day-old mice 24h prior to sepsis induction.RESULTS: Post-sepsis induction, Het pups had a mortality of 85.0% (n=20) and increased expression of the pro-inflammatory gene in the livers and affected hematologic profiles. Heme treatment 24h prior to sepsis induction significantly increased liver HO activity, reduced mortality to 24.5% (n=17), attenuated inflammatory responses, reduced spleen bacterial counts, and significantly increased peripheral neutrophils.CONCLUSIONS: A partial deficiency in HO-1 increased the progression and mortality in sepsis. Furthermore, induction of HO-1 significantly reduced the mortality even in Het pups. Thus, we conclude that HO-1 plays an important role in the protection against preterm sepsis.

  View details for PubMedID 29795214

• Neuro-inflammatory effects of photodegradative products of bilirubin SCIENTIFIC REPORTS Jasprova, J., Dal Ben, M., Hurny, D., Hwang, S., Zizalova, K., Kotek, J., Wong, R. J., Stevenson, D. K., Gazzin, S., Tiribelli, C., Vitek, L. 2018; 8: 7444

  Abstract

  Phototherapy was introduced in the early 1950's, and is the primary treatment of severe neonatal jaundice or Crigler-Najjar syndrome. Nevertheless, the potential biological effects of the products generated from the photodegradation of bilirubin during phototherapy remain unknown. This is very relevant in light of recent clinical observations demonstrating that the use of aggressive phototherapy can increase morbidity or even mortality, in extremely low birthweight (ELBW) infants. The aim of our study was to investigate the effects of bilirubin, lumirubin (LR, its major photo-oxidative product), and BOX A and B (its monopyrrolic oxidative products) on the central nervous system (CNS) using in vitro and ex vivo experimental models. The effects of bilirubin photoproducts on cell viability and expression of selected genes were tested in human fibroblasts, three human CNS cell lines (neuroblastoma SH-SY5Y, microglial HMC3, and glioblastoma U-87 cell lines), and organotypic rat hippocampal slices. Neither bilirubin nor its photo-oxidative products affected cell viability in any of our models. In contrast, LR in biologically-relevant concentrations (25 μM) significantly increased gene expression of several pro-inflammatory genes as well as production of TNF-α in organotypic rat hippocampal slices. These findings might underlie the adverse outcomes observed in ELBW infants undergoing aggressive phototherapy.

  View details for PubMedID 29748620

• Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY Ozen, M., Zhao, H., Kalish, F., Yang, Y., Folkins, A., Burd, I., Wong, R. J., Stevenson, D. K. 2018; 79 (5): e12829

  Abstract

  Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring.Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry.CD3+ CD4+ CD25+ (Tregs) and CD3+ CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+ CD8+ T cells, and an increase in CD4+ /CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI.Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.

  View details for PubMedID 29484761

• Identification of risk for neonatal haemolysis. Acta paediatrica (Oslo, Norway : 1992) Bhutani, V. K., Maisels, M. J., Schutzman, D. L., Castillo Cuadrado, M. E., Aby, J. L., Bogen, D. L., Christensen, R. D., Watchko, J. F., Wong, R. J., Stevenson, D. K. 2018

  Abstract

  AIM: To identify neonates at risk of haemolytic hyperbilirubinaemia through near-concurrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis.METHODS: Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n = 283) at 20 to <60 hours of age in five nurseries. TB/TcB values were assigned TB/TcB percentile risk values using the Bhutani hour-specific nomogram. In infants having two serial TB/TcB measurements (n = 76), TB rate of rise (ROR, mg/dL/h) was calculated.RESULTS: For the entire cohort (n = 283), 67.1% and 32.9% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.79 ± 1.84 vs 9.14 ± 2.25 mg/dL) and ETCOc (1.61 ± 0.45 vs 2.02 ± 1.35 ppm, p = 0.0002) were different between the groups. About 36.6% of infants with TB/TcB ≥75th percentile had ETCOc ≥ 2.0 ppm. In the subcohort of infants with serial TB/TcB measurements (n = 76), 44.7% and 55.3% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.28 ± 1.97 vs 9.53 ± 2.78 mg/dL), ETCOc (1.72 ± 0.48 vs 2.38 ± 1.89 ppm, p = 0.05) and TB ROR (0.011 ± 0.440 vs 0.172 ± 0.471 mg/dL/h) were different between the groups.CONCLUSION: The combined use of TB/TcB percentile risk assessments and ETCOc measurements can identify infants with haemolytic hyperbilirubinaemia. The addition of TB ROR can identify those infants with elimination disorders.

  View details for PubMedID 29532503

• Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth JOURNAL OF PEDIATRICS Crawford, N., Prendergast, D., Oehlert, J. W., Shaw, G. M., Stevenson, D. K., Rappaport, N., Sirota, M., Tishkoff, S. A., Sondheimer, N. 2018; 194: 40-+

  Abstract

  To examine linkages between mitochondrial genetics and preterm birth by assessing the risk for preterm birth associated with the inheritance of nuclear haplotypes that are ancestrally distinct from mitochondrial haplogroup.Genome-wide genotyping studies of cohorts of preterm and term individuals were evaluated. We determined the mitochondrial haplogroup and nuclear ancestry for individuals and developed a scoring for the degree to which mitochondrial ancestry is divergent from nuclear ancestry.Infants with higher degrees of divergent mitochondrial ancestry were at increased risk for preterm birth (0.124 for preterm vs 0.105 for term infants; P< .05). This finding was validated in 1 of 2 replication cohorts. We also observed that greater degrees of divergent ancestry correlated with earlier delivery within the primary study population, but this finding was not replicated in secondary cohorts born preterm.Individuals with divergent patterns of mitochondrial and nuclear ancestry are at increased risk for preterm birth. These findings may in part explain the higher rates of preterm birth in African Americans and in individuals with a matrilineal family history of preterm birth.

  View details for PubMedID 29249523

• A genome-wide association study identifies only two ancestry specific variants associated with spontaneous preterm birth SCIENTIFIC REPORTS Rappoport, N., Toung, J., Hadley, D., Wong, R. J., Fujioka, K., Reuter, J., Abbott, C. W., Oh, S., Hu, D., Eng, C., Huntsman, S., Bodian, D. L., Niederhuber, J. E., Hong, X., Zhang, G., Sikora-Wohfeld, W., Gignoux, C. R., Wang, H., Oehlert, J., Jelliffe-Pawlowski, L. L., Gould, J. B., Darmstadt, G. L., Wang, X., Bustamante, C. D., Snyder, M. P., Ziv, E., Patsopoulos, N. A., Muglia, L. J., Burchard, E., Shaw, G. M., O'Brodovich, H. M., Stevenson, D. K., Butte, A. J., Sirota, M. 2018; 8: 226

  Abstract

  Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.

  View details for PubMedID 29317701

• Prediction of cognitive and motor development in preterm children using exhaustive feature selection and cross-validation of near-term white matter microstructure NEUROIMAGE-CLINICAL Schadl, K., Vassar, R., Cahill-Rowley, K., Yeom, K. W., Stevenson, D. K., Rose, J. 2018; 17: 667–79

  View details for DOI 10.1016/j.nicl.2017.11.023

  View details for Web of Science ID 000426180300071

• Hemolysis and Glucose-6-Phosphate Dehydrogenase Deficiency-Related Neonatal Hyperbilirubinemia NEONATOLOGY Kaplan, M., Wong, R. J., Stevenson, D. K. 2018; 114 (3): 223–25

  Abstract

  Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency affecting more than 300 million individuals worldwide. Extreme neonatal hyperbilirubinemia, with its severe sequelae of bilirubin neurotoxicity and the potential of death, is the most devastating manifestation of G6PD deficiency. In a recent review of Favism, Luzzatto and Arese state that the pathophysiology of jaundice in G6PD-deficient neonates is different from that of favism, as there is little evidence of hemolysis in these infants.To explore the role of hemolysis in neonatal hyperbilirubinemia associated with G6PD deficiency.Previously published works including studies of endogenous production of carbon monoxide (CO), an index of heme catabolism, in hyperbilirubinemic G6PD-deficient neonates were reviewed to determine the role of hemolysis in this condition.Three studies demonstrated that endogenous CO production is elevated in G6PD-deficient neonates with extreme hyperbilirubinemia.Hemolysis is an important pathogenetic factor in G6PD deficiency-associated neonatal hyperbilirubinemia.

  View details for PubMedID 29940590

• Point-of-Care Fecal Calprotectin Monitoring in Preterm Infants at Risk for Necrotizing Enterocolitis. The Journal of pediatrics Nakayuenyongsuk, W. n., Christofferson, M. n., Stevenson, D. K., Sylvester, K. n., Lee, H. C., Park, K. T. 2018

  Abstract

  To establish baseline trends in fecal calprotectin, a protein excreted into the stool when there is neutrophilic inflammation in the bowel, in infants at risk for necrotizing enterocolitis (NEC).We performed a prospective observational cohort study in infants with a birth weight of <1500 g without existing bowel disease at a level IV neonatal intensive care unit from October 2015 to September 2016. Stools were collected once daily for 30 days or until 32 weeks postmenstrual age and processed using the Fecal Calprotectin High Range Quantitative Quantum Blue assay.In 64 preterm infants, during the first week after birth, 62% of infants had an initial stool sample with high baseline calprotectin levels (≥200 µg/g). In assessment of maternal and neonatal risk factors, maternal etiology for preterm birth (ie, eclamplsia or preeclampsia) was the only significant factor associated with high baseline calprotectin level. Two patients in the cohort developed NEC. Calprotectin levels for the entire cohort fluctuated during the observed period but generally increased in the third and fourth weeks after birth.At-risk infants had highly variable fecal calprotectin levels, with maternal causes for preterm birth associated with higher baseline levels. More longitudinal data in infants with NEC are necessary to determine whether acute rises in fecal calprotectin levels prior to clinical diagnosis can be confirmed as a diagnostic or prognostic biomarker.

  View details for PubMedID 29519542

• Simultaneously Monitoring Immune Response and Microbial Infections during Pregnancy through Plasma cfRNA Sequencing CLINICAL CHEMISTRY Pan, W., Ngo, T. M., Camunas-Soler, J., Song, C., Kowarsky, M., Blumenfeld, Y. J., Wong, R. J., Shaw, G. M., Stevenson, D. K., Quake, S. R. 2017; 63 (11): 1695–1704

  Abstract

  Plasma cell-free RNA (cfRNA) encompasses a broad spectrum of RNA species that can be derived from both human cells and microbes. Because cfRNA is fragmented and of low concentration, it has been challenging to profile its transcriptome using standard RNA-seq methods.We assessed several recently developed RNA-seq methods on cfRNA samples. We then analyzed the dynamic changes of both the human transcriptome and the microbiome of plasma during pregnancy from 60 women.cfRNA reflects a well-orchestrated immune modulation during pregnancy: an up-regulation of antiinflammatory genes and an increased abundance of antimicrobial genes. We observed that the plasma microbiome remained relatively stable during pregnancy. The bacteria Ureaplasma shows an increased prevalence and increased abundance at postpartum, which is likely to be associated with postpartum infection. We demonstrated that cfRNA-seq can be used to monitor viral infections. We detected a number of human pathogens in our patients, including an undiagnosed patient with a high load of human parvovirus B19 virus (B19V), which is known to be a potential cause of complications in pregnancy.Plasma cfRNA-seq demonstrates the potential to simultaneously monitor immune response and microbial infections during pregnancy.

  View details for PubMedID 28904056

• Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kowarsky, M., Camunas-Soler, J., Kertesz, M., De Vlaminck, I., Koh, W., Pan, W., Martin, L., Neff, N. F., Okamoto, J., Wong, R. J., Kharbanda, S., El-Sayed, Y., Blumenfeld, Y., Stevenson, D. K., Shaw, G. M., Wolfe, N. D., Quake, S. R. 2017; 114 (36): 9623–28

  Abstract

  Blood circulates throughout the human body and contains molecules drawn from virtually every tissue, including the microbes and viruses which colonize the body. Through massive shotgun sequencing of circulating cell-free DNA from the blood, we identified hundreds of new bacteria and viruses which represent previously unidentified members of the human microbiome. Analyzing cumulative sequence data from 1,351 blood samples collected from 188 patients enabled us to assemble 7,190 contiguous regions (contigs) larger than 1 kbp, of which 3,761 are novel with little or no sequence homology in any existing databases. The vast majority of these novel contigs possess coding sequences, and we have validated their existence both by finding their presence in independent experiments and by performing direct PCR amplification. When their nearest neighbors are located in the tree of life, many of the organisms represent entirely novel taxa, showing that microbial diversity within the human body is substantially broader than previously appreciated.

  View details for PubMedID 28830999

• Heme oxygenase-1 promoter polymorphisms: do they modulate neonatal hyperbilirubinemia? JOURNAL OF PERINATOLOGY Kaplan, M., Wong, R. J., Stevenson, D. K. 2017; 37 (8): 901–5

  Abstract

  The role of genetic factors in the modulation of serum bilirubin levels and the pathophysiology of neonatal hyperbilirubinemia is being increasingly recognized. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme by which heme is catabolized to biliverdin and thence to bilirubin, with the simultaneous release of equimolar quantities of ferrous iron (Fe3+) and carbon monoxide. Polymorphisms of the HO-1 gene promoter may modulate transcriptional activity, thereby augmenting or attenuating HO-1 expression with resultant modulation of the production of bilirubin. Few studies have related these polymorphisms to neonatal bilirubin metabolism and have reported conflicting results. In this clinical review, we surveyed the role of HO-1 gene promoter polymorphisms in the control of bilirubin production and further considered their role, if any, in the pathophysiology of neonatal hyperbilirubinemia.

  View details for PubMedID 28206992

• Interpregnancy Interval and Adverse Pregnancy Outcomes: An Analysis of Successive Pregnancies and Interpregnancy Interval and Pregnancy Outcomes: Causal or Not? OBSTETRICS AND GYNECOLOGY Mayo, J. A., Shachar, B., Stevenson, D. K., Shaw, G. M. 2017; 130 (2): 463

  View details for PubMedID 28742651

• . journal of maternal-fetal & neonatal medicine Shachar, B. Z., Mayo, J. A., Lyell, D. J., Stevenson, D. K., Shaw, G. M., Blumenfeld, Y. J. 2017: 1-7

  Abstract

  Approximately 10% of US couples are inter-racial/ethnic. Substantial variation in preterm birth (PTB) rates is seen when stratified by race/ethnicity, although most studies focused solely on maternal racial/ethnic demographics. Our aims were to analyze the contribution of paternal in addition to maternal race/ethnicity, and to evaluate risk of spontaneous PTB for previously understudied inter-racial/ethnic couples.California singleton live births from 2007 to 2010 were included. Race/ethnicity was determined based on self-report, obtained from birth certificates and defined as African American (AA), Hispanic, Asian, and White. Logistic regression was used to estimate odds ratios of spontaneous PTB at 20-23, 24-31, 32-36 and <37 weeks of gestation, with White-White couples as reference. Results were stratified by previous PTB, pre-gestational and gestational diabetes and hypertension. To investigate the paternal contribution to the risk for any given maternal race/ethnicity we assessed the rates of PTB among inter-racial/ethnic couples compared to the respective same-race couple. Odds ratios were adjusted for maternal age, parity, BMI, prenatal care, payor status, education and smoking.Among 1,664,939 live births, 13% (n = 216,417) were born to inter-racial/ethnic couples. Compared to White-White couples, risk for spontaneous PTB was increased across all inter-racial/ethnic couples with a non-White mother, except when the father was Asian. Patterns of association were similar after stratification by previous PTB, hypertension and diabetes. Paternal race/ethnicity was also a significant risk factor for PTB.Increased risks for spontaneous PTB were seen in most inter-racial/ethnic couple groupings. In addition to maternal race/ethnicity, paternal race/ethnicity was a significant risk factor in many inter-racial/ethnic couplings. Identifying such different risk profiles based on both maternal and paternal race/ethnicity may offer new lines of research inquiry for the underlying etiologies of PTB.

  View details for DOI 10.1080/14767058.2017.1293029

  View details for PubMedID 28399669

• Fetal de novo mutations and preterm birth. PLoS genetics Li, J., Oehlert, J., Snyder, M., Stevenson, D. K., Shaw, G. M. 2017; 13 (4)

  Abstract

  Preterm birth (PTB) affects ~12% of pregnancies in the US. Despite its high mortality and morbidity, the molecular etiology underlying PTB has been unclear. Numerous studies have been devoted to identifying genetic factors in maternal and fetal genomes, but so far few genomic loci have been associated with PTB. By analyzing whole-genome sequencing data from 816 trio families, for the first time, we observed the role of fetal de novo mutations in PTB. We observed a significant increase in de novo mutation burden in PTB fetal genomes. Our genomic analyses further revealed that affected genes by PTB de novo mutations were dosage sensitive, intolerant to genomic deletions, and their mouse orthologs were likely developmentally essential. These genes were significantly involved in early fetal brain development, which was further supported by our analysis of copy number variants identified from an independent PTB cohort. Our study indicates a new mechanism in PTB occurrence independently contributed from fetal genomes, and thus opens a new avenue for future PTB research.

  View details for DOI 10.1371/journal.pgen.1006689

  View details for PubMedID 28388617

• Multicenter Systems Analysis of Human Blood Reveals Immature Neutrophils in Males and During Pregnancy. Journal of immunology Blazkova, J., Gupta, S., Liu, Y., Gaudilliere, B., Ganio, E. A., Bolen, C. R., Saar-Dover, R., Fragiadakis, G. K., Angst, M. S., Hasni, S., Aghaeepour, N., Stevenson, D., Baldwin, N., Anguiano, E., Chaussabel, D., Altman, M. C., Kaplan, M. J., Davis, M. M., Furman, D. 2017; 198 (6): 2479-2488

  Abstract

  Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved. In this study, we identified a gene signature of immature-like neutrophils, characterized by the overexpression of genes encoding for several granule-containing proteins, which was found at higher levels (up to 3-fold) in young (20-30 y old) but not older (60 to >89 y old) males compared with females. Functional and phenotypic characterization of peripheral blood neutrophils revealed more mature and responsive neutrophils in young females, which also exhibited an elevated capacity in neutrophil extracellular trap formation at baseline and upon microbial or sterile autoimmune stimuli. The expression levels of the immature-like neutrophil signature increased linearly with pregnancy, an immune state of increased susceptibility to certain infections. Using mass cytometry, we also find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women.

  View details for DOI 10.4049/jimmunol.1601855

  View details for PubMedID 28179497

• Acylcarnitine Profiles Reflect Metabolic Vulnerability for Necrotizing Enterocolitis in Newborns Born Premature. journal of pediatrics Sylvester, K. G., Kastenberg, Z. J., Moss, R. L., Enns, G. M., Cowan, T. M., Shaw, G. M., Stevenson, D. K., Sinclair, T. J., Scharfe, C., Ryckman, K. K., Jelliffe-Pawlowski, L. L. 2017; 181: 80-85 e1

  Abstract

  To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis (NEC) with the use of routinely collected newborn screening data in infants born preterm.A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from 2005 to 2009 who had linked state newborn screening results. A model-development cohort of 94 110 preterm births from 2005 to 2008 was used to develop a risk-stratification model that was then applied to a validation cohort of 22 992 births from 2009.Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC. Each log unit increase in C5 and free carnitine /(C16 + 18:1) was associated with a 78% and a 76% increased risk for developing NEC, respectively (OR 1.78, 95% CI 1.53-2.02, and OR 1.76, 95% CI 1.51-2.06). Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified 89.8% of newborns with NEC in the model-development cohort (area under the curve 0.898, 95% CI 0.889-0.907) and 90.8% of the newborns with NEC in the validation cohort (area under the curve 0.908, 95% CI 0.901-0.930).Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies.

  View details for DOI 10.1016/j.jpeds.2016.10.019

  View details for PubMedID 27836286

• INDUCTION OF HEME OXYGENASE-1 ATTENUATES THE SEVERITY OF SEPSIS IN A NON-SURGICAL PRETERM MOUSE MODEL SHOCK Fujioka, K., Kalish, F., Zhao, H., Lu, S., Wong, S., Wong, R. J., Stevenson, D. K. 2017; 47 (2): 242-250

  Abstract

  Preterm sepsis is characterized by systemic bacterial invasion and inflammatory response. Its pathogenesis is unclear due to lack of proper animal models. Heme oxygenase-1 (HO-1) can affect physiologic and pathologic conditions through its anti-inflammatory, antioxidative, and anti-apoptotic properties. Since HO-1 is developmentally regulated, it may play a role in the pathogenesis of preterm sepsis. For this study, sepsis was induced using the non-surgical "cecal slurry" (CS) model. CS was given intraperitoneally at various doses to 4-day-old newborn mice to determine dose-dependent effects. The LD40 was then given and changes in bodyweight, bacterial colonization of organs, hematology, serum biochemistry, and immunomodulatory gene expression were determined. We found a dose-dependent mortality with an LD40 of 2.0 mg/g. Significant bacterial colonization and hematological changes (leukocytopenia, thrombocytopenia, and lymphocytopenia) and increased gene expression of pro-inflammatory cytokines, pattern-recognition receptors, and other genes related to immune responses were also observed. Twenty-four hours post-sepsis induction, bodyweight loss was associated with mortality and organ damage. Finally, to elucidate a protective role of HO-1, 30-μmol heme/kg was given subcutaneously 24 h pre-sepsis induction. HO activity in livers and spleens significantly increased 64% and 50% over age-matched controls 24 h post-heme administration. Importantly, heme significantly reduced mortality from 40.9% to 6.3% (P <0.005) and gene expression of pro-inflammatory cytokines (Ccl5, Cxcl10, IL-1b, and Ifng). We conclude that the CS model can be used as a model to study preterm sepsis. Because induction of HO-1 significantly reduced mortality, we speculate that HO-1 may confer protection against sepsis in preterm infants.

  View details for DOI 10.1097/SHK.0000000000000689

  View details for PubMedID 27454382

• Infiltration of myeloid cells in the pregnant uterus is affected by heme oxygenase-1 JOURNAL OF LEUKOCYTE BIOLOGY Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. 2017; 101 (1): 217-226

  Abstract

  Infiltrating myeloid cells in pregnant uteri play critical roles in the establishment of the placenta and maintenance of normal pregnancies. Their recruitment and proliferation are primarily mediated by the interactions of cytokines and chemokines secreted locally with their corresponding receptors. Heme oxygenase-1 (HO-1) has various physiologic properties that contribute to placental vascular development, with deficiencies in HO-1 associated with pregnancy disorders. Here, we investigated the effect of HO-1 on myeloid cell infiltration into pregnant uteri using a partial HO-1-deficient (Het, HO-1(+/-)) mouse model. With the use of flow cytometry, HO-1 was found predominantly expressed in circulating and uterine myeloid cells, specifically neutrophils and monocytes/macrophages. In pregnant Het uteri, the numbers of neutrophils and monocytes/macrophages were significantly reduced compared with pregnant wild-type (WT; HO-1(+/+)) uteri. With the use of BrdU in vivo assays, HO-1 deficiency did not affect cell proliferation or blood cell populations. With the use of PCR arrays, gene expression of cytokines (Csf1, Csf3), chemokines (Ccl1, Ccl2, Ccl6, Ccl8, Ccl11, Ccl12, Cxcl4, Cxcl9, Cxcl12), and their receptors (Ccr1, Ccr2, Ccr3, Ccr5) were also reduced significantly in Het compared with pregnant WT uteri. Moreover, with the use of flow cytometry, myeloid CSF1R and CCR2 expression in blood and uteri from both pregnant and nonpregnant mice was characterized, and a deficiency in HO-1 significantly reduced CCR2 expression in infiltrating uterine monocytes/macrophages and dendritic cells (DCs). These data reveal that HO-1 regulates not only cytokine/chemokine production in pregnant uteri but also myeloid cell receptor numbers, suggesting a role of HO-1 in the recruitment and maintenance of myeloid cells in pregnant uteri and subsequent effects on placental vascular formation.

  View details for DOI 10.1189/jlb.1A0116-020RR

  View details for PubMedID 27468759

• A Proteomic Clock of Human Pregnancy. American journal of obstetrics and gynecology Aghaeepour, N. n., Lehallier, B. n., Baca, Q. n., Ganio, E. A., Wong, R. J., Ghaemi, M. S., Culos, A. n., El-Sayed, Y. Y., Blumenfeld, Y. J., Druzin, M. L., Winn, V. D., Gibbs, R. S., Tibshirani, R. n., Shaw, G. M., Stevenson, D. K., Gaudilliere, B. n., Angst, M. S. 2017

  Abstract

  Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome.The recent availability of a highly-multiplexed platform affording the simultaneous measurement of 1,310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely-timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns due to fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins, and link such attributes to relevant immunological changes.Pregnant women participated in this longitudinal study. In two subsequent subsets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 wks), second (15-20 wks), and third (24-32 wks) trimesters, and 6 wks post-partum for analysis with a highly-multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piece-wise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term.An independently validated model consisting of 74 proteins strongly predicted gestational age (p = 3.8x10-14, R = 0.97). The model could be reduced to eight proteins without losing its predictive power (p = 1.7x10-3, R = 0.91). The three top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with STAT5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age.Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a "proteomic clock". Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a "clock" is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-relate pathologies and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that somatomammotropin hormone may critically regulate T-cell function during pregnancy.

  View details for PubMedID 29277631

• An immune clock of human pregnancy. Science immunology Aghaeepour, N. n., Ganio, E. A., Mcilwain, D. n., Tsai, A. S., Tingle, M. n., Van Gassen, S. n., Gaudilliere, D. K., Baca, Q. n., McNeil, L. n., Okada, R. n., Ghaemi, M. S., Furman, D. n., Wong, R. J., Winn, V. D., Druzin, M. L., El-Sayed, Y. Y., Quaintance, C. n., Gibbs, R. n., Darmstadt, G. L., Shaw, G. M., Stevenson, D. K., Tibshirani, R. n., Nolan, G. P., Lewis, D. B., Angst, M. S., Gaudilliere, B. n. 2017; 2 (15)

  Abstract

  The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.

  View details for PubMedID 28864494

• Heme Oxygenase Activity and Heme Binding in a Neonatal Mouse Model NEONATOLOGY Kourula, S., Ang, J., Zhao, H., Kalish, F., Vandenabeele, P., Sylvester, K. G., Wong, R. J., Stevenson, D. K. 2017; 112 (4): 376–83

  Abstract

  Severe hemolytic disease of the newborn leads to the release of pro-oxidative free heme (FH). Heme oxygenase (HO) is primarily responsible for detoxifying FH.To investigate the protective effects of HO in a model of heme overload.For in vitro studies, NIH3T3 HO-1-luc cells were incubated with 10, 30, or 60 µM FH or methemalbumin (MHA). HO-1 promoter activity was assessed 3, 6, and 24 h after treatment. Cell survival was indexed by viability assays. For in vivo studies, 1- and 5-week-old wild-type (Wt) or HO-1-heterozygous (Het, HO-1+/-) mice were given 60 µmol FH or MHA/kg intraperitoneally. After 24 h, plasma aspartate aminotransferease (AST)/alanine transaminase (ALT) and hemopexin, liver HO activity, and lipid peroxidation (LP) were determined.In HO-1-luc cells, HO-1 promoter activity peaked 6 h after incubation with 30 µM FH (1.6-fold) or 60 µM MHA (2.1-fold) over baseline. Twenty-four hours after exposure to 60 µM FH, a decrease in viability of 80% was found, compared with no decrease after exposure to 60 µM MHA. In 1-week-old Wt and HO-1 Het pups given 60 µmol FH/kg, HO activity significantly increased 3.5- and 3.1-fold, respectively. No changes in LP or AST/ALT levels were observed. In adult Wt and HO-1 Het mice, HO activity increased (3.0- and 2.6-fold, respectively). LP and AST levels significantly increased 28.4- and 2.7-fold, respectively, in adult HO-1 Het mice. Hemopexin levels at baseline were higher in adults compared with newborns for both Wt and Het mice. In addition, FH induced hemopexin levels in both adults and newborns, but to a lesser degree in newborns.FH is highly toxic in vitro, but its toxicity is abolished when bound to albumin. Newborns appear to be protected from the pro-oxidative effects of FH, which may be mediated by heme binding and a higher absolute HO activity at baseline and after FH-mediated induction.

  View details for PubMedID 28926834

• The Importance of Hemolysis and Its Clinical Detection in Neonates with Hyperbilirubinemia. Current pediatric reviews Wong, R. J., Bhutani, V. K., Stevenson, D. K. 2017; 13 (3): 193–98

  Abstract

  BACKGROUND: Hyperbilirubinemia is a benign transitional phenomenon that occurs in 60% to 80% of all term infants. The degree of hyperbilirubinemia and hence risk for developing bilirubin-induced neurologic dysfunction or BIND is dependent upon two major processes: (i) bilirubin production and its elimination.OBJECTIVE: The aim of this review is to address the importance of hemolysis and its clinical detection in neonates with hyperbilirubinemia.RESULTS: In newborns, an increased bilirubin production rate due to hemolysis is often the primary cause of hyperbilirubinemia during the first week of life. If undiagnosed or untreated, it may lead to an increased risk for BIND. Therefore, the ability to identify infants with hemolytic disease is important in assessing those at risk for developing BIND. In addition, an infant's genetic profile and bilirubin binding status can also affect their overall capacity to cope with the resultant tissue bilirubin load and affect risk and guide appropriate management strategies.CONCLUSION: Therefore, the determination of a newborn's bilirubin production rate is critical to the assessment of a newborn's risk for developing unpredictable extreme hyperbilirubinemia and preventing BIND.

  View details for PubMedID 28782473

• Risky Business: Meeting the Structural Needs of Transdisciplinary Science. The Journal of pediatrics Wise, P. H., Shaw, G. M., Druzin, M. L., Darmstadt, G. L., Quaintance, C. n., Mäkinen, E. n., Relman, D. A., Quake, S. R., Butte, A. J., Angst, M. S., Muglia, L. J., Macones, G. n., Driscoll, D. n., Ober, C. n., Simpson, J. L., Katz, M. n., Howse, J. n., Stevenson, D. K. 2017; 191: 255–58

  View details for PubMedID 29173314

• Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women. Proceedings of the National Academy of Sciences of the United States of America Callahan, B. J., DiGiulio, D. B., Goltsman, D. S., Sun, C. L., Costello, E. K., Jeganathan, P. n., Biggio, J. R., Wong, R. J., Druzin, M. L., Shaw, G. M., Stevenson, D. K., Holmes, S. P., Relman, D. A. 2017

  Abstract

  Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Previous studies have suggested that the maternal vaginal microbiota contributes to the pathophysiology of PTB, but conflicting results in recent years have raised doubts. We conducted a study of PTB compared with term birth in two cohorts of pregnant women: one predominantly Caucasian (n = 39) at low risk for PTB, the second predominantly African American and at high-risk (n = 96). We profiled the taxonomic composition of 2,179 vaginal swabs collected prospectively and weekly during gestation using 16S rRNA gene sequencing. Previously proposed associations between PTB and lower Lactobacillus and higher Gardnerella abundances replicated in the low-risk cohort, but not in the high-risk cohort. High-resolution bioinformatics enabled taxonomic assignment to the species and subspecies levels, revealing that Lactobacillus crispatus was associated with low risk of PTB in both cohorts, while Lactobacillus iners was not, and that a subspecies clade of Gardnerella vaginalis explained the genus association with PTB. Patterns of cooccurrence between L. crispatus and Gardnerella were highly exclusive, while Gardnerella and L. iners often coexisted at high frequencies. We argue that the vaginal microbiota is better represented by the quantitative frequencies of these key taxa than by classifying communities into five community state types. Our findings extend and corroborate the association between the vaginal microbiota and PTB, demonstrate the benefits of high-resolution statistical bioinformatics in clinical microbiome studies, and suggest that previous conflicting results may reflect the different risk profile of women of black race.

  View details for PubMedID 28847941

• Women's prepregnancy underweight as a risk factor for preterm birth: a retrospective study. bjog-an international journal of obstetrics and gynaecology Girsen, A. I., Mayo, J. A., Carmichael, S. L., Phibbs, C. S., Shachar, B. Z., Stevenson, D. K., Lyell, D. J., Shaw, G. M., Gould, J. B. 2016; 123 (12): 2001-2007

  Abstract

  To investigate the distribution of known factors for preterm birth (PTB) by severity of maternal underweight; to investigate the risk-adjusted relation between severity of underweight and PTB, and to assess whether the relation differed by gestational age.Retrospective cohort study.State of California, USA.Maternally linked hospital and birth certificate records of 950 356 California deliveries in 2007-2010 were analysed. Singleton live births of women whose prepregnancy body mass index (BMI) was underweight (<18.5 kg/m(2) ) or normal (18.50-24.99 kg/m(2) ) were analysed. Underweight BMI was further categorised as: severe (<16.00), moderate (16.00-16.99) or mild (17.00-18.49). PTB was grouped as 22-27, 28-31, 32-36 or <37 weeks (compared with 37-41 weeks). Adjusted multivariable Poisson regression modeling was used to estimate relative risk for PTB.Risk of PTB.About 72 686 (7.6%) women were underweight. Increasing severity of underweight was associated with increasing percent PTB: 7.8% (n = 4421) in mild, 9.0% (n = 1001) in moderate and 10.2% (475) in severe underweight. The adjusted relative risk of PTB also significantly increased: adjusted relative risk (aRR) = 1.22 (95% CI 1.19-1.26) in mild, aRR = 1.41 (95% CI 1.32-1.50) in moderate and aRR = 1.61 (95% CI 1.47-1.76) in severe underweight. These findings were similar in spontaneous PTB, medically indicated PTB, and the gestational age groupings.Increasing severity of maternal prepregnancy underweight BMI was associated with increasing risk-adjusted PTB at <37 weeks. This increasing risk was of similar magnitude in spontaneous and medically indicated births and in preterm delivery at 28-31 and at 32-36 weeks of gestation.Increasing severity of maternal underweight BMI was associated with increasing risk of preterm birth.

  View details for DOI 10.1111/1471-0528.14027

  View details for PubMedID 27172996

  View details for PubMedCentralID PMC5069076

• Leading by Example and Design: The Joseph St Geme Jr Leadership Award, 2016 PEDIATRICS Stevenson, D. K. 2016; 138 (5)

  View details for DOI 10.1542/peds.2016-2487

  View details for Web of Science ID 000387447000040

• Interpregnancy interval after live birth or pregnancy termination and estimated risk of preterm birth: a retrospective cohort study. bjog-an international journal of obstetrics and gynaecology Shachar, B. Z., Mayo, J. A., Lyell, D. J., Baer, R. J., Jeliffe-Pawlowski, L. L., Stevenson, D. K., Shaw, G. M. 2016; 123 (12): 2009-2017

  Abstract

  We assessed whether interpregnancy interval (IPI) length after live birth and after pregnancy termination was associated with preterm birth (PTB).Multiyear birth cohort.Fetal death, birth and infant death certificates in California merged with Office of Statewide Health Planning and Development.One million California live births (2007-10) after live birth and after pregnancy termination.Logistic regression was used to estimate odds ratios (ORs) of PTB of 20-36 weeks of gestation and its subcategories for IPIs after a live birth and after a pregnancy termination. We used conditional logistic regression (two IPIs/mother) to investigate associations within mothers.PTB relative to gestations of ≥ 37 weeks.Analyses included 971 211 women with IPI after live birth, and 138 405 women with IPI after pregnancy termination with 30.6% and 74.6% having intervals of <18 months, respectively. IPIs of <6 months or 6-11 months after live birth showed increased odds of PTB adjusted ORs for PTB of 1.71 (95% CI 1.65-1.78) and 1.20 (95% CI 1.16-1.24), respectively compared with intervals of 18-23 months. An IPI >36 months (versus 18-23 months) was associated with increased odds for PTB. Short IPI after pregnancy termination showed a decreased OR of 0.87 (95% CI 0.81-0.94). The within-mother analysis showed the association of increased odds of PTB for short IPI, but not for long IPI.Women with IPI <1 or >3 years after a live birth were at increased odds of PTB-an important group for intervention to reduce PTB. Short IPI after pregnancy termination was associated with reduced odds for PTB and needs to be further explored.Short and long IPI after live birth, but not after pregnancy termination, showed increased odds for PTB.

  View details for DOI 10.1111/1471-0528.14165

  View details for PubMedID 27405702

• Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy. Journal of immunology Fragiadakis, G. K., Baca, Q. J., Gherardini, P. F., Ganio, E. A., Gaudilliere, D. K., Tingle, M., Lancero, H. L., McNeil, L. S., Spitzer, M. H., Wong, R. J., Shaw, G. M., Darmstadt, G. L., Sylvester, K. G., Winn, V. D., Carvalho, B., Lewis, D. B., Stevenson, D. K., Nolan, G. P., Aghaeepour, N., Angst, M. S., Gaudilliere, B. L. 2016

  Abstract

  Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4(+) and CD8(+) T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal Tbet(+)CD4(+) T cells, CD8(+) T cells, B cells, and CD56(lo)CD16(+) NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.

  View details for PubMedID 27793998

• Identification of neonatal haemolysis: an approach to predischarge management of neonatal hyperbilirubinemia. Acta paediatrica (Oslo, Norway : 1992) Bhutani, V. K., Srinivas, S., Castillo Cuadrado, M. E., Aby, J. L., Wong, R. J., Stevenson, D. K. 2016; 105 (5): e189-94

  Abstract

  Relative contributions of increased production [by end-tidal carbon monoxide concentrations (ETCOc)] and decreased elimination of bilirubin to predischarge hour-specific total bilirubin (TB) levels were assessed in healthy late-preterm and term newborns. Secondly, we report predischarge ETCOc ranges to guide clinical management of hyperbilirubinemia.TB and ETCOc (≤3 timepoints) determinations of newborns aged between six hours and <6 days (n = 79) were stratified by postnatal age epochs. Hyperbilirubinemia risk was assessed by plotting TB values as a function of ETCOc.Stratifications of ETCOc (in ppm, mean, median and interquartile ranges) by postnatal age epochs (0-24, 24-48 and 48-72) were as follows: 2.0, 1.9, 1.8-2.2 (n = 11); 1.6, 1.5, 1.1-2.0 (n = 58); and 2.0, 1.8, 1.6-2.3 (n = 9), respectively. Infants with ETCOc ≥ 2.5 were at high risk, between 1.5 and 2.5 at moderate risk and ≤1.5 were at low risk. Risk due to haemolysis alone was not independent (p < 0.01). For infants with TB >75th percentile (n = 31), 23% had ETCO ≤1.5, and 77% had ETCOc > 1.5 (p < 0.00003).Near-simultaneous ETCOc and TB measurements in infants with TB >75th percentile accurately identify haemolytic hyperbilirubinemia.

  View details for DOI 10.1111/apa.13341

  View details for PubMedID 26802319

• Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model PEDIATRIC RESEARCH Fujioka, K., Kalish, F., Wong, R. J., Stevenson, D. K. 2016; 79 (2): 251-257

  Abstract

  Increased bilirubin production due to hemolysis can lead to neonatal hyperbilirubinemia. Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, by metalloporphyrins (Mps) may be an ideal preventive strategy for neonatal hemolytic disease. Zinc protoporphyrin (ZnPP) is a naturally occurring Mp, potent, not phototoxic, with minimal HO-1 upregulation, but is not orally absorbed. Recently, we designed a lipid-based ZnPP formulation (ZnPP-Lipid), which is orally absorbed by newborn mice. Here, we evaluated the efficacy of ZnPP-Lipid in heme-loaded newborn mice, a model analogous to hemolytic infants.After 24 h of heme administration (30 µmol/kg s.c.), 4-d-old mice were given 30 µmol ZnPP-Lipid/kg via intragastric injections. After 3 h, liver and brain HO activity were measured. HO-1 upregulation was assessed by determinations of HO-1 protein, promoter activity, and mRNA by Western blot, in vivo bioluminescence imaging, and RT-PCR, respectively.After heme loading, liver HO activity significantly increased ~1.6-fold, which was inhibited in a dose-dependent manner by ZnPP-Lipid. A dose of 30 µmol/kg returned activity to control levels. Brain HO activity was not inhibited. No significant increases in liver and brain HO-1 protein, promoter activity, and mRNA were observed.ZnPP-Lipid is effective and thus has potential for treating neonatal hyperbilirubinemia due to hemolysis.

  View details for DOI 10.1038/pr.2015.207

  View details for Web of Science ID 000372377200003

• Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression. PloS one Azuma, J., Wong, R. J., Morisawa, T., Hsu, M., Maegdefessel, L., Zhao, H., Kalish, F., Kayama, Y., Wallenstein, M. B., Deng, A. C., Spin, J. M., Stevenson, D. K., Dalman, R. L., Tsao, P. S. 2016; 11 (2)

  Abstract

  Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.

  View details for DOI 10.1371/journal.pone.0149288

  View details for PubMedID 26894432

• Neonatal Biomarkers of Inflammation: Correlates of Early Neurodevelopment and Gait in Very-Low-Birth-Weight Preterm Children AMERICAN JOURNAL OF PERINATOLOGY Rose, J., Vassar, R., Cahill-Rowley, K., Hintz, S. R., Stevenson, D. K. 2016; 33 (1): 71-78

  Abstract

  Neonatal biomarkers of inflammation were examined in relation to early neurodevelopment and gait in very-low-birth-weight (VLBW) preterm children. We hypothesized that preterm infants exposed to higher levels of neonatal inflammation would demonstrate lower scores on Bayley Scales of Infant Toddler Development, 3rd ed. (BSID-III) and slower gait velocity at 18 to 22 months adjusted age.A total of 102 VLBW preterm infants (birthweight [BW] ≤ 1,500 g, gestational age [GA] ≤ 32 weeks) admitted to neonatal intensive care unit [NICU] were recruited. Neonatal risk factors examined were GA at birth, BW, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, sepsis, and serum C-reactive protein (CRP), albumin, and total bilirubin over first 2 postnatal weeks. At 18 to 22 months, neurodevelopment was assessed with BSID-III and gait was assessed with an instrumented mat.Children with neonatal CRP ≥ 0.20 mg/dL (n = 52) versus < 0.20 mg/dL (n = 37) had significantly lower BSID-III composite cognitive (92.0 ± 13.1 vs. 100.1 ± 9.6, p = 0.002), language (83.9 ± 16.0 vs. 95.8 ± 14.2, p < 0.001), and motor scores (90.0 ± 13.2 vs. 98.8 ± 10.1, p = 0.002), and slower gait velocity (84.9 ± 19.0 vs. 98.0 ± 22.4 cm/s, p = 0.004). Higher neonatal CRP correlated with lower cognitive (rho =  - 0.327, p = 0.002), language (rho =  - 0.285, p = 0.007), and motor scores (rho =  - 0.257, p = 0.015), and slower gait (rho =  - 0.298, p = 0.008). Multivariate analysis demonstrated neonatal CRP ≥ 0.20 mg/dL significantly predicted BSID-III cognitive (adjusted R(2) = 0.104, p = 0.008), language (adjusted R(2) = 0.124, p = 0.001), and motor scores (adjusted R(2) = 0.122, p = 0.004).Associations between low-level neonatal inflammation and neurodevelopment suggest early biomarkers that may inform neuroprotective treatment for preterm children.

  View details for DOI 10.1055/s-0035-1557106

  View details for Web of Science ID 000367556500010

• A Randomized Trial of Phototherapy with Filtered Sunlight in African Neonates. New England journal of medicine Slusher, T. M., Olusanya, B. O., Vreman, H. J., Brearley, A. M., Vaucher, Y. E., Lund, T. C., Wong, R. J., Emokpae, A. A., Stevenson, D. K. 2015; 373 (12): 1115-1124

  Abstract

  Sequelae of severe neonatal hyperbilirubinemia constitute a substantial disease burden in areas where effective conventional phototherapy is unavailable. We previously found that the use of filtered sunlight for the purpose of phototherapy is a safe and efficacious method for reducing total bilirubin. However, its relative safety and efficacy as compared with conventional phototherapy are unknown.We conducted a randomized, controlled noninferiority trial in which filtered sunlight was compared with conventional phototherapy for the treatment of hyperbilirubinemia in term and late-preterm neonates in a large, urban Nigerian maternity hospital. The primary end point was efficacy, which was defined as a rate of increase in total serum bilirubin of less than 0.2 mg per deciliter per hour for infants up to 72 hours of age or a decrease in total serum bilirubin for infants older than 72 hours of age who received at least 5 hours of phototherapy; we prespecified a noninferiority margin of 10% for the difference in efficacy rates between groups. The need for an exchange transfusion was a secondary end point. We also assessed safety, which was defined as the absence of the need to withdraw therapy because of hyperthermia, hypothermia, dehydration, or sunburn.We enrolled 447 infants and randomly assigned 224 to filtered sunlight and 223 to conventional phototherapy. Filtered sunlight was efficacious on 93% of treatment days that could be evaluated, as compared with 90% for conventional phototherapy, and had a higher mean level of irradiance (40 vs. 17 μW per square centimeter per nanometer, P<0.001). Temperatures higher than 38.0°C occurred in 5% of the infants receiving filtered sunlight and in 1% of those receiving conventional phototherapy (P<0.001), but no infant met the criteria for withdrawal from the study for reasons of safety or required an exchange transfusion.Filtered sunlight was noninferior to conventional phototherapy for the treatment of neonatal hyperbilirubinemia and did not result in any study withdrawals for reasons of safety. (Funded by the Thrasher Research Fund, Salt Lake City, and the National Center for Advancing Translational Sciences of the National Institutes of Health; Clinical Trials.gov number, NCT01434810.).

  View details for DOI 10.1056/NEJMoa1501074

  View details for PubMedID 26376136

• Temporal and spatial variation of the human microbiota during pregnancy PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA DiGiulio, D. B., Callahan, B. J., McMurdie, P. J., Costello, E. K., Lyell, D. J., Robaczewska, A., Sun, C. L., Goltsman, D. S., Wong, R. J., Shaw, G., Stevenson, D. K., Holmes, S. P., Relman, D. A. 2015; 112 (35): 11060-11065

  Abstract

  Despite the critical role of the human microbiota in health, our understanding of microbiota compositional dynamics during and after pregnancy is incomplete. We conducted a case-control study of 49 pregnant women, 15 of whom delivered preterm. From 40 of these women, we analyzed bacterial taxonomic composition of 3,767 specimens collected prospectively and weekly during gestation and monthly after delivery from the vagina, distal gut, saliva, and tooth/gum. Linear mixed-effects modeling, medoid-based clustering, and Markov chain modeling were used to analyze community temporal trends, community structure, and vaginal community state transitions. Microbiota community taxonomic composition and diversity remained remarkably stable at all four body sites during pregnancy (P > 0.05 for trends over time). Prevalence of a Lactobacillus-poor vaginal community state type (CST 4) was inversely correlated with gestational age at delivery (P = 0.0039). Risk for preterm birth was more pronounced for subjects with CST 4 accompanied by elevated Gardnerella or Ureaplasma abundances. This finding was validated with a set of 246 vaginal specimens from nine women (four of whom delivered preterm). Most women experienced a postdelivery disturbance in the vaginal community characterized by a decrease in Lactobacillus species and an increase in diverse anaerobes such as Peptoniphilus, Prevotella, and Anaerococcus species. This disturbance was unrelated to gestational age at delivery and persisted for up to 1 y. These findings have important implications for predicting premature labor, a major global health problem, and for understanding the potential impact of a persistent, altered postpartum microbiota on maternal health, including outcomes of pregnancies following short interpregnancy intervals.

  View details for DOI 10.1073/pnas.1502875112

  View details for Web of Science ID 000360383200068

• Bilirubin production and hour-specific bilirubin levels. Journal of perinatology Bhutani, V. K., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2015; 35 (9): 735-738

  Abstract

  We assessed the relative contributions of increased bilirubin production (indexed by end-tidal carbon monoxide (CO) concentrations, corrected for ambient CO (ETCOc)) to hour-specific total bilirubin (TB) levels in healthy late preterm and term newborns.Post hoc analyses of concurrent ETCOc and TB (at 30±6 h of age) and follow-up TB levels at age 96±12 h and up to 168 h after birth were performed in a cohort of 641 term and late preterm infants.Increased bilirubin production (hour-specific ETCOc ⩾1.7 p.p.m. at age 30±6 h) was noted in ~80%, 42% and 32% of infants in the high-, intermediate- and low-risk TB zones, respectively. One infant with TB <40th percentile and ETCOc <1.7 p.p.m. developed TB ⩾95th percentile at age 168 h, probably due to decreased bilirubin elimination.Infants in the high-risk quartile of the hour-specific bilirubin nomogram have a higher mean bilirubin production. Infants with TB levels ⩾95th percentile without increased bilirubin production have impaired bilirubin elimination.

  View details for DOI 10.1038/jp.2015.32

  View details for PubMedID 25880796

• Implementing Mass Cytometry at the Bedside to Study the Immunological Basis of Human Diseases: Distinctive Immune Features in Patients with a History of Term or Preterm Birth. Cytometry. Part A : the journal of the International Society for Analytical Cytology Gaudillière, B., Ganio, E. A., Tingle, M., Lancero, H. L., Fragiadakis, G. K., Baca, Q. J., Aghaeepour, N., Wong, R. J., Quaintance, C., El-Sayed, Y. Y., Shaw, G. M., Lewis, D. B., Stevenson, D. K., Nolan, G. P., Angst, M. S. 2015; 87 (9): 817-829

  Abstract

  Single-cell technologies have immense potential to shed light on molecular and biological processes that drive human diseases. Mass cytometry (or Cytometry by Time Of Flight mass spectrometry, CyTOF) has already been employed in clinical studies to comprehensively survey patients' circulating immune system. As interest in the "bedside" application of mass cytometry is growing, the delineation of relevant methodological issues is called for. This report uses a newly generated dataset to discuss important methodological considerations when mass cytometry is implemented in a clinical study. Specifically, the use of whole blood samples versus peripheral blood mononuclear cells (PBMCs), design of mass-tagged antibody panels, technical and analytical implications of sample barcoding, and application of traditional and unsupervised approaches to analyze high-dimensional mass cytometry datasets are discussed. A mass cytometry assay was implemented in a cross-sectional study of 19 women with a history of term or preterm birth to determine whether immune traits in peripheral blood differentiate the two groups in the absence of pregnancy. Twenty-seven phenotypic and 11 intracellular markers were simultaneously analyzed in whole blood samples stimulated with lipopolysaccharide (LPS at 0, 0.1, 1, 10, and 100 ng mL(-1) ) to examine dose-dependent signaling responses within the toll-like receptor 4 (TLR4) pathway. Complementary analyses, grounded in traditional or unsupervised gating strategies of immune cell subsets, indicated that the prpS6 and pMAPKAPK2 responses in classical monocytes are accentuated in women with a history of preterm birth (FDR<1%). The results suggest that women predisposed to preterm birth may be prone to mount an exacerbated TLR4 response during the course of pregnancy. This important hypothesis-generating finding points to the power of single-cell mass cytometry to detect biologically important differences in a relatively small patient cohort. © 2015 International Society for Advancement of Cytometry.

  View details for DOI 10.1002/cyto.a.22720

  View details for PubMedID 26190063

• Heme oxygenase-1 promoter polymorphisms and risk of spina bifida. Birth defects research. Part A, Clinical and molecular teratology Fujioka, K., Yang, W., Wallenstein, M. B., Zhao, H., Wong, R. J., Stevenson, D. K., Shaw, G. M. 2015; 103 (9): 741-746

  Abstract

  Spina bifida is the most common form of neural tube defects (NTDs). Etiologies of NTDs are multifactorial, and oxidative stress is believed to play a key role in NTD development. Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, has multiple protective properties including mediating antioxidant processes, making it an ideal candidate for study. The inducible HO isoform (HO-1) has two functional genetic polymorphisms: (GT)n dinucleotide repeats and A(-413)T SNP (rs2071746), both of which can affect its promoter activity. However, no study has investigated a possible association between HO-1 genetic polymorphisms and risk of NTDs.This case-control study included 152 spina bifida cases (all myelomeningoceles) and 148 nonmalformed controls obtained from the California Birth Defects Monitoring Program reflecting births during 1990 to 1999. Genetic polymorphisms were determined by polymerase chain reaction and amplified fragment length polymorphisms/restriction fragment length polymorphisms using genomic DNA extracted from archived newborn blood spots. Genotype and haplotype frequencies of two HO-1 promoter polymorphisms between cases and controls were compared.For (GT)n dinucleotide repeat lengths and the A(-413)T SNP, no significant differences in allele frequencies or genotypes were found. Linkage disequilibrium was observed between the HO-1 polymorphisms (D': 0.833); however, haplotype analyses did not show increased risk of spina bifida overall or by race/ethnicity.Although, an association was not found between HO-1 polymorphisms and risk of spina bifida, we speculate that the combined effect of low HO-1 expression and exposures to known environmental oxidative stressors (low folate status or diabetes), may overwhelm antioxidant defenses and increase risk of NTDs and warrants further study. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23343

  View details for PubMedID 26173399

• Implementing Mass Cytometry at the Bedside to Study the Immunological Basis of Human Diseases: Distinctive Immune Features in Patients with a History of Term or Preterm Birth CYTOMETRY PART A Gaudilliere, B., Ganio, E. A., Tingle, M., Lancero, H. L., Fragiadakis, G. K., Baca, Q. J., Aghaeepour, N., Wong, R. J., Quaintance, C., El-Sayed, Y. Y., Shaw, G. M., Lewis, D. B., Stevenson, D. K., Nolan, G. P., Angst, M. S. 2015; 87A (9): 817-829

  Abstract

  Single-cell technologies have immense potential to shed light on molecular and biological processes that drive human diseases. Mass cytometry (or Cytometry by Time Of Flight mass spectrometry, CyTOF) has already been employed in clinical studies to comprehensively survey patients' circulating immune system. As interest in the "bedside" application of mass cytometry is growing, the delineation of relevant methodological issues is called for. This report uses a newly generated dataset to discuss important methodological considerations when mass cytometry is implemented in a clinical study. Specifically, the use of whole blood samples versus peripheral blood mononuclear cells (PBMCs), design of mass-tagged antibody panels, technical and analytical implications of sample barcoding, and application of traditional and unsupervised approaches to analyze high-dimensional mass cytometry datasets are discussed. A mass cytometry assay was implemented in a cross-sectional study of 19 women with a history of term or preterm birth to determine whether immune traits in peripheral blood differentiate the two groups in the absence of pregnancy. Twenty-seven phenotypic and 11 intracellular markers were simultaneously analyzed in whole blood samples stimulated with lipopolysaccharide (LPS at 0, 0.1, 1, 10, and 100 ng mL(-1) ) to examine dose-dependent signaling responses within the toll-like receptor 4 (TLR4) pathway. Complementary analyses, grounded in traditional or unsupervised gating strategies of immune cell subsets, indicated that the prpS6 and pMAPKAPK2 responses in classical monocytes are accentuated in women with a history of preterm birth (FDR<1%). The results suggest that women predisposed to preterm birth may be prone to mount an exacerbated TLR4 response during the course of pregnancy. This important hypothesis-generating finding points to the power of single-cell mass cytometry to detect biologically important differences in a relatively small patient cohort. © 2015 International Society for Advancement of Cytometry.

  View details for DOI 10.1002/cyto.a.22720

  View details for Web of Science ID 000360590500009

• Evaluation of a new end-tidal carbon monoxide monitor from the bench to the bedside. Acta paediatrica (Oslo, Norway : 1992) Castillo Cuadrado, M. E., Bhutani, V. K., Aby, J. L., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2015; 104 (6): e279-82

  View details for DOI 10.1111/apa.12938

  View details for PubMedID 25640053

• Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation PEDIATRIC RESEARCH Schulz, S., Chisholm, K. M., Zhao, H., Kalish, F., Yang, Y., Wong, R. J., Stevenson, D. K. 2015; 77 (5): 640-648

  Abstract

  Necrotizing enterocolitis (NEC), an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T-cell proportions in a murine NEC-like injury model.Intestinal injury was induced in 7-d-old wild-type (WT) or HO-1 heterozygous (HO-1 Het) pups by formula-feeding every 4 h for 24-78 h by oral gavage and exposures to 5%O2. Controls remained breastfed. HO-1 was induced in WT pups by administering heme preinjury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected intraperitoneally into HO-1 Het pups 12-24 h preinduction.Het mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (Toll-like receptor-4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to HO-1 Het pups decreased NEC scores and incidence and restored Treg/Teff ratios.HO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer intestinal protection.

  View details for DOI 10.1038/pr.2015.22

  View details for PubMedID 25665053

• Neonatal bilirubin binding capacity discerns risk of neurological dysfunction. Pediatric research Lamola, A. A., Bhutani, V. K., Du, L., Castillo Cuadrado, M., Chen, L., Shen, Z., Wong, R. J., Stevenson, D. K. 2015; 77 (2): 334-339

  View details for DOI 10.1038/pr.2014.191

  View details for PubMedID 25420178

• Copy Number Variation in Bronchopulmonary Dysplasia AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hoffmann, T. J., Shaw, G. M., Stevenson, D. K., Wang, H., Quaintance, C. C., Oehlert, J., Jelliffe-Pawlowski, L. L., Gould, J. B., Witte, J. S., O'Brodovich, H. M. 2014; 164 (10): 2672–75

  View details for DOI 10.1002/ajmg.a.36659

  View details for Web of Science ID 000342279600041

  View details for PubMedID 24975634

  View details for PubMedCentralID PMC4167221

• Swedish and American studies show that initiatives to decrease maternal obesity could play a key role in reducing preterm birth. Acta paediatrica (Oslo, Norway : 1992) Gould, J. B., Mayo, J., Shaw, G. M., Stevenson, D. K. 2014; 103 (6): 586-591

  Abstract

  Maternal obesity is a major source of preventable perinatal morbidity, but studies of the relationship between obesity and preterm birth have been inconsistent. This review looks at two major studies covering just under 3.5 million births, from California, USA, and Sweden.Inconsistent findings in previous studies appear to stem from the complex relationship between obesity and preterm birth. Initiatives to decrease maternal obesity represent an important strategy in reducing preterm birth.

  View details for DOI 10.1111/apa.12616

  View details for PubMedID 24575829

• Effects of light on metalloporphyrin-treated newborn mice. Acta paediatrica Wong, R. J., Schulz, S., Espadas, C., Vreman, H. J., Rajadas, J., Stevenson, D. K. 2014; 103 (5): 474-479

  Abstract

  Zinc protoporphyrin (ZnPP) is a promising metalloporphyrin with sufficient potency, but has poor solubility and is not absorbed well orally. Intragastric administration of ZnPP microparticles (30 μmol/kg) to 3-day-old mice resulted in a twofold increase in potency and no signs of phototoxicity.The use of polymeric particulate delivery systems can improve the stability and enhance intestinal absorption of ZnPP, while retaining HO inhibitory potency without photosensitising effects, and thus is potentially useful in treating neonatal hyperbilirubinemia.

  View details for DOI 10.1111/apa.12554

  View details for PubMedID 24417721

• Heme Oxygenase-1 Promoter Polymorphisms and Neonatal Jaundice NEONATOLOGY Kaplan, M., Renbaum, P., Hamrnernnan, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2014; 106 (4): 323-329

  Abstract

  Heme oxygenase (HO) is the initial, rate-limiting enzyme in the conversion of heme to bilirubin. Dinucleotide (GT)n repeat length in the promoter region of the encoding gene modulates transcription: shorter alleles, in contrast with longer allele counterparts, are associated with greater gene expression and should result in increased heme catabolism.We compared the rates of heme catabolism and plasma total bilirubin (TB) between HO-1 promoter genotypes of varying (GT)n repeat lengths in glucose-6-phosphate dehydrogenase (G6PD)-normal and -deficient neonates.HO-1 promoter length was determined from genomic DNA from previous studies by size discrimination of fluorescently-labeled PCR products with capillary electrophoresis. Sizing was confirmed by sequencing homozygote samples. Alleles were categorized as: short (≤24 GT repeats), medium (25-33 GT repeats), and long (≥34 GT repeats). Previously determined values for blood carboxyhemoglobin, corrected for inspired carbon monoxide (COHbc), and TB were used to determine the rate of heme catabolism and 3rd day TB values for each HO-1 promoter length genotype, respectively. G6PD Mediterranean was determined by PCR analysis.Neither COHbc nor TB values were significantly different between various HO-1 promoter genotypes for either G6PD-normal or -deficient neonates.In the steady state, HO-1 promoter genotypes, based on the length of (GT)n repeats, do not modulate heme catabolism or 3rd day TB values in either G6PD-normal or -deficient neonates.

  View details for DOI 10.1159/000365744

  View details for Web of Science ID 000344445400007

• Elevated mid-pregnancy tumor necrosis factor-alpha (TNF-alpha) and lipid patterns suggestive of hyperlipidemia in pregnancies resulting in early preterm birth Jelliffe-Pawlowski, L., Ryckman, K., Bedell, B., O'Brodovich, H., Gould, J., Lyell, D., Shaw, G., Murray, J., Stevenson, D. MOSBY-ELSEVIER. 2014: S375–S376

  View details for DOI 10.1016/j.ajog.2013.10.798

  View details for Web of Science ID 000330322600765

• Population-level correlates of preterm delivery among black and white women in the U.S. PloS one Carmichael, S. L., Cullen, M. R., Mayo, J. A., Gould, J. B., Loftus, P., Stevenson, D. K., Wise, P. H., Shaw, G. M. 2014; 9 (4)

  Abstract

  This study examined the ability of social, demographic, environmental and health-related factors to explain geographic variability in preterm delivery among black and white women in the US and whether these factors explain black-white disparities in preterm delivery.We examined county-level prevalence of preterm delivery (20-31 or 32-36 weeks gestation) among singletons born 1998-2002. We conducted multivariable linear regression analysis to estimate the association of selected variables with preterm delivery separately for each preterm/race-ethnicity group.The prevalence of preterm delivery varied two- to three-fold across U.S. counties, and the distributions were strikingly distinct for blacks and whites. Among births to blacks, regression models explained 46% of the variability in county-level risk of delivery at 20-31 weeks and 55% for delivery at 32-36 weeks (based on R-squared values). Respective percentages for whites were 67% and 71%. Models included socio-environmental/demographic and health-related variables and explained similar amounts of variability overall.Much of the geographic variability in preterm delivery in the US can be explained by socioeconomic, demographic and health-related characteristics of the population, but less so for blacks than whites.

  View details for DOI 10.1371/journal.pone.0094153

  View details for PubMedID 24740117

• Risks and benefits of comparative effectiveness research in preterm infants: SUPPORT. Journal of comparative effectiveness research Stevenson, D. K., Wong, R. J., Tyson, J. E. 2014; 3 (1): 17-21

  View details for DOI 10.2217/cer.13.85

  View details for PubMedID 24345253

• Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Frontiers in pharmacology Zhao, H., Ozen, M., Wong, R. J., Stevenson, D. K. 2014; 5: 295-?

  Abstract

  Pregnancy can be defined as a "permissible" process, where a semi-allogeneic fetus and placenta are allowed to grow and survive within the mother. Similarly, in tumor growth, antigen-specific malignant cells proliferate and evade into normal tissues of the host. The microenvironments of the placenta and tumors are amazingly comparable, sharing similar mechanisms exploited by fetal or cancer cells with regard to surviving in a hypoxic microenvironment, invading tissues via degradation and vasculogenesis, and escaping host attack through immune privilege. Heme oxygease-1 (HO-1) is a stress-response protein that has antioxidative, anti-apoptotic, pro-angiogenic, and anti-inflammatory properties. Although a large volume of research has been published in recent years investigating the possible role(s) of HO-1 in pregnancy and in cancer development, the molecular mechanisms that regulate these "yin-yang" processes have still not been fully elucidated. Here, we summarize and compare pregnancy and cancer development, focusing primarily on the function of HO-1 in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Due to the similarities of both processes, a thorough understanding of the molecular mechanisms of each process may reveal and guide the development of new approaches to prevent not only pregnancy disorders; but also, to study cancer.

  View details for DOI 10.3389/fphar.2014.00295

  View details for PubMedID 25642189

• Population-Level Correlates of Preterm Delivery among Black and White Women in the U.S. PloS one Carmichael, S. L., Cullen, M. R., Mayo, J. A., Gould, J. B., Loftus, P., Stevenson, D. K., Wise, P. H., Shaw, G. M. 2014; 9 (4)

  View details for DOI 10.1371/journal.pone.0094153

  View details for PubMedID 24740117

• Heme oxygenase-1 deficiency promotes the development of necrotizing enterocolitis-like intestinal injury in a newborn mouse model. American journal of physiology. Gastrointestinal and liver physiology Schulz, S., Wong, R. J., Jang, K. Y., Kalish, F., Chisholm, K. M., Zhao, H., Vreman, H. J., Sylvester, K. G., Stevenson, D. K. 2013; 304 (11): G991-G1001

  Abstract

  Necrotizing enterocolitis (NEC) is typified by mucosal destruction, which subsequently can lead to intestinal necrosis. Prematurity, enteral feeding, and bacterial colonization are the main risk factors and, combined with other stressors, can cause increased intestinal permeability, injury, and an exaggerated inflammatory response. Heme oxygenase-1 (HO-1) mediates intestinal protection due to anti-inflammatory, antioxidative, and antiapoptotic effects of its products carbon monoxide, biliverdin, and bilirubin. This study investigates a possible role of HO-1 in the pathogenesis of NEC using a newborn mouse model. We induced NEC-like intestinal injury in 7-day-old HO-1 heterozygous (HO-1 Het, Hmox1(+/-)) and wild-type (Wt, Hmox1(+/+)) mice by gavage feeding and hypoxic exposures. Control (Con) pups of both genotypes were dam-fed. Intestines of HO-1 Het Con pups appeared predisposed to injury, with higher histological damage scores, more TUNEL-positive cells, and a significant reduction in muscularis externa thickness compared with Wt Con pups. The increase in HO activity after HO-1 induction by the substrate heme or by hypoxic stress was significantly impaired in HO-1 Het pups. After induction of intestinal injury, HO-1 Het pups displayed significantly higher NEC incidence (78 vs. 43%), mortality (83 vs. 54%), and median scores (2.5 vs. 1.5) than Wt NEC pups. PCR array analyses revealed increased expressions of IL-1β, P-selectin, matrix metallopeptidase 2, collagen type XVIII-α1, serpine 1, and others in NEC-induced HO-1 Het ileal and jejunal tissues. We conclude that a partial HO-1 deficiency promotes experimental NEC-like intestinal injury, possibly mediated by exaggerated inflammation and disruption in tissue repair.

  View details for DOI 10.1152/ajpgi.00363.2012

  View details for PubMedID 23578787

• Transdisciplinary translational science and the case of preterm birth JOURNAL OF PERINATOLOGY Stevenson, D. K., Shaw, G. M., Wise, P. H., Norton, M. E., Druzin, M. L., Valantine, H. A., McFarland, D. A. 2013; 33 (4): 251-258

  Abstract

  Medical researchers have called for new forms of translational science that can solve complex medical problems. Mainstream science has made complementary calls for heterogeneous teams of collaborators who conduct transdisciplinary research so as to solve complex social problems. Is transdisciplinary translational science what the medical community needs? What challenges must the medical community overcome to successfully implement this new form of translational science? This article makes several contributions. First, it clarifies the concept of transdisciplinary research and distinguishes it from other forms of collaboration. Second, it presents an example of a complex medical problem and a concrete effort to solve it through transdisciplinary collaboration: for example, the problem of preterm birth and the March of Dimes effort to form a transdisciplinary research center that synthesizes knowledge on it. The presentation of this example grounds discussion on new medical research models and reveals potential means by which they can be judged and evaluated. Third, this article identifies the challenges to forming transdisciplines and the practices that overcome them. Departments, universities and disciplines tend to form intellectual silos and adopt reductionist approaches. Forming a more integrated (or 'constructionist'), problem-based science reflective of transdisciplinary research requires the adoption of novel practices to overcome these obstacles.

  View details for DOI 10.1038/jp.2012.133

  View details for PubMedID 23079774

• Predischarge Screening for Severe Neonatal Hyperbilirubinemia Identifies Infants Who Need Phototherapy JOURNAL OF PEDIATRICS Bhutani, V. K., Stark, A. R., Lazzeroni, L. C., Poland, R., Gourley, G. R., Kazmierczak, S., Meloy, L., Burgos, A. E., Hall, J. Y., Stevenson, D. K. 2013; 162 (3): 477-?

  Abstract

  To test whether the combined use of total plasma/serum bilirubin (TSB) levels and clinical risk factors more accurately identifies infants who receive phototherapy than does the use of either method alone.We recruited healthy infants of ≥35 weeks' gestation at 6 centers that practiced universal predischarge TSB screening. Transcutaneous bilirubin (TcB) was measured at 24 hours, with TSB at 24-60 hours and at 3- to 5- and 7- to 14-day follow-up visits. Clinical risk factors were identified systematically.Of 1157 infants, 1060 (92%) completed follow-up, and 982 (85%) had complete datasets for analysis. Infant characteristics included 25% were nonwhite and 55% were Hispanic/Latino; >90% were breastfed. During the first week, jaundice was documented in 84% of subjects. Predischarge TSB identified the 41 (4.2%) and 34 (3.5%) infants who received phototherapy before and after discharge, respectively. Prediction of postdischarge phototherapy was similar for combined clinical risk factors (earlier gestational age [GA], bruising, positive direct antiglobulin test, Asian race, exclusive breastfeeding, blood type incompatibility, jaundice extent) and age-adjusted TSB (area under the curve [AUC] = .86 vs .87), but combined screening was better (AUC = .95). TcB/TSB combined with GA alone was equally predictive (AUC = .95; 95% CI .93-.97).Jaundice is present in 4 of 5 (84%) healthy newborns. Predischarge TcB/TSB (adjusted for postnatal age) combined with specific clinical factors (especially GA) best predicts subsequent phototherapy use. Universal implementation of this strategy in the US should improve outcomes of healthy newborns discharged early.

  View details for DOI 10.1016/j.jpeds.2012.08.022

  View details for Web of Science ID 000315790100010

  View details for PubMedID 23043681

• Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial NEW ENGLAND JOURNAL OF MEDICINE Vaucher, Y. E., Peralta-Carcelen, M., Finer, N. N., Carlo, W. A., Gantz, M. G., Walsh, M. C., Laptook, A. R., Yoder, B. A., Faix, R. G., Das, A., Schibler, K., Rich, W., Newman, N. S., Vohr, B. R., Yolton, K., Heyne, R. J., Wilson-Costello, D. E., Evans, P. W., Goldstein, R. F., Acarregui, M. J., Adams-Chapman, I., Pappas, A., Hintz, S. R., Poindexter, B., Dusick, A. M., McGowan, E. C., Ehrenkranz, R. A., Bodnar, A., Bauer, C. R., Fuller, J., O'Shea, T. M., Myers, G. J., Higgins, R. D. 2012; 367 (26): 2495-2504

  Abstract

  Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses.Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age.The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P=0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P=0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P=0.046).We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.).

  View details for DOI 10.1056/NEJMoa1208506

  View details for Web of Science ID 000312714200007

  View details for PubMedID 23268664

• An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation JOURNAL OF PERINATOLOGY Maisels, M. J., Watchko, J. F., Bhutani, V. K., Stevenson, D. K. 2012; 32 (9): 660–64

  Abstract

  We provide an approach to the use of phototherapy and exchange transfusion in the management of hyperbilirubinemia in preterm infants of <35 weeks of gestation. Because there are limited data for evidence-based recommendations, these recommendations are, of necessity, consensus-based. The recommended treatment levels are based on operational thresholds for bilirubin levels and represent those levels beyond which it is assumed that treatment will likely do more good than harm. Long-term follow-up of a large population will be needed to evaluate whether or not these recommendations should be modified.

  View details for DOI 10.1038/jp.2012.71

  View details for Web of Science ID 000308278000003

  View details for PubMedID 22678141

• Effect of light exposure on metalloporphyrin-treated newborn mice PEDIATRIC RESEARCH Schulz, S., Wong, R. J., Kalish, F. S., Zhao, H., Jang, K. Y., Vreman, H. J., Stevenson, D. K. 2012; 72 (2): 161-168

  Abstract

  Neonatal hyperbilirubinemia arises from increased bilirubin production and decreased bilirubin elimination. Although phototherapy safely and effectively reduces bilirubin levels, recent evidence shows that it has adverse effects. Therefore, alternative treatments are warranted. Metalloporphyrins, competitive inhibitors of heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, effectively reduce bilirubin formation; however, many are photoreactive. Here, we investigated possible photosensitizing effects of chromium mesoporphyrin (CrMP) and zinc deuteroporphyrin bis-glycol (ZnBG).Administration of CrMP or ZnBG to 3-d-old mouse pups (3.75-30.0 μmol/kg intraperitoneally) and exposure to cool white (F20T12CW) and blue (TL20W/52) fluorescent lights (+L) for 3 h, resulted in a dose-dependent mortality (50% lethal dose (LD50) = 21.5 and 19.5 μmol/kg, respectively). In contrast to ZnBG, there was no significant difference in survival between the CrMP+L and CrMP groups. Following 30 μmol/kg ZnBG+L, we found significant weight loss, decreased liver antioxidant capacities, and increased aspartate aminotransaminase levels. At 6-d post-light exposure, ZnBG+L-treated pups showed gross and histologic skin changes at doses >7.5 μmol/kg. No lethality was observed following treatment with 30 μmol ZnBG/kg plus exposure to blue light-emitting diodes. Phototoxicity of ZnBG was dependent on light source, emission spectrum, and irradiance.Low doses of ZnBG (<3.75 μmol/kg) retained maximal HO inhibitory potency without photosensitizing effects, and therefore are potentially useful in treating neonatal hyperbilirubinemia.

  View details for DOI 10.1038/pr.2012.62

  View details for PubMedID 22580722

• A deficiency in haem oxygenase-1 induces foetal growth restriction by placental vasculature defects ACTA PAEDIATRICA Wong, R. J., Zhao, H., Stevenson, D. K. 2012; 101 (8): 827-834

  Abstract

  Haem oxygenase-1 (HO-1), the rate-limiting enzyme in haem degradation, plays a role in angiogenesis and vasculogenesis and is highly expressed in the placenta. Deficiencies in HO-1 are associated with several pregnancy disorders, such as recurrent miscarriages and pre-eclampsia. The unique combination of tissue protective, smooth muscle relaxing and angiogenesis regulatory properties makes HO-1 a key player in the maintenance of a healthy pregnancy through a direct effect on placental structural and vascular development, thus affecting foetal development. Conclusion:  Therefore, we conclude that HO-1 plays an important role in placental vasculature development and a deficiency in HO-1 may contribute to pregnancy complications, such as pre-eclampsia, spontaneous abortions and premature births.

  View details for DOI 10.1111/j.1651-2227.2012.02729.x

  View details for PubMedID 22594519

• Metalloporphyrins - an update. Frontiers in pharmacology Schulz, S., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2012; 3: 68-?

  Abstract

  Metalloporphyrins are structural analogs of heme and their potential use in the management of neonatal hyperbilirubinemia has been the subject of considerable research for more than three decades. The pharmacological basis for using this class of compounds to control bilirubin levels is the targeted blockade of bilirubin production through the competitive inhibition of heme oxygenase (HO), the rate-limiting enzyme in the bilirubin production pathway. Ongoing research continues in the pursuit of identifying ideal metalloporphyrins, which are safe and effective, by defining therapeutic windows and targeted interventions for the treatment of excessive neonatal hyperbilirubinemia.

  View details for DOI 10.3389/fphar.2012.00068

  View details for PubMedID 22557967

• Maternal Heme Oxygenase 1 Regulates Placental Vasculature Development via Angiogenic Factors in Mice BIOLOGY OF REPRODUCTION Zhao, H., Azuma, J., Kalish, F., Wong, R. J., Stevenson, D. K. 2011; 85 (5): 1005-1012

  Abstract

  The placental vasculature is critical for nutrient, gas, and waste exchange between the maternal and fetal systems. Its development depends on the proper expression and interaction of angiogenesis and associated growth factors. Heme oxygenase (HMOX), the enzyme for heme degradation, plays a role in angiogenesis and is highly expressed in the placenta. To evaluate the role of maternal HMOX1, the inducible HMOX isozyme, on placental vasculature formation, mice with a partial deficiency in Hmox1 (Hmox1(+/-)) were used. Three-dimensional images of placental vasculatures as well as spiral arteries from Hmox1(+/+) or Hmox1(+/-) placentas were created by vascular corrosion casting technique and imaged by micro-computerized tomography (microCT). The structures and morphologies of fetomaternal interfaces were observed by histological staining and the ultrastructure of uterine natural killer (uNK) cells, a major regulator in spiral artery remodeling, was analyzed by transmission electron microscopy. A group of growth factors and angiogenic factors from the decidua/mesometrial lymphoid aggregate of pregnancy (MLAp) as well as labyrinth regions were quantified using an angiogenesis PCR array kit and compared between Hmox1(+/+) or Hmox1(+/-) placentas. In conclusion, a partial deficiency of maternal Hmox1 resulted in the malformation of fetomaternal interface, insufficiency of spiral artery remodeling, and alteration of uNK cell differentiation and maturation. These changes were independent of the fetal genotype, but relied on the maternal HMOX1 level, which determined the balance of expression levels of pro- and antiangiogenic factors in the decidua/MLAp region. These results implied that Hmox1 polymorphisms among the human population might contribute to some unexplained cases of pregnancy disorders, such as fetal growth retardation and preeclampsia.

  View details for DOI 10.1095/biolreprod.111.093039

  View details for PubMedID 21778140

• Effects of Zinc Deuteroporphyrin Bis Glycol on Newborn Mice After Heme Loading PEDIATRIC RESEARCH He, C. X., Campbell, C. M., Zhao, H., Kalish, F. S., Schulz, S., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2011; 70 (5): 467-472

  Abstract

  Infants with hemolytic diseases frequently develop hyperbilirubinemia and are treated with phototherapy, which only eliminates bilirubin after its production. A better strategy might be to directly inhibit heme oxygenase (HO), the rate-limiting enzyme in bilirubin production. Metalloporphyrins (Mps) are heme analogs that competitively inhibit HO activity in vitro and in vivo and suppress plasma bilirubin levels in vivo. A promising Mp, zinc deuteroporphyrin bis glycol (ZnBG), is orally absorbed and effectively inhibits HO activity at relatively low doses. We determined the I(50) (the dose needed to inhibit HO activity by 50%) of orally administered ZnBG in vivo and then evaluated ZnBG's effects on in vivo bilirubin production, HO activity, HO protein levels, and HO-1 gene expression in newborn mice after heme loading, a model analogous to a hemolytic infant. The I(50) of ZnBG was found to be 4.0 μmol/kg body weight (BW). At a dose of 15 μmol/kg BW, ZnBG reduced in vivo bilirubin production, inhibited heme-induced liver HO activity and spleen HO activity to and below baseline, respectively, transiently induced liver and spleen HO-1 gene transcription, and induced liver and spleen HO-1 protein levels. We conclude that ZnBG may be an attractive compound for treating severe neonatal hyperbilirubinemia caused by hemolytic disease.

  View details for PubMedID 21785387

• Is phototherapy exposure associated with better or worse outcomes in 501-to 1000-g-birth-weight infants? ACTA PAEDIATRICA Hintz, S. R., Stevenson, D. K., Yao, Q., Wong, R. J., Das, A., Van Meurs, K. P., Morris, B. H., Tyson, J. E., Oh, W., Poole, W. K., Phelps, D. L., McDavid, G. E., Grisby, C., Higgins, R. D. 2011; 100 (7): 960-965

  Abstract

   To compare risk-adjusted outcomes at 18- to 22-month-corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.Outcomes at 18 to 22-month-corrected age included death, neurodevelopmental impairment (NDI) and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for centre and other potentially confounding variables.Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501- to 1000-g-BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI: 0.60-1.20), death or adverse neurodevelopmental endpoints. However, among infants 501-750 g BW, the rate of significant developmental impairment with MDI < 50 was significantly higher for NoPTx (29%) than PTx (12%) (p = 0.004).Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded because of bias from deaths before reaching conservative treatment threshold. The higher rate of MDI < 50 in the 501- to 750-g-BW NoPTx group is concerning and consistent with NRN Trial results.

  View details for DOI 10.1111/j.1651-2227.2011.02175.x

  View details for PubMedID 21272067

• Bilirubin Production and the Risk of Bilirubin Neurotoxicity SEMINARS IN PERINATOLOGY Stevenson, D. K., Vreman, H. J., Wong, R. J. 2011; 35 (3): 121-126

  Abstract

  Neonatal jaundice usually occurs in the transitional period after birth, presenting as an elevation of circulating bilirubin. Bilirubin neurotoxicity can occur if the levels of bilirubin become excessive (hyperbilirubinemia). This pathologic phenotype of newborn jaundice can develop because of excessive bilirubin production or impaired conjugation, with the risk for developing bilirubin-induced neurologic dysfunction, depending on the degree of the resultant bilirubin load. The plasma bilirubin level thus can be used to assess an infant's risk for developing bilirubin neurotoxicity relative to an infant's age in hours. Because all infants have an impaired conjugation ability, infants at greatest risk are those who have increased bilirubin production rates, because of hemolysis, for example. Therefore, developing potential preventive strategies as well as noninvasive technologies to treat and to identify infants with increased bilirubin production rates, respectively, are tantamount to reducing the incidence of bilirubin-induced neurologic dysfunction.

  View details for DOI 10.1053/j.semperi.2011.02.005

  View details for PubMedID 21641484

• Panhematin provides a therapeutic benefit in experimental pancreatitis GUT Habtezion, A., Kwan, R., Akhtar, E., Wanaski, S. P., Collins, S. D., Wong, R. J., Stevenson, D. K., Butcher, E. C., Omary, M. B. 2011; 60 (5): 671-679

  Abstract

  Acute pancreatitis (AP) can result in pancreatic necrosis and inflammation, with subsequent multi-organ failure. AP is associated with increased neutrophil recruitment and a rise in pro-inflammatory cytokines such as TNFα. Pretreatment with haemin, results in recruitment of haem-oxygenase-1 (HO-1)(+) macrophages and protects against experimental pancreatitis. It is not clear whether modulation of HO-1 after onset of disease has a protective role. In this study, we tested the utility of Panhematin, a water-soluble haemin formulation, in activating and inducing pancreatic HO-1, and as a therapeutic agent in treating mouse acute pancreatitis.We defined the distribution of radiolabelled haemin, then used in vivo HO-1-luciferase bioluminescence imaging and the CO-release assay to test Panhematin-induced upregulation of HO-1 transcription and activity, respectively. Using two well-defined AP murine models, we tested the therapeutic benefit of Panhematin, and quantified cytokine release using a luminex assay.Intravenously administered Panhematin induces rapid recruitment of HO-1(+) cells to the pancreas within 2 h and de novo splenic HO-1 transcription by 12 h. Despite high baseline spleen HO-1 activity, the pancreas is particularly responsive to Panhematin-mediated HO-1 induction. Panhematin-treated mice, at various time points after AP induction had significant reduction in mortality, pancreatic injury, together with upregulation of HO-1 and downregulation of pro-inflammatory cytokines and CXCL1, a potent neutrophil chemoattractant.Despite AP-associated mortality and morbidity, no effective treatment other than supportive care exists. We demonstrate that Panhematin leads to: (i) rapid induction and activation of pancreatic HO-1 with recruitment of HO-1(+) cells to the pancreas, (ii) amelioration of AP even when given late during the course of disease, and (iii) a decrease in leucocyte infiltration and pro-inflammatory cytokines including CXCL1. The utility of Panhematin at modest doses as a therapeutic in experimental pancreatitis, coupled with its current use and safety in humans, raises the potential of its applicability to human pancreatitis.

  View details for DOI 10.1136/gut.2010.217208

  View details for Web of Science ID 000289076700015

  View details for PubMedID 21159893

  View details for PubMedCentralID PMC3580958

• In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins JOURNAL OF PERINATOLOGY Wong, R. J., Vreman, H. J., Schulz, S., Kalish, F. S., Pierce, N. W., Stevenson, D. K. 2011; 31: S35-S41

  Abstract

  Neonatal jaundice results from an increased bilirubin production and decreased hepatic bilirubin conjugation and excretion. Severe hyperbilirubinemia is currently treated with phototherapy or exchange transfusion; however, its prevention by inhibiting bilirubin formation is a more logical strategy. Heme oxygenase (HO), with inducible (HO-1) and constitutive (HO-2) isoenzymes, is the rate-limiting enzyme in heme catabolism, producing equimolar amounts of bilirubin and carbon monoxide (CO). Metalloporphyrins (Mps) are heme derivatives that competitively inhibit HO and thereby suppress hyperbilirubinemia. No systematic studies have been reported evaluating whether the HO isoenzymes are inhibited differentially by various Mps. Identification of Mps that selectively inhibit the inducible HO-1 without affecting the 'housekeeping' HO-2 isoenzyme might be desirable in the clinical setting of hemolytic disease, in which the Hmox1 gene is greatly induced. Although bilirubin production is due to the activity of both HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity might provide the most selective approach for the treatment of hemolytic disease.We determined for the deutero-, proto-, meso- and bis-glycol porphyrins with zinc, tin and chromium as central atoms, respectively, the concentration needed for 50% inhibition (I(50)) of HO-1 and HO-2 activities in rat spleen and brain tissue.For a given Mp, HO-1 activity was less inhibited than that of HO-2. The order of inhibitor potency of each Mp was nearly identical for both isoenzymes. Tin mesoporphyrin was the most potent inhibitor for both isoenzymes. HO-2 selectivity was greatest for tin protoporphyrin. Conversely, the Zn compounds were least inhibitory toward HO-2. No Mp preferentially inhibited HO-1.Mps that produce a less inhibitory effect on HO-2, while limiting the response of the inducible HO-1, such as ZnPP, may be a useful clinical tool.

  View details for DOI 10.1038/jp.2010.173

  View details for Web of Science ID 000289236900006

  View details for PubMedID 21448202

• Phil Sunshine: Apgar Award recipient. Journal of perinatology Stevenson, D. K. 2011; 31: S2-5

  View details for DOI 10.1038/jp.2010.171

  View details for PubMedID 21448198

• Metalloporphyrins in the management of neonatal hyperbilirubinemia SEMINARS IN FETAL & NEONATAL MEDICINE Stevenson, D. K., Wong, R. J. 2010; 15 (3): 164-168

  Abstract

  Neonatal jaundice in the first week of life is a common problem in newborns. It is due to an imbalance of bilirubin production and its elimination, which can lead to significantly elevated levels of circulating bilirubin or hyperbilirubinemia. Use of phototherapy and/or exchange transfusion are the current modes for treating neonatal hyperbilirubinemia and preventing any neurologic damage. These strategies, however, only remove bilirubin that has already been formed. Preventing the production of excess bilirubin may be a more logical approach. Synthetic heme analogs, metalloporphyrins, are competitive inhibitors of heme oxygenase, the rate-limiting enzyme in bilirubin production, and their use has been proposed as an attractive alternative strategy for preventing or treating severe hyperbilirubinemia.

  View details for DOI 10.1016/j.siny.2009.11.004

  View details for PubMedID 20006567

• Understanding Neonatal Jaundice: A Perspective on Causation PEDIATRICS AND NEONATOLOGY Cohen, R. S., Wong, R. J., Stevenson, D. K. 2010; 51 (3): 143-148

  Abstract

  Neonatal jaundice can be best understood as a balance between the production and elimination of bilirubin, with a multitude of factors and conditions affecting each of these processes. When an imbalance results because of an increase in circulating bilirubin (or the bilirubin load) to significantly high levels (severe hyperbilirubinemia), it may cause permanent neurologic sequelae (kernicterus). In most infants, an increase in bilirubin production (e.g., due to hemolysis) is the primary cause of severe hyperbilirubinemia, and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and/or polymorphism. Combining information about bilirubin production and genetic information about bilirubin elimination with the tracking of bilirubin levels means that a relative assessment of jaundice risk might be feasible. Information on the level of bilirubin production and its rate of elimination may help to guide the clinical management of neonatal jaundice.

  View details for PubMedID 20675237

• Effect of Heme Oxygenase-1 Deficiency on Placental Development PLACENTA Zhao, H., Wong, R. J., Kalish, F. S., Nayak, N. R., Stevenson, D. K. 2009; 30 (10): 861-868

  Abstract

  Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway and highly expressed in the placenta. Deficiencies in HO-1, the inducible isoform, have been associated with pregnancy disorders, such as recurrent miscarriages, intrauterine growth retardation, and pre-eclampsia. The aim of this study was to identify if a deficiency in HO-1 affects placental development using a mouse model. When HO-1 heterozygote (Het, HO-1(+/-)) mice were cross-bred, an extremely low birth rate in homozygote (Mut, HO-1(-/-)) offspring (2.4%) and small litter sizes were observed. Placentas and fetuses from Het cross-breedings were relatively smaller and weighed less than those from wild-type (WT) cross-breedings at E12.5 and E15.5. Furthermore, Het placentas had significantly less HO-1 mRNA and protein levels than WT placentas, but no significant differences in placental HO activity. Interestingly, HO-2, the constituitive HO isoform, as well as iNOS and eNOS expression were significantly upregulated in Het placentas. Histological examination showed that the junctional zone (JZ) of Het placentas were markedly thinner than those of WT placentas and appeared to be due to an increase in apoptosis. Immunohistochemistry revealed that HO-1-expressing cells were located primarily in the JZ of Het placentas, specifically in the spongiotrophoblast layer. In addition, diastolic blood pressures and plasma soluble VEGFR-1 (sFlt-1) levels were significantly elevated in pregnant Het mice. We conclude that a partial deficiency in HO-1 is associated with morphological changes in the placenta and elevations in maternal diastolic blood pressure and plasma sFlt-1 levels, despite a compensatory increase in HO-2 expression.

  View details for DOI 10.1016/j.placenta.2009.07.012

  View details for Web of Science ID 000270706300006

  View details for PubMedID 19699520

  View details for PubMedCentralID PMC2771543

• Molecular mechanism and functional consequences of lansoprazole-mediated heme oxygenase-1 induction WORLD JOURNAL OF GASTROENTEROLOGY Schulz-Geske, S., Erdmann, K., Wong, R. J., Stevenson, D. K., Schroeder, H., Grosser, N. 2009; 15 (35): 4392-4401

  Abstract

  To investigate the molecular mechanism and functional consequences of heme oxygenase-1 (HO-1) activation by lansoprazole in endothelial cells and macrophages.Expression of HO-1 mRNA was analyzed by Northern blotting. Western blotting was used to determine the HO-1 and ferritin protein levels. NADPH-dependent reactive oxygen species (ROS) formation was measured with lucigenin-enhanced chemiluminescence. HO-1 promoter activity in mouse fibroblasts, stably transfected with a 15-kb HO-1 gene that drives expression of the reporter gene luciferase, was assessed using in vivo bioluminescence imaging.Lansoprazole increased HO-1 mRNA levels in endothelial cells and HO-1 protein levels in macrophages. In addition, lansoprazole-induced ferritin protein levels in both cell systems. Moreover, induction of the antioxidant proteins HO-1 and ferritin by lansoprazole was followed by a decrease in NADPH-mediated ROS formation. The radical scavenging properties of lansoprazole were diminished in the presence of the HO inhibitor, chromium mesoporphyrin IX. Induction of HO-1 gene expression by lansoprazole was not related to oxidative stress or to the activation of the mitogen-activated protein kinase pathway. However, the phosphatidylinositol 3-kinase inhibitor LY294002 showed a concentration-dependent inhibition of HO-1 mRNA and promoter activity.Activation of HO-1 and ferritin may account for the gastric protection of lansoprazole and is dependent on a pathway blocked by LY294002.

  View details for DOI 10.3748/wjg.15.4392

  View details for Web of Science ID 000270080500007

  View details for PubMedID 19764090

  View details for PubMedCentralID PMC2747059

• Dermal Carbon Monoxide Excretion in Neonatal Rats During Light Exposure PEDIATRIC RESEARCH Vreman, H. J., Knauer, Y., Wong, R. J., Chan, M., Stevenson, D. K. 2009; 66 (1): 66-69

  Abstract

  Total body, head, and trunk carbon monoxide (CO) excretion rates were measured separately by gas chromatography in 1- to 7-d-old Wistar rat pups exposed to the dark and to mixed blue (one Special Blue-F20T12/BB) and white (two Cool White-F20T12/CW) fluorescent light or blue light emitting diode (LED) sources. During 48-min cycled exposures to the dark and to either light source, total body CO excretion rapidly increased 1.9- and 1.4-fold, respectively, over dark control levels. When CO excretion rates from the head and trunk were measured separately during exposure to either light source, CO excretion from the head did not change significantly; however, a large mean 4.4-fold increase in CO excretion from the trunk was observed. When light intensity delivered by the blue LED source was varied, we found that trunk CO excretion increased with increasing light intensities. In the presence of riboflavin (10 micromol/kg), total body CO excretion increased 2.8- and 2.1-fold during exposure to the mixed fluorescent light and blue LED sources, respectively. We conclude that light-induced elevations in total body CO excretion may be caused by transdermally excreted CO, which is most likely produced through endogenous photosensitizer-mediated photooxidation of dermal biomolecules.

  View details for PubMedID 19342986

• Effects of sample dilution, peroxidise concentration, and chloride ion on the measurement of unbound bilirubin in premature newborns (vol 40, pg 261, 2007) CLINICAL BIOCHEMISTRY Ahlfors, C. E., Vreman, H. J., Wong, R. J., Bender, G., Oh, W., Morris, B. H., Stevenson, D. K. 2009; 42 (6): 547

  View details for DOI 10.1016/j.clinbiochem.2008.12.012

  View details for Web of Science ID 000264538300019

• Gastric protection by lansoprazole and the impact of heme oxygenase-1 and ferritin. World J Gastroenterol Schulz-Geske S, Erdmann K, Wong RJ, Stevenson DK, Schröder H, Grosser N. 2009; 15: 4392-401
• Photoisomers ? Obfuscating factors in clinical peroxidase measurements of unbound bilirubin? Pediatrics McDonagh AF, Vreman HJ, Wong RJ, Stevenson DK 2009; 123: 67-76
• Heme oxygenase-1 deficiency leads to disrupted response to acute stress in stem cells and progenitors BLOOD Cao, Y., Wagers, A. J., Karsunky, H., Zhao, H., Reeves, R., Wong, R. J., Stevenson, D. K., Weissman, I. L., Contag, C. H. 2008; 112 (12): 4494-4502

  Abstract

  An effective response to extreme hematopoietic stress requires an extreme elevation in hematopoiesis and preservation of hematopoietic stem cells (HSCs). These diametrically opposed processes are likely to be regulated by genes that mediate cellular adaptation to physiologic stress. Herein, we show that heme oxygenase-1 (HO-1), the inducible isozyme of heme degradation, is a key regulator of these processes. Mice lacking one allele of HO-1 (HO-1(+/-)) showed accelerated hematopoietic recovery from myelotoxic injury, and HO-1(+/-) HSCs repopulated lethally irradiated recipients with more rapid kinetics. However, HO-1(+/-) HSCs were ineffective in radioprotection and serial repopulation of myeloablated recipients. Perturbations in key stem cell regulators were observed in HO-1(+/-) HSCs and hematopoietic progenitors (HPCs), which may explain the disrupted response of HO-1(+/-) HPCs and HPCs to acute stress. Control of stem cell stress response by HO-1 presents opportunities for metabolic manipulation of stem cell-based therapies.

  View details for DOI 10.1182/blood-2007-12-127621

  View details for PubMedID 18509090

• Aggressive vs. conservative phototherapy for infants with extremely low birth weight NEW ENGLAND JOURNAL OF MEDICINE Morris, B. H., Oh, W., Tyson, J. E., Stevenson, D. K., Phelps, D. L., O'Shea, T. M., McDavid, G. E., Perritt, R. L., Van Meurs, K. P., Vohr, B. R., Grisby, C., Yao, Q., Pedroza, C., Das, A., Poole, W. K., Carlo, W. A., Duara, S., Laptook, A. R., Salhab, W. A., Shankaran, S., Poindexter, B. B., Fanaroff, A. A., Walsh, M. C., Rasmussen, M. R., Stoll, B. J., Cotten, C. M., Donovan, E. F., Ehrenkranz, R. A., Guillet, R., Higgins, R. D. 2008; 359 (18): 1885-1896

  Abstract

  It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)

  View details for Web of Science ID 000260454500005

  View details for PubMedID 18971491

  View details for PubMedCentralID PMC2821221

• Inhibition of heme oxygenase activity in newborn mice by azalanstat CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Morisawa, T., Wong, R. J., Bhutani, V. K., Vreman, H. J., Stevenson, D. K. 2008; 86 (10): 651-659

  Abstract

  Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, may be an ideal strategy for preventing neonatal jaundice. Although natural and synthetic heme analogs, called metalloporphyrins (Mps), have been extensively investigated for this purpose, some Mps are phototoxic, affect the activity of other enzymes, or induce HO-1 transcription-properties that may limit their clinical use. Another class of compounds, imidazole-dioxolanes, has been shown to selectively inhibit the inducible isozyme HO-1. Therefore, we investigated the efficacy of azalanstat (AZA), an imidazole-dioxolane, towards inhibiting HO activity in 7-day-old mice. We found that a single dose of AZA at 500 micromol.kg(-1) body mass (BM) administered i.p. significantly inhibited HO activity and reduced in vivo bilirubin production. In the spleen, HO inhibition (>50%) was observed within 0.25-3 h after administration. After 24 h, however, spleen HO activity, HO-1 protein, and HO-1 mRNA levels significantly increased 1.2-, 2.4-, and 4.0-fold, respectively. We conclude that AZA effectively inhibits in vivo HO activity only at a high dose and that it also induces spleen HO-1 gene transcription. Therefore, other imidazole-dioxolanes should be evaluated to determine whether they are more potent than AZA for use in treating neonatal jaundice.

  View details for DOI 10.1139/Y08-069

  View details for PubMedID 18841169

• Regulation of maternal and fetal hemodynamics by heme oxygenase in mice BIOLOGY OF REPRODUCTION Zhao, H., Wong, R. J., Doyle, T. C., Nayak, N., Vreman, H. J., Contag, C. H., Stevenson, D. K. 2008; 78 (4): 744-751

  Abstract

  Heme oxygenase (HMOX) regulates vascular tone and blood pressure through the production of carbon monoxide (CO), a vasodilator derived from the heme degradation pathway. During pregnancy, the maternal circulation undergoes significant adaptations to accommodate the hemodynamic demands of the developing fetus. Our objective was to investigate the role of HMOX on maternal and fetal hemodynamics during pregnancy in a mouse model. We measured and compared maternal tissue and placental HMOX activity and endogenous CO production, represented by excreted CO and carboxyhemoglobin levels, during pregnancy (Embryonic Days 12.5-15.5) to nonpregnant controls. Micro-ultrasound was used to monitor maternal abdominal aorta diameters as well as blood flow velocities and diameters of fetal umbilical arteries. Tin mesoporphyrin, a potent HMOX inhibitor, was used to inhibit HMOX activity. Changes in maternal vascular tone were monitored by tail cuff blood pressure measurements. Effects of HMOX inhibition on placental structures were assessed by histology. We showed that maternal tissue and placental HMOX activity and CO production were significantly elevated during pregnancy. When HMOX in the placenta was inhibited, maternal and fetal hemodynamics underwent significant changes, with maternal blood pressures increasing. We concluded that increases in maternal tissue and placental HMOX activity contribute to the regulation of peripheral vascular resistance and therefore are important for the maintenance of normal maternal vascular tone and fetal hemodynamic functions during pregnancy.

  View details for DOI 10.1095/biolreprod.107.064899

  View details for PubMedID 18094356

• Standardized bench method for evaluating the efficacy of phototherapy devices 4th International Bilirubin Workshop Vreman, H. J., Wong, R. J., Murdock, J. R., Stevenson, D. K. WILEY-BLACKWELL. 2008: 308–16

  Abstract

  As phototherapy (PT) devices employ a variety of broadband light sources, we developed and tested a standardized bench method for evaluating the efficacy of some devices.To evaluate efficacy, we quantified the in vitro photodegradation rate (expressed as t1/2) of unconjugated bilirubin in solution at 37 degrees C during exposure to a given light source at its mean delivered irradiance to the 2D body surface area (BSA) of newborn models. Reproducibility (between-day variation) of the method was determined at irradiance levels from 10 to 70 microW/cm2/nm on three different days.Between-day t1/2 measurements had coefficients of variation from 3% to 10%. When t1/2 values were normalized to the exposable 2D horizontal BSA, halogen lamp devices, without and with fiberoptics, were least effective (t1/2=60-108 min and 100-126 min for preterm and term models, respectively). Fluorescent tube devices had t1/2=19-78 min and 25-78 min, for preterm and term models, respectively. Light-emitting diode (LED)-based devices yielded the shortest t1/2 values (16-24 min) for preterm and term newborn models.We demonstrated the applicability of the method through the determination of the efficacy of several commercially available PT devices. This standardized method is reproducible and effectively evaluates the relative in vitro efficacy of various devices and may guide further in vitro and in vivo evaluations of devices.

  View details for DOI 10.1111/j.1651-2227.2007.00631.x

  View details for Web of Science ID 000253504300012

  View details for PubMedID 18241292

• Management of jaundice and prevention of severe neonatal hyperbilirubinemia in infants >= 35 weeks gestation NEONATOLOGY Bhutani, V. K., Maisels, M. J., Stark, A. R., Buonocore, G. 2008; 94 (1): 63-67

  Abstract

  Kernicterus is still occurring but should be largely preventable if health care personnel follow the recommendations listed in this guideline. These recommendations emphasize the importance of universal, systematic assessment of the risk of severe hyperbilirubinemia, lactation support, close follow-up, and prompt intervention when necessary. A systems-based approach to prevent severe neonatal hyperbilirubinemia should be implemented at all birthing facilities and coordinated with continuing ambulatory care. Translational research is needed to better understand the mechanisms of bilirubin neurotoxicity and potential therapeutic interventions.

  View details for DOI 10.1159/000113463

  View details for PubMedID 18204221

• Statin treatment increases formation of carbon monoxide and bilirubin in mice: a novel mechanism of in vivo antioxidant protection CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Muchova, L., Wong, R. J., Hsu, M., Morioka, O., Vitek, L., Zelenka, J., Schroeder, H., Stevenson, D. K. 2007; 85 (8): 800-810

  Abstract

  Heme oxygenase (HO) has a central role in cellular antioxidant defences and vascular protection, and it may mediate pleiotropic actions of drugs used in cardiovascular therapy. We investigated whether long-term use of statins upregulates HO activity and increases carbon monoxide (CO) and bilirubin levels in vivo. Adult FvB mice were given atorvastatin or rosuvastatin (5 mg/kg) daily by i.p. injections for 1, 2, or 3 weeks. HO activity, tissue CO, bilirubin, and antioxidant levels, total plasma bilirubin, and carboxyhemoglobin (COHb) were measured. Fold changes in heart HO activity significantly increased after 1, 2, and 3 weeks of atorvastatin (1.24 +/- 0.06 (p < or = 0.05); 1.29 +/- 0.26 (p < or = 0.03); 1.33 +/- 0.08 (p < 0.01), respectively) and 2 and 3 weeks of rosuvastatin (1.23 +/- 0.20 (p < or = 0.03); 1.63 +/- 0.42 (p < 0.01), respectively). Heart tissue CO and COHb levels also increased after 3 weeks with atorvastatin (1.30 +/- 0.24 (p < or = 0.05); 1.92 +/- 0.17 (p < or = 0.001), respectively) and rosuvastatin (1.47 +/- 0.13 (p < or = 0.004); 1.63 +/- 0.12 (p < or = 0.001), respectively). Significant increases in heart antioxidant levels were observed after statin treatment and corroborated by heart bilirubin content elevations. Antioxidant level increases were abolished by treatment with an HO inhibitor. These findings suggest that the induction of HO and the production of its products, CO and bilirubin, may be a mechanism by which statins exert antioxidant actions and confer cardioprotection in vivo.

  View details for DOI 10.1139/Y07-077

  View details for PubMedID 17901890

• (TA)(n) UGT 1A1 promoter polymorphism: A crucial factor in the pathophysiology of jaundice in G-6-PD deficient neonates PEDIATRIC RESEARCH Kaplan, M., Renbaum, P., Vreman, H. J., Wong, R. J., Levy-Lahad, E., Hammerman, C., Stevenson, D. K. 2007; 61 (6): 727-731

  Abstract

  Increased heme catabolism has been reported in glucose-6-phosphate dehydrogenase (G-6-PD)-normal neonates who were also homozygous for (TA)7/(TA)7 (UGT1A1*28) uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT) promoter polymorphism (Gilbert syndrome). As G-6-PD deficiency is associated with increased hemolysis, we hypothesized that in G-6-PD-deficient neonates who also have the (TA)7/(TA)7 UGT promoter genotype, steady-state hemolysis would be even further increased. Male G-6-PD-deficient neonates were sampled for plasma total bilirubin (PTB), blood carboxyhemoglobin corrected for inhaled carbon monoxide in ambient air (COHbc) (an index of heme catabolism), and UGT (TA)n promoter genotype determination and compared with previously published G-6-PD-normal neonates. Although COHbc values were higher in the G-6-PD-deficient than in the G-6-PD-normal cohorts (0.97 +/- 0.32% of total Hb (tHb) versus 0.76 +/- 0.19% of tHb, p < 0.001), PTB values were similar (9.2 +/- 3.4 mg/dL versus 8.9 +/- 3.0 mg/dL, respectively, p = 0.3). Within the G-6-PD-deficient group, although COHbc values were alike between the three UGT promoter genotypes, PTB was higher in the (TA)7/(TA)7 homozygotes (11.1 +/- 4.0 mg/dL) compared with (TA)6/(TA)7 heterozygotes (9.1 +/- 3.2 mg/dL, p = 0.03) and wild-type (TA)6/(TA)6 homozygotes (8.8 +/- 3.4 mg/dL, p = 0.02). In the steady state, similar rates of hemolysis, but increased PTB in the G-6-PD- deficient, (TA)7/(TA)7 homozygotes, imply that (TA)7/(TA)7, homozygosity is central to increased PTB.

  View details for DOI 10.1203/pdr.0b013e31805365c5

  View details for Web of Science ID 000246787300019

  View details for PubMedID 17426648

• The role of Bach1 in the induction of heme oxygenase by tin mesoporphyrin BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Abate, A., Zhao, H., Wong, R. J., Stevenson, D. K. 2007; 354 (3): 757-763

  Abstract

  Tin mesoporphyrin (SnMP), a competitive heme oxygenase (HO) inhibitor, also induces HO-1 mRNA and protein expression by a mechanism that is not fully understood. We examined whether the induction by SnMP is mediated by a de-repression of Bach1, a transcription factor that suppresses the HO-1 gene. Incubation of NIH3T3-HO-1-luc cells with SnMP attenuated HO activity with a concomitant increase in HO-1 mRNA and protein and a decrease in Bach1 and HO-2 proteins, which was not due to transcriptional down-regulation, but accelerated protein decay. Similarly, HO-1 protein degradation was increased by SnMP, despite of an elevation in HO-1 transcription. Transfection of Bach1 shRNA in Hepa cells raised basal HO-1 expression significantly, and SnMP treatment further increased HO-1 mRNA. In conclusion, SnMP induces HO-1 expression not only by de-repressing the HO-1 promoter by binding Bach1, but also by accelerating Bach1 degradation.

  View details for DOI 10.1016/j.bbrc.2007.01.050

  View details for PubMedID 17257585

• American Pediatric Society presidential address 2006: Science on the edge with life in the balance PEDIATRIC RESEARCH Stevenson, D. K. 2006; 60 (5): 630-635

  View details for DOI 10.1203/01.pdr.0000242308.49575.51

  View details for PubMedID 16988191

• Expression and regulation of heme oxygenase isozymes in the developing mouse cortex PEDIATRIC RESEARCH Zhao, H., Wong, R. J., Nguyen, X., Kalish, F., Mizobuchi, M., Vreman, H. J., Stevenson, D. K., Contag, C. H. 2006; 60 (5): 518-523

  Abstract

  Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, plays a role in neonatal jaundice. Understanding the regulation of the developmental expression patterns of the two HO isozymes, HO-1 and HO-2, is essential for targeting HO to control pathologic jaundice, and uncovering the fundamental role that they play in mammalian development. Here we characterized the ontogeny of HO-1 and HO-2 expression in the developing mouse cortex by in vivo bioluminescence imaging, quantitative RT-PCR, and Western blot. HO-2, the predominant isoform in the adult cortex, was relatively stable throughout all ages. HO-1 was observed to be progressively down-regulated in an age-related manner. HO-1 expression in the adult cortex was also the lowest among the eight adult tissues analyzed. Because there is a 283-bp CpG island region in the HO-1 promoter, we hypothesized that methylation of the island is responsible for the age-related HO-1 down-regulation in the cortex. Methylation status was assessed using regular and quantitative methylation-specific PCR and the CpG island was found to be hypomethylated at all ages. Therefore, we conclude that HO-1 gene expression in the cortex is developmentally-regulated and that methylation of the HO-1 CpG island is not associated with the down-regulation of the gene.

  View details for DOI 10.1203/01.PDR.0000242374.21415.f5

  View details for PubMedID 16966352

• Concentration of carbon monoxide (CO) in postmortem human tissues: Effect of environmental CO exposure Annual Meeting of the Society-of-Pediatric-Research Vreman, H. J., Wong, R. J., Stevenson, D. K., Smialek, J. E., Fowler, D. R., Li, n. L., Vigorito, R. D., Zielke, H. R. WILEY-BLACKWELL PUBLISHING, INC. 2006: 1182–90

  Abstract

  We studied how carbon monoxide (CO) is distributed within the human body through quantitation of CO concentrations in postmortem tissue samples from fatalities including possible CO exposure. Stored, frozen tissues were diced, sonicated in water, and 0.01-8.0 mg wet weight (ww) tissues were incubated with sulfosalicylic acid in CO-purged, septum-sealed vials. CO released into the headspace was quantitated by reduction gas chromatography. Mean tissue CO concentrations (pmol/mg ww) from subjects diagnosed to have no known CO exposure (control, N=14), died from fire (N=13), and CO asphyxiation (N=7), respectively, were: adipose (2;13;9), brain (3;13;65), muscle (15;97;297), heart (30;99;371), kidney (22;432;709, lung (54;690;2638), spleen (73;1366;3548), and blood (162;2238;5070). Carboxyhemoglobin concentrations were 1.4%, 25.2%, and 69.1% of total hemoglobin, respectively. We conclude that measurements of CO concentration in a variety of tissues can be used as markers for the degree of exogenous CO exposure and the identification of possible causes of death.

  View details for DOI 10.1111/j.1556-4029.2006.00212.x

  View details for PubMedID 17018107

• Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS HSU, M., Muchova, L., Morioka, I., Wong, R. J., Schroder, H., Stevenson, D. K. 2006; 343 (3): 738-744

  Abstract

  Heme oxygenase-1 (HO-1) plays a central role in antioxidant and anti-inflammatory actions, which may be mediated through its formation of biliverdin/bilirubin and carbon monoxide. HMG-CoA reductase inhibitors (statins) induce in vitro HO-1 expression and are reported to have pleiotropic benefits that reduce oxidative stress in the vasculature. We characterized the effects of statins on in vivo HO-1 expression in various extravascular tissues: liver, lung, brain, and heart. Adult mice were orally administered simvastatin, lovastatin, atorvastatin, or rosuvastatin. HO activity significantly increased in a statin- and tissue-specific manner, with all statins increasing heart and lung activity within 24 h. Significant elevations of HO-1 protein and mRNA were also observed in heart and lung after atorvastatin treatment. We conclude that in vivo HO-1 induction is statin- and tissue-specific. Through this pathway, statins may confer antioxidant and anti-inflammatory actions in the vasculature and extravascular systems.

  View details for DOI 10.1016/j.bbrc.2006.03.036

  View details for PubMedID 16563347

• Systemic effects of orally-administered zinc and tin (IV) metalloporphyrins on heme oxygenase expression in mice PEDIATRIC RESEARCH Morioka, I., Wong, R. J., Abate, A., Vreman, H. J., Contag, C. H., Stevenson, D. K. 2006; 59 (5): 667-672

  Abstract

  Some metalloporphyrins (Mps) inhibit heme oxygenase (HO), the rate-limiting enzyme in the production of bilirubin, and are potential compounds for the treatment of neonatal jaundice. We studied the safety and efficacy of Mps following oral administration. Adult HO-1-luc reporter mice were administered 30 micromol/kg body weight of tin mesoporphyrin (SnMP), zinc bis glycol deuteroporphyrin (ZnBG), or zinc protoporphyrin (ZnPP), or vehicle by oral gavage. Bilirubin production was measured as total body carbon monoxide (CO) excretion (VeCO). HO activity was quantitated via CO measurements by gas chromatography. HO-1 protein was determined by Western blot. HO-1 transcription levels were assessed by in vivo bioluminescence imaging. A significant 28% decrease in bilirubin production occurred within 3 h of SnMP treatment and persisted beyond 48 h. Bilirubin production decreased 15% and 9% by 3 h after administration of ZnBG and ZnPP, respectively, but returned to baseline within 48 h. Maximal inhibition of liver, spleen, and intestine HO activity was seen at 3 h with inhibitory effects decreasing in the order: SnMP > or = ZnBG > or = ZnPP. After SnMP treatment, HO-1 transcription increased 5.7-fold after 24 h. Furthermore, liver and spleen HO-1 protein significantly increased 3.7- and 2.0-fold, respectively, after 24 h. HO-1 transcription and protein were not affected in ZnBG- or ZnPP-treated mice. We conclude that the three Mps are absorbed at different rates in the mouse and affect bilirubin production and HO-1 expression in a tissue- and time-dependent manner.

  View details for DOI 10.1203/01.pdr.0000215088.71481.a6

  View details for PubMedID 16627879

• Transcutaneous bilirubinometry: A noninvasive tool for studying newborn jaundiced rats before and after exposure to light PEDIATRIC RESEARCH Vreman, H. J., Wong, R. J., Chan, M. L., Young, B. W., Stevenson, D. K. 2006; 59 (2): 203-209

  Abstract

  The homozygous Gunn rat is the most frequently used animal model for the study of neonatal jaundice. We evaluated the applicability of noninvasive transcutaneous bilirubin (TcB) measurements as an index of serum total bilirubin (STB) levels in neonatal rats by comparison to invasive STB measurements. TcB measurements were made during the first 96 h of life with the Model 101 Minolta/Air-Shields Jaundice Meter (JM) and SpectRx BiliCheck System (BC). Measurements with both devices displayed parallel TcB profiles, rapidly rising within 24 h, increasing during the next 6 h, then leveling off after 30 h. Linear regressions for the JM (n = 60) were as follows: STB (mg/dL) = 0.79 (JM) - 0.01 (units, r = 0.95, head); STB (mg/dL) = 0.82 (JM) + 1.51 (units, r = 0.95, upper back); and STB (mg/dL) = 0.74 (JM) + 1.60 (units, r = 0.91, lower back). Mean bias +/- imprecision were as follows: -0.02 +/- 3.99 mg/dL, -0.01 +/- 3.90, and 0.01 +/- 4.28 at the head, upper back, and lower back, respectively. For the BC, only lower back measurements were taken, and the regression was as follows: STB (mg/dL) = 0.77 (BC) + 1.65 mg/dL, (r = 0.93, n = 29) with a mean bias +/- imprecision of -1.08 +/- 3.08 mg/dL. When pups were exposed to light, correlations remained strong but intercepts increased. These results demonstrate that noninvasive TcB measurements correlate highly with STB in the Gunn rat during the first 96 h of life and after exposure to light. We conclude that JM measurements at the head and BC at the lower back reflect STB most reliably and consistently. Thus, in addition to being a useful tool for evaluating jaundice in human neonates, TcB methodology can be used successfully for the noninvasive monitoring of jaundice in neonatal Gunn rats pre- and postlight exposure.

  View details for DOI 10.1203/01.pdr.000196737.73851.8a

  View details for PubMedID 16439579

• The effectiveness of oral tin mesoporphyrin prophylaxis in reducing bilirubin production after an oral heme load in a transgenic mouse model BIOLOGY OF THE NEONATE DeSandre, G. H., Wong, R. J., Morioka, I., Contag, C. H., Stevenson, D. K. 2006; 89 (3): 139-146

  Abstract

  Neonatal jaundice is commonly encountered and rarely associated with morbidity and mortality. Nonetheless, infants with glucose-6-phosphate dehydrogenase deficiency often have hemolysis (a heme load) caused by an environmental oxidant trigger, thus increasing their risk for serious morbidity. The use of tin mesoporphyrin (SnMP) has been proposed for interdicting the development of severe hyperbilirubinemia in a variety of conditions.We studied the in vivo effects of prophylactic oral SnMP on heme oxygenase (HO) activity and bilirubin production, as indexed by the excretion rate of carbon monoxide (VeCO), following a subsequent oral heme load.Adult mice were exposed serially to heme and assessed for in vivo bilirubin production rates, HO-1 transcription and protein, and HO activity. The effect of prophylaxis with a single oral dose of SnMP prior to an oral heme load was assessed by measuring VeCOand tissue HO activities.After serial heme exposures, VeCO, HO-1 transcription and protein, and liver and spleen HO activities increased incrementally. After pretreatment with oral SnMP, bilirubin production decreased in response to an oral heme load. Also, heme-mediated increases in liver, spleen, and intestine HO activities were significantly dampened.A single oral dose of SnMP results in durable inhibition of bilirubin production and HO activity for at least 24 h in a mouse model of oral heme loading. Further studies are needed to fully elucidate the duration of this protection against hyperbilirubinemia due to a delayed heme load and any long-term consequences of prophylaxis with SnMP on HO-1 transcription and HO-1 protein.

  View details for DOI 10.1159/000088717

  View details for PubMedID 16205054

• Inhaled nitric oxide for premature infants with severe respiratory failure NEW ENGLAND JOURNAL OF MEDICINE Van Meurs, K. P., Wright, L. L., Ehrenkranz, R. A., Lemons, J. A., Ball, M. B., Poole, W. K., Perritt, R., Higgins, R. D., Oh, W., Hudak, M. L., Laptook, A. R., Shankaran, S., Finer, N. N., Carlo, W. A., Kennedy, K. A., Fridriksson, J. H., Steinhorn, R. H., Sokol, G. M., Konduri, G. G., Aschner, J. L., Stoll, B. J., D'Angio, C. T., Stevenson, D. K., Oh, W., Hensman, A., Gingras, D., Stoll, B. J., Jain, L., Hale, E., Seabrook, I., Sokol, G., Lorant, D., Appel, D. D., Miller, L., Chriscinske, D., Attwood, J., Steinhorn, R., Sautel, M., Van Meurs, K., Ball, B., Proud, D., Carlo, W. A., Cosby, S. S., Johnson, R. B., Fridriksson, J., Warner, B., Mersmann, M., Alexander, B., Shively, J., Mincey, H., Hoover, M., Sapienz, S., Stephenson, E., Finer, N. N., Rasmussen, M. R., Henderson, C., Demetrio, C., Rich, W., Joseph, C., Hudak, M., Osbeck, S., Case, E., Kellum, A., Hogans, L., D'Angio, C. T., Reubens, L., Hutton, G., Laptook, A., Madison, S., Hensley, G., Miller, N., Metoyer, G., Kennedy, K., McDavid, G., Emerson, D., Konduri, G., Paquette, M., Wong, S., Aschner, J., O'Shea, T. M., Peters, N., Hansell, B. J., Griffin, J., Adams, C., Shankaran, S., Bara, R. A., Muran, G., Weekfall, W., Ehrenkranz, R. A., Gettner, P., Caldwell, A., Oh, W., Fanaroff, A. A., Goldberg, R. N., Stoll, B. J., Lemons, J. A., Stevenson, D. K., Carlo, W. A., Donovan, E. F., Finer, N. N., Duara, S., Phelps, D. L., Laptook, A. R., TYSON, J. E., O'Shea, T. M., Shankaran, S., Ehrenkranz, R. A., Jobe, A., Poole, W. K., Hastings, B., Petrie, C., Higgins, R. D., Wright, L. L., McClure, E., BULAS, D., Mertens, D., Slovis, T., Avery, G., D'Alton, M., Poole, W. K., Fletcher, J. C., Gleason, C. A., Redmond, C. 2005; 353 (1): 13-22

  Abstract

  Inhaled nitric oxide is a controversial treatment for premature infants with severe respiratory failure. We conducted a multicenter, randomized, blinded, controlled trial to determine whether inhaled nitric oxide reduced the rate of death or bronchopulmonary dysplasia in such infants.We randomly assigned 420 neonates, born at less than 34 weeks of gestation, with a birth weight of 401 to 1500 g, and with respiratory failure more than four hours after treatment with surfactant to receive placebo (simulated flow) or inhaled nitric oxide (5 to 10 ppm). Infants with a response (an increase in the partial pressure of arterial oxygen of more than 10 mm Hg) were weaned according to protocol. Treatment with study gas was discontinued in infants who did not have a response.The rate of death or bronchopulmonary dysplasia was 80 percent in the nitric oxide group, as compared with 82 percent in the placebo group (relative risk, 0.97; 95 percent confidence interval, 0.86 to 1.06; P=0.52), and the rate of bronchopulmonary dysplasia was 60 percent versus 68 percent (relative risk, 0.90; 95 percent confidence interval, 0.75 to 1.08; P=0.26). There were no significant differences in the rates of severe intracranial hemorrhage or periventricular leukomalacia. Post hoc analyses suggest that rates of death and bronchopulmonary dysplasia are reduced for infants with a birth weight greater than 1000 g, whereas infants weighing 1000 g or less who are treated with inhaled nitric oxide have higher mortality and increased rates of severe intracranial hemorrhage.The use of inhaled nitric oxide in critically ill premature infants weighing less than 1500 g does not decrease the rates of death or bronchopulmonary dysplasia. Further trials are required to determine whether inhaled nitric oxide benefits infants with a birth weight of 1000 g or more.

  View details for PubMedID 16000352

• Monitoring age-related susceptibility of young mice to oral Salmonella enterica serovar typhimurium infection using an in vivo murine model PEDIATRIC RESEARCH Burns-Guydish, S. M., Olomu, I. N., Zhao, H., Wong, R. J., Stevenson, D. K., Contag, C. H. 2005; 58 (1): 153-158

  Abstract

  Neonates and young children are acutely susceptible to infections by gastrointestinal bacterial pathogens, such as Salmonella enterica serovar Typhimurium (S. typhimurium). To reveal age-related differences in susceptibility to this pathogen, we used in vivo bioluminescence imaging (BLI) to monitor the progression of infection in neonatal (1-wk-old), suckling (2-wk-old), juvenile (4-wk-old), and adult (6-wk-old) BALB/c mice. Mice were orally infected with various doses of a bioluminescent-labeled wild-type or mutant S. typhimurium strain, and progression of infection was monitored by BLI for 2 wks. We found that neonatal and suckling mice were more susceptible to the wild-type strain at inoculum sizes 4 and 2 log(10)'s lower for neonatal and suckling mice, respectively, than those for adult mice. At the lower inocula, newborn mice showed disseminated systemic infection as indicated by the pattern of photon emission assessed by BLI, whereas no bioluminescent signals were detectable in adult mice. In addition, an orgA(-) mutant strain of S. typhimurium with reduced virulence in adult mice produced systemic infection in newborn, suckling, and juvenile mice. Furthermore, as low as 3 log(10) CFU could be detected by BLI in tissue. The present study demonstrates that susceptibility to S. typhimurium infection decreases with age. Also, we established that BLI can be used to monitor the progression of infection in mice. Thus, this model of age-related susceptibility to S. typhimurium using BLI can be used to advance our understanding of the mechanisms involved in newborn susceptibility to infection.

  View details for DOI 10.1203/01.PDR.0000157725.44213.C4

  View details for PubMedID 15774831

• Phototherapy: Current methods and future directions SEMINARS IN PERINATOLOGY Vreman, H. J., Wong, R. J., Stevenson, D. K. 2004; 28 (5): 326-333

  Abstract

  Phototherapy is the most common therapeutic intervention used for the treatment of hyperbilirubinemia. Although it has become a mainstay since its introduction in 1958, a better understanding of the photobiology of bilirubin, characteristics of the phototherapy devices, the efficacy and safety considerations of phototherapy applications, and improvements in spectroradiometers and phototherapy devices are necessary for more predictable and improved clinical practices and outcomes. A step forward in instituting consistent, uniform, and effective use of phototherapy is the recent American Academy of Pediatrics clinical guideline on the management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation, which outlines a clinical strategy for the diagnosis of hyperbilirubinemia and contains direct recommendations for the application of phototherapy. This article reviews the parameters that determine the efficacy of phototherapy, briefly discusses current devices and methods used to deliver phototherapy, and speculates on future directions and studies that are still needed to complement our presently incomplete knowledge of the facets of this common mode of therapy.

  View details for DOI 10.1053/j.semperi.2004.09.003

  View details for PubMedID 15686263

• A primer on neonatal jaundice. Advances in pediatrics Stevenson, D. K., Wong, R. J., DeSandre, G. H., Vreman, H. J. 2004; 51: 263-288

  View details for PubMedID 15366777

• Effects of metalloporphyrins on heme oxygenase-1 transcription: correlative cell culture assays guide in vivo imaging. Molecular imaging Hajdena-Dawson, M., Zhang, W., Contag, P. R., Wong, R. J., Vreman, H. J., Stevenson, D. K., Contag, C. H. 2003; 2 (3): 138-149

  Abstract

  Heme oxygenase (HO) is the rate-limiting step in the heme degradation pathway and is a potential target for the control, or prevention, of pathologic jaundice in neonates. Metalloporphyrins (Mps), a diverse set of synthetic derivatives of heme, can competitively inhibit the HO enzymes. However, certain Mps are phototoxic and some increase transcription of HO-1, the inducible HO isozyme. Therefore, effective development of this class of compounds as therapeutics for treating pathologic jaundice will require rapid and integrated biological screens to identify the most efficacious and safe Mps. To study the safety of these compounds, we assessed their cytotoxic effects and measured luciferase activity by bioluminescent imaging (BLI) as an index of HO-1 transcription, first in live cell cultures and then in living transgenic reporter mice. A total of 12 Mps were first evaluated in the correlative cell culture assay. Based on results from this study, 2 Mps, zinc protoporphyrin (ZnPP) and zinc bis glycol porphyrin (ZnBG), were selected for further studies in the live animal model. In vitro BLI showed ZnPP to be a strong inducer of HO-1 transcription in comparison to ZnBG, which showed minimal induction. Cytotoxicity studies revealed that ZnPP was phototoxic, whereas ZnBG had no effect on cell viability. In vivo BLI showed that both ZnPP and ZnBG had minimal effects on the levels of HO-1 transcription in the animals. Furthermore, serum enzyme assays indicated that neither caused detectable liver toxicity. These findings, and especially those with ZnBG, support the use of selected Mps as therapies for pathologic jaundice. Coupling the high throughput advantage of cell culture with the capability of imaging for whole-body temporal analyses could accelerate and refine the preclinical phases of drug development. Thus, this study serves as a model for understanding the effects of specific compounds in relation to defined targets using an integrated approach.

  View details for PubMedID 14649057

• Heme oxygenase-2 protects against lipid peroxidation-mediated cell loss and impaired motor recovery after traumatic brain injury JOURNAL OF NEUROSCIENCE Chang, E. F., Wong, R. J., Vreman, H. J., Igarashi, T., Galo, E., Sharp, F. R., Stevenson, D. K., Noble-Haeusslein, L. J. 2003; 23 (9): 3689-3696

  Abstract

  After traumatic brain injury (TBI), substantial extracellular heme is released from hemoproteins during hemorrhage and cell injury. Heme oxygenase (HO) isozymes are thought to detoxify the pro-oxidant heme to the potent antioxidant, bilirubin. HO-1, the inducible isozyme, is expressed in glial populations after injury and may play a protective role. However, the role of HO-2, the predominant and constitutively expressed isozyme in the brain, remains unclear after TBI. We used a controlled cortical impact injury model to determine the extent and mechanism of damage between HO-2 knock-out (KO) (-/-) and wild-type (WT) (+/+) mice. The specific cellular and temporal expressions of HO-2 and HO-1 were characterized by immunocytochemistry and Western blots. HO-2 was immunolocalized in neurons both before and after TBI, whereas HO-1 was highly upregulated in glia only after TBI. HO activity determined by gas chromatography using brain sonicates from injured HO-2 KO mice was significantly less than that of HO-2 wild types, despite the induction of HO-1 expression after TBI. Cell loss was significantly greater in KO mice in areas including the cortex, the CA3 region of hippocampus, and the lateral dorsal thalamus. Furthermore, motor recovery after injury, as measured by the rotarod assay and an inclined beam-walking task, was compromised in the KO mice. Finally, brain tissue from injured HO-2 KO mice exhibited decreased ability to reduce oxidative stress, as measured with an Fe(2+)/ascorbic acid-mediated carbon monoxide generation assay for lipid peroxidation susceptibility. These findings demonstrate that HO-2 expression protects neurons against TBI by reducing lipid peroxidation via the catabolism of free heme.

  View details for Web of Science ID 000182700100016

  View details for PubMedID 12736340

• Selection of potential therapeutics based on in vivo spatiotemporal transcription patterns of heme oxygenase-1 JOURNAL OF MOLECULAR MEDICINE-JMM Zhang, W. S., Contag, P. R., Hardy, J., Zhao, H., Vreman, H. J., Hajdena-Dawson, M., Wong, R. J., Stevenson, D. K., Contag, C. H. 2002; 80 (10): 655-664

  Abstract

  Heme oxygenase (HO), a key catabolic enzyme in the conversion of heme to bilirubin, is an ideal target for reducing bilirubin production and preventing pathological jaundice in newborn infants. Metalloporphyrins (Mps) have been well characterized as competitive inhibitors of HO and have been evaluated as potential chemopreventive agents for neonatal jaundice. However, in addition to reducing HO activity, many Mps have been shown to increase HO-1 transcription, which would likely reduce their potential therapeutic utility. The differential effects of Mps on the transcription of HO-1 were therefore evaluated in living transgenic (Tg) reporter mice. Of the compounds evaluated, we observed that zinc bis-glycol porphyrin (ZnBG), a potent inhibitor of HO enzyme activity, did not alter HO-1 transcription patterns in Tg mice. Whole body images of HO-1 transcription patterns did, however; reveal increases in HO-1 transcription in Tg mice after treatment with other Mps, heme and cadmium chloride (CdCl(2)). Intravenous injections of CdCl(2) resulted in expression patterns that differed in tempo and location from those observed in Tg mice treated with intraperitoneal injections. Spatiotemporal analyses of transcriptional regulation in living animals accelerated the assessment of an adverse effect of Mps by revealing different patterns of HO-1 transcription. Among the known inhibitors of HO enzyme activity that were evaluated in this study, ZnBG did not significantly affect HO-1 transcription and therefore may be well suited for the prevention of neonatal jaundice.

  View details for DOI 10.1007/s00109-002-0375-x

  View details for PubMedID 12395150

• Carbon monoxide and bilirubin production in neonates SEMINARS IN PERINATOLOGY Stevenson, D. K., Vreman, H. J., Wong, R. J., Contag, C. H. 2001; 25 (2): 85-93

  Abstract

  Neonatal hyperbilirubinemia is a normal postnatal phenomenon resulting from a transitional imbalance between the production and elimination of bilirubin in the neonate. Bilirubin has been shown to be not only a potent antioxidant, but also toxic at excessive concentrations. As a result, the biology of bilirubin, its production, regulation, and measurements have been the focus of extensive studies. Bilirubin, carbon monoxide, and iron are derived from the degradation of heme, a ubiquitous two-step pathway catalyzed by the enzyme, heme oxygenase. It has been shown that these metabolically active products from the heme catabolic pathway may, in turn, influence many other biologic processes. This report provides a brief overview of these interrelationships in the hope that it may provide insight into the central role this pathway plays in the existence of most organisms.

  View details for PubMedID 11339670

• Bioluminescence for biological sensing in living mammals 26th Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue (ISOTT 98) Zhang, W. S., Contag, P. R., Madan, A., Stevenson, D. K., Contag, C. H. KLUWER ACADEMIC/PLENUM PUBL. 1999: 775–784

  View details for Web of Science ID 000085570200089

  View details for PubMedID 10659213

• FETAL HEMOGLOBIN OF TRANSFUSED NEONATES AND SPECTROPHOTOMETRIC MEASUREMENTS OF OXYHEMOGLOBIN AND CARBOXYHEMOGLOBIN JOURNAL OF CLINICAL MONITORING Mahoney, J. J., Wong, R. J., Vreman, H. J., Stevenson, D. K. 1991; 7 (2): 154-160

  Abstract

  The records of 32 neonates in an intensive care unit were examined retrospectively to determine if fetal hemoglobin concentrations could be predicted on the basis of gestational or postnatal age, or on the volume of red blood cell transfusions. In nontransfused neonates, the correlation between measured concentrations of fetal hemoglobin and post-natal age was r = 0.53 with a 17.2 standard error of prediction. In these same neonates, the correlation between measured fetal hemoglobin divided by birth weight and gestational age was r = 0.70, with a 9.6 standard error of prediction. A three-variable regression equation (the latter two variables plus calculated fetal hemoglobin) was found to have a high correlation with data for measured fetal hemoglobin (r = 0.97) and a relatively low 8.4 standard error of prediction. In transfused neonates, however, measured hemoglobin concentrations divided by birth weight correlated poorly with gestational age (r = 0.30 and a 12.4 standard error of prediction). In addition, the transfused neonates had low correlations when fetal hemoglobin concentrations alone were compared with the total volume of red blood cell transfusions (r = 0.35) and with postnatal age (r = 0.18) and the standard errors of prediction were all approximately 17. The correlations found between concentrations of fetal hemoglobin and age in transfused neonates were poorer than those reported in earlier nontransfused infant studies. Previous studies have also shown that neonatal blood containing fetal hemoglobin interferes with the spectrophotometric measurements of carboxyhemoglobin and oxyhemoglobin. Because of the imprecision in the predictions of fetal hemoglobin using age, weight, or the volume of transfusion, we conclude that fetal hemoglobin should be measured if accurate spectrophotometric determinations of carboxyhemoglobin and oxyhemoglobin are desired.

  View details for Web of Science ID A1991FH21600004

  View details for PubMedID 1712833

• PULMONARY EXCRETION OF CARBON-MONOXIDE IN THE HUMAN INFANT AS AN INDEX OF BILIRUBIN PRODUCTION .4. EFFECTS OF BREAST-FEEDING AND CALORIC-INTAKE IN THE 1ST POSTNATAL WEEK PEDIATRICS Stevenson, D. K., BARTOLETTI, A. L., OSTRANDER, C. R., Johnson, J. D. 1980; 65 (6): 1170-1172

  Abstract

  Measurements of the pulmonary excretion rate of carbon monoxide (VEco) as an index of bilirubin production in the first several days of life were taken from 64 breast-fed or bottle-fed infants. Twenty-one infants (greater than or equal to 37 weeks of gestation) were breast-fed; 43 infants (28 to 42 weeks of gestation) were bottle-fed a commercially prepared formula. Information pertaining to their caloric intake during the 24-hour period preceding VEco determination was taken from 38 of the 43 infants who were bottle-fed and they were placed into three groups based on their caloric intake: (1) less than or equal to 60 kcal/kg/day (19 infants); (2) 61 to 100 kcal/kg/day (7 infants); and (3) greater than 100 kcal/kg/day (12 infants). There was no significant difference in bilirubin production between bottle-fed and breast-fed infants. No effect of caloric deprivation on bilirubin production was demonstrated. The mean VEco values were 18.5 +/- 0.9 (SE) for group 1, 17.7 +/- 1.8 (SE) for group 2, and 16.2 +/- 1.1 (SE) microliter/kg/hr for group 3.

  View details for Web of Science ID A1980JU73500024

  View details for PubMedID 7375244

• PULMONARY EXCRETION OF CARBON-MONOXIDE IN THE HUMAN INFANT AS AN INDEX OF BILIRUBIN PRODUCTION .1. EFFECTS OF GESTATIONAL AND POSTNATAL AGE AND SOME COMMON NEONATAL ABNORMALITIES JOURNAL OF PEDIATRICS BARTOLETTI, A. L., Stevenson, D. K., OSTRANDER, C. R., Johnson, J. D. 1979; 94 (6): 952-955

  Abstract

  Using a single pass, flow-through system, the pulmonary excretion rate of endogenously produced carbon monoxide was measured as an index of bilirubin production in human infants with varying gestational and postnatal ages and with a variety of clinical abnormalities. No significant difference in VECO was found related to sex or gestational age. The mean VECO for a small group of Oriental infants was significantly increased. VECO decreased with increasing postnatal age. As expected, infants with hemolytic disease of the newborn had a markedly increased mean VECO. Infants with jaundice of unknown etiology also had an elevated mean VECO, implying that increased bilirubin production may be a factor contributing to the "nonphysiologic" bilirubinemias of these infants.

  View details for Web of Science ID A1979GX74400030

  View details for PubMedID 448544

• PULMONARY EXCRETION OF CARBON-MONOXIDE IN THE HUMAN NEWBORN-INFANT AS AN INDEX OF BILIRUBIN PRODUCTION .3. MEASUREMENT OF PULMONARY EXCRETION OF CARBON-MONOXIDE AFTER THE 1ST POSTNATAL WEEK IN PREMATURE-INFANTS PEDIATRICS Stevenson, D. K., BARTOLETTI, A. L., OSTRANDER, C. R., Johnson, J. D. 1979; 64 (5): 598-600

  Abstract

  Using a single pass, flow-through system, the excretion rate of endogenously produced carbon monoxide (VeCO) was measured as an index of bilirubin production in 41 Caucasian infants of various gestational ages after the first postnatal week. twenty-one were less than or equal to 32 weeks gestation. The mean slope for the 25 premature infants with multiple VeCO determinations was -0.21 +/- 0.11 (SE) microliters/kg/hour per day (P less than .025, one-tailed). Fifteen premature infants with at least three VeCO determinations during the first 30 days of life had an average decrease in total CO excreted of 1.33% per day compared to the extrapolated initial value of total CO excretion of 27.0 +/- 2.0 (SE) microliters/hour, giving a calculated maximum red cell life span of 75 days.

  View details for Web of Science ID A1979HT50800008

  View details for PubMedID 492832

• VMAP: Vaginal Microbiome Atlas during Pregnancy. JAMIA open Parraga-Leo, A., Oskotsky, T. T., Oskotsky, B., Wibrand, C., Roldan, A., Tang, A. S., Ha, C. W., Wong, R. J., Minot, S. S., Andreoletti, G., Kosti, I., Theis, K. R., Ng, S., Lee, Y. S., Diaz-Gimeno, P., Bennett, P. R., MacIntyre, D. A., Lynch, S. V., Romero, R., Tarca, A. L., Stevenson, D. K., Aghaeepour, N., Golob, J. L., Sirota, M. 2024; 7 (3): ooae099

  Abstract

  To enable interactive visualization of the vaginal microbiome across the pregnancy and facilitate discovery of novel insights and generation of new hypotheses.Vaginal Microbiome Atlas during Pregnancy (VMAP) was created with R shiny to generate visualizations of structured vaginal microbiome data from multiple studies.VMAP (http://vmapapp.org) visualizes 3880 vaginal microbiome samples of 1402 pregnant individuals from 11 studies, aggregated via open-source tool MaLiAmPi. Visualized features include diversity measures, VALENCIA community state types, and composition (phylotypes, taxonomy) that can be filtered by various categories.This work represents one of the largest and most geographically diverse aggregations of the vaginal microbiome in pregnancy to date and serves as a user-friendly resource to further analyze vaginal microbiome data and better understand pregnancies and associated outcomes.VMAP can be obtained from https://github.com/msirota/vmap.git and is currently deployed as an online app for non-R users.

  View details for DOI 10.1093/jamiaopen/ooae099

  View details for PubMedID 39345789

  View details for PubMedCentralID PMC11430916

• Surgical Necrotizing Enterocolitis and Spontaneous Intestinal Perforation Lead to Severe Growth Failure in Infants. Annals of surgery Speer, A. L., Lally, K. P., Pedroza, C., Zhang, Y., Poindexter, B. B., Chwals, W. J., Hintz, S. R., Besner, G. E., Stevenson, D. K., Ohls, R. K., Truog, W. E., Stoll, B. J., Rysavy, M. A., Das, A., Tyson, J. E., Blakely, M. L. 2024; 280 (3): 432-443

  Abstract

  We aimed to determine the incidence of growth failure in infants with necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) and whether initial laparotomy versus peritoneal drainage (PD) impacted the likelihood of growth failure.Infants with surgical NEC and SIP have high mortality, and most have neurodevelopmental impairment and poor growth. Existing literature on growth outcomes for these infants is limited.This is a preplanned secondary study of the Necrotizing Enterocolitis Surgery Trial dataset. The primary outcome was growth failure (Z-score for weight <-2.0) at 18 to 22 months. We used logistic regression, including diagnosis and treatment, as covariates. Secondary outcomes were analyzed using the Fisher exact or Pearson χ2 test for categorical variables and the Wilcoxon rank sum test or one-way ANOVA for continuous variables.Among 217 survivors, 207 infants (95%) had primary outcome data. Growth failure at 18 to 22 months occurred in 24/50 (48%) of NEC infants versus 65/157 (42%) SIP (P=0.4). The mean weight-for-age Z-score at 18 to 22 months in NEC infants was -2.05±0.99 versus -1.84±1.09 SIP (P=0.2), and the predicted mean weight-for-age Z-score SIP (Beta -0.27; 95% CI: -0.53, -0.01; P=0.041). Median declines in weight-for-age Z-score between birth and 18 to 22 months were significant in all infants but most severe (>2) in NEC infants (P=0.2).This first ever prospective study of growth outcomes in infants with surgical NEC or SIP demonstrates that growth failure is very common, especially in infants with NEC, and persists at 18-22 months.

  View details for DOI 10.1097/SLA.0000000000006378

  View details for PubMedID 39264354

• A Novel Stem Cell Model to Study Preeclampsia Endothelial Dysfunction. Reproductive sciences (Thousand Oaks, Calif.) Wu, Y., Sun, T., Medina, P., Narasimhan, P., Stevenson, D. K., Von Versen-Höynck, F., Armstrong, J., Wu, J. C., Sayed, N., Winn, V. D. 2024

  Abstract

  Preeclampsia is a common pregnancy complication affecting 5% to 7% of all pregnancies worldwide annually. While the pathogenesis is not fully understood, maternal endothelium dysfunction is thought to be a central component to preeclampsia development. Studies to dissect maternal endothelial dysfunction, particularly on a patient-specific basis, are hampered by limited access to systemic primary endothelial cells (ECs). The objective of this study was to establish a replenishable, patient-specific in vitro EC model to allow robust mechanistic studies to dissect endothelial dysfunction in preeclampsia. Induced pluripotent stem cells (iPSCs) from three women with a history of normotensive pregnancies were differentiated into ECs. The established ECs were exposed to pooled sera from normotensive pregnancies, preeclamptic pregnancies, normotensive postpartum for non-pregnant comparison and controls. Endothelial functions including nitric oxide (NO) release, cell migration, tube formation and viability were evaluated. Levels of NO release were significantly lower after incubation with preeclamptic sera compared to the fetal bovine serum (FBS) control, and normotensive and non-pregnant (postpartum) sera treatments were also lower than FBS but higher than preeclamptic sera treatments. Tube formation and cell migration were also impaired with preeclamptic sera compared to FBS controls. Cell viabilities remained unaffected by any sera treatment. Consistent outcomes were obtained across all three patient-specific lines treated with the same pooled sera. Establishment of patient-derived iPSC-ECs treated with pregnancy sera serves as a novel model to explore the interplay between individual maternal endothelial health and circulating factors that lead to endothelial dysfunction in preeclampsia.

  View details for DOI 10.1007/s43032-024-01590-z

  View details for PubMedID 39179924

  View details for PubMedCentralID 8592443

• Association of pregnancy complications and postpartum maternal leukocyte telomeres in two diverse cohorts: a nested case-control study. BMC pregnancy and childbirth Panelli, D. M., Wang, X., Mayo, J., Wong, R. J., Hong, X., Becker, M., Aghaeepour, N., Druzin, M. L., Zuckerman, B. S., Stevenson, D. K., Shaw DrPH, G. M., Bianco, K. 2024; 24 (1): 490

  Abstract

  Biologic strain such as oxidative stress has been associated with short leukocyte telomere length (LTL), as well as with preeclampsia and spontaneous preterm birth, yet little is known about their relationships with each other. We investigated associations of postpartum maternal LTL with preeclampsia and spontaneous preterm birth.This pilot nested case control study included independent cohorts of pregnant people with singleton gestations from two academic institutions: Cohort 1 (hereafter referred to as Suburban) were enrolled prior to 20 weeks' gestation between 2012 and 2018; and Cohort 2 (hereafter referred to as Urban) were enrolled at delivery between 2000 and 2012. Spontaneous preterm birth or preeclampsia were the selected pregnancy complications and served as cases. Cases were compared with controls from each study cohort of uncomplicated term births. Blood was collected between postpartum day 1 and up to 6 months postpartum and samples were frozen, then simultaneously thawed for analysis. Postpartum LTL was the primary outcome, measured using quantitative polymerase chain reaction (PCR) and compared using linear multivariable regression models adjusting for maternal age. Secondary analyses were done stratified by mode of delivery and self-reported level of stress during pregnancy.156 people were included; 66 from the Suburban Cohort and 90 from the Urban Cohort. The Suburban Cohort was predominantly White, Hispanic, higher income and the Urban Cohort was predominantly Black, Haitian, and lower income. We found a trend towards shorter LTLs among people with preeclampsia in the Urban Cohort (6517 versus 6913 bp, p = 0.07), but not in the Suburban Cohort. There were no significant differences in LTLs among people with spontaneous preterm birth compared to term controls in the Suburban Cohort (6044 versus 6144 bp, p = 0.64) or in the Urban Cohort (6717 versus 6913, p = 0.37). No differences were noted by mode of delivery. When stratifying by stress levels in the Urban Cohort, preeclampsia was associated with shorter postpartum LTLs in people with moderate stress levels (p = 0.02).Our exploratory results compare postpartum maternal LTLs between cases with preeclampsia or spontaneous preterm birth and controls in two distinct cohorts. These pilot data contribute to emerging literature on LTLs in pregnancy.

  View details for DOI 10.1186/s12884-024-06688-5

  View details for PubMedID 39033276

  View details for PubMedCentralID 5967638

• Mode of delivery predicts postpartum maternal leukocyte telomere length. European journal of obstetrics, gynecology, and reproductive biology Panelli, D. M., Mayo, J. A., Wong, R. J., Becker, M., Feyaerts, D., Marić, I., Wu, E., Gotlib, I. H., Gaudillière, B., Aghaeepour, N., Druzin, M. L., Stevenson, D. K., Shaw, G. M., Bianco, K. 2024; 300: 224-229

  Abstract

  Recent studies have suggested that pregnancy accelerates biologic aging, yet little is known about how biomarkers of aging are affected by events during the peripartum period. Given that immune shifts are known to occur following surgery, we explored the relation between mode of delivery and postpartum maternal leukocyte telomere length (LTL), a marker of biologic aging.Postpartum maternal blood samples were obtained from a prospective cohort of term, singleton livebirths without hypertensive disorders or peripartum infections between 2012 and 2018. The primary outcome was postpartum LTLs from one blood sample drawn between postpartum week 1 and up to 6 months postpartum, measured from thawed frozen peripheral blood mononuclear cells using quantitative PCR in basepairs (bp). Multivariable linear regression models compared LTLs between vaginal versus cesarean births, adjusting for age, body mass index, and nulliparity as potential confounders. Analyses were conducted in two mutually exclusive groups: those with LTL measured postpartum week 1 and those measured up to 6 months postpartum. Secondarily, we compared multiomics by mode of delivery using machine-learning methods to evaluate whether other biologic changes occurred following cesarean. These included transcriptomics, metabolomics, microbiomics, immunomics, and proteomics (serum and plasma).Of 67 included people, 50 (74.6 %) had vaginal and 17 (25.4 %) had cesarean births. LTLs were significantly shorter after cesarean in postpartum week 1 (5755.2 bp cesarean versus 6267.8 bp vaginal, p = 0.01) as well as in the later draws (5586.6 versus 5945.6 bp, p = 0.04). After adjusting for confounders, these differences persisted in both week 1 (adjusted beta -496.1, 95 % confidence interval [CI] -891.1, -101.1, p = 0.01) and beyond (adjusted beta -396.8; 95 % CI -727.2, -66.4. p = 0.02). Among the 15 participants who also had complete postpartum multiomics data available, there were predictive signatures of vaginal versus cesarean births in transcriptomics (cell-free [cf]RNA), metabolomics, microbiomics, and proteomics that did not persist after false discovery correction.Maternal LTLs in postpartum week 1 were nearly 500 bp shorter following cesarean. This difference persisted several weeks postpartum, even though other markers of inflammation had normalized. Mode of delivery should be considered in any analyses of postpartum LTLs and further investigation into this phenomenon is warranted.

  View details for DOI 10.1016/j.ejogrb.2024.07.026

  View details for PubMedID 39032311

• Predicting Preterm Birth Using Proteomics. Clinics in perinatology Marić, I., Stevenson, D. K., Aghaeepour, N., Gaudillière, B., Wong, R. J., Angst, M. S. 2024; 51 (2): 391-409

  Abstract

  The complexity of preterm birth (PTB), both spontaneous and medically indicated, and its various etiologies and associated risk factors pose a significant challenge for developing tools to accurately predict risk. This review focuses on the discovery of proteomics signatures that might be useful for predicting spontaneous PTB or preeclampsia, which often results in PTB. We describe methods for proteomics analyses, proteomics biomarker candidates that have so far been identified, obstacles for discovering biomarkers that are sufficiently accurate for clinical use, and the derivation of composite signatures including clinical parameters to increase predictive power.

  View details for DOI 10.1016/j.clp.2024.02.011

  View details for PubMedID 38705648

• Solving the Puzzle of Preterm Birth. Clinics in perinatology Stevenson, D. K., Winn, V. D., Shaw, G. M., England, S. K., Wong, R. J. 2024; 51 (2): 291-300

  Abstract

  Solving the puzzle of preterm birth has been challenging and will require novel integrative solutions as preterm birth likely arises from many etiologies. It has been demonstrated that many sociodemographic and psychological determinants of preterm birth relate to its complex biology. It is this understanding that has enabled the development of a novel preventative strategy, which integrates the omics profile (genome, epigenome, transcriptome, proteome, metabolome, microbiome) with sociodemographic, environmental, and psychological determinants of individual pregnant people to solve the puzzle of preterm birth.

  View details for DOI 10.1016/j.clp.2024.02.001

  View details for PubMedID 38705641

• Preterm Birth. Clinics in perinatology Wong, R. J., Shaw, G. M., Stevenson, D. K. 2024; 51 (2): xxv-xxvi

  View details for DOI 10.1016/j.clp.2024.03.002

  View details for PubMedID 38705657

• Identifying therapeutic candidates for endometriosis through a transcriptomics-based drug repositioning approach. iScience Oskotsky, T. T., Bhoja, A., Bunis, D., Le, B. L., Tang, A. S., Kosti, I., Li, C., Houshdaran, S., Sen, S., Vallvé-Juanico, J., Wang, W., Arthurs, E., Govil, A., Mahoney, L., Lang, L., Gaudilliere, B., Stevenson, D. K., Irwin, J. C., Giudice, L. C., McAllister, S. L., Sirota, M. 2024; 27 (4): 109388

  Abstract

  Existing medical treatments for endometriosis-related pain are often ineffective, underscoring the need for new therapeutic strategies. In this study, we applied a computational drug repurposing pipeline to stratified and unstratified disease signatures based on endometrial gene expression data to identify potential therapeutics from existing drugs, based on expression reversal. Of 3,131 unique genes differentially expressed by at least one of six endometriosis signatures, only 308 (9.8%) were in common; however, 221 out of 299 drugs identified, (73.9%) were shared. We selected fenoprofen, an uncommonly prescribed NSAID that was the top therapeutic candidate for further investigation. When testing fenoprofen in an established rat model of endometriosis, fenoprofen successfully alleviated endometriosis-associated vaginal hyperalgesia, a surrogate marker for endometriosis-related pain. These findings validate fenoprofen as a therapeutic that could be utilized more frequently for endometriosis and suggest the utility of the aforementioned computational drug repurposing approach for endometriosis.

  View details for DOI 10.1016/j.isci.2024.109388

  View details for PubMedID 38510116

  View details for PubMedCentralID PMC10952035

• Is it time for a precision health approach to the management of newborn hyperbilirubinemia? Journal of perinatology : official journal of the California Perinatal Association Stevenson, D. K., Wells, G. S., Wong, R. J. 2024

  Abstract

  Newborn hyperbilirubinemia during the first two weeks of life is one of most common problems requiring management decisions by a pediatrician. However, high bilirubin levels in the circulation have been associated with neurologic injury under a variety of conditions encountered in the newborn infant, such as hemolysis. The risk for developing dangerous hyperbilirubinemia is multifactorial and is determined by a complex set of factors related to a newborn infant's genetic capacities as well as intra- and extrauterine exposures. To this end, a precision health approach based on the integration of prenatal genetic and postnatal diagnostic measures might improve the management of neonatal hyperbilirubinemia.

  View details for DOI 10.1038/s41372-024-01941-3

  View details for PubMedID 38514741

  View details for PubMedCentralID 225223

• Vascular health years after a hypertensive disorder of pregnancy: The EPOCH Study. American heart journal Miller, H. E., Tierney, S., Stefanick, M. L., Mayo, J. A., Sedan, O., Rosas, L. G., Melbye, M., Boyd, H. A., Stevenson, D. K., Shaw, G. M., Winn, V. D., Hlatky, M. A. 2024

  Abstract

  Preeclampsia is associated with a two-fold increase in a woman's lifetime risk of developing atherosclerotic cardiovascular disease (ASCVD), but the reasons for this association are uncertain. The objective of this study was to examine the associations between vascular health and a hypertensive disorder of pregnancy among women ≥ 2 years postpartum.Pre-menopausal women with a history of either a hypertensive disorder of pregnancy (cases: preeclampsia or gestational hypertension) or a normotensive pregnancy (controls) were enrolled. Participants were assessed for standard ASCVD risk factors and underwent vascular testing, including measurements of blood pressure, endothelial function, and carotid artery ultrasound. The primary outcomes were blood pressure, ASCVD risk, reactive hyperemia index measured by EndoPAT and carotid intima-medial thickness. The secondary outcomes were augmentation index normalized to 75 beats per minute and pulse wave amplitude measured by EndoPAT, and carotid elastic modulus and carotid beta-stiffness measured by carotid ultrasound.Participants had a mean age of 40.7 years and were 5.7 years since their last pregnancy. In bivariate analyses cases (N=68) were more likely than controls (N=71) to have hypertension (18% vs. 4%, p=0.034), higher calculated ASCVD risk (0.6 vs 0.4, p=0.02), higher blood pressures (systolic: 118.5 vs. 111.6 mm Hg, p=0.0004; diastolic: 75.2 vs 69.8 mm Hg, p=0.0004), and higher augmentation index values (7.7 vs. 2.3 p=0.03). They did not, however, differ significantly in carotid intima-media thickness (0.5 vs. 0.5, p=0.29) or reactive hyperemia index (2.1 vs 2.1, p=0.93), nor in pulse wave amplitude (416 vs 326, p=0.11), carotid elastic modulus (445 vs 426, p=0.36), or carotid beta stiffness (2.8 vs 2.8, p=0.86).Women with a prior hypertensive disorder of pregnancy had higher ASCVD risk and blood pressures several years postpartum, but did not have more endothelial dysfunction or subclinical atherosclerosis.

  View details for DOI 10.1016/j.ahj.2024.03.004

  View details for PubMedID 38484963

• Reassessing acquired neonatal intestinal diseases using unsupervised machine learning. Pediatric research Gipson, D. R., Chang, A. L., Lure, A. C., Mehta, S. A., Gowen, T., Shumans, E., Stevenson, D., de la Cruz, D., Aghaeepour, N., Neu, J. 2024

  Abstract

  Acquired neonatal intestinal diseases have an array of overlapping presentations and are often labeled under the dichotomous classification of necrotizing enterocolitis (which is poorly defined) or spontaneous intestinal perforation, hindering more precise diagnosis and research. The objective of this study was to take a fresh look at neonatal intestinal disease classification using unsupervised machine learning.Patients admitted to the University of Florida Shands Neonatal Intensive Care Unit January 2013-September 2019 diagnosed with an intestinal injury, or had imaging findings of portal venous gas, pneumatosis, abdominal free air, or had an abdominal drain placed or exploratory laparotomy during admission were included. Congenital gastroschisis, omphalocele, intestinal atresia, malrotation were excluded. Data was collected via retrospective chart review with subsequent hierarchal, unsupervised clustering analysis.Five clusters of intestinal injury were identified: Cluster 1 deemed the "Low Mortality" cluster, Cluster 2 deemed the "Mature with Inflammation" cluster, Cluster 3 deemed the "Immature with High Mortality" cluster, Cluster 4 deemed the "Late Injury at Full Feeds" cluster, and Cluster 5 deemed the "Late Injury with High Rate of Intestinal Necrosis" cluster.Unsupervised machine learning can be used to cluster acquired neonatal intestinal injuries. Future study with larger multicenter datasets is needed to further refine and classify types of intestinal diseases.Unsupervised machine learning can be used to cluster types of acquired neonatal intestinal injury. Five major clusters of acquired neonatal intestinal injury are described, each with unique features. The clusters herein described deserve future, multicenter study to determine more specific early biomarkers and tailored therapeutic interventions to improve outcomes of often devastating neonatal acquired intestinal injuries.

  View details for DOI 10.1038/s41390-024-03074-x

  View details for PubMedID 38413766

  View details for PubMedCentralID 8096612

• Author Correction: Abrupt perturbation and delayed recovery of the vaginal ecosystem following childbirth. Nature communications Costello, E. K., DiGiulio, D. B., Robaczewska, A., Symul, L., Wong, R. J., Shaw, G. M., Stevenson, D. K., Holmes, S. P., Kwon, D. S., Relman, D. A. 2024; 15 (1): 1744

  View details for DOI 10.1038/s41467-024-46160-8

  View details for PubMedID 38409135

• Corrigendum: Advances and potential of omics studies for understanding the development of food allergy. Frontiers in allergy Sindher, S. B., Chin, A. R., Aghaeepour, N., Prince, L., Maecker, H., Shaw, G. M., Stevenson, D., Nadeau, K. C., Snyder, M., Khatri, P., Boyd, S. D., Winn, V. D., Angst, M. S., Chinthrajah, R. S. 2024; 5: 1373485

  Abstract

  [This corrects the article DOI: 10.3389/falgy.2023.1149008.].

  View details for DOI 10.3389/falgy.2024.1373485

  View details for PubMedID 38464397

  View details for PubMedCentralID PMC10921899

• Integrating evidence and causal mapping of factors that influence medication decision-making by pregnant women at risk of hypertensive disorder: protocol for a scoping review. BMJ open Lee, Y. J., Taft, A., Stevenson, D. K., Darmstadt, G. L. 2024; 14 (2): e074775

  Abstract

  INTRODUCTION: In 2018, the American College of Obstetricians and Gynecologists recommended low-dose aspirin to prevent the onset of pre-eclampsia among women who were at high risk. Factors influencing women's acceptance of this recommendation span multiple sectors and levels. Understanding how these factors interact will help stakeholders design effective population-level intervention strategies. Our study aims to identify and map relationships among factors influencing the medication decisions of pregnant women at risk of hypertensive disorders.METHODS AND ANALYSIS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines will be followed for this review. A research librarian developed a comprehensive search strategy to retrieve published and unpublished English studies after 1 January 1980, involving factors that influence pregnant women's uptake and adherence to medication for gestational hypertensive disorders. This literature includes perceptions, patterns, acceptance, refusal, tendencies, probability and service utilisation. We will search PubMed, Embase, Web of Science and CINAHL. Reference lists of the selected papers will be searched manually to identify more relevant studies. A two-stage independent screening, consisting of title and abstract screening, followed by full-text screening, will be conducted by two independent reviewers to identify eligible articles. Extracted data will be recorded in a customised variable extraction form and input into a Microsoft Access database. The PRISMA-ScR will be used to guide the presentation of the results, which will be presented in a table and causal map to demonstrate the relationships between extracted variables and medication uptake and adherence. A conceptual simulation model will be formulated to validate the logic of the relationships between variables and identify knowledge gaps. Lastly, experts and stakeholders will be invited to critique and comment on the results.ETHICS AND DISSEMINATION: This study does not require ethical approval. The full review results will be presented at a relevant conference and submitted to a peer-reviewed scientific journal for publication.

  View details for DOI 10.1136/bmjopen-2023-074775

  View details for PubMedID 38316590

• Large-scale proteomics in the first trimester of pregnancy predict psychopathology and temperament in preschool children: an exploratory study. Journal of child psychology and psychiatry, and allied disciplines Buthmann, J. L., Miller, J. G., Aghaeepour, N., King, L. S., Stevenson, D. K., Shaw, G. M., Wong, R. J., Gotlib, I. H. 2024

  Abstract

  Understanding the prenatal origins of children's psychopathology is a fundamental goal in developmental and clinical science. Recent research suggests that inflammation during pregnancy can trigger a cascade of fetal programming changes that contribute to vulnerability for the emergence of psychopathology. Most studies, however, have focused on a handful of proinflammatory cytokines and have not explored a range of prenatal biological pathways that may be involved in increasing postnatal risk for emotional and behavioral difficulties.Using extreme gradient boosted machine learning models, we explored large-scale proteomics, considering over 1,000 proteins from first trimester blood samples, to predict behavior in early childhood. Mothers reported on their 3- to 5-year-old children's (N = 89, 51% female) temperament (Child Behavior Questionnaire) and psychopathology (Child Behavior Checklist).We found that machine learning models of prenatal proteomics predict 5%-10% of the variance in children's sadness, perceptual sensitivity, attention problems, and emotional reactivity. Enrichment analyses identified immune function, nervous system development, and cell signaling pathways as being particularly important in predicting children's outcomes.Our findings, though exploratory, suggest processes in early pregnancy that are related to functioning in early childhood. Predictive features included far more proteins than have been considered in prior work. Specifically, proteins implicated in inflammation, in the development of the central nervous system, and in key cell-signaling pathways were enriched in relation to child temperament and psychopathology measures.

  View details for DOI 10.1111/jcpp.13948

  View details for PubMedID 38287782

• Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth. Science advances Wang, C., Wang, Y. J., Ying, L., Wong, R. J., Quaintance, C. C., Hong, X., Neff, N., Wang, X., Biggio, J. R., Mesiano, S., Quake, S. R., Alvira, C. M., Cornfield, D. N., Stevenson, D. K., Shaw, G. M., Li, J. 2024; 10 (3): eadk1057

  Abstract

  Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.

  View details for DOI 10.1126/sciadv.adk1057

  View details for PubMedID 38241369

  View details for PubMedCentralID PMC10798565

• Discovery of sparse, reliable omic biomarkers with Stabl. Nature biotechnology Hédou, J., Marić, I., Bellan, G., Einhaus, J., Gaudillière, D. K., Ladant, F. X., Verdonk, F., Stelzer, I. A., Feyaerts, D., Tsai, A. S., Ganio, E. A., Sabayev, M., Gillard, J., Amar, J., Cambriel, A., Oskotsky, T. T., Roldan, A., Golob, J. L., Sirota, M., Bonham, T. A., Sato, M., Diop, M., Durand, X., Angst, M. S., Stevenson, D. K., Aghaeepour, N., Montanari, A., Gaudillière, B. 2024

  Abstract

  Adoption of high-content omic technologies in clinical studies, coupled with computational methods, has yielded an abundance of candidate biomarkers. However, translating such findings into bona fide clinical biomarkers remains challenging. To facilitate this process, we introduce Stabl, a general machine learning method that identifies a sparse, reliable set of biomarkers by integrating noise injection and a data-driven signal-to-noise threshold into multivariable predictive modeling. Evaluation of Stabl on synthetic datasets and five independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used sparsity-promoting regularization methods while maintaining predictive performance; it distills datasets containing 1,400-35,000 features down to 4-34 candidate biomarkers. Stabl extends to multi-omic integration tasks, enabling biological interpretation of complex predictive models, as it hones in on a shortlist of proteomic, metabolomic and cytometric events predicting labor onset, microbial biomarkers of pre-term birth and a pre-operative immune signature of post-surgical infections. Stabl is available at https://github.com/gregbellan/Stabl .

  View details for DOI 10.1038/s41587-023-02033-x

  View details for PubMedID 38168992

  View details for PubMedCentralID 7003173

• Longitudinal Triglyceride Profiling in Preterm Infants Suggests Dynamic and Age-Specific Trajectories Reiss, J., Ding, Chang, A., Phongpreecha, T., Lyon, A., Long, J. Z., Jordan, B. K., Scottoline, B., Snyder, M., Sylvester, K., Stevenson, D. K., Aghaeepour, N., Shaw, G. M. SAGE PUBLICATIONS LTD. 2024: 600-602

  View details for Web of Science ID 001307337600598

• The placental vasculature is affected by changes in gene expression and glycogen-rich cells in a diet-induced obesity mouse model. PloS one Zhao, H., Wong, R. J., Stevenson, D. K. 2023; 18 (11): e0294185

  Abstract

  Maternal obesity is a risk factor for pregnancy complications. Obesity caused by a high-fat diet (HFD) may alter maternal glucose/glycogen metabolism. Here, our objective was to investigate whether the placental vasculature is altered via changes in gene expression and glycogen-rich cells using a preclinical mouse model of diet-induced obesity. We subjected female FVB/N mice to one of three feeding regimens: regular chow (RC) given at preconception and during pregnancy (Control); RC given at preconception and then a HFD during pregnancy (HFD-P); or HFD initiated 4 weeks preconception and during pregnancy (HFD-PreCP). Daily food consumption and weekly maternal weights were recorded. Maternal blood glucose levels were measured at preconception and 4 gestational epochs (E6.5-E9.5, E10.5-E12.5, E13.5-E15.5, E16.5-E19.5). At E8.5-E16.5, total RNA in placentas were isolated for gene expression analyses. Placentas were also collected for HE and periodic acid Schiff's (PAS) staining and glycogen content assays. Dams in the HFD-P and HFD-PreCP groups gained significantly more weight than controls. Pre- and antenatal glucose levels were also significantly higher (15%-30%) in HFD-PreCP dams. Expression of several placental genes were also altered in HFD dams compared with controls. Consumption of the HFD also led to phenotypic and morphologic changes in glycogen trophoblasts (GlyTs) and uterine natural killer (uNK) cells. Alterations in vascularity were also observed in the labyrinth of HFD-PreCP placentas, which correlated with decreased placental efficiency. Overall, we observed that a HFD induces gestational obesity in mice, alters expression of placental genes, affects glucose homeostasis, and alters glycogen-positive GlyTs and uNK cells. All these changes may lead to impaired placental vascular development, and thus heighten the risk for pregnancy complications.

  View details for DOI 10.1371/journal.pone.0294185

  View details for PubMedID 37948457

  View details for PubMedCentralID PMC10637699

• MALE FIRSTBORN AND SUBSEQUENT PREGNANCY LOSS - A REAPPRAISAL USING REAL-WORLD DATA. Roger, J., Costello, J., Rosenstein, M. G., Rajkovic, A., Cakmak, H., Shaw, G., Stevenson, D., Glymour, M., Lathi, R., Sirota, M. ELSEVIER SCIENCE INC. 2023: E81-E82

  View details for Web of Science ID 001084670200191

• Deep representation learning identifies associations between physical activity and sleep patterns during pregnancy and prematurity. NPJ digital medicine Ravindra, N. G., Espinosa, C., Berson, E., Phongpreecha, T., Zhao, P., Becker, M., Chang, A. L., Shome, S., Marić, I., De Francesco, D., Mataraso, S., Saarunya, G., Thuraiappah, M., Xue, L., Gaudillière, B., Angst, M. S., Shaw, G. M., Herzog, E. D., Stevenson, D. K., England, S. K., Aghaeepour, N. 2023; 6 (1): 171

  Abstract

  Preterm birth (PTB) is the leading cause of infant mortality globally. Research has focused on developing predictive models for PTB without prioritizing cost-effective interventions. Physical activity and sleep present unique opportunities for interventions in low- and middle-income populations (LMICs). However, objective measurement of physical activity and sleep remains challenging and self-reported metrics suffer from low-resolution and accuracy. In this study, we use physical activity data collected using a wearable device comprising over 181,944 h of data across N = 1083 patients. Using a new state-of-the art deep learning time-series classification architecture, we develop a 'clock' of healthy dynamics during pregnancy by using gestational age (GA) as a surrogate for progression of pregnancy. We also develop novel interpretability algorithms that integrate unsupervised clustering, model error analysis, feature attribution, and automated actigraphy analysis, allowing for model interpretation with respect to sleep, activity, and clinical variables. Our model performs significantly better than 7 other machine learning and AI methods for modeling the progression of pregnancy. We found that deviations from a normal 'clock' of physical activity and sleep changes during pregnancy are strongly associated with pregnancy outcomes. When our model underestimates GA, there are 0.52 fewer preterm births than expected (P = 1.01e - 67, permutation test) and when our model overestimates GA, there are 1.44 times (P = 2.82e - 39, permutation test) more preterm births than expected. Model error is negatively correlated with interdaily stability (P = 0.043, Spearman's), indicating that our model assigns a more advanced GA when an individual's daily rhythms are less precise. Supporting this, our model attributes higher importance to sleep periods in predicting higher-than-actual GA, relative to lower-than-actual GA (P = 1.01e - 21, Mann-Whitney U). Combining prediction and interpretability allows us to signal when activity behaviors alter the likelihood of preterm birth and advocates for the development of clinical decision support through passive monitoring and exercise habit and sleep recommendations, which can be easily implemented in LMICs.

  View details for DOI 10.1038/s41746-023-00911-x

  View details for PubMedID 37770643

  View details for PubMedCentralID 3796350

• Challenges to the study of gender dysphoria. Acta paediatrica (Oslo, Norway : 1992) Stevenson, D. K., Murray, J. C., Muglia, L. J., Wong, R. J., Katz, M. 2023

  View details for DOI 10.1111/apa.16975

  View details for PubMedID 37724910

• Corrigendum to Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth [The Journal of Pediatrics 194(2018):40-46.e4]. The Journal of pediatrics Crawford, N., Prendergast, D., Oehlert, J. W., Shaw, G. M., Stevenson, D. K., Rappaport, N., Sirota, M., Tishkoff, S. A., Sondheimer, N. 2023: 113345

  View details for DOI 10.1016/j.jpeds.2023.01.017

  View details for PubMedID 37495478

• A "Gold Standard" Test for Diagnosing and Quantifying Hemolysis in Neonates and Infants. Journal of perinatology : official journal of the California Perinatal Association Christensen, R. D., Bahr, T. M., Wong, R. J., Vreman, H. J., Bhutani, V. K., Stevenson, D. K. 2023

  Abstract

  Identifying "gold standard" diagnostic tests can promote evidence-based neonatology practice. Hemolysis is a pathological shortening of the erythrocyte lifespan, differing from erythrocyte senescence in responsible mechanisms and clinical implications. Diagnosing hemolysis goes beyond a binary (yes vs. no) determination. It is characterized according to magnitude, and as acute vs. chronic, and genetically based vs. not. For neonates with significant hyperbilirubinemia or anemia, detecting hemolysis and quantifying its magnitude provides diagnostic clarity. The 2022 American Academy of Pediatrics (AAP) Clinical Practice Guideline on management of hyperbilirubinemia in the newborn states that hemolysis is a risk factor for developing significant hyperbilirubinemia and neurotoxicity. The guideline recommends identifying hemolysis from any cause, but specific guidance is not provided. A spectrum of laboratory tests has been endorsed as diagnostic methods for hemolysis. Herein we examine these laboratory tests and recommend one as the "gold standard" for diagnosing and quantifying hemolysis in neonates and infants.

  View details for DOI 10.1038/s41372-023-01730-4

  View details for PubMedID 37468612

  View details for PubMedCentralID 4623764

• Abrupt perturbation and delayed recovery of the vaginal ecosystem following childbirth. Nature communications Costello, E. K., DiGiulio, D. B., Robaczewska, A., Symul, L., Wong, R. J., Shaw, G. M., Stevenson, D. K., Holmes, S. P., Kwon, D. S., Relman, D. A. 2023; 14 (1): 4141

  Abstract

  The vaginal ecosystem is closely tied to human health and reproductive outcomes, yet its dynamics in the wake of childbirth remain poorly characterized. Here, we profile the vaginal microbiota and cytokine milieu of participants sampled longitudinally throughout pregnancy and for at least one year postpartum. We show that delivery, regardless of mode, is associated with a vaginal pro-inflammatory cytokine response and the loss of Lactobacillus dominance. By contrast, neither the progression of gestation nor the approach of labor strongly altered the vaginal ecosystem. At 9.5-months postpartum-the latest timepoint at which cytokines were assessed-elevated inflammation coincided with vaginal bacterial communities that had remained perturbed (highly diverse) from the time of delivery. Time-to-event analysis indicated a one-year postpartum probability of transitioning to Lactobacillus dominance of 49.4%. As diversity and inflammation declined during the postpartum period, dominance by L. crispatus, the quintessential health-associated commensal, failed to return: its prevalence before, immediately after, and one year after delivery was 41%, 4%, and 9%, respectively. Revisiting our pre-delivery data, we found that a prior live birth was associated with a lower odds of L. crispatus dominance in pregnant participants-an outcome modestly tempered by a longer ( > 18-month) interpregnancy interval. Our results suggest that reproductive history and childbirth in particular remodel the vaginal ecosystem and that the timing and degree of recovery from delivery may help determine the subsequent health of the woman and of future pregnancies.

  View details for DOI 10.1038/s41467-023-39849-9

  View details for PubMedID 37438386

  View details for PubMedCentralID 4355684

• Persistent Bacterial Vaginosis and Risk for Spontaneous Preterm Birth. American journal of perinatology Blumenfeld, Y. J., Marić, I., Stevenson, D. K., Gibbs, R. S., Shaw, G. M. 2023

  Abstract

   The aim of this study was to determine the association between persistent bacterial vaginosis (BV) in pregnancy and risk for spontaneous preterm birth (sPTB). Retrospective data from IBM MarketScan Commercial Database were analyzed. Women aged between 12 and 55 years with singleton gestations were included and linked to an outpatient medications database and medications prescribed during the pregnancy were analyzed. BV in pregnancy was determined based on both a diagnosis of BV and treatment with metronidazole and/or clindamycin, and persistent treatment of BV was defined as BV in more than one trimester or BV requiring more than one antibiotic prescription. Odds ratios were calculated comparing sPTB frequencies in those with BV, or persistent BV, to women without BV in pregnancy. Survival analysis using Kaplan-Meier curves for the gestational age at delivery was also performed. Among a cohort of 2,538,606 women, 216,611 had an associated International Classification of Diseases, 9th Revision or 10th Revision code for diagnosis of BV alone, and 63,817 had both a diagnosis of BV and were treated with metronidazole and/or clindamycin. Overall, the frequency of sPTB among women treated with BV was 7.5% compared with 5.7% for women without BV who did not receive antibiotics. Relative to those without BV in pregnancy, odds ratios for sPTB were highest in those treated for BV in both the first and second trimester (1.66 [95% confidence interval [CI]: 1.52, 1.81]) or those with three or more prescriptions in pregnancy (1.48 [95% CI: 1.35, 1.63]. Persistent BV may have a higher risk for sPTB than a single episode of BV in pregnancy.· Persistent BV beyond one trimester may increase the risk for sPTB.. · Persistent BV requiring more than one prescription may increase the risk for sPTB.. · Almost half of antibiotic prescriptions treating BV in pregnancy are filled after 20 weeks gestation..

  View details for DOI 10.1055/s-0043-1770703

  View details for PubMedID 37379861

• Breath: The Exhaust of Metabolism JOURNAL OF PEDIATRICS Stevenson, D. K., Maric, I., Wong, R. J. 2023; 257: 1-3

  View details for DOI 10.1018/j.jpeds.2023.03.002

  View details for Web of Science ID 001030453900001

• Development of a Urine Metabolomics Biomarker-Based Prediction Model for Preeclampsia during Early Pregnancy. Metabolites Zhang, Y., Sylvester, K. G., Jin, B., Wong, R. J., Schilling, J., Chou, C. J., Han, Z., Luo, R. Y., Tian, L., Ladella, S., Mo, L., Maric, I., Blumenfeld, Y. J., Darmstadt, G. L., Shaw, G. M., Stevenson, D. K., Whitin, J. C., Cohen, H. J., McElhinney, D. B., Ling, X. B. 2023; 13 (6)

  Abstract

  Preeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we examined a cohort of 60 pregnant women and collected 478 urine samples between gestational weeks 8 and 20 for comprehensive metabolomic profiling. By employing liquid chromatography mass spectrometry (LCMS/MS), we identified the structures of seven out of 26 metabolomics biomarkers detected. Utilizing the XGBoost algorithm, we developed a predictive model based on these seven metabolomics biomarkers to identify individuals at risk of developing PE. The performance of the model was evaluated using 10-fold cross-validation, yielding an area under the receiver operating characteristic curve of 0.856. Our findings suggest that measuring urinary metabolomics biomarkers offers a noninvasive approach to assess the risk of PE prior to its onset.

  View details for DOI 10.3390/metabo13060715

  View details for PubMedID 37367874

• Multiomic signals associated with maternal epidemiological factors contributing to preterm birth in low- and middle-income countries. Science advances Espinosa, C. A., Khan, W., Khanam, R., Das, S., Khalid, J., Pervin, J., Kasaro, M. P., Contrepois, K., Chang, A. L., Phongpreecha, T., Michael, B., Ellenberger, M., Mehmood, U., Hotwani, A., Nizar, A., Kabir, F., Wong, R. J., Becker, M., Berson, E., Culos, A., De Francesco, D., Mataraso, S., Ravindra, N., Thuraiappah, M., Xenochristou, M., Stelzer, I. A., Marić, I., Dutta, A., Raqib, R., Ahmed, S., Rahman, S., Hasan, A. S., Ali, S. M., Juma, M. H., Rahman, M., Aktar, S., Deb, S., Price, J. T., Wise, P. H., Winn, V. D., Druzin, M. L., Gibbs, R. S., Darmstadt, G. L., Murray, J. C., Stringer, J. S., Gaudilliere, B., Snyder, M. P., Angst, M. S., Rahman, A., Baqui, A. H., Jehan, F., Nisar, M. I., Vwalika, B., Sazawal, S., Shaw, G. M., Stevenson, D. K., Aghaeepour, N. 2023; 9 (21): eade7692

  Abstract

  Preterm birth (PTB) is the leading cause of death in children under five, yet comprehensive studies are hindered by its multiple complex etiologies. Epidemiological associations between PTB and maternal characteristics have been previously described. This work used multiomic profiling and multivariate modeling to investigate the biological signatures of these characteristics. Maternal covariates were collected during pregnancy from 13,841 pregnant women across five sites. Plasma samples from 231 participants were analyzed to generate proteomic, metabolomic, and lipidomic datasets. Machine learning models showed robust performance for the prediction of PTB (AUROC = 0.70), time-to-delivery (r = 0.65), maternal age (r = 0.59), gravidity (r = 0.56), and BMI (r = 0.81). Time-to-delivery biological correlates included fetal-associated proteins (e.g., ALPP, AFP, and PGF) and immune proteins (e.g., PD-L1, CCL28, and LIFR). Maternal age negatively correlated with collagen COL9A1, gravidity with endothelial NOS and inflammatory chemokine CXCL13, and BMI with leptin and structural protein FABP4. These results provide an integrated view of epidemiological factors associated with PTB and identify biological signatures of clinical covariates affecting this disease.

  View details for DOI 10.1126/sciadv.ade7692

  View details for PubMedID 37224249

• Postpartum long-acting reversible contraception among privately insured: national analysis 2007-2016, by term and preterm birth. Contraception Shaw, J. G., Goldthwaite, L. M., Marić, I., Shaw, K. A., Stevenson, D. K., Shaw, G. M. 2023: 110065

  Abstract

  To investigate postpartum long-acting reversible contraception (LARC) use among privately insured women, with specific consideration of use after preterm delivery.We used the national IBM® MarketScan® Commercial Database to identify singleton deliveries from 2007-2016, spontaneous preterm birth, and follow up ≤12 weeks postpartum. We assessed ≤12 week postpartum LARC placement overall and after spontaneous preterm deliveries, across study years. We examined timing of placement, rates of postpartum follow-up, and state-level variation in postpartum LARC.Among 3,132,107 singleton deliveries, 6.6% were spontaneous preterm. Over the time period, total postpartum LARC use increased: 4.8% to 11.7% for intrauterine devices (IUDs), 0.2% to 2.4% for implants. In 2016, those who experienced a spontaneous preterm birth were less likely to initiate postpartum IUDs compared to their peers (10.2% vs 11.8%, p<0.001), minimally more likely to initiate implants (2.7% vs 2.4%, p=0.04) and more likely to present for postpartum care (61.7% vs 55.9%, p<0.001). LARC placement prior to hospital discharge was rare (preterm: 8 per 10,000 deliveries vs all others: 6.3 per 10,000 deliveries, p=0.002). State level analysis showed wide variation in postpartum LARC (range 6%-32%).While postpartum LARC use increased among the privately insured 2007 to 2016, few received LARC prior to hospital discharge. Those experiencing preterm birth were no more likely to receive inpatient LARC. Postpartum follow-up remained low and regional variation of LARC was high, highlighting the need for efforts to remove barriers to inpatient postpartum LARC for all who desire it-public and privately insured alike.Among the half of U.S. births that are privately insured, postpartum LARC is increasing after both term and preterm births, yet exceedingly few (<0.1%) received LARC prior to hospital discharge.

  View details for DOI 10.1016/j.contraception.2023.110065

  View details for PubMedID 37210023

• Noninvasive Prenatal Testing Using Circulating DNA and RNA: Advances, Challenges, and Possibilities. Annual review of biomedical data science Moufarrej, M. N., Bianchi, D. W., Shaw, G. M., Stevenson, D. K., Quake, S. R. 2023

  Abstract

  Prenatal screening using sequencing of circulating cell-free DNA has transformed obstetric care over the past decade and significantly reduced the number of invasive diagnostic procedures like amniocentesis for genetic disorders. Nonetheless, emergency care remains the only option for complications like preeclampsia and preterm birth, two of the most prevalent obstetrical syndromes. Advances in noninvasive prenatal testing expand the scope of precision medicine in obstetric care. In this review, we discuss advances, challenges, and possibilities toward the goal of providing proactive, personalized prenatal care. The highlighted advances focus mainly on cell-free nucleic acids; however, we also review research that uses signals from metabolomics, proteomics, intact cells, and the microbiome. We discuss ethical challenges in providing care. Finally, we look to future possibilities, including redefining disease taxonomy and moving from biomarker correlation to biological causation. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-biodatasci-020722-094144

  View details for PubMedID 37196360

• Generalizability of the Necrotizing Enterocolitis Surgery Trial (NEST) to the Target Population of Eligible Infants. The Journal of pediatrics Rysavy, M. A., Eggleston, B., Dahabreh, I., Tyson, J. E., Patel, R. M., Watterberg, K. L., Greenberg, R. G., Pedroza, C., Trotta, M., Stevenson, D. K., Stoll, B. J., Lally, K. P., Das, A., Blakely, M. L. 2023: 113453

  Abstract

  To evaluate whether infants randomized in the NICHD Neonatal Research Network Necrotizing Enterocolitis Surgery Trial (NEST) differed from eligible infants and whether differences affected the generalizability of trial results.Secondary analysis of infants enrolled in NEST (born 2010-2017, with follow-up through 2019) at 20 U.S. academic medical centers and an observational dataset of eligible infants through 2013. Infants born ≤1000 g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8 weeks were eligible. The target population included trial-eligible infants (randomized and non-randomized) born during the first half of the study with available detailed pre-operative data. Using model-based weighting methods, we estimated the effect of initial laparotomy versus peritoneal drain had the target population been randomized.The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). Rates of the primary composite outcome, death or neurodevelopmental impairment, were similar (69% vs 72%). Effect estimates for initial laparotomy versus drain weighted to the target population were largely unchanged from the original trial after accounting for pre-operative diagnosis of necrotizing enterocolitis (aRR [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]).Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results.

  View details for DOI 10.1016/j.jpeds.2023.113453

  View details for PubMedID 37169336

• Target-agnostic drug prediction integrated with medical record analysis uncovers differential associations of statins with increased survival in COVID-19 patients. PLoS computational biology Sperry, M. M., Oskotsky, T. T., Marić, I., Kaushal, S., Takeda, T., Horvath, V., Powers, R. K., Rodas, M., Furlong, B., Soong, M., Prabhala, P., Goyal, G., Carlson, K. E., Wong, R. J., Kosti, I., Le, B. L., Logue, J., Hammond, H., Frieman, M., Stevenson, D. K., Ingber, D. E., Sirota, M., Novak, R. 2023; 19 (5): e1011050

  Abstract

  Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.

  View details for DOI 10.1371/journal.pcbi.1011050

  View details for PubMedID 37146076

• STABL Enables Reliable and Selective biomarker Discovery in Predictive Modeling of High Dimensional Omics Data Verdonk, F., Hedou, J., Maric, I., Bellan, G., Einhaus, J., Gaudilliere, D., Ladant, F., Stelzer, I., Feyaerts, D., Tsai, A., Bonham, A., Angst, M., Aghaeepour, N., Stevenson, D., Tibshirani, R., Gaudilliere, B. LIPPINCOTT WILLIAMS & WILKINS. 2023: 814-821

  View details for Web of Science ID 001058985600289

• Vaginal Progesterone is Associated with Intrahepatic Cholestasis of Pregnancy. American journal of perinatology Tsur, A., Leonard, S. A., Kan, P., Datoc, I., Girsen, A., Shaw, G. M., Stevenson, D. K., El-Sayed, Y. Y., Druzin, M. L., Blumenfeld, Y. J. 2023

  Abstract

  Background The frequency of intrahepatic cholestasis of pregnancy peaks during the third trimester of pregnancy when plasma progesterone levels are highest. Furthermore, twin pregnancies are characterized by higher progesterone levels than singletons, and have a higher frequency of cholestasis. Therefore, we hypothesized that exogenous progestogens administered for reducing the risk of spontaneous preterm birth may increase the risk of cholestasis. Objectives Utilizing the large IBM MarketScan Commercial Claims and Encounters Database, we investigated the frequency of cholestasis in patients treated with vaginal progesterone or intramuscular 17alpha-hydroxyprogesterone caproate for the prevention of preterm birth. Study design We identified 1,776,092 live-born singleton pregnancies between 2010-2014. We confirmed 2nd and 3rd trimester administration of progestogens by cross-referencing the dates of progesterone prescriptions with the dates of scheduled pregnancy events such as nuchal translucency scan, fetal anatomy scan, glucose challenge test, and Tdap vaccination. We excluded pregnancies with missing data regarding timing of scheduled pregnancy events, or progesterone treatment prescribed only during the 1st trimester. Cholestasis of pregnancy was identified based on prescriptions for ursodeoxycholic acid. We used multivariable logistic regression to estimate adjusted (for maternal age) odds ratios for cholestasis in patients treated with vaginal progesterone, and in patients treated with 17alpha-hydroxyprogesterone caproate compared to those not treated with any type of progestogen (the reference group). Results The final cohort consisted of 870,599 pregnancies. Among patients treated with vaginal progesterone during the 2nd and 3rd trimester, the frequency of cholestasis was significantly higher than the reference group (0.75% vs 0.23%, aOR 3.16, 95% CI 2.23-4.49). In contrast, there was no significant association between 17alpha-hydroxyprogesterone caproate and cholestasis (0.27%, aOR 1.12, 95% CI 0.58-2.16) Conclusions Using a robust dataset, we observed that vaginal progesterone but not intramuscular 17alpha-hydroxyprogesterone caproate was associated with an increased risk for intrahepatic cholestasis of pregnancy.

  View details for DOI 10.1055/a-2081-2573

  View details for PubMedID 37100422

• Large-scale correlation network construction for unraveling the coordination of complex biological systems NATURE COMPUTATIONAL SCIENCE Becker, M., Nassar, H., Espinosa, C., Stelzer, I. A., Feyaerts, D., Berson, E., Bidoki, N. H., Chang, A. L., Saarunya, G., Culos, A., De Francesco, D., Fallahzadeh, R., Liu, Q., Kim, Y., Maric, I., Mataraso, S. J., Payrovnaziri, S., Phongpreecha, T., Ravindra, N. G., Stanley, N., Shome, S., Tan, Y., Thuraiappah, M., Xenochristou, M., Xue, L., Shaw, G., Stevenson, D., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2023

  View details for DOI 10.1038/s43588-023-00429-y

  View details for Web of Science ID 000968297800002

• Microbiome Preterm Birth DREAM Challenge: Crowdsourcing Machine Learning Approaches to Advance Preterm Birth Research. medRxiv : the preprint server for health sciences Golob, J. L., Oskotsky, T. T., Tang, A. S., Roldan, A., Chung, V., Ha, C. W., Wong, R. J., Flynn, K. J., Parraga-Leo, A., Wibrand, C., Minot, S. S., Andreoletti, G., Kosti, I., Bletz, J., Nelson, A., Gao, J., Wei, Z., Chen, G., Tang, Z. Z., Novielli, P., Romano, D., Pantaleo, E., Amoroso, N., Monaco, A., Vacca, M., De Angelis, M., Bellotti, R., Tangaro, S., Kuntzleman, A., Bigcraft, I., Techtmann, S., Bae, D., Kim, E., Jeon, J., Joe, S., Theis, K. R., Ng, S., Lee Li, Y. S., Diaz-Gimeno, P., Bennett, P. R., MacIntyre, D. A., Stolovitzky, G., Lynch, S. V., Albrecht, J., Gomez-Lopez, N., Romero, R., Stevenson, D. K., Aghaeepour, N., Tarca, A. L., Costello, J. C., Sirota, M. 2023

  Abstract

  Globally, every year about 11% of infants are born preterm, defined as a birth prior to 37 weeks of gestation, with significant and lingering health consequences. Multiple studies have related the vaginal microbiome to preterm birth. We present a crowdsourcing approach to predict: (a) preterm or (b) early preterm birth from 9 publicly available vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from raw sequences via an open-source tool, MaLiAmPi. We validated the crowdsourced models on novel datasets representing 331 samples from 148 pregnant individuals. From 318 DREAM challenge participants we received 148 and 121 submissions for our two separate prediction sub-challenges with top-ranking submissions achieving bootstrapped AUROC scores of 0.69 and 0.87, respectively. Alpha diversity, VALENCIA community state types, and composition (via phylotype relative abundance) were important features in the top performing models, most of which were tree based methods. This work serves as the foundation for subsequent efforts to translate predictive tests into clinical practice, and to better understand and prevent preterm birth.

  View details for DOI 10.1101/2023.03.07.23286920

  View details for PubMedID 36945505

  View details for PubMedCentralID PMC10029035

• VMAP: Vaginal Microbiome Atlas During Pregnancy. medRxiv : the preprint server for health sciences Parraga-Leo, A., Oskotsky, T. T., Oskotsky, B., Wibrand, C., Roldan, A., Tang, A., Ha, C. W., Wong, R. J., Minot, S. S., Andreoletti, G., Kosti, I., Theis, K. R., Ng, S., Lee, Y. S., Diaz-Gimeno, P., Bennett, P. R., MacIntyre, D. A., Lynch, S. V., Romero, R., Tarca, A. L., Stevenson, D. K., Aghaeepour, N., Golob, J., Sirota, M. 2023

  Abstract

  The vaginal microbiome has been shown to be associated with pregnancy outcomes including preterm birth (PTB) risk. Here we present VMAP: Vaginal Microbiome Atlas during Pregnancy (http://vmapapp.org), an application to visualize features of 3,909 vaginal microbiome samples of 1,416 pregnant individuals from 11 studies, aggregated from raw public and newly generated sequences via an open-source tool, MaLiAmPi. Our visualization tool (http://vmapapp.org) includes microbial features such as various measures of diversity, VALENCIA community state types (CST), and composition (via phylotypes and taxonomy). This work serves as a resource for the research community to further analyze and visualize vaginal microbiome data in order to better understand both healthy term pregnancies and those associated with adverse outcomes.

  View details for DOI 10.1101/2023.03.21.23286947

  View details for PubMedID 36993193

  View details for PubMedCentralID PMC10055588

• Large-scale correlation network construction for unraveling the coordination of complex biological systems. Nature computational science Becker, M., Nassar, H., Espinosa, C., Stelzer, I. A., Feyaerts, D., Berson, E., Bidoki, N. H., Chang, A. L., Saarunya, G., Culos, A., De Francesco, D., Fallahzadeh, R., Liu, Q., Kim, Y., Marić, I., Mataraso, S. J., Payrovnaziri, S. N., Phongpreecha, T., Ravindra, N. G., Stanley, N., Shome, S., Tan, Y., Thuraiappah, M., Xenochristou, M., Xue, L., Shaw, G., Stevenson, D., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2023; 3 (4): 346-359

  Abstract

  Advanced measurement and data storage technologies have enabled high-dimensional profiling of complex biological systems. For this, modern multiomics studies regularly produce datasets with hundreds of thousands of measurements per sample, enabling a new era of precision medicine. Correlation analysis is an important first step to gain deeper insights into the coordination and underlying processes of such complex systems. However, the construction of large correlation networks in modern high-dimensional datasets remains a major computational challenge owing to rapidly growing runtime and memory requirements. Here we address this challenge by introducing CorALS (Correlation Analysis of Large-scale (biological) Systems), an open-source framework for the construction and analysis of large-scale parametric as well as non-parametric correlation networks for high-dimensional biological data. It features off-the-shelf algorithms suitable for both personal and high-performance computers, enabling workflows and downstream analysis approaches. We illustrate the broad scope and potential of CorALS by exploring perspectives on complex biological processes in large-scale multiomics and single-cell studies.

  View details for DOI 10.1038/s43588-023-00429-y

  View details for PubMedID 38116462

  View details for PubMedCentralID PMC10727505

• Leveraging electronic health records to identify risk factors for recurrent pregnancy loss across two medical centers: a case-control study. Research square Roger, J., Xie, F., Costello, J., Tang, A., Liu, J., Oskotsky, T., Woldemariam, S., Kosti, I., Le, B., Snyder, M. P., Giudice, L. C., Torgerson, D., Shaw, G. M., Stevenson, D. K., Rajkovic, A., Glymour, M. M., Aghaeepour, N., Cakmak, H., Lathi, R. B., Sirota, M. 2023

  Abstract

  Recurrent pregnancy loss (RPL), defined as 2 or more pregnancy losses, affects 5-6% of ever-pregnant individuals. Approximately half of these cases have no identifiable explanation. To generate hypotheses about RPL etiologies, we implemented a case-control study comparing the history of over 1,600 diagnoses between RPL and live-birth patients, leveraging the University of California San Francisco (UCSF) and Stanford University electronic health record databases. In total, our study included 8,496 RPL (UCSF: 3,840, Stanford: 4,656) and 53,278 Control (UCSF: 17,259, Stanford: 36,019) patients. Menstrual abnormalities and infertility-associated diagnoses were significantly positively associated with RPL in both medical centers. Age-stratified analysis revealed that the majority of RPL-associated diagnoses had higher odds ratios for patients <35 compared with 35+ patients. While Stanford results were sensitive to control for healthcare utilization, UCSF results were stable across analyses with and without utilization. Intersecting significant results between medical centers was an effective filter to identify associations that are robust across center-specific utilization patterns.

  View details for DOI 10.21203/rs.3.rs-2631220/v1

  View details for PubMedID 36993325

  View details for PubMedCentralID PMC10055527

• Advances and potential of omics studies for understanding the development of food allergy. Frontiers in allergy Sindher, S. B., Chin, A. R., Aghaeepour, N., Prince, L., Maecker, H., Shaw, G. M., Stevenson, D. K., Nadeau, K. C., Snyder, M., Khatri, P., Boyd, S. D., Winn, V. D., Angst, M. S., Chinthrajah, R. S. 2023; 4: 1149008

  Abstract

  The prevalence of food allergy continues to rise globally, carrying with it substantial safety, economic, and emotional burdens. Although preventative strategies do exist, the heterogeneity of allergy trajectories and clinical phenotypes has made it difficult to identify patients who would benefit from these strategies. Therefore, further studies investigating the molecular mechanisms that differentiate these trajectories are needed. Large-scale omics studies have identified key insights into the molecular mechanisms for many different diseases, however the application of these technologies to uncover the drivers of food allergy development is in its infancy. Here we review the use of omics approaches in food allergy and highlight key gaps in knowledge for applying these technologies for the characterization of food allergy development.

  View details for DOI 10.3389/falgy.2023.1149008

  View details for PubMedID 37034151

  View details for PubMedCentralID PMC10080041

• Breath: The Exhaust of Metabolism. The Journal of pediatrics Stevenson, D. K., Marić, I., Wong, R. J. 2023

  View details for DOI 10.1016/j.jpeds.2023.03.002

  View details for PubMedID 36925060

• Associations between pregnancy glucose measurements and risk of preterm birth: a retrospective cohort study of commercially insured women in the United States from 2003-2021. Annals of epidemiology Liang, R., Panelli, D. M., Stevenson, D. K., Rehkopf, D. H., Shaw, G. M. 2023

  Abstract

  To investigate associations between glucose measurements during pregnancy and risk of preterm birth (PTB).Retrospective cohort study of commercially insured women with singleton live births in the United States from 2003-2021 using longitudinal medical claims, socioeconomic data, and eight glucose results from different types of fasting and post-load tests performed between 24-28 weeks of gestation for gestational diabetes screening. Risk ratios of PTB (<37 weeks) were estimated via Poisson regression for z-standardized glucose measures. Non-linear relationships for continuous glucose measures were examined via generalized additive models.Elevations in all eight glucose measures were associated with increased risk (adjusted risk ratio point estimates: 1.05-1.19) of PTB for 196,377 women with non-fasting 50-gram glucose challenge test (one glucose result), 31,522 women with complete 100-gram, 3-hour fasting oral glucose tolerance test (OGTT) results (four glucose results), and 10,978 women with complete 75-gram, 2-hour fasting OGTT results (three glucose results). Associations were consistent after adjusting for and stratifying by sociodemographic and clinical factors. Substantial non-linear relationships (U-, J-, and S-shaped) were observed between several glucose measurements and PTB.Elevations in various glucose measures were linearly and non-linearly associated with increased risk of PTB, even before diagnostic thresholds for gestational diabetes.

  View details for DOI 10.1016/j.annepidem.2023.03.002

  View details for PubMedID 36905977

• Heme, Heme Oxygenase-1, Statins, and SARS-CoV-2. Antioxidants (Basel, Switzerland) Stevenson, D. K., Vreman, H. J., Wong, R. J. 2023; 12 (3)

  Abstract

  Heme, a metalloporphyrin, or more specifically, a tetrapyrrole containing ferrous iron, is an ancient molecule [...].

  View details for DOI 10.3390/antiox12030614

  View details for PubMedID 36978862

• Stabl: sparse and reliable biomarker discovery in predictive modeling of high-dimensional omic data. Research square Hédou, J., Marić, I., Bellan, G., Einhaus, J., Gaudillière, D. K., Ladant, F. X., Verdonk, F., Stelzer, I. A., Feyaerts, D., Tsai, A. S., Ganio, E. A., Sabayev, M., Gillard, J., Bonham, T. A., Sato, M., Diop, M., Angst, M. S., Stevenson, D., Aghaeepour, N., Montanari, A., Gaudillière, B. 2023

  Abstract

  High-content omic technologies coupled with sparsity-promoting regularization methods (SRM) have transformed the biomarker discovery process. However, the translation of computational results into a clinical use-case scenario remains challenging. A rate-limiting step is the rigorous selection of reliable biomarker candidates among a host of biological features included in multivariate models. We propose Stabl, a machine learning framework that unifies the biomarker discovery process with multivariate predictive modeling of clinical outcomes by selecting a sparse and reliable set of biomarkers. Evaluation of Stabl on synthetic datasets and four independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used SRMs at similar predictive performance. Stabl readily extends to double- and triple-omics integration tasks and identifies a sparser and more reliable set of biomarkers than those selected by state-of-the-art early- and late-fusion SRMs, thereby facilitating the biological interpretation and clinical translation of complex multi-omic predictive models. The complete package for Stabl is available online at https://github.com/gregbellan/Stabl.

  View details for DOI 10.21203/rs.3.rs-2609859/v1

  View details for PubMedID 36909508

  View details for PubMedCentralID PMC10002850

• Molecular Mechanisms of Pregnancy-Related Vascular Remodeling and Pregnancy Complications. International journal of molecular sciences Stevenson, D. K., Wong, R. J., Nayak, N. R. 2023; 24 (4)

  Abstract

  The purpose of this editorial is to highlight the various observations made in this Special Issue in the International Journal of Molecular Sciences [...].

  View details for DOI 10.3390/ijms24043712

  View details for PubMedID 36835124

• Shorter maternal leukocyte telomere length following cesarean birth: Implications for future research Panelli, D. M., Mayo, J. A., Wong, R. J., Becker, M., Maric, I., Wu, E., Gotlib, I. H., Aghaeepour, N., Druzin, M. L., Stevenson, D. K., Shaw, G. M., Bianco, K. MOSBY-ELSEVIER. 2023: S456-S457

  View details for Web of Science ID 000909337401260

• Prefrontal activation in preschool children is associated with maternal adversity and child temperament: A preliminary fNIRS study of inhibitory control DEVELOPMENTAL PSYCHOBIOLOGY Miller, J. G., Hyat, M., Perlman, S. B., Wong, R. J., Shaw, G. M., Stevenson, D. K., Gotlib, I. H. 2023; 65 (1): e22351

  Abstract

  Exposure to adversity is a well-documented risk factor for cognitive, behavioral, and mental health problems. In fact, the consequences of adversity may be intergenerational. A growing body of research suggests that maternal exposures to adversity, including those prior to childbirth, are associated with offspring biobehavioral development. In a sample of 36 mothers and their preschool-age children (mean child age = 4.21 ± 0.92 years), we used functional near-infrared spectroscopy to replicate and extend this work to include brain activation during inhibitory control in young children. We found that measures of maternal exposure to adversity, including cumulative, childhood, and preconception exposures, were significantly and positively associated with activation in the right frontopolar prefrontal cortex (PFC) and in the left temporal and parietal clusters during inhibitory control. In addition, and consistent with previous findings, children's increased negative affect and decreased effortful control were associated with increased right PFC activation during inhibitory control. These findings provide preliminary evidence that maternal and dispositional risk factors are linked to alterations in PFC functioning during the preschool years. Children of mothers with a history of exposure to adversity, as well as children who are less temperamentally regulated, may require increased neural resources to meet the cognitive demands of inhibitory control.

  View details for DOI 10.1002/dev.22351

  View details for Web of Science ID 000895767900001

  View details for PubMedID 36567657

• ALTERATIONS IN PLACENTAL GENE EXPRESSION AND GLYCOGEN-POSITIVE CELLS IN OBESE PREGNANT MICE Zhao, H., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS LTD. 2023: NP66

  View details for Web of Science ID 000972423800064

• A novel in vitro stem cell model to study maternal endothelial function in preeclampsia Wu, Y., Sun, T., Medina, P., Iyer, P., Stevenson, D. K., Wu, J., Sayed, N., Winn, V. D. MOSBY-ELSEVIER. 2023: S10

  View details for Web of Science ID 000909337400012

• Early prediction and longitudinal modeling of preeclampsia from multiomics. Patterns (New York, N.Y.) Maric, I., Contrepois, K., Moufarrej, M. N., Stelzer, I. A., Feyaerts, D., Han, X., Tang, A., Stanley, N., Wong, R. J., Traber, G. M., Ellenberger, M., Chang, A. L., Fallahzadeh, R., Nassar, H., Becker, M., Xenochristou, M., Espinosa, C., De Francesco, D., Ghaemi, M. S., Costello, E. K., Culos, A., Ling, X. B., Sylvester, K. G., Darmstadt, G. L., Winn, V. D., Shaw, G. M., Relman, D. A., Quake, S. R., Angst, M. S., Snyder, M. P., Stevenson, D. K., Gaudilliere, B., Aghaeepour, N. 2022; 3 (12): 100655

  Abstract

  Preeclampsia is a complex disease of pregnancy whose physiopathology remains unclear. We developed machine-learning models for early prediction of preeclampsia (first 16weeks of pregnancy) and over gestation by analyzing six omics datasets from a longitudinal cohort of pregnant women. For early pregnancy, a prediction model using nine urine metabolites had the highest accuracy and was validated on an independent cohort (area under the receiver-operating characteristic curve [AUC]= 0.88, 95% confidence interval [CI] [0.76, 0.99] cross-validated; AUC= 0.83, 95% CI [0.62,1] validated). Univariate analysis demonstrated statistical significance of identified metabolites. An integrated multiomics model further improved accuracy (AUC= 0.94). Several biological pathways were identified including tryptophan, caffeine, and arachidonic acid metabolisms. Integration with immune cytometry data suggested novel associations between immune and proteomic dynamics. While further validation in a larger population is necessary, these encouraging results can serve as a basis for a simple, early diagnostic test for preeclampsia.

  View details for DOI 10.1016/j.patter.2022.100655

  View details for PubMedID 36569558

• Real world external validation of metabolic gestational age assessment in Kenya. PLOS global public health Hawken, S., Ward, V., Bota, A. B., Lamoureux, M., Ducharme, R., Wilson, L. A., Otieno, N., Munga, S., Nyawanda, B. O., Atito, R., Stevenson, D. K., Chakraborty, P., Darmstadt, G. L., Wilson, K. 2022; 2 (11): e0000652

  Abstract

  Using data from Ontario Canada, we previously developed machine learning-based algorithms incorporating newborn screening metabolites to estimate gestational age (GA). The objective of this study was to evaluate the use of these algorithms in a population of infants born in Siaya county, Kenya. Cord and heel prick samples were collected from newborns in Kenya and metabolic analysis was carried out by Newborn Screening Ontario in Ottawa, Canada. Postnatal GA estimation models were developed with data from Ontario with multivariable linear regression using ELASTIC NET regularization. Model performance was evaluated by applying the models to the data collected from Kenya and comparing model-derived estimates of GA to reference estimates from early pregnancy ultrasound. Heel prick samples were collected from 1,039 newborns from Kenya. Of these, 8.9% were born preterm and 8.5% were small for GA. Cord blood samples were also collected from 1,012 newborns. In data from heel prick samples, our best-performing model estimated GA within 9.5 days overall of reference GA [mean absolute error (MAE) 1.35 (95% CI 1.27, 1.43)]. In preterm infants and those small for GA, MAE was 2.62 (2.28, 2.99) and 1.81 (1.57, 2.07) weeks, respectively. In data from cord blood, model accuracy slightly decreased overall (MAE 1.44 (95% CI 1.36, 1.53)). Accuracy was not impacted by maternal HIV status and improved when the dating ultrasound occurred between 9 and 13 weeks of gestation, in both heel prick and cord blood data (overall MAE 1.04 (95% CI 0.87, 1.22) and 1.08 (95% CI 0.90, 1.27), respectively). The accuracy of metabolic model based GA estimates in the Kenya cohort was lower compared to our previously published validation studies, however inconsistency in the timing of reference dating ultrasounds appears to have been a contributing factor to diminished model performance.

  View details for DOI 10.1371/journal.pgph.0000652

  View details for PubMedID 36962760

  View details for PubMedCentralID PMC10021775

• Author Correction: Prediction of gestational age using urinary metabolites in term and preterm pregnancies. Scientific reports Contrepois, K., Chen, S., Ghaemi, M. S., Wong, R. J., Jehan, F., Sazawal, S., Baqui, A. H., Stringer, J. S., Rahman, A., Nisar, M. I., Dhingra, U., Khanam, R., Ilyas, M., Dutta, A., Mehmood, U., Deb, S., Hotwani, A., Ali, S. M., Rahman, S., Nizar, A., Ame, S. M., Muhammad, S., Chauhan, A., Khan, W., Raqib, R., Das, S., Ahmed, S., Hasan, T., Khalid, J., Juma, M. H., Chowdhury, N. H., Kabir, F., Aftab, F., Quaiyum, A., Manu, A., Yoshida, S., Bahl, R., Pervin, J., Price, J. T., Rahman, M., Kasaro, M. P., Litch, J. A., Musonda, P., Vwalika, B., Shaw, G., Stevenson, D. K., Aghaeepour, N., Snyder, M. P. 2022; 12 (1): 19753

  View details for DOI 10.1038/s41598-022-23715-7

  View details for PubMedID 36396676

• LEVERAGING ELECTRONIC HEALTH RECORD DATA TO IDENTIFY PHENOTYPES ASSOCIATED WITH PREGNANCY LOSS MAY LEAD TO IMPROVED UNDERSTANDING OF RECURRENT PREGNANCY LOSS Roger, J., Tang, A., Woldemariam, S., Oskotsky, T., Wen, T., Liu, J., Kosti, I., Le, B., Cakmak, H., Snyder, M., Aghaeepour, N., Shaw, G., Stevenson, D., Giudice, L. C., Glymour, M., Rajkovic, A., Lathi, R., Sirota, M. ELSEVIER SCIENCE INC. 2022: E107

  View details for Web of Science ID 000891804600262

• Bilirubin-induced neurotoxicity and visuocortical dysfunction. Journal of perinatology : official journal of the California Perinatal Association Good, W. V., Wong, R. J., Norcia, A. M., Stevenson, D. K., Slagel, T., Hou, C., Bhutani, V. K. 2022

  View details for DOI 10.1038/s41372-022-01417-2

  View details for PubMedID 35618749

• Prediction of gestational age using urinary metabolites in term and preterm pregnancies. Scientific reports Contrepois, K., Chen, S., Ghaemi, M. S., Wong, R. J., Alliance for Maternal and Newborn Health Improvement (AMANHI), Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), Shaw, G., Stevenson, D. K., Aghaeepour, N., Snyder, M. P., Jehan, F., Sazawal, S., Baqui, A. H., Nisar, M. I., Dhingra, U., Khanam, R., Ilyas, M., Dutta, A., Mehmood, U., Deb, S., Hotwani, A., Ali, S. M., Rahman, S., Nizar, A., Ame, S. M., Muhammad, S., Chauhan, A., Khan, W., Raqib, R., Das, S., Ahmed, S., Hasan, T., Khalid, J., Juma, M. H., Chowdhury, N. H., Kabir, F., Aftab, F., Quaiyum, M. A., Manu, A., Yoshida, S., Bahl, R., Rahman, A., Pervin, J., Price, J. T., Rahman, M., Kasaro, M. P., Litch, J. A., Musonda, P., Vwalika, B., Stringer, J. S. 2022; 12 (1): 8033

  Abstract

  Assessment of gestational age (GA) is key to provide optimal care during pregnancy. However, its accurate determination remains challenging in low- and middle-income countries, where access to obstetric ultrasound is limited. Hence, there is an urgent need to develop clinical approaches that allow accurate and inexpensive estimations of GA. We investigated the ability of urinary metabolites to predict GA at time of collection in a diverse multi-site cohort of healthy and pathological pregnancies (n=99) using a broad-spectrum liquid chromatography coupled with mass spectrometry (LC-MS) platform. Our approach detected a myriad of steroid hormones and their derivatives including estrogens, progesterones, corticosteroids, and androgens which were associated with pregnancy progression. We developed a restricted model that predicted GA with high accuracy using three metabolites (rho=0.87, RMSE=1.58weeks) that was validated in an independent cohort (n=20). The predictions were more robust in pregnancies that went to term in comparison to pregnancies that ended prematurely. Overall, we demonstrated the feasibility of implementing urine metabolomics analysis in large-scale multi-site studies and report a predictive model of GA with a potential clinical value.

  View details for DOI 10.1038/s41598-022-11866-6

  View details for PubMedID 35577875

• Leukocyte telomere dynamics across gestation in uncomplicated pregnancies and associations with stress. BMC pregnancy and childbirth Panelli, D. M., Leonard, S. A., Wong, R. J., Becker, M., Mayo, J. A., Wu, E., Girsen, A. I., Gotlib, I. H., Aghaeepour, N., Druzin, M. L., Shaw, G. M., Stevenson, D. K., Bianco, K. 2022; 22 (1): 381

  Abstract

  Short leukocyte telomere length is a biomarker associated with stress and morbidity in non-pregnant adults. Little is known, however, about maternal telomere dynamics in pregnancy. To address this, we examined changes in maternal leukocyte telomere length (LTL) during uncomplicated pregnancies and explored correlations with perceived stress.In this pilot study, maternal LTL was measured in blood collected from nulliparas who delivered live, term, singleton infants between 2012 and 2018 at a single institution. Participants were excluded if they had diabetes or hypertensive disease. Samples were collected over the course of pregnancy and divided into three time periods: < 200/7 weeks (Timepoint 1); 201/7 to 366/7 weeks (Timepoint 2); and 370/7 to 9-weeks postpartum (Timepoint 3). All participants also completed a survey assessing a multivariate profile of perceived stress at the time of enrollment in the first trimester. LTL was measured using quantitative polymerase chain reaction (PCR). Wilcoxon signed-rank tests were used to compare LTL differences within participants across all timepoint intervals. To determine whether mode of delivery affected LTL, we compared postpartum Timepoint 3 LTLs between participants who had vaginal versus cesarean birth. Secondarily, we evaluated the association of the assessed multivariate stress profile and LTL using machine learning analysis.A total of 115 samples from 46 patients were analyzed. LTL (mean ± SD), expressed as telomere to single copy gene (T/S) ratios, were: 1.15 ± 0.26, 1.13 ± 0.23, and 1.07 ± 0.21 for Timepoints 1, 2, and 3, respectively. There were no significant differences in LTL between Timepoints 1 and 2 (LTL T/S change - 0.03 ± 0.26, p = 0.39); 2 and 3 (- 0.07 ± 0.29, p = 0.38) or Timepoints 1 and 3 (- 0.07 ± 0.21, p = 0.06). Participants who underwent cesareans had significantly shorter postpartum LTLs than those who delivered vaginally (T/S ratio: 0.94 ± 0.12 cesarean versus 1.12 ± 0.21 vaginal, p = 0.01). In secondary analysis, poor sleep quality was the main stress construct associated with shorter Timepoint 1 LTLs (p = 0.02) and shorter mean LTLs (p = 0.03).In this cohort of healthy pregnancies, maternal LTLs did not significantly change across gestation and postpartum LTLs were shorter after cesarean than after vaginal birth. Significant associations between sleep quality and short LTLs warrant further investigation.

  View details for DOI 10.1186/s12884-022-04693-0

  View details for PubMedID 35501726

• Validation of the Assessment of Parent and Child Adversity (APCA) in Mothers and Young Children. Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53 King, L. S., Humphreys, K. L., Shaw, G. M., Stevenson, D. K., Gotlib, I. H. 2022: 1-16

  Abstract

  Advancing understanding of how early adversity arises, manifests, and contributes to health difficulties depends on accurate measurement of children's experiences. In early life, exposure to adversity is often intertwined with that of one's caregivers. We present preliminary psychometric properties of a novel measure of adversity, the Assessment of Parent and Child Adversity (APCA), which simultaneously characterizes parents' and children's adversity.During pregnancy, women reported their past adverse experiences. When their children were ages 3-5 years (47% female), 97 mothers (71% White, 17% Hispanic/Latinx) completed the APCA, the Childhood Trauma Questionnaire, and the Benevolent Childhood Experiences scale. They reported their current symptoms of depression and anxiety and their child's emotional and behavioral problems. Using the APCA, we distinguished between maternal adversity during different life periods and obtained metrics of child witnessing of and direct exposure to adversity.The APCA demonstrated validity with other measures of maternal adverse experiences, maternal positive childhood experiences, and maternal symptoms of psychopathology. Children whose mothers experienced greater adversity, particularly in the prenatal period, had more emotional and behavioral problems, as did children who were directly exposed to greater adversity.The APCA has good usability and validity. Leveraging the ability of the APCA to distinguish between adversity during different life stages and originating from different sources, our findings highlight potentially distinct effects of different aspects of maternal and child adversity on difficulties in maternal and child mental health.

  View details for DOI 10.1080/15374416.2022.2042696

  View details for PubMedID 35500216

• Gestational Dating by Urine Metabolic Profile at High Resolution Weekly Sampling Timepoints: Discovery and Validation. Frontiers in molecular medicine Sylvester, K. G., Hao, S., Li, Z., Han, Z., Tian, L., Ladella, S., Wong, R. J., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Whitin, J. C., McElhinney, D. B., Ling, X. B. 2022; 2: 844280

  Abstract

  Background: Pregnancy triggers longitudinal metabolic alterations in women to allow precisely-programmed fetal growth. Comprehensive characterization of such a "metabolic clock" of pregnancy may provide a molecular reference in relation to studies of adverse pregnancy outcomes. However, a high-resolution temporal profile of metabolites along a healthy pregnancy remains to be defined. Methods: Two independent, normal pregnancy cohorts with high-density weekly urine sampling (discovery: 478 samples from 19 subjects at California; validation: 171 samples from 10 subjects at Alabama) were studied. Urine samples were profiled by liquid chromatography-mass spectrometry (LC-MS) for untargeted metabolomics, which was applied for gestational age dating and prediction of time to delivery. Results: 5,473 urinary metabolic features were identified. Partial least-squares discriminant analysis on features with robust signals (n = 1,716) revealed that the samples were distributed on the basis of the first two principal components according to their gestational age. Pathways of bile secretion, steroid hormone biosynthesis, pantohenate, and CoA biosynthesis, benzoate degradation, and phenylpropanoid biosynthesis were significantly regulated, which was collectively applied to discover and validate a predictive model that accurately captures the chronology of pregnancy. With six urine metabolites (acetylcholine, estriol-3-glucuronide, dehydroepiandrosterone sulfate, α-lactose, hydroxyexanoy-carnitine, and l-carnitine), models were constructed based on gradient-boosting decision trees to date gestational age in high accordance with ultrasound results, and to accurately predict time to delivery. Conclusion: Our study characterizes the weekly baseline profile of the human pregnancy metabolome, which provides a high-resolution molecular reference for future studies of adverse pregnancy outcomes.

  View details for DOI 10.3389/fmmed.2022.844280

  View details for PubMedID 39086969

  View details for PubMedCentralID PMC11285704

• Frequency of cerclage in consecutive pregnancies of women with history of preterm birth. Journal of neonatal-perinatal medicine Khorshid, A., Mayo, J., Chueh, J., Shaw, G. M., Stevenson, D., Ness, A. 2022

  Abstract

  BACKGROUND: Serial cervical length screening is performed in women with a history of preterm birth to determine indication for cerclage placement. Our aim is to evaluate the frequency of cerclage placement in consecutive pregnancies with preterm birth history to determine whether performing serial cervical length screening for women with a history of late (34-36 6/7 weeks) spontaneous preterm birth (SPTB) should be reconsidered.METHODS: Retrospective evaluation of cerclage frequency and gestational age of delivery for consecutive singleton births for 69,671 women whose first birth was a SPTB.RESULTS: History of late SPTB was associated with a lower frequency of cerclage than history of early SPTB (0.83% vs 4.88%, OR 0.16, 95% CI 0.14-0.18). Rates of recurrent SPTB were lower for women with history of late SPTB than those with history of early SPTB (13.45%, 3.74% early, 9.71% late vs 20.69%, 9.12% early, 11.57% late).CONCLUSION: Women with a history of late PTB have a lower risk of recurrent PTB than those with a history of early PTB but constitute most of those undergoing serial cervical length screening for potential cerclage placement. Practice guidelines for screening women with a history of late PTB should be re-evaluated.

  View details for DOI 10.3233/NPM-210834

  View details for PubMedID 35404291

• Multiomics Modeling of Preterm Birth in Low- and Middle-Income Countries Espinosa Bernal, C. A., Shaw, G. M., Stevenson, D. K., Aghaeepour, N., MOMI Consortium SPRINGER HEIDELBERG. 2022: 49-50

  View details for Web of Science ID 000762765300020

• Alterations of Placental Gene Expression in Obese Pregnant Mice Zhao, H., Wong, R. J., Stevenson, D. K. SPRINGER HEIDELBERG. 2022: 217-218

  View details for Web of Science ID 000762765300444

• Early prediction of preeclampsia in pregnancy with cell-free RNA. Nature Moufarrej, M. N., Vorperian, S. K., Wong, R. J., Campos, A. A., Quaintance, C. C., Sit, R. V., Tan, M., Detweiler, A. M., Mekonen, H., Neff, N. F., Baruch-Gravett, C., Litch, J. A., Druzin, M. L., Winn, V. D., Shaw, G. M., Stevenson, D. K., Quake, S. R. 2022

  Abstract

  Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an opportunity to study the development of pregnancy-related complications in a non-invasive manner and to bridge gaps in clinical care1-4. Here we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia, a multi-organ syndrome that is the second largest cause of maternal death globally5. We find that changes in cfRNA gene expression between normotensive and preeclamptic mothers are marked and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial and immune cell types and tissues that reflect key aspects of preeclampsia physiology6-9, suggest new hypotheses for disease progression and correlate with maternal organ health. This enabled the identification and independent validation of a panel of 18 genes that when measured between 5 and 16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of preeclampsia long before clinical symptoms manifest themselves. Tests based on these observations could help predict and manage who is at risk for preeclampsia-an important objective for obstetric care10,11.

  View details for DOI 10.1038/s41586-022-04410-z

  View details for PubMedID 35140405

• MULTIOMICS LONGITUDINAL MODELING OF PREECLAMPTIC PREGNANCIES Espinosa, C., Maric, I., Contrepois, K., Moufarrej, M., Stelzer, I. S., Feyaerts, D., Han, X., Tang, A., Wong, R. J., Darmstadt, G. L., Winn, V. D., Shaw, G. M., Relman, D. A., Quake, S. R., Angst, M. S., Snyder, M., Stevenson, D. K., Gaudilliere, B., Aghaeepour, N. BMJ PUBLISHING GROUP. 2022: 309

  View details for DOI 10.1136/jim-2022-WRMC.400

  View details for Web of Science ID 000737295900421

• Revealing the impact of lifestyle stressors on the risk of adverse pregnancy outcomes with multitask machine learning. Frontiers in pediatrics Becker, M., Dai, J., Chang, A. L., Feyaerts, D., Stelzer, I. A., Zhang, M., Berson, E., Saarunya, G., De Francesco, D., Espinosa, C., Kim, Y., Maric, I., Mataraso, S., Payrovnaziri, S. N., Phongpreecha, T., Ravindra, N. G., Shome, S., Tan, Y., Thuraiappah, M., Xue, L., Mayo, J. A., Quaintance, C. C., Laborde, A., King, L. S., Dhabhar, F. S., Gotlib, I. H., Wong, R. J., Angst, M. S., Shaw, G. M., Stevenson, D. K., Gaudilliere, B., Aghaeepour, N. 2022; 10: 933266

  Abstract

  Psychosocial and stress-related factors (PSFs), defined as internal or external stimuli that induce biological changes, are potentially modifiable factors and accessible targets for interventions that are associated with adverse pregnancy outcomes (APOs). Although individual APOs have been shown to be connected to PSFs, they are biologically interconnected, relatively infrequent, and therefore challenging to model. In this context, multi-task machine learning (MML) is an ideal tool for exploring the interconnectedness of APOs on the one hand and building on joint combinatorial outcomes to increase predictive power on the other hand. Additionally, by integrating single cell immunological profiling of underlying biological processes, the effects of stress-based therapeutics may be measurable, facilitating the development of precision medicine approaches.Objectives: The primary objectives were to jointly model multiple APOs and their connection to stress early in pregnancy, and to explore the underlying biology to guide development of accessible and measurable interventions.Materials and Methods: In a prospective cohort study, PSFs were assessed during the first trimester with an extensive self-filled questionnaire for 200 women. We used MML to simultaneously model, and predict APOs (severe preeclampsia, superimposed preeclampsia, gestational diabetes and early gestational age) as well as several risk factors (BMI, diabetes, hypertension) for these patients based on PSFs. Strongly interrelated stressors were categorized to identify potential therapeutic targets. Furthermore, for a subset of 14 women, we modeled the connection of PSFs to the maternal immune system to APOs by building corresponding ML models based on an extensive single cell immune dataset generated by mass cytometry time of flight (CyTOF).Results: Jointly modeling APOs in a MML setting significantly increased modeling capabilities and yielded a highly predictive integrated model of APOs underscoring their interconnectedness. Most APOs were associated with mental health, life stress, and perceived health risks. Biologically, stressors were associated with specific immune characteristics revolving around CD4/CD8 T cells. Immune characteristics predicted based on stress were in turn found to be associated with APOs.Conclusions: Elucidating connections among stress, multiple APOs simultaneously, and immune characteristics has the potential to facilitate the implementation of ML-based, individualized, integrative models of pregnancy in clinical decision making. The modifiable nature of stressors may enable the development of accessible interventions, with success tracked through immune characteristics.

  View details for DOI 10.3389/fped.2022.933266

  View details for PubMedID 36582513

• Maternal stress and its consequences - biological strain. American journal of perinatology Stevenson, D. K., Gotlib, I. H., Buthmann, J. L., Maric, I., Aghaeepour, N., Gaudilliere, B., Angst, M. S., Darmstadt, G. L., Druzin, M. L., Wong, R. J., Shaw, G. M., Katz, M. 2022

  Abstract

  Understanding the role of stress in pregnancy and its consequences is important, particularly given documented associations between maternal stress and preterm birth and other pathologic outcomes. Physical and psychological stressors can elicit the same biological responses, known as biological strain. Chronic stressors, like poverty and racism (race-based discriminatory treatment), may create a legacy or trajectory of biological strain that no amount of coping can relieve in the absence of larger-scale socio-behavioral or societal changes. An integrative approach that takes into consideration simultaneously social and biological determinants of stress may provide the best insights into risk for preterm birth. The most successful computational approaches and the most predictive machine-learning models are likely to be those that combine information about the stressors and the biological strain (for example, as measured by different omics) experienced during pregnancy.

  View details for DOI 10.1055/a-1798-1602

  View details for PubMedID 35292943

• Effects of emollient therapy with sunflower seed oil on neonatal growth and morbidity in Uttar Pradesh, India: a cluster-randomized, open-label, controlled trial. The American journal of clinical nutrition Kumar, V., Kumar, A., Mishra, S., Kan, P., Ashraf, S., Singh, S., Blanks, K. J., Baiocchi, M., Limcaoco, M., Ghosh, A. K., Kumar, A., Krishna, R., Stevenson, D. K., Tian, L., Darmstadt, G. L. 2022

  Abstract

  Newborn oil massage is a widespread practice. Vigorous massage with potentially harmful products and forced removal of vernix may disrupt skin barrier integrity. Hospitalized, very preterm infants treated with sunflower seed oil (SSO) have demonstrated improved growth but community-based data on growth and health outcomes are lacking.We aimed to test whether SSO therapy enhances neonatal growth and reduces morbidity at population-level.We conducted an open-label, controlled trial in rural Uttar Pradesh, India, randomly allocating 276 village clusters equally to comparison (usual care) and intervention comprised of promotion of improved massage practices exclusively with SSO, using intention-to-treat and per-protocol mixed-effects regression analysis.We enrolled 13,478 and 13,109 newborn infants in demographically similar intervention and comparison arms, respectively. Adherence to exclusive SSO increased from 22.6% of intervention infants enrolled in the first study quartile to 37.2% in the last quartile. Intervention infants gained significantly more weight by 0.94 grams/kilogram/day (g/kg/d) [95% confidence interval (CI): 0.07, 1.82, p = 0.03] than comparison infants by intention-to-treat analysis. Restricted cubic spline regression revealed the largest benefits in weight gain (2-4 g/kg/day) occurred in infants <2000 g. Weight gain in intervention infants was higher by 1.31 g/kg/d (95% CI: 0.17, 2.46, p = 0.02) by per-protocol analysis. Morbidities were similar by intention-to-treat analysis but in per-protocol analysis rates of hospitalization and of any illness were reduced by 36% [odds ratio (OR): 0.64; 95% CI: 0.44, 0.94, p = 0.02] and 44% (OR: 0.56; 95% CI: 0.40, 0.77, p<0.001), respectively, in treated infants.SSO therapy improved neonatal growth, and reduced morbidities when applied exclusively, across the facility-community continuum of care at population-level. Further research is needed to improve demand for recommended therapy inside hospital as well as in community settings, and to confirm these results in other settings. Clinical Trial Registry: The trial was registered at the ISRCTN (ISRCTN38965585) and CTRI (CTRI/2014/12/005282) registries with WHO UTN # U1111-1158-4665.

  View details for DOI 10.1093/ajcn/nqab430

  View details for PubMedID 34982820

• Cellular aging and pregnancy complications: Examining maternal leukocyte telomere length in two diverse cohorts. Panelli, D. M., Wang, X., Wong, R. J., Cruz, G., Hong, X., Aghaeepour, N., Druzin, M. L., Shaw, G. M., Zuckerman, B. S., Stevenson, D. K., Bianco, K. MOSBY-ELSEVIER. 2022: S646

  View details for Web of Science ID 000737459401371

• MULTIOMICS MODELING OF PRETERM BIRTH IN LOW- AND MIDDLE-INCOME COUNTRIES Bernal, C., Maric, I., Stevenson, D. K., Aghaeepour, N. BMJ PUBLISHING GROUP. 2022: 310-311

  View details for DOI 10.1136/jim-2022-WRMC.403

  View details for Web of Science ID 000737295900424

• Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation. BMJ open Huang, Q., Hao, S., You, J., Yao, X., Li, Z., Schilling, J., Thyparambil, S., Liao, W., Zhou, X., Mo, L., Ladella, S., Davies-Balch, S. R., Zhao, H., Fan, D., Whitin, J. C., Cohen, H. J., McElhinney, D. B., Wong, R. J., Shaw, G. M., Stevenson, D. K., Sylvester, K. G., Ling, X. B. 2021; 11 (11): e050963

  Abstract

  OBJECTIVE: This study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.STUDY DESIGN: Retrospective discovery and longitudinal confirmation.SETTING: Maternity units from two US hospitals.PARTICIPANTS: Six previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.OUTCOME MEASURES: Biomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.RESULTS: Our discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks' gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.CONCLUSIONS: Our study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

  View details for DOI 10.1136/bmjopen-2021-050963

  View details for PubMedID 34824115

• Black swans and ambitious overgeneralization in newborn intensive care. Pediatric research Stevenson, D. K., Wong, R. J., Shaw, G. M., Aghaeepour, N., Maric, I., Prince, L. S., Reiss, J. D., Katz, M. 2021

  View details for DOI 10.1038/s41390-021-01771-5

  View details for PubMedID 34601493

• Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial. Annals of surgery Blakely, M. L., Tyson, J. E., Lally, K. P., Hintz, S. R., Eggleston, B., Stevenson, D. K., Besner, G. E., Das, A., Ohls, R. K., Truog, W. E., Nelin, L. D., Poindexter, B. B., Pedroza, C., Walsh, M. C., Stoll, B. J., Geller, R., Kennedy, K. A., Dimmitt, R. A., Carlo, W. A., Cotten, C. M., Laptook, A. R., Van Meurs, K. P., Calkins, K. L., Sokol, G. M., Sanchez, P. J., Wyckoff, M. H., Patel, R. M., Frantz, I. D., Shankaran, S., D'Angio, C. T., Yoder, B. A., Bell, E. F., Watterberg, K. L., Martin, C. A., Harmon, C. M., Rice, H., Kurkchubasche, A. G., Sylvester, K., Dunn, J. C., Markel, T. A., Diesen, D. L., Bhatia, A. M., Flake, A., Chwals, W. J., Brown, R., Bass, K. D., St Peter, S. D., Shanti, C. M., Pegoli, W. J., Skarda, D., Shilyansky, J., Lemon, D. G., Mosquera, R. A., Peralta-Carcelen, M., Goldstein, R. F., Vohr, B. R., Purdy, I. B., Hines, A. C., Maitre, N. L., Heyne, R. J., DeMauro, S. B., McGowan, E. C., Yolton, K., Kilbride, H. W., Natarajan, G., Yost, K., Winter, S., Colaizy, T. T., Laughon, M. M., Lakshminrusimha, S., Higgins, R. D., Eunice Kennedy Shriver National Institute of Child Health, H. D. 2021; 274 (4): e370-e380

  Abstract

  OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP).SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown.METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches.RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%.CONCLUSIONS: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

  View details for DOI 10.1097/SLA.0000000000005099

  View details for PubMedID 34506326

• HO-1 Genetic Variants Display Racial Diversity and May Impact Hypertensive Disorders in Pregnancy. Sun, T., Mousavi, N., Wong, R. J., Sayed, N., Wu, J. C., Stevenson, D. K., Gymrek, M., Winn, V. D. SPRINGER HEIDELBERG. 2021: 105A

  View details for Web of Science ID 000675441000144

• Noninvasive Prediction of Preeclampsia in Pregnancy with Circulating RNA. Moufarrej, M. N., Wong, R. J., Campos, A. A., Quaintance, C. C., Sit, R. V., Tan, M., Neff, N. F., Druzin, M. L., Winn, V. D., Shaw, G. M., Stevenson, D. K., Quake, S. R. SPRINGER HEIDELBERG. 2021: 75A

  View details for Web of Science ID 000675441000068

• Multi-Omic, Longitudinal Profile of Third-Trimester Pregnancies Identifies a Molecular Switch That Predicts the Onset of Labor. Stelzer, I., Ghaemi, M., Han, X., Ando, K., Hedou, J., Feyaerts, D., Peterson, L., Ganio, E., Tsai, A., Tsai, E., Rumer, K., Stanley, N., Fallazadeh, R., Becker, M., Culos, A., Gaudilliere, D., Wong, R., Winn, V., Shaw, G., Snyder, M., Stevenson, D., Contrepois, K., Angst, M., Aghaeepour, N., Gaudilliere, B. SPRINGER HEIDELBERG. 2021: 233A-234A

  View details for Web of Science ID 000675441000486

• Trends in Spontaneous and Medically Indicated Preterm Birth in Twins versus Singletons: A California Cohort 2007 to 2011. American journal of perinatology Ness, A., Mayo, J. A., El-Sayed, Y. Y., Druzin, M. L., Stevenson, D. K., Shaw, G. M. 2021

  Abstract

  OBJECTIVE: The study aimed to describe preterm birth (PTB) rates, subtypes, and risk factors in twins compared with singletons to better understand reasons for the decline in PTB rate between 2007 and 2011.STUDY DESIGN: This was a retrospective population-based analysis using the California linked birth certificates and maternal-infant hospital discharge records from 2007 to 2011. The main outcomes were overall, spontaneous (following spontaneous labor or preterm premature rupture of membranes), and medically indicated PTB at various gestational age categories: <37, <32, and 34 to 36 weeks in twins and singletons.RESULTS: Among the 2,290,973 singletons and 28,937 twin live births pairs included, overall PTB <37 weeks decreased by 8.46% (6.77-6.20%) in singletons and 7.17% (55.31-51.35%) in twins during the study period. In singletons, this was primarily due to a 24.91% decrease in medically indicated PTB with almost no change in spontaneous PTB, whereas in twins indicated PTB declined 7.02% and spontaneous PTB by 7.39%.CONCLUSION: Recent declines in PTB in singletons appear to be largely due to declines in indicated PTB, whereas both spontaneous and indicated PTB declined in twins.KEY POINTS: · The declines in PTB noted between 2006 and 2014 occurred in both singleton and twins.. · Declines were mostly in medically indicated PTB.. · Interventions proposed as causing the declines in singletons would not apply to twins..

  View details for DOI 10.1055/s-0041-1729161

  View details for PubMedID 33934321

• Greenspace, Air Pollution, Neighborhood Factors, and Preeclampsia in a Population-Based Case-Control Study in California INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH Weber, K. A., Yang, W., Lyons, E., Stevenson, D. K., Padula, A. M., Shaw, G. M. 2021; 18 (10)

  Abstract

  To investigate preeclampsia etiologies, we examined relationships between greenspace, air pollution, and neighborhood factors. Data were from hospital records and geocoded residences of 77,406 women in San Joaquin Valley, California from 2000 to 2006. Preeclampsia was divided into mild, severe, or superimposed onto pre-existing hypertension. Greenspace within 100 and 500 m residential buffers was estimated from satellite data using normalized difference vegetation index (NDVI). Air quality data were averaged over pregnancy from daily 24-h averages of nitrogen dioxide, particulate matter <10 µm (PM10) and <2.5 µm (PM2.5), and carbon monoxide. Neighborhood socioeconomic (SES) factors included living below the federal poverty level and median annual income using 2000 US Census data. Odds of preeclampsia were estimated using logistic regression. Effect modification was assessed using Wald tests. More greenspace (500 m) was inversely associated with superimposed preeclampsia (OR = 0.57). High PM2.5 and low SES were associated with mild and severe preeclampsia. We observed differences in associations between greenspace (500 m) and superimposed preeclampsia by neighborhood income and between greenspace (500 m) and severe preeclampsia by PM10, overall and among those living in higher SES neighborhoods. Less greenspace, high particulate matter, and high-poverty/low-income neighborhoods were associated with preeclampsia, and effect modification was observed between these exposures. Further research into exposure combinations and preeclampsia is warranted.

  View details for DOI 10.3390/ijerph18105127

  View details for Web of Science ID 000654887800001

  View details for PubMedID 34066190

• Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial. Journal of perinatology : official journal of the California Perinatal Association Adams-Chapman, I., Watterberg, K. L., Nolen, T. L., Hirsch, S., Cole, C. A., Cotten, C. M., Oh, W., Poindexter, B. B., Zaterka-Baxter, K. M., Das, A., Lacy, C. B., Scorsone, A. M., Duncan, A. F., DeMauro, S. B., Goldstein, R. F., Colaizy, T. T., Wilson-Costello, D. E., Purdy, I. B., Hintz, S. R., Heyne, R. J., Myers, G. J., Fuller, J., Merhar, S., Harmon, H. M., Peralta-Carcelen, M., Kilbride, H. W., Maitre, N. L., Vohr, B. R., Natarajan, G., Mintz-Hittner, H., Quinn, G. E., Wallace, D. K., Olson, R. J., Orge, F. H., Tsui, I., Gaynon, M., Hutchinson, A. K., He, Y., Winter, T. W., Yang, M. B., Haider, K. M., Cogen, M. S., Hug, D., Bremer, D. L., Donahue, J. P., Lucas, W. R., Phelps, D. L., Higgins, R. D., Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, Archer, S. W., Sokol, G. M., Gunn, S., Herron, D. E., Hines, A. C., Hynes, E., Papile, L., Smiley, L., Tyson, J. E., Kennedy, K. A., Khan, A. M., Duncan, A., Mosquera, R., Allain, E., Arldt-McAlister, J., Brown, S., Dempsey, A. G., Eason, E., El-Ali, F., Garcia, C., Kumar, K., John, J., Jones, P. M., Lillie, M. L., Martin, K., Martin, S. C., McDavid, G. E., EdS, S. M., Ozsoy, H., Rodgers, S., Sperry, D., Stephens, E. K., Ta, V., Wong, C., Wright, S. L., Sanchez, P. J., Nelin, L. D., Jadcherla, S. R., Graf, A. E., Luzader, P., Fortney, C. A., Besner, G. E., Parikh, N. A., Rogers, D. L., Golden, R. P., Jordan, C. O., Wallace, D., Gantz, M. G., Bann, C. M., Auman, J. O., Crawford, M. M., Gabrio, J., Huitema, C. M., Pickett, J. W., VonLehmden, A. M., Van Meurs, K. P., Stevenson, D. K., Ball, M. B., Chinn, S., Proud, M. S., Bentley, B., DeAnda, M. E., DeBattista, A. M., Earhart, B., Huffman, L. C., Krueger, C. E., Lucash, R., Weiss, H. E., Carlo, W. A., Ambalavanan, N., Collins, M. V., Cosby, S. S., Quinn, R. J., Denson, B. R., Arciniegas-Bernal, A. M., Biasini, F. J., Johnston, K. C., Patterson, C. S., Phillips, V. A., Whitley, S., Devaskar, U., Garg, M., Chanlaw, T., Geller, R., Bell, E. F., Brumbaugh, J. E., Johnson, K. J., Walker, J. R., Goeke, C. A., Johnson, K. M., Merriss, A., Nohr, J. L., Longmuir, S. Q., Drack, A. V., Eastman, D. L., Larson, S. A., Gertsch, K. R., Bell, V. P., Ohls, R. K., Beauman, S. S., Dupont, T., Hanson, M. R., Hartenberger, C. H., Kuan, E., Kunkel, S. J., Lowe, J., Morgan, N. A., Hallman, M. K., Schmidt, B., Kirpalani, H., Abbasi, S., Chaudhary, A. S., Mancini, T., Anninger, W. V., Bernbaum, J. C., Binenbaum, G., Cook, N., Davidson, S. L., Gerdes, M., Hurt, H., Mills, M. D., Ricciardelli, M., Rockwell, K. J., Snyder, J., Yau, S. M., D'Angio, C., Lakshminrusimha, S., Reynolds, A. M., Bean, S. A., Carmen, M. F., Chess, P. R., Jensen, R., Ramchandran, R. S., Turner, A. M., Williams, A., Sacilowski, M. G., Wadkins, H., Hunn, J., Horan, A., Bowman, M., Hartley-McAndrew, M., Zorn, W., Farooq, O., Yost, K., Merzbach, J., Fallone, C., Binion, K., Orme, C., Sabaratnam, P., Wyckoff, M. H., Brion, L. P., Vasil, D. M., Adams, S. S., Cha, C., Cisneros, J., De Leon, M. M., Eubanks, F., Godowic, L., Grau, L., Guzman, A., Heyne, E., Lee, L. E., Lira, H. C., Mozaffari, A., Pavageau, L., Boatman, C. T., Wright, R., Shankaran, S., Sood, B. G., Bara, R., Agarwal, P., Bajaj, M., Chawla, S., Childs, K., February, M., Goldston, L. A., Johnson, M. E., Lulic-Botica, M., Panaitescu, B., Woldt, E., Gleason, C. A., Allen, M. C., Boyle, R. J., Clemons, T., D'Alton, M. E., Das, A., Everett, D., Kauffman, R. E., Miodovnik, M., O'Shea, T. M., Smith, L., Weiner, S. J., Willinger, M. 2021

  Abstract

  OBJECTIVE: This study evaluates the 24-month follow-up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial.STUDY DESIGN: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score <85, moderate or severe cerebral palsy, blindness, or hearing loss that prevents communication despite amplification were assessed.RESULTS: Primary outcome was determined for 605/638 (95%). The mean gestational age was 25.8±1.3 weeks and mean birthweight was 805±192g. Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p=0.40).CONCLUSIONS: Treatment group did not affect the risk of death or survival with moderate/severe NDI. Despite early termination, this study represents the largest RCT of extremely preterm infants treated with myo-inositol with neurodevelopmental outcome data.

  View details for DOI 10.1038/s41372-021-01018-5

  View details for PubMedID 33758387

• Proteomic signatures predict preeclampsia in individual cohorts but not across cohorts - implications for clinical biomarker studies. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians Ghaemi, M. S., Tarca, A. L., Romero, R. n., Stanley, N. n., Fallahzadeh, R. n., Tanada, A. n., Culos, A. n., Ando, K. n., Han, X. n., Blumenfeld, Y. J., Druzin, M. L., El-Sayed, Y. Y., Gibbs, R. S., Winn, V. D., Contrepois, K. n., Ling, X. B., Wong, R. J., Shaw, G. M., Stevenson, D. K., Gaudilliere, B. n., Aghaeepour, N. n., Angst, M. S. 2021: 1–8

  Abstract

  Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over 1000 plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care.The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes.Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE.The model derived in the Stanford cohort was highly significant (p = 3.9E-15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort (p = 9.7E-01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant (p = 1.0E-21, AUC = 0.73), but failed validation in the Stanford cohort (p = 7.3E-02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford (p = 1.1E-454, R = 0.92) and Detroit cohorts (p = 1.1.E-92, R = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences.Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the "same" clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power.

  View details for DOI 10.1080/14767058.2021.1888915

  View details for PubMedID 33653202

• Inflammation-induced alterations in maternal-fetal Heme Oxygenase (HO) are associated with sustained innate immune cell dysregulation in mouse offspring. PloS one Ozen, M., Zhao, H., Kalish, F., Yang, Y., Jantzie, L. L., Wong, R. J., Stevenson, D. K. 2021; 16 (6): e0252642

  Abstract

  Heme oxygenase-1 (HO-1) is an evolutionarily conserved stress response enzyme and important in pregnancy maintenance, fetal and neonatal outcomes, and a variety of pathologic conditions. Here, we investigated the effects of an exposure to systemic inflammation late in gestation [embryonic day (E)15.5] on wild-type (Wt) and HO-1 heterozygous (Het, HO-1+/-) mothers, fetuses, and offspring. We show that alterations in fetal liver and spleen HO homeostasis during inflammation late in gestation can lead to a sustained dysregulation of innate immune cell populations and intracellular myeloid HO-1 expression in the spleen through young adolescence [postnatal day 25] in mice.

  View details for DOI 10.1371/journal.pone.0252642

  View details for PubMedID 34086785

• Deleterious and Protective Psychosocial and Stress-Related Factors Predict Risk of Spontaneous Preterm Birth. American journal of perinatology Becker, M. n., Mayo, J. A., Phogat, N. K., Quaintance, C. C., Laborde, A. n., King, L. n., Gotlib, I. H., Gaudilliere, B. n., Angst, M. S., Shaw, G. M., Stevenson, D. K., Aghaeepour, N. n., Dhabhar, F. S. 2021

  Abstract

   The aim of the study was to: (1) Identify (early in pregnancy) psychosocial and stress-related factors that predict risk of spontaneous preterm birth (PTB, gestational age <37 weeks); (2) Investigate whether "protective" factors (e.g., happiness/social support) decrease risk; (3) Use the Dhabhar Quick-Assessment Questionnaire for Stress and Psychosocial Factors™ (DQAQ-SPF™) to rapidly quantify harmful or protective factors that predict increased or decreased risk respectively, of PTB. This is a prospective cohort study. Relative risk (RR) analyses investigated association between individual factors and PTB. Machine learning-based interdependency analysis (IDPA) identified factor clusters, strength, and direction of association with PTB. A nonlinear model based on support vector machines was built for predicting PTB and identifying factors that most strongly predicted PTB. Higher levels of deleterious factors were associated with increased RR for PTB: General anxiety (RR = 8.9; 95% confidence interval or CI = 2.0,39.6), pain (RR = 5.7; CI = 1.7,17.0); tiredness/fatigue (RR = 3.7; CI = 1.09,13.5); perceived risk of birth complications (RR = 4; CI = 1.6,10.01); self-rated health current (RR = 2.6; CI = 1.0,6.7) and previous 3 years (RR = 2.9; CI = 1.1,7.7); and divorce (RR = 2.9; CI = 1.1,7.8). Lower levels of protective factors were also associated with increased RR for PTB: low happiness (RR = 9.1; CI = 1.25,71.5); low support from parents/siblings (RR = 3.5; CI = 0.9,12.9), and father-of-baby (RR = 3; CI = 1.1,9.9). These factors were also components of the clusters identified by the IDPA: perceived risk of birth complications (p < 0.05 after FDR correction), and general anxiety, happiness, tiredness/fatigue, self-rated health, social support, pain, and sleep (p < 0.05 without FDR correction). Supervised analysis of all factors, subject to cross-validation, produced a model highly predictive of PTB (AUROC or area under the receiver operating characteristic = 0.73). Model reduction through forward selection revealed that even a small set of factors (including those identified by RR and IDPA) predicted PTB. These findings represent an important step toward identifying key factors, which can be assessed rapidly before/after conception, to predict risk of PTB, and perhaps other adverse pregnancy outcomes. Quantifying these factors, before, or early in pregnancy, could identify women at risk of delivering preterm, pinpoint mechanisms/targets for intervention, and facilitate the development of interventions to prevent PTB.· Newly designed questionnaire used for rapid quantification of stress and psychosocial factors early during pregnancy.. · Deleterious factors predict increased preterm birth (PTB) risk.. · Protective factors predict decreased PTB risk..

  View details for DOI 10.1055/s-0041-1729162

  View details for PubMedID 34015838

• Explaining the Black-White Disparity in Preterm Birth: A Consensus Statement From a Multi-Disciplinary Scientific Work Group Convened by the March of Dimes. Frontiers in reproductive health Braveman, P., Dominguez, T. P., Burke, W., Dolan, S. M., Stevenson, D. K., Jackson, F. M., Collins, J. W., Driscoll, D. A., Haley, T., Acker, J., Shaw, G. M., McCabe, E. R., Hay, W. W., Thornburg, K., Acevedo-Garcia, D., Cordero, J. F., Wise, P. H., Legaz, G., Rashied-Henry, K., Frost, J., Verbiest, S., Waddell, L. 2021; 3: 684207

  Abstract

  In 2017-2019, the March of Dimes convened a workgroup with biomedical, clinical, and epidemiologic expertise to review knowledge of the causes of the persistent Black-White disparity in preterm birth (PTB). Multiple databases were searched to identify hypothesized causes examined in peer-reviewed literature, 33 hypothesized causes were reviewed for whether they plausibly affect PTB and either occur more/less frequently and/or have a larger/smaller effect size among Black women vs. White women. While definitive proof is lacking for most potential causes, most are biologically plausible. No single downstream or midstream factor explains the disparity or its social patterning, however, many likely play limited roles, e.g., while genetic factors likely contribute to PTB, they explain at most a small fraction of the disparity. Research links most hypothesized midstream causes, including socioeconomic factors and stress, with the disparity through their influence on the hypothesized downstream factors. Socioeconomic factors alone cannot explain the disparity's social patterning. Chronic stress could affect PTB through neuroendocrine and immune mechanisms leading to inflammation and immune dysfunction, stress could alter a woman's microbiota, immune response to infection, chronic disease risks, and behaviors, and trigger epigenetic changes influencing PTB risk. As an upstream factor, racism in multiple forms has repeatedly been linked with the plausible midstream/downstream factors, including socioeconomic disadvantage, stress, and toxic exposures. Racism is the only factor identified that directly or indirectly could explain the racial disparities in the plausible midstream/downstream causes and the observed social patterning. Historical and contemporary systemic racism can explain the racial disparities in socioeconomic opportunities that differentially expose African Americans to lifelong financial stress and associated health-harming conditions. Segregation places Black women in stressful surroundings and exposes them to environmental hazards. Race-based discriminatory treatment is a pervasive stressor for Black women of all socioeconomic levels, considering both incidents and the constant vigilance needed to prepare oneself for potential incidents. Racism is a highly plausible, major upstream contributor to the Black-White disparity in PTB through multiple pathways and biological mechanisms. While much is unknown, existing knowledge and core values (equity, justice) support addressing racism in efforts to eliminate the racial disparity in PTB.

  View details for DOI 10.3389/frph.2021.684207

  View details for PubMedID 36303973

• Corrigendum: Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation. Frontiers in pediatrics Moufarrej, M. N., Wong, R. J., Shaw, G. M., Stevenson, D. K., Quake, S. R. 2021; 9: 680201

  Abstract

  [This corrects the article DOI: 10.3389/fped.2020.605219.].

  View details for DOI 10.3389/fped.2021.680201

  View details for PubMedID 33903851

  View details for PubMedCentralID PMC8065098

• Effect of sunflower seed oil emollient therapy on newborn infant survival in Uttar Pradesh, India: A community-based, cluster randomized, open-label controlled trial. PLoS medicine Kumar, A., Mishra, S., Singh, S., Ashraf, S., Kan, P., Ghosh, A. K., Kumar, A., Krishna, R., Stevenson, D. K., Tian, L., Elias, P. M., Darmstadt, G. L., Kumar, V. 2021; 18 (9): e1003680

  Abstract

  Hospitalized preterm infants with compromised skin barrier function treated topically with sunflower seed oil (SSO) have shown reductions in sepsis and neonatal mortality rate (NMR). Mustard oil and products commonly used in high-mortality settings may possibly harm skin barrier integrity and enhance risk of infection and mortality in newborn infants. We hypothesized that SSO therapy may reduce NMR in such settings.This was a population-based, cluster randomized, controlled trial in 276 clusters in rural Uttar Pradesh, India. All newborn infants identified through population-based surveillance in the study clusters within 7 days of delivery were enrolled from November 2014 to October 2016. Exclusive, 3 times daily, gentle applications of 10 ml of SSO to newborn infants by families throughout the neonatal period were recommended in intervention clusters (n = 138 clusters); infants in comparison clusters (n = 138 clusters) received usual care, such as massage practice typically with mustard oil. Primary analysis was by intention-to-treat with NMR and post-24-hour NMR as the primary outcomes. Secondary analysis included per-protocol analysis and subgroup analyses for NMR. Regression analysis was adjusted for caste, first-visit weight, delivery attendant, gravidity, maternal age, maternal education, sex of the infant, and multiple births. We enrolled 13,478 (52.2% male, mean weight: 2,575.0 grams ± standard deviation [SD] 521.0) and 13,109 (52.0% male, mean weight: 2,607.0 grams ± SD 509.0) newborn infants in the intervention and comparison clusters, respectively. We found no overall difference in NMR in the intervention versus the comparison clusters [adjusted odds ratio (aOR) 0.96, 95% confidence interval (CI) 0.84 to 1.11, p = 0.61]. Acceptance of SSO in the intervention arm was high at 89.3%, but adherence to exclusive applications of SSO was 30.4%. Per-protocol analysis showed a significant 58% (95% CI 42% to 69%, p < 0.01) reduction in mortality among infants in the intervention group who were treated exclusively with SSO as intended versus infants in the comparison group who received exclusive applications of mustard oil. A significant 52% (95% CI 12% to 74%, p = 0.02) reduction in NMR was observed in the subgroup of infants weighing ≤1,500 g (n = 589); there were no statistically significant differences in other prespecified subgroup comparisons by low birth weight (LBW), birthplace, and wealth. No severe adverse events (SAEs) were attributable to the intervention. The study was limited by inability to mask allocation to study workers or participants and by measurement of emollient use based on caregiver responses and not actual observation.In this trial, we observed that promotion of SSO therapy universally for all newborn infants was not effective in reducing NMR. However, this result may not necessarily establish equivalence between SSO and mustard oil massage in light of our secondary findings. Mortality reduction in the subgroup of infants ≤1,500 g was consistent with previous hospital-based efficacy studies, potentially extending the applicability of emollient therapy in very low-birth-weight (VLBW) infants along the facility-community continuum. Further research is recommended to develop and evaluate therapeutic regimens and continuum of care delivery strategies for emollient therapy for newborn infants at highest risk of compromised skin barrier function.ISRCTN Registry ISRCTN38965585 and Clinical Trials Registry-India (CTRI/2014/12/005282) with WHO UTN # U1111-1158-4665.

  View details for DOI 10.1371/journal.pmed.1003680

  View details for PubMedID 34582448

• Decreased Mortality Rate Among COVID-19 Patients Prescribed Statins: Data From Electronic Health Records in the US. Frontiers in medicine Maric, I., Oskotsky, T., Kosti, I., Le, B., Wong, R. J., Shaw, G. M., Sirota, M., Stevenson, D. K. 2021; 8: 639804

  Abstract

  The severe respiratory illness due to SARS-CoV-2, the virus responsible for coronavirus disease 2019 (COVID-19), is triggered by an intense pro-inflammatory host response. Statins, prescribed primarily for lipid reduction, are known to have anti-inflammatory and immunomodulatory properties and have been associated with a reduced mortality rate among COVID-19 patients taking statins as reported in two recent retrospective studies. However, a meta-analysis that included nine studies showed that statin use did not improve in-hospital outcomes of those with COVID-19. In addition, concerns regarding the use of statins and an increase in COVID-19 infections have been raised, as statins may increase the expression of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the SARS-CoV-2 virus. Our goal was to investigate the effect of statins in COVID-19 patients in a large, diverse patient population across the United States containing nearly 120,000 patients diagnosed with COVID-19. We used propensity score matching of demographics, comorbidities, and medication indication to compare statin-treated patients (N = 2,297) with matched controls (N = 4,594). We observed a small, but statistically significant, decrease in mortality among patients prescribed statins (16.1%) when compared with matched COVID-19-positive controls (18.0 to 20.6%). These results support previous evidence that statins do not increase COVID-19-related mortality and may, in fact, have a mitigating effect on severity of the disease reflected in a slight reduction in mortality. Mixed findings on effects of statins in COVID-19 patients reported in the literature should prompt prospective randomized controlled trials in order to define better who might be advantaged with respect to clinical outcomes.

  View details for DOI 10.3389/fmed.2021.639804

  View details for PubMedID 33614688

• Measuring Variation in Interpregnancy Interval: Identifying Hotspots for Improvement Initiatives. American journal of perinatology Karakash, S. D., Main, E. K., Chang, S. C., Shaw, G. M., Stevenson, D. K., Gould, J. B. 2021

  Abstract

   The study aimed to determine if single year birth certificate data can be used to identify regional and hospital variation in rates of short interpregnancy interval (IPI < 6 months). IPI was estimated for multiparous women ages 15 to 44 years with singleton live births between 2015 and 2016. Perinatal outcomes, place of birth, maternal race, and data for IPI calculations were obtained by using birth certificates. IPI frequencies are presented as observed rates. The cohort included 562,039 multiparous women. Short IPI rates were similar to those obtained with analyses by using linked longitudinal data and confirmed the association with preterm birth. Short IPI rates varied by race and Hispanic nativity. There was substantial hospital (0.8-9%) and regional (2.9-6.2%) variation in short IPI rates. IPI rates can be reliably obtained from current year birth certificate data. This can be a useful tool for quality improvement projects targeting interventions and rapidly assessing their progress to promote optimal birth spacing.· Near-real time regional and hospital IPI rates can be reliably obtained from current year birth certificate data.. · Substantial variations in rates of short IPI exist between hospital and perinatal regions.. · IPI rates from individual birth certificates can be a tool to target and assess interventions..

  View details for DOI 10.1055/s-0041-1728819

  View details for PubMedID 33940645

• DECREASED MORTALITY RATE AMONG COVID-19 PATIENTS USING STATINS: DATA FROM US ELECTRONIC HEALTH RECORDS Oskotsky, T., Maric, I., Kosti, I., Le, B. L., Wong, R. J., Shaw, G. M., Sirota, M., Stevenson, D. K. BMJ PUBLISHING GROUP. 2021: 219–20

  View details for DOI 10.1136/jim-2021-WRMC.262

  View details for Web of Science ID 000608729100280

• Re: Association of Preconception Paternal Health on Perinatal Outcomes: Analysis of US Claims Data JOURNAL OF UROLOGY Kasman, A. M., Zhang, C. A., Li, S., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2021; 205 (1): 291

  View details for Web of Science ID 000597318700085

• Data-Driven Modeling of Pregnancy-Related Complications. Trends in molecular medicine Espinosa, C. n., Becker, M. n., Marić, I. n., Wong, R. J., Shaw, G. M., Gaudilliere, B. n., Aghaeepour, N. n., Stevenson, D. K. 2021

  Abstract

  A healthy pregnancy depends on complex interrelated biological adaptations involving placentation, maternal immune responses, and hormonal homeostasis. Recent advances in high-throughput technologies have provided access to multiomics biological data that, combined with clinical and social data, can provide a deeper understanding of normal and abnormal pregnancies. Integration of these heterogeneous datasets using state-of-the-art machine-learning methods can enable the prediction of short- and long-term health trajectories for a mother and offspring and the development of treatments to prevent or minimize complications. We review advanced machine-learning methods that could: provide deeper biological insights into a pregnancy not yet unveiled by current methodologies; clarify the etiologies and heterogeneity of pathologies that affect a pregnancy; and suggest the best approaches to address disparities in outcomes affecting vulnerable populations.

  View details for DOI 10.1016/j.molmed.2021.01.007

  View details for PubMedID 33573911

• PERSISTENT BACTERIAL VAGINOSIS AND RISK FOR SPONTANEOUS PRETERM BIRTH Blumenfeld, Y. J., Maric, I., Stevenson, D. K., Shaw, G. M. BMJ PUBLISHING GROUP. 2021: 127–28

  View details for DOI 10.1136/jim-2021-WRMC.58

  View details for Web of Science ID 000608729100076

• IN VITRO INHIBITORY POTENCY OF D-PENICILLAMINE ON HEME OXYGENASE ISOZYME ACTIVITY Fuwa, K., Konecny, C. M., Stevenson, D. K., Wong, R. J. BMJ PUBLISHING GROUP. 2021: 111–12

  View details for DOI 10.1136/jim-2021-WRMC.22

  View details for Web of Science ID 000608729100040

• METABOLIC PATTERNS OF INFANTS BORN TO MOTHERS WITH PREECLAMPSIA AND DIABETES SHOW UNDERLYING METABOLIC VULNERABILITY Reiss, J., Chang, A., Mayo, J., Stevenson, D. K., Shaw, G. M., Aghaeepour, N., Sylvester, K. BMJ PUBLISHING GROUP. 2021: 196

  View details for DOI 10.1136/jim-2021-WRMC.206

  View details for Web of Science ID 000608729100224

• Maternal metabolic profiling to assess fetal gestational age and predict preterm delivery: a two-centre retrospective cohort study in the US. BMJ open Sylvester, K. G., Hao, S., You, J., Zheng, L., Tian, L., Yao, X., Mo, L., Ladella, S., Wong, R. J., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Whitin, J. C., McElhinney, D. B., Ling, X. B. 2020; 10 (12): e040647

  Abstract

  OBJECTIVES: The aim of this study was to develop a single blood test that could determine gestational age and estimate the risk of preterm birth by measuring serum metabolites. We hypothesised that serial metabolic modelling of serum analytes throughout pregnancy could be used to describe fetal gestational age and project preterm birth with a high degree of precision.STUDY DESIGN: A retrospective cohort study.SETTING: Two medical centres from the USA.PARTICIPANTS: Thirty-six patients (20 full-term, 16 preterm) enrolled at Stanford University were used to develop gestational age and preterm birth risk algorithms, 22 patients (9 full-term, 13 preterm) enrolled at the University of Alabama were used to validate the algorithms.OUTCOME MEASURES: Maternal blood was collected serially throughout pregnancy. Metabolic datasets were generated using mass spectrometry.RESULTS: A model to determine gestational age was developed (R2=0.98) and validated (R2=0.81). 66.7% of the estimates fell within ±1week of ultrasound results during model validation. Significant disruptions from full-term pregnancy metabolic patterns were observed in preterm pregnancies (R2=-0.68). A separate algorithm to predict preterm birth was developed using a set of 10 metabolic pathways that resulted in an area under the curve of 0.96 and 0.92, a sensitivity of 0.88 and 0.86, and a specificity of 0.96 and 0.92 during development and validation testing, respectively.CONCLUSIONS: In this study, metabolic profiling was used to develop and test a model for determining gestational age during full-term pregnancy progression, and to determine risk of preterm birth. With additional patient validation studies, these algorithms may be used to identify at-risk pregnancies prompting alterations in clinical care, and to gain biological insights into the pathophysiology of preterm birth. Metabolic pathway-based pregnancy modelling is a novel modality for investigation and clinical application development.

  View details for DOI 10.1136/bmjopen-2020-040647

  View details for PubMedID 33268420

• Reproductive sequelae of parental severe illness before the pandemic: implications for the COVID-19 pandemic. Fertility and sterility Kasman, A. M., Bhambhvani, H. P., Li, S., Zhang, C. A., Stevenson, D. K., Shaw, G. M., Simard, J. F., Eisenberg, M. L. 2020; 114 (6): 1242–49

  Abstract

  OBJECTIVE: To investigate, with pre-COVID-19 data, whether parental exposure to severe systemic infections near the time of conception is associated with pregnancy outcomes.DESIGN: Retrospective cohort study.SETTING: Population-based study covering births within the United States from 2009 to2016.PARTICIPANTS: The IBM MarketScan Research database covers reimbursed health care claims data on inpatient and outpatient encounters that are privately insured through employment-sponsored health insurance. Our analytic sample included pregnancies to paired fathers and mothers.INTERVENTIONS(S): Parental preconception exposure (0-6 months before conception) to severe systemic infection (e.g., sepsis, hypotension, respiratory failure, critical care evaluation).MAIN OUTCOME MEASURE(S): Preterm birth (i.e., live birth before 37 weeks) and pregnancy loss.RESULT(S): A total of 999,866 pregnancies were recorded with 214,057 pregnancy losses (21.4%) and 51,759 preterm births (5.2%). Mothers receiving intensive care in the preconception period had increased risk of pregnancy loss, as did fathers. Mothers with preconception sepsis had higher risk of preterm birth and pregnancy loss, and paternal sepsis exposure was associated with an increased risk of pregnancy loss. Similar results were noted for hypotension. In addition, a dose response was observed for both mothers and fathers between preconception time in intensive care and the risk of preterm birth and pregnancy loss.CONCLUSION(S): In a pre-COVID-19 cohort, parental preconception severe systemic infection was associated with increased odds of preterm birth and pregnancy loss when conception was soon after the illness.

  View details for DOI 10.1016/j.fertnstert.2020.09.153

  View details for PubMedID 33280730

• Divergent patterns of mitochondrial and nuclear ancestry are associated with the risk for preterm birth Crawford, N., Prendergast, D. B., Oehlert, J. W., Shaw, G. M., Stevenson, D. K., Rappaport, N., Sirota, M., Tishkoff, S. A., Sondheimer, N. SPRINGERNATURE. 2020: 971

  View details for Web of Science ID 000598482603366

• Singleton preterm birth rates for racial and ethnic groups during the coronavirus disease 2019 pandemic in California. American journal of obstetrics and gynecology Main, E. K., Chang, S., Carpenter, A. M., Wise, P. H., Stevenson, D. K., Shaw, G. M., Gould, J. B. 2020

  View details for DOI 10.1016/j.ajog.2020.10.033

  View details for PubMedID 33203528

• Integration of mechanistic immunological knowledge into a machine learning pipeline improves predictions NATURE MACHINE INTELLIGENCE Culos, A., Tsai, A. S., Stanley, N., Becker, M., Ghaemi, M. S., McIlwain, D. R., Fallahzadeh, R., Tanada, A., Nassar, H., Espinosa, C., Xenochristou, M., Ganio, E., Peterson, L., Han, X., Stelzer, I. A., Ando, K., Gaudilliere, D., Phongpreecha, T., Maric, I., Chang, A. L., Shaw, G. M., Stevenson, D. K., Bendall, S., Davis, K. L., Fantl, W., Nolan, G. P., Hastie, T., Tibshirani, R., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2020

  View details for DOI 10.1038/s42256-020-00232-8

  View details for Web of Science ID 000579336000001

• In-hospital mortality and morbidity among extremely preterm infants in relation to maternal body mass index. Journal of perinatology : official journal of the California Perinatal Association Chawla, S., Laptook, A. R., Smith, E. A., Tan, S., Natarajan, G., Wyckoff, M. H., Ambalavanan, N., Bell, E. F., Van Meurs, K. P., Stevenson, D. K., Werner, E. F., Greenberg, R. G., Das, A., Shankaran, S., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network 2020

  Abstract

  OBJECTIVE: The objective of this paper is to compare in-hospital survival and survival without major morbidities in extremely preterm infants in relation to maternal body mass index (BMI).METHODS: This retrospective cohort study included extremely preterm infants (gestational age 220/7-286/7 weeks). This study was conducted at National Institute of Child Health and Human Development Neonatal Research Network sites. Primary outcome was survival without any major morbidity.RESULTS: Maternal BMI data were available for 2415 infants. Survival without any major morbidity was not different between groups: 30.8% in the underweight/normal, 28.1% in the overweight, and 28.5% in the obese (P=0.65). However, survival was lower in the obese group (76.5%) compared with overweight group (83.2%) (P=0.02). Each unit increase in maternal BMI was associated with decreased odds of infant survival (P<0.01).CONCLUSIONS: Survival without any major morbidity was not associated with maternal obesity. An increase in maternal prepregnancy BMI was associated with decreased odds of infant survival.

  View details for DOI 10.1038/s41372-020-00847-0

  View details for PubMedID 33024258

• Dysregulation of hypoxia-inducible factor-1alpha (Hif1alpha) expression in the Hmox1-deficient placenta. Placenta Zhao, H., Narasimhan, P., Kalish, F., Wong, R. J., Stevenson, D. K. 2020; 99: 108–16

  Abstract

  INTRODUCTION: Severe hypoxia exists in placentas during early pregnancy, with reoxygenation during mid-gestation. Hypoxia-inducible factor-1alpha (Hif1alpha), an oxygen sensor, initiates placental vascular development. We have shown that the placental vasculature in Hmox1-deficient (Hmox1+/-, Het) pregnancies is impaired, with morphological defects similar to Hif1alpha-deficient placentas.MATERIALS AND METHODS: Whole wild-type (WT) and Het mouse placentas were collected at E8.5 (1%-3% O2) and E9.5-15.5 (8%-10% O2). mRNA levels were determined using real-time RT-PCR or PCR arrays and protein levels using Western blot. Bone marrow-derived macrophages (BMDMs) from WT, Het, and Hmox1 knockout (KO) mice, representing different Hmox1 cellular levels, were generated to study the role of Hmox1 on Hif1alpha 's response to hypoxia-reoxygenation and gestational age-specific placental lysates.RESULTS: Hif1alpha was expressed in WT and Het placentas throughout gestation, with protein levels peaking at E8.5 and mRNA levels significantly upregulated from E9.5-E13.5, but significantly lower in Het placentas. Genes associated with angiogenesis (Vegfa, Vegfr1, Mmp2, Cxcl12, Angpt1, Nos3), antioxidants (Sod1, Gpx1), and transcription factors (Ap2, Bach1, Nrf2) were significantly different in Het placentas. In response to in vitro hypoxia-reoxygenation and to WT or Het placental lysates, Hif1alpha transcription was lower in Het and Hmox1 KO BMDMs compared with WT BMDMs.DISCUSSION: These findings suggest that deficiencies in Hmox1 underlie the insufficient placental Hif1alpha response to hypoxia-reoxygenation during gestation and subsequently impair downstream placental vascular formation. Therefore, a dysregulation of Hif1alpha expression caused by any genetic defect or environmental influence in early pregnancy could be the root cause of pregnancy disorders.

  View details for DOI 10.1016/j.placenta.2020.07.015

  View details for PubMedID 32784053

• Towards personalized medicine in maternal and child health: integrating biologic and social determinants. Pediatric research Stevenson, D. K., Wong, R. J., Aghaeepour, N., Maric, I., Angst, M. S., Contrepois, K., Darmstadt, G. L., Druzin, M. L., Eisenberg, M. L., Gaudilliere, B., Gibbs, R. S., Gotlib, I. H., Gould, J. B., Lee, H. C., Ling, X. B., Mayo, J. A., Moufarrej, M. N., Quaintance, C. C., Quake, S. R., Relman, D. A., Sirota, M., Snyder, M. P., Sylvester, K. G., Hao, S., Wise, P. H., Shaw, G. M., Katz, M. 2020

  View details for DOI 10.1038/s41390-020-0981-8

  View details for PubMedID 32454518

• Effects of Selective Exclusion of Patients on Preterm Birth Test Performance OBSTETRICS AND GYNECOLOGY McElrath, T. F., Cantonwine, D., Stevenson, D. K., Shaw, G. M., Aghaeepour, N., Quake, S. 2020; 135 (5): 1228–29

  View details for Web of Science ID 000570209400048

• Postpartum LARC Among the Privately Insured-Use After Preterm and Term Births Goldthwaite, L., Maric, I., Shaw, K. A., Stevenson, D. K., Shaw, G. LIPPINCOTT WILLIAMS & WILKINS. 2020: 108S–109S

  View details for Web of Science ID 000554572900377

• Early prediction of preeclampsia via machine learning. American journal of obstetrics & gynecology MFM Maric, I., Tsur, A., Aghaeepour, N., Montanari, A., Stevenson, D. K., Shaw, G. M., Winn, V. D. 2020; 2 (2): 100100

  Abstract

  BACKGROUND: Early prediction of preeclampsia is challenging because of poorly understood causes, various risk factors, and likely multiple pathogenic phenotypes of preeclampsia. Statistical learning methods are well-equipped to deal with a large number of variables, such as patients' clinical and laboratory data, and to select the most informative features automatically.OBJECTIVE: Our objective was to use statistical learning methods to analyze all available clinical and laboratory data that were obtained during routine prenatal visits in early pregnancy and to use them to develop a prediction model for preeclampsia.STUDY DESIGN: This was a retrospective cohort study that used data from 16,370 births at Lucile Packard Children Hospital at Stanford, CA, from April 2014 to January 2018. Two statistical learning algorithms were used to build a predictive model: (1) elastic net and (2) gradient boosting algorithm. Models for all preeclampsia and early-onset preeclampsia (<34 weeks gestation) were fitted with the use of patient data that were available at <16 weeks gestational age. The 67 variables that were considered in the models included maternal characteristics, medical history, routine prenatal laboratory results, and medication intake. The area under the receiver operator curve, true-positive rate, and false-positive rate were assessed via cross-validation.RESULTS: Using the elastic netalgorithm, we developed a prediction model that contained a subset of the most informative features from all variables. The obtained prediction model for preeclampsia yielded an area under the curve of 0.79 (95% confidence interval, 0.75-0.83), sensitivity of 45.2%, and false-positive rate of 8.1%. The prediction model for early-onset preeclampsia achieved an area under the curve of 0.89 (95% confidence interval, 0.84-0.95), true-positive rate of 72.3%, and false-positive rate of 8.8%.CONCLUSION: Statistical learning methods in a retrospective cohort study automatically identified a set of significant features for prediction and yielded high prediction performance for preeclampsia risk from routine early pregnancy information.

  View details for DOI 10.1016/j.ajogmf.2020.100100

  View details for PubMedID 33345966

• Progressive Metabolic Dysfunction and Nutritional Variability Precedes Necrotizing Enterocolitis. Nutrients Sinclair, T. J., Ye, C., Chen, Y., Zhang, D., Li, T., Ling, X. B., Cohen, H. J., Shaw, G. M., Stevenson, D. K., Chace, D., Clark, R. H., Sylvester, K. G. 2020; 12 (5)

  Abstract

  Necrotizing Enterocolitis (NEC) is associated with prematurity, enteral feedings, and enteral dysbiosis. Accordingly, we hypothesized that along with nutritional variability, metabolic dysfunction would be associated with NEC onset. Methods: We queried a multicenter longitudinal database that included 995 preterm infants (<32 weeks gestation) and included 73 cases of NEC. Dried blood spot samples were obtained on day of life 1, 7, 28, and 42. Metabolite data from each time point included 72 amino acid (AA) and acylcarnitine (AC) measures. Nutrition data were averaged at each of the same time points. Odds ratios and 95% confidence intervals were calculated using samples obtained prior to NEC diagnosis and adjusted for potential confounding variables. Nutritional and metabolic data were plotted longitudinally to determine relationship to NEC onset. Results: Day 1 analyte levels of alanine, phenylalanine, free carnitine, C16, arginine, C14:1/C16, and citrulline/phenylalanine were associated with the subsequent development of NEC. Over time, differences in individual analyte levels associated with NEC onset shifted from predominantly AAs at birth to predominantly ACs by day 42. Subjects who developed NEC received significantly lower weight-adjusted total calories (p < 0.001) overall, a trend that emerged by day of life 7 (p = 0.020), and persisted until day of life 28 (p < 0.001) and 42 (p < 0.001). Conclusion: Premature infants demonstrate metabolic differences at birth. Metabolite abnormalities progress in parallel to significant differences in nutritional delivery signifying metabolic dysfunction in premature newborns prior to NEC onset. These observations provide new insights to potential contributing pathophysiology of NEC and opportunity for clinical care-based prevention.

  View details for DOI 10.3390/nu12051275

  View details for PubMedID 32365850

• Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth-Weight Infants: A Randomized Clinical Trial. JAMA pediatrics Arnold, C., Tyson, J. E., Pedroza, C., Carlo, W. F., Stevenson, D. K., Wong, R., Dempsey, A., Khan, A., Fonseca, R., Wyckoff, M., Moreira, A., Lasky, R. 2020

  Abstract

  Importance: Cycled (intermittent) phototherapy (PT) might adequately control peak total serum bilirubin (TSB) level and avoid mortality associated with usual care (continuous PT) among extremely low-birth-weight (ELBW) infants (401-1000 g).Objective: To identify a cycled PT regimen that substantially reduces PT exposure, with an increase in mean peak TSB level lower than 1.5 mg/dL in ELBW infants.Design, Setting, and Participants: This dose-finding randomized clinical trial of cycled PT vs continuous PT among 305 ELBW infants in 6 US newborn intensive care units was conducted from March 12, 2014, to November 14, 2018.Interventions: Two cycled PT regimens (≥15 min/h and ≥30 min/h) were provided using a simple, commercially available timer to titrate PT minutes per hour against TSB level. The comparator arm was usual care (continuous PT).Main Outcomes and Measures: Mean peak TSB level and total PT hours through day 14 in all 6 centers and predischarge brainstem auditory-evoked response wave V latency in 1 center. Mortality and major morbidities were secondary outcomes despite limited power.Results: Consent was requested for 452 eligible infants and obtained for 305 (all enrolled) (mean [SD] birth weight, 749 [152] g; gestational age, 25.7 [1.9] weeks; 81 infants [27%] were multiple births; 137 infants [45%] were male; 112 [37%] were black infants; and 107 [35%] were Hispanic infants). Clinical and demographic characteristics of the groups were similar at baseline. After a preplanned interim analysis of 100 infants, the regimen of 30 min/h or more was discontinued, and the study proceeded with 2 arms. Comparing 128 infants receiving PT of 15 min/h or more with 128 infants receiving continuous PT among those surviving to 14 days, mean peak TSB levels were 7.1 vs 6.4 mg/dL (adjusted difference, 0.7; 95% CI, 0.4-1.1 mg/dL) and mean total PT hours were 34 vs 72 (adjusted difference, -39; 95% CI, -45 to -32). Wave V latency adjusted for postmenstrual age was similar in 37 infants receiving 15 min/h or more of PT and 33 infants receiving continuous PT: 7.42 vs 7.32 milliseconds (difference, 0.10; 95% CI, -0.11 to 0.30 millisecond). The relative risk for death was 0.79 (95% CI, 0.40-1.54), with a risk difference of -4.5% (95% CI, -10.9 to 2.0). Morbidities did not differ between groups.Conclusions and Relevance: Cycled PT can substantially reduce total PT with little increase in peak TSB level. A large, randomized trial is needed to assess whether cycled PT would increase survival and survival without impairment in small, preterm infants.Trial Registration: ClinicalTrials.gov Identifier: NCT01944696.

  View details for DOI 10.1001/jamapediatrics.2020.0559

  View details for PubMedID 32338720

• Association of preconception paternal health on perinatal outcomes: analysis of U.S. claims data. Fertility and sterility Kasman, A. M., Zhang, C. A., Li, S., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2020

  Abstract

  OBJECTIVE: To assess whether paternal health is associated with maternal peripartum and neonatal outcomes.DESIGN: Retrospective cohort study.SETTING: University research departments.PATIENT(S): Analytic sample of children born to paired fathers and mothers covering live births within the United States between 2009-2016.INTERVENTION(S): Paternal health status (e.g., metabolic syndrome diagnoses, individual chronic disease diagnoses).MAIN OUTCOME MEASURE(S): Primary outcome of preterm birth (i.e., live birth before 37 weeks), and secondary outcomes of low birth weight, neonatal intensive care unit (NICU) stay, gestational diabetes, preeclampsia, eclampsia, and length of maternal stay.RESULT(S): The IBM Marketscan Research database covers reimbursed health care claims data on inpatient and outpatient encounters who are privately insured through employment-sponsored health insurance. We assessed 785,809 singleton live births, with 6.6% born preterm. The presence of paternal comorbidities was associated with higher odds of preterm birth, low birth weight (LBW), and NICU stay. After adjusting for maternal factors, fathers with most or all components of the metabolic syndrome had 19% higher odds of having a child born preterm (95% CI 1.11-1.28), 23% higher odds of LBW (95% CI 1.01-1.51), and 28% higher odds of NICU stay (95% CI 1.08-1.52). Maternal morbidity (e.g., gestational diabetes or preeclampsia) was also positively associated with preconception paternal health.CONCLUSION(S): Increased preconception paternal comorbidity may be associated with negative infant and maternal outcomes. Although the paternal effect remains modest, these findings highlight the importance of the health of both parents, particularly the mother, on healthy pregnancy.

  View details for DOI 10.1016/j.fertnstert.2019.12.026

  View details for PubMedID 32147174

• Neonatal Brain Microstructure and Machine-Learning-Based Prediction of Early Language Development in Children Born VeryPreterm. Pediatric neurology Vassar, R., Schadl, K., Cahill-Rowley, K., Yeom, K., Stevenson, D., Rose, J. 2020

  Abstract

  BACKGROUND: Very-low-birth-weight preterm infants have a higher rate of language impairments compared with children born full term. Early identification of preterm infants at risk for language delay is essential to guide early intervention at the time of optimal neuroplasticity. This study examined near-term structural brain magnetic resonance imaging (MRI) and white matter microstructure assessed on diffusion tensor imaging (DTI) in relation to early language development in children born very preterm.METHODS: A total of 102 very-low-birth-weight neonates (birthweight≤1500g, gestational age ≤32-weeks) were recruited to participate from 2010 to 2011. Near-term structural MRI was evaluated for white matter and cerebellar abnormalities. DTI fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were assessed. Language development was assessed with Bayley Scales of Infant-Toddler Development-III at 18 to 22months adjusted age. Multivariate models with leave-one-out cross-validation and exhaustive feature selection identified three brain regions most predictive of language function. Distinct logistic regression models predicted high-risk infants, defined by language scores >1 S.D. below average.RESULTS: Of 102 children, 92 returned for neurodevelopmental testing. Composite language score mean±S.D. was 89.0±16.0; 31 of 92 children scored <85, including 15 of 92 scoring<70, suggesting moderate-to-severe delay. Children with cerebellar asymmetry had lower receptive language subscores (P=0.016). Infants at high risk for language impairments were predicted based on regional white matter microstructure on DTI with high accuracy (sensitivity, specificity) for composite (89%, 86%), expressive (100%, 90%), and receptive language (100%, 90%).CONCLUSIONS: Multivariate models of near-term structural MRI and white matter microstructure on DTI may assist in identification of preterm infants at risk for language impairment, guiding early intervention.

  View details for DOI 10.1016/j.pediatrneurol.2020.02.007

  View details for PubMedID 32279900

• Multi-Omic, Longitudinal Profile of Third-Trimester Pregnancies Identifies a Molecular Switch That Predicts the Onset of Labor. Stelzer, I., Ghaemi, M., Han, X., Ando, K., Peterson, L., Contrepois, K., Ganio, E., Tsai, A., Tsai, E., Rumer, K., Stanley, N., Fallazadeh, R., Becker, M., Culos, A., Gaudilliere, D., Wong, R., Winn, V., Shaw, G., Stevenson, D., Snyder, M., Angst, M., Aghaeepour, N., Gaudilliere, B. SPRINGER HEIDELBERG. 2020: 89A

  View details for Web of Science ID 000525432600082

• Dysregulation of HIF1a Impairs Placental Angiogenesisin Heme Oxygenase-1-Deficient Pregnancies. Zhao, H., Narasimhan, P., Kalish, F., Winn, V. D., Wong, R. J., Stevenson, D. K. SPRINGER HEIDELBERG. 2020: 256A

  View details for Web of Science ID 000525432601139

• Cellular Aging in Pregnancy: Telomere Dynamics Across Gestation. Panelli, D. M., Leonard, S. A., Wong, R. J., Girsen, A. I., Baskovic, M., Stevenson, D. K., Bianco, K. SPRINGER HEIDELBERG. 2020: 127A–128A

  View details for Web of Science ID 000525432600181

• Preterm birth outcomes among Asian women by maternal place of birth. Journal of perinatology : official journal of the California Perinatal Association Girsen, A. I., Mayo, J. A., Datoc, I. A., Karakash, S. n., Gould, J. B., Stevenson, D. K., El-Sayed, Y. Y., Shaw, G. M. 2020

  Abstract

  To investigate overall, spontaneous, and medically indicated preterm birth (PTB) rates between US-born and non-US-born Asian women living in California.Nulliparous women with a singleton livebirth and Asian race in California between 2007 and 2011 were investigated. The prevalence of overall (<37 weeks), spontaneous, and medically indicated PTB was examined by self-reported race and place of birth among ten Asian subgroups.There were marked differences in PTB rates between the individual Asian subgroups. After adjustments, non-US-born Chinese, Japanese, Vietnamese, and Indian women had lower odds of overall PTB and Chinese, Vietnamese, Cambodian, and Indian women had lower odds of spontaneous PTB compared with their US-born counterparts.Further investigation of biological and social factors contributing to these lower odds of spontaneous PTB among the non-US-born Asian population could potentially offer clues for reducing the burden of PTB among the US born.

  View details for DOI 10.1038/s41372-020-0633-1

  View details for PubMedID 32094480

• Vaginal progesterone treatment is associated with intrahepatic cholestasis of pregnancy Tsur, A., Kan, P., Datoc, I., Leonard, S. A., Girsen, A., Shaw, G. M., Stevenson, D. K., El-Sayed, Y. Y., Druzin, M. L., Blumenfeld, Y. J. MOSBY-ELSEVIER. 2020: S58–S59

  View details for DOI 10.1016/j.ajog.2019.11.084

  View details for Web of Science ID 000504997300069

• Do women who delivered at 34-36 weeks need serial transvaginal ultrasound cervical lengths? Ness, A., Chueh, J., Mayo, J. A., Shaw, G. M., El Sayed, Y., Stevenson, D. K. MOSBY-ELSEVIER. 2020: S401

  View details for DOI 10.1016/j.ajog.2019.11.644

  View details for Web of Science ID 000504997300627

• Effects of Selective Exclusion of Patients on Preterm Birth Test Performance. Obstetrics and gynecology McElrath, T. F., Cantonwine, D. n., Stevenson, D. K., Shaw, G. M., Aghaeepour, N. n., Quake, S. n. 2020; 135 (5): 1228–29

  View details for DOI 10.1097/AOG.0000000000003855

  View details for PubMedID 32332399

• Outcome of cerclage in pregnancies without a prior preterm birth Chueh, J., Ness, A., Mayo, J. A., El-Sayed, Y. Y., Shaw, G. M., Stevenson, D. K. MOSBY-ELSEVIER. 2020: S672–S673

  View details for DOI 10.1016/j.ajog.2019.11.1103

  View details for Web of Science ID 000504997301409

• Oil and gas production and spontaneous preterm birth in the San Joaquin Valley, CA: A case-control study. Environmental epidemiology (Philadelphia, Pa.) Gonzalez, D. J., Sherris, A. R., Yang, W. n., Stevenson, D. K., Padula, A. M., Baiocchi, M. n., Burke, M. n., Cullen, M. R., Shaw, G. M. 2020; 4 (4): e099

  Abstract

  Recent studies report an association between preterm birth and exposure to unconventional oil and gas wells. There has been limited previous study on exposure to conventional wells, which are common in California. Our objective was to determine whether exposure to well sites was associated with increased odds of spontaneous preterm birth (delivery at <37 weeks).We conducted a case-control study using data on 27,913 preterm birth cases and 197,461 term birth controls. All births were without maternal comorbidities and were located in the San Joaquin Valley, CA, between 1998 and 2011. We obtained data for 83,559 wells in preproduction or production during the study period. We assessed exposure using inverse distance-squared weighting and, for each birth and trimester, we assigned an exposure tertile. Using logistic regression, we estimated adjusted odds ratios (ORs) for the association between exposure to well sites and preterm birth at 20-27, 28-31, and 32-36 weeks.We observed increased ORs for preterm birth with high exposure to wells in the first and second trimesters for births delivered at ≤31 weeks (adjusted ORs, 1.08-1.14). In stratified analyses, the associations were confined to births to Hispanic and non-Hispanic Black women and to women with ≤12 years of educational attainment. In a secondary analysis, we found evidence that exposure to wells in preproduction is associated with higher concentrations of particulate matter.We found evidence that exposure to oil and gas well sites is associated with increased risk of spontaneous preterm birth.

  View details for DOI 10.1097/EE9.0000000000000099

  View details for PubMedID 32832838

  View details for PubMedCentralID PMC7423522

• Sixty years of phototherapy for neonatal jaundice: from serendipitous observation to standardized treatment and rescue for millions. Journal of perinatology : official journal of the California Perinatal Association Hansen, T. W., Jeffrey Maisels, M. n., Ebbesen, F. n., Vreman, H. J., Stevenson, D. K., Wong, R. J., Bhutani, V. K. 2020

  View details for DOI 10.1038/s41372-020-0712-3

  View details for PubMedID 32561834

• Still- and Live Births in the Periviable Period. Annals of epidemiology Elser, H. n., Gemmill, A. n., Casey, J. A., Karasek, D. n., Bruckner, T. n., Mayo, J. A., Lee, H. C., Stevenson, D. K., Shaw, G. M., Catalano, R. n. 2020

  Abstract

  We use data from California, where 13% of US births occur, to address two questions arising from efforts in the first decade of this century to avoid stillbirth before 25 6/7 weeks of gestation (i.e., in the periviable period). First, did stillbirths decline in the first decade of this century? Second, if stillbirths did decline, did periviable live births increase simultaneously? Answering these questions would seem important given that periviable infants represent <1% of live births but account for roughly 40% of infant mortality and 20% of hospital-based obstetric costs in the US.We constructed 240 monthly conception cohorts, starting with that conceived in January 1991, from 9,880,536 singleton pregnancies that reached the 20 0/7 week of gestation. We used time-series design and Box-Jenkins methods that address confounding by autocorrelation, including secular trends and seasonality to answer our questions.We detected a downward shift in stillbirths in April 2007 that coincided with an upward shift in periviable live births.Our findings imply that, since 2007, fewer Californians than expected from history and from the size of conception cohorts reaching 20 0/7 weeks of gestation, have had to contend with the sequelae of stillbirth, but more than expected likely have had to contend with those of periviable birth.

  View details for DOI 10.1016/j.annepidem.2020.07.002

  View details for PubMedID 32648545

• Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation. Frontiers in pediatrics Moufarrej, M. N., Wong, R. J., Shaw, G. M., Stevenson, D. K., Quake, S. R. 2020; 8: 605219

  Abstract

  In recent years, there have been major advances in the application of non-invasive techniques to predict pregnancy-related complications, for example by measuring cell-free RNA (cfRNA) in maternal blood. In contrast to cell-free DNA (cfDNA), which is already in clinical use to diagnose fetal aneuploidy, circulating RNA levels can correspond with tissue-specific gene expression and provide a snapshot of prenatal health across gestation. Here, we review the physiologic origins of cfRNA and its novel applications and corresponding challenges to monitor fetal and maternal health and predict pregnancy-related complications.

  View details for DOI 10.3389/fped.2020.605219

  View details for PubMedID 33381480

  View details for PubMedCentralID PMC7767905

• VoPo leverages cellular heterogeneity for predictive modeling of single-cell data. Nature communications Stanley, N. n., Stelzer, I. A., Tsai, A. S., Fallahzadeh, R. n., Ganio, E. n., Becker, M. n., Phongpreecha, T. n., Nassar, H. n., Ghaemi, S. n., Maric, I. n., Culos, A. n., Chang, A. L., Xenochristou, M. n., Han, X. n., Espinosa, C. n., Rumer, K. n., Peterson, L. n., Verdonk, F. n., Gaudilliere, D. n., Tsai, E. n., Feyaerts, D. n., Einhaus, J. n., Ando, K. n., Wong, R. J., Obermoser, G. n., Shaw, G. M., Stevenson, D. K., Angst, M. S., Gaudilliere, B. n., Aghaeepour, N. n. 2020; 11 (1): 3738

  Abstract

  High-throughput single-cell analysis technologies produce an abundance of data that is critical for profiling the heterogeneity of cellular systems. We introduce VoPo (https://github.com/stanleyn/VoPo), a machine learning algorithm for predictive modeling and comprehensive visualization of the heterogeneity captured in large single-cell datasets. In three mass cytometry datasets, with the largest measuring hundreds of millions of cells over hundreds of samples, VoPo defines phenotypically and functionally homogeneous cell populations. VoPo further outperforms state-of-the-art machine learning algorithms in classification tasks, and identified immune-correlates of clinically-relevant parameters.

  View details for DOI 10.1038/s41467-020-17569-8

  View details for PubMedID 32719375

• Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index. PloS one Borkowski, K., Newman, J. W., Aghaeepour, N., Mayo, J. A., Blazenovic, I., Fiehn, O., Stevenson, D. K., Shaw, G. M., Carmichael, S. L. 2020; 15 (11): e0239115

  Abstract

  Spontaneous preterm birth (sPTB) is a major cause of infant morbidity and mortality. While metabolic changes leading to preterm birth are unknown, several factors including dyslipidemia and inflammation have been implicated and paradoxically both low (<18.5 kg/m2) and high (>30 kg/m2) body mass indices (BMIs) are risk factors for this condition. The objective of the study was to identify BMI-associated metabolic perturbations and potential mid-gestation serum biomarkers of preterm birth in a cohort of underweight, normal weight and obese women experiencing either sPTB or full-term deliveries (n = 102; n = 17/group). For this purpose, we combined untargeted metabolomics and lipidomics with targeted metabolic profiling of major regulators of inflammation and metabolism, including oxylipins, endocannabinoids, bile acids and ceramides. Women who were obese and had sPTB showed elevated oxidative stress and dyslipidemia characterized by elevated serum free fatty acids. Women who were underweight-associated sPTB also showed evidence of dyslipidemia characterized by elevated phospholipids, unsaturated triglycerides, sphingomyelins, cholesteryl esters and long-chain acylcarnitines. In normal weight women experiencing sPTB, the relative abundance of 14(15)-epoxyeicosatrienoic acid and 14,15-dihydroxyeicosatrienoic acids to other regioisomers were altered at mid-pregnancy. This phenomenon is not yet associated with any biological process, but may be linked to estrogen metabolism. These changes were differentially modulated across BMI groups. In conclusion, using metabolomics we observed distinct BMI-dependent metabolic manifestations among women who had sPTB. These observations suggest the potential to predict sPTB mid-gestation using a new set of metabolomic markers and BMI stratification. This study opens the door to further investigate the role of cytochrome P450/epoxide hydrolase metabolism in sPTB.

  View details for DOI 10.1371/journal.pone.0239115

  View details for PubMedID 33201881

• High-throughput quantitation of serological ceramides/dihydroceramides by LC/MS/MS: Pregnancy baseline biomarkers and potential metabolic messengers. Journal of pharmaceutical and biomedical analysis Huang, Q. n., Hao, S. n., Yao, X. n., You, J. n., Li, X. n., Lai, D. n., Han, C. n., Schilling, J. n., Hwa, K. Y., Thyparambil, S. n., Whitin, J. n., Cohen, H. J., Chubb, H. n., Ceresnak, S. R., McElhinney, D. B., Wong, R. J., Shaw, G. M., Stevenson, D. K., Sylvester, K. G., Ling, X. B. 2020; 192: 113639

  Abstract

  Ceramides and dihydroceramides are sphingolipids that present in abundance at the cellular membrane of eukaryotes. Although their metabolic dysregulation has been implicated in many diseases, our knowledge about circulating ceramide changes during the pregnancy remains limited. In this study, we present the development and validation of a high-throughput liquid chromatography-tandem mass spectrometric method for simultaneous quantification of 16 ceramides and 10 dihydroceramides in human serum within 5 min. by using stable isotope-labeled ceramides as internal standards. This method employs a protein precipitation method for high throughput sample preparation, reverse phase isocratic elusion for chromatographic separation, and Multiple Reaction Monitoring for mass spectrometric detection. To qualify for clinical applications, our assay has been validated against the FDA guidelines for Lower Limit of Quantitation (1 nM), linearity (R2>0.99), precision (imprecision<15 %), accuracy (inaccuracy<15 %), extraction recovery (>90 %), stability (>85 %), and carryover (<0.01 %). With enhanced sensitivity and specificity from this method, we have, for the first time, determined the serological levels of ceramides and dihydroceramides to reveal unique temporal gestational patterns. Our approach could have value in providing insights into disorders of pregnancy.

  View details for DOI 10.1016/j.jpba.2020.113639

  View details for PubMedID 33017796

• TREATMENT WITH LANSOPRAZOLE IMPROVES PREGNANCY OUTCOME IN MICE Iwatani, S., Le, B. L., Konecny, C. M., Vijayakumar, D., Wong, R. T., Sirota, M., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2020: A149–A150

  View details for DOI 10.1136/jim-2019-WMRC.345

  View details for Web of Science ID 000507513300345

• Multiomic immune clockworks of pregnancy. Seminars in immunopathology Peterson, L. S., Stelzer, I. A., Tsai, A. S., Ghaemi, M. S., Han, X. n., Ando, K. n., Winn, V. D., Martinez, N. R., Contrepois, K. n., Moufarrej, M. N., Quake, S. n., Relman, D. A., Snyder, M. P., Shaw, G. M., Stevenson, D. K., Wong, R. J., Arck, P. n., Angst, M. S., Aghaeepour, N. n., Gaudilliere, B. n. 2020

  Abstract

  Preterm birth is the leading cause of mortality in children under the age of five worldwide. Despite major efforts, we still lack the ability to accurately predict and effectively prevent preterm birth. While multiple factors contribute to preterm labor, dysregulations of immunological adaptations required for the maintenance of a healthy pregnancy is at its pathophysiological core. Consequently, a precise understanding of these chronologically paced immune adaptations and of the biological pacemakers that synchronize the pregnancy "immune clock" is a critical first step towards identifying deviations that are hallmarks of peterm birth. Here, we will review key elements of the fetal, placental, and maternal pacemakers that program the immune clock of pregnancy. We will then emphasize multiomic studies that enable a more integrated view of pregnancy-related immune adaptations. Such multiomic assessments can strengthen the biological plausibility of immunological findings and increase the power of biological signatures predictive of preterm birth.

  View details for DOI 10.1007/s00281-019-00772-1

  View details for PubMedID 32020337

• Personalized charts for the fetal corpus callosum length JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE Tsur, A., Weisz, B., Rosenblat, O., Shai, D., Derazne, E., Stevenson, D. K., Achiron, R., Katorza, E. 2019; 32 (23): 3931–38

  View details for DOI 10.1080/14767058.2018.1479389

  View details for Web of Science ID 000483785400006

• Failed umbilical artery catheterization and adverse outcomes in extremely low birth weight infants JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE Wallenstein, M. B., Shaw, G. M., Yang, W., Stevenson, D. K. 2019; 32 (21): 3566–70

  View details for DOI 10.1080/14767058.2018.1468430

  View details for Web of Science ID 000478069900010

• Single Cell Transcriptomes Derived from Human Cervical and Uterine Tissue during Pregnancy ADVANCED BIOSYSTEMS Koh, W., Wu, A., Penland, L., Treutlein, B., Neff, N. F., Mantalas, G. L., Blumenfeld, Y. J., El-Sayed, Y. Y., Stevenson, D. K., Shaw, G. M., Quake, S. R. 2019; 3 (11)

  View details for DOI 10.1002/adbi.201800336

  View details for Web of Science ID 000498192300005

• Single Cell Transcriptomes Derived from Human Cervical and Uterine Tissue during Pregnancy. Advanced biosystems Koh, W., Wu, A., Penland, L., Treutlein, B., Neff, N. F., Mantalas, G. L., Blumenfeld, Y. J., El-Sayed, Y. Y., Stevenson, D. K., Shaw, G. M., Quake, S. R. 2019; 3 (11): e1800336

  Abstract

  This work presents the workflow for generating single cell transcriptomes derived from primary human uterine and cervical tissue obtained during planned cesarean hysterectomies. In total, a catalogue of 310 single cell transcriptomes are obtained, cell types present in these biopsies are inferred, and specific genes defining each of the cellular types present in the tissue are identified. Further validation of the inferred cell identity is also demonstrated via meta-analysis of independent repositories in literature generated by bulk sequenced data of fluorescence-activated cell sorting sorted cells.

  View details for DOI 10.1002/adbi.201800336

  View details for PubMedID 32648692

• Increased Carbon Monoxide Washout Rates in Newborn Infants. Neonatology Stevenson, D. K., Wong, R. J., Ostrander, C. R., Maric, I., Vreman, H. J., Cohen, R. S. 2019: 1–5

  Abstract

  BACKGROUND: Endogenous carbon monoxide (CO) production is primarily due to heme degradation, which also results in the equimolar production of bilirubin. Thus, estimates of total body CO production can serve as indices of total body bilirubin formation. The elimination rate of CO from a person's body (CO washout rate) after exposure to an elevated ambient CO concentration is determined by a variety of factors, and is very different between babies and adults.OBJECTIVE: We determined CO washout rates for babies using a simplified technique to measure total body CO excretion rates (VeCO).METHODS: Using a simplified technique, we measured the times to reach an approximate steady state after a change in ambient CO concentration (decay time constant) and CO washout rates in normal newborn infants using non-linear least squares curve fitting.RESULTS: We found a mean CO washout time of 18.7 ± 4.2 min and a CO equilibration (decay time) constant of 0.12 ± 0.04/min (0.08-0.21) for newborn infants.CONCLUSIONS: We confirm that CO washout rates for babies are much faster than those for adults. Therefore, measurements of carboxyhemoglobin (COHb) or end-tidal CO (ETCO), corrected for ambient CO, (COHbc and ETCOc, respectively) can be used as surrogates for VeCO and can provide accurate estimates of endogenous CO (VCO) and bilirubin production rates under normal environmental conditions. Such measurements can be used to identify infants with severe hyperbilirubinemia due to hemolysis and thus at high risk for bilirubin neurotoxicity.

  View details for DOI 10.1159/000503635

  View details for PubMedID 31634890

• Development and validation of a machine learning model for prediction of shoulder dystocia. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology Tsur, A., Batsry, L., Toussia-Cohen, S., Rosenstein, M. G., Barak, O., Brezinov, Y., Yoeli-Ullman, R., Sivan, E., Sirota, M., Druzin, M. L., Stevenson, D. K., Blumenfeld, Y. J., Aran, D. 2019

  Abstract

  OBJECTIVE: We sought to develop a machine learning (ML) model for prediction of shoulder dystocia (ShD) and to externally validate the model accuracy and potential clinical efficacy in optimizing the use of cesarean delivery (CD) in the context of suspected macrosomia.STUDY DESIGN: We used electronic health records (EHR) from the Sheba Medical Center in Israel to develop the model (derivation cohort) and EHR from the University of California San Francisco Medical Center to validate the model accuracy and clinical efficacy (validation cohort). Subsequent to inclusion and exclusion criteria, the derivation cohort consisted of 686 deliveries [131 complicated by ShD], and the validation cohort of 2,584 deliveries [31 complicated by ShD]. For each of these deliveries, we collected maternal and neonatal delivery outcomes coupled with maternal demographics, obstetric clinical data and sonographic biometric measurements of the fetus. Biometric measurements and their derived estimated fetal weight were adjusted (aEFW) to the date of the delivery. A ML pipeline was utilized to develop the model.RESULTS: In the derivation cohort, the ML model provided significantly better prediction than the current paradigm: using nested cross validation the area under the receiver operator characteristics curve (AUC) of the model was 0.793 ±0.041, outperforming aEFW and diabetes (0.745 ±0.044, p-value =1e-16). The following risk modifiers had a positive beta >0.02 increasing the risk of ShD: aEFW (0.164), pregestational diabetes (0.047), prior ShD (0.04), female fetal sex (0.04) and adjusted abdominal circumference (0.03). The following risk modifiers had a negative beta < -0.02 protective of ShD: adjusted biparietal diameter (-0.08) and maternal height (-0.03). In the validation cohort the model outperformed aEFW and diabetes (AUC=0.866 vs. 0.784, p-value =0.00007). Additionally, in the validation cohort, among the subgroup of 273 women carrying a fetus with aEFW above 4,000 g, the aEFW had no predictive power (AUC=0.548), and the model performed significantly better (0.775, p-value =0.0002). A risk-score threshold of 0.5 stratified 42.9% of deliveries to the high-risk group that included 90.9% of ShD cases and all cases accompanied by maternal or newborn complications. A more specific threshold of 0.7 stratified only 27.5% of the deliveries to the high-risk groups that included 72.7% of ShD cases, and all those accompanied by newborn complications.CONCLUSION: We developed a ML model for prediction of ShD. We externally validated the model performance in a different cohort. The model predicted ShD better than EFW+ maternal diabetes and was able to stratify the risk of ShD and neonatal injury in the context of suspected macrosomia. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/uog.21878

  View details for PubMedID 31587401

• Preterm birth phenotypes in women with autoimmune rheumatic diseases: A population based cohort study. BJOG : an international journal of obstetrics and gynaecology Kolstad, K. D., Mayo, J. A., Chung, L., Chaichian, Y., Kelly, V. M., Druzin, M., Stevenson, D. K., Shaw, G. M., Simard, J. F. 2019

  Abstract

  OBJECTIVE: To investigate preterm birth (PTB) phenotypes in women with different autoimmune rheumatic diseases in a large population-based cohort.DESIGN: Retrospective cohort study.SETTING: California, USA.POPULATION: All live singleton births in California between 2007 and 2011 were analyzed. Patients with autoimmune disease at delivery were identified by ICD-9 codes for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and juvenile idiopathic arthritis (JIA).METHODS: Maternally linked hospital and birth certificate records of 2,481,516 deliveries were assessed (SLE n=2,272, RA n=1,501, SSc n=88, JIA n=187, DM/PM n=38). Multivariable Poisson regression models estimated risk ratios (RRs) for different PTB phenotypes (relative to term deliveries) for each autoimmune disease compared to the general obstetric population adjusting for maternal age, race/ethnicity, body mass index, smoking, education, payer, parity, and prenatal care.MAIN OUTCOME MEASURES: PTB was assessed overall (20-36 weeks) and by subphenotype: pre-term premature rupture of membranes (PPROM), spontaneous, or medically indicated PTB. Risk of PTB overall and each phenotype was partitioned by gestational age: early (20-31 weeks) and late (32-36 weeks).RESULTS: Risks for PTB were elevated for each autoimmune disease evaluated: SLE (RR 3.27 95%CI 3.01-3.56), RA (RR 2.04 95%CI 1.79-2.33), SSc (RR 3.74 95%CI 2.51-5.58), JIA (RR 2.23 95%CI 1.54-3.23), and DM/PM (RR 5.26 95%CI 3.12-8.89). These elevated risks were observed for the majority of PTB phenotypes as well.CONCLUSIONS: Women with systemic autoimmune diseases appear to have an elevated risk of various PTB phenotypes. Therefore, preconception counseling and close monitoring during pregnancy is crucial.

  View details for DOI 10.1111/1471-0528.15970

  View details for PubMedID 31571337

• Prediction of Gait Impairment in Toddlers Born Preterm From Near-Term Brain Microstructure Assessed With DTI, Using Exhaustive Feature Selection and Cross-Validation. Frontiers in human neuroscience Cahill-Rowley, K., Schadl, K., Vassar, R., Yeom, K. W., Stevenson, D. K., Rose, J. 2019; 13: 305

  Abstract

  To predict gait impairment in toddlers born preterm with very-low-birth-weight (VLBW), from near-term white-matter microstructure assessed with diffusion tensor imaging (DTI), using exhaustive feature selection, and cross-validation.Near-term MRI and DTI of 48 bilateral and corpus callosum regions were assessed in 66 VLBW preterm infants; at 18-22 months adjusted-age, 52/66 participants completed follow-up gait assessment of velocity, step length, step width, single-limb support and the Toddle Temporal-spatial Deviation Index (TDI). Multiple linear models with exhaustive feature selection and leave-one-out cross-validation were employed in this prospective cohort study: linear and logistic regression identified three brain regions most correlated with gait outcome.Logistic regression of near-term DTI correctly classified infants high-risk for impaired gait velocity (93% sensitivity, 79% specificity), right and left step length (91% and 93% sensitivity, 85% and 76% specificity), single-limb support (100% and 100% sensitivity, 100% and 100% specificity), step width (85% sensitivity, 80% specificity), and Toddle TDI (85% sensitivity, 75% specificity). Linear regression of near-term brain DTI and toddler gait explained 32%-49% variance in gait temporal-spatial parameters. Traditional MRI methods did not predict gait in toddlers.Near-term brain microstructure assessed with DTI and statistical learning methods predicted gait impairment, explaining substantial variance in toddler gait. Results indicate that at near term age, analysis of a set of brain regions using statistical learning methods may offer more accurate prediction of outcome at toddler age. Infants high risk for single-limb support impairment were most accurately predicted. As a fundamental element of biped gait, single-limb support may be a sensitive marker of gait impairment, influenced by early neural correlates that are evolutionarily and developmentally conserved. For infants born preterm, early prediction of gait impairment can help guide early, more effective intervention to improve quality of life.• Accurate prediction of toddler gait from near-term brain microstructure on DTI.• Use of machine learning analysis of neonatal neuroimaging to predict gait.• Early prediction of gait impairment to guide early treatment for children born preterm.

  View details for DOI 10.3389/fnhum.2019.00305

  View details for PubMedID 31619977

  View details for PubMedCentralID PMC6760000

• Prediction of Gait Impairment in Toddlers Born Preterm From Near-Term Brain Microstructure Assessed With DTI, Using Exhaustive Feature Selection and Cross-Validation FRONTIERS IN HUMAN NEUROSCIENCE Cahill-Rowley, K., Schadl, K., Vassar, R., Yeom, K. W., Stevenson, D. K., Rose, J. 2019; 13

  View details for DOI 10.3389/fnhum.2019.00305

  View details for Web of Science ID 000486616900001

• Adrenal function links to early postnatal growth and blood pressure at age 6 in children born extremely preterm PEDIATRIC RESEARCH Watterberg, K. L., Hintz, S. R., Do, B., Vohr, B. R., Lowe, J., Newman, J. E., Wallace, D., Lacy, C., Davis, E., Granger, D. A., Shankaran, S., Payne, A., Higgins, R. D., Jobe, A. H., Caplan, M. S., Polin, R. A., Laptook, A. R., Hensman, A. M., Vieira, E., Little, E., Johnson, K., Alksninis, B., Keszler, M., Knoll, A. M., Leach, T. M., McGowan, E. C., Watson, V. E., Walsh, M. C., Fanaroff, A. A., Wilson-Costello, D. E., Newman, N. S., Siner, B. S., Zadell, A., DiFiore, J., Bhola, M., Friedman, H. G., Yalcinkaya, G., Goldberg, R. N., Cotten, C., Gustafson, K. E., Goldstein, R. F., Ashley, P., Auten, K. J., Fisher, K. A., Foy, K. A., Freedman, S. F., Lohmeyer, M. B., Malcolm, W. F., Wallace, D. K., Carlton, D. P., Stoll, B. J., Adams-Chapman, I., Buchter, S., Piazza, A. J., Carter, S., Fritz, S., Hale, E. C., Hutchinson, A. K., LaRossa, M., Loggins, Y., Bottcher, D., Archer, S., Poindexter, B. B., Sokol, G. M., Harmon, H. M., Papile, L., Hines, A. C., Wilson, L. D., Herron, D. E., Smiley, L., Kennedy, K. A., Tyson, J. E., Duncan, A. F., Dempsey, A. G., John, J., Jones, P. M., Lillie, M., Siddiki, S., Sperry, D. K., Blaisdell, C. J., Pemberton, V., Das, A., Gantz, M. G., Auman, J., Hammond, J. A., Poole, W., Van Meurs, K. P., Stevenson, D. K., Ball, M., DeAnda, M., Goodlin, G. T., Frantz, I. D., Fiascone, J. M., Kurfiss, A., MacKinnon, B. L., Nylen, E., Brussa, A., Sibley, C., Carlo, W. A., Ambalavanan, N., Collins, M., Cosby, S. S., Phillips, V. A., Domanovich, K., Whitley, S., Smith, L., Kiser, C. R., Finer, N. N., Garey, D., Rasmussen, M. R., Wozniak, P. R., Vaucher, Y. E., Fuller, M. G., Akshoomoff, N., Rich, W., Arnell, K., Bridge, R., Bell, E. F., Colaizy, T. T., Widness, J. A., Klein, J. M., Johnson, K. J., Acarregui, M. J., Eastman, D. L., Wilgenbusch, T. L., Ohls, R. K., Fuller, J., Thomson, R. A., Brown, S., Sanchez, P. J., Heyne, R. J., Rosenfeld, C. R., Salhab, W. A., Brion, L., Adams, S. S., Allen, J., Grau, L., Guzman, A., Hensley, G., Heyne, E. T., Hickman, J. F., Lee, L. E., Leps, M. H., Madden, L. A., Martin, M., Miller, N. A., Morgan, J. S., Solis, A., Boatman, C., Vasil, D. M., Yoder, B. A., Faix, R. G., Baker, S., Osborne, K. A., Rau, C. A., Winter, S., Cunningham, S. D., Ford, A. C., Pappas, A., Sood, B. G., Bara, R., Slovis, T. L., Goldston, L. A., Johnson, M., Eunice Kennedy Shriver Natl Inst C, Neonatal Res Network 2019; 86 (3): 339–47

  View details for DOI 10.1038/s41390-018-0243-1

  View details for Web of Science ID 000481648100011

• Reply to: Transpyloric feeds and bronchopulmonary dysplasia. Journal of perinatology : official journal of the California Perinatal Association Wallenstein, M. B., Brooks, C., Kline, T. A., Beck, R. Q., Yang, W., Shaw, G. M., Stevenson, D. K. 2019

  View details for DOI 10.1038/s41372-019-0458-y

  View details for PubMedID 31431655

• Sixty years of phototherapy for neonatal jaundice - from serendipitous observation to standardized treatment and rescue for millions. Journal of perinatology : official journal of the California Perinatal Association Hansen, T. W., Maisels, M. J., Ebbesen, F., Vreman, H. J., Stevenson, D. K., Wong, R. J., Bhutani, V. K. 2019

  Abstract

  A breakthrough discovery 60 years ago by Cremer et al. has since changed the way we treat infants with hyperbilirubinemia and saved the lives of millions from death and disabilities. "Photobiology" has evolved by inquiry of diverse light sources: fluorescent tubes (wavelength range of 400-520nm; halogen spotlights that emit circular footprints of light; fiberoptic pads/blankets (mostly, 400-550nm range) that can be placed in direct contact with skin; and the current narrow-band blue light-emitting diode (LED) light (450-470nm), which overlaps the peak absorption wavelength (458nm) for bilirubin photoisomerization. Excessive bombardment with photons has raised concerns for oxidative stress in very low birthweight versus term infants treated aggressively with phototherapy. Increased emphasis on prescribing phototherapy as a "drug" that is dosed cautiously and judiciously is needed. In this historical review, we chronicled the basic to the neurotoxic components of severe neonatal hyperbilirubinemia and the use of standardized interventions.

  View details for DOI 10.1038/s41372-019-0439-1

  View details for PubMedID 31420582

• Maternal Height and Risk of Preeclampsia among Race/Ethnic Groups AMERICAN JOURNAL OF PERINATOLOGY Maric, I., Mayo, J. A., Druzin, M. L., Wong, R. J., Winn, V. D., Stevenson, D. K., Shaw, G. M. 2019; 36 (8): 864–71

  View details for DOI 10.1055/s-0038-1675205

  View details for Web of Science ID 000474763600013

• Reply to: 'Early transyploric feeding: an old wine in a new bottle'. Journal of perinatology : official journal of the California Perinatal Association Wallenstein, M. B., Brooks, C., Kline, T. A., Beck, R. Q., Yang, W., Shaw, G. M., Stevenson, D. K. 2019

  View details for DOI 10.1038/s41372-019-0418-6

  View details for PubMedID 31222155

• Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia. Frontiers in immunology Han, X., Ghaemi, M. S., Ando, K., Peterson, L. S., Ganio, E. A., Tsai, A. S., Gaudilliere, D. K., Stelzer, I. A., Einhaus, J., Bertrand, B., Stanley, N., Culos, A., Tanada, A., Hedou, J., Tsai, E. S., Fallahzadeh, R., Wong, R. J., Judy, A. E., Winn, V. D., Druzin, M. L., Blumenfeld, Y. J., Hlatky, M. A., Quaintance, C. C., Gibbs, R. S., Carvalho, B., Shaw, G. M., Stevenson, D. K., Angst, M. S., Aghaeepour, N., Gaudilliere, B. 2019; 10: 1305

  Abstract

  Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preeclampsia. However, prior analyses primarily focused on the static assessment of select immune cell subsets have provided limited information for the prediction of preeclampsia. Here, we used a high-dimensional mass cytometry immunoassay to characterize the dynamic changes of over 370 immune cell features (including cell distribution and functional responses) in maternal blood during healthy and preeclamptic pregnancies. We found a set of eight cell-specific immune features that accurately identified patients well before the clinical diagnosis of preeclampsia (median area under the curve (AUC) 0.91, interquartile range [0.82-0.92]). Several features recapitulated previously known immune dysfunctions in preeclampsia, such as elevated pro-inflammatory innate immune responses early in pregnancy and impaired regulatory T (Treg) cell signaling. The analysis revealed additional novel immune responses that were strongly associated with, and preceded the onset of preeclampsia, notably abnormal STAT5ab signaling dynamics in CD4+T cell subsets (AUC 0.92, p = 8.0E-5). These results provide a global readout of the dynamics of the maternal immune system early in pregnancy and lay the groundwork for identifying clinically-relevant immune dysfunctions for the prediction and prevention of preeclampsia.

  View details for DOI 10.3389/fimmu.2019.01305

  View details for PubMedID 31263463

  View details for PubMedCentralID PMC6584811

• Association between Policy Changes for Oxygen Saturation Alarm Settings and Neonatal Morbidity and Mortality in Infants Born Very Preterm JOURNAL OF PEDIATRICS Foglia, E. E., Carper, B., Gantz, M., DeMauro, S. B., Lakshminrusimha, S., Walsh, M., Schmidt, B., Caplan, M. S., Laptook, A. R., Keszler, M., Hensman, A. M., Knoll, A. M., Little, E., Vieira, E., Basso, K. M., Keller, J. A., Hibbs, A., Fanaroff, A. A., Newman, N. S., Payne, A. H., Schibler, K., Donovan, E. F., Grisby, C., Bridges, K., Alexander, B., Fischer, E. E., Mincey, H. L., Hessling, J., Jackson, L., Kirker, K., Muthig, G., Tepe, S., Cotten, C., Goldberg, R. N., Auten, K. J., Fisher, K. A., Finkle, J., Carlton, D. P., Stoll, B. J., Hale, E. C., Loggins, Y., Bottcher, D., Mackie, C., Higgins, R. D., Archer, S., Poindexter, B. B., Sokol, G. M., Herron, D. E., Miller, L., Wilson, L., Kennedy, K. A., Tyson, J. E., McDavid, G. E., Arldt-McAlister, J., Burson, K., Garcia, C., Harris, B., Lis, A. E., Martin, K., Martin, S. C., Rodgers, S., Simmons, M. C., Pierce, P. L., Das, A., Wallace, D., Poole, W., Auman, J., Crawford, M. M., Huitema, C., Zaterka-Baxter, K. M., Van Meurs, K. P., Stevenson, D. K., Adams, M. M., Ball, M., Ismail, M., Palmquist, A. W., Proud, M. S., Carlo, W. A., Ambalavanan, N., Collins, M., Cosby, S. S., Bell, E. F., Colaizy, T. T., Widness, J. A., Johnson, K. J., Walker, J. R., Watterberg, K. L., Ohls, R. K., Lacy, C., Hartenberger, C. H., Beauman, S., Hanson, M., Wyckoff, M. H., Brion, L. P., Salhab, W. A., Rosenfeld, C. R., Vasil, D. M., Chen, L., Guzman, A., Hensley, G., Lee, L. E., Leps, M. H., Miller, N. A., Morgan, J. S., Pavageau, L., Shankaran, S., Pappas, A., Bara, R., Natarajan, G., Eunice Kennedy Shriver Natl Inst C 2019; 209: 17-+

  Abstract

  To determine the impact of policy changes for pulse oximetry oxygen saturation (SpO2) alarm limits on neonatal mortality and morbidity among infants born very preterm.This was a retrospective cohort study of infants born very preterm in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants were classified based on treatment at a hospital with an SpO2 alarm policy change and study epoch (before vs after policy change). We used a generalized linear mixed model to determine the effect of hospital group and epoch on the primary outcomes of mortality and severe retinopathy of prematurity (ROP) and secondary outcomes of necrotizing enterocolitis, bronchopulmonary dysplasia, and any ROP.There were 3809 infants in 10 hospitals with an SpO2 alarm policy change and 3685 infants in 9 hospitals without a policy change. The nature of most policy changes was to narrow the SpO2 alarm settings. Mortality was lower in hospitals without a policy change (aOR 0.63; 95% CI 0.50-0.80) but did not differ between epochs in policy change hospitals. The odds of bronchopulmonary dysplasia were greater for hospitals with a policy change (aOR 1.65; 95% CI 1.36-2.00) but did not differ for hospitals without a policy change. Severe ROP and necrotizing enterocolitis did not differ between epochs for either group. The adjusted odds of any ROP were lower in recent years in both hospital groups.Changing SpO2 alarm policies was not associated with reduced mortality or increased severe ROP among infants born very preterm.

  View details for DOI 10.1016/j.jpeds.2019.01.048

  View details for Web of Science ID 000468615300006

  View details for PubMedID 30961990

  View details for PubMedCentralID PMC6535348

• Prolonged duration of early antibiotic therapy in extremely premature infants PEDIATRIC RESEARCH Greenberg, R. G., Chowdhury, D., Hansen, N., Smith, P., Stoll, B. J., Sanchez, P. J., Das, A., Puopolo, K. M., Mukhopadhyay, S., Higgins, R. D., Cotten, C., Caplan, M. S., Polin, R. A., Laptook, A. R., Keszler, M., Hensman, A. M., Basso, K. M., Vieira, E., Little, E., Walsh, M. C., Fanaroff, A. A., Hibbs, A., Newman, N. S., Siner, B. S., Truog, W. E., Kilbride, H. W., Pallotto, E. K., Gauldin, C., Holmes, A., Johnson, K., Knutson, A., Poindexter, B. B., Schibler, K., Alexander, B., Grisby, C., Jackson, L. D., Kirker, K., Muthig, G., Goldberg, R. N., Fisher, K. A., Grimes, S., Finkle, J., Laughon, M. M., Bose, C. L., Bernhardt, J., Bose, G., Carlton, D. P., Hale, E. C., Blackwelder, A., Loggins, Y. C., Bottcher, D., Archer, S., Sokol, G. M., Wilson, L., Herron, D. E., Kennedy, K. A., Tyson, J. E., Arldt-McAlister, J., Burson, K., Garcia, C., Harris, B., Martin, K., Martin, S. C., McDavid, G. E., Rodgers, S., Tate, P., Wright, S. L., Nelin, L. D., Jadcherla, S. R., Luzader, P., Fortney, C. A., Besner, G. E., Parikh, N. A., Wallace, D., Gantz, M. G., Auman, J., Crawford, M. M., Gabrio, J., Huitema, C., Zaterka-Baxter, K. M., Van Meurs, K. P., Adams, M. M., Stevenson, D. K., Ball, M., Palmquist, A. W., Proud, M. S., Frantz, I. D., Fiascone, J. M., MacKinnon, B. L., Nylen, E., Carlo, W. A., Ambalavanan, N., Collins, M., Cosby, S. S., Devaskar, U., Garg, M., Chanlaw, T., Geller, R., Bell, E. F., Ellsbury, D. L., Widness, J. A., Colaizy, T. T., Johnson, K. J., Campbell, D. B., Walker, J. R., Watterberg, K. L., Ohls, R. K., Lacy, C., Tomson, R. A., Hartenberger, C., Beauman, S., Schmidt, B., Kirpalani, H., DeMauro, S. B., Dysart, K. C., Chaudhary, A. S., Abbasi, S., Mancini, T., Cucinotta, D. M., Jensen, E. A., D'Angio, C. T., Guillet, R., Lakshminrusimha, S., Reynolds, A., Reubens, L. J., Jensen, R., Maffett, D., Wadkins, H. M., Sacilowski, M. G., Williams, A., Guilford, S., Rowan, M., Prinzing, D. M., Hunn, J., Scorsone, A., Wynn, K., Bowman, M., Phelps, D. L., Horan, A., Wyckoff, M. H., Brion, L. P., Chen, L., Guzman, A., Morgan, J. S., Pavageau, L., Vasil, D. M., Torres, L. E., Faix, R. G., Yoder, B. A., Osborne, K. A., Bird, K., Burnett, J., Jensen, J. J., Spencer, C., Weaver-Lewis, K., Zanetti, K., Shankaran, S., Barks, J., Bara, R., Johnson, M., Christensen, M., Wiggins, S., Ehrenkranz, R. A., Jacobs, H., Cervone, P., Konstantino, M., Poulsen, J., Taft, J., Eunice Kennedy Shriver Natl Inst C 2019; 85 (7): 994–1000

  Abstract

  Prolonged early antibiotics in extremely premature infants may have negative effects. We aimed to assess prevalence and outcomes of provision of prolonged early antibiotics to extremely premature infants in the absence of culture-confirmed infection or NEC.Cohort study of infants from 13 centers born without a major birth defect from 2008-2014 who were 401-1000 grams birth weight, 22-28 weeks gestation, and survived ≥5 days without culture-confirmed infection, NEC, or spontaneous intestinal perforation. We determined the proportion of infants who received prolonged early antibiotics, defined as ≥5 days of antibiotic therapy started at ≤72 h of age, by center and over time. Associations between prolonged early antibiotics and adverse outcomes were assessed using multivariable logistic regression.A total of 5730 infants were included. The proportion of infants receiving prolonged early antibiotics varied from 30-69% among centers and declined from 49% in 2008 to 35% in 2014. Prolonged early antibiotics was not significantly associated with death (adjusted odds ratio 1.17 [95% CI: 0.99-1.40], p = 0.07) and was not associated with NEC.The proportion of extremely premature infants receiving prolonged early antibiotics decreased, but significant center variation persists. Prolonged early antibiotics were not significantly associated with increased odds of death or NEC.

  View details for DOI 10.1038/s41390-019-0300-4

  View details for Web of Science ID 000468524800018

  View details for PubMedID 30737489

• Early transpyloric vs gastric feeding in preterm infants: a retrospective cohort study JOURNAL OF PERINATOLOGY Wallenstein, M. B., Brooks, C., Kline, T. A., Beck, R. Q., Yang, W., Shaw, G. M., Stevenson, D. K. 2019; 39 (6): 837–41

  View details for DOI 10.1038/s41372-019-0372-3

  View details for Web of Science ID 000468895300010

• The effect of light wavelength on in vitro bilirubin photodegradation and photoisomer production (vol 85, pg 865, 2019) PEDIATRIC RESEARCH Vreman, H. J., Kourula, S., Jasprova, J., Ludvikova, L., Klan, P., Muchova, L., Vitek, L., Cline, B. K., Wong, R. J., Stevenson, D. K. 2019; 85 (6): 905

  View details for DOI 10.1038/s41390-019-0356-1

  View details for Web of Science ID 000466408300029

• Discordance in Antenatal Corticosteroid Use and Resuscitation Following Extremely Preterm Birth JOURNAL OF PEDIATRICS Rysavy, M. A., Bell, E. F., Iams, J. D., Carlo, W. A., Li, L., Mercer, B. M., Hintz, S. R., Stoll, B. J., Vohr, B. R., Shankaran, S., Walsh, M. C., Brumbaugh, J. E., Colaizy, T. T., Das, A., Higgins, R. D., Caplan, M. S., Polin, R. A., Laptook, A. R., Hensman, A. M., Oh, W., Keszler, M., Burke, R., Caskey, M., Johnson, K., Alksninis, B., Leach, T. M., Stephens, B. E., Watson, V. E., Ventura, S., Basso, K. M., Vieira, E., Halbrook, A., Fanaroff, A. A., Hibbs, A., Wilson-Costello, D. E., Newman, N. S., Siner, B. S., Bhola, M., Yalcinkaya, G., Friedman, H. G., Truog, W. E., Pallotto, E. K., Kilbride, H. W., Gauldin, C., Holmes, A., Johnson, K., Schibler, K., Donovan, E. F., Bridges, K., Alexander, B., Grisby, C., Hessling, J., Fischer, E. E., Jackson, L. D., Kirker, K., Mincey, H. L., Muthig, G., Gratton, T. L., Steichen, J. J., Yolton, K., Goldberg, R. N., Goldstein, R. F., Fisher, K. A., Auten, K. J., Foy, K. A., Grimes, S., Finkle, J., Gustafson, K. E., Lohmeyer, M. B., Laughon, M. M., Bose, C. L., Bernhardt, J., Bose, G., Clark, C., Carlton, D. P., Hale, E. C., Adams-Chapman, I., LaRossa, M., Carter, S. L., Archer, S., Poindexter, B. B., Dusick, A. M., Cook, A. B., Herron, D. E., Hamer, F., Lytle, C., Miller, L. C., Minnich, H. M., Wilson, L., Nelin, L. D., Jadcherla, S. R., Luzader, P., Fortney, C. A., Besner, G. E., Parikh, N. A., Poole, W., Wallace, D., Newman, J. E., Auman, J., Crawford, M. M., Huitema, C., Zaterka-Baxter, K. M., Van Meurs, K. P., Stevenson, D. K., Adams, M. M., Ball, M., Palmquist, A. W., Proud, M. S., Bruno, E., DeAnda, M., DeBattista, A. M., Kohn, J. G., Krueger, C. E., Weiss, H. E., Frantz, I. D., Fiascone, J. M., MacKinnon, B. L., Nylen, E., Furey, A., McGowan, E. C., Sibley, C. E., Brussa, A. K., Ambalavanan, N., Peralta-Carcelen, M., Collins, M., Cosby, S. S., Biasini, F. J., Johnston, K. C., Nelson, K. G., Patterson, C. S., Phillips, V. A., Whitley, S., Soong, A. D., Kiser, C., Smith, L., Kryzwanski, S., Rector, R., Ryan, S., Domnanovich, K., Rodrigues, L., Devaskar, U., Garg, M., Purdy, I. B., Chanlaw, T., Geller, R., Finer, N. N., Vaucher, Y. E., Kaegi, D., Rasmussen, M. R., Arnell, K., Demetrio, C., Fuller, M. G., Henderson, C., Rich, W., West, R., Ellsbury, D. L., Widness, J. A., Johnson, K. J., Campbell, D. B., Walker, J. R., Eastman, D. L., Duara, S., Bauer, C. R., Everett-Thomas, R., Hiriart-Fajardo, S., Rigaud, A., Calejo, M., Eguaras, S., Berkowits, M., Garcia, A., Pierre, H., Stoerger, A., Watterberg, K. L., Ohls, R. K., Fuller, J. F., Lacy, C., Montman, R. A., Lowe, J. R., Duncan, A., Brown, S., Wussow, T., Hartenberger, C., Rohr, J., Schmidt, B., Kirpalani, H., DeMauro, S. B., Chaudhary, A. S., Abbasi, S., Mancini, T., Cucinotta, D., Phelps, D. L., Myers, G. J., Reubens, L. J., Burnell, E., Hust, D., Johnson, J., Jensen, R. L., Kushner, E., Merzbach, J., Yost, K., Zwetsch, L., Lakshminrusimha, S., Reynolds, A., Farooq, O., Williams, A., Kennedy, K. A., Alaniz, N., Burson, K., Evans, P. W., Green, C., Harris, B., Jiminez, M., Lis, A. E., Martin, S., McDavid, G. E., Morris, B. H., Poundstone, M., Robichaux, P., Siddiki, S., Simmons, M. C., Tate, P., Wright, S. L., Sanchez, P. J., Heyne, R. J., Salhab, W. A., Rosenfeld, C. R., Brion, L. P., Chen, L., Guzman, A., Leps, M. H., Miller, N. A., Vasil, D. M., Torres, L. E., Hensley, G., Adams, S. S., Madden, L. A., Heyne, E., Morgan, J. S., Boatman, C., Faix, R. G., Yoder, B. A., Bodnar, A., Osborne, K. A., Baker, S., Bird, K., Burnett, J., Jensen, J. J., Spencer, C., Steffen, M., Weaver-Lewis, K., Winter, S., Zanetti, K., O'Shea, T., Dillard, R. G., Washburn, L. K., Jackson, B. G., Peters, N., Chiu, K., Allred, D., Goldstein, D. J., Halfond, R., Peterson, C., Waldrep, E. L., Welch, C. D., Morris, M., Hounshell, G., Pappas, A., Barks, J., Bara, R., Goldston, L. A., Johnson, M., Muran, G., Sumner, L., Sawaya, K., Weingarden, K., Christensen, M., Wiggins, S., Ehrenkranz, R. A., Jacobs, H., Butler, C. G., Cervone, P., Greisman, S., Konstantino, M., Poulsen, J., Taft, J., Williams, J., Romano, E., Eunice Kennedy Shriver Natl Inst C 2019; 208: 156-+

  View details for DOI 10.1016/j.jpeds.2018.12.063

  View details for Web of Science ID 000465236700029

• The effect of light wavelength on in vitro bilirubin photodegradation and photoisomer production PEDIATRIC RESEARCH Vreman, H. J., Kourula, S., Jasprova, J., Ludvikova, L., Klan, P., Muchova, L., Vitek, L., Cline, B. K., Wong, R. J., Stevenson, D. K. 2019; 85 (6): 865–73

  View details for DOI 10.1038/s41390-019-0310-2

  View details for Web of Science ID 000466408300024

• Early transpyloric vs gastric feeding in preterm infants: a retrospective cohort study. Journal of perinatology : official journal of the California Perinatal Association Wallenstein, M. B., Brooks, C., Kline, T. A., Beck, R. Q., Yang, W., Shaw, G. M., Stevenson, D. K. 2019

  Abstract

  BACKGROUND: Neonatal transpyloric feeding (TPF) has not been rigorously studied since the 1980s. Our objective was to evaluate early TPF, defined as TPF initiated within the first week after birth, among preterm infants in the setting of modern neonatal practice.STUDY DESIGN: A retrospective cohort study was conducted between 2013 and 2017 for all extremely low birth weight (ELBW) infants born in a tertiary neonatal intensive care unit where early TPF is a common practice. Infants were excluded if they did not receive enteral feeding within the first week after birth or if they died prior to initiation of enteral feeding. The primary outcome was death or bronchopulmonary dysplasia (BPD). The association between early TPF and the primary outcome was assessed using multivariable logistic regression, with adjustment for gestational age, birth weight, and intubation status.RESULT: The study sample included 368 ELBW infants. Twenty-seven percent received early TPF. Death or BPD occurred in 58% of infants who received early TPF compared with 67% of infants who received gastric feeding, adjusted odds ratio 0.6, 95% confidence interval 0.3-0.9. Growth and adverse gastrointestinal outcomes did not differ between the two groups.CONCLUSION: Early TPF is associated with reduced risk of death or BPD among ELBW infants. Further investigation in the form of a randomized controlled trial is required to confirm a causal association between early TPF and improved clinical outcomes.

  View details for PubMedID 30967655

• Stillbirth and Live Birth at Periviable Gestational Age: A Comparison of Prevalence and Risk Factors AMERICAN JOURNAL OF PERINATOLOGY Carmichael, S. L., Blumenfeld, Y. J., Mayo, J. A., Profit, J., Shaw, G. M., Hintz, S. R., Stevenson, D. K. 2019; 36 (5): 537–44

  View details for DOI 10.1055/s-0038-1670633

  View details for Web of Science ID 000463944600016

• A pilot study showing a stronger H1N1 influenza vaccination response during pregnancy in women who subsequently deliver preterm JOURNAL OF REPRODUCTIVE IMMUNOLOGY Andorf, S., Bhattacharya, S., Gaudilliere, B., Shaw, G. M., Stevenson, D. K., Butte, A. J., Sirota, M. 2019; 132: 16–20

  View details for DOI 10.1016/j.jri.2019.02.004

  View details for Web of Science ID 000466622600003

• Parental age and stillbirth: a population-based cohort of nearly 10 million California deliveries from 1991 to 2011 ANNALS OF EPIDEMIOLOGY Mayo, J. A., Lu, Y., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2019; 31: 32–37

  View details for DOI 10.1016/j.annepidem.2018.12.001

  View details for Web of Science ID 000462806400007

• The contributions of genetics to premature birth PEDIATRIC RESEARCH Stevenson, D. K., Wong, R. J., Shaw, G. M., Li, J., Wise, P. H., Davis, J. M. 2019; 85 (4): 416–17

  View details for DOI 10.1038/s41390-019-0292-0

  View details for Web of Science ID 000460127000003

• Vasa previa and extreme prematurity: a population-based study JOURNAL OF PERINATOLOGY Yeaton-Massey, A., Girsen, A., Mayo, J. A., Blumenfeld, Y. J., El-Sayed, Y. Y., Stevenson, D. K., Shaw, G. M. 2019; 39 (3): 475–80

  View details for DOI 10.1038/s41372-019-0319-8

  View details for Web of Science ID 000459549600018

• Understanding health disparities JOURNAL OF PERINATOLOGY Stevenson, D. K., Wong, R. J., Aghaeepour, N., Angst, M. S., Darmstadt, G. L., DiGiulio, D. B., Druzin, M. L., Gaudilliere, B., Gibbs, R. S., Gould, J. B., Katzl, M., Li, J., Moufarrej, M. N., Quaintancel, C. C., Quake, S. R., Reiman, D. A., Shawl, G. M., Snyder, M. P., Wang, X., Wisel, P. H. 2019; 39 (3): 354–58

  View details for DOI 10.1038/s41372-018-0298-1

  View details for Web of Science ID 000459549600003

• Soluble Factors in the Murine Placenta Regulate Gene Expression in Alternatively-Activated Macrophages. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2019: 293A

  View details for Web of Science ID 000459610400682

• Preeclampsia and Preterm Birth Risk in Women Receiving Dialysis During Pregnancy: A Population-Based Cohort Study. Do, S. C., O'Shaughnessy, M. M., Mayo, J., Girsen, A. I., Shaw, G. M., Stevenson, D. K., Druzin, M. L. SAGE PUBLICATIONS INC. 2019: 178A–179A

  View details for Web of Science ID 000459610400342

• Genetic variants associated with patent ductus arteriosus in extremely preterm infants JOURNAL OF PERINATOLOGY Dagle, J. M., Ryckman, K. K., Spracklen, C. N., Momany, A. M., Cotten, C., Levy, J., Page, G. P., Bell, E. F., Carlo, W. A., Shankaran, S., Goldberg, R. N., Ehrenkranz, R. A., Tyson, J. E., Stoll, B. J., Murray, J. C., Murray, J., Ambalavanan, N., Schibler, K., Sood, B. G., Stevenson, D. K., Van Meurs, K. P., Frantz, I. D., Das, A., Higgins, R. D., Johnson, K. J., Jobe, A. H., Laptook, A. R., Oh, W., Rubin, L. P., Hensman, A. M., Fanaroff, A. A., Walsh, M. C., Newman, N. S., Siner, B. S., Donovan, E. F., Narendran, V., Alexander, B., Grisby, C., Hessling, J., Mersmann, M., Mincey, H. L., Auten, K. J., Hale, E. C., Wright, L. L., Yaffe, S. J., McClure, E. M., Poindexter, B. B., Lemons, J. A., Appel, D. D., Herron, D. E., Wilson, L. D., Poole, W., McDonald, S. A., Hastings, B. K., Zaterka-Baxter, K. M., Auman, J., Schaefer, S. E., Ball, M., Collins, M., Cosby, S. S., Finer, N. N., Rasmussen, M. R., Kaegi, D., Arnell, K., Demetrio, C., Rich, W., Bauer, C. R., Duara, S., Everett-Thomas, R., Papile, L., Lacy, C., Korones, S. B., Bada, H. S., Hudson, T., Salhab, W. A., Madison, S., Kennedy, K. A., Morris, B. H., Akpa, E. G., Cluff, P. A., Franco, C., Lis, A. E., McDavid, G. E., Tate, P., O'Shea, T., Peters, N. J., Konduri, G., Bara, R., Muran, G., Gettner, P., Konstantino, M., Poulsen, J., Eunice Kennedy Shriver Natl Inst C 2019; 39 (3): 401–8

  Abstract

  Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants.Preterm infants (n = 1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables.SNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p < 0.01). None of the associations were significant after correction for multiple comparisons.We identified several common genetic variants associated with PDA. These findings may inform further studies on genetic risk factors for PDA in preterm infants.

  View details for PubMedID 30518802

• Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia. Han, X., Ghaemi, M. S., Ando, K., Peterson, L., Ganio, E. A., Tsai, A. S., Gaudilliere, D., Einhaus, J., Tsai, E. S., Stanley, N. M., Culos, A., Taneda, A. H., Fallahzadeh, R., Wong, R. J., Winn, V. D., Stevenson, D. K., Angst, M. S., Aghaeepour, N., Gaudilliere, B. SAGE PUBLICATIONS INC. 2019: 271A

  View details for Web of Science ID 000459610400616

• Data-Driven Queries between Medications and Spontaneous Preterm Birth among 2.5 Million Pregnancies: Association with Genital Herpes and Antiviral Drugs. Maric, I., Borisenko, E., Winn, V. D., Weber, K. A., Wong, R. J., Aziz, N., Blumenfeld, Y. J., El-Sayed, Y. Y., Stevenson, D. K., Shaw, G. M. SAGE PUBLICATIONS INC. 2019: 389A

  View details for Web of Science ID 000459610400965

• Correction: The effect of light wavelength on in vitro bilirubin photodegradation and photoisomer production. Pediatric research Vreman, H. J., Kourula, S., Jasprova, J., Ludvikova, L., Klan, P., Muchova, L., Vitek, L., Cline, B. K., Wong, R. J., Stevenson, D. K. 2019

  Abstract

  Following publication of this article, the authors noticed that an incorrect affiliation was assigned to the author "Lucie Muchova". The original article has now been updated so that the author "Lucie Muchova" is associated with the "Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Katerinska 32, 120 00 Prague, Czech Republic". This has been corrected in both the PDF and HTML versions of the article.

  View details for PubMedID 30814644

• A pilot study showing a stronger H1N1 influenza vaccination response during pregnancy in women who subsequently deliver preterm. Journal of reproductive immunology Andorf, S., Bhattacharya, S., Gaudilliere, B., Shaw, G. M., Stevenson, D. K., Butte, A. J., Sirota, M. 2019; 132: 16–20

  Abstract

  PROBLEM: Preterm birth (PTB), or the delivery of an infant prior to 37 weeks of gestation, is a major health concern. Although a variety of social, environmental, and maternal factors have been implicated in PTB, causes of preterm labor have remained largely unknown. There is evidence of effectiveness and safety of influenza vaccination during pregnancy, however fewer studies have looked at vaccination response as an indicator of an innate host response that may be associated with adverse pregnancy outcomes. We carried out a pilot study to analyze the flu vaccine response during pregnancy of women who later deliver preterm or term.METHOD OF STUDY: We performed a secondary analysis of the individual-level data from an influenza vaccination response study (openly available from ImmPort) measured by hemagglutination inhibition assay of 91 pregnant women with term deliveries and 11 women who went on to deliver preterm. Flu vaccination responses for H1N1 and H3N2 influenza strains were compared between term and preterm deliveries.RESULTS: Women who went on to deliver preterm showed a significantly (P< 0.001) greater flu vaccine response for the H1N1 strain than women who delivered at term. The vaccine response for H3N2 was not significantly different between these two groups (P= 0.97).CONCLUSIONS: Although the sample size is limited and additional validation is required, our findings suggest an increased activation of the maternal immune system as shown by the stronger vaccination response to H1N1 in women who subsequently delivered preterm, in comparison to women who delivered at term.

  View details for PubMedID 30852461

• Neurodevelopmental outcomes among extremely premature infants with linear growth restriction JOURNAL OF PERINATOLOGY Meyers, J. M., Tan, S., Bell, E. F., Duncan, A. F., Guillet, R., Stoll, B. J., D'Angio, C. T., Caplan, M. S., Laptook, A. R., Keszler, M., Vohr, B. R., Hensman, A. M., Vieira, E., Little, E., Alksninis, B., Keszler, M., Knoll, A. M., Leach, T. M., McGowan, E. C., Watson, V. E., Walsh, M. C., Fanaroff, A. A., Hibbs, A., Newman, N. S., Payne, A. H., Wilson-Costello, D. E., Siner, B. S., Bhola, M., Yalcinkaya, G., Friedman, H. G., Truog, W. E., Pallotto, E. K., Kilbride, H. W., Gauldin, C., Holmes, A., Johnson, K., Knutson, A., Poindexter, B. B., Schibler, K., Alexander, B., Grisby, C., Gratton, T. L., Jackson, L., Kirker, K., Muthig, G., Tepe, S., Yolton, K., Goldberg, R. N., Cotten, C., Goldstein, R. F., Malcolm, W. F., Ashley, P. L., Fisher, K. A., Finkle, J., Gustafson, K. E., Laughon, M. M., Bose, C. L., Bernhardt, J., Bose, G., Wereszczak, J., Carlton, D. P., Hale, E. C., Adams-Chapman, H., Loggins, Y., Carter, S. L., LaRossa, M., Wineski, L. C., Bottcher, D., Mackie, C., Higgins, R. D., Archer, S., Sokol, G. M., Papile, L., Harmon, H. M., Hines, A. C., Wilson, L., Herron, D. E., Gunn, S., Smiley, L., Kennedy, K. A., Tyson, J. E., Allain, E., Arldt-McAlister, J., Dempsey, A. G., Garcia, C., John, J., Jones, P. M., Lillie, L. M., Martin, K., Martin, S. C., McDavid, G. E., Rodgers, S., Siddiki, S., Sperry, D., Wright, S. L., Sanchez, P. J., Nelin, L. D., Jadcherla, S. R., Fortney, C. A., Luzader, P., Besner, G. E., Parikh, N. A., Das, A., Wallace, D., Newman, J. E., Auman, J., Crawford, M., Gabrio, J., Gantz, M. G., Huitema, C., Zaterka-Baxter, K. M., Van Meurs, K. P., Stevenson, D. K., Hintz, S. R., Ball, M., Proud, M. S., Bentley, B., DeAnda, M., DeBattista, A. M., Earhart, B., Huffman, L. C., Krueger, C. E., Lucash, R., Weiss, H. E., Carlo, W. A., Ambalavanan, N., Peralta-Carcelen, M., Collins, M., Cosby, S. S., Biasini, F. J., Johnston, K. C., Patterson, C. S., Phillips, V. A., Whitley, S., Devaskar, U., Garg, M., Purdy, I. B., Chanlaw, T., Geller, R., Colaizy, T. T., Brumbaugh, J. E., Ellsbury, D. L., Johnson, K. J., Walker, J. R., Campbell, D. B., Eastman, D. L., Watterberg, K. L., Lowe, J. R., Fuller, J. F., Ohls, R. K., Lacy, C., Duncan, A. F., Dupont, T., Kuan, E., Beauman, S., Schmidt, B., Kirpalani, H., DeMauro, S. B., Chaudhary, A. S., Abbasi, S., Mancini, T., Bernbaum, J. C., Gerdes, M., Hurt, H., Cook, N., Cucinotta, D. M., Lakshminrusimha, S., Reynolds, A., Jensen, R. L., Merzbach, J., Myers, G. J., Williams, A., Yost, K., Zorn, W., Wynn, K., Maffett, D., Prinzing, D., Hunn, J., Guilford, S., Osman, F., Rowan, M., Sacilowski, M. G., Wadkins, H. M., Bowman, M., Fallone, C., Binion, K., Orme, C., Scorsone, A., Andrews-Hartley, M., Wyckoff, M. H., Brion, L. P., Vasil, D. M., Chen, L., Heyne, R. J., Adams, S. S., Heyne, E., Guzman, A., Lee, L. E., Boatman, C., Shankaran, S., Pappas, A., Natarajan, G., Chawla, S., Bajaj, M., February, M., Agarwal, P., Childs, K., Woldt, E., Bara, R., Goldston, L. A., Barks, J., Christensen, M., Wiggins, S., White, D., Eunice Kennedy Shriver Natl Inst 2019; 39 (2): 193–202

  Abstract

  To compare neurodevelopmental outcomes in linear growth-restricted (LGR) infants born <29 weeks with and without weight gain out of proportion to linear growth.We compared 2-year neurodevelopmental outcomes between infants with and without LGR and between LGR infants with and without weight gain out of proportion to linear growth. The outcomes were Bayley-III cognitive, motor, and language scores, cerebral palsy, Gross Motor Function Classification System (GMFCS) level ≥ 2, and neurodevelopmental impairment.In total, 1227 infants were analyzed. LGR infants were smaller and less mature at birth, had higher BMI, and had lower Bayley-III language scores (82.3 vs. 85.0, p < 0.05). Among infants with LGR, infants with high BMI had lower language scores compared with those with low-to-normal BMI (80.8 vs. 83.3, p < 0.05), and were more likely to have GMFCS level ≥2 and neurodevelopmental impairment.Among infants with LGR, weight gain out of proportion to linear growth was associated with poorer neurodevelopmental outcomes.

  View details for PubMedID 30353080

• Vasa previa and extreme prematurity: a population-based study. Journal of perinatology : official journal of the California Perinatal Association Yeaton-Massey, A., Girsen, A. I., Mayo, J. A., Blumenfeld, Y. J., El-Sayed, Y. Y., Stevenson, D. K., Shaw, G. M. 2019

  Abstract

  OBJECTIVE: To determine population-based risks of preterm birth associated with vasa previa.STUDY DESIGN: Included were 945,950 singleton, live birth cesarean deliveries with and without vasa previa (gestational ages 24-41 weeks) in California between 2007 and 2012. Odds ratios (ORs) of preterm birth were estimated using logistic regression.RESULTS: In total, 586 were complicated by vasa previa (0.06%). In total, 369 (63%) of those with vasa previa were delivered <37 weeks, compared with 91,662 (10%) of those without. Odds of extreme and very preterm birth were substantially higher for pregnancies with vasa previaeven after controlling for comorbidities known to contribute to prematurity, with ORs of 4.6 (95% confidence interval, CI: 1.7-12.5) and 16.0 (95% CI: 10.3-24.8), respectively.CONCLUSION: Based on these population-based data, most patients with vasa previa are delivered between 32 and 36 weeks gestation; however, a clinically significant portion occur before 32 weeks. These data are helpful in counseling patients with vasa previa regarding prematurity risk.

  View details for PubMedID 30692614

• The effect of light wavelength on in vitro bilirubin photodegradation and photoisomer production. Pediatric research Vreman, H. J., Kourula, S., Jasprova, J., Ludvikova, L., Klan, P., Muchova, L., Vitek, L., Cline, B. K., Wong, R. J., Stevenson, D. K. 2019

  Abstract

  BACKGROUND: The action spectrum for bilirubin photodegradation has been intensively studied. However, questions still remain regarding which light wavelength most efficiently photodegrades bilirubin. In this study, we determined the in vitro effects of different irradiation wavelength ranges on bilirubin photodegradation.METHODS: In our in vitro method, normalized absolute irradiance levels of 4.2*1015photons/cm2/s from light-emitting diodes (ranging from 390-530nm) and 10-nm band-pass filters were used to irradiate bilirubin solutions (25mg/dL in 4% human serum albumin). Bilirubin and its major photoisomer concentrations were determined; the half-life time of bilirubin (t1/2) was calculated for each wavelength range, and the spectral characteristics for bilirubin photodegradation products were obtained for key wavelengths.RESULTS: The in vitro photodegradation of bilirubin at 37°C decreased linearly as the wavelengthwas increased from 390 to 500nm with t1/2 decreasing from 63 to 17min, respectively. At 460±10nm, a significantly lower rate of photodegradation and thus higher t1/2 (31min) than that at 500nm (17min) was demonstrated.CONCLUSION: In our system, the optimum bilirubin photodegradation and lumirubin production rates occurred between 490 and 500nm. Spectra shapes were remarkably similar, suggesting that lumirubin production was the major process of bilirubin photodegradation.

  View details for PubMedID 30710116

• The contributions of genetics to premature birth. Pediatric research Stevenson, D. K., Wong, R. J., Shaw, G. M., Li, J., Wise, P. H., Davis, J. M. 2019

  View details for PubMedID 30644444

• Low-dose lipopolysaccharide exposure can increase in vivo bilirubin production rates in newborn mice. Acta paediatrica (Oslo, Norway : 1992) Iwatani, S. n., Jacobsen, D. R., Wong, R. J., Stevenson, D. K. 2019

  Abstract

  Neonatal hemolysis increases bilirubin production rates, which can then lead to severe hyperbilirubinemia and bilirubin neurotoxicity. During hemolysis, heme is degraded by heme oxygenase (HO), which can be induced under stress conditions. It is known that neonatal sepsis is a risk factor for hemolysis and severe hyperbilirubinemia. Here, we evaluated if an exposure to lipopolysaccharide (LPS) to induce sepsis can upregulate HO-1, further increasing in vivo bilirubin production rates in mouse pups under heme loads.3-day-old pups were given LPS (1250 μg/kg) or saline (controls). Liver HO enzyme activity, HO-1 mRNA, and HO-1 protein were measured post-LPS exposure. We then assessed the effects of LPS treatment on in vivo bilirubin production rates after heme loading.Liver HO activity significantly increased (142%) over controls 24 hours after treatment with LPS (1250 μg/kg) without mortality. Liver HO-1 mRNA was significantly upregulated 2.47-fold at 24 hours post-LPS administration, while liver HO-1 protein increased 1.29-fold 24 hours post-LPS treatment. After heme loading, pups exposed to LPS had significantly higher bilirubin production rates (1.30-fold) compared with age-matched, saline-treated controls.Low-dose LPS treatment can upregulate liver HO-1 expression and may underlie the severe hyperbilirubinemia seen in septic infants, particularly when undergoing hemolysis.

  View details for DOI 10.1111/apa.15143

  View details for PubMedID 31860732

• Data-driven queries between medications and spontaneous preterm birth among 2.5 million pregnancies. Birth defects research Marić, I. n., Winn, V. D., Borisenko, E. n., Weber, K. A., Wong, R. J., Aziz, N. n., Blumenfeld, Y. J., El-Sayed, Y. Y., Stevenson, D. K., Shaw, G. M. 2019

  Abstract

  Our goal was to develop an approach that can systematically identify potential associations between medication prescribed in pregnancy and spontaneous preterm birth (sPTB) by mining large administrative "claims" databases containing hundreds of medications. One such association that we illustrate emerged with antiviral medications used for herpes treatment.IBM MarketScan® databases (2007-2016) were used. A pregnancy cohort was established using International Classification of Diseases (ICD-9/10) codes. Multiple hypothesis testing and the Benjamini-Hochberg procedure that limited false discovery rate at 5% revealed, among 863 medications, five that showed odds ratios (ORs) <1. The statistically strongest was an association between antivirals and sPTB that we illustrate as a real example of our approach, specifically for treatment of genital herpes (GH). Three groups of women were identified based on diagnosis of GH and treatment during the first 36 weeks of pregnancy: (a) GH without treatment; (b) GH treated with antivirals; (c) no GH or treatment.We identified 2,538,255 deliveries. 0.98% women had a diagnosis of GH. Among them, 60.0% received antiviral treatment. Women with treated GH had OR < 1, (OR [95% CI] = 0.91 [0.85, 0.98]). In contrast, women with untreated GH had a small increased risk of sPTB (OR [95% CI] =1.22 [1.14, 1.32]).Data-driven approaches can effectively generate new hypotheses on associations between medications and sPTB. This analysis led us to examine the association with GH treatment. While unknown confounders may impact these findings, our results indicate that women with untreated GH have a modest increased risk of sPTB.

  View details for DOI 10.1002/bdr2.1580

  View details for PubMedID 31433567

• Pravastatin improves fetal survival in mice with a partial deficiency of heme oxygenase-1 PLACENTA Tsur, A., Kalish, F., Burgess, J., Nayak, N. R., Zhao, H., Casey, K. M., Druzin, M. L., Wong, R. J., Stevenson, D. K. 2019; 75: 1–8

  View details for DOI 10.1016/j.placenta.2018.11.001

  View details for Web of Science ID 000457628400001

• Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy BIOINFORMATICS Ghaemi, M., DiGiulio, D. B., Contrepois, K., Callahan, B., Ngo, T. M., Lee-McMullen, B., Lehallier, B., Robaczewska, A., Mcilwain, D., Rosenberg-Hasson, Y., Wong, R. J., Quaintance, C., Culos, A., Stanley, N., Tanada, A., Tsai, A., Gaudilliere, D., Ganio, E., Han, X., Ando, K., McNeil, L., Tingle, M., Wise, P., Maric, I., Sirota, M., Wyss-Coray, T., Winn, V. D., Druzin, M. L., Gibbs, R., Darmstadt, G. L., Lewis, D. B., Nia, V., Agard, B., Tibshirani, R., Nolan, G., Snyder, M. P., Relman, D. A., Quake, S. R., Shaw, G. M., Stevenson, D. K., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2019; 35 (1): 95–103

  View details for DOI 10.1093/bioinformatics/bty537

  View details for Web of Science ID 000459313900012

• “Following Through”: Addressing the Racial Inequality for Preterm Infants and Their Families Pediatric Research Stevenson, D. K., Wong, R. J., Profit, J. J., Shaw, G. M., Wang, C. J., Lee, H. C. 2019

  View details for DOI 10.1038/s41390-019-0602-6

• Improving the prediction of shoulder dystocia using artificial intelligence - a novel approach Tsur, A., Batsry, L., Barak, O., Brezinov, Y., Toussia-Cohen, S., Yoeli-Ullman, R., Sivan, E., Blumenfeld, Y. J., Druzin, M. L., Stevenson, D. K., Aran, D. MOSBY-ELSEVIER. 2019: S435–S436

  View details for DOI 10.1016/j.ajog.2018.11.679

  View details for Web of Science ID 000454249402136

• "Following through": addressing the racial inequality for preterm infants and their families. Pediatric research Stevenson, D. K., Wong, R. J., Profit, J. n., Shaw, G. M., Jason Wang, C. n., Lee, H. C. 2019

  View details for DOI 10.1038/s41390-019-0602-6

  View details for PubMedID 31581171

• IN VITRO INHIBITORY POTENCY OF ZINC PROTOPORPHYRIN MICROSPHERES ON HEME OXYGENASE ISOZYME ACTIVITY Jacobsen, D., Iwatani, S., Onderdonk, Z., Wong, R. T., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2019: 117

  View details for DOI 10.1136/jim-2018-000939.115

  View details for Web of Science ID 000457712500125

• A NOVEL POINT-OF-CARE DEVICE FOR MEASURING GLUCOSE-6-PHOSPHATE DEHYDROGENASE ENZYME DEFICIENCY Montiel, C., Kunda, M., Stevenson, D. K., Wong, R. J., Bhutani, V. K. BMJ PUBLISHING GROUP. 2019: 117

  View details for DOI 10.1136/jim-2018-000939.116

  View details for Web of Science ID 000457712500126

• BILIRUBIN PRODUCTION IS INCREASED IN NEWBORN MICE TREATED WITH LIPOPOLYSACCHARIDE Iwatani, S., Jacobsen, D., Wong, R. T., Onderdonk, Z., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2019: 117–18

  View details for DOI 10.1136/jim-2018-000939.117

  View details for Web of Science ID 000457712500127

• IMPACT OF CARDIAC ALGORITHM ON CYTOGENETIC TESTING Floyd, B. J., Hintz, S. R., Suarez, C. J., Cherry, A., Yu, L., Benitz, W., Priest, J. R., Wright, G. E., Bhombal, S., Davis, A., Chock, V. Y., Weigel, N., Kobayashi, D., Fluharty, B., Stevenson, D. BMJ PUBLISHING GROUP. 2019: 207

  View details for DOI 10.1136/jim-2018-000939.327

  View details for Web of Science ID 000457712500337

• Pravastatin improves fetal survival in mice with a partial deficiency of heme oxygenase-1. Placenta Tsur, A. n., Kalish, F. n., Burgess, J. n., Nayak, N. R., Zhao, H. n., Casey, K. M., Druzin, M. L., Wong, R. J., Stevenson, D. K. 2019; 75: 1–8

  Abstract

  Statins induce heme oxygenase-1 (HO-1) expression in vitro and in vivo. Low HO-1 expression is associated with pregnancy complications, e.g. preeclampsia and recurrent miscarriages. Here, we investigated the effects of pravastatin on HO-1 expression, placental development, and fetal survival in mice with a partial HO-1 deficiency.At E14.5, untreated pregnant wild-type (WT, n=13-18), untreated HO-1+/- (Het, n=6-9), and Het mice treated with pravastatin (Het+Pravastatin, n=12-14) were sacrificed. Numbers of viable fetuses/resorbed concepti were recorded. Maternal livers and placentas were harvested for HO activity. Hematoxylin and eosin (H&E) and CD31 immunohistochemical staining were performed on whole placentas.Compared with WT, HO activity in Het livers (65±18%, P<0.001) and placentas (74±7%, P<0.001) were significantly decreased. Number of viable fetuses per dam was significantly lower in Untreated Het dams (6.0±2.2) compared with WT (9.1±1.4, P<0.01), accompanied by a higher relative risk (RR) for concepti resorption (17.1, 95% CI 4.0-73.2). In Hets treated with pravastatin, maternal liver and placental HO activity increased, approaching levels of WT controls (to 83±7% and 87±14%, respectively). The number of viable fetuses per dam increased to 7.7±2.5 with a decreased RR for concepti resorption (2.7, 95% CI 1.2-5.9). In some surviving Untreated Het placentas, there were focal losses of cellular architecture and changes suggestive of reduced blood flow in the labyrinth. These findings were absent in Het+Pravastatin placentas.Pravastatin induces maternal liver and placental HO activity, may affect placental function and improve fetal survival in the context of a partial deficiency of HO-1.

  View details for PubMedID 30712660

• Parental age and stillbirth: a population-based cohort of nearly 10 million California deliveries from 1991 to 2011. Annals of epidemiology Mayo, J. A., Lu, Y., Stevenson, D. K., Shaw, G. M., Eisenberg, M. L. 2018

  Abstract

  PURPOSE: Parental age at delivery in the United States has been rising. Advanced maternal and paternal ages have been associated with adverse pregnancy outcomes including stillbirth. However, these relationships come from studies that often do not present results for both mother and father concurrently. The purpose of this study was to estimate the risk of stillbirth for maternal and paternal age in the same cohort of deliveries.METHODS: This is a population-based cohort study of all live birth and stillbirth deliveries in California from 1991 to 2011. The individual associations between maternal and paternal ages and stillbirth were estimated with hazard ratios from Cox proportional hazard models. Age was modeled continuously with restricted cubic splines to account for nonlinear relationships. Mean parental age was used as the referent group.RESULTS: J-shaped associations between maternal and paternal ages were observed in crude models where older mothers and fathers had the highest hazard ratios for stillbirth. In maternal models, after adjusting for maternal and paternal covariates, young maternal age no longer showed increased hazard ratio for stillbirth, whereas the association with older mothers remained. In adjusted paternal models, the relationship between young paternal age and stillbirth was unchanged while the hazard ratio for older fathers was slightly smaller.CONCLUSIONS: After adjusting for both parents' age, education, race/ethnicity, along with parity, older mothers and fathers were independently associated with elevated hazard ratios for stillbirth.

  View details for PubMedID 30642694

• Author Correction: Enabling precision medicine in neonatology, an integrated repository for preterm birth research. Scientific data Sirota, M., Thomas, C. G., Liu, R., Zuhl, M., Banerjee, P., Wong, R. J., Quaintance, C. C., Leite, R., Chubiz, J., Anderson, R., Chappell, J., Kim, M., Grobman, W., Zhang, G., Rokas, A., Muglia, L. J., Ober, C., England, S. K., Macones, G., Driscoll, D., Parry, S., Shaw, G. M., Stevenson, D. K., Simpson, J. L., Thomson, E., Butte, A. J., March of Dimes Prematurity Research Centers, Driscoll, D., Macones, G., Muglia, L. J., Ober, C., Stevenson, D. K. 2018; 5 (1): 3

  Abstract

  The original version of the Data Descriptor contained errors in the author list and affiliations. Rita Leite's first name was misspelled as "Rite" and affiliations 4 and 5 were incorrectly swapped. In addition, members of the March of Dimes Prematurity Research Center consortium were not listed in the agreed positions within the author list. These errors have now been corrected in the HTML and PDF versions.

  View details for PubMedID 30563979

• Enabling precision medicine in neonatology, an integrated repository for preterm birth research (vol 5, 180219, 2018) SCIENTIFIC DATA Sirota, M., Thomas, C. G., Liu, R., Zuhl, M., Banerjee, P., Wong, R. J., Quaintance, C. C., Leite, R., Chubiz, J., Anderson, R., Chappell, J., Kim, M., Grobman, W., Zhang, G., Rokas, A., Muglia, L. J., Ober, C., England, S. K., Macones, G., Driscoll, D., Parry, S., Shaw, G. M., Stevenson, D. K., Simpson, J., Thomson, E., Butte, A. J., March Dimes Prematurity Res Ctrs 2018; 5

  View details for DOI 10.1038/s41597-018-0004-3

  View details for Web of Science ID 000453586800001

• Behavioral problems are associated with cognitive and language scores in toddlers born extremely preterm. Early human development Lowe, J. R., Fuller, J. F., Do, B. T., Vohr, B. R., Das, A., Hintz, S. R., Watterberg, K. L., Higgins, R. D., Eunice Kennedy Shriver National Institute of Child Health, Human Development Neonatal Research Network 2018; 128: 48–54

  Abstract

  OBJECTIVE: To evaluate the relationship of parent-reported child behaviors on the Child Behavior Checklist (CBCL) to cognition, language, and motor skills on the Bayley Scales of Infant and Toddler Development - III (Bayley-III) in toddlers born extremely preterm.STUDY DESIGN: Toddlers born extremely preterm (gestational ages 22 0/7 to 26 6/7 weeks) were tested at 22-26 months corrected age with Bayley-III while parents completed the CBCL. Socio-demographic variables and medical history were recorded. Linear regression models were used to assess the relationship of Bayley-III cognitive, motor, and language scores with CBCL scores, adjusting for medical and socio-demographic factors.RESULTS: Internalizing, affective, and pervasive development problem behavior scores on the CBCL correlated significantly with lower Bayley-III cognitive, language, and motor scores on unadjusted and adjusted analyses. Although externalizing and anxiety problems were significantly associated with cognitive and language scores on unadjusted analysis, the relationships were not significant after adjusting for socio-economic factors. CBCL scores were similar for boys and girls, with the exception of the pervasive developmental problem scale; boys had significantly more problems than girls (p = 0.02).CONCLUSIONS: This study showed that parent reported behavior problems were related to lower cognitive, language, and motor development in toddlers born extremely preterm. Early findings of behavioral problems in toddlers born extremely premature may help identify children at greater risk for later learning difficulties. Adding a measure of behavior to the evaluation of these children may help better understand factors that can contribute to delays, especially in cognition and language.

  View details for PubMedID 30522091

• Prediction of cognitive and motor development in preterm children using exhaustive feature selection and cross-validation of near-term white matter microstructure. NeuroImage. Clinical Schadl, K., Vassar, R., Cahill-Rowley, K., Yeom, K. W., Stevenson, D. K., Rose, J. 2018; 17: 667-679

  Abstract

  Advanced neuroimaging and computational methods offer opportunities for more accurate prognosis. We hypothesized that near-term regional white matter (WM) microstructure, assessed on diffusion tensor imaging (DTI), using exhaustive feature selection with cross-validation would predict neurodevelopment in preterm children.Near-term MRI and DTI obtained at 36.6 ± 1.8 weeks postmenstrual age in 66 very-low-birth-weight preterm neonates were assessed. 60/66 had follow-up neurodevelopmental evaluation with Bayley Scales of Infant-Toddler Development, 3rd-edition (BSID-III) at 18-22 months. Linear models with exhaustive feature selection and leave-one-out cross-validation computed based on DTI identified sets of three brain regions most predictive of cognitive and motor function; logistic regression models were computed to classify high-risk infants scoring one standard deviation below mean.Cognitive impairment was predicted (100% sensitivity, 100% specificity; AUC = 1) by near-term right middle-temporal gyrus MD, right cingulate-cingulum MD, left caudate MD. Motor impairment was predicted (90% sensitivity, 86% specificity; AUC = 0.912) by left precuneus FA, right superior occipital gyrus MD, right hippocampus FA. Cognitive score variance was explained (29.6%, cross-validated Rˆ2 = 0.296) by left posterior-limb-of-internal-capsule MD, Genu RD, right fusiform gyrus AD. Motor score variance was explained (31.7%, cross-validated Rˆ2 = 0.317) by left posterior-limb-of-internal-capsule MD, right parahippocampal gyrus AD, right middle-temporal gyrus AD.Search in large DTI feature space more accurately identified neonatal neuroimaging correlates of neurodevelopment.

  View details for DOI 10.1016/j.nicl.2017.11.023

  View details for PubMedID 29234600

  View details for PubMedCentralID PMC5722472

• Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank. Metabolomics : Official journal of the Metabolomic Society La Frano, M. R., Carmichael, S. L., Ma, C., Hardley, M., Shen, T., Wong, R., Rosales, L., Borkowski, K., Pedersen, T. L., Shaw, G. M., Stevenson, D. K., Fiehn, O., Newman, J. W. 2018; 14 (11): 151

  Abstract

  Population-based biorepositories are important resources, but sample handling can affect data quality.Identify metabolites of value for clinical investigations despite extended postcollection freezing delays, using protocols representing a California mid-term pregnancy biobank.Blood collected from non-pregnant healthy female volunteers (n = 20) underwent three handling protocols after 30 min clotting at room temperature: (1) ideal-samples frozen (- 80 °C) within 2 h of collection; (2) delayed freezing-samples held at room temperature for 3 days, then 4 °C for 9 days, the median times for biobank samples, and then frozen; (3) delayed freezing with freeze-thaw-the delayed freezing protocol with a freeze-thaw cycle simulating retrieved sample sub-aliquoting. Mass spectrometry-based untargeted metabolomic analyses of primary metabolism and complex lipids and targeted profiling of oxylipins, endocannabinoids, ceramides/sphingoid-bases, and bile acids were performed. Metabolite concentrations and intraclass correlation coefficients (ICC) were compared, with the ideal protocol as the reference.Sixty-two percent of 428 identified compounds had good to excellent ICCs, a metric of concordance between measurements of samples handled with the different protocols. Sphingomyelins, phosphatidylcholines, cholesteryl esters, triacylglycerols, bile acids and fatty acid diols were the least affected by non-ideal handling, while sugars, organic acids, amino acids, monoacylglycerols, lysophospholipids, N-acylethanolamides, polyunsaturated fatty acids, and numerous oxylipins were altered by delayed freezing. Freeze-thaw effects were assay-specific with lipids being most stable.Despite extended post-collection freezing delays characteristic of some biobanks of opportunistically collected clinical samples, numerous metabolomic compounds had both stable levels and good concordance.

  View details for DOI 10.1007/s11306-018-1450-9

  View details for PubMedID 30830400

• Enabling precision medicine in neonatology, an integrated repository for preterm birth research. Scientific data Sirota, M., Thomas, C. G., Liu, R., Zuhl, M., Banerjee, P., Wong, R. J., Quaintance, C. C., Leite, R., Chubiz, J., Anderson, R., Chappell, J., Kim, M., Grobman, W., Zhang, G., Rokas, A., England, S. K., Parry, S., Shaw, G. M., Simpson, J. L., Thomson, E., Butte, A. J., March of Dimes Prematurity Research Centers, Driscoll, D., Macones, G., Muglia, L. J., Ober, C., Stevenson, D. K. 2018; 5: 180219

  Abstract

  Preterm birth, or the delivery of an infant prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. In the last decade, the advent and continued development of molecular profiling technologies has enabled researchers to generate vast amount of 'omics' data, which together with integrative computational approaches, can help refine the current knowledge about disease mechanisms, diagnostics, and therapeutics. Here we describe the March of Dimes' Database for Preterm Birth Research (http://www.immport.org/resources/mod), a unique resource that contains a variety of 'omics' datasets related to preterm birth. The database is open publicly, and as of January 2018, links 13 molecular studies with data across tens of thousands of patients from 6 measurement modalities. The data in the repository are highly diverse and include genomic, transcriptomic, immunological, and microbiome data. Relevant datasets are augmented with additional molecular characterizations of almost 25,000 biological samples from public databases. We believe our data-sharing efforts will lead to enhanced research collaborations and coordination accelerating the overall pace of discovery in preterm birth research.

  View details for PubMedID 30398470

• Enabling precision medicine in neonatology, an integrated repository for preterm birth research SCIENTIFIC DATA Sirota, M., Thomas, C. G., Liu, R., Zuhl, M., Banerjee, P., Wong, R. J., Quaintance, C. C., Leite, R., Chubiz, J., Anderson, R., Chappell, J., Kim, M., Grobman, W., Zhang, G., Rokas, A., England, S. K., Parry, S., Shaw, G. M., Simpson, J., Thomson, E., Butte, A. J., March Dimes Prematurity Res Ctr 2018; 5

  View details for DOI 10.1038/sdata.2018.219

  View details for Web of Science ID 000449252700001

• Maternal Height and Risk of Preeclampsia among Race/Ethnic Groups. American journal of perinatology Maric, I., Mayo, J. A., Druzin, M. L., Wong, R. J., Winn, V. D., Stevenson, D. K., Shaw, G. M. 2018

  Abstract

  OBJECTIVE: Shorter maternal height has been associated with preeclampsia risk in several populations. It has been less evident whether an independent contribution to the risk exists from maternal height consistently across different races/ethnicities. We investigated associations between maternal height and risk of preeclampsia for different races/ethnicities.STUDY DESIGN: California singleton live births from 2007 to 2011 were analyzed. Logistic regression was used to estimate adjusted odds ratios for the association between height and preeclampsia after stratification by race/ethnicity. To determine the contribution of height that is as independent of body composition as possible, we performed one analysis adjusted for body mass index (BMI) and the other for weight. Additional analyses were performed stratified by parity, and the presence of preexisting/gestational diabetes and autoimmune conditions.RESULTS: Among 2,138,012 deliveries, 3.1% preeclampsia/eclampsia cases were observed. The analysis, adjusted for prepregnancy weight, revealed an inverse relation between maternal height and risk of mild and severe preeclampsia/eclampsia. When the analysis was adjusted for BMI, an inverse relation between maternal height was observed for severe preeclampsia/eclampsia. These associations were observed for each race/ethnicity.CONCLUSION: Using a large and diverse cohort, we demonstrated that shorter height, irrespective of prepregnancy weight or BMI, is associated with an increased risk of severe preeclampsia/eclampsia across different races/ethnicities.

  View details for PubMedID 30396225

• Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank METABOLOMICS La Frano, M. R., Carmichael, S. L., Ma, C., Hardley, M., Shen, T., Wong, R., Rosales, L., Borkowski, K., Pedersen, T. L., Shaw, G. M., Stevenson, D. K., Fiehn, O., Newman, J. W. 2018; 14 (11)

  View details for DOI 10.1007/s11306-018-1450-9

  View details for Web of Science ID 000450525400001

• Transcutaneous bilirubinometer use and practices surrounding jaundice in 150 California newborn intensive care units JOURNAL OF PERINATOLOGY Bhatt, D. R., Kristensen-Cabrera, A., Lee, H. C., Weerasinghe, S., Stevenson, D. K., Bhutani, V. K., Maisels, M., Ramanathan, R. 2018; 38 (11): 1532–35

  View details for DOI 10.1038/s41372-018-0154-3

  View details for Web of Science ID 000449174800015

• Need for Reassessment of Early Transpyloric Feeding in Preterm Infants JAMA PEDIATRICS Wallenstein, M. B., Stevenson, D. K. 2018; 172 (11): 1004–5

  View details for DOI 10.1001/jamapediatrics.2018.2035

  View details for Web of Science ID 000449215800006

• Application of machine-learning to predict early spontaneous preterm birth among nulliparous non-Hispanic black and white women ANNALS OF EPIDEMIOLOGY Weber, A., Darmstadt, G. L., Gruber, S., Foeller, M. E., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 2018; 28 (11): 783–89

  View details for DOI 10.1016/j.annepidem.2018.08.008

  View details for Web of Science ID 000450020400006

• Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study. BMJ (Clinical research ed.) Khandwala, Y. S., Baker, V. L., Shaw, G. M., Stevenson, D. K., Lu, Y., Eisenberg, M. L. 2018; 363: k4372

  Abstract

  OBJECTIVE: To evaluate the impact of advanced paternal age on maternal and perinatal outcomes in the United States.DESIGN: Retrospective, population based cohort study.SETTING: US.POPULATION: 40529905 documented live births between 2007 and 2016.MAIN OUTCOME MEASURES: Primary perinatal outcomes were gestational age, birth weight, Apgar score at five minutes, admission to a neonatal intensive care unit, need for postpartum antibiotics, and seizures. Primary maternal outcomes were gestational diabetes and pre-eclampsia. Secondary outcome was the number of preventable perinatal events.RESULTS: Higher paternal age was associated with an increased risk of premature birth, low birth weight, and low Apgar score. After adjustment for maternal age, infants born to fathers aged 45 years or older had 14% higher odds of premature birth (odds ratio 1.14, 95% confidence interval 1.13 to 1.15), independent of gestational age, and 18% higher odds of seizures (1.18, 0.97 to 1.44) compared with infants of fathers aged 25 to 34 years. The odds of gestational diabetes was 34% higher (1.34, 1.29 to 1.38) in mothers with the oldest partners. 13.2% (95% confidence interval 12.5% to 13.9%) of premature births and 18.2% (17.5% to 18.9%) of gestational diabetes in births associated with older fathers were estimated to be attributable to advanced paternal age.CONCLUSIONS: Advanced paternal age is associated with negative effects on both mothers and offspring. Given the relatively low prevalence of advanced paternal age in the US, population level impacts are currently modest. Nevertheless, as advanced paternal age has doubled in the US over the past generation, further investigation is warranted of the impact on birth outcomes and public health.

  View details for PubMedID 30381468

• Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study BMJ-BRITISH MEDICAL JOURNAL Khandwala, Y. S., Baker, V. L., Shaw, G. M., Stevenson, D. K., Lu, Y., Eisenberg, M. L. 2018; 363

  View details for DOI 10.1136/bmj.k4372

  View details for Web of Science ID 000449564200004

• Weaning of Moderately Preterm Infants from the Incubator to the Crib: A Randomized Clinical Trial. The Journal of pediatrics Shankaran, S., Bell, E. F., Laptook, A. R., Saha, S., Newman, N. S., Kazzi, S. N., Barks, J., Stoll, B. J., Bara, R., Gabrio, J., Childs, K., Das, A., Higgins, R. D., Carlo, W. A., Sanchez, P. J., Carlton, D. P., Pavageau, L., Malcolm, W. F., D'Angio, C. T., Ohls, R. K., Poindexter, B. B., Sokol, G. M., Van Meurs, K. P., Colaizy, T. T., Khmour, A., Puopolo, K. M., Garg, M., Walsh, M. C., Eunice Kennedy Shriver National Institute of Child Health, a. H., Polin, R. A., Keszler, M., Hensman, A. M., Vieira, E., Hibbs, A. M., Siner, B. S., Truog, W. E., Pallotto, E. K., Kilbride, H. W., Gauldin, C., Holmes, A., Johnson, K., Schibler, K., Kallapur, S. G., Grisby, C., Alexander, B., Fischer, E. E., Jackson, L., Kirker, K., Jennings, J., Wuertz, S., Muthig, G., Cotten, C. M., Goldberg, R. N., Roach, T., Finkle, J., Fisher, K. A., Laughon, M. M., Bose, C. L., Bernhardt, J., Clark, C., Kicklighter, S. D., Rhodes-Ryan, G., Hale, E. C., Loggins, Y., Bottcher, D. I., Archer, S. W., Harmon, H., Herron, D. E., Wright-Coltart, S. I., Nelin, L. D., Jadcherla, S. R., Luzader, P., Gutentag, J., Park, C., Shadd, J. C., Sullivan, M., Grothause, J. L., Stein, M., Clark, E., Sullivan, R. A., Wallace, D., Zaterka-Baxter, K. M., Crawford, M., Auman, J. O., Stevenson, D. K., Herfert, L. A., Ball, M. B., Goodlin, G. T., Proud, M. S., Williams, R. J., Ambalavanan, N., Collins, M. V., Cosby, S. S., Chanlaw, T., Geller, R., Ellsbury, D. L., Brumbaugh, J. E., Johnson, K. J., Campbell, D. B., Walker, J. R., Watterberg, K., Lacy, C. B., Beauman, S. S., Hartenberger, C., Kirpalani, H., Eichenwald, E. C., DeMauro, S. B., Cook, N., Chaudhary, A. S., Abbasi, S., Mancini, T., Cucinotta, D., Lakshminrusimha, S., Guillet, R., Scorsone, A. M., Hunn, J., Jensen, R., Wadkins, H. I., Guilford, S., Williams, A., Wyckoff, M., Brion, L. P., Vasil, D. M., Chen, L., Torres, L. E., Pappas, A., Panaitescu, B., Handel, S., White, D. F., Christensen, M., Wiggins, S. A. 2018

  Abstract

  OBJECTIVE: To assess whether length of hospital stay is decreased among moderately preterm infants weaned from incubator to crib at a lower vs higher weight.STUDY DESIGN: This trial was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants with gestational ages 29-33 weeks, birthweight <1600 g, and in an incubator were randomly assigned to a weaning weight of 1600 or 1800 g. Within 60 to 100 g of weaning weight, the incubator temperature was decreased by 1.0°C to 1.5°C every 24 hours until 28.0°C. The infants were weaned to the crib following stable temperature at 36.5°C to 37.4°C for 8 to 12hours. Clothing and bedcoverings were standardized. The primary outcome was length of hospital stay from birth to discharge; secondary outcomes included length of stay and growth velocity from weaning to discharge. Adverse events were monitored.RESULTS: Of 1565 infants screened, 885 were eligible, and 366 enrolled-187 to the 1600-g and 179 to the 1800-g group. Maternal and neonatal characteristics did not differ among weight groups. Length of hospital stay was a median of 43 days in the lower and 41 days in the higher weight group (P=.12). Growth velocity from completion of weaning to discharge was higher in the lower weight group, 13.7 g/kg/day vs 12.8g/kg/day (P=.005). Groups did not differ in adverse events.CONCLUSIONS: Among moderately preterm neonates, weaning from incubator to crib at a lower weight did not decrease length of stay, but was safe and was accompanied by higher weight gain after weaning.TRIAL REGISTRATION: ClinicalTrials.govNCT02160002.

  View details for PubMedID 30337189

• Behavioral Deficits at 18-22 Months of Age Are Associated with Early Cerebellar Injury and Cognitive and Language Performance in Children Born Extremely Preterm. The Journal of pediatrics Duncan, A. F., Bann, C. M., Dempsey, A., Peralta-Carcelen, M., Hintz, S., Eunice Kennedy Shriver National Institute of Child Health and Development Neonatal Research Network, Jobe, A. H., Caplan, M. S., Laptook, A. R., Vohr, B. R., Oh, W., Hensman, A. M., Alksninis, B., Andrews, D., Angela, K., Barnett, S., Cashore, B., Caskey, M., Francis, K., Gingras, D., Johnson, K., Leach, T. M., Stephens, B. E., Watson, V. E., Walsh, M. C., Fanaroff, A. A., Newman, N. S., Wilson-Costello, D. E., Siner, B. S., Zadell, A., DiFiore, J., Bhola, M., Friedman, H. G., Yalcinkaya, G., Bulas, D., Goldberg, R. N., Cotten, C. M., Goldstein, R. F., Ashley, P., Auten, K. J., Fisher, K. A., Foy, K. A., Freedman, S. F., Gustafson, K. E., Lohmeyer, M. B., Malcolm, W. F., Wallace, D. K., Carlton, D. P., Stoll, B. J., Adams-Chapman, I., Buchter, S., Piazza, A. J., Carter, S., Fritz, S., Hale, E. C., Hutchinson, A. K., LaRossa, M. M., Higgins, R. D., Archer, S. W., Sokol, G. M., Poindexter, B. B., Dusick, A. M., Lemons, J. A., Wilson, L. D., Hamer, F., Cook, A. B., Herron, D. E., Lytle, C., Minnich, H. M., Berberich, M. A., Blaisdell, C. J., Gail, D. B., Kiley, J. P., Das, A., Gantz, M. G., Newman, J. E., Cheng, H., Hastings, B. K., McClure, E. M., Auman, J. O., Huitema, C. P., Poole, W. K., Pickett, J. W., Wallace, D., Wrage, L. A., Zaterka-Baxter, K. M., Van Meurs, K. P., Stevenson, D. K., Ball, M. B., Barnes, P. D., Bentley, B., Bruno, E. F., DeAnda, M. E., DeBattista, A. M., Kohn, J. G., Proud, M. S., Pyle, R. P., Weiss, H. E., Frantz, I. D., Fiascone, J. M., McGowan, E. C., Furey, A., MacKinnon, B. L., Nylen, E., Brussa, A., Sibley, C., Carlo, W. A., Ambalavanan, N., Collins, M. V., Cosby, S. S., Phillips, V. A., Bailey, K. J., Biasini, F. J., Hopkins, M., Johnston, K. C., Nelson, K. G., Patterson, C. S., Rector, R. V., Rodriguez, L., Soong, A., Whitley, S., York, S., Finer, N. N., Rasmussen, M. R., Wozniak, P. R., Vaucher, Y. E., Rich, W., Arnell, K., Barbieri-Welge, R., Ben-Tall, A., Bridge, R., Demetrio, C., Fuller, M. G., Ito, E., Lukasik, M., Pontillo, D., Posin, D., Runyan, C., Wilkes, J., Zlotnik, P., Bell, E. F., Widness, J. A., Acarregui, M. J., Klein, J. M., Colaizy, T. T., Johnson, K. J., Eastman, D. L., Duara, S., Bauer, C. R., Everett-Thomas, R., Calejo, M., Diaz, A. N., Frade Eguaras, S. M., Garcia, A., Hamlin-Smith, K., Berkowits, M. H., Hiriart-Fajardo, S., Mathews, E. O., Pierre, H., Riguard, A., Stroerger, A., Watterberg, K. L., Ohls, R. K., Fuller, J., Rohr, J., Lacy, C. B., Lowe, J., Montman, R., Brown, S., Laroia, N., Phelps, D. L., Myers, G. J., Markowitz, G. D., Reubens, L. J., Hust, D., Augostino, L., Johnson, J. B., Burnell, E., Gelbard, H., Jensen, R. L., Kushner, E., Merzbach, J., Mink, J., Torres, C., Wang, D., Yost, K., Sanchez, P. J., Rosenfeld, C. R., Salhab, W. A., Heyne, R. J., Adams, S. S., Allen, J., Grau, L., Guzman, A., Hensley, G., Heyne, E. T., Hickman, J. F., Leps, M. H., Madden, L. A., Martin, M., Miller, N. A., Morgan, J. S., Solis, A., Torres, L. E., Boatman, C. T., Vasil, D. M., Kennedy, K. A., Tyson, J. E., Evans, P. W., Akpa, E. G., Alaniz, N. I., Harris, B. F., Green, C., Jiminez, M., Lis, A. E., Martin, S., McDavid, G. E., Morris, B. H., Poundstone, M. L., Reddoch, S., Siddiki, S., Pierce Tate, P. L., Wright, S. L., Yoder, B. A., Faix, R. G., Baker, S., Bird, K., Bullwinkle, A. E., Burnett, J., Cole, L., Osborne, K. A., Spencer, C., Steele, R. E., Steffen, M., Weaver-Lewis, K., O'Shea, T. M., Dillard, R. G., Washburn, L. K., Peters, N. J., Jackson, B. G., Chiu, K., Allred, D. E., Goldstein, D. J., Halfond, R., Peterson, C., Waldrep, E. L., Welch, C. D., Morris, M. W., Hounshell, G. W., Shankaran, S., Sood, B. G., Slovis, T. L., Pappas, A., Bara, R., Billian, E., Goldston, L. A., Johnson, M. 2018

  Abstract

  OBJECTIVE: To investigate associations in toddlers born extremely preterm (<28weeks) between neonatal neuroimaging and 18- to 22-month developmental and behavioral outcomes.STUDY DESIGN: Cohort analysis from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Surfactant Positive Airway Pressure and Pulse Oximetry Trial Neuroimaging and Neurodevelopmental Outcomes Study of infants born extremely preterm. Subjects underwent cranial ultrasonography and near-term magnetic resonance imaging (MRI). At 18-22 months of corrected age, the assessment included the Brief Infant Toddler Social Emotional Assessment (BITSEA) Problem and Competence Scale scores and the Bayley Scales of Infant Development, Third Edition (Bayley-III). The BITSEA Problem Scale assesses dysregulation; the Competence Scale assesses social-emotional competence. We examined associations of Problem and Competence scores and positive screen rates with cranial ultrasonography and near-term MRI. Mean BITSEA and Bayley-III scores were compared using ANOVA and positive screen rates with the chi2 test. We computed correlations between BITSEA and Bayley-III scores.RESULTS: Of the 397 children, positive BITSEA screens were found in 34% for the Problem score and 26% for the Competence score. Presence of lesions on near-term MRI that included cerebellar lesions were significantly associated with lower BITSEA Competence but not with Problem scores; Competence scores were inversely related to the presence/significance of lesions. Positive screens on Competence scores and on both Competence and Problem scores were significantly associated with Bayley-III cognitive and language scores <85 (P<.001).CONCLUSIONS: Social-emotional competence contributes to deficits in cognitive and language development. Presence of injury on near-term MRI that includes cerebellar lesions is associated with later social-emotional competence and may be a useful predictor to guide early assessment and intervention.TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063 and NCT00233324.

  View details for PubMedID 30292492

• Metagenomic analysis with strain-level resolution reveals fine-scale variation in the human pregnancy microbiome GENOME RESEARCH Goltsman, D., Sun, C. L., Proctor, D. M., DiGiulio, D. B., Robaczewska, A., Thomas, B. C., Shaw, G. M., Stevenson, D. K., Holmes, S. P., Banfield, J. F., Relman, D. A. 2018; 28 (10): 1467–80

  View details for DOI 10.1101/gr.236000.118

  View details for Web of Science ID 000446043800004

• Bilirubin binding in jaundiced newborns: from bench to bedside? PEDIATRIC RESEARCH Ahlfors, C. E., Bhutani, V. K., Wong, R. J., Stevenson, D. K. 2018; 84 (4): 494–98

  View details for DOI 10.1038/s41390-018-0010-3

  View details for Web of Science ID 000458016800001

• Prethreshold retinopathy of prematurity: VEGF inhibition without VEGF inhibitors JOURNAL OF PERINATOLOGY Gaynon, M. W., Wong, R. J., Stevenson, D. K., Sunshine, P. 2018; 38 (10): 1295–1300

  View details for DOI 10.1038/s41372-018-0177-9

  View details for Web of Science ID 000446499400003

• Metagenomic analysis with strain-level resolution reveals fine-scale variation in the human pregnancy microbiome. Genome research Goltsman, D. S., Sun, C. L., Proctor, D. M., DiGiulio, D. B., Robaczewska, A., Thomas, B. C., Shaw, G. M., Stevenson, D. K., Holmes, S. P., Banfield, J. F., Relman, D. A. 2018

  Abstract

  Recent studies suggest that the microbiome has an impact on gestational health and outcome. However, characterization of the pregnancy-associated microbiome has largely relied on 16S rRNA gene amplicon-based surveys. Here, we describe an assembly-driven, metagenomics-based, longitudinal study of the vaginal, gut, and oral microbiomes in 292 samples from 10 subjects sampled every three weeks throughout pregnancy. Nonhuman sequences in the amount of 1.53 Gb were assembled into scaffolds, and functional genes were predicted for gene- and pathway-based analyses. Vaginal assemblies were binned into 97 draft quality genomes. Redundancy analysis (RDA) of microbial community composition at all three body sites revealed gestational age to be a significant source of variation in patterns of gene abundance. In addition, health complications were associated with variation in community functional gene composition in the mouth and gut. The diversity of Lactobacillus iners-dominated communities in the vagina, unlike most other vaginal community types, significantly increased with gestational age. The genomes of co-occurring Gardnerella vaginalis strains with predicted distinct functions were recovered in samples from two subjects. In seven subjects, gut samples contained strains of the same Lactobacillus species that dominated the vaginal community of that same subject and not other Lactobacillus species; however, these within-host strains were divergent. CRISPR spacer analysis suggested shared phage and plasmid populations across body sites and individuals. This work underscores the dynamic behavior of the microbiome during pregnancy and suggests the potential importance of understanding the sources of this behavior for fetal development and gestational outcome.

  View details for PubMedID 30232199

• Need for Reassessment of Early Transpyloric Feeding in Preterm Infants. JAMA pediatrics Wallenstein, M. B., Stevenson, D. K. 2018

  View details for PubMedID 30242307

• Extreme Preterm Infant Rates of Overweight and Obesity at School Age in the SUPPORT Neuroimaging and Neurodevelopmental Outcomes Cohort. The Journal of pediatrics Vohr, B. R., Heyne, R., Bann, C. M., Das, A., Higgins, R. D., Hintz, S. R., Eunice Kennedy Shriver National Institute of Child Health, a. D., Jobe, A. H., Caplan, M. S., Polin, R. A., Laptook, A. R., Hensman, A. M., McGowan, E. C., Vieira, E., Little, E., Johnson, K., Alksninis, B., Keszler, M. L., Knoll, A. M., Leach, T. M., Watson, V. E., Walsh, M. C., Fanaroff, A. A., Wilson-Costello, D. E., Payne, A., Newman, N. S., Taylor, H. G., Siner, B. S., Zadell, A., DiFiore, J., Bhola, M., Friedman, H. G., Yalcinkaya, G., Bulas, D., Goldberg, R. N., Cotten, C. M., Goldstein, R. F., Gustafson, K. E., Ashley, P., Auten, K. J., Fisher, K. A., Foy, K. A., Freedman, S. F., Lohmeyer, M. B., Malcolm, W. F., Wallace, D. K., Carlton, D. P., Stoll, B. J., Adams-Chapman, I., Buchter, S., Piazza, A. J., Carter, Fritz, S., Hale, E. C., Hutchinson, A. K., LaRossa, M. M., Loggins, Y., Bottcher, D., Archer, S. W., Poindexter, B. B., Sokol, G. M., Harmon, H. M., Papile, L., Hines, A. C., Wilson, L. D., Herron, D. E., Smiley, L., Kennedy, K. A., Tyson, J. E., Duncan, A. F., Dempsey, A. G., John, J., Jones, P. M., Lillie, M. L., Siddiki, S., Sperry, D. K., Berberich, M. A., Blaisdell, C. J., Gail, D. B., Kiley, J. P., Wallace, D., Gantz, M. G., Newman, J. E., Auman, J. O., Hammond, J. A., Poole, W. K., Van Meurs, K. P., Stevenson, D. K., DeAnda, M. E., Ball, M. B., Goodlin, G. T., Frantz, I. D., Fiascone, J. M., McGowan, E. C., Furey, A., MacKinnon, B. L., Nylen, E., Brussa, A., Sibley, C., Carlo, W. A., Ambalavanan, N., Peralta-Carcelen, M., Collins, M. V., Cosby, S. S., Phillips, V. A., Bailey, K. J., Biasini, F. J., Hopkins, M., Johnston, K. C., Nelson, K. G., Patterson, C. S., Rector, R. V., Rodriguez, L., Soong, A., Whitley, S., York, S., Guest, K., Smith, L. A., Finer, N. N., Garey, D., Rasmussen, M. R., Wozniak, P. R., Vaucher, Y. E., Fuller, M. G., Akshoomoff, N., Rich, W., Arnell, K., Bridge, R., Bell, E. F., Colaizy, T. T., Widness, J. A., Klein, J. M., Johnson, K. J., Acarregui, M. J., Eastman, D. L., Wilgenbusch, T. L., Watterberg, K. L., Ohls, R. K., Fuller, J., Lowe, J., Rohr, J., Lacy, C. B., Montman, R., Brown, S., Sanchez, P. J., Rosenfeld, C. R., Salhab, W. A., Brion, L., Adams, S. S., Allen, J., Grau, L., Guzman, A., Hensley, G., Heyne, E. T., Hickman, J. F., Leps, M. H., Madden, L. A., Martin, M., Miller, N. A., Morgan, J. S., Solis, A., Lee, L. E., Boatman, C. T., Vasil, D. M., Yoder, B. A., Faix, R. G., Winter, S., Baker, S., Osborne, K. A., Rau, C. A., Cunningham, S., Ford, A., Shankaran, S., Pappas, A., Sood, B. G., Bara, R., Slovis, T. L., Billian, E., Goldston, L. A., Johnson, M. 2018; 200: 132

  Abstract

  OBJECTIVE: To identify rates of overweight (body mass index [BMI] ≥85th percentile) and obesity (BMI ≥95th percentile) at 6-7 years of age and associated risk factors among extremely preterm infants born at<28 weeks of gestation.STUDY DESIGN: Anthropometrics, blood pressure, and active and sedentary activity levels were prospectively assessed. Three groups were compared, those with a BMI ≥85th percentile (overweight or obese for age, height, and sex) and ≥95th percentile (obese) vs <85th percentile. Multiple regression analyses estimated the relative risks of BMI ≥85th percentile and ≥95th percentile associated with perinatal and early childhood factors.RESULTS: Of 388 children, 22% had a BMI of ≥85th percentile and 10% were obese. Children with obesity and overweight compared with normal weight children had higher body fat (subscapular skinfold and triceps skinfold >85th percentile), central fat (waist circumference >90th percentile), spent more time in sedentary activity (20.5 vs 18.2 vs 16.7 hours/week), and had either systolic and/or diastolic hypertension (24% vs 26% vs 14%), respectively. Postdischarge weight gain velocities from 36 weeks postmenstrual age to 18 months, and 18 months to 6-7 years were independently associated with a BMI of ≥85th percentile, whereas weight gain velocity from 18 months to 6-7 years was associated with obesity.CONCLUSIONS: One in 5 former extremely preterm infants is overweight or obese and has central obesity at early school age. Postdischarge weight gain velocities were associated with overweight and obesity. These findings suggest the obesity epidemic is spreading to the most extremely preterm infants.TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063 and NCT0000.

  View details for PubMedID 29793869

• Hypoxia regulates placental angiogenesis via alternatively activated macrophages AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY Zhao, H., Kalish, F. S., Wong, R. J., Stevenson, D. K. 2018; 80 (3)

  View details for DOI 10.1111/aji.12989

  View details for Web of Science ID 000445327800011

• The uncertain fate of the National Institutes of Health (NIH) pediatric research portfolio: In support of an investment strategy to improve the public health of the nation through perinatal research PEDIATRIC RESEARCH Stevenson, D. K., Shaw, G. M., Katz, M. 2018; 84 (3): 321–22

  View details for DOI 10.1038/s41390-018-0036-6

  View details for Web of Science ID 000451231500006

• In Vitro Study on the Effect of Maraviroc or Dolutegravir on Bilirubin to Albumin Binding PEDIATRIC INFECTIOUS DISEASE JOURNAL Schreiner, C. N., Ahlfors, C. E., Wong, R. J., Stevenson, D. K., Clarke, D. F., Mirochnick, M. 2018; 37 (9): 908–9

  Abstract

  We performed an in vitro evaluation of the effect of maraviroc or dolutegravir on bilirubin to albumin binding. At typical treatment and low albumin concentrations, maraviroc had no impact, while dolutegravir affected bilirubin to albumin binding to an equivalent extent as sulfisoxazole. However in vivo, neither is likely to significantly impact bilirubin to albumin binding because of their low concentrations relative to albumin.

  View details for PubMedID 29561509

• Application of machine-learning to predict early spontaneous preterm birth among nulliparous non-Hispanic black and white women. Annals of epidemiology Weber, A., Darmstadt, G. L., Gruber, S., Foeller, M. E., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 2018

  Abstract

  PURPOSE: Spontaneous preterm birth is a leading cause of perinatal mortality in the United States, occurring disproportionately among non-Hispanic black women compared to other race-ethnicities. Clinicians lack tools to identify first-time mothers at risk for spontaneous preterm birth. This study assessed prediction of early (<32weeks) spontaneous preterm birth among non-Hispanic black and white women by applying state-of-the-art machine-learning to multilevel data from a large birth cohort.METHODS: Data from birth certificate and hospital discharge records for 336,214 singleton births to nulliparous women in California from 2007 to 2011 were used in cross-validated regressions, with multiple imputation for missing covariate data. Residential census tract information was overlaid for 281,733 births. Prediction was assessed with areas under the receiver operator characteristic curves (AUCs).RESULTS: Cross-validated AUCs were low (0.62 [min=0.60, max=0.63] for non-Hispanic blacks and 0.63 [min=0.61, max=0.65] for non-Hispanic whites). Combining racial-ethnic groups improved prediction (cross-validated AUC=0.67 [min=0.65, max=0.68]), approaching what others have achieved using biomarkers. Census tract-level information did not improve prediction.CONCLUSIONS: The resolution of administrative data was inadequate to precisely predict individual risk for early spontaneous preterm birth despite the use of advanced statistical methods.

  View details for PubMedID 30236415

• Transcutaneous bilirubinometer use and practices surrounding jaundice in 150 California newborn intensive care units. Journal of perinatology : official journal of the California Perinatal Association Bhatt, D. R., Kristensen-Cabrera, A. I., Lee, H. C., Weerasinghe, S., Stevenson, D. K., Bhutani, V. K., Maisels, M. J., Ramanathan, R. 2018

  Abstract

  OBJECTIVES: Transcutaneous bilirubin measurements (TcBs) provide a noninvasive method for screening infants for hyperbilirubinemia and have been used extensively in term and late preterm newborns in well baby nurseries, offices, and outpatient clinics. Several studies have also demonstrated the utility of TcBs as a screening tool for infants >28 weeks' gestation and their ability to reduce the need for blood sampling. The objectives of this study are to identify how often TcBs are used among California Newborn Intensive Care Units (NICUs) in preterm, late preterm and term infants, and other aspects of jaundice management.METHODS: We conducted a survey on TcB use and practices relating to jaundice management in 150 California NICUs between April and October 2016.RESULTS: TcB screening is routinely used in 28% (42/150) of NICUs. Only 7% (11/150) of NICUs use TcB in preterm infants <28 weeks. Practice varied similarly across NICU levels of care. Among the subset of NICUs that responded to questions related to phototherapy and screening practices, prophylactic phototherapy was used in 38% (23/59) and 90% (55/61) screened for glucose-6-phosphate dehydrogenase deficiency based on race, ethnicity, and/or family history.CONCLUSION(S): Despite studies validating the accuracy of TcB in preterm infants >28 weeks, only 28% of California NICUs routinely use TcB devices. TcB screening in infants <28 weeks gestation is not widely used and no recommendation can be made in this regard until there is more experience with its application using a standardized protocol in these infants and on a large scale.

  View details for PubMedID 30120424

• Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics JOURNAL OF PERINATOLOGY Jelliffe-Pawlowski, L. L., Rand, L., Bedell, B., Baer, R. J., Oltmann, S. P., Norton, M. E., Shaw, G. M., Stevenson, D. K., Murray, J. C., Ryckman, K. K. 2018; 38 (8): 963–72

  Abstract

  To evaluate if mid-pregnancy immune and growth-related molecular factors predict preterm birth (PTB) with and without (±) preeclampsia.Included were 400 women with singleton deliveries in California in 2009-2010 (200 PTB and 200 term) divided into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15-20 serum samples using multiplex technology. Linear discriminate analysis was used to create a discriminate function. Model performance was assessed using area under the receiver operating characteristic curve (AUC).Twenty-five serum biomarkers along with maternal age <34 years and poverty status identified >80% of women with PTB ± preeclampsia with best performance in women with preterm preeclampsia (AUC = 0.889, 95% confidence interval (0.822-0.959) training; 0.883 (0.804-0.963) testing).Together with maternal age and poverty status, mid-pregnancy immune and growth factors reliably identified most women who went on to have a PTB ± preeclampsia.

  View details for PubMedID 29795450

• Identification of risk for neonatal haemolysis ACTA PAEDIATRICA Bhutani, V. K., Maisels, M., Schutzman, D. L., Cuadrado, M., Aby, J. L., Bogen, D. L., Christensen, R. D., Watchko, J. F., Wong, R. J., Stevenson, D. K. 2018; 107 (8): 1350–56

  View details for DOI 10.1111/apa.14316

  View details for Web of Science ID 000438490100012

• The uncertain fate of the National Institutes of Health (NIH) pediatric research portfolio: In support of an investment strategy to improve the public health of the nation through perinatal research. Pediatric research Stevenson, D. K., Shaw, G. M., Katz, M. 2018

  View details for PubMedID 29976966

• Natural Selection Has Differentiated the Progesterone Receptor among Human Populations AMERICAN JOURNAL OF HUMAN GENETICS Li, J., Hong, X., Mesiano, S., Muglia, L. J., Wang, X., Snyder, M., Stevenson, D. K., Shaw, G. M. 2018; 103 (1): 45–57

  View details for DOI 10.1016/j.ajhg.2018.05.009

  View details for Web of Science ID 000438168800004

• Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics (vol 38, pg 946, 2018) JOURNAL OF PERINATOLOGY Jelliffe-Pawlowski, L. L., Rand, L., Bedell, B., Baer, R. J., Oltman, S. P., Norton, M. E., Shaw, G. M., Stevenson, D. K., Murray, J. C., Ryckman, K. K. 2018; 38 (7): 946

  Abstract

  This Article was originally published under Nature Research's License to Publish, but has nowbeen made available under a [CC BY 4.0] license. The PDF and HTML versions of the Articlehave been modified accordingly.

  View details for PubMedID 29941898

• Heme oxygenase-1 deficiency promotes severity of sepsis in a non-surgical preterm mouse model PEDIATRIC RESEARCH Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. 2018; 84 (1): 139–45

  View details for DOI 10.1038/s41390-018-0028-6

  View details for Web of Science ID 000442163400024

• Residential agricultural pesticide exposures and risks of preeclampsia ENVIRONMENTAL RESEARCH Shaw, G. M., Yang, W., Roberts, E. M., Aghaeepour, N., Mayo, J. A., Weber, K. A., Maric, I., Carmichael, S. L., Winn, V. D., Stevenson, D. K., English, P. B. 2018; 164: 546–55

  View details for DOI 10.1016/j.envres.2018.03.020

  View details for Web of Science ID 000431387100065

• Failed umbilical artery catheterization and adverse outcomes in extremely low birth weight infants. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians Wallenstein, M. B., Shaw, G. M., Yang, W., Stevenson, D. K. 2018: 1–5

  Abstract

  PURPOSE: To determine whether successful catheterization of the umbilical artery is associated with a reduced risk of death or neurodevelopment impairment among critically ill extremely low birth weight (ELBW) infants.STUDY DESIGN: A retrospective chart review was conducted between 2007 and 2014 at Stanford University for all ELBW infants that required intubation immediately after birth. The primary outcome was death or neurodevelopmental impairment at 18-22 months. We measured the association of successful umbilical artery catheterization with the primary outcome using multivariable logistic regression with adjustment for gestational age. Bayesian analysis was also performed due to small sample size.RESULTS: Eighty-four ELBW infants met inclusion criteria. Successful umbilical artery catheterization occurred in 88% of infants and failed catheterization in 12%. Death or neurodevelopmental impairment occurred in 41% of infants with successful catheterization, compared to 60% of infants with failed catheterization of the umbilical artery, adjusted odds ratio 0.3, 95% confidence interval 0.1-1.3, p=.11. The Bayesian analysis indicated a 92% posterior probability of reduced death or neurodevelopmental impairment with successful catheterization and a 68% posterior probability of reduced death or neurodevelopmental by absolute risk difference of 20% or more, adjusted relative risk 0.74, 95% confidence interval 0.45-1.14.CONCLUSIONS: Among critically ill ELBW infants, successful catheterization of the umbilical artery compared to failed catheterization was not statistically significantly associated with the primary outcome. However, the Bayesian analysis indicated a high likelihood of benefit associated with successful umbilical artery catheterization.

  View details for PubMedID 29681181

• Point-of-Care Fecal Calprotectin Monitoring in Preterm Infants at Risk for Necrotizing Enterocolitis JOURNAL OF PEDIATRICS Nakayuenyongsuk, W., Christofferson, M., Stevenson, D. K., Sylvester, K., Lee, H. C., Park, K. T. 2018; 196: 98-+

  View details for DOI 10.1016/j.jpeds.2017.12.069

  View details for Web of Science ID 000432452300019

• Filtered Sunlight Phototherapy, A Novel Treatment for Moderate-Severe Hyperbilirubinemia, is No Less Efficacious than Conventional Phototherapy in Neonates in Ogbomoso, Nigeria Slusher, T. M., Vreman, H., Brearley, A., Adeleke, O., Vaucher, Y., Wong, R., Stevenson, D., Gbadero, D. AMER ACAD PEDIATRICS. 2018

  View details for DOI 10.1542/peds.142.1_MeetingAbstract.513

  View details for Web of Science ID 000540807300472

• Occurrence of Selected Structural Birth Defects Among Women With Preeclampsia and Other Hypertensive Disorders AMERICAN JOURNAL OF EPIDEMIOLOGY Weber, K. A., Mayo, J. A., Carmichael, S. L., Stevenson, D. K., Winn, V. D., Shaw, G. M. 2018; 187 (4): 668–76

  Abstract

  To explore a potential association between preeclampsia and selected birth defects, we examined the prevalence of certain birth defects among women with hypertensive disorders including preeclampsia. We analyzed data from 2,499,536 singleton live births in California from 2007 to 2011, including maternal and infant demographics from birth certificates as well as clinical details from delivery hospitalization records. We examined defect groups that were recognizable at birth (e.g., spina bifida and cleft lip). Hypertensive disorders included preexisting hypertension, gestational hypertension, mild preeclampsia, severe preeclampsia/eclampsia, and preeclampsia superimposed on preexisting hypertension. Relative risk values with 95% confidence intervals for each birth defect were calculated by hypertensive group, as well as independent and joint associations of hypertensive and diabetic disorders. Risks of each type of birth defect were higher among offspring of women with hypertensive disorders compared with those without. The risks of birth defects among offspring of women with only a hypertensive disorder were significantly higher than that among women with neither hypertensive nor diabetic disorders (relative risks ranged from 1.37 to 2.77). Risks of birth defects were highest among those born to women with both hypertensive and diabetic disorders compared with those with neither (relative risks ranged from 1.80 to 6.22). These findings support the existence of an association between preeclampsia and certain birth defects and suggest that diabetes may be a contributing factor.

  View details for PubMedID 29020134

• Antecedents and Outcomes of Abnormal Cranial Imaging in Moderately Preterm Infants JOURNAL OF PEDIATRICS Natarajan, G., Shankaran, S., Saha, S., Laptook, A., Das, A., Higgins, R., Stoll, B. J., Bell, E. F., Carlo, W. A., D'Angio, C., DeMauro, S. B., Sanchez, P., Van Meurs, K., Vohr, B., Newman, N., Hale, E., Walsh, M., Eunice Kennedy Shriver Natl Inst C 2018; 195: 66-+

  Abstract

  To describe the frequency and findings of cranial imaging in moderately preterm infants (born at 290/7-336/7 weeks of gestation) across centers, and to examine the association between abnormal imaging and clinical characteristics.We used data from the Neonatal Research Network Moderately Preterm Registry, including the most severe early (≤28 days) and late (>28 days) cranial imaging. Stepwise logistic regression and CART analysis were performed after adjustment for gestational age, antenatal steroid use, and center.Among 7021 infants, 4184 (60%) underwent cranial imaging. These infants had lower gestational ages and birth weights and higher rates of small for gestational age, outborn birth, cesarean delivery, neonatal resuscitation, and treatment with surfactant, compared with those without imaging (P < .0001). Imaging abnormalities noted in 15% of the infants included any intracranial hemorrhage (13.2%), grades 3-4 intracranial hemorrhage (1.7%), cystic periventricular leukomalacia (2.6%), and ventriculomegaly (6.6%). Histologic chorioamnionitis (OR, 1.47; 95% CI, 1.19-1.83), gestational age (0.95; 95% CI, 0.94-0.97), antenatal steroids (OR, 0.55; 95% CI, 0.41-0.74), and cesarean delivery (OR, 0.66; 95% CI, 0.53-0.81) were associated with abnormal imaging. The center with the highest rate of cranial imaging, compared with the lowest, had a higher risk of abnormal imaging (OR, 2.08; 95% CI, 1.10-3.92). On the classification and regression-tree model, cesarean delivery, center, antenatal steroids, and chorioamnionitis, in that order, predicted abnormal imaging.Among the 60% of moderately preterm infants with cranial imaging, 15% had intracranial hemorrhage, cystic periventricular leukomalacia or late ventriculomegaly. Further correlation of imaging and long-term neurodevelopmental outcomes in moderately preterm infants is needed.

  View details for PubMedID 29395186

• Delivery Room Resuscitation and Short-Term Outcomes in Moderately Preterm Infants JOURNAL OF PEDIATRICS Bajaj, M., Natarajan, G., Shankaran, S., Wyckoff, M., Laptook, A. R., Bell, E. F., Stoll, B. J., Carlo, W. A., Vohr, B. R., Saha, S., Van Meurs, K. P., Sanchez, P. J., D'Angio, C. T., Higgins, R. D., Das, A., Newman, N., Walsh, M. C., Eunice Kennedy Shriver 2018; 195: 33-+

  Abstract

  To describe the frequency and extent of delivery room resuscitation and evaluate the association of delivery room resuscitation with neonatal outcomes in moderately preterm (MPT) infants.This was an observational cohort study of MPT infants delivered at 290/7 to 336/7 weeks' gestational age (GA) enrolled in the Neonatal Research Network MPT registry. Infants were categorized into 5 groups based on the highest level of delivery room intervention: routine care, oxygen and/or continuous positive airway pressure, bag and mask ventilation, endotracheal intubation, and cardiopulmonary resuscitation including chest compressions and/or epinephrine use. The association of antepartum and intrapartum risk factors and discharge outcomes with the intensity of resuscitation was evaluated.Of 7014 included infants, 1684 (24.0%) received routine care and no additional resuscitation, 2279 (32.5%) received oxygen or continuous positive airway pressure, 1831 (26.1%) received bag and mask ventilation, 1034 (14.7%) underwent endotracheal intubation, and 186 (2.7%) received cardiopulmonary resuscitation. Among the antepartum and intrapartum factors, increasing GA, any exposure to antenatal steroids and prolonged rupture of membranes decreased the likelihood of receipt of all levels of resuscitation. Infants who were small for GA (SGA) had increased risk of delivery room resuscitation. Among the neonatal outcomes, respiratory support at 28 days, days to full oral feeds and length of stay were significantly associated with the intensity of delivery room resuscitation. Higher intensity of resuscitation was associated with increased risk of mortality.The majority of MPT infants receive some level of delivery room resuscitation. Increased intensity of delivery room interventions was associated with prolonged respiratory and nutritional support, increased mortality, and a longer length of stay.

  View details for PubMedID 29306493

• Outcome of Preterm Infants with Transient Cystic Periventricular Leukomalacia on Serial Cranial Imaging Up to Term Equivalent Age JOURNAL OF PEDIATRICS Sarkar, S., Shankaran, S., Barks, J., Do, B. T., Laptook, A. R., Das, A., Ambalavanan, N., Van Meurs, K. P., Bell, E. F., Sanchez, P. J., Hintz, S. R., Wyckoff, M. H., Stoll, B. J., Carlo, W. A., Eunice Kennedy Shriver Natl Inst C 2018; 195: 59-+

  Abstract

  To determine the outcome of preterm infants whose cystic periventricular leukomalacia "disappeared" on serial screening cranial imaging studies.Infants ≤26 weeks of gestation born between 2002 and 2012 who had cranial imaging studies at least twice, the most abnormal study at <28 days of age and another closest to 36 weeks, were reviewed. The outcome of late death (after 36 weeks postmenstrual age) or neurodevelopmental impairment (NDI) in surviving infants at 18-26 months corrected age was compared between the infants with no cystic periventricular leukomalacia on both studies and cystic periventricular leukomalacia that disappeared (cystic periventricular leukomalacia at <28 days but not at 36 weeks), persisted (cystic periventricular leukomalacia on both studies), or appeared late (cystic periventricular leukomalacia only at 36 weeks). Predictors of NDI were evaluated by logistic regression.Of 7063 eligible infants, 433 (6.1%) had cystic periventricular leukomalacia. Among the 433 infants with cystic periventricular leukomalacia, cystic periventricular leukomalacia disappeared in 76 (18%), persisted in 87 (20%), and 270 (62%) had late cystic periventricular leukomalacia. Loss to follow-up ranged between 3% and 13%. Death or NDI was more common in infants with disappeared cystic periventricular leukomalacia compared with those with no cystic periventricular leukomalacia (38 of 72 [53%] vs 1776 of 6376 [28%]; OR [95% CI] 2.8 [1.8-4.6]). Disappeared, persistent, and late cystic periventricular leukomalacia were all also independently associated with NDI (OR 1.17, 1.21, and 1.16, respectively).Infants with "disappeared" cystic periventricular leukomalacia are at increased risk of adverse outcome similar to infants with persistent or late cystic periventricular leukomalacia.

  View details for PubMedID 29398046

• A directory for neonatal intensive care: potential for facilitating network-based research in neonatology. Journal of perinatology : official journal of the California Perinatal Association Ariagno, R. L., Lee, H. C., Stevenson, D. K., Benjamin, D. K., Smith, P. B., Escobedo, M. B., Bhatt, D. R. 2018

  Abstract

  Directories of contact information have evolved over time from thick paperback times such as the "Yellow Pages" to electronic forms that are searchable and have other functionalities. In our clinical specialty, the development of a professional directory helped to promote collaboration in clinical care, education, and quality improvement. However, there are opportunities for increasing the utility of the directory by taking advantage of modern web-based tools, and expanding the use of the directory to fill a gap in the area of collaborative research.

  View details for DOI 10.1038/s41372-018-0097-8

  View details for PubMedID 29545621

• Maternal Height and Risk of Preeclampsia. Maric, I., Mayo, J. A., Druzin, M. L., Wong, R. J., Winn, V. D., Stevenson, D. K., Shaw, G. M. SAGE PUBLICATIONS INC. 2018: 207A–208A

  View details for Web of Science ID 000429928200458

• Pravastatin Induces Heme Oxygenase Activity and Enhances Placental Development in a Murine Model. Tsur, A., Kalish, F., Burgess, J., Zhao, H., Casey, K. M., Druzin, M. L., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2018: 155A–156A

  View details for Web of Science ID 000429928200299

• The Effects of Hypoxia and Progesterone/Estrogen on Polarized Macrophages In Vitro. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2018: 301A–302A

  View details for Web of Science ID 000429928200747

• Heme Oxygenase-1 Deficiency Results in T-Cell Dysregulation in Offspring of Mothers Exposed to Late Gestational Inflammation Ozen, M., Zhao, H., Kalish, F., Yang, Y., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2018: 248A–249A

  View details for Web of Science ID 000429928200583

• Mass Cytometry and Proteomic Based Prediction of the Onset of Labor. Ando, K., Han, X., Ghaemi, S., Tsai, A., Ganio, E., Gaudilliere, D., Culos, T., Shaw, G., Wong, R., Stevenson, D., Carvalho, B., Tingle, M., Angst, M., Aghaeepor, N., Gaudilliere, B., Stanford March Dimes Prematurity SAGE PUBLICATIONS INC. 2018: 153A

  View details for Web of Science ID 000429928200292

• Pravastatin improves pregnancy outcome and placental development in heme oxygenase-1 deficient mice Tsur, A., Kalish, F., Burgess, J., Zhao, H., Casey, K., Druzin, M. L., Wong, R. J., Stevenson, D. K. MOSBY-ELSEVIER. 2018: S202

  View details for Web of Science ID 000422946900324

• Personalized charts for the fetal corpus callosum length. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians Tsur, A. n., Weisz, B. n., Rosenblat, O. n., Shai, D. n., Derazne, E. n., Stevenson, D. K., Achiron, R. n., Eldad Katorza, n. n. 2018: 1–151

  Abstract

  To personally customize the antenatal ultrasound charts for the fetal corpus callosum (CC) length.A retrospective analysis of fetal neuro-sonography scans. Cases were grouped as normal neuro-sonographic evaluation (normal) or as high risk and suspected brain anomaly (abnormal). The normal group was subcategorized according to Cignini's CC length charts. Data of fetuses with a CC length between the 5th-95th percentile served for creating new charts, describing the ratio of the CC length to the major biometric parameters as a function of gestational age (GA).A total of 410 measurements were included. Of them 255 were normal and 155 abnormal. The CC length/estimated fetal weight (EFW) ratio had the strongest linear association with GA (R2 = 0.929). Applying charts using this ratio to the normal group, significantly increased the percent of CC length measurements defined as normal from 84.7 to 94.5% (p < 0.001). Conversely, applying these charts to the abnormal group nonsignificantly decreased the number of measurement defined as normal from 89 to 83.2% (p = 0.137) Conclusions: The CC length/EFW ratio is strongly and linearly associated with GA. Using this personalized ratio may improve the diagnostic accuracy of CC evaluation by adjusting the CC length to the fetus natural proportions.

  View details for PubMedID 29779410

• Bilirubin Production Is Increased in Newborn Mice Exposed to Isoflurane. Neonatology Iwatani, S., Burgess, J., Kalish, F., Wong, R. J., Stevenson, D. K. 2018; 115 (1): 21-27

  Abstract

  Increased bilirubin production due to hemolysis can lead to severe neonatal hyperbilirubinemia and, if left untreated, to bilirubin neurotoxicity. Post-cardiac surgery newborns have been shown to be at an increased risk for developing hyperbilirubinemia and also hemolysis. Isoflurane (ISO), a volatile anesthetic agent routinely used in newborn surgery, has been reported to upregulate heme oxygenase 1 (HO-1) expression. HO is the rate-limiting enzyme in the bilirubin production pathway.Here, we evaluated whether ISO exposure induces HO-1 and further increases bilirubin production in a hemolytic newborn mouse model.Three-day-old newborn mice were exposed to 2% ISO for 18 min or air. Liver HO activity and HO-1 protein were measured after exposure to ISO. Next, we evaluated the effect of ISO exposure on bilirubin production as indexed by the total body excretion rate of carbon monoxide following heme loading.ISO significantly increased liver HO activity 120% and 116% at 24 and 48 h, respectively, after exposure. HO-1 protein levels also similarly increased after ISO exposure, but the increases were not statistically significant compared with controls. After heme loading, ISO-exposed pups had significantly higher bilirubin production rates (1.24-fold), and also peaked earlier, than age-matched nonexposed pups.ISO exposure can induce HO-1 expression in the liver and may explain the development of severe hyperbilirubinemia in postsurgical infants, especially in those undergoing hemolysis.

  View details for DOI 10.1159/000492421

• EXPOSURE TO ISOFLURANE INCREASES BILIRUBIN PRODUCTION IN NEWBORN MICE Burgess, J., Iwatani, S., Kalish, F., Onderdonk, Z., Zehnder, V. K., Vreman, H. J., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2018: 204–5

  View details for DOI 10.1136/jim-2017-000663.332

  View details for Web of Science ID 000432007400343

• TREATMENT WITH PRAVASTATIN IMPROVES PREGNANCY OUTCOME AND PLACENTAL DEVELOPMENT IN HEME OXYGENASE-1-DEFICIENT MICE Tsur, A., Kalish, F., Burgess, J., Zhao, H., Casey, K. M., Druzin, M. L., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2018: 241–42

  View details for DOI 10.1136/jim-2017-000663.422

  View details for Web of Science ID 000432007400432

• Out-of-hospital births in California 1991-2011 JOURNAL OF PERINATOLOGY Girsen, A. I., Mayo, J. A., Lyell, D. J., Blumenfeld, Y. J., Stevenson, D. K., El-Sayed, Y. Y., Shaw, G. M., Druzin, M. L., Stanford Univ Sch Med 2018; 38 (1): 41–45

  Abstract

  We investigated the frequencies and characteristics of out-of-hospital births in a 20-year period in California, where 1 of every 7 births in the United States occurs.Birth certificate records of deliveries in California between 1991 and 2011 were analyzed. Out-of-hospital births were assessed by year, parity, gestational age and maternal race/ethnicity.In the 20-year period there were 10 593,904 deliveries, of which 46 243 occurred out of hospital (0.44%). Out-of-hospital births decreased from 0.54 to 0.38% per year between 1991 and 2004, and increased from 0.41% in 2005 to 0.61% in 2011. In contrast, preterm out-of-hospital births declined from 7.2% in 2006 to 5.0% in 2011. The frequency of vaginal birth after cesarean in the out-of-hospital birth cohort increased from 1.2% (n=19) in 1996 to 4.2% (n=82) in 2011.California birth records from a 20-year period show an increase in out-of-hospital births from years 2005 to 2011, following a period of decline from 1991 to 2004.

  View details for PubMedID 29120453

• Residential Agricultural Pesticide Exposures and Risks of Spontaneous Preterm Birth EPIDEMIOLOGY Shaw, G. M., Yang, W., Roberts, E. M., Kegley, S. E., Stevenson, D. K., Carmichael, S. L., English, P. B. 2018; 29 (1): 8–21

  Abstract

  Pesticides exposures are aspects of the human exposome that have not been sufficiently studied for their contribution to risk for preterm birth. We investigated risks of spontaneous preterm birth from potential residential exposures to 543 individual chemicals and 69 physicochemical groupings that were applied in the San Joaquin Valley of California during the study period, 1998-2011.The study population was derived from birth certificate data linked with Office of Statewide Health Planning and Development maternal and infant hospital discharge data. After exclusions, the analytic study base included 197,461 term control births and 27,913 preterm case births. Preterm cases were more narrowly defined as 20-23 weeks (n = 515), 24-27 weeks (n = 1,792), 28-31 weeks (n = 3,098), or 32-36 weeks (n = 22,508).The frequency of any (versus none) pesticide exposure was uniformly lower in each preterm case group relative to the frequency in term controls, irrespective of gestational month of exposure. All odds ratios were below 1.0 for these any versus no exposure comparisons. The majority of odds ratios were below 1.0, many of them statistically precise, for preterm birth and exposures to specific chemical groups or chemicals.This study showed a general lack of increased risk of preterm birth associated with a range of agriculture pesticide exposures near women's residences.

  View details for DOI 10.1097/EDE.0000000000000758

  View details for Web of Science ID 000417683700009

  View details for PubMedID 28926371

  View details for PubMedCentralID PMC5718919

• A candidate gene analysis of very low birth weight infants with clinical chorioamnionitis Spiegel, A. M., Li, J., Oehlert, J. W., Mayo, J. A., Quaintance, C. C., Druzin, M. L., El-Sayed, Y. Y., Stevenson, D. K., Shaw, G. M., Gibbs, R. S. MOSBY-ELSEVIER. 2017: 721

  View details for Web of Science ID 000416950700055

• Nulliparous teenagers and preterm birth in California JOURNAL OF PERINATAL MEDICINE Mayo, J. A., Shachar, B., Stevenson, D. K., Shaw, G. M. 2017; 45 (8): 959–67

  Abstract

  Young maternal age is one of the numerous risk factors for delivery before 37 weeks of gestation, yet the mechanisms are unclear. The purpose of the current study was to investigate the association between teenagers and the risk of preterm birth (PTB) in a large and recent cohort study.We conducted a population-based retrospective cohort study using 2007-2011 California birth certificate records linked with hospital discharge indices and United States census data for nulliparous 13-20 year olds who gave birth to singletons. Maternal age was examined categorically at 1 year intervals. PTB was defined as delivery at <37 weeks of gestation with further distinction between <32 and 32-36 weeks, and between spontaneous and medically indicated deliveries. Adjusted multivariable logistic regression was used to estimate odds ratios (OR) for PTB.The prevalence of PTB was highest among the youngest (13 year olds, 14.5%) and lowest among the oldest (20 year olds, 6.7%). After adjusting for maternal and paternal race/ethnicity, paternal age, initiation of prenatal care, source of payment, pre-pregnancy body-mass-index (BMI), height, smoking, and poverty; young mothers of ages 13, 14, 15, and 16 years had increased odds for spontaneous PTB at <32 weeks [OR (CI): 3.76 (1.83-7.75), 1.65 (1.10-2.48), 1.55 (1.24-1.93), 1.19 (1.00-1.42), respectively] compared to 20 year olds. All teenagers, excluding 19 year olds, had elevated odds of spontaneous PTB at 32-36 weeks.Nulliparous teenagers were at increased risk for spontaneous PTB, especially those 16 years or younger. Medically indicated PTB was not associated with young age.

  View details for DOI 10.1515/jpm-2016-0313

  View details for Web of Science ID 000415085900008

  View details for PubMedID 28343179

• Preterm Birth Phenotypes in Women with Autoimmune Diseases Kolstad, K. D., Mayo, J. A., Chung, L., Chaichian, Y., Kelly, V. M., Druzin, M., Stevenson, D. K., Shaw, G. M., Simard, J. F. WILEY. 2017

  View details for Web of Science ID 000411824102207

• An immune clock of human pregnancy SCIENCE IMMUNOLOGY Aghaeepour, N., Ganio, E. A., Mcilwain, D., Tsai, A. S., Tingle, M., Van Gassen, S., Gaudilliere, D. K., Baca, Q., McNeil, L., Okada, R., Ghaemi, M. S., Furman, D., Wong, R. J., Winn, V. D., Druzin, M. L., El-Sayed, Y. Y., Quaintance, C., Gibbs, R., Darmstadt, G. L., Shaw, G. M., Stevenson, D. K., Tibshirani, R., Nolan, G. P., Lewis, D. B., Angst, M. S., Gaudilliere, B. 2017; 2 (15)

  View details for DOI 10.1126/sciimmunol.aan2946

  View details for Web of Science ID 000434327200004

• Social disadvantage and the black-white disparity in spontaneous preterm delivery among California births PLOS ONE Carmichael, S. L., Kan, P., Padula, A. M., Rehkopf, D. H., Oehlert, J. W., Mayo, J. A., Weber, A. M., Wise, P. H., Shaw, G. M., Stevenson, D. K. 2017; 12 (8): e0182862

  Abstract

  We examined the contribution of social disadvantage to the black-white disparity in preterm birth. Analyses included linked vital and hospital discharge records from 127,358 black and 615,721 white singleton California births from 2007-11. Odds ratios (OR) were estimated by 4 logistic regression models for 2 outcomes: early (<32 wks) and moderate (32-36 wks) spontaneous preterm birth (ePTB, mPTB), stratified by 2 race-ethnicity groups (blacks and whites). We then conducted a potential impact analysis. The OR for less than high school education (vs. college degree) was 1.8 (95% confidence interval 1.6, 2.1) for ePTB among whites but smaller for the other 3 outcome groups (ORs 1.3-1.4). For all 4 groups, higher census tract poverty was associated with increased odds (ORs 1.03-1.05 per 9% change in poverty). Associations were less noteworthy for the other variables (payer, and tract percent black and Gini index of income inequality). Setting 3 factors (education, poverty, payer) to 'favorable' values was associated with lower predicted probability of ePTB (25% lower among blacks, 31% among whites) but a 9% higher disparity, compared to probabilities based on observed values; for mPTB, respective percentages were 28% and 13% lower probability, and 17% lower disparity. Results suggest that social determinants contribute to preterm delivery and its disparities, and that future studies should focus on ePTB and more specific factors related to social circumstances.

  View details for PubMedID 28800643

• STUDIES ON BILIRUBIN (BR) METABOLISM IN THE BRAIN Hansen, T. R., Whitin, J. C., Pierce, N. W., Hwang, S., Wong, R. J., Vreman, H. J., Stevenson, D. K. WILEY. 2017: 14–15

  View details for Web of Science ID 000405213500019

• A DEFICIENCY IN HEME OXYGENASE-1 EXPRESSION IS ASSOCIATED WITH AN INCREASE IN THE PROGRESSION OF NEONATAL SEPSIS Fujioka, K., Wong, R. J., Stevenson, D. K. WILEY. 2017: 28

  View details for Web of Science ID 000405213500044

• INDUCTION OF HEME OXYGENASE-1 IS PROTECTIVE AGAINST SEPSIS IN A PRETERM MOUSE MODEL Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2017: 32

  View details for Web of Science ID 000401276500058

• Maternal prepregnancy body mass index and risk of bronchopulmonary dysplasia. Pediatric research Carmichael, S. L., Kan, P., Gould, J. B., Stevenson, D. K., Shaw, G. M., Lee, H. C. 2017

  Abstract

  BackgroundWe examined the relationship between women's prepregnancy BMI and development of bronchopulmonary dysplasia (BPD) in their preterm offspring, hypothesizing that obesity-associated inflammation may increase risk.MethodsWe studied infants born in California between 2007 and 2011, using linked data from California Perinatal Quality Care Collaborative neonatal intensive care units, hospital discharge, and vital statistics. We included infants with birthweight <1,500 g or gestational age at birth of 22-29 weeks. BPD was defined as continuous supplemental oxygen use at 36 weeks' postmenstrual age.ResultsAmong 12,621 infants, 4,078 (32%) had BPD. After adjustment for maternal race/ethnicity, age, education, payer source, and infant sex, BMI status underweight I (BMI <16.9, odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3-2.1) and obesity III (BMI ⩾40.0, OR 1.3, 95% CI 1.0-1.6) were associated with an increased risk of BPD. When considering maternal BMI as a continuous variable, a nonlinear association with BPD was observed for male infants and infants delivered at 25-29 weeks of gestational age, but not for other subgroups.ConclusionBoth high and low maternal BMI were associated with increased BPD risk. These findings support the notion that BPD is a multi-factorial disease that may sometimes have its origins in utero and be influenced by maternal inflammation.Pediatric Research advance online publication, 31 May 2017; doi:10.1038/pr.2017.90.

  View details for DOI 10.1038/pr.2017.90

  View details for PubMedID 28399116

• Genome-wide association study of sepsis in extremely premature infants. Archives of disease in childhood. Fetal and neonatal edition Srinivasan, L., Page, G., Kirpalani, H., Murray, J. C., Das, A., Higgins, R. D., Carlo, W. A., Bell, E. F., Goldberg, R. N., Schibler, K., Sood, B. G., Stevenson, D. K., Stoll, B. J., Van Meurs, K. P., Johnson, K. J., Levy, J., McDonald, S. A., Zaterka-Baxter, K. M., Kennedy, K. A., Sánchez, P. J., Duara, S., Walsh, M. C., Shankaran, S., Wynn, J. L., Cotten, C. M. 2017

  Abstract

  To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants.Previously generated GWA data from the Neonatal Research Network's anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10(-5). Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points.Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10(-8)); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values<0.001 and FDR<20%).No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.

  View details for DOI 10.1136/archdischild-2016-311545

  View details for PubMedID 28283553

• Elevation of Reactive Oxidative Species in Uterine Myeloid Cells During Early Pregnancy. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2017: 230A

  View details for Web of Science ID 000399043900567

• The Complex Relationship of Obesity and Spontaneous Preterm Birth. Tsur, A., Mayo, J., Shaw, G. M., Stevenson, D. K., Gould, J. B. SAGE PUBLICATIONS INC. 2017: 189A

  View details for Web of Science ID 000399043900436

• What factors are related to recurrent preterm birth among underweight women? journal of maternal-fetal & neonatal medicine Girsen, A. I., Mayo, J. A., Wallenstein, M. B., Gould, J. B., Carmichael, S. L., Stevenson, D. K., Lyell, D. J., Shaw, G. M. 2017: 1-19

  Abstract

  Our objective was to identify factors associated with recurrent preterm birth among underweight women.Maternally linked hospital and birth certificate records of deliveries in California between 2007 and 2010 were used. Consecutive singleton pregnancies of women with underweight body mass index (BMI <18.5 kg/m(2)) in the first pregnancy were analyzed. Pregnancies were categorized based on outcome of the first and second birth as: term-term; term-preterm; preterm-term and preterm-preterm.We analyzed 4971 women with underweight BMI in the first pregnancy. Of these, 670 had at least one preterm birth. Among these 670, 86 (21.8%) women experienced a recurrent preterm birth. Odds for first term - second preterm birth were decreased for increases in maternal age (aOR: 0.90, 95%CI: 0.95-0.99) whereas inter-pregnancy interval <6 months was related to both first term - second preterm birth (aOR:1.66, 95%CI: 1.21-2.28) and first preterm birth - second term birth (aOR: 1.43, 95%CI: 1.04-1.96). Factors associated with recurrent preterm birth were: negative or no change in pre-pregnancy weight between pregnancies (aOR: 1.67, 95%CI: 1.07-2.60), inter-pregnancy interval <6 months (aOR: 2.14, 95%CI: 1.29-3.56), and maternal age in the first pregnancy (aOR: 0.93, 95%CI: 0.90-0.97).Recurrent preterm birth among underweight women was associated with younger age, short inter-pregnancy interval, and negative or no weight change between pregnancies.

  View details for DOI 10.1080/14767058.2017.1292243

  View details for PubMedID 28166677

• Skin-to-skin contact after birth and the natural course of neurosteroid levels in healthy term newborns. Journal of perinatology McCallie, K. R., Gaikwad, N. W., Castillo Cuadrado, M. E., Aleman, M., Madigan, J. E., Stevenson, D. K., Bhutani, V. K. 2017

  Abstract

  To determine the postnatal course of neurosteroid levels in relation to gender, mode of delivery and the extent of skin-to-skin (STS) contact during the first days of life in healthy term newborns.Prospective observational study of 39 neonates in which parents recorded total duration of STS in the first 2 days and nine neurosteroids (dehydroepiandrosterone-sulfate, progesterone, pregnenolone, pregnenolone-sulfate, allopregnanolone, isopregnanolone, epipregnanolone, pregnanolone and pregnanolone-sulfate) were assayed from blood samples at birth and at 1-2 days of age.All nine neurosteroid levels declined significantly during the first 2 days of life. Gender did not significantly affect the change in neurosteroid levels. The decline in neurosteroid levels was generally more pronounced in vaginal deliveries, and there was a trend toward a larger decline with more exposure to STS.Ongoing studies may better characterize the role of neurosteroids and the influence of STS in more critically ill and premature neonates.

  View details for DOI 10.1038/jp.2016.268

  View details for PubMedID 28102853

• The Relationship of Nosocomial Infection Reduction to Changes in Neonatal Intensive Care Unit Rates of Bronchopulmonary Dysplasia JOURNAL OF PEDIATRICS Lapcharoensap, W., Kan, P., Powers, R. J., Shaw, G. M., Stevenson, D. K., Gould, J. B., Wirtschafter, D. D., Lee, H. C. 2017; 180: 105-?

  Abstract

  To examine whether recent reductions in rates of nosocomial infection have contributed to changes in rates of bronchopulmonary dysplasia (BPD) in a population-based cohort.This was a retrospective, population-based cohort study that used the California Perinatal Quality Care Collaborative database from 2006 to 2013. Eligible infants included those less than 30 weeks' gestational age and less than 1500 g who survived to 3 days of life. Primary variables of interest were rates of nosocomial infections and BPD. Adjusted rates of nosocomial infections and BPD from a baseline period (2006-2010) were compared with a later period (2011-2013). The correlation of changes in rates across periods for both variables was assessed by hospital of care.A total of 22 967 infants from 129 hospitals were included in the study. From the first to second time period, the incidence of nosocomial infections declined from 24.7% to 15% and BPD declined from 35% to 30%. Adjusted hospital rates of BPD and nosocomial infections were correlated positively with a calculated 8% reduction of BPD rates attributable to reductions in nosocomial infections.Successful interventions to reduce rates of nosocomial infections may have a positive impact on other comorbidities such as BPD. The prevention of nosocomial infections should be viewed as a significant component in avoiding long-term neonatal morbidities.

  View details for DOI 10.1016/j.jpeds.2016.09.030

  View details for Web of Science ID 000390028100022

• The Importance of Hemolysis and Its Clinical Detection in Neonates with Hyperbilirubinemia CURRENT PEDIATRIC REVIEWS Wong, R. J., Bhutani, V. K., Stevenson, D. K. 2017; 13 (3): 193–98

  View details for DOI 10.2174/1573396313666170807121444

  View details for Web of Science ID 000441366300007

• HEME OXYGENASE-1 DEFICIENCY INCREASES THE SEVERITY OF SEPSIS IN A PRETERM MOUSE MODEL Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2017: 114–15

  View details for DOI 10.1136/jim-2016-000365.39

  View details for Web of Science ID 000433055100040

• IDENTIFICATION OF RISK FOR NEONATAL HEMOLYSIS: A MULTI-CENTER STUDY Bhutani, V. K., Cuadrado, C. E., Schutzman, D. L., Aby, J. L., Bogen, D. L., Christensen, R. D., Watchko, J. F., Maisels, M., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2017: 123

  View details for DOI 10.1136/jim-2016-000365.57

  View details for Web of Science ID 000433055100058

• CYCLED PHOTOTHERAPY IS A SAFE AND EFFECTIVE TREATMENT FOR SMALL PREMATURE INFANTS WITH HYPERBILIRUBINEMIA Arnold, C. C., Tyson, J. E., Cuadrado, C. E., Dempsey, A. G., Khan, A. M., Pedroza, C., Bhutani, V. K., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2017: 150–51

  View details for DOI 10.1136/jim-2016-000365.120

  View details for Web of Science ID 000433055100121

• The twin preterm birth problem: do preterm birth subtypes matter? Ness, A., Mayo, J., Stevenson, D. K., Shaw, G. M. MOSBY-ELSEVIER. 2017: S199

  View details for Web of Science ID 000414256401282

• 'The obesity paradox': a reconsideration of obesity and the risk of preterm birth. Journal of perinatology : official journal of the California Perinatal Association Tsur, A. n., Mayo, J. A., Wong, R. J., Shaw, G. M., Stevenson, D. K., Gould, J. B. 2017

  Abstract

  The association between obesity and spontaneous preterm births (sPTBs) has been shown to be influenced by obesity-attendant comorbidities. Our objective was to better understand the complex relationship of obesity and its attendant comorbidities with sPTBs.A retrospective analysis utilizing maternally linked hospital and birth certificate records of 2 049 196 singleton California deliveries from 2007 to 2011. Adjusted relative risks (aRRs) for sPTBs were estimated using multivariate Poisson regression modeling.Obese women had higher aRRs for sPTBs than their normal body mass index (BMI) controls. aRRs (95% confidence interval) increased with increasing BMI category: Obese I=1.10 (1.08 to 1.12); Obese II=1.15 (1.12 to 1.18); and Obese III=1.26 (1.22 to 1.30). When comparing only obese women without comorbidities to their normal BMI controls, aRRs reversed, that is, obese women had lower aRRs of sPTBs: Obese I=0.96 (0.94 to 0.98), Obese II=0.95 (0.91 to 0.98); and Obese III=0.98 (0.94 to 1.03). This same reversal of aRR direction was also observed among women with comorbidities: 0.92 (0.89 to 0.96); 0.89 (0.85 to 0.93); and 0.89 (0.85 to 0.93), respectively. Increasing BMI increased the aRRs for sPTBs among patients with gestational diabetes (P<0.05), while decreasing the risk among patients with chronic hypertension and pregnancy-related hypertensive disease (P<0.05).The obesity and preterm birth paradox is an example of what has been described as 'Simpson's Paradox'. Unmeasured confounding factors mediated by comorbidities may explain the observed protective effect of obesity upon conditioning on the presence or absence of comorbidities and thus resolve the paradox.Journal of Perinatology advance online publication, 27 July 2017; doi:10.1038/jp.2017.104.

  View details for PubMedID 28749482

• Survival and Neurodevelopmental Outcomes among Periviable Infants. New England journal of medicine Younge, N., Goldstein, R. F., Bann, C. M., Hintz, S. R., Patel, R. M., Smith, P. B., Bell, E. F., Rysavy, M. A., Duncan, A. F., Vohr, B. R., Das, A., Goldberg, R. N., Higgins, R. D., Cotten, C. M. 2017; 376 (7): 617-628

  Abstract

  Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes.We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death.Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time (adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [95% CI, 1.28 to 1.99], respectively).The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633 .).

  View details for DOI 10.1056/NEJMoa1605566

  View details for PubMedID 28199816

• Risk of recurrent preterm birth among women according to change in partner JOURNAL OF PERINATAL MEDICINE Baer, R. J., Yang, J., Chambers, C. D., Ryckman, K. K., Saftlas, A. F., Berghella, V., Schetter, C. D., Shaw, G. M., Stevenson, D. K., Jelliffe-Pawlowski, L. L. 2017; 45 (1): 63-70

  Abstract

  There is well-established literature indicating change in partner as a risk for preeclampsia, yet the research on the risk of preterm birth after a change in partners has been sparse and inconsistent. Using a population of California live born singletons, we aimed to determine the risk of preterm birth after a change in partner between the first and second pregnancies. The risk of preterm and early term delivery in the second pregnancy was calculated for mothers who did or did not change partners between births with the referent group as women who delivered both pregnancies at term and did not change partners. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. Relative to women who delivered at 39 weeks or later in the second pregnancy and did not change partners, preterm birth risks were somewhat lower for women who changed partners between the first and second pregnancies compared to those women who did not change partners. For example, 10.6% of women who did not change partners and delivered their second pregnancy before 34 weeks also delivered their first pregnancy before 34 weeks, while 8.5% of women who changed partners delivered before 34 weeks. Findings suggest partner change may alter the risk of preterm birth.

  View details for DOI 10.1515/jpm-2016-0207

  View details for Web of Science ID 000393201100009

  View details for PubMedCentralID PMC5380385

• The Relationship of Nosocomial Infection Reduction to Changes in Neonatal Intensive Care Unit Rates of Bronchopulmonary Dysplasia. journal of pediatrics Lapcharoensap, W., Kan, P., Powers, R. J., Shaw, G. M., Stevenson, D. K., Gould, J. B., Wirtschafter, D. D., Lee, H. C. 2016

  Abstract

  To examine whether recent reductions in rates of nosocomial infection have contributed to changes in rates of bronchopulmonary dysplasia (BPD) in a population-based cohort.This was a retrospective, population-based cohort study that used the California Perinatal Quality Care Collaborative database from 2006 to 2013. Eligible infants included those less than 30 weeks' gestational age and less than 1500 g who survived to 3 days of life. Primary variables of interest were rates of nosocomial infections and BPD. Adjusted rates of nosocomial infections and BPD from a baseline period (2006-2010) were compared with a later period (2011-2013). The correlation of changes in rates across periods for both variables was assessed by hospital of care.A total of 22 967 infants from 129 hospitals were included in the study. From the first to second time period, the incidence of nosocomial infections declined from 24.7% to 15% and BPD declined from 35% to 30%. Adjusted hospital rates of BPD and nosocomial infections were correlated positively with a calculated 8% reduction of BPD rates attributable to reductions in nosocomial infections.Successful interventions to reduce rates of nosocomial infections may have a positive impact on other comorbidities such as BPD. The prevention of nosocomial infections should be viewed as a significant component in avoiding long-term neonatal morbidities.

  View details for DOI 10.1016/j.jpeds.2016.09.030

  View details for PubMedID 27742123

• Inflammatory biomarkers and spontaneous preterm birth among obese women. journal of maternal-fetal & neonatal medicine Wallenstein, M. B., Jelliffe-Pawlowski, L. L., Yang, W., Carmichael, S. L., Stevenson, D. K., Ryckman, K. K., Shaw, G. M. 2016; 29 (20): 3317-3322

  Abstract

  To identify associations between second-trimester serum inflammatory biomarkers and preterm birth among obese women.In this nested case-control study, we compared 65 serum inflammatory biomarkers in obese women whose pregnancies resulted in early spontaneous preterm birth (<32 weeks gestation, n = 34) to obese women whose pregnancies resulted in term birth (n = 34). These women were selected from a larger population-based California cohort. Random forest and classification and regression tree techniques were employed to identify biomarkers of importance, and adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using logistic regression.Random forest and classification and regression tree techniques found that soluble vascular endothelial growth factor receptor-3 (sVEGFR3), soluble interleukin-2 receptor alpha-chain (sIL-2RA) and soluble tumor necrosis factor receptor-1 (sTNFR1) were related to preterm birth. Using multivariable logistic regression to compare preterm cases and term controls, decreased serum levels of sVEGFR3 and increased serum levels of sIL-2RA and sTNFR1 were associated with increased risk of preterm birth among obese women, aOR = 3.2 (95% CI: 1.0-9.9), aOR = 2.8 (95% CI: 0.9-9.0), and aOR = 4.1 (95% CI: 1.2-14.1), respectively.In this pilot study, we identified three serum biomarkers indicative of inflammation to be associated with spontaneous preterm birth among obese women: sVEGFR3, sIL-2RA and sTNFR1.

  View details for DOI 10.3109/14767058.2015.1124083

  View details for PubMedID 26700828

• Improving publication rates in a collaborative clinical trials research network. Seminars in perinatology Archer, S. W., Carlo, W. A., Truog, W. E., Stevenson, D. K., Van Meurs, K. P., Sánchez, P. J., Das, A., Devaskar, U., Nelin, L. D., Petrie Huitema, C. M., Crawford, M. M., Higgins, R. D. 2016; 40 (6): 410-417

  Abstract

  Unpublished results can bias biomedical literature, favoring positive over negative findings, primary over secondary analyses, and can lead to duplicate studies that unnecessarily endanger subjects and waste resources. The Neonatal Research Network's (NRN) publication policies for approving, reviewing, and tracking abstracts and papers work to combat these problems. In 2003, the NRN restricted investigators with unfinished manuscripts from proposing new ones and in 2010, urged authors to complete long-outstanding manuscripts. Data from 1991 to 2015 were analyzed to determine effectiveness of these policy changes. The NRN has achieved an overall publication rate of 78% for abstracts. For 1990-2002, of 137 abstracts presented, 43 (31%) were published within 2 years; for 2003-2009, after the manuscript completion policy was instituted, of 140 abstracts presented, 68 (49%) were published within 2 years. Following the effort in 2010, the rate increased to 64%. The NRN surpassed reported rates by developing a comprehensive process, holding investigators accountable and tracking abstracts from presentation to publication.

  View details for DOI 10.1053/j.semperi.2016.05.003

  View details for PubMedID 27423510

• Extreme hyperbilirubinemia and rescue exchange transfusion in California from 2007 to 2012. Journal of perinatology Bhutani, V. K., Meng, N. F., Knauer, Y., Danielsen, B. H., Wong, R. J., Stevenson, D. K., Gould, J. B. 2016; 36 (10): 853-857

  Abstract

  To evaluate the impact of statewide learning collaboratives that used national guidelines to manage jaundice on the serial prevalence of extreme hyperbilirubinemia (EHB, total bilirubin ⩾25 mg dl(-1)) and exchange transfusions introduced in California Perinatal Quality Care Collaborative (CPQCC) hospitals in 2007.Adverse outcomes were retrieved from statewide databases on re-admissions for live births ⩾35 weeks' gestation (2007 to 2012) in diverse CPQCC hospitals. Individual and cumulative select perinatal risk factors and frequencies were the outcomes measures.For 3 172 762 babies (2007 to 2012), 92.5% were ⩾35 weeks' gestation. Statewide EHB and exchange rates decreased from 28.2 to 15.3 and 3.6 to 1.9 per 100 000 live births, respectively. From 2007 to 2012, the trends for TB>25 mg dl(-1) rates were -0.92 per 100 000 live births per year (95% CI: -3.71 to 1.87, P=0.41 and R(2)=0.17).National guidelines complemented by statewide learning collaboratives can decrease or modify outcomes among all birth facilities and impact clinical practice behavior.

  View details for DOI 10.1038/jp.2016.106

  View details for PubMedID 27442156

• 50 Years Ago in TheJournal ofPediatrics: Identification of the Pigment in Amniotic Fluid of Erythroblastosis as Bilirubin. journal of pediatrics Stevenson, D. K. 2016; 176: 22-?

  View details for DOI 10.1016/j.jpeds.2016.03.013

  View details for PubMedID 27568248

• Growth Outcomes of Preterm Infants Exposed to Different Oxygen Saturation Target Ranges from Birth. journal of pediatrics Navarrete, C. T., Wrage, L. A., Carlo, W. A., Walsh, M. C., Rich, W., Gantz, M. G., Das, A., Schibler, K., Newman, N. S., Piazza, A. J., Poindexter, B. B., Shankaran, S., Sánchez, P. J., Morris, B. H., Frantz, I. D., Van Meurs, K. P., Cotten, C. M., Ehrenkranz, R. A., Bell, E. F., Watterberg, K. L., Higgins, R. D., Duara, S. 2016; 176: 62-68 e4

  Abstract

  To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO2]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA) and less growth failure at 36 weeks PMA and 18-22 months corrected age.We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n = 402, PMA 26 ± 1 weeks, birth weight 839 ± 186 g) or higher (91%-95%, n = 408, PMA 26 ± 1 weeks, birth weight 840 ± 191 g) SpO2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA; and 18-22 months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight <10th percentile at 36 weeks PMA and 18-22 months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression.Growth outcomes including growth at 36 weeks PMA and 18-22 months corrected age, as well as growth velocity were similar in the lower and higher SpO2 target groups.Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants.

  View details for DOI 10.1016/j.jpeds.2016.05.070

  View details for PubMedID 27344218

• Body Mass Index Change between Pregnancies and Risk of Spontaneous Preterm Birth. American journal of perinatology Riley, K. L., Carmichael, S. L., Mayo, J. A., Shachar, B. Z., Girsen, A. I., Wallenstein, M. B., Gould, J. B., Stevenson, D. K., Shaw, G. M. 2016; 33 (10): 1017-1022

  Abstract

  Objective Studies have reported an increased risk of spontaneous preterm birth associated with elevated prepregnancy body mass index (BMI) among nulliparous but not multiparous women. We examined whether changes in BMI and weight between pregnancies contributed to risk of preterm birth among obese (BMI > 29 kg/m(2)) women. Study Design This study utilized maternally linked California birth records of sequential singleton births between 2007 and 2010. Preterm birth was defined as 20 to 31 or 32 to 36 weeks of gestation. BMI was examined as category change and by tertile of weight change. Primary analyses included women without diabetes or hypertensive disorders; these women were compared with those without prior preterm birth, women with preterm deliveries preceded by spontaneous preterm labor, and women without any exclusions (i.e., diabetes or hypertensive disorders). Results Analyses showed that obesity was not associated with increased risk of spontaneous preterm birth among multiparous women. Women whose BMI increased had a decreased risk of spontaneous preterm birth at 32 to 36 weeks. Change in BMI or weight between pregnancies did not substantively alter results. Conclusion Among multiparous women, obesity was associated with reduced risk of spontaneous preterm delivery. This observed association is complex and may be influenced by maternal age, gestational age, placental insufficiency, and altered immune response.

  View details for DOI 10.1055/s-0036-1572533

  View details for PubMedID 27128743

• Recurrence of Preterm Birth and Early Term Birth. Obstetrics and gynecology Yang, J., Baer, R. J., Berghella, V., Chambers, C., Chung, P., Coker, T., Currier, R. J., Druzin, M. L., Kuppermann, M., Muglia, L. J., Norton, M. E., Rand, L., Ryckman, K., Shaw, G. M., Stevenson, D., Jelliffe-Pawlowski, L. L. 2016; 128 (2): 364-372

  Abstract

  To examine recurrent preterm birth and early term birth in women's initial and immediately subsequent pregnancies.This retrospective cohort study included 163,889 women who delivered their first and second liveborn singleton neonates between 20 and 44 weeks of gestation in California from 2005 through 2011. Data from hospital discharge records and birth certificates were used for analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models adjusted for risk factors.Shorter gestational duration in the first pregnancy increased the risk of subsequent preterm birth (both early, before 32 weeks of gestation, and later, from 32 to 36 weeks of gestation) as well as early term birth (37-38 weeks of gestation). Compared with women with a prior term birth, women with a prior early preterm birth (before 32 weeks of gestation) were at the highest risk for a subsequent early preterm birth (58/935 [6.2%] compared with 367/118,505 [0.3%], adjusted OR 23.3, 95% CI 17.2-31.7). Women with a prior early term birth had more than a twofold increased risk for subsequent preterm birth (before 32 weeks of gestation: 171/36,017 [0.5%], adjusted OR 2.0, 95% CI 1.6-2.3; from 32 to 36 weeks of gestation: 2,086/36,017 [6.8%], adjusted OR 3.0, 95% CI 2.9-3.2) or early term birth (13,582/36,017 [37.7%], adjusted OR 2.2, 95% CI 2.2-2.3).Both preterm birth and early term birth are associated with these outcomes in a subsequent pregnancy. Increased clinical attention and research efforts may benefit from a focus on women with a prior early term birth as well as those with prior preterm birth.

  View details for DOI 10.1097/AOG.0000000000001506

  View details for PubMedID 27400000

• Hyperbilirubinemia in Preterm Neonates CLINICS IN PERINATOLOGY Bhutani, V. K., Wong, R. J., Stevenson, D. K. 2016; 43 (2): 215-?

  Abstract

  Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion. Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin. In this article, we review the evolving evidence for bilirubin-induced brain injury in preterm infants and highlight the clinical approaches that minimize the risk of bilirubin neurotoxicity.

  View details for DOI 10.1016/j.clp.2016.01.001

  View details for PubMedID 27235203

• Preterm Birth as a Calendar Event or Immunologic Anomaly JAMA PEDIATRICS Wallenstein, M. B., Shaw, G. M., Stevenson, D. K. 2016; 170 (6): 525–26

  View details for PubMedID 27089062

• Preterm Neonates: Beyond the Guidelines for Neonatal Hyperbilirubinemia CLINICS IN PERINATOLOGY Stevenson, D. K., Bhutani, V. K. 2016; 43 (2): XVII-XVIII

  View details for PubMedID 27235216

• Phototherapy and the Risk of Photo-Oxidative Injury in Extremely Low Birth Weight Infants CLINICS IN PERINATOLOGY Stevenson, D. K., Wong, R. J., Arnold, C. C., Pedroza, C., Tyson, J. E. 2016; 43 (2): 291-?

  Abstract

  Phototherapy has been used to treat newborns with jaundice for more than 50 years with the presumption that it is safe and effective for all infants. In fact, this presumption may not be true for all infants, especially the smallest and most immature. The safety and efficacy of phototherapy have never really been questioned or adequately tested in the latter, yet clinical applications of phototherapy have been further refined as its mechanisms of action have been better understood and alternative light sources have become available. This article addresses what is known about the possible risks of photo-oxidative injury in extremely low birth weight infants.

  View details for DOI 10.1016/j.clp.2016.01.005

  View details for PubMedID 27235208

• Identification of neonatal haemolysis: an approach to predischarge management of neonatal hyperbilirubinemia ACTA PAEDIATRICA Bhutani, V. K., Srinivas, S., Cuadrado, M. E., Aby, J. L., Wong, R. J., Stevenson, D. K. 2016; 105 (5): E189-E194

  Abstract

  Relative contributions of increased production [by end-tidal carbon monoxide concentrations (ETCOc)] and decreased elimination of bilirubin to predischarge hour-specific total bilirubin (TB) levels were assessed in healthy late-preterm and term newborns. Secondly, we report predischarge ETCOc ranges to guide clinical management of hyperbilirubinemia.TB and ETCOc (≤3 timepoints) determinations of newborns aged between six hours and <6 days (n = 79) were stratified by postnatal age epochs. Hyperbilirubinemia risk was assessed by plotting TB values as a function of ETCOc.Stratifications of ETCOc (in ppm, mean, median and interquartile ranges) by postnatal age epochs (0-24, 24-48 and 48-72) were as follows: 2.0, 1.9, 1.8-2.2 (n = 11); 1.6, 1.5, 1.1-2.0 (n = 58); and 2.0, 1.8, 1.6-2.3 (n = 9), respectively. Infants with ETCOc ≥ 2.5 were at high risk, between 1.5 and 2.5 at moderate risk and ≤1.5 were at low risk. Risk due to haemolysis alone was not independent (p < 0.01). For infants with TB >75th percentile (n = 31), 23% had ETCO ≤1.5, and 77% had ETCOc > 1.5 (p < 0.00003).Near-simultaneous ETCOc and TB measurements in infants with TB >75th percentile accurately identify haemolytic hyperbilirubinemia.

  View details for DOI 10.1111/apa.13341

  View details for Web of Science ID 000373921200001

• The effect of hematocrit on in vitro bilirubin photoalteration PEDIATRIC RESEARCH Linfield, D. T., Lamola, A. A., Mei, E., Hwang, A. Y., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2016; 79 (3): 387-390

  Abstract

  Phototherapy using light in the spectral range of 410-500 nm, which overlaps the absorption of bilirubin, is the common treatment for neonatal hyperbilirubinemia. Hemoglobin (Hb) absorbs light strongly throughout this same range and thus can compete with bilirubin for this light and consequently reduce the efficacy of phototherapy. Here, we determined the effect of hematocrit (Hct) on in vitro bilirubin photoalteration using narrow-band blue (450 nm) light-emitting diodes (LEDs).Suspensions with Hcts from 0 to 80% and 16 ± 1 mg/dl bilirubin were prepared by mixing red blood cells (RBCs), bilirubin (30 mg/dl) in 4% human serum albumin, and normal saline. Aliquots of each suspension were exposed to blue light at equal irradiances. Before and after 60 min of exposure, bilirubin levels in supernatants (n = 46) were measured using a diazo-dye method.Bilirubin photoalteration steeply decreased by ~60% as Hct increased from 0 to 10%. Over the clinically relevant range of 30-70% Hct, the decrease was significant, but less drastic, exhibiting a quasi-linear dependence on Hct.Bilirubin photoalteration under blue light in vitro is significantly reduced as Hct increases. Clinical studies are warranted to confirm these in vitro observations that Hct can affect the efficacy of phototherapy.

  View details for DOI 10.1038/pr.2015.240

  View details for PubMedID 26571225

• Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model. Pediatric research Fujioka, K., Kalish, F., Wong, R. J., Stevenson, D. K. 2016; 79 (2): 251-257

  Abstract

  Increased bilirubin production due to hemolysis can lead to neonatal hyperbilirubinemia. Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, by metalloporphyrins (Mps) may be an ideal preventive strategy for neonatal hemolytic disease. Zinc protoporphyrin (ZnPP) is a naturally occurring Mp, potent, not phototoxic, with minimal HO-1 upregulation, but is not orally absorbed. Recently, we designed a lipid-based ZnPP formulation (ZnPP-Lipid), which is orally absorbed by newborn mice. Here, we evaluated the efficacy of ZnPP-Lipid in heme-loaded newborn mice, a model analogous to hemolytic infants.After 24 h of heme administration (30 µmol/kg s.c.), 4-d-old mice were given 30 µmol ZnPP-Lipid/kg via intragastric injections. After 3 h, liver and brain HO activity were measured. HO-1 upregulation was assessed by determinations of HO-1 protein, promoter activity, and mRNA by Western blot, in vivo bioluminescence imaging, and RT-PCR, respectively.After heme loading, liver HO activity significantly increased ~1.6-fold, which was inhibited in a dose-dependent manner by ZnPP-Lipid. A dose of 30 µmol/kg returned activity to control levels. Brain HO activity was not inhibited. No significant increases in liver and brain HO-1 protein, promoter activity, and mRNA were observed.ZnPP-Lipid is effective and thus has potential for treating neonatal hyperbilirubinemia due to hemolysis.

  View details for DOI 10.1038/pr.2015.207

  View details for PubMedID 26488552

• Expression of Heme Oxygenase-1 in Immune Cells During Late Gestational Inflammation. Ozen, M., Zhao, H., Kalish, F., Yang, Y., Lewis, D. B., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2016: 338A

  View details for Web of Science ID 000372879200930

• Heme Oxygenase-1 Expression in Myeloid Cells Affects Oxidative Stress, Uterine Infiltration and Placental Angiogenesis in Early Pregnancy. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2016: 68A–69A

  View details for Web of Science ID 000372879200052

• A Multi-Omics Analysis of Human Nucleus-Coded Mitochondrial Genes with Mouse Extraembryonic Tissue/Placenta Phenotypes: Implications in Mitochondria-Mediated Maternal and Fetal Complications. Hu, G., Chen, R., Deng, X., Li, Z., Mo, L., Hao, S., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Jiang, X., Sylvester, K. G., Ling, X. B. SAGE PUBLICATIONS INC. 2016: 320A

  View details for Web of Science ID 000372879200871

• Failed endotracheal intubation and adverse outcomes among extremely low birth weight infants. Journal of perinatology Wallenstein, M. B., Birnie, K. L., Arain, Y. H., Yang, W., Yamada, N. K., Huffman, L. C., Palma, J. P., Chock, V. Y., Shaw, G. M., Stevenson, D. K. 2016; 36 (2): 112-115

  Abstract

  To quantify the importance of successful endotracheal intubation on the first attempt among extremely low birth weight (ELBW) infants who require resuscitation after delivery.A retrospective chart review was conducted for all ELBW infants ⩽1000 g born between January 2007 and May 2014 at a level IV neonatal intensive care unit. Infants were included if intubation was attempted during the first 5 min of life or if intubation was attempted during the first 10 min of life with heart rate <100. The primary outcome was death or neurodevelopmental impairment. The association between successful intubation on the first attempt and the primary outcome was assessed using multivariable logistic regression with adjustment for birth weight, gestational age, gender and antenatal steroids.The study sample included 88 ELBW infants. Forty percent were intubated on the first attempt and 60% required multiple intubation attempts. Death or neurodevelopmental impairment occurred in 29% of infants intubated on the first attempt, compared with 53% of infants that required multiple attempts, adjusted odds ratio 0.4 (95% confidence interval 0.1 to 1.0), P<0.05.Successful intubation on the first attempt is associated with improved neurodevelopmental outcomes among ELBW infants. This study confirms the importance of rapid establishment of a stable airway in ELBW infants requiring resuscitation after birth and has implications for personnel selection and role assignment in the delivery room.Journal of Perinatology advance online publication, 5 November 2015; doi:10.1038/jp.2015.158.

  View details for DOI 10.1038/jp.2015.158

  View details for PubMedID 26540244

• Leading by Example and Design: The Joseph St Geme Jr Leadership Award, 2016. Pediatrics Stevenson, D. K. 2016; 138 (5)

  View details for PubMedID 27940790

• EXPRESSION PATTERNS OF HEME OXYGENASE-1 IN IMMUNE CELLS DURING LATE GESTATIONAL INFLAMMATION Ozen, M., Zhao, H., Kalish, F., Yang, Y., Lewis, D. B., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 281

  View details for DOI 10.1136/jim-d-15-00013.337

  View details for Web of Science ID 000368699600346

• Neonatal Biomarkers of Inflammation: Correlates of Early Neurodevelopment and Gait in Very-Low-Birth-Weight Preterm Children. American journal of perinatology Rose, J., Vassar, R., Cahill-Rowley, K., Hintz, S. R., Stevenson, D. K. 2016; 33 (1): 71-8

  Abstract

  Neonatal biomarkers of inflammation were examined in relation to early neurodevelopment and gait in very-low-birth-weight (VLBW) preterm children. We hypothesized that preterm infants exposed to higher levels of neonatal inflammation would demonstrate lower scores on Bayley Scales of Infant Toddler Development, 3rd ed. (BSID-III) and slower gait velocity at 18 to 22 months adjusted age.A total of 102 VLBW preterm infants (birthweight [BW] ≤ 1,500 g, gestational age [GA] ≤ 32 weeks) admitted to neonatal intensive care unit [NICU] were recruited. Neonatal risk factors examined were GA at birth, BW, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, sepsis, and serum C-reactive protein (CRP), albumin, and total bilirubin over first 2 postnatal weeks. At 18 to 22 months, neurodevelopment was assessed with BSID-III and gait was assessed with an instrumented mat.Children with neonatal CRP ≥ 0.20 mg/dL (n = 52) versus < 0.20 mg/dL (n = 37) had significantly lower BSID-III composite cognitive (92.0 ± 13.1 vs. 100.1 ± 9.6, p = 0.002), language (83.9 ± 16.0 vs. 95.8 ± 14.2, p < 0.001), and motor scores (90.0 ± 13.2 vs. 98.8 ± 10.1, p = 0.002), and slower gait velocity (84.9 ± 19.0 vs. 98.0 ± 22.4 cm/s, p = 0.004). Higher neonatal CRP correlated with lower cognitive (rho =  - 0.327, p = 0.002), language (rho =  - 0.285, p = 0.007), and motor scores (rho =  - 0.257, p = 0.015), and slower gait (rho =  - 0.298, p = 0.008). Multivariate analysis demonstrated neonatal CRP ≥ 0.20 mg/dL significantly predicted BSID-III cognitive (adjusted R(2) = 0.104, p = 0.008), language (adjusted R(2) = 0.124, p = 0.001), and motor scores (adjusted R(2) = 0.122, p = 0.004).Associations between low-level neonatal inflammation and neurodevelopment suggest early biomarkers that may inform neuroprotective treatment for preterm children.

  View details for DOI 10.1055/s-0035-1557106

  View details for PubMedID 26212060

• Chorioamnionitis and Culture-Confirmed, Early-Onset Neonatal Infections. Pediatrics Wortham, J. M., Hansen, N. I., Schrag, S. J., Hale, E., Van Meurs, K., Sánchez, P. J., Cantey, J. B., Faix, R., Poindexter, B., Goldberg, R., Bizzarro, M., Frantz, I., Das, A., Benitz, W. E., Shane, A. L., Higgins, R., Stoll, B. J. 2016; 137 (1): 1-11

  Abstract

  Current guidelines for prevention of neonatal group B streptococcal disease recommend diagnostic evaluations and empirical antibiotic therapy for well-appearing, chorioamnionitis-exposed newborns. Some clinicians question these recommendations, citing the decline in early-onset group B streptococcal disease rates since widespread intrapartum antibiotic prophylaxis implementation and potential antibiotic risks. We aimed to determine whether chorioamnionitis-exposed newborns with culture-confirmed, early-onset infections can be asymptomatic at birth.Multicenter, prospective surveillance for early-onset neonatal infections was conducted during 2006-2009. Early-onset infection was defined as isolation of a pathogen from blood or cerebrospinal fluid collected ≤ 72 hours after birth. Maternal chorioamnionitis was defined by clinical diagnosis in the medical record or by histologic diagnosis by placental pathology. Hospital records of newborns with early-onset infections born to mothers with chorioamnionitis were reviewed retrospectively to determine symptom onset.Early-onset infections were diagnosed in 389 of 396,586 live births, including 232 (60%) chorioamnionitis-exposed newborns. Records for 229 were reviewed; 29 (13%) had no documented symptoms within 6 hours of birth, including 21 (9%) who remained asymptomatic at 72 hours. Intrapartum antibiotic prophylaxis exposure did not differ significantly between asymptomatic and symptomatic infants (76% vs 69%; P = .52). Assuming complete guideline implementation, we estimated that 60 to 1400 newborns would receive diagnostic evaluations and antibiotics for each infected asymptomatic newborn, depending on chorioamnionitis prevalence.Some infants born to mothers with chorioamnionitis may have no signs of sepsis at birth despite having culture-confirmed infections. Implementation of current clinical guidelines may result in early diagnosis, but large numbers of uninfected asymptomatic infants would be treated.

  View details for DOI 10.1542/peds.2015-2323

  View details for PubMedID 26719293

• Preterm birth rates by gestational age and demographic factors in twins compared to singletons in California 2007-2010 Ness, A., Mayo, J., Stevenson, D. K., Shaw, G. MOSBY-ELSEVIER. 2016: S374–S375

  View details for DOI 10.1016/j.ajog.2015.10.760

  View details for Web of Science ID 000367092800706

• A LIPID FORMULATION OF ZINC PROTOPORPHYRIN FOR THE PREVENTION OF NEONATAL HYPERBILIRUBINEMIA DUE TO CHRONIC HEMOLYSIS Konecny, C. M., Fujioka, K., Wong, S., Lu, S., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 253–54

  View details for DOI 10.1136/jim-d-15-00013.274

  View details for Web of Science ID 000368699600283

• IN VIVO INDUCTION OF HEME OXYGENASE-1 BY ASPIRIN Konecny, C. M., Wong, S., Lu, S., Fujioka, K., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 181

  View details for DOI 10.1136/jim-d-15-00013.108

  View details for Web of Science ID 000368699600118

• IDENTIFICATION OF NEONATAL HEMOLYSIS IN THE WELL BABY NURSERY Srinivas, S., Cuadrado, M., Wong, R. J., Stevenson, D. K., Bhutani, V. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 287

  View details for DOI 10.1136/jim-d-15-00013.351

  View details for Web of Science ID 000368699600360

• Risk of recurrent preterm birth among women according to change in paternity Baer, R. J., Yang, J., Chambers, C. D., Ryckman, K., Shaw, G. M., Stevenson, D. K., Schetter, C., Saftlas, A. F., Berghella, V., Jelliffe-Pawlowski, L. L. MOSBY-ELSEVIER. 2016: S324

  View details for DOI 10.1016/j.ajog.2015.10.651

  View details for Web of Science ID 000367092800600

• INDUCTION OF HEME OXYGENASE-1 ATTENUATES THE SEVERITY OF SEPSIS IN A NON-SURGICAL NEONATAL MOUSE MODEL Fujioka, K., Lu, S., Wong, S., Kalish, F., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2016: 253

  View details for DOI 10.1136/jim-d-15-00013.273

  View details for Web of Science ID 000368699600282

• Teenage pregnancy, body mass index, and preterm birth Mayo, J., Shachar, B., Stevenson, D. K., Shaw, G. M. MOSBY-ELSEVIER. 2016: S394–S395

  View details for DOI 10.1016/j.ajog.2015.10.800

  View details for Web of Science ID 000367092800743

• Association between gestational duration in first pregnancies and birth timing in second pregnancies Yang, J., Baer, R. J., Berghella, V., Chambers, C., Chung, P., Coker, T., Currier, R. J., Druzin, M. L., Kuppermann, M., Muglia, L. J., Norton, M. E., Rand, L., Ryckman, K., Shaw, G. M., Stevenson, D., Wise, P., Jelliffe-Pawlowski, L. L. MOSBY-ELSEVIER. 2016: S442

  View details for DOI 10.1016/j.ajog.2015.10.898

  View details for Web of Science ID 000367092800837

• Neonatal brain microstructure correlates of neurodevelopment and gait in preterm children 18-22 mo of age: an MRI and DTI study PEDIATRIC RESEARCH Rose, J., Cahill-Rowley, K., Vassar, R., Yeom, K. W., Stecher, X., Stevenson, D. K., Hintz, S. R., Barnea-Goraly, N. 2015; 78 (6): 700-708

  Abstract

  Near-term brain structure was examined in preterm infants in relation to neurodevelopment. We hypothesized that near-term macrostructural brain abnormalities identified using conventional magnetic resonance imaging (MRI), and white matter (WM) microstructure detected using diffusion tensor imaging (DTI), would correlate with lower cognitive and motor development and slower, less-stable gait at 18-22 mo of age.One hundred and two very-low-birth-weight preterm infants (≤1,500 g birth weight; ≤32 wk gestational age) were recruited prior to routine near-term brain MRI at 36.6 ± 1.8 wk postmenstrual age. Cerebellar and WM macrostructure was assessed on conventional structural MRI. DTI was obtained in 66 out of 102 and WM microstructure was assessed using fractional anisotropy and mean diffusivity (MD) in six subcortical brain regions defined by DiffeoMap neonatal atlas. Neurodevelopment was assessed with Bayley-Scales-of-Infant-Toddler-Development, 3rd-Edition (BSID-III); gait was assessed using an instrumented mat.Neonates with cerebellar abnormalities identified using MRI demonstrated lower mean BSID-III cognitive composite scores (89.0 ± 10.1 vs. 97.8 ± 12.4; P = 0.002) at 18-22 mo. Neonates with higher DTI-derived left posterior limb of internal capsule (PLIC) MD demonstrated lower cognitive and motor composite scores (r = -0.368; P = 0.004; r = -0.354; P = 0.006) at 18-22 mo; neonates with higher genu MD demonstrated slower gait velocity (r = -0.374; P = 0.007). Multivariate linear regression significantly predicted cognitive (adjusted r(2) = 0.247; P = 0.002) and motor score (adjusted r(2) = 0.131; P = 0.017).Near-term cerebellar macrostructure and PLIC and genu microstructure were predictive of early neurodevelopment and gait.

  View details for DOI 10.1038/pr.2015.157

  View details for PubMedID 26322412

• Reply to Keelan and Payne: Microbiota-related pathways for preterm birth PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA DiGiulio, D. B., Stevenson, D. K., Shaw, G., Lyell, D. J., Relman, D. A. 2015; 112 (47): E6415

  View details for PubMedID 26515091

• Effects of race/ethnicity and BMI on the association between height and risk for spontaneous preterm birth. American journal of obstetrics and gynecology Shachar, B. Z., Mayo, J. A., Lee, H. C., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Gould, J. B. 2015; 213 (5): 700 e1-9

  Abstract

  Short height and obesity have each been associated with increased risk for preterm birth (PTB). However, the effect of short height on PTB risk, across different race/ethnicities and body mass index (BMI) categories, has not been studied. Our objective was to determine the influence of maternal height on the risk for PTB within race/ethnic groups, BMI groups, or adjusted for weight.All California singleton live births from 2007 through 2010 were included from birth certificate data (vital statistics) linked to hospital discharge data. Prepregnancy BMI (kg/m(2)) was categorized as underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), or obese (≥30.0). Maternal race/ethnicity was categorized as: non-Hispanic white, non-Hispanic black, Hispanic, and Asian. Maternal height was classified into 5 categories (shortest, short, middle, tall, tallest) based on racial/ethnic-specific height distributions, with the middle category serving as reference. Poisson regression models were used to estimate relative risks for the association between maternal height and risk of spontaneous PTB (<37 weeks and <32 weeks). Models were stratified on race/ethnicity and BMI. Generalized additive regression models were used to detect nonlinearity of the association. Covariates considered were: maternal age, weight, parity, prenatal care, education, medical payment, previous PTB, gestational and pregestational diabetes, pregestational hypertension, preeclampsia/eclampsia, and smoking.Among 1,655,385 California singleton live births, 5.2% were spontaneous PTB <37 weeks. Short stature (first height category) was associated with increased risk for PTB for non-Hispanic whites and Hispanics across all BMI categories. Among obese women, tall stature (fifth category) was associated with reduced risk for spontaneous PTB for non-Hispanic whites, Asians, and Hispanics. The same pattern of association was seen for height and risk for spontaneous PTB <32 weeks. In the generalized additive regression model plots, short stature was associated with increased risk for spontaneous PTB of <32 and <37 weeks of gestation among whites and Asians. However, this association was not observed for blacks and Hispanics.Maternal shorter height is associated with a modest increased risk for spontaneous PTB regardless of BMI. Our results suggest that PTB risk assessment should consider race/ethnicity-specific height with respect to the norm in addition to BMI assessment.

  View details for DOI 10.1016/j.ajog.2015.07.005

  View details for PubMedID 26187451

  View details for PubMedCentralID PMC4631690

• Role of infant sex in the association between air pollution and preterm birth ANNALS OF EPIDEMIOLOGY Cossi, M., Zuta, S., Padula, A. M., Gould, J. B., Stevenson, D. K., Shaw, G. M. 2015; 25 (11): 874-876

  View details for DOI 10.1016/j.annepidem.2015.08.005

  View details for PubMedID 26475983

• Effects of race/ethnicity and BMI on the association between height and risk for spontaneous preterm birth AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Shachar, B. Z., Mayo, J. A., Lee, H. C., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Gould, J. B. 2015; 213 (5)

  View details for DOI 10.1016/j.ajog.2015.07.005

  View details for Web of Science ID 000365763400027

  View details for PubMedID 26187451

• Prepregnancy Obesity and Risks of Stillbirth PLOS ONE Carmichael, S. L., Blumenfeld, Y. J., Mayo, J., Wei, E., Gould, J. B., Stevenson, D. K., Shaw, G. M. 2015; 10 (10)

  Abstract

  We examined the association of maternal obesity with risk of stillbirth, focusing on whether the pattern of results varied by gestational age or maternal race-ethnicity or parity.Analyses included 4,012 stillbirths and 1,121,234 liveborn infants delivered in California from 2007-2010. We excluded stillbirths due to congenital anomalies, women with hypertensive disorders or diabetes, and plural births, to focus on fetuses and women without these known contributing conditions. We used Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CI). Separate models were run for stillbirths delivered at 20-23, 24-27, 28-31, 32-36, 37-41 weeks, relative to liveborn deliveries at 37-41 weeks.For stillbirth at 20-23 weeks, RRs were elevated for all race-ethnicity and parity groups. The RR for a 20-unit change in BMI (which reflects the approximate BMI difference between a normal weight and an Obese III woman) was 3.5 (95% CI 2.2, 5.6) for nulliparous white women and ranged from 1.8 to 5.0 for other sub-groups. At 24-27 weeks, the association was significant (p<0.05) only for multiparous non-Hispanic whites; at 28-31 weeks, for multiparous whites and nulliparous whites and blacks; at 32-36 weeks, for multiparous whites and nulliparous blacks; and at 37-41 weeks, for all groups except nulliparous blacks. The pattern of results was similar when restricted to stillbirths due to unknown causes and somewhat stronger when restricted to stillbirths attributable to obstetric causes.Increased risks were observed across all gestational ages, and some evidence of heterogeneity of the associations was observed by race-ethnicity and parity.

  View details for DOI 10.1371/journal.pone.0138549

  View details for PubMedID 26466315

• Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia. journal of pediatrics Gage, S., Kan, P., Lee, H. C., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 167 (4): 875-880 e1

  Abstract

  To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD).Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007-2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma.Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07).Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants.

  View details for DOI 10.1016/j.jpeds.2015.06.048

  View details for PubMedID 26254835

• Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia. journal of pediatrics Gage, S., Kan, P., Lee, H. C., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 167 (4): 875-880 e1

  Abstract

  To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD).Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007-2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma.Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07).Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants.

  View details for DOI 10.1016/j.jpeds.2015.06.048

  View details for PubMedID 26254835

• Heightened risk of preterm birth and growth restriction after a first-born son ANNALS OF EPIDEMIOLOGY Bruckner, T. A., Mayo, J. A., Gould, J. B., Stevenson, D. K., Lewis, D. B., Shaw, G. M., Carmichael, S. L. 2015; 25 (10): 743-747

  Abstract

  In Scandinavia, delivery of a first-born son elevates the risk of preterm delivery and intrauterine growth restriction of the next-born infant. External validity of these results remains unclear. We test this hypothesis for preterm delivery and growth restriction using the linked California birth cohort file. We examined the hypothesis separately by race and/or ethnicity.We retrieved data on 2,852,976 births to 1,426,488 mothers with at least two live births. Our within-mother tests applied Cox proportional hazards (preterm delivery, defined as less than 37 weeks gestation) and linear regression models (birth weight for gestational age percentiles).For non-Hispanic whites, Hispanics, Asians, and American Indian and/or Alaska Natives, analyses indicate heightened risk of preterm delivery and growth restriction after a first-born male. The race-specific hazard ratios for preterm delivery range from 1.07 to 1.18. Regression coefficients for birth weight for gestational age percentile range from -0.73 to -1.49. The 95% confidence intervals for all these estimates do not contain the null. By contrast, we could not reject the null for non-Hispanic black mothers.Whereas California findings generally support those from Scandinavia, the null results among non-Hispanic black mothers suggest that we do not detect adverse outcomes after a first-born male in all racial and/or ethnic groups.

  View details for DOI 10.1016/j.annepidem.2015.07.002

  View details for PubMedID 26265442

• Maternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth. BJOG : an international journal of obstetrics and gynaecology Jelliffe-Pawlowski, L. L., Baer, R. J., Blumenfeld, Y. J., Ryckman, K. K., O'Brodovich, H. M., Gould, J. B., Druzin, M. L., El-Sayed, Y. Y., Lyell, D. J., Stevenson, D. K., Shaw, G. M., Currier, R. J. 2015; 122 (11): 1484-1493

  Abstract

  To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes.Population-based cohort.California, United States of America.From a total population of 1 004 039 live singleton births in 2009 and 2010, 841 665 pregnancies with linked birth certificate and hospital discharge records were included.Characteristics were compared for term and preterm deliveries by PTB subtype using logistic regression and odds ratios adjusted for maternal characteristics and obstetric factors present in final stepwise models and 95% confidence intervals. First-trimester and second-trimester serum marker levels were analysed in a subset of 125 202 pregnancies with available first-trimester and second-trimester serum biomarker results.PTB by subtype.In fully adjusted models, ten characteristics and three serum biomarkers were associated with increased risk in each PTB subtype (Black race/ethnicity, pre-existing hypertension with and without pre-eclampsia, gestational hypertension with pre-eclampsia, pre-existing diabetes, anaemia, previous PTB, one or two or more previous caesarean section(s), interpregnancy interval ≥ 60 months, low first-trimester pregnancy-associated plasma protein A, high second-trimester α-fetoprotein, and high second-trimester dimeric inhibin A). These risks occurred in 51.6-86.2% of all pregnancies ending in PTB depending on subtype. The highest risk observed was for medically indicated PTB <32 weeks in women with pre-existing hypertension and pre-eclampsia (adjusted odds ratio 89.7, 95% CI 27.3-111.2).Our findings suggest a shared aetiology across PTB subtypes. These commonalities point to targets for further study and exploration of risk reduction strategies.Findings suggest a shared aetiology across preterm birth subtypes. Patterns may inform risk reduction efforts.

  View details for DOI 10.1111/1471-0528.13495

  View details for PubMedID 26111589

• Serological Targeted Analysis of an ITIH4 Peptide Isoform: A Preterm Birth Biomarker and Its Associated SNP Implications JOURNAL OF GENETICS AND GENOMICS Tan, Z., Hu, Z., Cai, E. Y., Alev, C., Yang, T., Li, Z., Sung, J., El-Sayed, Y. Y., Shaw, G. M., Stevenson, D. K., Butte, A. J., Sheng, G., Sylvester, K. G., Cohen, H. J., Ling, X. B. 2015; 42 (9): 507-510

  View details for DOI 10.1016/j.jgg.2015.06.001

  View details for PubMedID 26408095

• Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA Stoll, B. J., Hansen, N. I., Bell, E. F., Walsh, M. C., Carlo, W. A., Shankaran, S., Laptook, A. R., Sánchez, P. J., Van Meurs, K. P., Wyckoff, M., Das, A., Hale, E. C., Ball, M. B., Newman, N. S., Schibler, K., Poindexter, B. B., Kennedy, K. A., Cotten, C. M., Watterberg, K. L., D'Angio, C. T., DeMauro, S. B., Truog, W. E., Devaskar, U., Higgins, R. D. 2015; 314 (10): 1039-1051

  Abstract

  Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers.Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012.Extremely preterm birth.Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex.Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation.Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions.clinicaltrials.gov Identifier: NCT00063063.

  View details for DOI 10.1001/jama.2015.10244

  View details for PubMedID 26348753

• Exome Sequencing of Neonatal Blood Spots and the Identification of Genes Implicated in Bronchopulmonary Dysplasia. American journal of respiratory and critical care medicine Li, J., Yu, K., Oehlert, J., Jeliffe-Pawlowski, L. L., Gould, J. B., Stevenson, D. K., Snyder, M., Shaw, G. M., O'Brodovich, H. M. 2015; 192 (5): 589-596

  Abstract

  Bronchopulmonary dysplasia (BPD), a prevalent severe lung disease of premature infants, has a strong genetic component. Large-scale genome-wide association studies for common variants have not revealed its genetic basis.Given the historical high mortality rate of extremely preterm infants who now survive and develop BPD, we hypothesized that risk loci underlying this disease are under severe purifying selection during evolution; thus, rare variants likely explain greater risk of the disease.We performed exome sequencing on 50 BPD-affected and unaffected twin pairs using DNA isolated from neonatal blood spots and identified genes affected by extremely rare nonsynonymous mutations. Functional genomic approaches were then used to systematically compare these affected genes.We identified 258 genes with rare nonsynonymous mutations in patients with BPD. These genes were highly enriched for processes involved in pulmonary structure and function including collagen fibril organization, morphogenesis of embryonic epithelium, and regulation of Wnt signaling pathway; displayed significantly elevated expression in fetal and adult lungs; and were substantially up-regulated in a murine model of BPD. Analyses of mouse mutants revealed their phenotypic enrichment for embryonic development and the cyanosis phenotype, a clinical manifestation of BPD.Our study supports the role of rare variants in BPD, in contrast with the role of common variants targeted by genome-wide association studies. Overall, our study is the first to sequence BPD exomes from newborn blood spot samples and identify with high confidence genes implicated in BPD, thereby providing important insights into its biology and molecular etiology.

  View details for DOI 10.1164/rccm.201501-0168OC

  View details for PubMedID 26030808

• Determinants of chronic lung disease severity in the first year of life; A population based study. Pediatric pulmonology Gage, S., Kan, P., Oehlert, J., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 50 (9): 878-888

  Abstract

  First, create a clinical severity score for patients with chronic lung disease of infancy (CLDi) following neonatal intensive care unit (NICU) stay. Second, using California wide population-based data, identify factors associated with clinical severity of CLDi at 4-9 months corrected gestational age (CGA).Pediatric pulmonologists ranked and weighted eight factors reflecting clinical severity of CLDi. Utilizing these data we scored and assigned these to 4-9 month old CGA moderate/severe bronchopulmonary dysplasia (BPD) infants, born<30 weeks gestational age (GA), within the California High Risk Infant Follow up (HRIF) program. Infants were studied relative to factors from the California Perinatal Quality Care Collaborative (CPQCC).We received survey responses from 43/88 pediatric pulmonologists from 28/53 North American training centers who are experts in CLDi. Strong agreement between ranking (72-100%) of respiratory system parameters and weighting (out of 100 points weighting was within 20 points) was observed with severity of CLDi. Data from 940 CLDi premature infants <30 weeks GA were obtained. Infants with severe CLDi scores at 4-9 months CGA (relative to a zero score) showed positive associations with being male, odds ratio[OR] = 2.45[confidence interval (CI) 1.26-4.77]), >30 ventilator days, OR = 3.82 (1.30-11.2), postnatal steroids OR = 3.94 (1.94-7.84), and a surprising inverse association with retinopathy of prematurity stage 3-4, OR = 0.24 (0.09-0.67) CONCLUSIONS: The CLDi clinical severity score allowed for standardized assessment of pulmonary morbidity, and evaluation of risk factors in the NICU for CLDi following NICU discharge. These observations point to risk factors associated with CLDi outcomes at 4-9 months CGA. Pediatr Pulmonol. 2015; 50:878-888. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ppul.23148

  View details for PubMedID 25651820

• Bilirubin production and hour-specific bilirubin levels JOURNAL OF PERINATOLOGY Bhutani, V. K., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2015; 35 (9): 735-738

  Abstract

  We assessed the relative contributions of increased bilirubin production (indexed by end-tidal carbon monoxide (CO) concentrations, corrected for ambient CO (ETCOc)) to hour-specific total bilirubin (TB) levels in healthy late preterm and term newborns.Post hoc analyses of concurrent ETCOc and TB (at 30±6 h of age) and follow-up TB levels at age 96±12 h and up to 168 h after birth were performed in a cohort of 641 term and late preterm infants.Increased bilirubin production (hour-specific ETCOc ⩾1.7 p.p.m. at age 30±6 h) was noted in ~80%, 42% and 32% of infants in the high-, intermediate- and low-risk TB zones, respectively. One infant with TB <40th percentile and ETCOc <1.7 p.p.m. developed TB ⩾95th percentile at age 168 h, probably due to decreased bilirubin elimination.Infants in the high-risk quartile of the hour-specific bilirubin nomogram have a higher mean bilirubin production. Infants with TB levels ⩾95th percentile without increased bilirubin production have impaired bilirubin elimination.

  View details for DOI 10.1038/jp.2015.32

  View details for Web of Science ID 000360408600015

• Determinants of chronic lung disease severity in the first year of life; A population based study PEDIATRIC PULMONOLOGY Gage, S., Kan, P., Oehlert, J., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 50 (9): 878-888

  Abstract

  First, create a clinical severity score for patients with chronic lung disease of infancy (CLDi) following neonatal intensive care unit (NICU) stay. Second, using California wide population-based data, identify factors associated with clinical severity of CLDi at 4-9 months corrected gestational age (CGA).Pediatric pulmonologists ranked and weighted eight factors reflecting clinical severity of CLDi. Utilizing these data we scored and assigned these to 4-9 month old CGA moderate/severe bronchopulmonary dysplasia (BPD) infants, born<30 weeks gestational age (GA), within the California High Risk Infant Follow up (HRIF) program. Infants were studied relative to factors from the California Perinatal Quality Care Collaborative (CPQCC).We received survey responses from 43/88 pediatric pulmonologists from 28/53 North American training centers who are experts in CLDi. Strong agreement between ranking (72-100%) of respiratory system parameters and weighting (out of 100 points weighting was within 20 points) was observed with severity of CLDi. Data from 940 CLDi premature infants <30 weeks GA were obtained. Infants with severe CLDi scores at 4-9 months CGA (relative to a zero score) showed positive associations with being male, odds ratio[OR] = 2.45[confidence interval (CI) 1.26-4.77]), >30 ventilator days, OR = 3.82 (1.30-11.2), postnatal steroids OR = 3.94 (1.94-7.84), and a surprising inverse association with retinopathy of prematurity stage 3-4, OR = 0.24 (0.09-0.67) CONCLUSIONS: The CLDi clinical severity score allowed for standardized assessment of pulmonary morbidity, and evaluation of risk factors in the NICU for CLDi following NICU discharge. These observations point to risk factors associated with CLDi outcomes at 4-9 months CGA. Pediatr Pulmonol. 2015; 50:878-888. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ppul.23148

  View details for Web of Science ID 000360091000007

• Temporal and spatial variation of the human microbiota during pregnancy. Proceedings of the National Academy of Sciences of the United States of America DiGiulio, D. B., Callahan, B. J., McMurdie, P. J., Costello, E. K., Lyell, D. J., Robaczewska, A., Sun, C. L., Goltsman, D. S., Wong, R. J., Shaw, G., Stevenson, D. K., Holmes, S. P., Relman, D. A. 2015

  Abstract

  Despite the critical role of the human microbiota in health, our understanding of microbiota compositional dynamics during and after pregnancy is incomplete. We conducted a case-control study of 49 pregnant women, 15 of whom delivered preterm. From 40 of these women, we analyzed bacterial taxonomic composition of 3,767 specimens collected prospectively and weekly during gestation and monthly after delivery from the vagina, distal gut, saliva, and tooth/gum. Linear mixed-effects modeling, medoid-based clustering, and Markov chain modeling were used to analyze community temporal trends, community structure, and vaginal community state transitions. Microbiota community taxonomic composition and diversity remained remarkably stable at all four body sites during pregnancy (P > 0.05 for trends over time). Prevalence of a Lactobacillus-poor vaginal community state type (CST 4) was inversely correlated with gestational age at delivery (P = 0.0039). Risk for preterm birth was more pronounced for subjects with CST 4 accompanied by elevated Gardnerella or Ureaplasma abundances. This finding was validated with a set of 246 vaginal specimens from nine women (four of whom delivered preterm). Most women experienced a postdelivery disturbance in the vaginal community characterized by a decrease in Lactobacillus species and an increase in diverse anaerobes such as Peptoniphilus, Prevotella, and Anaerococcus species. This disturbance was unrelated to gestational age at delivery and persisted for up to 1 y. These findings have important implications for predicting premature labor, a major global health problem, and for understanding the potential impact of a persistent, altered postpartum microbiota on maternal health, including outcomes of pregnancies following short interpregnancy intervals.

  View details for DOI 10.1073/pnas.1502875112

  View details for PubMedID 26283357

• Association of HMOX1 gene promoter polymorphisms with hyperbilirubinemia in the early neonatal period PEDIATRICS INTERNATIONAL Katayama, Y., Yokota, T., Zhao, H., Wong, R. J., Stevenson, D. K., Taniguchi-Ikeda, M., Nakamura, H., Iijima, K., Morioka, I. 2015; 57 (4): 645-649

  Abstract

  Heme oxygenase (HO) is the rate-limiting enzyme in the heme degradation pathway that produces bilirubin. The promoter region of human heme oxygenase-1 (HMOX1) contains a polymorphic (GT)n repeat that can regulate gene expression. Here, we investigated the association of (GT)n repeat length in the HMOX1 promoter region with neonatal hyperbilirubinemia in a population of Japanese term neonates.Using polymerase chain reaction and fragment analysis, we determined the number of (GT)n repeats in 149 Japanese neonates. To omit the effects of the G71R mutation in uridine diphosphoglucuronosyltransferase on hyperbilirubinemia, we excluded 41 neonates with the G71R mutation. As a result, 25 neonates with hyperbilirubinemia and 83 non-hyperbilirubinemic controls were included in this prospective case-control study. Allele and genotype frequencies of (GT)n repeats in the HMOX1 gene were compared between hyperbilirubinemic and non-hyperbilirubinemic control neonates.The prevalence of short alleles (< 22 (GT)n repeats) was significantly higher in hyperbilirubinemic than in control neonates (18% vs 7%, P = 0.015). Hyperbilirubinemia was more frequent in homozygous or heterozygous short allele carriers than control neonates (28% vs 11%, respectively, P = 0.03). Possession of short alleles was significantly associated with the development of neonatal hyperbilirubinemia (OR, 3.1; 95%CI: 1.03-9.53).Infants carrying short alleles (< 22 (GT)n repeats) in the HMOX1 gene promoter region appear to be at a higher risk for developing neonatal hyperbilirubinemia.

  View details for DOI 10.1111/ped.12591

  View details for Web of Science ID 000360501500024

• Association of HMOX1 gene promoter polymorphisms with hyperbilirubinemia in the early neonatal period. Pediatrics international : official journal of the Japan Pediatric Society Katayama, Y., Yokota, T., Zhao, H., Wong, R. J., Stevenson, D. K., Taniguchi-Ikeda, M., Nakamura, H., Iijima, K., Morioka, I. 2015; 57 (4): 645-9

  Abstract

  Heme oxygenase (HO) is the rate-limiting enzyme in the heme degradation pathway that produces bilirubin. The promoter region of human heme oxygenase-1 (HMOX1) contains a polymorphic (GT)n repeat that can regulate gene expression. Here, we investigated the association of (GT)n repeat length in the HMOX1 promoter region with neonatal hyperbilirubinemia in a population of Japanese term neonates.Using polymerase chain reaction and fragment analysis, we determined the number of (GT)n repeats in 149 Japanese neonates. To omit the effects of the G71R mutation in uridine diphosphoglucuronosyltransferase on hyperbilirubinemia, we excluded 41 neonates with the G71R mutation. As a result, 25 neonates with hyperbilirubinemia and 83 non-hyperbilirubinemic controls were included in this prospective case-control study. Allele and genotype frequencies of (GT)n repeats in the HMOX1 gene were compared between hyperbilirubinemic and non-hyperbilirubinemic control neonates.The prevalence of short alleles (< 22 (GT)n repeats) was significantly higher in hyperbilirubinemic than in control neonates (18% vs 7%, P = 0.015). Hyperbilirubinemia was more frequent in homozygous or heterozygous short allele carriers than control neonates (28% vs 11%, respectively, P = 0.03). Possession of short alleles was significantly associated with the development of neonatal hyperbilirubinemia (OR, 3.1; 95%CI: 1.03-9.53).Infants carrying short alleles (< 22 (GT)n repeats) in the HMOX1 gene promoter region appear to be at a higher risk for developing neonatal hyperbilirubinemia.

  View details for DOI 10.1111/ped.12591

  View details for PubMedID 25625535

• Case 1: Lactic Acidosis and Respiratory Distress in a 10-Day-Old Infant. NeoReviews Wallenstein, M. B., Olson, K., Peng, D. M., Stevenson, D. K., Shaw, G. M., Palma, J. P., Bain, L. C. 2015; 16 (7): e431-e433

  View details for PubMedID 26236172

• Evaluation of a new end-tidal carbon monoxide monitor from the bench tothe bedside ACTA PAEDIATRICA Cuadrado, M. E., Bhutani, V. K., Aby, J. L., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2015; 104 (6): E279-E282

  View details for DOI 10.1111/apa.12938

  View details for Web of Science ID 000354528100008

• Spatial and temporal patterns in preterm birth in the United States PEDIATRIC RESEARCH Byrnes, J., Mahoney, R., Quaintance, C., Gould, J. B., Carmichael, S., Shaw, G. M., Showen, A., Phibbs, C., Stevenson, D. K., Wise, P. H. 2015; 77 (6): 836-844

  Abstract

  Despite years of research, the etiologies of preterm birth remain unclear. In order to help generate new research hypotheses, this study explored spatial and temporal patterns of preterm birth in a large, total-population dataset.Data on 145 million US births in 3,000 counties from the Natality Files of the National Center for Health Statistics for 1971-2011 were examined. State trends in early (<34 wk) and late (34-36 wk) preterm birth rates were compared. K-means cluster analyses were conducted to identify gestational age distribution patterns for all US counties over time.A weak association was observed between state trends in <34 wk birth rates and the initial absolute <34 wk birth rate. Significant associations were observed between trends in <34 wk and 34-36 wk birth rates and between white and African American <34 wk births. Periodicity was observed in county-level trends in <34 wk birth rates. Cluster analyses identified periods of significant heterogeneity and homogeneity in gestational age distributional trends for US counties.The observed geographic and temporal patterns suggest periodicity and complex, shared influences among preterm birth rates in the United States. These patterns could provide insight into promising hypotheses for further research.

  View details for DOI 10.1038/pr.2015.55

  View details for PubMedID 25760546

• Serial aEEG recordings in a cohort of extremely preterm infants: feasibility and safety JOURNAL OF PERINATOLOGY Davis, A. S., Gantz, M. G., Do, B., Shankaran, S., Hamrick, S. E., Kennedy, K. A., TYSON, J. E., Chalak, L. F., Laptook, A. R., Goldstein, R. F., Hintz, S. R., Das, A., Higgins, R. D., Ball, M. B., HALE, E. C., Van Meurs, K. P. 2015; 35 (5): 373-378

  Abstract

  Objective:Amplitude-integrated electroencephalography (aEEG) monitoring is increasing in the neonatal population, but the safety and feasibility of performing aEEG in extremely preterm infants have not been systematically evaluated.Study Design:Inborn infants 23(0/7) to 28(6/7) weeks gestation or birth weight 401 to 1000 g were eligible. Serial, 6-h aEEG recordings were obtained from first week of life until 36 weeks postmenstrual age. Adverse events were documented, and surveys evaluated the impact of the aEEGs on routine care. Success of performing aEEGs according to protocol and aEEG quality were assessed.Result:A total of 102 infants were enrolled, with 755 recordings performed. 83% of recordings were performed according to schedule, and 96% were without adverse event. Bedside nurses reported no interference with routine care for 89% of recordings. 92% of recordings had acceptable signal quality.Conclusion:Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.Journal of Perinatology advance online publication, 4 December 2014; doi:10.1038/jp.2014.217.

  View details for DOI 10.1038/jp.2014.217

  View details for PubMedID 25474559

• Unique Roles of Infiltrating Myeloid Cells in the Murine Uterus during Early to Midpregnancy. Journal of immunology Zhao, H., Kalish, F., Schulz, S., Yang, Y., Wong, R. J., Stevenson, D. K. 2015; 194 (8): 3713-3722

  Abstract

  Leukocyte infiltration into the uterus is a characteristic feature in early to midpregnancy, but the composition and function of these leukocytes are not well understood. Using a pregnant murine model, we showed that myeloid cells and uterine NK (uNK) cells were the predominant populations in uteri during early to midgestation, whereas T and B cells were constrained. Uterine myeloid populations included cells that infiltrated from the circulation (myeloid-derived suppressor cells [MDSCs], monocyte-derived macrophages [Mφs], and dendritic cells [DCs]) or proliferated from resident precursors (resident Mφs [Re-Mφs] and DCs). CD11b(hi)Ly6-G(hi) cells, representing neutrophils in both blood and uterine MDSCs, significantly increased from embryonic days 8.5 to 9.5. To understand their putative functions, we used anti-Gr-1 Ab to deplete circulating neutrophils and uterine MDSCs. In the absence of MDSC suppression, uterine DCs, T cells, and regulatory T cells expanded. Conversely, uterine MDSCs responded to LPS-induced inflammation and transformed into CD14(+)-activated neutrophils, resulting in an upregulation of tolerogenic DCs. A high dose of LPS (2.5 μg/mouse) significantly increased the influx of neutrophils and production of proinflammatory cytokines, such as IL-1β and TNF-α, resulting in the reduction of Re-Mφs and uNK cells, and led to placental hemorrhages and fetal deaths. In summary, uterine MDSCs are important in early to midpregnancy by responding to the maternal immunologic milieu and protecting uNK cells and Re-Mφs via MDSC's suppressive and anti-inflammatory functions. Upsetting this delicate immune balance by factors leading to either insufficient MDSCs or excessive neutrophil infiltration in the fetomaternal interface may contribute to pregnancy failure.

  View details for DOI 10.4049/jimmunol.1401930

  View details for PubMedID 25780045

• Effect of Heme Oxygenase-1 on the immunosuppressive Function of DecIdual Myeloid Cells. Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2015: 325A

  View details for Web of Science ID 000351407202446

• Acute Subclinical Maternal Inflammation in Late Pregnancy Ozen, M., Zhao, H., Winn, V. D., Lewis, D. B., Kalish, F., Palmer, T. D., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2015: 89A–90A

  View details for Web of Science ID 000351407200104

• Cognitive Outcomes After Neonatal Encephalopathy PEDIATRICS Pappas, A., Shankaran, S., McDonald, S. A., Vohr, B. R., Hintz, S. R., Ehrenkranz, R. A., Tyson, J. E., Yolton, K., Das, A., Bara, R., Hammond, J., Higgins, R. D. 2015; 135 (3): E624-E634

  Abstract

  To describe the spectrum of cognitive outcomes of children with and without cerebral palsy (CP) after neonatal encephalopathy, evaluate the prognostic value of early developmental testing and report on school services and additional therapies.The participants of this study are the school-aged survivors of the National Institute of Child Health and Human Development Neonatal Research Network randomized controlled trial of whole-body hypothermia. Children underwent neurologic examinations and neurodevelopmental and cognitive testing with the Bayley Scales of Infant Development-II at 18 to 22 months and the Wechsler intelligence scales and the Neuropsychological Assessment-Developmental Neuropsychological Assessment at 6 to 7 years. Parents were interviewed about functional status and receipt of school and support services. We explored predictors of cognitive outcome by using multiple regression models.Subnormal IQ scores were identified in more than a quarter of the children: 96% of survivors with CP had an IQ <70, 9% of children without CP had an IQ <70, and 31% had an IQ of 70 to 84. Children with a mental developmental index <70 at 18 months had, on average, an adjusted IQ at 6 to 7 years that was 42 points lower than that of those with a mental developmental index >84 (95% confidence interval, -49.3 to -35.0; P < .001). Twenty percent of children with normal IQ and 28% of those with IQ scores of 70 to 84 received special educational support services or were held back ≥1 grade level.Cognitive impairment remains an important concern for all children with neonatal encephalopathy.

  View details for DOI 10.1542/peds.2014-1566

  View details for PubMedID 25713280

• Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort. JAMA pediatrics Lapcharoensap, W., Gage, S. C., Kan, P., Profit, J., Shaw, G. M., Gould, J. B., Stevenson, D. K., O'Brodovich, H., Lee, H. C. 2015; 169 (2)

  View details for DOI 10.1001/jamapediatrics.2014.3676

  View details for PubMedID 25642906

• Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort. JAMA pediatrics Lapcharoensap, W., Gage, S. C., Kan, P., Profit, J., Shaw, G. M., Gould, J. B., Stevenson, D. K., O'Brodovich, H., Lee, H. C. 2015; 169 (2)

  Abstract

  Bronchopulmonary dysplasia (BPD) remains a serious morbidity in very low-birth-weight (VLBW) infants (<1500 g). Deregionalization of neonatal care has resulted in an increasing number of VLBW infants treated in community hospitals with unknown impact on the development of BPD.To identify individual risk factors for BPD development and hospital variation of BPD rates across all levels of neonatal intensive care units (NICUs) within the California Perinatal Quality Care Collaborative.Retrospective cohort study (January 2007 to December 2011) from the California Perinatal Quality Care Collaborative including more than 90% of California's NICUs. Eligible VLBW infants born between 22 to 29 weeks' gestational age.Varying levels of intensive care.Bronchopulmonary dysplasia was defined as continuous supplemental oxygen use at 36 weeks' postmenstrual age. A combined outcome of BPD or mortality prior to 36 weeks was used. Multivariable logistic regression accounting for hospital as a random effect and gestational age as a risk factor was used to assess individual risk factors for BPD. This model was applied to determine risk-adjusted rates of BPD across hospitals and assess associations between levels of care and BPD rates.The study cohort included 15 779 infants, of which 1534 infants died prior to 36 weeks' postmenstrual age. A total of 7081 infants, or 44.8%, met the primary outcome of BPD or death prior to 36 weeks. Combined BPD or death rates across 116 NICUs varied from 17.7% to 73.4% (interquartile range, 38.7%-54.1%). Compared with level IV NICUs, the risk for developing BPD was higher for level II NICUs (odds ratio, 1.23; 95% CI, 1.02-1.49) and similar for level III NICUs (odds ratio, 1.04; 95% CI, 0.95-1.14).Bronchopulmonary dysplasia or death prior to 36 weeks' postmenstrual age affects approximately 45% of VLBW infants across California. The wide variability in BPD occurrence across hospitals could offer insights into potential risk or preventive factors. Additionally, our findings suggest that increased regionalization of NICU care may reduce BPD among VLBW infants.

  View details for DOI 10.1001/jamapediatrics.2014.3676

  View details for PubMedID 25642906

• New technique for umbilical artery catheter placement in the neonate. journal of pediatrics Wallenstein, M. B., Stevenson, D. K. 2015; 166 (2): 501-?

  View details for DOI 10.1016/j.jpeds.2014.10.027

  View details for PubMedID 25453247

• Neonatal bilirubin binding capacity discerns risk of neurological dysfunction. Pediatric research Lamola, A. A., Bhutani, V. K., Du, L., Castillo Cuadrado, M., Chen, L., Shen, Z., Wong, R. J., Stevenson, D. K. 2015; 77 (2): 334-339

  Abstract

  Bilirubin binding capacity (BBC) defines the dynamic relationship between an infant's level of unbound or "free" bilirubin and his/her ability to "tolerate" increasing bilirubin loads. BBC is not synonymous with albumin (Alb) levels because Alb binding of bilirubin is confounded by a variety of molecular, biologic, and metabolic factors.We utilized a novel modification of a previously developed hematofluorometric method to directly assay BBC in whole blood from preterm and term neonates and then combined these data with an archived database. Total bilirubin (TB) was also measured, and multiple regression modeling was used to determine whether BBC in combination with TB measurements can assess an infant's risk for developing bilirubin-induced neurotoxicity.TB and BBC levels ranged from 0.7-22.8 to 6.3-47.5 mg/dl, respectively. Gestational age (GA) correlated with BBC (r = 0.54; P < 0.0002) with a slope of 0.93 mg/dl/wk by logistic regression. Our calculations demonstrate that recently recommended GA-modulated TB thresholds for phototherapy and exchange transfusion correspond to 45 and 67% saturation of our observed regression line, respectively.We speculate that the spread of BBC levels around the regression line (±5.8 mg/dl) suggests that individualized BBC assays would provide a robust approach to gauge risk of bilirubin neurotoxicity compared with TB and GA.

  View details for DOI 10.1038/pr.2014.191

  View details for PubMedID 25420178

• Neonatal hemolysis and risk of bilirubin-induced neurologic dysfunction. Seminars in fetal & neonatal medicine Wong, R. J., Stevenson, D. K. 2015; 20 (1): 26-30

  Abstract

  The pathologic phenotype of severe hyperbilirubinemia in the newborn infant is primarily due to excessive bilirubin production and/or impaired conjugation, resulting in an increased bilirubin load. This may, in turn, increase an infant's risk for the development of bilirubin-induced neurologic dysfunction (BIND). The highest-risk infants are those with increased bilirubin production rates due to hemolysis. Several immune and non-immune conditions have been found to cause severe hemolysis, and these are often exacerbated in those infants with perinatal sepsis and genetic predispositions. Therefore, identification of these infants, with novel technologies, is paramount in reducing the incidence of BIND and the long-term neurologic sequelae for these at-risk infants.

  View details for DOI 10.1016/j.siny.2014.12.005

  View details for PubMedID 25560401

• Causes and timing of death in extremely premature infants from 2000 through 2011. New England journal of medicine Patel, R. M., Kandefer, S., Walsh, M. C., Bell, E. F., Carlo, W. A., Laptook, A. R., Sánchez, P. J., Shankaran, S., Van Meurs, K. P., Ball, M. B., Hale, E. C., Newman, N. S., Das, A., Higgins, R. D., Stoll, B. J. 2015; 372 (4): 331-340

  Abstract

  Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).

  View details for DOI 10.1056/NEJMoa1403489

  View details for PubMedID 25607427

• Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis, and immunomodulation FRONTIERS IN PHARMACOLOGY Zhao, H., Ozen, M., Wong, R. J., Stevenson, D. K. 2015; 5

  View details for DOI 10.3389/fphar.2014.00295

  View details for Web of Science ID 000348209600001

• Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics Hintz, S. R., Barnes, P. D., Bulas, D., Slovis, T. L., Finer, N. N., Wrage, L. A., Das, A., Tyson, J. E., Stevenson, D. K., Carlo, W. A., Walsh, M. C., Laptook, A. R., Yoder, B. A., Van Meurs, K. P., Faix, R. G., Rich, W., Newman, N. S., Cheng, H., Heyne, R. J., Vohr, B. R., Acarregui, M. J., Vaucher, Y. E., Pappas, A., Peralta-Carcelen, M., Wilson-Costello, D. E., Evans, P. W., Goldstein, R. F., Myers, G. J., Poindexter, B. B., McGowan, E. C., Adams-Chapman, I., Fuller, J., Higgins, R. D. 2015; 135 (1): e32-42

  Abstract

  Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age.Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors.Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes.Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

  View details for DOI 10.1542/peds.2014-0898

  View details for PubMedID 25554820

• Prediction of early spontaneous preterm birth using placental, lipid, and immune related markers Jelliffe-Pawlowski, L., Ryckman, K., Bedell, B., Baer, R., O'Brodovich, H., Gould, J., Currier, R., Shaw, G., Murray, J., Stevenson, D. MOSBY-ELSEVIER. 2015: S292

  View details for DOI 10.1016/j.ajog.2014.10.792

  View details for Web of Science ID 000361140900581

• THE EFFECT OF HEMATOCRIT ON IN VITRO BILIRUBIN PHOTOALTERATION UNDER BLUE AND BLUE-GREEN LIGHT Linfield, D. T., Mei, E., Hwang, A. Y., Vreman, H. J., Lamola, A. A., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 133

  View details for Web of Science ID 000346600700174

• EFFICACY AND SAFETY OF A NEW HEME FORMULATION FOR USE IN THE STUDY OF SEVERE NEONATAL HYPERBILIRUBINEMIA Lin, D. N., Wagner, M., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 149–50

  View details for Web of Science ID 000346600700225

• HEME OXYGENASE-1 PROMOTER POLYMORPHISMS AND RISK OF SPINA BIFIDA Fujioka, K., Yang, W., Wallenstein, M. B., Zhao, H., Wong, R. J., Stevenson, D. K., Shaw, G. M. LIPPINCOTT WILLIAMS & WILKINS. 2015: 174–75

  View details for Web of Science ID 000346600700308

• THE EFFECT OF HEMATOCRIT ON IN VITRO BILIRUBIN PHOTOALTERATION UNDER BLUE AND BLUE-GREEN LIGHT Linfield, D. T., Mei, E., Hwang, A. Y., Vreman, H. J., Lamola, A. A., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 147–48

  View details for Web of Science ID 000346600700219

• A MURINE MODEL OF ACUTE SUBCLINICAL MATERNAL INFLAMMATION IN LATE PREGNANCY Ozen, M., Zhao, H., Winn, V. D., Kalish, F., Palmer, T. D., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 190

  View details for Web of Science ID 000346600700359

• Evaluation of a cumulative first trimester characteristic and serum marker risk score for predicting early spontaneous preterm birth Jelliffe-Pawlowski, L. L., Baer, R., Blumenfeld, Y., Chambers, C., Druzin, M., El-Sayed, Y., Kuppermann, M., Lyell, D., Norton, M., O'Brodovich, H., Ryckman, K., Shaw, G., Stevenson, D., Currier, R. MOSBY-ELSEVIER. 2015: S142

  View details for DOI 10.1016/j.ajog.2014.10.305

  View details for Web of Science ID 000361140900260

• Spontaneous preterm birth risk among inter-racial/ethnic couples Shachar, B., Mayo, J., Lyell, D., Stevenson, D., Shaw, G., Blumenfeld, Y. MOSBY-ELSEVIER. 2015: S82

  View details for DOI 10.1016/j.ajog.2014.10.177

  View details for Web of Science ID 000361140900133

• IN VIVO INHIBITION OF HEME OXYGENASE ACTIVITY IN THE HEME-LOADED NEWBORN MOUSE USING A MICROPARTICLE FORMULATION OF ZINC PROTOPORPHYRIN Fujioka, K., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2015: 213

  View details for Web of Science ID 000346600700435

• Antenatal magnesium sulfate exposure and acute cardiorespiratory events in preterm infants AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY De Jesus, L. C., Sood, B. G., Shankaran, S., Kendrick, D., Das, A., Bell, E. F., Stoll, B. J., Laptook, A. R., Walsh, M. C., Carlo, W. A., Sanchez, P. J., Van Meurs, K. P., Bara, R., Hale, E. C., Newman, N. S., Ball, M. B., Higgins, R. D. 2015; 212 (1)

  Abstract

  Antenatal magnesium (anteMg) is used for various obstetric indications including fetal neuroprotection. Infants exposed to anteMg may be at risk for respiratory depression and delivery room (DR) resuscitation. The study objective was to compare the risk of acute cardiorespiratory events among preterm infants who were and were not exposed to anteMg.This was a retrospective analysis of prospective data collected in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Generic Database from April 1, 2011, through March 31, 2012. The primary outcome was DR intubation or respiratory support at birth or on day 1 of life. Secondary outcomes were invasive mechanical ventilation, hypotension treatment, neonatal morbidities, and mortality. Logistic regression analysis evaluated the risk of primary outcome after adjustment for covariates.We evaluated 1544 infants <29 weeks' gestational age (1091 in anteMg group and 453 in nonexposed group). Mothers in the anteMg group were more likely to have higher education, pregnancy-induced hypertension, and antenatal corticosteroids, while their infants were younger in gestation and weighed less (P < .05). The primary outcome (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.88-1.65) was similar between groups. Hypotension treatment (OR, 0.70; 95% CI, 0.51-0.97) and invasive mechanical ventilation (OR, 0.54; 95% CI, 0.41-0.72) were significantly less in the anteMg group.Among preterm infants age <29 weeks' gestation, anteMg exposure was not associated with an increase in cardiorespiratory events in the early newborn period. The safety of anteMg as measured by the need for DR intubation or respiratory support on day 1 of life was comparable between groups.

  View details for DOI 10.1016/j.ajog.2014.07.023

  View details for PubMedID 25046806

• Heme oxygenase and the immune system in normal and pathological pregnancies. Frontiers in pharmacology Ozen, M., Zhao, H., Lewis, D. B., Wong, R. J., Stevenson, D. K. 2015; 6: 84-?

  View details for DOI 10.3389/fphar.2015.00084

  View details for PubMedID 25964759

• Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics Hintz, S. R., Barnes, P. D., Bulas, D., Slovis, T. L., Finer, N. N., Wrage, L. A., Das, A., Tyson, J. E., Stevenson, D. K., Carlo, W. A., Walsh, M. C., Laptook, A. R., Yoder, B. A., Van Meurs, K. P., Faix, R. G., Rich, W., Newman, N. S., Cheng, H., Heyne, R. J., Vohr, B. R., Acarregui, M. J., Vaucher, Y. E., Pappas, A., Peralta-Carcelen, M., Wilson-Costello, D. E., Evans, P. W., Goldstein, R. F., Myers, G. J., Poindexter, B. B., McGowan, E. C., Adams-Chapman, I., Fuller, J., Higgins, R. D. 2015; 135 (1): e32-42

  View details for DOI 10.1542/peds.2014-0898

  View details for PubMedID 25554820

• Heme oxygenase and the immune system in normal and pathological pregnancies. Frontiers in pharmacology Ozen, M., Zhao, H., Lewis, D. B., Wong, R. J., Stevenson, D. K. 2015; 6: 84-?

  Abstract

  Normal pregnancy is an immunotolerant state. Many factors, including environmental, socioeconomic, genetic, and immunologic changes by infection and/or other causes of inflammation, may contribute to inter-individual differences resulting in a normal or pathologic pregnancy. In particular, imbalances in the immune system can cause many pregnancy-related diseases, such as infertility, abortions, pre-eclampsia, and preterm labor, which result in maternal/fetal death, prematurity, or small-for-gestational age newborns. New findings imply that myeloid regulatory cells and regulatory T cells (Tregs) may mediate immunotolerance during normal pregnancy. Effector T cells (Teffs) have, in contrast, been implicated to cause adverse pregnancy outcomes. Furthermore, feto-maternal tolerance affects the developing fetus. It has been shown that the Treg/Teff balance affects litter size and adoptive transfer of pregnancy-induced Tregs can prevent fetal rejection in the mouse. Heme oxygenase-1 (HO-1) has a protective role in many conditions through its anti-inflammatory, anti-apoptotic, antioxidative, and anti-proliferative actions. HO-1 is highly expressed in the placenta and plays a role in angiogenesis and placental vascular development and in regulating vascular tone in pregnancy. In addition, HO-1 is a major regulator of immune homeostasis by mediating crosstalk between innate and adaptive immune systems. Moreover, HO-1 can inhibit inflammation-induced phenotypic maturation of immune effector cells and pro-inflammatory cytokine secretion and promote anti-inflammatory cytokine production. HO-1 may also be associated with T-cell activation and can limit immune-based tissue injury by promoting Treg suppression of effector responses. Thus, HO-1 and its byproducts may protect against pregnancy complications by its immunomodulatory effects, and the regulation of HO-1 or its downstream effects has the potential to prevent or treat pregnancy complications and prematurity.

  View details for DOI 10.3389/fphar.2015.00084

  View details for PubMedID 25964759

• Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy A Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Shankaran, S., Laptook, A. R., Pappas, A., McDonald, S. A., Das, A., Tyson, J. E., Poindexter, B. B., Schibler, K., Bell, E. F., Heyne, R. J., Pedroza, C., Bara, R., Van Meurs, K. P., Grisby, C., Huitema, C. M., Garg, M., Ehrenkranz, R. A., Shepherd, E. G., Chalak, L. F., Hamrick, S. E., Khan, A. M., Reynolds, A. M., Laughon, M. M., Truog, W. E., Dysart, K. C., Carlo, W. A., Walsh, M. C., Watterberg, K. L., Higgins, R. D. 2014; 312 (24): 2629-2639

  Abstract

  Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.A randomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.clinicaltrials.gov Identifier: NCT01192776.

  View details for DOI 10.1001/jama.2014.16058

  View details for PubMedID 25536254

• Traffic-related air pollution and risk of preterm birth in the San Joaquin Valley of California ANNALS OF EPIDEMIOLOGY Padula, A. M., Mortimer, K. M., Tager, I. B., Hammond, S. K., Lurmann, F. W., Yang, W., Stevenson, D. K., Shaw, G. M. 2014; 24 (12): 888-895

  Abstract

  To evaluate associations between traffic-related air pollution during pregnancy and preterm birth in births in four counties in California during years 2000 to 2006.We used logistic regression to examine the association between the highest quartile of ambient air pollutants (carbon monoxide, nitrogen dioxide, particulate matter <10 and 2.5 μm) and traffic density during pregnancy and each of five levels of prematurity based on gestational age at birth (20-23, 24-27, 28-31, 32-33, and 34-36 weeks) versus term (37-42 weeks). We examined trimester averages and the last month and the last 6 weeks of pregnancy. Models were adjusted for birthweight, maternal age, race/ethnicity, education, prenatal care, and birth costs payment. Neighborhood socioeconomic status (SES) was evaluated as a potential effect modifier.There were increased odds ratios (ORs) for early preterm birth for those exposed to the highest quartile of each pollutant during the second trimester and the end of pregnancy (adjusted OR, 1.4-2.8). Associations were stronger among mothers living in low SES neighborhoods (adjusted OR, 2.1-4.3). We observed exposure-response associations for multiple pollutant exposures and early preterm birth. Inverse associations during the first trimester were observed.The results confirm associations between traffic-related air pollution and prematurity, particularly among very early preterm births and low SES neighborhoods.

  View details for DOI 10.1016/j.annepidem.2014.10.004

  View details for Web of Science ID 000345497100004

  View details for PubMedCentralID PMC4355392

• Direct Antiglobulin Titer Strength and Hyperbilirubinemia PEDIATRICS Kaplan, M., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2014; 134 (5): E1340-E1344

  Abstract

  We recently demonstrated that direct antiglobulin titer (DAT) positive, blood group A or B newborns born to group O mothers had a high incidence of hyperbilirubinemia, attributable to increased hemolysis. We reanalyzed our data asking whether increasing DAT strength plays a modulating role in the pathophysiology of the hemolysis and hyperbilirubinemia.Data from previously published DAT-positive, ABO-heterospecific neonates were analyzed for hyperbilirubinemia and hemolysis according to strength of DAT. DAT was measured by using a gel agglutination technique and reported as values ranging from DAT ± to DAT ++++. Hemolysis was evaluated by blood carboxyhemoglobin corrected for inspired, ambient CO (COHbc), and expressed as percent total hemoglobin (tHb). Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile on the hour-specific nomogram.Hyperbilirubinemia was more prevalent in those with DAT ++ readings (16 of 20, 80%) than those both DAT ± (37 of 87 [42.5%], relative risk: 1.88, 95% confidence interval: 1.35-2.61) and DAT + (32 of 56 [57.1%], relative risk: 1.40, 95% confidence interval: 1.02-1.92). COHbc values were higher for those with DAT ++ (1.45 ± 0.49% tHb [mean ± SD]) than those DAT ± (1.20 ± 0.37% tHb, P = .01) or DAT + (1.22 ± 0.37% tHb, P = .02).DAT ++ readings were associated with a higher incidence of hyperbilirubinemia and higher COHbc values than DAT ± or DAT + counterparts. Increasing DAT strength may be a modulator of hemolysis and hyperbilirubinemia in ABO-heterospecific neonates. DAT strength, and not merely DAT presence or absence, should be taken into consideration in the management of ABO-heterospecific newborns.

  View details for DOI 10.1542/peds.2014-1290

  View details for Web of Science ID 000344385900009

• Direct antiglobulin titer strength and hyperbilirubinemia. Pediatrics Kaplan, M., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2014; 134 (5): e1340-4

  Abstract

  We recently demonstrated that direct antiglobulin titer (DAT) positive, blood group A or B newborns born to group O mothers had a high incidence of hyperbilirubinemia, attributable to increased hemolysis. We reanalyzed our data asking whether increasing DAT strength plays a modulating role in the pathophysiology of the hemolysis and hyperbilirubinemia.Data from previously published DAT-positive, ABO-heterospecific neonates were analyzed for hyperbilirubinemia and hemolysis according to strength of DAT. DAT was measured by using a gel agglutination technique and reported as values ranging from DAT ± to DAT ++++. Hemolysis was evaluated by blood carboxyhemoglobin corrected for inspired, ambient CO (COHbc), and expressed as percent total hemoglobin (tHb). Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile on the hour-specific nomogram.Hyperbilirubinemia was more prevalent in those with DAT ++ readings (16 of 20, 80%) than those both DAT ± (37 of 87 [42.5%], relative risk: 1.88, 95% confidence interval: 1.35-2.61) and DAT + (32 of 56 [57.1%], relative risk: 1.40, 95% confidence interval: 1.02-1.92). COHbc values were higher for those with DAT ++ (1.45 ± 0.49% tHb [mean ± SD]) than those DAT ± (1.20 ± 0.37% tHb, P = .01) or DAT + (1.22 ± 0.37% tHb, P = .02).DAT ++ readings were associated with a higher incidence of hyperbilirubinemia and higher COHbc values than DAT ± or DAT + counterparts. Increasing DAT strength may be a modulator of hemolysis and hyperbilirubinemia in ABO-heterospecific neonates. DAT strength, and not merely DAT presence or absence, should be taken into consideration in the management of ABO-heterospecific newborns.

  View details for DOI 10.1542/peds.2014-1290

  View details for PubMedID 25332496

• Functional status at 18 months of age as a predictor of childhood disability after neonatal hypoxic-ischemic encephalopathy DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Natarajan, G., Shankaran, S., Pappas, A., Bann, C., Tyson, J. E., McDonald, S., Das, A., Hintz, S., Vohr, B., Higgins, R. 2014; 56 (11): 1052-1058

  Abstract

  In children with neonatal hypoxic-ischemic encephalopathy (HIE), we examined the association between 18-month functional status by parental report and disability at 6-7 years.Prospective observational study involving participants in the NICHD randomized controlled trial of hypothermia for HIE. Parent questionnaires-Functional Status-II (FS-II), Impact on Family (IOF) and Family Resource Scale (FRS) at 18 months were correlated with 6- to 7-year developmental assessments. Disability at 6-7 years was defined as IQ < 70, gross motor functional classification scale level III-V, bilateral blindness, deafness, or epilepsy.Rates of severe HIE (32 vs. 15%), public insurance (73% vs. 47%) and IOF scales were higher and mean (SD) FS-II independence (I) {54 (SD 35) vs. 98 (SD 8)} and general health (GH) {87 (SD 14) vs. 98 (SD 6)} scores were significantly lower in children with disability (n=37) at 6-7 years, compared to those (n=74) without disability. FS-II I scores were significantly associated with disability (OR 0.92; 95% CI 0.87-0.97; p=0.003). On path analysis, severe HIE, greater IOF and public insurance were associated with poorer 18-month FS-II I scores, which, in turn, were associated with disability at 6 to 7 years.Poor independent functioning by parental report at 18 months in children with HIE was associated with childhood disability.

  View details for DOI 10.1111/dmcn.12512

  View details for Web of Science ID 000343803100012

  View details for PubMedCentralID PMC4324462

• Prophylactic Indomethacin and Intestinal Perforation in Extremely Low Birth Weight Infants PEDIATRICS Kelleher, J., Salas, A. A., Bhat, R., Ambalavanan, N., Saha, S., Stoll, B. J., Bell, E. F., Walsh, M. C., Laptook, A. R., Sanchez, P. J., Shankaran, S., VanMeurs, K. P., Hale, E. C., Newman, N. S., Ball, M. B., Das, A., Higgins, R. D., Peralta-Carcelen, M., Carlo, W. A. 2014; 134 (5): E1369-E1377

  View details for DOI 10.1542/peds.2014-0183

  View details for Web of Science ID 000344385900013

• End-tidal carbon monoxide and hemolysis JOURNAL OF PERINATOLOGY Tidmarsh, G. F., Wong, R. J., Stevenson, D. K. 2014; 34 (8): 577-581

  Abstract

  Hemolytic disease in newborns can result from a number of conditions, which can place such infants at an increased risk for the development of severe hyperbilirubinemia. Because the catabolism of heme produces equimolar amounts of carbon monoxide (CO) and bilirubin, measurements of end-tidal breath CO (corrected for ambient CO) or ETCOc can serve as an index of hemolysis as well as of bilirubin production from any cause. Elevated levels of ETCOc have been correlated with blood carboxyhemoglobin levels and thus hemolysis. However, the detection of hemolysis can be a clinically challenging problem in newborns. Here, we describe the importance of determining ETCOc levels and their application in identifying infants at risk for developing hyperbilirubinemia associated with hemolysis and other causes of increased bilirubin production.

  View details for DOI 10.1038/jp.2014.66

  View details for Web of Science ID 000339706400001

  View details for PubMedID 24743136

• Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial (SUPPORT). journal of pediatrics Stevens, T. P., Finer, N. N., Carlo, W. A., Szilagyi, P. G., Phelps, D. L., Walsh, M. C., Gantz, M. G., Laptook, A. R., Yoder, B. A., Faix, R. G., Newman, J. E., Das, A., Do, B. T., Schibler, K., Rich, W., Newman, N. S., Ehrenkranz, R. A., Peralta-Carcelen, M., Vohr, B. R., Wilson-Costello, D. E., Yolton, K., Heyne, R. J., Evans, P. W., Vaucher, Y. E., Adams-Chapman, I., McGowan, E. C., Bodnar, A., Pappas, A., Hintz, S. R., Acarregui, M. J., Fuller, J., Goldstein, R. F., Bauer, C. R., O'Shea, T. M., Myers, G. J., Higgins, R. D. 2014; 165 (2): 240-249 e4

  Abstract

  To explore the early childhood pulmonary outcomes of infants who participated in the National Institute of Child Health and Human Development's Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT), using a factorial design that randomized extremely preterm infants to lower vs higher oxygen saturation targets and delivery room continuous positive airway pressure (CPAP) vs intubation/surfactant.The Breathing Outcomes Study, a prospective secondary study to the Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial, assessed respiratory morbidity at 6-month intervals from hospital discharge to 18-22 months corrected age (CA). Two prespecified primary outcomes-wheezing more than twice per week during the worst 2-week period and cough longer than 3 days without a cold-were compared for each randomized intervention.One or more interviews were completed for 918 of the 922 eligible infants. The incidences of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between the study arms of either randomized intervention. Infants randomized to lower vs higher oxygen saturation targets had a similar risk of death or respiratory morbidity (except for croup and treatment with oxygen or diuretics at home). Infants randomized to CPAP vs intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs 36.5%; P < .05), respiratory illnesses diagnosed by a doctor (47.7% vs 55.2%; P < .05), and physician or emergency room visits for breathing problems (68.0% vs 72.9%; P < .05) by 18-22 months CA.Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18-22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.

  View details for DOI 10.1016/j.jpeds.2014.02.054

  View details for PubMedID 24725582

• Surgery and neurodevelopmental outcome of very low-birth-weight infants. JAMA pediatrics Morriss, F. H., Saha, S., Bell, E. F., Colaizy, T. T., Stoll, B. J., Hintz, S. R., Shankaran, S., Vohr, B. R., Hamrick, S. E., Pappas, A., Jones, P. M., Carlo, W. A., Laptook, A. R., Van Meurs, K. P., Sánchez, P. J., Hale, E. C., Newman, N. S., Das, A., Higgins, R. D. 2014; 168 (8): 746-754

  Abstract

  Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low-birth-weight infants.A retrospective cohort analysis was conducted of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998 through 2009 and evaluated at 18 to 22 months' corrected age. Twenty-two academic neonatal intensive care units participated. Inclusion criteria were birth weight 401 to 1500 g, survival to 12 hours, and availability for follow-up. A total of 12 111 infants were included in analyses.Surgical procedures; surgery also was classified by expected anesthesia type as major (general anesthesia) or minor (nongeneral anesthesia).Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted mean scores of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006.A total of 2186 infants underwent major surgery, 784 had minor surgery, and 9141 infants did not undergo surgery. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% CI, 1.08-1.55). For patients who had major surgery compared with those who had no surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery, the adjusted risk of neurodevelopmental impairment was greater and the adjusted mean Bayley scores were lower.Major surgery in very low-birth-weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18 to 22 months' corrected age. The role of general anesthesia is implicated but remains unproven.

  View details for DOI 10.1001/jamapediatrics.2014.307

  View details for PubMedID 24934607

• Combined elevated midpregnancy tumor necrosis factor alpha and hyperlipidemia in pregnancies resulting in early preterm birth. American journal of obstetrics and gynecology Jelliffe-Pawlowski, L. L., Ryckman, K. K., Bedell, B., O'Brodovich, H. M., Gould, J. B., Lyell, D. J., Borowski, K. S., Shaw, G. M., Murray, J. C., Stevenson, D. K. 2014; 211 (2): 141 e1-9

  View details for DOI 10.1016/j.ajog.2014.02.019

  View details for PubMedID 24831886

• Prevention of traumatic stress in mothers of preterms: 6-month outcomes. Pediatrics Shaw, R. J., St John, N., Lilo, E., Jo, B., Benitz, W., Stevenson, D. K., Horwitz, S. M. 2014; 134 (2): e481-8

  View details for DOI 10.1542/peds.2014-0529

  View details for PubMedID 25049338

• Combined elevated midpregnancy tumor necrosis factor alpha and hyperlipidemia in pregnancies resulting in early preterm birth. American journal of obstetrics and gynecology Jelliffe-Pawlowski, L. L., Ryckman, K. K., Bedell, B., O'Brodovich, H. M., Gould, J. B., Lyell, D. J., Borowski, K. S., Shaw, G. M., Murray, J. C., Stevenson, D. K. 2014; 211 (2): 141 e1-9

  Abstract

  The objective of the study was to determine whether pregnancies resulting in early preterm birth (PTB) (<30 weeks) were more likely than term pregnancies to have elevated midtrimester serum tumor necrosis factor alpha (TNF-α) levels combined with lipid patterns suggestive of hyperlipidemia.In 2 nested case-control samples drawn from California and Iowa cohorts, we examined the frequency of elevated midpregnancy serum TNF-α levels (in the fourth quartile [4Q]) and lipid patterns suggestive of hyperlipidemia (eg, total cholesterol, low-density-lipoproteins, or triglycerides in the 4Q, high-density lipoproteins in the first quartile) (considered independently and by co-occurrence) in pregnancies resulting in early PTB compared with those resulting in term birth (n = 108 in California and n = 734 in Iowa). Odds ratios (ORs) and 95% confidence intervals (CIs) estimated in logistic regression models were used for comparisons.Early preterm pregnancies were 2-4 times more likely than term pregnancies to have a TNF-α level in the 4Q co-occurring with indicators of hyperlipidemia (37.5% vs 13.9% in the California sample (adjusted OR, 4.0; 95% CI, 1.1-16.3) and 26.3% vs 14.9% in the Iowa sample (adjusted OR, 2.7; 95% CI, 1.1-6.3). No differences between early preterm and term pregnancies were observed when TNF-α or target lipid abnormalities occurred in isolation. Observed differences were not explicable to any maternal or infant characteristics.Pregnancies resulting in early PTB were more likely than term pregnancies to have elevated midpregnancy TNF-α levels in combination with lipid patterns suggestive of hyperlipidemia.

  View details for DOI 10.1016/j.ajog.2014.02.019

  View details for PubMedID 24831886

  View details for PubMedCentralID PMC4117727

• Prevention of traumatic stress in mothers of preterms: 6-month outcomes. Pediatrics Shaw, R. J., St John, N., Lilo, E., Jo, B., Benitz, W., Stevenson, D. K., Horwitz, S. M. 2014; 134 (2): e481-8

  Abstract

  Symptoms of posttraumatic stress disorder are a well-recognized phenomenon in mothers of preterm infants, with implications for maternal health and infant outcomes. This randomized controlled trial evaluated 6-month outcomes from a skills-based intervention developed to reduce symptoms of posttraumatic stress disorder, anxiety, and depression.One hundred five mothers of preterm infants were randomly assigned to (1) a 6- or 9-session intervention based on principles of trauma-focused cognitive behavior therapy with infant redefinition or (2) a 1-session active comparison intervention based on education about the NICU and parenting of the premature infant. Outcome measures included the Davidson Trauma Scale, the Beck Depression Inventory II, and the Beck Anxiety Inventory. Participants were assessed at baseline, 4 to 5 weeks after birth, and 6 months after the birth of the infant.At the 6-month assessment, the differences between the intervention and comparison condition were all significant and sizable and became more pronounced when compared with the 4- to 5-week outcomes: Davidson Trauma Scale (Cohen's d = -0.74, P < .001), Beck Anxiety Inventory (Cohen's d = -0.627, P = .001), Beck Depression Inventory II (Cohen's d = -0.638, P = .002). However, there were no differences in the effect sizes between the 6- and 9-session interventions.A brief 6-session intervention based on principles of trauma-focused cognitive behavior therapy was effective at reducing symptoms of trauma, anxiety, and depression in mothers of preterm infants. Mothers showed increased benefits at the 6-month follow-up, suggesting that they continue to make use of techniques acquired during the intervention phase.

  View details for DOI 10.1542/peds.2014-0529

  View details for PubMedID 25049338

• Maternal prepregnancy body mass index and risk of spontaneous preterm birth. Paediatric and perinatal epidemiology Shaw, G. M., Wise, P. H., Mayo, J., Carmichael, S. L., Ley, C., Lyell, D. J., Shachar, B. Z., Melsop, K., Phibbs, C. S., Stevenson, D. K., Parsonnet, J., Gould, J. B. 2014; 28 (4): 302-311

  Abstract

  Findings from studies examining risk of preterm birth associated with elevated prepregnancy body mass index (BMI) have been inconsistent.Within a large population-based cohort, we explored associations between prepregnancy BMI and spontaneous preterm birth across a spectrum of BMI, gestational age, and racial/ethnic categories. We analysed data for 989 687 singleton births in California, 2007-09. Preterm birth was grouped as 20-23, 24-27, 28-31, or 32-36 weeks gestation (compared with 37-41 weeks). BMI was categorised as <18.5 (underweight); 18.5-24.9 (normal); 25.0-29.9 (overweight); 30.0-34.9 (obese I); 35.0-39.9 (obese II); and ≥40.0 (obese III). We assessed associations between BMI and spontaneous preterm birth of varying severity among non-Hispanic White, Hispanic, and non-Hispanic Black women.Analyses of mothers without hypertension and diabetes, adjusted for age, education, height, and prenatal care initiation, showed obesity categories I-III to be associated with increased risk of spontaneous preterm birth at 20-23 and 24-27 weeks among those of parity 1 in each race/ethnic group. Relative risks for obese III and preterm birth at 20-23 weeks were 6.29 [95% confidence interval (CI) 3.06, 12.9], 4.34 [95% CI 2.30, 8.16], and 4.45 [95% CI 2.53, 7.82] for non-Hispanic Whites, non-Hispanic Blacks, and Hispanics, respectively. A similar, but lower risk, pattern was observed for women of parity ≥2 and preterm birth at 20-23 weeks. Underweight was associated with modest risks for preterm birth at ≥24 weeks among women in each racial/ethnic group regardless of parity.The association between women's prepregnancy BMI and risk of spontaneous preterm birth is complex and is influenced by race/ethnicity, gestational age, and parity.

  View details for DOI 10.1111/ppe.12125

  View details for PubMedID 24810721

• The ethics and practice of neonatal resuscitation at the limits of viability: an international perspective ACTA PAEDIATRICA Fanaroff, J. M., Hascoet, J., Hansen, T., Levene, M., Norman, M., Papageorgiou, A., Shinwell, E., van de Bor, M., Stevenson, D. K., IPC 2014; 103 (7): 701–8

  Abstract

  Premature infants at the limits of viability raise difficult ethical, legal, social and economic questions. Neonatologists attending an international Collegium were surveyed about delivery room behaviour, and the approach taken by selected countries practicing 'modern' medicine was explored.There were strong preferences for comfort care at 22 weeks and full resuscitation at 24 weeks. Resuscitation was a grey area at 23 weeks. Cultural, social and legal factors also had a considerable impact on decision-making.

  View details for DOI 10.1111/apa.12633

  View details for Web of Science ID 000337572700016

  View details for PubMedID 24635758

• Investigation of maternal environmental exposures in association with self-reported preterm birth. Reproductive toxicology Patel, C. J., Yang, T., Hu, Z., Wen, Q., Sung, J., El-Sayed, Y. Y., Cohen, H., Gould, J., Stevenson, D. K., Shaw, G. M., Ling, X. B., Butte, A. J. 2014; 45: 1-7

  Abstract

  Identification of maternal environmental factors influencing preterm birth risks is important to understand the reasons for the increase in prematurity since 1990. Here, we utilized a health survey, the US National Health and Nutrition Examination Survey (NHANES) to search for personal environmental factors associated with preterm birth. 201 urine and blood markers of environmental factors, such as allergens, pollutants, and nutrients were assayed in mothers (range of N: 49-724) who answered questions about any children born preterm (delivery <37 weeks). We screened each of the 201 factors for association with any child born preterm adjusting by age, race/ethnicity, education, and household income. We attempted to verify the top finding, urinary bisphenol A, in an independent study of pregnant women attending Lucile Packard Children's Hospital. We conclude that the association between maternal urinary levels of bisphenol A and preterm birth should be evaluated in a larger epidemiological investigation.

  View details for DOI 10.1016/j.reprotox.2013.12.005

  View details for PubMedID 24373932

• Developmental outcomes of very preterm infants with tracheostomies. journal of pediatrics DeMauro, S. B., D'Agostino, J. A., Bann, C., Bernbaum, J., Gerdes, M., Bell, E. F., Carlo, W. A., D'Angio, C. T., Das, A., Higgins, R., Hintz, S. R., Laptook, A. R., Natarajan, G., Nelin, L., Poindexter, B. B., Sanchez, P. J., Shankaran, S., Stoll, B. J., Truog, W., Van Meurs, K. P., Vohr, B., Walsh, M. C., Kirpalani, H. 2014; 164 (6): 1303-10 e2

  Abstract

  To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.Retrospective cohort study from 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N = 8683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI; a composite of ≥1 of developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed the impact of timing by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.Tracheostomies were associated with all neonatal morbidities examined and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without (OR adjusted for center 7.0, 95% CI 5.2-9.5). After adjustment for potential confounders, odds of death or NDI remained higher (OR 3.3, 95% CI 2.4-4.6), but odds of death alone were lower (OR 0.4, 95% CI 0.3-0.7) among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life (aOR 0.5, 95% CI 0.3-0.9).Tracheostomy in preterm infants is associated with adverse developmental outcomes and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.

  View details for DOI 10.1016/j.jpeds.2013.12.014

  View details for PubMedID 24472229

• The gender gap in academic medicine: comparing results from a multifaceted intervention for stanford faculty to peer and national cohorts. Academic medicine Valantine, H. A., Grewal, D., Ku, M. C., Moseley, J., Shih, M., Stevenson, D., Pizzo, P. A. 2014; 89 (6): 904-911

  Abstract

  To assess whether the proportion of women faculty, especially at the full professor rank, increased from 2004 to 2010 at Stanford University School of Medicine after a multifaceted intervention.The authors surveyed gender composition and faculty satisfaction five to seven years after initiating a multifaceted intervention to expand recruitment and development of women faculty. The authors assessed pre/post relative change and rates of increase in women faculty at each rank, and faculty satisfaction; and differences in pre/post change and estimated rate of increase between Stanford and comparator cohorts (nationally and at peer institutions).Post intervention, women faculty increased by 74% (234 to 408), with assistant, associate, and full professors increasing by 66% (108 to 179), 87% (74 to 138), and 75% (52 to 91), respectively. Nationally and at peer institutions, women faculty increased by about 30% (30,230 to 39,200 and 4,370 to 5,754, respectively), with lower percentages at each rank compared with Stanford. Estimated difference (95% CI) in annual rate of increase was larger for Stanford versus the national cohort: combined ranks 0.36 (0.17 to 0.56), P = .001; full professor 0.40 (0.18 to 0.62), P = .001; and versus the peer cohort: combined ranks 0.29 (0.07 to 0.51), P = .02; full professor 0.37 (0.14 to 0.60), P = .003. Stanford women faculty satisfaction increased from 48% (2003) to 71% (2008).Increased satisfaction and proportion of women faculty, especially full professors, suggest that the intervention may ameliorate the gender gap in academic medicine.

  View details for DOI 10.1097/ACM.0000000000000245

  View details for PubMedID 24871242

• Safety and Efficacy of Filtered Sunlight in Treatment of Jaundice in African Neonates PEDIATRICS Slusher, T. M., Vreman, H. J., Olusanya, B. O., Wong, R. J., Brearley, A. M., Vaucher, Y. E., Stevenson, D. K. 2014; 133 (6): E1568-E1574

  Abstract

  Evaluate safety and efficacy of filtered-sunlight phototherapy (FS-PT).Term/late preterm infants #14 days old with clinically significant jaundice, assessed by total bilirubin (TB) levels, were recruited from a maternity hospital in Lagos, Nigeria. Sunlight was filtered with commercial window-tinting films that remove most UV and significant levels of infrared light and transmit effective levels of therapeutic blue light. After placing infants under an FS-PT canopy, hourly measurements of axillary temperatures, monitoring for sunburn, dehydration, and irradiances of filtered sunlight were performed. Treatment was deemed safe and efficacious if infants were able to stay in FS-PT for $5 hours and rate of rise of TB was ,0.2 mg/dL/h for infants #72 hours of age or TB decreased for infants .72 hours of age.A total of 227 infants received 258 days of FS-PT. No infant developed sunburn or dehydration. On 85 (33%) of 258 treatment days, infants were removed briefly from FS-PT due to minor temperature-related adverse events. No infant met study exit criteria. FS-PT was efficacious in 92% (181/197) of evaluable treatment days. Mean 6 SD TB change was –0.06 6 0.19 mg/dL/h. The mean 6 SD (range) irradiance of FS-PT was 38 6 22 (2–115) mW/cm2/nm, measured by the BiliBlanket Meter II.With appropriate monitoring, filtered sunlight is a novel, practical, and inexpensive method of PT that potentially offers safe and efficacious treatment strategy for management of neonatal jaundice in tropical countries where conventional PT treatment is not available.

  View details for DOI 10.1542/peds.2013-3500

  View details for Web of Science ID 000337172600012

  View details for PubMedID 24864170

• The Initiative on Subspecialty Clinical Training and Certification (SCTC) : Background and Recommendations PEDIATRICS Stevenson, D. K., McGuinness, G. A., Bancroft, J. D., Boyer, D. M., Cohen, A. R., Gilhooly, J. T., Hazinski, M. F., Holmboe, E. S., Jones, D., Land, M. L., Long, S. S., Norwood, V. F., Schumacher, D. J., Sectish, T. C., St Geme, J. W., West, D. C. 2014; 133: S53-S57

  View details for DOI 10.1542/peds.2013-3861C

  View details for Web of Science ID 000338342300001

• Pediatric Subspecialty Fellowship Clinical Training Project: Recent Graduates and Midcareer Survey Comparison PEDIATRICS Freed, G. L., Dunham, K. M., Moran, L. M., Spera, L., McGuinness, G. A., Stevenson, D. K. 2014; 133: S70-S75

  View details for DOI 10.1542/peds.2013-3861E

  View details for Web of Science ID 000338342300004

• Pediatric Subspecialty Fellowship Clinical Training Project: Current Fellows PEDIATRICS Freed, G. L., Dunham, K. M., Moran, L. M., Spera, L., McGuinness, G. A., Stevenson, D. K. 2014; 133: S58-S63

  View details for DOI 10.1542/peds.2013-3861G

  View details for Web of Science ID 000338342300002

• Fellowship Program Directors Perspectives on Fellowship Training PEDIATRICS Freed, G. L., Dunham, K. M., Moran, L. M., Spera, L., McGuinness, G. A., Stevenson, D. K. 2014; 133: S64-S69

  View details for DOI 10.1542/peds.2013-3861D

  View details for Web of Science ID 000338342300003

• Specialty Specific Comparisons Regarding Perspectives on Fellowship Training PEDIATRICS Freed, G. L., Dunham, K. M., Moran, L. M., Spera, L., McGuinness, G. A., Stevenson, D. K. 2014; 133: S76-S77

  View details for DOI 10.1542/peds.2013-3861F

  View details for Web of Science ID 000338342300005

• Dynamic Alterations in the Murine Myeloid Cell Population during Pregnancy Zhao, H., Kalish, F., Schulz, S., Yang, Y., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2014: 417A–418A

  View details for Web of Science ID 000333813003356

• Maternal Characteristics and Mid-Pregnancy Serum Markers in Spontaneous and Medically Indicated Preterm Birth Jelliffe-Pawlowski, L. L., Baer, R. J., O'Brodovich, H. M., Stevenson, D. K., Gould, J. B., Shaw, G. M., Currier, R. J. SAGE PUBLICATIONS INC. 2014: 239A

  View details for Web of Science ID 000333813002170

• Maternal Body Mass and Risk for Premature Birth among 1.2 Million California Births Shaw, G. M., Wise, P. H., Mayo, J., Carmichael, S. L., Ley, C., Lyell, D. J., Shachar, B., Melsop, K., Phibbs, C. S., Stevenson, D. K., Parsonnet, J., Gould, J. B. SAGE PUBLICATIONS INC. 2014: 340A

  View details for Web of Science ID 000333813003131

• Apolipoprotein E genotype and outcome in infants with hypoxic-ischemic encephalopathy. Pediatric research Cotten, C. M., Goldstein, R. F., McDonald, S. A., Goldberg, R. N., Salhab, W. A., Carlo, W. A., Tyson, J. E., Finer, N. N., Walsh, M. C., Ehrenkranz, R. A., Laptook, A. R., Guillet, R., Schibler, K., Van Meurs, K. P., Poindexter, B. B., Stoll, B. J., O'Shea, T. M., Duara, S., Das, A., Higgins, R. D., Shankaran, S. 2014; 75 (3): 424-430

  Abstract

  Background:Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE).Methods:We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-.Results:A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups.Conclusion:Disability was not associated with the APOE genotype in this cohort of HIE survivors.

  View details for DOI 10.1038/pr.2013.235

  View details for PubMedID 24322171

• Brain microstructural development at near-term age in very-low-birth-weight preterm infants: An atlas-based diffusion imaging study. NeuroImage Rose, J., Vassar, R., Cahill-Rowley, K., Guzman, X. S., Stevenson, D. K., Barnea-Goraly, N. 2014; 86: 244-256

  Abstract

  At near-term age the brain undergoes rapid growth and development. Abnormalities identified during this period have been recognized as potential predictors of neurodevelopment in children born preterm. This study used diffusion tensor imaging (DTI) to examine white matter (WM) microstructure in very-low-birth-weight (VLBW) preterm infants to better understand regional WM developmental trajectories at near-term age. DTI scans were analyzed in a cross-sectional sample of 45 VLBW preterm infants (BW≤1500g, GA≤32weeks) within a cohort of 102 neonates admitted to the NICU and recruited to participate prior to standard-of-care MRI, from 2010 to 2011, 66/102 also had DTI. For inclusion in this analysis, 45 infants had DTI, no evidence of brain abnormality on MRI, and were scanned at PMA ≤40weeks (34.7-38.6). White matter microstructure was analyzed in 19 subcortical regions defined by DiffeoMap neonatal brain atlas, using threshold values of trace <0.006mm(2)s(-1) and FA >0.15. Regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and temporal-spatial trajectories of development were examined in relation to PMA and brain region location. Posterior regions within the corona radiata (CR), corpus callosum (CC), and internal capsule (IC) demonstrated significantly higher mean FA values compared to anterior regions. Posterior regions of the CR and IC demonstrated significantly lower RD values compared to anterior regions. Centrally located projection fibers demonstrated higher mean FA and lower RD values than peripheral regions including the posterior limb of the internal capsule (PLIC), cerebral peduncle, retrolenticular part of the IC, posterior thalamic radiation, and sagittal stratum. Centrally located association fibers of the external capsule had higher FA and lower RD than the more peripherally-located superior longitudinal fasciculus (SLF). A significant relationship between PMA-at-scan and FA, MD, and RD was demonstrated by a majority of regions, the strongest correlations were observed in the anterior limb of the internal capsule, a region undergoing early stages of myelination at near-term age, in which FA increased (r=.433, p=.003) and MD (r=-.545, p=.000) and RD (r=-.540, p=.000) decreased with PMA-at-scan. No correlation with PMA-at-scan was observed in the CC or SLF, regions that myelinate later in infancy. Regional patterns of higher FA and lower RD were observed at this near-term age, suggestive of more advanced microstructural development in posterior compared to anterior regions within the CR, CC, and IC and in central compared to peripheral WM structures. Evidence of region-specific rates of microstructural development was observed. Temporal-spatial patterns of WM microstructure development at near-term age have important implications for interpretation of near-term DTI and for identification of aberrations in typical developmental trajectories that may signal future impairment.

  View details for DOI 10.1016/j.neuroimage.2013.09.053

  View details for PubMedID 24091089

• Mortality and Morbidity of VLBW Infants With Trisomy 13 or Trisomy 18 PEDIATRICS Boghossian, N. S., Hansen, N. I., Bell, E. F., Stoll, B. J., Murray, J. C., Carey, J. C., Adams-Chapman, I., Shankaran, S., Walsh, M. C., Laptook, A. R., Faix, R. G., Newman, N. S., Hale, E. C., Das, A., Wilson, L. D., Hensman, A. M., Grisby, C., Collins, M. V., Vasil, D. M., Finkle, J., Maffett, D., Ball, M., Lacy, C. B., Bara, R., Higgins, R. D., Eunice Kennedy Shriver Natl Inst C 2014; 133 (2): 226–35

  Abstract

  Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects.Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994-2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18.Of 52,262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis.In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.

  View details for DOI 10.1542/peds.2013-1702

  View details for Web of Science ID 000333413600008

  View details for PubMedID 24446439

  View details for PubMedCentralID PMC3904274

• Neonatal physiological correlates of near-term brain development on MRI and DTI in very-low-birth-weight preterm infants. NeuroImage. Clinical Rose, J., Vassar, R., Cahill-Rowley, K., Stecher Guzman, X., Hintz, S. R., Stevenson, D. K., Barnea-Goraly, N. 2014; 5: 169-177

  Abstract

  Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age. Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Children's Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin. Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = -.322, p = .009; r= -.381, p= .002), lower mean albumin (r = -.276, p= .029; r= -.385, p= .002), and lower mean bilirubin (r = -.293, p= .020; r= -.337 p= .007). Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants.

  View details for DOI 10.1016/j.nicl.2014.05.013

  View details for PubMedID 25068107

• Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials. Trials Sood, B. G., Keszler, M., Garg, M., Klein, J. M., Ohls, R., Ambalavanan, N., Cotten, C. M., Malian, M., Sanchez, P. J., Lakshminrusimha, S., Nelin, L. D., Van Meurs, K. P., Bara, R., Saha, S., Das, A., Wallace, D., Higgins, R. D., Shankaran, S. 2014; 15: 486-?

  Abstract

  Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.CLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.

  View details for DOI 10.1186/1745-6215-15-486

  View details for PubMedID 25496504

• Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation or surgical necrotizing enterocolitis JOURNAL OF PERINATOLOGY Wadhawan, R., Oh, W., Hintz, S. R., Blakely, M. L., Das, A., Bell, E. F., Saha, S., Laptook, A. R., Shankaran, S., Stoll, B. J., Walsh, M. C., Higgins, R. D. 2014; 34 (1): 64-70

  Abstract

  To determine if extremely low birth weight infants with surgical necrotizing enterocolitis have a higher risk of death or neurodevelopmental impairment and neurodevelopmental impairment among survivors (secondary outcome) at 18-22 months corrected age compared with infants with spontaneous intestinal perforation and infants without necrotizing enterocolitis or spontaneous intestinal perforation.Retrospective analysis of the Neonatal Research Network very low birth weight registry, evaluating extremely low birth weight infants born between 2000 and 2005. The study infants were designated into three groups: (1) spontaneous intestinal perforation without necrotizing enterocolitis; (2) surgical necrotizing enterocolitis (Bell's stage III); and (3) neither spontaneous intestinal perforation nor necrotizing enterocolitis. Multivariate logistic regression analysis was performed to evaluate the association between the clinical group and death or neurodevelopmental impairment, controlling for multiple confounding factors including center.Infants with surgical necrotizing enterocolitis had the highest rate of death before hospital discharge (53.5%) and death or neurodevelopmental impairment (82.3%) compared with infants in the spontaneous intestinal perforation group (39.1 and 79.3%) and no necrotizing enterocolitis/no spontaneous intestinal perforation group (22.1 and 53.3%; P<0.001). Similar results were observed for neurodevelopmental impairment among survivors. On logistic regression analysis, both spontaneous intestinal perforation and surgical necrotizing enterocolitis were associated with increased risk of death or neurodevelopmental impairment (adjusted odds ratio 2.21, 95% confidence interval (CI): 1.5, 3.2 and adjusted OR 2.11, 95% CI: 1.5, 2.9, respectively) and neurodevelopmental impairment among survivors (adjusted OR 2.17, 95% CI: 1.4, 3.2 and adjusted OR 1.70, 95% CI: 1.2, 2.4, respectively).Spontaneous intestinal perforation and surgical necrotizing enterocolitis are associated with a similar increase in the risk of death or neurodevelopmental impairment and neurodevelopmental impairment among extremely low birth weight survivors at 18-22 months corrected age.

  View details for DOI 10.1038/jp.2013.128

  View details for PubMedID 24135709

• CHEMOPREVENTION OF NEONATAL JAUNDICE USING POLYMERIC PARTICULATE DELIVERY OF ZINC PROTOPORPHYRIN Wong, R. J., Espadas, C., Inayathullah, M., Lechuga-Ballesteros, D., Kalish, F., Rajadas, J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2014: 156

  View details for Web of Science ID 000336284900053

• SPECIAL FEATURE William A Silverman lecture JOURNAL OF PERINATOLOGY Stevenson, D. K. 2014; 34 (1): 1–5

  Abstract

  This is the text of the William A Silverman lecture given by Dr David K Stevenson at the Pediatric Academic Societies Annual Meeting in Washington, DC, May 4-7, 2013.

  View details for PubMedID 23970208

• EFFICACY AND SAFETY OF BLUE-GREEN LIGHT FOR PHOTOTHERAPY Linfield, D. T., Lin, D., Schulz, S., Vreman, H. J., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2014: 155–56

  View details for Web of Science ID 000336284900052

• Outcomes of extremely low birthweight infants with acidosis at birth. Archives of disease in childhood. Fetal and neonatal edition Randolph, D. A., Nolen, T. L., Ambalavanan, N. n., Carlo, W. A., Peralta-Carcelen, M. n., Das, A. n., Bell, E. F., Davis, A. S., Laptook, A. R., Stoll, B. J., Shankaran, S. n., Higgins, R. D. 2014

  Abstract

  To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birthweight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable.The study population consisted of ELBW infants born between 2002 and 2007 at National Institute of Child Health and Development (NICHD) Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH<7 or base excess (BE) <-12, to death/NDI in ELBW infants. In addition, a multivariable model predicting death/NDI was developed.3979 patients were identified of whom 249 had a cord gas pH<7 or BE<-12 mEq/L. 2124 patients (53%) had the primary outcome of death/NDI. After adjustment for confounding variables, pH<7 and BE<-12 mEq/L were each significantly associated with death/NDI (OR=2.5 (1.6, 4.2) and OR=1.5 (1.1, 2.0), respectively). However, inclusion of pH or BE did not improve the ability of the multivariable model to predict death/NDI.Perinatal acidosis is significantly associated with death/NDI in ELBW infants. Perinatal acidosis is infrequent in ELBW infants, however, and other factors are more important in predicting death/NDI.

  View details for PubMedID 24554564

• Death or Neurodevelopmental Impairment at 18 to 22 Months Corrected Age in a Randomized Trial of Early Dexamethasone to Prevent Death or Chronic Lung Disease in Extremely Low Birth Weight Infants JOURNAL OF PEDIATRICS Stark, A. R., Carlo, W. A., Vohr, B. R., Papile, L. A., Saha, S., Bauer, C. R., Oh, W., Shankaran, S., Tyson, J. E., Wright, L. L., Poole, W. K., Das, A., Stoll, B. J., Fanaroff, A. A., Korones, S. B., Ehrenkranz, R. A., Stevenson, D. K., Peralta-Carcelen, M., Wilson-Costello, D. E., Bada, H. S., Heyne, R. J., Johnson, Y. R., Lee, K. G., Steichen, J. J. 2014; 164 (1): 34-?

  Abstract

  To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.Evaluation of infants at 18-22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index and the Psychomotor Developmental Index. NDI was defined as moderate or severe cerebral palsy, Mental Developmental Index or Psychomotor Developmental Index <70, blindness, or hearing impairment.Death or NDI at 18-22 months corrected age was similar in the dexamethasone and placebo groups (65% vs 66%, P = .99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50% vs 41%, P = .42 for weight less than 10th percentile); 49% of infants in the placebo group received treatment with corticosteroid compared with 32% in the dexamethasone group (P = .02).The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.

  View details for DOI 10.1016/j.jpeds.2013.07.027

  View details for PubMedID 23992673

• Treatment of neonatal jaundice with filtered sunlight in Nigerian neonates: study protocol of a non-inferiority, randomized controlled trial TRIALS Slusher, T. M., Olusanya, B. O., Vreman, H. J., Wong, R. J., Brearley, A. M., Vaucher, Y. E., Stevenson, D. K. 2013; 14

  Abstract

  Severe neonatal jaundice and its progression to kernicterus is a leading cause of death and disability among newborns in poorly-resourced countries, particularly in sub-Saharan Africa. The standard treatment for jaundice using conventional phototherapy (CPT) with electric artificial blue light sources is often hampered by the lack of (functional) CPT devices due either to financial constraints or erratic electrical power. In an attempt to make phototherapy (PT) more readily available for the treatment of pathologic jaundice in underserved tropical regions, we set out to test the hypothesis that filtered sunlight phototherapy (FS-PT), in which potentially harmful ultraviolet and infrared rays are appropriately screened, will be as efficacious as CPT.This prospective, non-blinded randomized controlled non-inferiority trial seeks to enroll infants with elevated total serum/plasma bilirubin (TSB, defined as 3 mg/dl below the level recommended by the American Academy of Pediatrics for high-risk infants requiring PT) who will be randomly and equally assigned to receive FS-PT or CPT for a total of 616 days at an inner-city maternity hospital in Lagos, Nigeria. Two FS-PT canopies with pre-tested films will be used. One canopy with a film that transmits roughly 33% blue light (wavelength range: 400 to 520 nm) will be used during sunny periods of a day. Another canopy with a film that transmits about 79% blue light will be used during overcast periods of the day. The infants will be moved from one canopy to the other as needed during the day with the goal of keeping the blue light irradiance level above 8 μW/cm²/nm.Primary outcome: FS-PT will be as efficacious as CPT in reducing the rate of rise in bilirubin levels. Secondary outcome: The number of infants requiring exchange transfusion under FS-PT will not be more than those under CPT.This novel study offers the prospect of an effective treatment for infants at risk of severe neonatal jaundice and avoidable exchange transfusion in poorly-resourced settings without access to (reliable) CPT in the tropics.ClinicalTrials.gov Identifier: NCT01434810.

  View details for DOI 10.1186/1745-6215-14-446

  View details for Web of Science ID 000329516800001

  View details for PubMedID 24373547

  View details for PubMedCentralID PMC3879162

• Could genetic polymorphisms related to oxidative stress modulate effects of heavy metals for risk of human preterm birth? Reproductive toxicology Shachar, B. Z., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 2013; 42: 24-26

  Abstract

  Human preterm birth (PTB) is a complex medical outcome influenced by a combination of genetic and environmental factors. Research on the causative factors of PTB has mostly focused on demographic, socio-behavioral and environmental risk factors. Recent studies turn the spotlight on the effects of heavy metals exposure on adverse pregnancy outcomes. Here we present and evaluate the hypothesis that heavy metals may cause PTB through oxidative stress, and that this effect may be modified by polymorphisms in genes related to oxidative stress. Indeed, accumulating data suggest that the risk of PTB is correlated with polymorphisms in genes involved in detoxification, oxidative stress and lipid metabolism. These and other polymorphisms have independently been associated with susceptibility to the adverse effects of heavy metals.

  View details for DOI 10.1016/j.reprotox.2013.06.072

  View details for PubMedID 23811355

• Immunogenicity of Haemophilus influenzae type b protein conjugate vaccines in very low birth weight infants. Pediatric infectious disease journal D'Angio, C. T., Murray, T. E., Li, L., Heyne, R. J., O'Shea, T. M., Schelonka, R. L., Shankaran, S., Duara, S., Goldberg, R. N., Stoll, B. J., Stevenson, D. K., Vohr, B. R., Phelps, D. L., Carlo, W. A., Pichichero, M. E., Das, A., Higgins, R. D. 2013; 32 (12): 1400-1402

  View details for DOI 10.1097/01.inf.0000437263.04493.7c

  View details for PubMedID 24569312

• Early working memory as a racially and ethnically neutral measure of outcome in extremely preterm children at 18-22months. Early human development Lowe, J. R., Duncan, A. F., Bann, C. M., Fuller, J., Hintz, S. R., Das, A., Higgins, R. D., Watterberg, K. L. 2013; 89 (12): 1055-1061

  Abstract

  Difficulties with executive function have been found in preterm children, resulting in difficulties with learning and school performance.This study evaluated the relationship of early working memory as measured by object permanence items to the cognitive and language scores on the Bayley Scales-III in a cohort of children born extremely preterm.Logistic regression models were conducted to compare object permanence scores derived from the Bayley Scales-III by race/ethnicity and maternal education, controlling for medical covariates.Extremely preterm toddlers (526), who were part of a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's multi-center study, were evaluated at 18-22 months corrected age.Object permanence scores derived from the Bayley Developmental Scales were compared by race/ethnicity and maternal education, controlling for medical covariates.There were no significant differences in object permanence mastery and scores among the treatment groups after controlling for medical and social variables, including maternal education and race/ethnicity. Males and children with intraventricular hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia were less likely to demonstrate object permanence mastery and had lower object permanence scores. Children who attained object permanence mastery had significantly higher Bayley Scales-III cognitive and language scores after controlling for medical and socio-economic factors.Our measure of object permanence is free of influence from race, ethnic and socio-economic factors. Adding this simple task to current clinical practice could help detect early executive function difficulties in young children.

  View details for DOI 10.1016/j.earlhumdev.2013.08.009

  View details for PubMedID 23993309

  View details for PubMedCentralID PMC3830714

• Evaluation of window-tinting films for sunlight phototherapy. Journal of tropical pediatrics Vreman, H. J., Slusher, T. M., Wong, R. J., Schulz, S., Olusanya, B. O., Stevenson, D. K. 2013; 59 (6): 496-501

  Abstract

  We evaluated nine semi-transparent plastic window-tinting films for their ability to block ultraviolet A (UVA) and infrared (IR) radiation and transmit therapeutic blue light (400-520 nm) for treating jaundiced newborns. For indoor testing, three light sources (TL/52 special blue fluorescent, Black Light UVA and IR heat lamps) were positioned above each film and measured successively using a thermocouple thermometer, UVA radiometer and blue light irradiance meter, placed below each film. For outdoor testing, the same setup was used with the sun at zenith and a cloudless sky. Compared with unfiltered radiation, blue light transmission through films ranged from 24 to 83%, UVA transmission was 0.1-7.1% and reductions in IR heat were 6-12°C and 5-10°C for heat lamp and sun, respectively. The data suggest that most of the relatively low-cost window-tinting films tested can effectively reduce sunlight UV and IR and offer a range of significant attenuations of therapeutic blue light.

  View details for DOI 10.1093/tropej/fmt062

  View details for PubMedID 23880667

• Integrating multiple 'omics' analyses identifies serological protein biomarkers for preeclampsia BMC MEDICINE Liu, L. Y., Yang, T., Ji, J., Wen, Q., Morgan, A. A., Jin, B., Chen, G., Lyell, D. J., Stevenson, D. K., Ling, X. B., Butte, A. J. 2013; 11

  Abstract

  Preeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-'omics' based discovery approach.Seven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment.In addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively.Both early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE.

  View details for DOI 10.1186/1741-7015-11-236

  View details for Web of Science ID 000329052900001

  View details for PubMedID 24195779

  View details for PubMedCentralID PMC4226208

• Apgar scores at 10 min and outcomes at 6-7 years following hypoxic-ischaemic encephalopathy ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Natarajan, G., Shankaran, S., Laptook, A. R., Pappas, A., Bann, C. M., McDonald, S. A., Das, A., Higgins, R. D., Hintz, S. R., Vohr, B. R. 2013; 98 (6): F473-F479

  Abstract

  To determine the association between 10 min Apgar scores and 6-7-year outcomes in children with perinatal hypoxic-ischaemic encephalopathy (HIE) enrolled in the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) whole body cooling randomised controlled trial (RCT).Evaluations at 6-7 years included the Wechsler Preschool and Primary Scale of Intelligence III or Wechsler Intelligence Scale for Children IV and Gross Motor Functional Classification Scale. Primary outcome was death/moderate or severe disability. Logistic regression was used to examine the association between 10 min Apgar scores and outcomes after adjusting for birth weight, gestational age, gender, outborn status, hypothermia treatment and centre.In the study cohort (n=174), 64/85 (75%) of those with 10 min Apgar score of 0-3 had death/disability compared with 40/89 (45%) of those with scores >3. Each point increase in 10 min Apgar scores was associated with a significantly lower adjusted risk of death/disability, death, death/IQ <70, death/cerebral palsy (CP) and disability, IQ<70 and CP among survivors (all p<0.05). Among the 24 children with a 10 min Apgar score of 0, five (20.8%) survived without disability. The risk-adjusted probabilities of death/disability were significantly lower in cooled infants with Apgar scores of 0-3; there was no significant interaction between cooling and Apgar scores (p=0.26).Among children with perinatal HIE enrolled in the NICHD cooling RCT, 10 min Apgar scores were significantly associated with school-age outcomes. A fifth of infants with 10 min Apgar score of 0 survived without disability to school age, suggesting the need for caution in limiting resuscitation to a specified duration.

  View details for DOI 10.1136/archdischild-2013-303692

  View details for Web of Science ID 000325556000003

  View details for PubMedID 23896791

• Prevention of Traumatic Stress in Mothers With Preterm Infants: A Randomized Controlled Trial PEDIATRICS Shaw, R. J., St John, N., Lilo, E. A., Jo, B., Benitz, W., Stevenson, D. K., Horwitz, S. M. 2013; 132 (4): E886-E894

  Abstract

  The current study evaluates a treatment intervention developed with the goal of reducing symptoms of posttraumatic stress, depression, and anxiety in parents of premature infants.A total of 105 mothers of preterm infants (25-34 weeks' gestational age; >600 g) were randomized to receive a 6-session intervention developed to target parental trauma as well as facilitate infant redefinition (n = 62) or to an active comparison group (n = 43). Mothers in the intervention group received a combination of trauma-focused treatments, including psychoeducation, cognitive restructuring, progressive muscle relaxation, and development of their trauma narrative. The intervention also incorporated material targeting infant redefinition, defined as the process of changing the mother's negative perceptions of her infant and the parenting experience.Mothers in the intervention group reported a greater reduction in both trauma symptoms (Cohen's d = 0.41, P = .023) and depression (Cohen's d = 0.59, P < .001) compared with the comparison group. Patients under both conditions improved significantly in terms of anxiety, with no differences between groups. Results of the moderator analysis showed that mothers with higher ratings of baseline NICU stress benefited more from the intervention compared with mothers who had lower ratings (P = .036).This short, highly manualized intervention for mothers of preterm infants statistically significantly reduced symptoms of trauma and depression. The intervention is feasible, can be delivered with fidelity, and has high ratings of maternal satisfaction. Given that improvements in mothers' distress may lead to improved infant outcomes, this intervention has the potential for a high public health impact.

  View details for DOI 10.1542/peds.2013-1331

  View details for Web of Science ID 000325095400010

  View details for PubMedID 23999956

  View details for PubMedCentralID PMC3784295

• Prevention of traumatic stress in mothers with preterm infants: a randomized controlled trial. Pediatrics Shaw, R. J., St John, N., Lilo, E. A., Jo, B., Benitz, W., Stevenson, D. K., Horwitz, S. M. 2013; 132 (4): e886-94

  Abstract

  The current study evaluates a treatment intervention developed with the goal of reducing symptoms of posttraumatic stress, depression, and anxiety in parents of premature infants.A total of 105 mothers of preterm infants (25-34 weeks' gestational age; >600 g) were randomized to receive a 6-session intervention developed to target parental trauma as well as facilitate infant redefinition (n = 62) or to an active comparison group (n = 43). Mothers in the intervention group received a combination of trauma-focused treatments, including psychoeducation, cognitive restructuring, progressive muscle relaxation, and development of their trauma narrative. The intervention also incorporated material targeting infant redefinition, defined as the process of changing the mother's negative perceptions of her infant and the parenting experience.Mothers in the intervention group reported a greater reduction in both trauma symptoms (Cohen's d = 0.41, P = .023) and depression (Cohen's d = 0.59, P < .001) compared with the comparison group. Patients under both conditions improved significantly in terms of anxiety, with no differences between groups. Results of the moderator analysis showed that mothers with higher ratings of baseline NICU stress benefited more from the intervention compared with mothers who had lower ratings (P = .036).This short, highly manualized intervention for mothers of preterm infants statistically significantly reduced symptoms of trauma and depression. The intervention is feasible, can be delivered with fidelity, and has high ratings of maternal satisfaction. Given that improvements in mothers' distress may lead to improved infant outcomes, this intervention has the potential for a high public health impact.

  View details for DOI 10.1542/peds.2013-1331

  View details for PubMedID 23999956

• Neurodevelopmental outcome of extremely low birth weight infants with Candida infection. journal of pediatrics Adams-Chapman, I., Bann, C. M., Das, A., Goldberg, R. N., Stoll, B. J., Walsh, M. C., Sánchez, P. J., Higgins, R. D., Shankaran, S., Watterberg, K. L., Duara, S., Miller, N. A., Heyne, R. J., Peralta-Carcelen, M., Goldstein, R. F., Steichen, J. J., Bauer, C. R., Hintz, S. R., Evans, P. W., Acarregui, M. J., Myers, G. J., Vohr, B. R., Wilson-Costello, D. E., Pappas, A., Vaucher, Y. E., Ehrenkranz, R. A., McGowan, E. C., Dillard, R. G., Fuller, J., Benjamin, D. K. 2013; 163 (4): 961-7 e3

  Abstract

  OBJECTIVE: Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birth weight (ELBW) infants enrolled in the Candida study were evaluated based on infection status. STUDY DESIGN: ELBW infants born at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers between March 2004 and July 2007 who were screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317 of the 1515 infants (87%) enrolled in the Candida study. The Bayley Scales of Infant Development-II or -III was administered at 18 months' adjusted age. A secondary comparison was performed with 864 infants enrolled in the NRN Generic Database during the same cohort who were never screened for sepsis and therefore not eligible for the Candida study. RESULTS: Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83, 95% CI 1.01-3.33, P = .047). CONCLUSIONS: In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.

  View details for DOI 10.1016/j.jpeds.2013.04.034

  View details for PubMedID 23726546

• Cerebral Palsy and Growth Failure at 6 to 7 Years PEDIATRICS Vohr, B. R., Stephens, B. E., McDonald, S. A., Ehrenkranz, R. A., Laptook, A. R., Pappas, A., Hintz, S. R., Shankaran, S., Higgins, R. D., Das, A. 2013; 132 (4): E905-E914

  View details for DOI 10.1542/peds.2012-3915

  View details for Web of Science ID 000325095400012

  View details for PubMedID 24019415

• Raltegravir in vitro effect on bilirubin binding. Pediatric infectious disease journal Clarke, D. F., Wong, R. J., Wenning, L., Stevenson, D. K., Mirochnick, M. 2013; 32 (9): 978-980

  Abstract

  Drugs that displace bilirubin from albumin may increase the risk of kernicterus in neonates. We evaluated the effect of raltegravir on bilirubin-albumin binding in pooled neonatal serum using the peroxidase method. Raltegravir had minimal effect on bilirubin-albumin binding at concentrations of 5 and 10 µM, caused a small but statistically significant increase in unbound bilirubin at 100 µM and caused potentially harmful increases at 500 and 1000 µM. Our data suggest that the effect of raltegravir on neonatal bilirubin binding is unlikely to be clinically significant at typical peak concentrations reached with usual dosing.

  View details for DOI 10.1097/INF.0b013e31829044a8

  View details for PubMedID 23470680

• A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia. Pediatrics Wang, H., St Julien, K. R., Stevenson, D. K., Hoffmann, T. J., Witte, J. S., Lazzeroni, L. C., Krasnow, M. A., Quaintance, C. C., Oehlert, J. W., Jelliffe-Pawlowski, L. L., Gould, J. B., Shaw, G. M., O'Brodovich, H. M. 2013; 132 (2): 290-297

  Abstract

  Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

  View details for DOI 10.1542/peds.2013-0533

  View details for PubMedID 23897914

• The effect of hematocrit on the efficacy of phototherapy for neonatal jaundice PEDIATRIC RESEARCH Lamola, A. A., Bhutani, V. K., Wong, R. J., Stevenson, D. K., McDonagh, A. F. 2013; 74 (1): 54-60

  Abstract

  Background:The therapeutic phototherapy action spectrum ranges from 420 to 500nm. However, a recent report of improved efficacy offluorescent "turquoise"light (~490 nm) compared toblue light(~450 nm) underscores the need to define an optimal action spectrum for precision-targeted phototherapy using very narrow wavelength ranges.Methods:We used a current semi-empirical model of theoptical properties of skinfor robust calculations of the fraction of light absorbed by bilirubin at various wavelengths that could be confounded by hemoglobin, melanin and skin thickness. Applying assumptions regarding the wavelength dependence of bilirubin photochemistry, "action spectra"wereassembled from the calculated values.Results:All the calculated action spectra displayed a peak between 472 and 480 nm (most at 476 nm), which is a significant shift from the well-reported 460 nm absorption peak of bilirubin. Interestingly, the relative amplitudes of the action spectra showed an inverse relationship with hematocrit.Conclusion:We speculate that narrow range of light at 476 nmshould be 60% more effective than blue (broad-band) fluorescent lamps. Because hemoglobin serves as a major competitor of bilirubin for light absorption, the calculations also predict that the efficacy of phototherapy is dependent on the hematocrit.A high hematocrit could reduce therapeutic efficiency.Pediatric Research (2013); doi:10.1038/pr.2013.67.

  View details for DOI 10.1038/pr.2013.67

  View details for PubMedID 23604171

• Ten-year review of major birth defects in VLBW infants. Pediatrics Adams-Chapman, I., Hansen, N. I., Shankaran, S., Bell, E. F., Boghossian, N. S., Murray, J. C., Laptook, A. R., Walsh, M. C., Carlo, W. A., Sánchez, P. J., Van Meurs, K. P., Das, A., Hale, E. C., Newman, N. S., Ball, M. B., Higgins, R. D., Stoll, B. J. 2013; 132 (1): 49-61

  Abstract

  OBJECTIVE:Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.METHODS:Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.RESULTS:A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41-3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).CONCLUSIONS:Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.

  View details for DOI 10.1542/peds.2012-3111

  View details for PubMedID 23733791

• Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States? JOURNAL OF PERINATOLOGY Watchko, J. F., Kaplan, M., Stark, A. R., Stevenson, D. K., Bhutani, V. K. 2013; 33 (7): 499-504

  Abstract

  Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common X-linked enzymopathy can lead to severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus in the United States. Neonatal testing for G6PD deficiency is not yet routine and the American Academy of Pediatrics recommends testing only in jaundiced newborns who are receiving phototherapy whose family history, ethnicity, or geographic origin suggest risk for the condition, or for infants whose response to phototherapy is poor. Screening tests for G6PD deficiency are available, are suitable for use in newborns and have been used in birth hospitals. However, US birth hospitals experience is limited and no national consensus has emerged regarding the need for newborn G6PD testing, its effectiveness or the best approach. Our review of current state of G6PD deficiency screening highlights research gaps and informs specific operational challenges to implement universal newborn G6PD testing concurrent to bilirubin screening in the United States.

  View details for DOI 10.1038/jp.2013.14

  View details for Web of Science ID 000321000800001

  View details for PubMedID 23429543

• Peptidomic Identification of Serum Peptides Diagnosing Preeclampsia. PloS one Wen, Q., Liu, L. Y., Yang, T., Alev, C., Wu, S., Stevenson, D. K., Sheng, G., Butte, A. J., Ling, X. B. 2013; 8 (6): e65571

  Abstract

  We sought to identify serological markers capable of diagnosing preeclampsia (PE). We performed serum peptide analysis (liquid chromatography mass spectrometry) of 62 unique samples from 31 PE patients and 31 healthy pregnant controls, with two-thirds used as a training set and the other third as a testing set. Differential serum peptide profiling identified 52 significant serum peptides, and a 19-peptide panel collectively discriminating PE in training sets (n = 21 PE, n = 21 control; specificity = 85.7% and sensitivity = 100%) and testing sets (n = 10 PE, n = 10 control; specificity = 80% and sensitivity = 100%). The panel peptides were derived from 6 different protein precursors: 13 from fibrinogen alpha (FGA), 1 from alpha-1-antitrypsin (A1AT), 1 from apolipoprotein L1 (APO-L1), 1 from inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), 2 from kininogen-1 (KNG1), and 1 from thymosin beta-4 (TMSB4). We concluded that serum peptides can accurately discriminate active PE. Measurement of a 19-peptide panel could be performed quickly and in a quantitative mass spectrometric platform available in clinical laboratories. This serum peptide panel quantification could provide clinical utility in predicting PE or differential diagnosis of PE from confounding chronic hypertension.

  View details for DOI 10.1371/journal.pone.0065571

  View details for PubMedID 23840341

  View details for PubMedCentralID PMC3686758

• Peptidomic Identification of Serum Peptides Diagnosing Preeclampsia PLOS ONE Wen, Q., Liu, L. Y., Yang, T., Alev, C., Wu, S., Stevenson, D. K., Sheng, G., Butte, A. J., Ling, X. B. 2013; 8 (6)

  Abstract

  We sought to identify serological markers capable of diagnosing preeclampsia (PE). We performed serum peptide analysis (liquid chromatography mass spectrometry) of 62 unique samples from 31 PE patients and 31 healthy pregnant controls, with two-thirds used as a training set and the other third as a testing set. Differential serum peptide profiling identified 52 significant serum peptides, and a 19-peptide panel collectively discriminating PE in training sets (n = 21 PE, n = 21 control; specificity = 85.7% and sensitivity = 100%) and testing sets (n = 10 PE, n = 10 control; specificity = 80% and sensitivity = 100%). The panel peptides were derived from 6 different protein precursors: 13 from fibrinogen alpha (FGA), 1 from alpha-1-antitrypsin (A1AT), 1 from apolipoprotein L1 (APO-L1), 1 from inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), 2 from kininogen-1 (KNG1), and 1 from thymosin beta-4 (TMSB4). We concluded that serum peptides can accurately discriminate active PE. Measurement of a 19-peptide panel could be performed quickly and in a quantitative mass spectrometric platform available in clinical laboratories. This serum peptide panel quantification could provide clinical utility in predicting PE or differential diagnosis of PE from confounding chronic hypertension.

  View details for DOI 10.1371/journal.pone.0065571

  View details for Web of Science ID 000322361200025

  View details for PubMedCentralID PMC3686758

• Association of early-preterm birth with abnormal levels of routinely collected first- and second-trimester biomarkers AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Jelliffe-Pawlowski, L. L., Shaw, G. M., Currier, R. J., Stevenson, D. K., Baer, R. J., O'Brodovich, H. M., Gould, J. B. 2013; 208 (6)

  Abstract

  The purpose of this study was to examine the relationship between typically measured prenatal screening biomarkers and early-preterm birth in euploid pregnancies.The study included 345 early-preterm cases (<30 weeks of gestation) and 1725 control subjects who were drawn from a population-based sample of California pregnancies who had both first- and second-trimester screening results. Logistic regression analyses were used to compare patterns of biomarkers in cases and control subjects and to develop predictive models. Replicability of the biomarker early-preterm relationships that was revealed by the models was evaluated by examination of the frequency and associated adjusted relative risks (RRs) for early-preterm birth and for preterm birth in general (<37 weeks of gestation) in pregnancies with identified abnormal markers compared with pregnancies without these markers in a subsequent independent California cohort of screened pregnancies (n = 76,588).The final model for early-preterm birth included first-trimester pregnancy-associated plasma protein A in the ≤5th percentile, second-trimester alpha-fetoprotein in the ≥95th percentile, and second-trimester inhibin in the ≥95th percentile (odds ratios, 2.3-3.6). In general, pregnancies in the subsequent cohort with a biomarker pattern that were found to be associated with early-preterm delivery in the first sample were at an increased risk for early-preterm birth and preterm birth in general (<37 weeks of gestation; adjusted RR, 1.6-27.4). Pregnancies with ≥2 biomarker abnormalities were at particularly increased risk (adjusted RR, 3.6-27.4).When considered across cohorts and in combination, abnormalities in routinely collected biomarkers reveal predictable risks for early-preterm birth.

  View details for DOI 10.1016/j.ajog.2013.02.012

  View details for Web of Science ID 000320596600029

  View details for PubMedID 23395922

  View details for PubMedCentralID PMC3672244

• HEME OXYGENASE-1 DEFICIENCY IMPAIRS ADAPTIVE IMMUNITY IN THE INTESTINES OF YOUNG MICE VIA CHANGES IN T-REGULATORY CELLS Schulz, S., Chisholm, K. M., Kalish, F., Zhao, H., Yang, Y., Wong, R. J., Stevenson, D. K. SPRINGER. 2013: S93–S94

  View details for Web of Science ID 000342430900268

• The Transformation of Child Health Research Innovation, Market Failure, and the Public Good JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Stoll, B. J., Stevenson, D. K., Wise, P. H. 2013; 309 (17): 1779-1780

  View details for Web of Science ID 000318235600023

  View details for PubMedID 23632719

• Early Sepsis Does Not Increase the Risk of Late Sepsis in Very Low Birth Weight Neonates JOURNAL OF PEDIATRICS Wynn, J. L., Hansen, N. I., Das, A., Cotten, C. M., Goldberg, R. N., Sanchez, P. J., Bell, E. F., Van Meurs, K. P., Carlo, W. A., Laptook, A. R., Higgins, R. D., Benjamin, D. K., Stoll, B. J. 2013; 162 (5): 942-U92

  Abstract

  To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS).Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the National Institute of Child Health and Human Development Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained ≤72 hours of birth (EOS) or >72 hours (LOS) and antimicrobial therapy for ≥5 days or death <5 days while receiving therapy. Regression models were used to assess risk of death or LOS by 120 days and LOS by 120 days among survivors to discharge or 120 days, adjusting for gestational age and other covariates.Of 34 396 infants studied, 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120 days did not differ overall for infants with EOS compared with those without EOS [risk ratio (RR): 0.99 (0.89-1.09)] but was reduced in infants born at <25 weeks gestation [RR: 0.87 (0.76-0.99), P = .048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR: 0.88 (0.75-1.02)], but LOS risk was reduced in infants with birth weight 401-750 g who had EOS [RR: 0.80 (0.64-0.99), P = .047].Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.

  View details for DOI 10.1016/j.jpeds.2012.11.027

  View details for Web of Science ID 000317836300016

  View details for PubMedID 23295144

  View details for PubMedCentralID PMC3622770

• Neurodevelopmental outcomes of extremely low-gestational-age neonates with low-grade periventricular-intraventricular hemorrhage. JAMA pediatrics Payne, A. H., Hintz, S. R., Hibbs, A. M., Walsh, M. C., Vohr, B. R., Bann, C. M., Wilson-Costello, D. E. 2013; 167 (5): 451-459

  Abstract

  Low-grade periventricular-intraventricular hemorrhage is a common neurologic morbidity among extremely low-gestational-age neonates, yet the outcomes associated with this morbidity are not fully understood. In a contemporary multicenter cohort, we evaluated the impact of such hemorrhages on early (18-22 month) neurodevelopmental outcomes of extremely premature infants.To compare neurodevelopmental outcomes at 18 to 22 months' corrected age for extremely low-gestational-age infants with low-grade (grade 1 or 2) periventricular-intraventricular hemorrhage with those of infants with either no hemorrhage or severe (grade 3 or 4) hemorrhage demonstrated on cranial ultrasonography.Longitudinal observational study.Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.A total of 1472 infants born at less than 27 weeks' gestational age between January 1, 2006, and December 31, 2008, with ultrasonography results within the first 28 days of life and surviving to 18 to 22 months with complete follow-up assessments were eligible.Low-grade periventricular-intraventricular hemorrhage.Outcomes included cerebral palsy; gross motor functional limitation; cognitive and language scores according to the Bayley Scales of Infant Development, 3rd Edition; and composite measures of neurodevelopmental impairment. Regression modeling evaluated the association of hemorrhage severity with adverse outcomes while controlling for potentially confounding variables and center differences.Low-grade hemorrhage was not associated with significant differences in unadjusted or adjusted risk of any adverse neurodevelopmental outcome compared with infants without hemorrhage. Compared with low-grade hemorrhage, severe hemorrhage was associated with decreased adjusted continuous cognitive (β, -3.91 [95% CI, -6.41 to -1.42]) and language (β, -3.19 [-6.19 to -0.19]) scores as well as increased odds of each adjusted categorical outcome except severe cognitive impairment (odds ratio [OR], 1.46 [0.74 to 2.88]) and mild language impairment (OR, 1.35 [0.88 to 2.06]).At 18 to 22 months, the neurodevelopmental outcomes of extremely low-gestational-age infants with low-grade periventricular-intraventricular hemorrhage are not significantly different from those without hemorrhage. Additional study at school age and beyond would be informative.

  View details for DOI 10.1001/jamapediatrics.2013.866

  View details for PubMedID 23460139

• Considering the vascular hypothesis for the pathogenesis of small intestinal atresia: A case control study of genetic factors AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gupta, T., Yang, W., Iovannisci, D. M., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Lammer, E. J. 2013; 161A (4): 702-710

  Abstract

  Small intestinal atresia (SIA) is a rare congenital occlusion of the small intestine. SIA development, particularly in the jejunum and ileum, has been associated with in utero disruption of vascular supply. However, the number of studies of the vascular hypothesis is limited. This study considers the vascular hypothesis by exploring risks associated with 32 SNPs of genes involved in vascular processes of homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. A total of 206 SIA cases were ascertained by the California Birth Defects Monitoring Program, and 573 infants with no major congenital anomalies by their first birthday were selected as controls. Genomic DNA was genotyped for 32 SNPs involving the following genes: MTHFR, F2, F5, F7, SERPINE1, FGB, ITGA2, ITGB3, SELE, ICAM1, MMP3, TNF, LTA, NOS3, AGTR1, AGT, NPPA, ADD1, SCNN1A, GNB3, and ADRB2. Risks were estimated as odds ratios, adjusted for maternal age and race, with 95% confidence intervals. Cases were considered collectively and by subgroups based on atresia location (duodenal/jejunum/ileum). Three SNPs had reduced risk: SERPINE1 11053 T/G, MMP3 (-1171) A6/A5, and ADRB2 gln27glu. Two had increased risk: ITGA2 873 G/A and NPPA 2238 T/C. No intestinal subphenotypes showed a unique pattern of SNP associations. The association of two SNPs with increased risk lends some, albeit limited, support to vascular impairment as a possible mechanism leading to SIA. These results also identify genes meriting further exploration in SIA studies. Hence, this study makes an important contribution by exploring the long-held but not well-investigated vascular hypothesis.

  View details for DOI 10.1002/ajmg.a.35775

  View details for Web of Science ID 000316631300012

• Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. journal of pediatrics Bhutani, V. K., Stark, A. R., Lazzeroni, L. C., Poland, R., Gourley, G. R., Kazmierczak, S., Meloy, L., Burgos, A. E., Hall, J. Y., Stevenson, D. K. 2013; 162 (3): 477-482 e1

  Abstract

  To test whether the combined use of total plasma/serum bilirubin (TSB) levels and clinical risk factors more accurately identifies infants who receive phototherapy than does the use of either method alone.We recruited healthy infants of ≥35 weeks' gestation at 6 centers that practiced universal predischarge TSB screening. Transcutaneous bilirubin (TcB) was measured at 24 hours, with TSB at 24-60 hours and at 3- to 5- and 7- to 14-day follow-up visits. Clinical risk factors were identified systematically.Of 1157 infants, 1060 (92%) completed follow-up, and 982 (85%) had complete datasets for analysis. Infant characteristics included 25% were nonwhite and 55% were Hispanic/Latino; >90% were breastfed. During the first week, jaundice was documented in 84% of subjects. Predischarge TSB identified the 41 (4.2%) and 34 (3.5%) infants who received phototherapy before and after discharge, respectively. Prediction of postdischarge phototherapy was similar for combined clinical risk factors (earlier gestational age [GA], bruising, positive direct antiglobulin test, Asian race, exclusive breastfeeding, blood type incompatibility, jaundice extent) and age-adjusted TSB (area under the curve [AUC] = .86 vs .87), but combined screening was better (AUC = .95). TcB/TSB combined with GA alone was equally predictive (AUC = .95; 95% CI .93-.97).Jaundice is present in 4 of 5 (84%) healthy newborns. Predischarge TcB/TSB (adjusted for postnatal age) combined with specific clinical factors (especially GA) best predicts subsequent phototherapy use. Universal implementation of this strategy in the US should improve outcomes of healthy newborns discharged early.

  View details for DOI 10.1016/j.jpeds.2012.08.022

  View details for PubMedID 23043681

• Efficacy of phototherapy devices and outcomes among extremely low birth weight infants: multi-center observational study JOURNAL OF PERINATOLOGY Morris, B. H., TYSON, J. E., Stevenson, D. K., Oh, W., Phelps, D. L., O'Shea, T. M., MCDAVID, G. E., Van Meurs, K. P., Vohr, B. R., Grisby, C., Yao, Q., Kandefer, S., Wallace, D., Higgins, R. D. 2013; 33 (2): 126-133

  Abstract

  Evaluate the efficacy of phototherapy (PT) devices and the outcomes of extremely premature infants treated with those devices.This substudy of the National Institute of Child Health and Human Development Neonatal Research Network PT trial included 1404 infants treated with a single type of PT device during the first 24±12 h of treatment. The absolute (primary outcome) and relative decrease in total serum bilirubin (TSB) and other measures were evaluated. For infants treated with one PT type during the 2-week intervention period (n=1223), adjusted outcomes at discharge and 18 to 22 months corrected age were determined.In the first 24 h, the adjusted absolute (mean (±s.d.)) and relative (%) decrease in TSB (mg dl(-1)) were: light-emitting diodes (LEDs) -2.2 (±3), -22%; Spotlights -1.7 (±2), -19%; Banks -1.3 (±3), -8%; Blankets -0.8 (±3), -1%; (P<0.0002). Some findings at 18 to 22 months differed between groups.LEDs achieved the greatest initial absolute reduction in TSB but were similar to Spots in the other performance measures. Long-term effects of PT devices in extremely premature infants deserve rigorous evaluation.

  View details for DOI 10.1038/jp.2012.39

  View details for Web of Science ID 000314434200008

  View details for PubMedID 22499082

  View details for PubMedCentralID PMC3570170

• High quality genome-wide genotyping from archived dried blood spots without DNA amplification. PloS one St Julien, K. R., Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., O'Brodovich, H. M., Krasnow, M. A. 2013; 8 (5)

  Abstract

  Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.

  View details for DOI 10.1371/journal.pone.0064710

  View details for PubMedID 23737996

• Integrating multiple 'omics' analyses identifies serological protein biomarkers for preeclampsia. BMC medicine Liu, L. Y., Yang, T., Ji, J., Wen, Q., Morgan, A. A., Jin, B., Chen, G., Lyell, D. J., Stevenson, D. K., Ling, X. B., Butte, A. J. 2013; 11: 236-?

  Abstract

  Preeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-'omics' based discovery approach.Seven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment.In addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively.Both early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE.

  View details for DOI 10.1186/1741-7015-11-236

  View details for PubMedID 24195779

• Transcriptomics and proteomics ensemble analyses reveal serological protein panel for preeclampsia diagnosis 33rd Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM) Liu, L., Cooper, M., Yang, T., Ji, J., Wen, Q., Chen, G., Morgan, A., Stevenson, D., Ling, X., Butte, A. MOSBY-ELSEVIER. 2013: S272–S272

  View details for Web of Science ID 000313393500640

• High Quality Genome-Wide Genotyping from Archived Dried Blood Spots without DNA Amplification. PloS one St Julien, K. R., Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., O'Brodovich, H. M., Krasnow, M. A. 2013; 8 (5): e64710

  Abstract

  Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.

  View details for DOI 10.1371/journal.pone.0064710

  View details for PubMedID 23737996

  View details for PubMedCentralID PMC3667813

• Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Shankaran, S., Barnes, P. D., Hintz, S. R., Laptook, A. R., Zaterka-Baxter, K. M., McDonald, S. A., Ehrenkranz, R. A., Walsh, M. C., Tyson, J. E., Donovan, E. F., Goldberg, R. N., Bara, R., Das, A., Finer, N. N., Sanchez, P. J., Poindexter, B. B., Van Meurs, K. P., Carlo, W. A., Stoll, B. J., Duara, S., Guillet, R., Higgins, R. D. 2012; 97 (6): F398-F404

  Abstract

  The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia.Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age.Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability.Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.

  View details for DOI 10.1136/archdischild-2011-301524

  View details for Web of Science ID 000311022800003

  View details for PubMedID 23080477

• Introductory address for the John Howland Award recipient, Philip A. Pizzo, MD PEDIATRIC RESEARCH Stevenson, D. K. 2012; 72 (3): 321-323

  View details for DOI 10.1038/pr.2012.82

  View details for PubMedID 22717691

• Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns? JOURNAL OF PERINATOLOGY Tyson, J. E., Pedroza, C., Langer, J., Green, C., Morris, B., Stevenson, D., Van Meurs, K. P., Oh, W., Phelps, D., O'Shea, M., MCDAVID, G. E., Grisby, C., Higgins, R. 2012; 32 (9): 677-684

  Abstract

  Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low-birth-weight (ELBW; ≤ 1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12 to 36 h. The effect of AgPT on outcomes (death, impairment, profound impairment, death or impairment (primary outcome), and death or profound impairment) at 18 to 22 months of corrected age was related to BW stratum (501 to 750 g; 751 to 1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.Baseline illness severity was well characterized using mechanical ventilation and FiO(2) at 24 h age. Among mechanically ventilated infants ≤ 750 g BW (n=684), a reduction in impairment and in profound impairment was offset by higher mortality (P for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.

  View details for DOI 10.1038/jp.2012.64

  View details for Web of Science ID 000308278000006

  View details for PubMedID 22652561

  View details for PubMedCentralID PMC3558278

• Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes JOURNAL OF PEDIATRICS Vohr, B. R., Stephens, B. E., Higgins, R. D., Bann, C. M., Hintz, S. R., Das, A., Newman, J. E., Peralta-Carcelen, M., Yolton, K., Dusick, A. M., Evans, P. W., Goldstein, R. F., Ehrenkranz, R. A., Pappas, A., Adams-Chapman, I., Wilson-Costello, D. E., Bauer, C. R., Bodnar, A., Heyne, R. J., Vaucher, Y. E., Dillard, R. G., Acarregui, M. J., McGowan, E. C., Myers, G. J., Fuller, J. 2012; 161 (2): 222-?

  Abstract

  To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development's Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006-2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008-2011 (period 2).Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates.Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001).Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.

  View details for DOI 10.1016/j.jpeds.2012.01.057

  View details for Web of Science ID 000306693800013

  View details for PubMedID 22421261

• Empiric Antifungal Therapy and Outcomes in Extremely Low Birth Weight Infants with Invasive Candidiasis JOURNAL OF PEDIATRICS Greenberg, R. G., Benjamin, D. K., Gantz, M. G., Cotten, C. M., Stoll, B. J., Walsh, M. C., Sanchez, P. J., Shankaran, S., Das, A., Higgins, R. D., Miller, N. A., Auten, K. J., Walsh, T. J., Laptook, A. R., Carlo, W. A., Kennedy, K. A., Finer, N. N., Duara, S., Schibler, K., Ehrenkranz, R. A., Van Meurs, K. P., Frantz, I. D., Phelps, D. L., Poindexter, B. B., Bell, E. F., O'Shea, T. M., Watterberg, K. L., Goldberg, R. N., Smith, P. B. 2012; 161 (2): 264-?

  Abstract

  To assess the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants.This was a cohort study of infants with a birth weight ≤ 1000 g receiving care at Neonatal Research Network sites. All infants had at least one positive culture for Candida. Empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of empiric antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).A total of 136 infants developed invasive candidiasis. The incidence of death or NDI was lower in infants who received empiric antifungal therapy (19 of 38; 50%) compared with those who had not (55 of 86; 64%; OR, 0.27; 95% CI, 0.08-0.86). There was no significant difference between the groups for any single outcome or other combined outcomes.Empiric antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.

  View details for DOI 10.1016/j.jpeds.2012.01.053

  View details for Web of Science ID 000306693800020

  View details for PubMedID 22424952

  View details for PubMedCentralID PMC3380169

• Feasibility Study of Early Blood Pressure Management in Extremely Preterm Infants JOURNAL OF PEDIATRICS Batton, B. J., Li, L., Newman, N. S., Das, A., Watterberg, K. L., Yoder, B. A., Faix, R. G., Laughon, M. M., Van Meurs, K. P., Carlo, W. A., Higgins, R. D., Walsh, M. C. 2012; 161 (1): 65-?

  Abstract

  To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.This was a prospective pilot RCT of infants 23-0/7 to 26-6/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. A total of 161 infants (44%) were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study because of the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.This pilot RCT was not feasible because of low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.

  View details for DOI 10.1016/j.jpeds.2012.01.014

  View details for Web of Science ID 000305753700016

  View details for PubMedID 22336574

  View details for PubMedCentralID PMC3357442

• Childhood Outcomes after Hypothermia for Neonatal Encephalopathy NEW ENGLAND JOURNAL OF MEDICINE Shankaran, S., Pappas, A., McDonald, S. A., Vohr, B. R., Hintz, S. R., Epi, M. S., Yolton, K., Gustafson, K. E., Leach, T. M., Green, C., Bara, R., Huitema, C. M., Ehrenkranz, R. A., Tyson, J. E., Das, A., Hammond, J., Peralta-Carcelen, M., Evans, P. W., Heyne, R. J., Wilson-Costello, D. E., Vaucher, Y. E., Bauer, C. R., Dusick, A. M., Adams-Chapman, I., Goldstein, R. F., Guillet, R., Papile, L., Higgins, R. D. 2012; 366 (22): 2085-2092

  Abstract

  We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available.In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70.Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P=0.87). Attention-executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P=0.19), and visuospatial dysfunction occurred in 4% and 3% (P=0.80).The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.).

  View details for DOI 10.1056/NEJMoa1112066

  View details for Web of Science ID 000304613400008

  View details for PubMedID 22646631

  View details for PubMedCentralID PMC3459579

• Risk of bronchopulmonary dysplasia by second-trimester maternal serum levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol PEDIATRIC RESEARCH Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., Oehlert, J. W., Quaintance, C., Santos, A. J., Baer, R. J., Currier, R. J., O'Brodovich, H. M., Gould, J. B. 2012; 71 (4): 399-406

  Abstract

  Although maternal serum α-fetoprotein (AFP), human chorionic gonandotropin (hCG), and estriol play important roles in immunomodulation and immunoregulation during pregnancy, their relationship with the development of bronchopulmonary dysplasia (BPD) in young infants is unknown despite BPD being associated with pre- and postnatal inflammatory factors.We found that these serum biomarkers were associated with an increased risk of BPD. Risks were especially high when AFP and/or hCG levels were above the 95th percentile and/or when unconjugated estriol (uE3) levels were below the 5th percentile (relative risks (RRs) 3.1-6.7). Risks increased substantially when two or more biomarker risks were present (RRs 9.9-75.9).Data suggested that pregnancies that had a biomarker risk and yielded an offspring with BPD were more likely to have other factors present that suggested early intrauterine fetal adaptation to stress, including maternal hypertension and asymmetric growth restriction.The objective of this population-based study was to examine whether second-trimester levels of AFP, hCG, and uE3 were associated with an increased risk of BPD.

  View details for DOI 10.1038/pr.2011.73

  View details for Web of Science ID 000301884500013

  View details for PubMedID 22391642

  View details for PubMedCentralID PMC3616500

• Metalloporphyrins - an update FRONTIERS IN PHARMACOLOGY Schulz, S., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2012; 3

  Abstract

  Metalloporphyrins are structural analogs of heme and their potential use in the management of neonatal hyperbilirubinemia has been the subject of considerable research for more than three decades. The pharmacological basis for using this class of compounds to control bilirubin levels is the targeted blockade of bilirubin production through the competitive inhibition of heme oxygenase (HO), the rate-limiting enzyme in the bilirubin production pathway. Ongoing research continues in the pursuit of identifying ideal metalloporphyrins, which are safe and effective, by defining therapeutic windows and targeted interventions for the treatment of excessive neonatal hyperbilirubinemia.

  View details for DOI 10.3389/fphar.2012.00068

  View details for Web of Science ID 000209177700066

  View details for PubMedCentralID PMC3337460

• EFFECT OF A LOW DOSE OF ZINC DEUTEROPORPHYRIN BIS GLYCOL IN INHIBITING HEME OXYGENASE ACTIVITY AFTER HEME-LOADING Katayama, Y., Kalish, F. S., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2012: 210

  View details for Web of Science ID 000298634401301

• CONSIDERING A VASCULAR PATHOGENESIS OF SMALL INTESTINAL ATRESIA: RISKS ASSOCIATED WITH 32 SINGLE NUCLEOTIDE POLYMORPHISMS INVOLVED IN HOMOCYSTEINE METABOLISM, COAGULATION, CELL-CELL INTERACTIONS, INFLAMMATORY RESPONSE, AND BLOOD PRESSURE REGULATION Gupta, T., Yang, W., Iovannisci, D. M., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Lammer, E. J. LIPPINCOTT WILLIAMS & WILKINS. 2012: 202

  View details for Web of Science ID 000298634401271

• HEME OXYGENASE-1 DEFICIENCY PROMOTES NECROTIZING ENTEROCOLITIS DEVELOPMENT IN A MURINE MOUSE MODEL Western Regional Meeting of the American-Federation-for-Medical-Research Schulz, S., Jang, K., Kalish, F. S., Zhao, H., Vreman, H. J., Sylvester, K. S., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2012: 158–58

  View details for Web of Science ID 000298634401114

• IN VITRO BILIRUBIN PHOTODESTRUCTION ACTION SPECTRUM REVISITED Western Regional Meeting of the American-Federation-for-Medical-Research Schulz, S., Vreman, H. J., Wong, R. J., Cline, B., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2012: 210–10

  View details for Web of Science ID 000298634401302

• The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants PEDIATRIC RESEARCH Lasky, R. E., Church, M. W., Orlando, M. S., Morris, B. H., Parikh, N. A., Tyson, J. E., McDavid, G. E., Oh, W., Stevenson, D. K., Van Meurs, K. P., Guillet, R., Phelps, D. L. 2012; 71 (1): 77-84

  Abstract

  This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g).BAER latencies of 751-1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501-750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results.The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management.Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.

  View details for DOI 10.1038/pr.2011.17

  View details for Web of Science ID 000303453600012

  View details for PubMedID 22289854

  View details for PubMedCentralID PMC3326602

• Association of Antenatal Corticosteroids With Mortality and Neurodevelopmental Outcomes Among Infants Born at 22 to 25 Weeks' Gestation JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Carlo, W. A., McDonald, S. A., Fanaroff, A. A., Vohr, B. R., Stoll, B. J., Ehrenkranz, R. A., Andrews, W. W., Wallace, D., Das, A., Bell, E. F., Walsh, M. C., Laptook, A. R., Shankaran, S., Poindexter, B. B., Hale, E. C., Newman, N. S., Davis, A. S., Schibler, K., Kennedy, K. A., Sanchez, P. J., Van Meurs, K. P., Goldberg, R. N., Watterberg, K. L., Faix, R. G., Frantz, I. D., Higgins, R. D. 2011; 306 (21): 2348-2358

  Abstract

  Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24 to 34 weeks' gestational age, but not before 24 weeks due to lack of data. However, many infants born before 24 weeks' gestation are provided intensive care.To determine if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation.Cohort study of data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N = 10,541) born at 22 to 25 weeks' gestation between January 1, 1993, and December 31, 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Logistic regression models generated adjusted odds ratios (AORs), controlling for maternal and neonatal variables.Mortality and neurodevelopmental impairment at 18 to 22 months' corrected age.Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97]).Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months.

  View details for Web of Science ID 000297680300020

  View details for PubMedID 22147379

• Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants JOURNAL OF PEDIATRICS Carlo, W. A., McDonald, S. A., Tyson, J. E., Stoll, B. J., Ehrenkranz, R. A., Shankaran, S., Goldberg, R. N., Das, A., Schendel, D., Thorsen, P., Skogstrand, K., Hougaard, D. M., Oh, W., Laptook, A. R., Duara, S., Fanaroff, A. A., Donovan, E. F., Korones, S. B., Stevenson, D. K., Papile, L., Finer, N. N., O'Shea, T. M., Poindexter, B. B., Wright, L. L., Ambalavanan, N., Higgins, R. D. 2011; 159 (6): 919-U77

  Abstract

  To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants.Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1β; IL-8; tumor necrosis factor-α; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants.IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-β, soluble IL rα, macrophage inflammatory protein 1β) were found to be altered on days 0-4 in infants who developed CP.CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.

  View details for DOI 10.1016/j.jpeds.2011.05.042

  View details for Web of Science ID 000296849400010

  View details for PubMedID 21798559

  View details for PubMedCentralID PMC3215787

• Predictive Value of an Early Amplitude Integrated Electroencephalogram and Neurologic Examination PEDIATRICS Shankaran, S., Pappas, A., McDonald, S. A., Laptook, A. R., Bara, R., Ehrenkranz, R. A., Tyson, J. E., Goldberg, R., Donovan, E. F., Fanaroff, A. A., Das, A., Poole, W. K., Walsh, M., Higgins, R. D., Welsh, C., Salhab, W., Carlo, W. A., Poindexter, B., Stoll, B. J., Guillet, R., Finer, N. N., Stevenson, D. K., Bauer, C. R. 2011; 128 (1): E112-E120

  Abstract

  To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia.Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19).The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.

  View details for DOI 10.1542/peds.2010-2036

  View details for Web of Science ID 000292299500015

  View details for PubMedID 21669899

  View details for PubMedCentralID PMC3124102

• Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Laughon, M. M., Langer, J. C., Bose, C. L., Smith, P. B., Ambalavanan, N., Kennedy, K. A., Stoll, B. J., Buchter, S., Laptook, A. R., Ehrenkranz, R. A., Cotten, C. M., Wilson-Costello, D. E., Shankaran, S., Van Meurs, K. P., Davis, A. S., Gantz, M. G., Finer, N. N., Yoder, B. A., Faix, R. G., Carlo, W. A., Schibler, K. R., Newman, N. S., Rich, W., Das, A., Higgins, R. D., Walsh, M. C. 2011; 183 (12): 1715-1722

  Abstract

  Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.We assessed infants of 23-30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000-2004.Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and Fi(O(2)), and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.

  View details for DOI 10.1164/rccm.201101-0055OC

  View details for Web of Science ID 000292305600024

  View details for PubMedID 21471086

  View details for PubMedCentralID PMC3136997

• The Need for Technologies to Prevent Bilirubin-Induced Neurologic Dysfunction Syndrome SEMINARS IN PERINATOLOGY Bhutani, V. K., Stevenson, D. K. 2011; 35 (3): 97-100

  Abstract

  Dramatic improvements in the overall socioeconomic conditions have yet to impact the unacceptably high maternal (approximately 1500 maternal deaths daily, worldwide) and neonatal morbidity and mortality (more than 10,000 deaths per daily 200,000 live-births, worldwide) in the developing nations. Thus, nations with emerging markets have unique health-societal needs. All infants require a safer transition from a birthing facility to home during the first week after birth and providing for a nurturing environment to prevent neonatal illnesses is integral to "good clinical practice." The unmonitored occurrence of severe hyperbilirubinemia and kernicterus are emblematic of a fractured maternal child healthcare system. The "know-do" gaps that span private versus public health care systems in the emerging markets have led us to conclude that building an interdisciplinary leadership approach to provide innovative strategies and affordable technologies will help bridge and access existing social barriers in the micro- and macro-health environments. Thus, unfettered access, global benchmarks, and culturally relevant strategies are dependent on evidence-based affordable technologies to successfully transform societal health care practices. Implementation of jaundice-related technologies should serve as a template for other affordable newborn health products.

  View details for DOI 10.1053/j.semperi.2011.02.002

  View details for PubMedID 21641481

• Heme Oxygenase-1 Deletion Affects Stress Erythropoiesis PLOS ONE Cao, Y., Kusy, S., Luong, R., Wong, R. J., Stevenson, D. K., Contag, C. H. 2011; 6 (5)

  Abstract

  Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-α. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

  View details for DOI 10.1371/journal.pone.0020634

  View details for PubMedID 21655188

• Quantitating carbon monoxide production from heme by vascular plant preparations in vitro PLANT PHYSIOLOGY AND BIOCHEMISTRY Vreman, H. J., Wong, R. J., Stevenson, D. K. 2011; 49 (1): 61-68

  Abstract

  Heme in animals is mainly degraded enzymatically, producing a predictable amount of carbon monoxide (CO). Under some conditions, alternative sources of CO production are important, such as lipid peroxidation and photo-oxidation. Less is known about CO production in plants as a reflection of enzymatic activity or coupled oxidation, but a sensitive assay for CO production in plants would be a valuable tool to explore the various sources in plants as the conditions of the reactions and mechanisms are defined. Using gas chromatography, we determined the requirements for heme-supported in vitro CO generation by exogenous reactants (NADPH, tissue supernatant, oxygen), optimum reaction conditions (time, temperature, pH, light), and effects of various cofactors and substrates using supernatants from Spinacia oleracea (spinach) leaf and Solanum tuberosa (potato) tuber homogenates. We then determined the CO production rate distribution between organ (root, stem, leaf, flower, fruit) supernatants in a number of commercially available plant species. CO production ranged from 4-65 nmol CO/h/g fresh weight and occurred in all vascular plant tissues examined, with the highest rates in chloroplast-containing tissues. In spinach leaves, CO production was concentrated (>2-fold) in the particulate fraction, whereas in potato tubers, the particulate fraction accounted for <50% of the rates in homogenates. We conclude that gas chromatography is uniquely suited for the determination of CO production in pigmented, heterogeneous plant tissue preparations.

  View details for DOI 10.1016/j.plaphy.2010.09.021

  View details for PubMedID 21055958

• Early-Childhood Neurodevelopmental Outcomes Are Not Improving for Infants Born at < 25 Weeks' Gestational Age PEDIATRICS Hintz, S. R., Kendrick, D. E., Wilson-Costello, D. E., Das, A., Bell, E. F., Vohr, B. R., Higgins, R. D. 2011; 127 (1): 62-70

  Abstract

  We compared neurodevelopmental outcomes at 18 to 22 months' corrected age of infants born with extremely low birth weight at an estimated gestational age of <25 weeks during 2 periods: 1999-2001 (epoch 1) and 2002-2004 (epoch 2).We conducted a multicenter, retrospective analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Perinatal and neonatal variables and outcomes were compared between epochs. Neurodevelopmental outcomes at 18 to 22 months' corrected age were evaluated with neurologic exams and Bayley Scales of Infant Development II. Logistic regression analyses determined the independent risk of epoch for adverse outcomes.Infant survival was similar between epochs (epoch 1, 35.4%, vs epoch 2, 32.3%; P = .09). A total of 411 of 452 surviving infants in epoch 1 and 405 of 438 surviving infants in epoch 2 were evaluated at 18 to 22 months' corrected age. Cesarean delivery (P = .03), surgery for patent ductus arteriosus (P = .004), and late sepsis (P = .01) were more common in epoch 2, but postnatal steroid use was dramatically reduced (63.5% vs 32.8%; P < .0001). Adverse outcomes at 18 to 22 months' corrected age were common in both epochs. Moderate-to-severe cerebral palsy was diagnosed in 11.1% of surviving infants in epoch 1 and 14.9% in epoch 2 (adjusted odds ratio [OR]: 1.52 [95% confidence interval (CI): 0.86-2.71]; P = .15), the Mental Developmental Index was <70 in 44.9% in epoch 1 and 51% in epoch 2 (OR: 1.30 [95% CI: 0.91-1.87]; P = .15), and neurodevelopmental impairment was diagnosed in 50.1% of surviving infants in epoch 1 and 58.7% in epoch 2 (OR: 1.4 [95% CI: 0.98-2.04]; P = .07).Early-childhood outcomes for infants born at <25 weeks' estimated gestational age were unchanged between the 2 periods.

  View details for DOI 10.1542/peds.2010-1150

  View details for PubMedID 21187312

• HEME OXYGENASE-1 DEFICIENCY IMPAIRS PLACENTAL VASCULAR FORMATION AND EMBRYONIC DEVELOPMENT Zhao, H., Azuma, J., Kalish, F. S., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 167

  View details for Web of Science ID 000285542500299

• HEME OXYGENASE-1 IS PROTECTIVE IN AN EXPERIMENTAL MODEL OF ABDOMINAL AORTIC ANEURYSM Azuma, J., Wong, R. J., Maegdefessel, L., Zhao, H., Kalish, F. S., Deng, A., Stevenson, D. K., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2011: 150

  View details for Web of Science ID 000285542500236

• THE INHIBITORY POTENCY OF LOW DOSES OF ZINC DEUTEROPORPHYRIN BIS GLYCOL ON HEME OXYGENASE ACTIVITY IN 3-DAY-OLD MICE Western Regional Meeting of the American-Federation-for-Medical-Research Katayama, Y., Shaw, N., Yaffe, Z. A., He, C. X., Kalish, F. S., Schulz-Geske, S., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 170–70

  View details for Web of Science ID 000285542500310

• HEME OXYGENASE-1 EXPRESSION IS DIFFERENTIALLY REGULATED IN VITRO BY METALLOPORPHYRINS Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Zhao, H., Kalish, F. S., McCarthy, E., Vreman, H. J., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 196–96

  View details for Web of Science ID 000285542500399

• EFFECT OF FLUORESCENT LIGHT EXPOSURE ON METALLOPORHYRIN-TREATED NEWBORN MICE Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Kalish, F. S., Zhao, H., Katayama, Y., Champion, K. A., Vreman, H. J., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 126–26

  View details for Web of Science ID 000285542500152

• ROLE OF IIEME OXYGENASE IN A MURINE MODEL OF EARLY NECROTIZING ENTEROCOLITIS Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Kalish, F. S., Jang, K. Y., Zhao, H., Huey, M., Vreman, H. J., Sylvester, K. S., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 126–27

  View details for Web of Science ID 000285542500153

• Beneficial Effects of Heme Oxygenase-1 Expression and Activity in Experimental Abdominal Aortic Aneurysm Azuma, J., Wong, R., Maegdefessel, L., Zhao, H., Deng, A., Stevenson, D. K., Tsao, P. S., Kalish, F. S. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231600755

• Hemolysis and Hyperbilirubinemia in Antiglobulin Positive, Direct ABO Blood Group Heterospecific Neonates JOURNAL OF PEDIATRICS Kaplan, M., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2010; 157 (5): 772-777

  Abstract

  We quantified hemolysis and determined the incidence of hyperbilirubinemia in neonates who were direct antiglobulin titer (DAT)-positive, ABO heterospecific, and compared variables among O-A and O-B subgroups.Plasma total bilirubin (PTB) was determined before the neonates were discharged from the hospital and more frequently when clinically warranted, in neonates who were DAT positive with blood group A or B and with mothers who had blood group O. Heme catabolism (and therefore bilirubin production) was indexed by blood carboxyhemoglobin corrected for inspired carbon monoxide (COHbc). Hyperbilirubinemia was defined as any PTB concentration >95th percentile on the hour-of-life-specific bilirubin nomogram.Of 164 neonates, 111 were O-A and 53 O-B. Overall, hyperbilirubinemia developed 85 neonates (51.8%), and it tended to be more prevalent in the O-B neonates than O-A neonates (62.3% versus 46.8%; P = .053). Hyperbilirubinemia developed in more O-B newborns than O-A newborns at <24 hours (93.9% versus 48.1%; P< .0001). COHbc values were globally higher than our previously published newborn values. Babies in whom hyperbilirubinemia developed had higher COHbc values than the already high values of babies who were non-hyperbilirubinemic, and O-B newborns tended to have higher values than their O-A counterparts.DAT-positive, ABO heterospecificity is associated with increased hemolysis and a high incidence of neonatal hyperbilirubinemia. O-B heterospecificity tends to confer even higher risk than O-A counterparts.

  View details for DOI 10.1016/j.jpeds.2010.05.024

  View details for Web of Science ID 000283045900020

  View details for PubMedID 20598320

  View details for PubMedCentralID PMC2951500

• Seizures in Extremely Low Birth Weight Infants Are Associated with Adverse Outcome JOURNAL OF PEDIATRICS Davis, A. S., Hintz, S. R., Van Meurs, K. P., Li, L., Das, A., Stoll, B. J., Walsh, M. C., Pappas, A., Bell, E. F., Laptook, A. R., Higgins, R. D. 2010; 157 (5): 720-U47

  Abstract

  To examine risk factors for neonatal clinical seizures and to determine the independent association with death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.A total of 6499 ELBW infants (401-1000 g) surviving to 36 weeks postmenstrual age (PMA) were included in this retrospective study. Unadjusted comparisons were performed between infants with (n = 414) and without (n = 6085) clinical seizures during the initial hospitalization. Using multivariate logistic regression modeling, we examined the independent association of seizures with late death (after 36 weeks PMA) or NDI after controlling for multiple demographic, perinatal, and neonatal variables.Infants with clinical seizures had a greater proportion of neonatal morbidities associated with poor outcome, including severe intraventricular hemorrhage, sepsis, meningitis, and cystic periventricular leukomalacia (all P < .01). Survivors were more likely to have NDI or moderate-severe cerebral palsy at 18 to 22 months corrected age (both P < .01). After adjusting for multiple confounders, clinical seizures remained significantly associated with late death or NDI (odds ratio, 3.15; 95% CI, 2.37-4.19).ELBW infants with clinical seizures are at increased risk for adverse neurodevelopmental outcome, independent of multiple confounding factors.

  View details for DOI 10.1016/j.jpeds.2010.04.065

  View details for PubMedID 20542294

• Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical Judgment PEDIATRICS Benjamin, D. K., Stoll, B. J., Gantz, M. G., Walsh, M. C., Sanchez, P. J., Das, A., Shankaran, S., Higgins, R. D., Auten, K. J., Miller, N. A., Walsh, T. J., Laptook, A. R., Carlo, W. A., Kennedy, K. A., Finer, N. N., Duara, S., Schibler, K., Chapman, R. L., Van Meurs, K. P., Frantz, I. D., Phelps, D. L., Poindexter, B. B., Bell, E. F., O'Shea, T. M., Watterberg, K. L., Goldberg, R. N. 2010; 126 (4): E865-E873

  Abstract

  Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low birth weight (<1000-g) infants. We quantified risk factors that predict infection in premature infants at high risk and compared clinical judgment with a prediction model of invasive candidiasis.The study involved a prospective observational cohort of infants≤1000 g birth weight at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures were obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: (1) potentially modifiable risk factors; and (2) a clinical model at time of blood culture to predict candidiasis.Invasive candidiasis occurred in 137 of 1515 (9.0%) infants and was documented by positive culture from ≥1 of these sources: blood (n=96); cerebrospinal fluid (n=9); urine obtained by catheterization (n=52); or other sterile body fluid (n=10). Mortality rate was not different for infants who had positive blood culture compared with those with isolated positive urine culture. Incidence of candida varied from 2% to 28% at the 13 centers that enrolled≥50 infants. Potentially modifiable risk factors included central catheter, broad-spectrum antibiotics (eg, third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model had an area under the receiver operating characteristic curve of 0.79 and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis.Previous antibiotics, presence of a central catheter or endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.

  View details for DOI 10.1542/peds.2009-3412

  View details for Web of Science ID 000282526100014

  View details for PubMedID 20876174

  View details for PubMedCentralID PMC3045840

• Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network PEDIATRICS Stoll, B. J., Hansen, N. I., Bell, E. F., Shankaran, S., Laptook, A. R., Walsh, M. C., Hale, E. C., Newman, N. S., Schibler, K., Carlo, W. A., Kennedy, K. A., Poindexter, B. B., Finer, N. N., Ehrenkranz, R. A., Duara, S., Sanchez, P. J., O'Shea, T. M., Goldberg, R. N., Van Meurs, K. P., Faix, R. G., Phelps, D. L., Frantz, I. D., Watterberg, K. L., Saha, S., Das, A., Higgins, R. D. 2010; 126 (3): 443-456

  Abstract

  This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at or=24 weeks survive, high rates of morbidity among survivors continue to be observed.

  View details for DOI 10.1542/peds.2009-2959

  View details for Web of Science ID 000281535700006

  View details for PubMedID 20732945

  View details for PubMedCentralID PMC2982806

• Impact of Timing of Birth and Resident Duty-Hour Restrictions on Outcomes for Small Preterm Infants PEDIATRICS Bell, E. F., Hansen, N. I., Morriss, F. H., Stoll, B. J., Ambalavanan, N., Gould, J. B., Laptook, A. R., Walsh, M. C., Carlo, W. A., Shankaran, S., Das, A., Higgins, R. D. 2010; 126 (2): 222-231

  Abstract

  The goal was to examine the impact of birth at night, on the weekend, and during July or August (the first months of the academic year) and the impact of resident duty-hour restrictions on mortality and morbidity rates for very low birth weight infants.Outcomes were analyzed for 11,137 infants with birth weights of 501 to 1250 g who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network registry in 2001-2005. Approximately one-half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessments at 18 to 22 months were completed for 4508 infants. Mortality rate, short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth.There was no effect of the timing of birth on mortality rate and no impact on the risks of short-term morbidities except that the risk of retinopathy of prematurity (stage > or =2) was higher after the introduction of duty-hour restrictions and the risk of retinopathy of prematurity requiring operative treatment was lower for infants born during the late night than during the day. There was no impact of the timing of birth on neurodevelopmental outcome except that the risk of hearing impairment or death was slightly lower among infants born in July or August.In this network, the timing of birth had little effect on the risks of death and morbidity for very low birth weight infants, which suggests that staffing patterns were adequate to provide consistent care.

  View details for DOI 10.1542/peds.2010-0456

  View details for Web of Science ID 000280565700005

  View details for PubMedID 20643715

• Heptavalent Pneumococcal Conjugate Vaccine Immunogenicity in Very-Low-Birth-Weight, Premature Infants PEDIATRIC INFECTIOUS DISEASE JOURNAL D'Angio, C. T., Heyne, R. J., O'Shea, T. M., Schelonka, R. L., Shankaran, S., Duara, S., Goldberg, R. N., Stoll, B. J., Van Meurs, K. P., Vohr, B. R., Das, A., Li, L., Burton, R. L., Hastings, B., Phelps, D. L., Sanchez, P. J., Carlo, W. A., Stevenson, D. K., Higgins, R. D. 2010; 29 (7): 600-606

  Abstract

  The heptavalent pneumococcal CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (< or =1500 g) infants.To assess PCV-7 immunogenicity in very-low-birth-weight, premature infants. We hypothesized that the frequency of postvaccine antibody concentrations > or =0.15 microg/mL would vary directly with birth weight.This was a multicenter observational study. Infants 401 to 1500 g birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 National Institute of Child Health and Human Development Neonatal Research Network centers. Infants received PCV-7 at 2, 4, and 6 months after birth and had blood drawn 4 to 6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay.Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 +/- 2.2 (mean +/- standard deviation) weeks gestation and 1008 +/- 282 g birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001 to 1500 g birth weight were more likely than those 401 to 1000 g to achieve antibody concentrations > or =0.15 microg/mL against the least 2 immunogenic serotypes (6B: 96% vs. 85%, P = 0.003 and 23F: 97% vs. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw, and Caucasian race were each independently associated with antibody concentrations <0.35 microg/mL against serotypes 6B and/or 23F.When compared with larger premature infants, infants weighing < or =1000 g at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes.

  View details for DOI 10.1097/INF.0b013e3181d264a6

  View details for Web of Science ID 000279348900004

  View details for PubMedID 20234331

  View details for PubMedCentralID PMC2949965

• Target Ranges of Oxygen Saturation in Extremely Preterm Infants. NEW ENGLAND JOURNAL OF MEDICINE Carlo, W. A., Finer, N. N., Walsh, M. C., Rich, W., Gantz, M. G., Laptook, A. R., Yoder, B. A., Faix, R. G., Das, A., Poole, W. K., Schibler, K., Newman, N. S., Ambalavanan, N., Frantz, I. D., Piazza, A. J., Sanchez, P. J., Morris, B. H., Laroia, N., Phelps, D. L., Poindexter, B. B., Cotten, C. M., Van Meurs, K. P., Duara, S., Narendran, V., Sood, B. G., O'Shea, T. M., Bell, E. F., Ehrenkranz, R. A., Watterberg, K. L., Higgins, R. D., Jobe, A. H., Caplan, M. S., Oh, W., Hensman, A. M., Gingras, D., Barnett, S., LILLIE, S., Francis, K., Andrews, D., Angela, K., Fanaroff, A. A., SINER, B. S., Zadell, A., DiFiore, J., Donovan, E. F., Bridges, K., Alexander, B., Grisby, C., Mersmann, M. W., Mincey, H. L., Hessling, J., Goldberg, R. N., Auten, K. J., Fisher, K. A., Foy, K. A., Siaw, G., Stoll, B. J., Buchter, S., Carlton, D. P., HALE, E. C., Hutchinson, A. K., Archer, S. W., Lemons, J. A., HAMER, F., Herron, D. E., Miller, L. C., Wilson, L. D., Berberich, M. A., Blaisdell, C. J., Gail, D. B., Kiley, J. P., Cunningham, M., Hastings, B. K., Irene, A. R., Auman, J. O., Huitema, C. P., Pickett, J. W., Wallace, D., Zaterka-Baxter, K. M., Stevenson, D. K., Ball, M. B., Proud, M. S., Fiascone, J. M., Furey, A., MacKinnon, B. L., Nylen, E., Collins, M. V., Cosby, S. S., Phillips, V. A., Rasmussen, M. R., Wozniak, P. R., Arnell, K., Bridge, R., Demetrio, C., Widness, J. A., Klein, J. M., Johnson, K. J., Everett-Thomas, R., Ohls, R. K., Rohr, J., Lacy, C. B., Markowitz, G. D., Reubens, L. J., BURNELL, E., Rosenfeld, C. R., Salhab, W. A., Guzman, A., Hensley, G., Lepps, M. H., Miller, N. A., Allen, J., Grau, L., Martin, M., Solis, A., Vasil, D. M., Wilder, K., Kennedy, K. A., TYSON, J. E., HARRIS, B. F., Lis, A. E., Martin, S., MCDAVID, G. E., Tate, P. L., Wright, S. L., Burnett, J., Jensen, J. J., Osborne, K. A., Spencer, C., Weaver-Lewis, K., Peters, N. J., Shankaran, S., Bara, R., Billian, E., Johnson, M., Bhandari, V., Jacobs, H. C., Cervone, P., Gettner, P., Konstantino, M., Poulsen, J., Taft, J., Avery, G., Gleason, C. A., Allen, M. C., Bangdiwala, S. I., Blaisdell, C. J., Boyle, R. J., Clemons, T., D'Alton, M. E., Das, A., Gail, D. B., Hunt, C., Keszler, M., Poole, W. K., Redmond, C. K., Ross, M. G., Thomson, M. A., WEINER, S. J., Willinger, M., Markowitz, G. D., Hutchinson, A. K., Wallace, D. K., Freedman, S. F. 2010; 362 (21): 1959-1969

  Abstract

  Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes.We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant.The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events.A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)

  View details for DOI 10.1056/NEJMoa0911781

  View details for Web of Science ID 000278054000004

  View details for PubMedID 20472937

  View details for PubMedCentralID PMC2891970

• Early CPAP versus Surfactant in Extremely Preterm Infants. NEW ENGLAND JOURNAL OF MEDICINE Finer, N. N., Carlo, W. A., Walsh, M. C., Rich, W., Gantz, M. G., Laptook, A. R., Yoder, B. A., Faix, R. G., Das, A., Poole, W. K., Donovan, E. F., Newman, N. S., Ambalavanan, N., Frantz, I. D., Buchter, S., Sanchez, P. J., Kennedy, K. A., Laroia, N., Poindexter, B. B., Cotten, C. M., Van Meurs, K. P., Duara, S., Narendran, V., Sood, B. G., O'Shea, T. M., Bell, E. F., Bhandari, V., Watterberg, K. L., Higgins, R. D. 2010; 362 (21): 1970-1979

  Abstract

  There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants.We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen).A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups.The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

  View details for Web of Science ID 000278054000005

  View details for PubMedID 20472939

  View details for PubMedCentralID PMC3071534

• Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants ACTA PAEDIATRICA Oh, W., Stevenson, D. K., TYSON, J. E., Morris, B. H., Ahlfors, C. E., Bender, G. J., Wong, R. J., Perritt, R., Vohr, B. R., Van Meurs, K. P., Vreman, H. J., Das, A., Phelps, D. L., O'Shea, T. M., Higgins, R. D. 2010; 99 (5): 673-678

  Abstract

  To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18-22 months corrected age in extremely low birth weight infants.Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 +/- 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18-22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. CONCLUSIONs: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18-22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.

  View details for DOI 10.1111/j.1651-2227.2010.01688.x

  View details for Web of Science ID 000276034800011

  View details for PubMedID 20105142

  View details for PubMedCentralID PMC2875328

• Perinatal Systemic Inflammatory Response Syndrome and Retinopathy of Prematurity PEDIATRIC RESEARCH Sood, B. G., Madan, A., Saha, S., Schendel, D., Thorsen, P., Skogstrand, K., Hougaard, D., Shankaran, S., Carlo, W., NICHD Neonatal Res Network 2010; 67 (4): 394–400

  Abstract

  Fetal and neonatal inflammation is associated with several morbidities of prematurity. Its relationship to retinopathy of prematurity (ROP) has not been investigated. Our objective was to determine the relationship between cytokine levels and ROP in the first 3 postnatal wks. Data for this study were derived from the NICHD Cytokine Study. Dried blood spots (DBS) were obtained from infants <1000 g on days 0-1, 3 +/- 1, 7 +/- 2, 14 +/- 3, and 21 +/- 3. Infants were classified into three groups-no, mild, and severe ROP. Multiplex Luminex assay was used to quantify 20 cytokines. Temporal profiles of cytokines were evaluated using mixed-effects models after controlling for covariates. Of 1074 infants enrolled, 890 were examined for ROP and 877 included in the analysis. ROP was associated with several clinical characteristics on unadjusted analyses. Eight cytokines remained significantly different across ROP groups in adjusted analyses. IL-6 and IL-17 showed significant effects in early time periods (D0-3); TGF-beta, brain-derived neurotrophic factor (BDNF), and regulated on activation, normal T cell expressed and secreted (RANTES) in later time periods (D7-21) and IL-18, C-reactive protein (CRP), and neurotrophin-4 (NT-4) in both early and later time periods. We conclude that perinatal inflammation may be involved in the pathogenesis of ROP.

  View details for DOI 10.1203/PDR.0b013e3181d01a36

  View details for Web of Science ID 000275881600011

  View details for PubMedID 20032809

  View details for PubMedCentralID PMC2873779

• ELEVATED EXHALED CARBON MONOXIDE CONCENTRATION IN HEMOGLOBINOPATHIES AND ITS RELATION TO RED BLOOD CELL TRANSFUSION THERAPY PEDIATRIC HEMATOLOGY AND ONCOLOGY James, E. B., Vreman, H. J., Wong, R. J., Stevenson, D. K., Vichinsky, E., Schumacher, L., Hall, J. Y., Simon, J., Golden, D. W., Harmatz, P. 2010; 27 (2): 112-121

  Abstract

  In this study, the authors examined a possible role of measurements of end-tidal carbon monoxide (CO), corrected for inhaled CO (ETCOc), as a noninvasive screening tool for hemoglobinopathies and as an indicator for when transfusions would be required in patients receiving chronic transfusions. ETCOc measurements were obtained in subjects with sickle cell disease (n = 18), thalassemia (n = 21), and healthy controls (n = 62). ETCOc values less than 3 parts per million (ppm) yielded a positive predictive value of 93% and negative predictive value of 94% in identifying hemoglobinopathies. Subsequently, 7 subjects with thalassemia had laboratory parameters and ETCOc measured over 2 transfusion cycles. ETCOc values were 4.90 +/- 0.32 ppm (mean +/- SD), with 89% of values being above normal (>or=3 ppm). Pretransfusion ETCOc levels significantly correlated with pretransfusion reticulocyte count (r = .96, P <.001), but not with pretransfusion hemoglobin (r = .44, P = .16) or pretransfusion soluble transferrin receptors (sTfR, r = .52, P = .10). In conclusion, we found that patients with hemoglobinopathies have ETCOc values above the range for healthy controls and ETCOc measurements can be used as an adjunct to hemoglobin measurements to determine the proper timing of transfusions.

  View details for DOI 10.3109/08880010903536227

  View details for Web of Science ID 000275286100004

  View details for PubMedID 20201692

• MOLECULAR MECHANISM OF HEME OXYGENASE-1 INDUCTION BY STATINS Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Kalish, F. S., Zhao, H., Vreman, H. J., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2010: 208–

  View details for Web of Science ID 000273638400380

• Predicting Time to Hospital Discharge for Extremely Preterm Infants PEDIATRICS Hintz, S. R., Bann, C. M., Ambalavanan, N., Cotten, M., Das, A., Higgins, R. D. 2010; 125 (1): E146-E154

  Abstract

  As extremely preterm infant mortality rates have decreased, concerns regarding resource use have intensified. Accurate models for predicting time to hospital discharge could aid in resource planning, family counseling, and stimulate quality-improvement initiatives.To develop, validate, and compare several models for predicting the time to hospital discharge for infants <27 weeks' estimated gestational age, on the basis of time-dependent covariates as well as the presence of 5 key risk factors as predictors.We conducted a retrospective analysis of infants <27 weeks' estimated gestational age who were born between July 2002 and December 2005 and survived to discharge from a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network site. Time to discharge was modeled as continuous (postmenstrual age at discharge) and categorical (early and late discharge) variables. Three linear and logistic regression models with time-dependent covariate inclusion were developed (perinatal factors only, perinatal + early-neonatal factors, and perinatal + early-neonatal + later factors). Models for early and late discharge that used the cumulative presence of 5 key risk factors as predictors were also evaluated. Predictive capabilities were compared by using the coefficient of determination (R(2)) for the linear models and the area under the curve (AUC) of the receiver operating characteristic curve for the logistic models.Data from 2254 infants were included. Prediction of postmenstrual age at discharge was poor. However, models that incorporated later clinical characteristics were more accurate in predicting early or late discharge (AUC: 0.76-0.83 [full models] vs 0.56-0.69 [perinatal factor models]). In simplified key-risk-factors models, the predicted probabilities for early and late discharge compared favorably with the observed rates. Furthermore, the AUC (0.75-0.77) was similar to those of the models that included the full factor set.Prediction of early or late discharge is poor if only perinatal factors are considered, but it improves substantially with knowledge of later-occurring morbidities. Predictive models that use a few key risk factors are comparable to the full models and may offer a clinically applicable strategy.

  View details for DOI 10.1542/peds.2009-0810

  View details for PubMedID 20008430

• IN VITRO POTENCY OF ZINC BIS GLYCOL PORPHYRIN ON LIVER TISSUE FOLLOWING A HEME LOAD Barlow, A., Yung, A. W., He, C. X., Rhine, I., Hempel, I., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2010: 141–42

  View details for Web of Science ID 000273638400152

• EFFICACY OF ZINC BIS GLYCOL PORPHYRIN IN INHIBITING HEME OXYGENASE ACTIVITY IN THE HEME-LOADED NEWBORN MOUSE He, C. X., Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. BMJ PUBLISHING GROUP. 2010: 142

  View details for Web of Science ID 000273638400153

• AGE-DEPENDENT EXPRESSION OF HEME OXYGENASE-1 IN MICE FOLLOWING ORAL ADMINISTRATION OF ZING BIS GLYCOL PORPHYRIN Western Regional Meeting of the American-Federation-for-Medical-Research He, C. X., Zhao, H., Kalish, F., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2010: 162–63

  View details for Web of Science ID 000273638400223

• Synchronized Nasal Intermittent Positive-Pressure Ventilation and Neonatal Outcomes PEDIATRICS Bhandari, V., Finer, N. N., Ehrenkranz, R. A., Saha, S., Das, A., Walsh, M. C., Engle, W. A., Van Meurs, K. P. 2009; 124 (2): 517-526

  Abstract

  Synchronized nasal intermittent positive-pressure ventilation (SNIPPV) use reduces reintubation rates compared with nasal continuous positive airway pressure (NCPAP). Limited information is available on the outcomes of infants managed with SNIPPV.To compare the outcomes of infants managed with SNIPPV (postextubation or for apnea) to infants not treated with SNIPPV at 2 sites.Clinical retrospective data was used to evaluate the use of SNIPPV in infants

  View details for DOI 10.1542/peds.2008-1302

  View details for Web of Science ID 000268377000011

  View details for PubMedID 19651577

  View details for PubMedCentralID PMC2924622

• Neonatal brain structure on MRI and diffusion tensor imaging, sex, and neurodevelopment in very-low-birthweight preterm children DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Rose, J., Butler, E. E., Lamont, L. E., Barnes, P. D., Atlas, S. W., Stevenson, D. K. 2009; 51 (7): 526-535

  Abstract

  The neurological basis of an increased incidence of cerebral palsy (CP) in preterm males is unknown. This study examined neonatal brain structure on magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) at term-equivalent age, sex, and neurodevelopment at 1 year 6 months on the basis of the Amiel-Tison neurological examination, Gross Motor Function Classification System, and Bayley Scales of Infant Development in 78 very-low-birthweight preterm children (41 males, 37 females; mean gestational age 27.6 wks, SD 2.5; mean birthweight 1021 g, SD 339). Brain abnormalities on MRI and DTI were not different between males and females except in the splenium of the corpus callosum, where males had lower DTI fractional anisotropy (p=0.025) and a higher apparent diffusion coefficient (p=0.013), indicating delayed splenium development. In the 26 infants who were at higher risk on the basis of DTI, males had more abnormalities on MRI (p=0.034) and had lower fractional anisotropy and a higher apparent diffusion coefficient in the splenium (p=0.049; p=0.025) and right posterior limb of the internal capsule (PLIC; p=0.003; p=0.033). Abnormal neurodevelopment was more common in males (n=9) than in females (n=2; p=0.036). Children with abnormal neurodevelopment had more abnormalities on MRI (p=0.014) and reduced splenium and right PLIC fractional anisotropy (p=0.001; p=0.035). In children with abnormal neurodevelopment, right PLIC fractional anisotropy was lower than left (p=0.035), whereas in those with normal neurodevelopment right PLIC fractional anisotropy was higher than left (p=0.001). Right PLIC fractional anisotropy correlated to neurodevelopment (rho=0.371, p=0.002). Logistic regression predicted neurodevelopment with 94% accuracy; only right PLIC fractional anisotropy was a significant logistic coefficient. Results indicate that the higher incidence of abnormal neurodevelopment in preterm males relates to greater incidence and severity of brain abnormalities, including reduced PLIC and splenium development.

  View details for DOI 10.1111/j.1469-8749.2008.03231.x

  View details for PubMedID 19459915

• Inhaled Nitric Oxide for Preterm Premature Rupture of Membranes, Oligohydramnios, and Pulmonary Hypoplasia AMERICAN JOURNAL OF PERINATOLOGY Chock, V. Y., Van Meurs, K. P., Hintz, S. R., Ehrenkranz, R. A., Lemons, J. A., Kendrick, D. E., Stevenson, D. K. 2009; 26 (4): 317-322

  Abstract

  We sought to determine if inhaled nitric oxide (iNO) administered to preterm infants with premature rupture of membranes (PPROM), oligohydramnios, and pulmonary hypoplasia improved oxygenation, survival, or other clinical outcomes. Data were analyzed from infants with suspected pulmonary hypoplasia, oligohydramnios, and PPROM enrolled in the National Institute of Child Health and Development Neonatal Research Network Preemie Inhaled Nitric Oxide (PiNO) trial, where patients were randomized to receive placebo (oxygen) or iNO at 5 to 10 ppm. Outcome variables assessed were PaO (2) response, mortality, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Twelve of 449 infants in the PiNO trial met criteria. Six infants received iNO and six received placebo. The iNO group had a mean increase in PaO (2) of 39 +/- 50 mm Hg versus a mean decrease of 11 +/- 15 mm Hg in the control group. Mortality was 33% versus 67%, BPD (2/5) 40% versus (2/2) 100%, and severe IVH or PVL (1/5) 20% versus (1/2) 50% in the iNO and control groups, respectively. None of these changes were statistically significant. Review of a limited number of cases from a large multicenter trial suggests that iNO use in the setting of PPROM, oligohydramnios, and suspected pulmonary hypoplasia improves oxygenation and may decrease the rate of BPD and death without increasing severe IVH or PVL. However, the small sample size precludes definitive conclusions. Further studies are required to determine if iNO is of benefit in this specific patient population.

  View details for DOI 10.1055/s-0028-1104743

  View details for PubMedID 19067285

• Impact of Postnatal Corticosteroid Use on Neurodevelopment at 18 to 22 Months' Adjusted Age: Effects of Dose, Timing, and Risk of Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants PEDIATRICS Wilson-Costello, D., Walsh, M. C., Langer, J. C., Guillet, R., Laptook, A. R., Stoll, B. J., Shankaran, S., Finer, N. N., Van Meurs, K. P., Engle, W. A., Das, A. 2009; 123 (3): e430-e437

  Abstract

  Postnatal steroid use decreases lung inflammation but increases impairment. We hypothesized that increased dose is associated with increased neurodevelopmental impairment, lower postmenstrual age at exposure increases impairment, and risk of bronchopulmonary dysplasia modifies the effect of postnatal corticosteroid.Steroid dose and timing of exposure beyond 7 days was assessed among 2358 extremely low birth weight infants nested in a prospective trial, with 1667 (84%) survivors examined at 18 to 22 months' postmenstrual age. Logistic regression tested the relationship between impairment (Bayley Mental Developmental Index/Psychomotor Developmental Index of <70, disabling cerebral palsy, or sensory impairment), total dose (tertiles: <0.9, 0.9-1.9, and >/=1.9 mg/kg), and postmenstrual age at first dose. Separate logistic regression tested effect modification according to bronchopulmonary dysplasia severity (Romagnoli risk > 0.5 as high risk, n = 2336 (99%) for days of life 4-7).Three hundred sixty-six (16%) neonates were steroid-treated (94% dexamethasone). Treated neonates were smaller and less mature; 72% of those treated were at high risk for bronchopulmonary dysplasia. Exposure was associated with neurodevelopmental impairment/death. Impairment increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg dose was associated with a 2.0-point reduction on the Mental Developmental Index and a 40% risk increase for disabling cerebral palsy. Older age did not mitigate the harm. Treatment after 33 weeks' postmenstrual age was associated with greatest harm despite not receiving the highest dose. The relationship between steroid exposure and impairment was modified by the bronchopulmonary dysplasia risk, with those at highest risk experiencing less harm.Higher steroid dose was associated with increased neurodevelopmental impairment. There is no "safe" window for steroid use in extremely low birth weight infants. Neonates with low bronchopulmonary dysplasia risk should not be exposed. A randomized trial of steroid use in infants at highest risk is warranted.

  View details for DOI 10.1542/peds.2008-1928

  View details for Web of Science ID 000263825500057

  View details for PubMedID 19204058

  View details for PubMedCentralID PMC2846831

• Commentary on the bilirubin supplement JOURNAL OF PERINATOLOGY Stevenson, D. K. 2009; 29: S2-S3

  View details for DOI 10.1038/jp.2008.220

  View details for Web of Science ID 000263604400002

  View details for PubMedID 19177055

• Safe and effective devices for use in the neonatal intensive care unit: NICHD Workshop Summary. Biomed Instrum Technol Raju TNK, Stevenson DK, Higgins, RD, Stark AR 2009; 43: 408-18
• ROSUVASTATIN SUPPRESSES THE DEVELOPMENT OF EXPERIMENTAL ABDOMINAL AORTIC ANEURYSMS IN MICE THROUGH THE INDUCTION OF HEME OXYGENASE-1 Azuma, J., Wong, R. J., Morisawa, T., Hsu, M., Stevenson, D. K., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2009: 107

  View details for Web of Science ID 000270092400044

• DOSE-DEPENDENT EFFECTS OF ZINC BIS GLYCOL PORPHYRIN ON THE EXPRESSION OF HEME OXYGENASE IN NEWBORN MICE Campbell, C. M., Morisawa, T., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 177

  View details for Web of Science ID 000270092400294

• REAL-TIME, NONINVASIVE MEASUREMENTS OF PLASMA BILIRUBIN LEVELS USING VISIBLE LIGHT SPECTROSCOPY Knauer, Y., Fierro, M., van Thillo, E., Benaron, D. A., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 177–78

  View details for Web of Science ID 000270092400295

• EXERCISE-INDUCED AORTIC HEME OXYGENASE ACTIVITY IS ASSOCIATED WITH ATTENUATION OF EXPERIMENTAL ABDOMINAL AORTIC ANEURYSM DISEASE Schultz, G. M., Tedesco, M. M., Morisawa, T., Azuma, J., Wong, R. J., Stevenson, D. K., Dalman, R. L. LIPPINCOTT WILLIAMS & WILKINS. 2009: 107–8

  View details for Web of Science ID 000270092400046

• A NEW MOUSE MODEL OF NEONATAL BRAIN INJURY Western Regional Meeting of the American-Federation-for-Medical-Research Knauer, Y., Wong, R. J., Zhao, H., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 129–30

  View details for Web of Science ID 000270092400124

• Federation of Pediatric Organizations Task Force on Women in Pediatrics: Considerations for Part-Time Training and Employment for Research-Intensive Fellows and Faculty JOURNAL OF PEDIATRICS Alexander, D., Boat, T., Britto, M., Burke, A., Homes, A., Sectish, T., Stanton, B., Stevenson, D. 2009; 154 (1): 1-3

  View details for DOI 10.1016/j.jpeds.2008.08.010

  View details for Web of Science ID 000262272500001

  View details for PubMedID 19187728

• AGE-DEPENDENT EXPRESSION OF HEME OXYGENASE-1 IN MICE FOLLOWING ORAL ADMINISTRATION OF CHROMIUM MESOPORPHYRIN Western Regional Meeting of the American-Federation-for-Medical-Research He, C. X., Morisawa, T., Zhao, H., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: 177–77

  View details for Web of Science ID 000270092400293

• Failure to Predict Hemolysis and Hyperbilirubinemia by IgG Subclass in Blood Group A or B Infants Born to Group O Mothers PEDIATRICS Kaplan, M., Na'amad, M., Kenan, A., Rudensky, B., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2009; 123 (1): E132-E137

  Abstract

  Direct antibody titer-positive, blood group A or B neonates who are born to group O mothers may be at risk for hemolysis and hyperbilirubinemia. Immunoglobulin G1 and immunoglobulin G3 subclasses are associated with increased hemolysis relative to immunoglobulin G2 and immunoglobulin G4. We investigated whether identification of immunoglobulin G subclass 1 or 3 may be predictive of hemolysis and hyperbilirubinemia.Direct antibody titer-positive, blood group A and B neonates born to group O mothers were tested for the presence of immunoglobulin G subclasses 1 and 3 in umbilical cord blood by using a commercially available gel testing technology. By inference, neonates in whom neither immunoglobulin G1 nor immunoglobulin G3 were detected were designated immunoglobulin G2 and/or 4. Mandatory plasma total bilirubin was measured at discharge, and additional measurements performed as clinically indicated. Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile for hour of life. Blood carboxyhemoglobin and total hemoglobin concentrations were also measured on the predischarge sample. Measured carboxyhemoglobin, expressed as percentage of total hemoglobin, was corrected for ambient carbon monoxide to derive "corrected carboxyhemoglobin," a sensitive index of heme catabolism. The corrected carboxyhemoglobin/total hemoglobin ratio was calculated to correct for any differences in total hemoglobin mass between groups.Eighty-two infants were studied, 18 of whom were designated as immunoglobulin G1, 0 as immunoglobulin G3, and 64 as immunoglobulin G2 and/or 4. The incidence of plasma total bilirubin >95th percentile was similar between the subgroupings. Corrected carboxyhemoglobin values and corrected carboxyhemoglobin/total hemoglobin ratio were also similar between the subgroupings.Immunoglobulin G1 was found in 22% of direct antibody titer-positive, group A and B neonates who were born to group O mothers, whereas immunoglobulin G3 was rare. Hemolysis and hyperbilirubinemia could not be predicted by this gel technique that enabled identification of these immunoglobulin G subclasses.

  View details for DOI 10.1542/peds.2008-2617

  View details for Web of Science ID 000262046400077

  View details for PubMedID 19114458

• Photoisomers: Obfuscating Factors in Clinical Peroxidase Measurements of Unbound Bilirubin? PEDIATRICS McDonagh, A. F., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2009; 123 (1): 67-76

  Abstract

  The objectives of the study were to measure the effect of 4Z,15E-bilirubin on peroxidase free bilirubin measurements and to review the literature on this topic.4Z,15E-Bilirubin was generated in situ in serum or serum albumin solution through controlled irradiation of isomerically pure 4Z,15Z-bilirubin IXalpha, under conditions in which the total amount of bilirubin remained constant. Reactions were monitored by difference spectroscopy, to ensure that solutions were not irradiated beyond the initial photostationary state and that concentrations of other isomers were kept to a minimum. Prepared in this way, 10% to 25% of the total bilirubin in the final solutions was in the form of the 4Z,15E-isomer. Free bilirubin in the solutions was measured with a peroxidase method, before and after irradiation. The use of bovine serum albumin as a surrogate for human albumin in in vitro studies also was investigated.The findings of previous studies are not altogether consistent, with a common flaw in several being the failure to measure photoisomer concentrations. For bilirubin in serum albumin solution, conversion of approximately 25% of the 4Z,15Z-isomer to 4Z,15E-bilirubin led to a much smaller decrease (<20%) in the apparent free bilirubin concentration; for bilirubin in serum, conversion of approximately 15% of the 4Z,15Z-isomer to photoisomers resulted in a much larger increase ( approximately 40%). Irradiation of bilirubin in bovine serum albumin solution generated a very different array of photoisomers than that observed in human albumin solutions.The effect of photoisomers on the accuracy and specificity of free 4Z,15Z-bilirubin measurements remains uncertain. In a clinical setting, free bilirubin measurements need to be interpreted with caution when samples contain photoisomers. Irradiated bovine albumin solutions of isomerically impure bilirubin used in previous studies are poor models for investigating the effects of phototherapy in humans and the albumin binding of photoisomers.

  View details for DOI 10.1542/peds.2008-0492

  View details for Web of Science ID 000262046400010

  View details for PubMedID 19117862

• Treatmeant with Rosuvastatin Suppresses the Development of Experimental Abdominal Aortic Aneurysms in Mice by Heme Oxygenase-1 Induction Azuma, J., Wong, R. J., Morisawa, T., Hus, M., Stevenson, D. K., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2008: S1052

  View details for Web of Science ID 000262104504178

• Community supports after surviving extremely low-birth-weight, extremely preterm birth - Special outpatient services in early childhood ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Hintz, S. R., Kendrick, D. E., Vohr, B. R., Poole, W. K., Higgins, R. D. 2008; 162 (8): 748-755

  Abstract

  To determine special outpatient services (SOS) use, need, associated factors, and neurodevelopmental and functional outcomes among extremely preterm infants at 18 to 22 months' corrected age.Retrospective analysis.National Institute of Child Health and Human Development (NICHD) Neonatal Research Network.Infants younger than 28 weeks' gestational age who had been born weighing less than 1000 g at an NICHD Neonatal Research Network center from January 1, 1997, to December 31, 2000, and who were receiving follow-up at 18 to 22 months' corrected age.Questionnaires were administered at the 18- to 22-month follow-up visit regarding SOS use since hospital discharge and the current need for SOS (social work, visiting nurse, medical specialty, early intervention, speech and language services, occupational therapy and physical therapy, and neurodevelopmental and behavioral services).The use of and need for SOS were analyzed by gestational age. Logistic regression analysis identified factors independently associated with the use of more than 5 services and with the need for any services.Of 2315 infants, 54.7% used more than 3 SOS by 18 to 22 months, and 19.1% used 6 to 7 SOS. The need for any SOS was reported by approximately 37%. The following variables that were commonly associated with adverse neurodevelopmental outcomes were also associated with the use of more than 5 SOS: sepsis, birth weight, postnatal corticosteroid use, bronchopulmonary dysplasia, and cystic periventricular leukomalacia or grade 3 or 4 intraventricular hemorrhage. Male sex was associated with the need for any SOS. Although high SOS use was more likely among children with adverse neurodevelopmental outcomes, a reported need for SOS was common even among those with mild developmental impairment (39.7%) and mild cerebral palsy (42.2%).High SOS use is common, has identifiable neonatal risk factors, and is associated with neurodevelopmental impairment. Extremely preterm survivors have substantial need for community supports regardless of their impairment level. Efforts to improve comprehensive delivery of family-centered community-based services are urgently needed.

  View details for PubMedID 18678807

• Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure JOURNAL OF PERINATOLOGY Ambalavanan, N., Van Meurs, K. P., Perritt, R., Carlo, W. A., Ehrenkranz, R. A., Stevenson, D. K., Lemons, J. A., Poole, W. K., Higgins, R. D. 2008; 28 (6): 420-426

  Abstract

  To identify the variables that predict death/physiologic bronchopulmonary dysplasia (BPD) in preterm infants with severe respiratory failure.The study was a secondary analysis of data from the NICHD Neonatal Research Network trial of inhaled nitric oxide (iNO) in preterm infants. Stepwise logistic regression models and Classification and Regression Tree (CART) models were developed for the outcome of death or physiologic BPD (O(2) at 36 weeks post-menstrual age).Death and/or BPD was associated with lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index and outborn status, but not the magnitude of response in PaO(2) to iNO. The positive predictive value of the CART model was 82% at 95% sensitivity.The major factors associated with death/BPD were an increased severity of respiratory failure, lower birth weight, male gender and outborn status, but not the magnitude of initial response to iNO.

  View details for DOI 10.1038/jp.2008.18

  View details for Web of Science ID 000256437600007

  View details for PubMedID 18337740

  View details for PubMedCentralID PMC2776028

• Readmission for neonatal jaundice in California, 1991-2000: Trends and implications PEDIATRICS Burgos, A. E., Schmitt, S. K., Stevenson, D. K., Phibbs, C. S. 2008; 121 (4): E864-E869

  Abstract

  We sought to describe population-based trends, potential risk factors, and hospital costs of readmission for jaundice for term and late preterm infants.Birth-cohort data were obtained from the California Office of Statewide Health Planning and Development and contained infant vital statistics data linked to infant and maternal hospital discharge summaries. The study population was limited to healthy, routinely discharged infants through the use of multiple exclusion criteria. All linked readmissions occurred within 14 days of birth. International Classification of Diseases, Ninth Revision, codes were used to further limit the sample to readmission for jaundice. Hospital discharge records were the source of diagnoses, hospital charges, and length-of-stay information. Hospital costs were estimated using hospital-specific ratios of costs to charges and adjusted to 1991.Readmission rates for jaundice generally rose after 1994 and peaked in 1998 at 11.34 per 1000. The readmission rate for late preterm infants (as a share of all infants) over the study period remained at <2 per 1000. Factors associated with increased likelihood of hospital readmission for jaundice included gestational age 34 to 39 weeks, birth weight of <2500 g, male gender, Medicaid or private insurance, and Asian race. Factors associated with a decreased likelihood of readmission for jaundice were cesarean section delivery and black race. The mean cost of readmission for all infants was $2764, with a median cost of $1594.Risk-adjusted readmission rates for jaundice rose following the 1994 hyperbilirubinemia guidelines and declined after postpartum length-of-stay legislation in 1998. In 2000, the readmission rate remained 6% higher than in 1991. These findings highlight the complex relationship among newborn physiology, socioeconomics, race or ethnicity, public policy, clinical guidelines, and physician practice. These trend data provide the necessary baseline to study whether revised guidelines will change practice patterns or improve outcomes. Cost data also provide a break-even point for prevention strategies.

  View details for DOI 10.1542/peds.2007-1214

  View details for PubMedID 18381515

• Severe hemolysis with normal blood count in a glucose-6-phosphate dehydrogenase deficient neonate JOURNAL OF PERINATOLOGY Kaplan, M., Hammerman, C., Vreman, H. J., Wong, R. J., Stevenson, D. K. 2008; 28 (4): 306-309

  Abstract

  A premature glucose-6-phosphate dehydrogenase (G-6-PD) deficient neonate was readmitted for exponential rise in the plasma bilirubin concentration to 33.0 mg dl(-1). Blood carboxyhemoglobin (2.8% of total hemoglobin, >threefold normal value) confirmed the presence of hemolysis; however, hematological indices were unchanged from the birth hospitalization. Serum unbound bilirubin, although present, was probably at a concentration insufficient to cause bilirubin encephalopathy. In G-6-PD deficient neonates, severe hemolysis may occur in the absence of hematological changes typical of a hemolytic process.

  View details for DOI 10.1038/sj.jp.7211919

  View details for Web of Science ID 000254782000012

  View details for PubMedID 18379570

• Heme oxygenase-1 and simvastatin: molecular mechanisms and in vivo effects 49th Annual Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology Hinkelmann, U., Schulz, S., Grosser, N., Wong, R. J., Morisawa, T., Stevenson, D. K., Muchova, L., Schroeder, H. SPRINGER. 2008: 58–58

  View details for Web of Science ID 000254204900282

• Upregulation of the HO-1 gene by proton pump inhibitors - molecular mechanisms and functinal consequences 49th Annual Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology Schulz, S., Grosser, N., Erdmann, K., Hinkelmann, U., Wong, R. J., Stevenson, D. K., Schroeder, H. SPRINGER. 2008: 60–60

  View details for Web of Science ID 000254204900291

• Efficacy of chromium mesoporphyrin in inhibiting heme oxygenase activity in heme-loaded newborn mice Western Regional Meeting of the American-Federation-for-Medical-Research Morisawa, T., Xiao, H. H., Wong, R. J., Bhutani, V. K., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 198–98

  View details for Web of Science ID 000252793300297

• Time-dependent effects of chromium mesoporphyrin on the inhibition of heme oxygenase activity in newborn mice Western Regional Meeting of the American-Federation-for-Medical-Research Xiao, H. H., Morisawa, T., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 260–61

  View details for Web of Science ID 000252793301130

• On the caffeination of prematurity NEW ENGLAND JOURNAL OF MEDICINE Stevenson, D. K. 2007; 357 (19): 1967–68

  View details for DOI 10.1056/NEJMe078200

  View details for Web of Science ID 000250732500014

  View details for PubMedID 17989390

• Neonatal microstructural development of the internal capsule on diffusion tensor imaging correlates with severity of gait and motor deficits DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Rose, J., Mirmiran, M., Butler, E. E., Lin, C. Y., Barnes, P. D., Kermoian, R., Stevenson, D. K. 2007; 49 (10): 745-750

  Abstract

  Neonatal microstructural development in the posterior limbs of the internal capsule (PLIC) was assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA) in 24 very-low-birthweight preterm infants at 37 weeks' gestational age and compared with the children's gait and motor deficits at 4 years of age. There were 14 participants with normal neonatal FA values (seven females, seven males; born at 27.6 weeks [SD 2.3] gestational age; birthweight 1027g [SD 229]) and 10 participants with low FA values in the PLIC (four females, six males; born at 28.4 weeks [SD 2.0] gestational age; birthweight 1041g [SD 322]). Seven of the 10 children with low FA and none of the children with normal FA had been diagnosed with CP by the time of gait testing. Among children with low neonatal FA, there was a strong negative correlation between FA of the combined left and right side PLIC and log NI (r=-0.89, p=0.001) and between FA and GMFCS (r=-0.65, p=0.04) at 4 years of age. There was no correlation between FA and gait NI or GMFCS at 4 years of age among children with normal neonatal FA. This preliminary study suggests neonatal DTI may be an important predictor of the severity of future gait and motor deficits.

  View details for PubMedID 17880643

• Beware of the weaker sex: Don't get too close to your twin brother PEDIATRICS Stevenson, D. K., Tyson, J. E. 2007; 120 (3): 638-639

  View details for DOI 10.1542/peds.2007-0950

  View details for PubMedID 17766536

• Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide JOURNAL OF PEDIATRICS Hintz, S. R., Van Meurs, K. P., Perritt, R., Poole, W. K., Das, A., Stevenson, D. K., Ehrenkranz, R. A., Lemons, J. A., Vohr, B. R., Heyne, R., Childers, D. O., Peralta-Carcelen, M., Dusick, A., Johnson, Y. R., Morris, B., Dillard, R., Vaucher, Y., Steichen, J., Adams-Chapman, I., Konduri, G., Myers, G. J., De Ungria, M., Tyson, J. E., Higgins, R. D. 2007; 151 (1): 16-22

  Abstract

  We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group.Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness.Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43).In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.

  View details for DOI 10.1016/j.jpeds.2007.03.017

  View details for Web of Science ID 000247851900007

  View details for PubMedID 17586184

  View details for PubMedCentralID PMC2770191

• Inhaled nitric oxide in infants > 1500 g and < 34 weeks gestation with severe respiratory failure JOURNAL OF PERINATOLOGY Van Meurs, K. P., Hintz, S. R., Ehrenkranz, R. A., Lemons, J. A., Ball, M. B., Poole, W. K., Perritt, R., Das, A., Higgins, R. D., Stevenson, D. K. 2007; 27 (6): 347-352

  Abstract

  Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD).Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO.Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P=0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P=0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P=0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P=0.21).Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.

  View details for DOI 10.1038/sj.jp.7211690

  View details for Web of Science ID 000246905800005

  View details for PubMedID 17443204

• Chronic administration of statins increases bilirubin and carbon monoxide formation in the heart - A novel mechanism of antioxidant protection 76th Congress of the European-Atherosclerosis-Society/15th Paavo Nurmi Symposium Muchova, L., Wong, R. J., HSU, M., Morioka, I., Zelenka, J., Vitek, L., Schroder, H., Stevenson, D. K. ELSEVIER IRELAND LTD. 2007: 206–

  View details for Web of Science ID 000247869100830

• Interobserver reliability and accuracy of cranial ultrasound scanning interpretation in premature infants JOURNAL OF PEDIATRICS Hintz, S. R., Slovis, T., Bulas, D., Van Meurs, K. P., Perritt, R., Stevenson, D. K., Poole, W. K., Das, A., Higgins, R. D. 2007; 150 (6): 592-596

  Abstract

  To assess interobserver reliability between 2 central readers of cranial ultrasound scanning (CUS) and accuracy of local, compared with central, interpretations.The study was a retrospective analysis of CUS data from the National Institute of Child Health and Human Development (NICHD) trial of inhaled nitric oxide for premature infants. Interobserver reliability of 2 central readers was assessed with kappa or weighted kappa. Accuracy of local, compared with central, interpretations was assessed by using sensitivity and specificity.CUS from 326 infants had both central reader and local interpretations. Central reader agreement for grade 3/4 intraventricular hemorrhage (IVH), grade 3/4 IVH or periventricular leukomalacia (PVL), grade of IVH, and degree of ventriculomegaly was very good (kappa = 0.84, 0.81, 0.79, and 0.75, respectively). Agreement was poor for lower grade IVH and for PVL alone. Local interpretations were highly accurate for grade 3/4 IVH or PVL (sensitivity, 87%-90%; specificity, 92%-93%), but sensitivity was poor-to-fair for grade 1/2 IVH (48%-68%) and PVL (20%-44%).Our findings demonstrate reliability and accuracy of highly unfavorable CUS findings, but suggest caution when interpreting mild to moderate IVH or white matter injury.

  View details for DOI 10.1016/j.jpeds.2007.02.012

  View details for PubMedID 17517240

• Effects of sample dilution, peroxidase concentration, and chloride ion on the measurement of unbound bilirubin in premature newborns CLINICAL BIOCHEMISTRY Ahlfors, C. E., Vreman, H. J., Wong, R. J., Bender, G. J., Oh, W., Morris, B. H., Stevenson, D. K. 2007; 40 (3-4): 261-267

  Abstract

  To assess the effects of sample dilution, peroxidase concentration, and chloride ion (Cl(-)) on plasma unbound bilirubin (B(f)) measurements made using a commercial peroxidase methodology (UB Analyzer) in a study population of ill, premature newborns.B(f) was measured with a UB Analyzer in 74 samples at the standard 42-fold sample dilution and compared with B(f) measured at a 2-fold sample dilution using a FloPro Analyzer. B(f) was measured at two peroxidase concentrations to determine whether the peroxidase steady state B(f) (B(fss)) measurements were significantly less than the equilibrium B(f) (B(feq)), in which case it was necessary to calculate B(feq) from the two B(fss) measurements. B(f) was also measured before and after adding 100 mmol/L Cl(-) to the UB Analyzer assay buffer.B(feq) at the 42-fold dilution was nearly 10-fold less than but it correlated significantly with B(feq) at the 2-fold dilution (mean 8.2+/-5.2 nmol/L versus 73.5+/-70 nmol/L, respectively, p<0.0001; correlation r=0.6). The two UB Analyzer B(fss) measurements were significantly less than B(feq) in 42 of 74 (57%) samples, and Cl(-) increased B(feq) in 66 of 74 (89%) samples by a mean of 82+/-67%.B(fss) measured by the UB Analyzer at the standard 42-fold sample dilution using assay buffer without Cl(-) and a single peroxidase concentration is significantly less than the B(feq) in undiluted plasma. Accurate B(f) measurements can be made only in minimally diluted serum or plasma.

  View details for DOI 10.1016/j.clinbiochem.2006.09.006

  View details for Web of Science ID 000244193000020

  View details for PubMedID 17069786

  View details for PubMedCentralID PMC1945224

• The potential Salmonella aroA(-) vaccine strain is safe and effective in young BALB/c mice NEONATOLOGY Burns-Guydish, S. M., Zhao, H., Stevenson, D. K., Contag, C. H. 2007; 91 (2): 114-120

  Abstract

  Due to the increased susceptibility of neonates to pathogens including those with mutations, the use of live vaccine strategies in the human population may present a potential risk to the young.The specific aim of this study was to assess the risk that prospective Salmonella enterica serovar Typhimurium vaccine strains pose for the neonate and determine whether the strains are an effective vaccine by assessing the adaptive immune response.To evaluate the susceptibility of young mice to potential vaccine strains, S. typhimuriumaroA(-) and Delta phoP mutant strains were labeled by chromosomal insertion of the lux operon--this serves as a readily traceable marker of infection using noninvasive imaging methods. BALB/c mice ages 1, 2, 4, and 6 weeks of age were fed the bioluminescent aroA(-) or Delta phoP strains and the course of infection was monitored by in vivobioluminescence imaging. In addition, blood samples were collected post-inoculation to assess the IgG response of mice to S. typhimurium LPS.Young BALB/c mice were not susceptible to the aroA(-) strain in contrast to their susceptibility to the Delta phoP strain at a dose of 10(9) colony forming units. Delivery by oral feeding of the aroA(-) and Delta phoP strains in young mice also produced a robust IgG anti-LPS response.Here, we report that young 2-week-old mice orally fed the bioluminescent aroA(-) S. typhimurium strain were not susceptible to infection and elicited a protective immune response.

  View details for DOI 10.1159/000097128

  View details for PubMedID 17344661

• Chronic administration of statins on in vivo heme oxygenase expression: a novel mechanism of antioxidant protection. Muchova, L., Hsu, M., Wong, R. J., Morioka, I., Schroder, H., Stevenson, D. K. B C DECKER INC. 2007: S88

  View details for DOI 10.1097/00042871-200701010-00080

  View details for Web of Science ID 000247692400082

• Regulation of murine maternal and fetal hemodynamic function by heme oxygenase. Zhao, H., Wong, R. J., Doyle, T. C., Contag, C. H., Stevenson, D. K. B C DECKER INC. 2007: S116

  View details for DOI 10.1097/00042871-200701010-00252

  View details for Web of Science ID 000247692400254

• Comparison of heme oxygenase activity in gut-associated lymphoid tissues and the intestine. 8th Conference of the Western Student Medical Research Forum/Western Section of the American-Federation-for-Medical-Research/Western Association-of-Physicians/Western-Society-for-Pediatric-Research/Western-Society-for-Clinical-Investigation Burns-Guydisli, S. M., Wong, R. J., Kafsh, F., Contag, C. H., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: S117–S118

  View details for Web of Science ID 000247692400262

• Efficacy of azalanstat in inhibiting heme oxygenase activity in newborn mice. 8th Conference of the Western Student Medical Research Forum/Western Section of the American-Federation-for-Medical-Research/Western Association-of-Physicians/Western-Society-for-Pediatric-Research/Western-Society-for-Clinical-Investigation Morisawa, T., Wong, R. J., Bhutani, V. K., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: S89–S89

  View details for Web of Science ID 000247692400087

• Inhibition of heme oxygenase activity following repeated heme loads by tin mesoporphyrin in newborn mice. 8th Conference of the Western Student Medical Research Forum/Western Section of the American-Federation-for-Medical-Research/Western Association-of-Physicians/Western-Society-for-Pediatric-Research/Western-Society-for-Clinical-Investigation Wong, R. J., Morioka, I., Muchova, L., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: S88–S88

  View details for Web of Science ID 000247692400083

• Heme oxygenase 1 deficiency compromises stress responses of hematopoietic stem cells. 48th Annual Meeting of the American-Society-of-Hematology Cao, Y., Wagers, A. J., Karsunky, H., Zhao, H., Reeves, R., Wang, R. J., Stevenson, D. K., Weissman, I. L., Contag, C. H. AMER SOC HEMATOLOGY. 2006: 395A–395A

  View details for Web of Science ID 000242440001612

• End-tidal carbon monoxide measurements in infant respiratory distress syndrome ACTA PAEDIATRICA Krediet, T. G., Cirkel, G. A., Vreman, H. J., Wong, R. J., Stevenson, D. K., Groenendaal, F., Egberts, J., van Bel, F. 2006; 95 (9): 1075-1082

  Abstract

  RDS involving inflammatory and oxidative processes may lead to increased production of carbon monoxide (CO).The relationship between end-tidal CO, corrected for inhaled CO (ETCOc), and RDS severity was investigated in preterm infants as well as the value of early ETCOc measurements to predict chronic lung disease.78 infants (30 no RDS, 32 moderate RDS, 16 severe RDS) were included. ETCOc was measured using the CO-Stat End Tidal Breath Analyzer.ETCOc was significantly higher in RDS compared to no RDS during the first week (p<0.05). Severity of RDS was the most significant independent variable in a stepwise regression model related to ETCOc (F-test: 18.17). Negative predictive value of early (within first 12 h of life) ETCOc measurement (<2.5 ppm) for development of chronic lung disease was excellent (100%).During severe RDS, inflammation may contribute to increased lipid peroxidation leading to increased local CO production in the lung, indicated by increased ETCOc. Early ETCOc determinations may be helpful to exclude occurrence of chronic lung disease.

  View details for DOI 10.1080/08035250500537017

  View details for Web of Science ID 000240122500009

  View details for PubMedID 16938753

• Neonatal hyperbilirubinemia in African American males: The importance of glucose-6-phosphate dehydrogenase deficiency JOURNAL OF PEDIATRICS Kaplan, M., Herschel, M., Hammerman, C., Hoyer, J. D., Heller, G. Z., Stevenson, D. K. 2006; 149 (1): 83-88

  Abstract

  To perform risk factor analysis for the prediction of hyperbilirubinemia in an African American male neonatal cohort.A database of 500 previously published term and near-term African American male neonates was further analyzed to determine the role of risk factors for hyperbilirubinemia. Factors studied included birth weight >/=4.0 kg, gestational age /=75(th) percentile. Hyperbilirubinemia was defined as any bilirubin value >/=95(th) percentile on the hour-of-life-specific bilirubin nomogram.Forty-three (8.6%) neonates developed hyperbilirubinemia. At 48 +/- 12 hours, median transcutaneous bilirubin was 8.3 mg/dL, 75(th) percentile 10.0 mg/dL, and 95(th) percentile 12.6 mg/dL. Of the risk factors, only exclusive breast-feeding, G-6-PD deficiency and predischarge bilirubin >/=75(th) percentile were significant (Adjusted Odds Ratios [95% Confidence Intervals; CI] 3.15 [1.39-7.14], P = .006; 4.96 [2.28-10.80], P = .001; and 7.47 [3.50-15.94], P < .0001, respectively). G-6-PD-deficient neonates who were also premature and breast-feeding had the highest incidence of hyperbilirubinemia (60%).African American male neonates may be at higher risk for hyperbilirubinemia than previously thought. Screening for G-6-PD deficiency and predischarge bilirubin determination may be useful adjuncts in hyperbilirubinemia prediction in these newborns.

  View details for DOI 10.1016/j.jpeds.2006.02.011

  View details for Web of Science ID 000239352000023

  View details for PubMedID 16860133

• Promoting antenatal steroid use for fetal maturation: Results from the California Perinatal Quality Care Collaborative JOURNAL OF PEDIATRICS Wirtschafter, D. D., Danielsen, B. H., Main, E. K., Korst, L. M., Gregory, K. D., Wertz, A., Stevenson, D. K., Gould, J. B. 2006; 148 (5): 606-612

  Abstract

  The California Perinatal Quality Care Collaborative (CPQCC) was formed to seek perinatal care improvements by creating a confidential multi-institutional database to identify topics for quality improvement (QI). We aimed to evaluate this approach by assessing antenatal steroid administration before preterm (24 to 33 weeks of gestation) delivery. We hypothesized that mean performance would improve and the number of centers performing below the lowest quartile of the baseline year would decrease.In 1998, a statewide QI cycle targeting antenatal steroid use was announced, calling for the evaluation of the 1998 baseline data, dissemination of recommended interventions using member-developed educational materials, and presentations to California neonatologists in 1999-2000. Postintervention data were assessed for the year 2001 and publicly released in 2003. A total of 25 centers voluntarily participated in the intervention.Antenatal steroid administration rate increased from 76% of 1524 infants in 1998 to 86% of 1475 infants in 2001 (P < .001). In 2001, 23 of 25 hospitals exceeded the 1998 lower-quartile cutoff point of 69.3%.Regional collaborations represent an effective strategy for improving the quality of perinatal care.

  View details for DOI 10.1016/j.jpeds.2005.12.058

  View details for Web of Science ID 000237885500019

  View details for PubMedID 16737870

• Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: Outcomes through 18 months adjusted age PEDIATRICS Blakely, M. L., TYSON, J. E., Lally, K. P., McDonald, S., Stoll, B. J., Stevenson, D. K., Poole, W. K., Jobe, A. H., Wright, L. L., Higgins, R. D. 2006; 117 (4): E680-E687

  Abstract

  Extremely low birth weight (ELBW; < or =1000 g) infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP) are treated surgically with either initial laparotomy or peritoneal drain placement. The only published data comparing these therapies are from small, retrospective, single-center studies that do not address outcomes beyond nursery discharge. The objective of this study was to conduct a prospective, multicenter, observational study to (1) develop a hypothesis about the relative effect of these 2 therapies on risk-adjusted outcomes through 18 to 22 months in ELBW infants and (2) to obtain data that would be useful in designing and conducting a successful trial of this hypothesis.A prospective, cohort study was conducted at 16 clinical centers within the National Institute of Child Health and Human Development Neonatal Research Network. To assist in risk adjustment, the attending pediatric surgeon recorded the preoperative diagnosis and intraoperative diagnosis and identified infants who were considered to be too ill for laparotomy. Predefined measures of short- and longer-term outcome included (1) either predischarge death or prolonged parenteral nutrition (>85 days) after enrollment and (2) either death or neurodevelopmental impairment on a standardized examination at 18 to 22 months' adjusted age.Severe NEC or IP occurred in 156 (5.2%) of 2987 ELBW infants; 80 were treated with initial drainage, and 76 were treated with initial laparotomy. By 18 to 22 months, 78 (50%) had died; 112 (72%) had died or were shown to be impaired. Outcome was worse in the subgroup with NEC. Laparotomy was never performed in 76% (28 of 36) of drain-treated survivors.Drainage was commonly used, and outcome was poor. Our findings, particularly the risk-adjusted odds ratio favoring laparotomy for death or impairment, indicate the need for a large, multicenter clinical trial to assess the effect of the initial surgical therapy on outcome at > or =18 months.

  View details for DOI 10.1542/peds.2005-1273

  View details for Web of Science ID 000236540500010

  View details for PubMedID 16549503

• The effect of tin-mesoporphyrin on Bach 1 expression Experimental Biology 2006 Annual Meeting Abate, A., Zhao, H., Wong, R. J., Stevenson, D. K. FEDERATION AMER SOC EXP BIOL. 2006: A1344–A1344

  View details for Web of Science ID 000236326204408

• Studies in hemolysis in glucose-6-phosphate dehydrogenase-deficient African American neonates Annual Meeting of the Pediatric-Academic-Societies Kaplan, M., Herschel, M., Hammerman, C., Karrison, T., Hoyer, J. D., Stevenson, D. K. ELSEVIER SCIENCE BV. 2006: 177–82

  Abstract

  The role of hemolysis in the mechanism and prediction of hyperbilirubinemia was contrasted between glucose-6-phosphate dehydrogenase (G-6-PD)-deficient and -normal African American neonates.Corrected end tidal carbon monoxide (ETCOc) values from the subset of male neonates born to non-smoking African American mothers, drawn from a previously published study, were analyzed. The relationship between ETCOc and bilirubin values, the latter represented as percentiles on the hour of life specific bilirubin nomogram, was determined. Hyperbilirubinemia was defined as any bilirubin value > or =95th percentile for hour of life.18.6% of 59 G-6-PD-deficient neonates developed hyperbilirubinemia, compared with 7.5% of 362 controls (relative risk 2.50, 95% confidence interval 1.31 to 4.76). As reported, ETCOc values (median, interquartile range) were significantly higher among G-6-PD-deficient neonates than controls (2.4 [2.0-2.9] vs. 2.1 [1.7-2.5] ppm, p<0.001. However, higher ETCOc values were limited to those G-6-PD-deficient neonates with lower bilirubin percentiles: among those whose bilirubin value did not exceed the 95th percentile ETCOc was 2.30 [2.00-2.85] vs. 2.00 [1.70-2.40] ppm in controls, p=0.001. In contrast, among the hyperbilirubinemic neonates ETCOc values were similar between G-6-PD-deficient neonates and controls: 2.7 [2.03-3.33] vs. 2.6 [2.33-3.45] ppm, p=0.9. In the G-6-PD-deficient neonates ETCOc > or =75th percentile contributed no additional predictive value for hyperbilirubinemia (likelihood ratio 1.8).G-6-PD-deficient African American neonates have increased hemolysis and increased rate of hyperbilirubinemia, but the hemolysis is neither a predominant factor in the pathogenesis of hyperbilirubinemia nor is it predictive of hyperbilirubinemia, over and above the already increased risk conferred by G-6-PD deficiency.

  View details for DOI 10.1016/j.cca.2005.08.015

  View details for Web of Science ID 000235646400023

  View details for PubMedID 16188248

• Selectivity of imidazole-dioxolane compounds for in vitro inhibition of microsomal haem oxygenase isoforms BRITISH JOURNAL OF PHARMACOLOGY Kinobe, R. T., Vlahakis, J. Z., Vreman, H. J., Stevenson, D. K., Brien, J. F., Szarek, W. A., Nakatsu, K. 2006; 147 (3): 307-315

  Abstract

  Haem oxygenases (HO) are involved in the catalytic breakdown of haem to generate carbon monoxide (CO), iron and biliverdin. It is widely accepted that products of haem catabolism are involved in biological signaling in many physiological processes. Conclusions to most studies in this field have gained support from the judicious use of synthetic metalloporphyrins such as chromium mesoporphyrin (CrMP) to selectively inhibit HO. However, metalloporphyrins have also been found to inhibit other haem-dependent enzymes, such as nitric oxide synthase (NOS), cytochromes P-450 (CYPs) and soluble guanylyl cyclase (sGC), induce the expression of HO-1 or exhibit varied toxic effects. To obviate some of these problems, we have been examining non-porphyrin HO inhibitors and the present study describes imidazole-dioxolane compounds with high selectivity for inhibition of HO-1 (rat spleen microsomes) compared to HO-2 (rat brain microsomes) in vitro. (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane hydrochloride) was identified as the most selective inhibitor with a concentration of 0.6 microM inhibiting HO-1(inducible) by 50% compared with 394 microM for HO-2 (constitutive). These compounds were found to have no effects on the catalytic activities of rat brain NOS and lung sGC, but were potent inhibitors of microsomal CYP2E1 and CYP3A1/3A2 activities. In conclusion, we have identified imidazole-dioxolanes that are able to inhibit microsomal HO in vitro with high selectivity for HO-1 compared to HO-2, and little or no effect on the activities of neuronal NOS and sGC. These molecules could be used to facilitate studies on the elucidation of physiological roles of HO/CO in biological systems.

  View details for DOI 10.1038/sj.bjp.0706555

  View details for Web of Science ID 000235152100010

  View details for PubMedID 16331285

  View details for PubMedCentralID PMC1751307

• Dose-dependent effects of tin mesoporphyrin on heme oxygenase activity inhibition in newborn mice. Western Regional Meeting of the American-Federation-for-Medical-Research Morioka, I., Wong, R. J., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2006: S128–S128

  View details for Web of Science ID 000235301500293

• Heme oxygenase activity in the mouse placenta during fetal development. Zhao, H., Wong, R. J., Morioka, Kalish, F. A., Stevenson, D. K. B C DECKER INC. 2006: S128

  View details for Web of Science ID 000235301500294

• Metalloporphyrin inhibition of in vitro mouse heme oxygenase isozyme activity. Western Regional Meeting of the American-Federation-for-Medical-Research Pierce, N. W., Wong, R. J., Morioka, I., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2006: S120–S121

  View details for Web of Science ID 000235301500251

• Statins as tissue-specific inducers of in vivo heme oxygenase expression Western Regional Meeting of the American-Federation-for-Medical-Research HSU, M., Muchova, L., Morioka, I., Wong, R. J., Schroder, H., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2006: S86–S86

  View details for Web of Science ID 000235301500051

• Statins as tissue-specific inducers of in vivo heme oxygenase expression. Western Regional Meeting of the American-Federation-for-Medical-Research HSU, M., Muchova, L., Morioka, I., Wong, R. J., Schroder, H., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2006: S121–S121

  View details for Web of Science ID 000235301500252

• Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy NEW ENGLAND JOURNAL OF MEDICINE Shankaran, S., Laptook, A. R., Ehrenkranz, R. A., TYSON, J. E., McDonald, S. A., Donovan, E. F., Fanaroff, A. A., Poole, W. K., Wright, L. L., Higgins, R. D., Finer, N. N., Carlo, W. A., Duara, S., Oh, W., Cotten, C. M., Stevenson, D. K., Stoll, B. J., Lemons, J. A., Guillet, R., Jobe, A. H. 2005; 353 (15): 1574-1584

  Abstract

  Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain.We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability.Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20).Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.

  View details for Web of Science ID 000232486000011

  View details for PubMedID 16221780

• Inhaled nitric oxide - Reply NEW ENGLAND JOURNAL OF MEDICINE Van Meurs, K., Stevenson, D. 2005; 353 (15): 1627

  View details for Web of Science ID 000232486000025

• Apigenin decreases hemin-mediated heme oxygenase-1 induction FREE RADICAL BIOLOGY AND MEDICINE Abate, A., Yang, G., Wong, R. J., Schroder, H., Stevenson, D. K., Dennery, P. A. 2005; 39 (6): 711-718

  Abstract

  Hemin is a strong inducer of heme oxygenase-1 (HO-1) expression in vitro and in vivo. Whereas moderate overexpression of HO-1 is protective against oxidative stress, uncontrolled levels of HO-1 can be detrimental. Therefore, we evaluated the effects of apigenin (APG), a flavonoid involved in a number of phosphorylation pathways and also known to inhibit inducible genes, such as iNOS and COX-2, on HO-1 expression. Incubation of mouse embryonic fibroblasts with APG (5--40 microM) decreased hemin-induced HO-1 protein and mRNA expression. APG also reduced the induction of HO-1 promoter activity, as assessed by bioluminescence imaging, in NIH3T3 cells transfected with the 15-kb HO-1 promoter fused with the reporter gene luciferase (HO-1-luc). Furthermore, through the use of specific inhibitors, APG's effect was found to be unrelated to its PKC, CK 2, PI 3 K, p38, or ERK inhibitory activities. Quercetin (10--40 microM), also a flavonoid, also inhibited hemin-induced HO-1 expression. Additionally, in vivo studies using HO-1-luc transgenic mice showed that APG (50 mg/kg) decreased hemin-induced HO activity and HO-1 protein expression in the liver. These results suggest that hemin-induced HO-1 expression can be attenuated by flavonoids, such as APG.

  View details for DOI 10.1016/j.freeradbiomed.2005.01.020

  View details for PubMedID 16109301

• Reducing Candida infections during neonatal intensive care: Management choices, infection control, and fluconazole prophylaxis JOURNAL OF PEDIATRICS Long, S. S., Stevenson, D. K. 2005; 147 (2): 135-141

  View details for DOI 10.1016/j.jpeds.2005.04.033

  View details for Web of Science ID 000231785000002

  View details for PubMedID 16126036

• Determination of carbon monoxide (CO) in rodent tissue: Effect of heme administration and environmental CO exposure ANALYTICAL BIOCHEMISTRY Vreman, H. J., Wong, R. J., Kadotani, T., Stevenson, D. K. 2005; 341 (2): 280-289

  Abstract

  Carbon monoxide (CO), produced endogenously during heme degradation, is considered a messenger molecule in vascular and neurologic tissues. To study this role, it is important to determine CO concentration in target tissues pre- and post-perturbations. Here, we describe a sensitive and reproducible method, which is linear and accurate, and provide some examples of its application for quantitation of CO concentrations in tissues pre- and post-perturbations. Tissues from adult rats and mice were sonicated (20% w/w), and volumes representing 0.04-8 mg fresh weight (FW) were incubated at 0 degrees C for 30 min with sulfosalicylic acid. CO liberated into the headspace was quantitated by gas chromatography. Tissue CO concentrations (mean+/-SD, pmol CO/mg FW) were as follows: blood (47+/-10, 45+/-5), muscle (4+/-4, 10+/-1), kidney (5+/-2, 7+/-2), heart (6+/-3, 6+/-1), spleen (11+/-3, 6+/-1), liver (4+/-1, 5+/-1), intestine (2+/-1, 4+/-2), lung (2+/-1, 3+/-1), testes (1+/-1, 2+/-1), and brain (2+/-1, 2+/-0) in untreated rat (n=3) and mouse (n=5), respectively. Between the rat and the mouse, only CO concentrations in the muscle and spleen were significantly different (p0.05). Endogenous CO generation, after administration of heme arginate to mice (n=3), increased CO concentrations by 0-43 pmol/mg FW. Exposure of mice (n=3) to 500 ppm CO for 30 min yielded significantly elevated CO concentrations by 4-2603 pmol/mg FW in all tissues over the native state. While blood had the highest CO concentration for all conditions, muscle, kidney, heart, spleen, and liver, all rich in hemoglobin and/or other CO-binding hemoproteins, also contained substantial CO concentrations. Intestine, lung, testes, and brain contained the lowest CO concentrations.

  View details for DOI 10.1016/j.ab.2005.03.019

  View details for PubMedID 15907874

• Glucose-6-phosphate dehydrogenase activity in term and near-term, male African American neonates CLINICA CHIMICA ACTA Kaplan, M., Hoyer, J. D., Herschel, M., Hammerman, C., Stevenson, D. K. 2005; 355 (1-2): 113-117

  Abstract

  We determined values for glucose-6-phosphate dehydrogenase (G-6-PD) activity in African American neonates.G-6-PD activity was measured on umbilical cord blood from term and near-term healthy, male neonates. Neonates were stratified according to the number of neonates for each numerical unit of G-6-PD activity. Corrected end tidal carbon monoxide (ETCOc), a non-invasive index of hemolysis, was performed on each neonate. At least one predischarge transcutaneous bilirubin determination was performed.Five hundred neonates were studied. Two subpopulations were apparent, with no overlap between the subgroups. Mean value for the 64 (12.8%) infants with the lower values (G-6-PD deficient) was 2.7+/-1.1 U/g Hb, range 0.4-6.6 U/g Hb, while that for the 436 neonates with the higher values (G-6-PD normal) was 21.8+/-2.9 U/g Hb, range 14.5-33.8 U/g Hb. No significant differences in activity were noted between those neonates <37 weeks gestational age and those >37 weeks. Enzyme activity in the lower range in both groups was not related to the development of hyperbilirubinemia. G-6-PD enzyme activity did not correlate with ETCOc values either for the entire cohort or for the individual subsets.G-6-PD-deficient neonates formed a separate subgroup from those with normal enzyme activity. The data supplied should facilitate interpretation of G-6-PD test results.

  View details for DOI 10.1016/j.cccn.2004.12.008

  View details for Web of Science ID 000228707500014

  View details for PubMedID 15820485

• Reduction in red blood cell transfusions among preterm infants: Results of a randomized trial with an in-line blood gas and chemistry monitor PEDIATRICS Widness, J. A., Madan, A., Grindeanu, L. A., Zimmerman, B., Wong, D. K., Stevenson, D. K. 2005; 115 (5): 1299-1306

  Abstract

  Critically ill, extremely premature infants develop anemia because of intensive laboratory blood testing and undergo multiple red blood cell (RBC) transfusions in the early weeks of life. To date, researchers have had only limited success in finding ways to reduce transfusions significantly in this patient population.To reduce RBC transfusions for these infants by using a point-of-care bedside monitor that returns analyzed blood to the patient.This was a prospective, 2-center, randomized, open, controlled, clinical trial with a 1:1 assignment of extremely low birth weight infants (weighing 500-1000 g at birth) to control or monitor groups and analysis with the intention-to-treat approach. Predefined RBC transfusion criteria were applied uniformly in the 2 groups.Clinical treatment of study subjects with an in-line, ex vivo, bedside monitor that withdraws blood through an umbilical artery catheter, analyzes blood gases and sodium, potassium, and hematocrit levels, and returns the sample to the patient.The total volume and number of RBC transfusions during the first 2 weeks of life and the total volume of blood removed for laboratory testing.The trial was terminated prematurely when one center's NICU changed its standard method of laboratory testing. In the first 2 weeks of life, there was a nonsignificant 17% lower cumulative RBC transfusion volume in the monitor group (n = 46), compared with the control group (n = 47). However, data from the first week only (the period of greater catheter use) demonstrated a significant 33% lower cumulative RBC transfusion volume in the monitor group. Cumulative phlebotomy loss was approximately 25% less in the monitor group throughout the 2-week study period. There was no difference between groups in neonatal mortality, morbidity, and neurodevelopmental outcome rates at 18 to 24 months. This is the first randomized trial documenting that RBC transfusions administered to neonates can by reduced by decreasing laboratory phlebotomy loss.As long as an umbilical artery catheter is available for blood sampling with an in-line blood gas and chemistry monitor, significant reductions in neonatal RBC transfusions can be achieved. The patients most likely to benefit from monitor use are the smallest, most critically ill newborns.

  View details for DOI 10.1542/peds.2004-1680

  View details for Web of Science ID 000228833500029

  View details for PubMedID 15867038

  View details for PubMedCentralID PMC2867083

• Apigenin decreases hemin-mediated heme oxygenase-1 induction Experimental Biology 2005 Meeting/35th International Congress of Physiological Sciences Abate, A., Yang, G., Wong, R. J., Schroder, H., Stevenson, D. K., Dennery, P. A. FEDERATION AMER SOC EXP BIOL. 2005: A1378–A1378

  View details for Web of Science ID 000227610902563

• Neonatal bilirubin production-conjugation imbalance: effect of glucose-6-phosphate dehydrogenase deficiency and borderline prematurity Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Kaplan, M., Muraca, M., Vreman, H. J., Hammerman, C., Vilei, M. T., Rubaltelli, F. F., Stevenson, D. K. BMJ PUBLISHING GROUP. 2005: 123–27

  View details for Web of Science ID 000230340700008

• Is carbon monoxide-mediated cyclic guanosine monophosphate production responsible for low blood pressure in neonatal respiratory distress syndrome? JOURNAL OF APPLIED PHYSIOLOGY van Bel, F., Latour, V., Vreman, H. J., Wong, R. J., Stevenson, D. K., Steendijk, P., Egberts, J., Krediet, T. G. 2005; 98 (3): 1044-1049

  Abstract

  Infant respiratory distress syndrome (RDS) involves inflammatory processes, causing an increased expression of inducible heme oxygenase with subsequent production of carbon monoxide (CO). We hypothesized that increased production of CO during RDS might be responsible for increased plasma levels of vasodilatory cGMP and, consequently, low blood pressure observed in infants with RDS. Fifty-two infants (no-RDS, n = 21; RDS, n = 31), consecutively admitted to the neonatal intensive care unit (NICU) between January and October 2003 were included. Hemoglobin-bound carbon monoxide (COHb), plasma cGMP, plasma nitric oxide (NOx), and bilirubin were determined at 0-12, 48-72, and at 168 h postnatally, with simultaneous registration of arterial blood pressure. Infants with RDS had higher levels of cGMP and COHb compared with no-RDS infants (RDS vs. no-RDS: cGMP ranging from 76 to 101 vs. 58 to 82 nmol/l; COHb ranging from 1.2 to 1.4 vs. 0.9 to 1.0%). Highest values were reached at 48-72 h [RDS vs. no-RDS mean (SD): cGMP 100 (39) vs. 82 (25) nmol/l (P < 0.001); COHb 1.38 (0.46) vs. 0.91 (0.26)% (P < 0.0001)]. Arterial blood pressure was lower and more blood pressure support was needed in RDS infants at that point of time [RDS vs. no-RDS mean (SD): mean arterial blood pressure 33 (6) vs. 42 (5) mmHg (P < 0.05)]. NOx was not different between groups and did not vary with time. Multiple linear regression analysis showed a significant correlation between cGMP and COHb, suggesting a causal relationship. Mean arterial blood pressure appeared to be primarily correlated to cGMP levels (P < 0.001). We conclude that a CO-mediated increase in cGMP causes systemic vasodilation with a consequent lower blood pressure and increased need for blood pressure support in preterm infants with RDS.

  View details for DOI 10.1152/japplphysiol.00760.2004

  View details for Web of Science ID 000226863100036

  View details for PubMedID 15516362

• Reduction in hospital readmission rates for hyperbilirubinemia is associated with use of transcutaneous bilirubin measurements CLINICAL CHEMISTRY Stevenson, D. K., Wong, R. J., Vreman, H. J. 2005; 51 (3): 481-482

  View details for DOI 10.1373/clinchem.2004.046789

  View details for Web of Science ID 000227230600001

  View details for PubMedID 15738511

• Pentaerythritol tetranitrate reduces free radical formation in endothelial cells and macrophages involvement of HEME oxygenase-1 46th Spring Meeting of the Deutsche-Gesellschaft-fur-Experimentelle-und-Klinische-Pharmakologie-und-Toxikologie Schulz, S., Oberle-Plumpe, S., Grosser, N., Abate, A., Vreman, H. J., Dennery, P. A., Stevenson, D. K., Schroder, H. SPRINGER. 2005: R40–R40

  View details for Web of Science ID 000229046800166

• Attenuation of heme induction following exposure to tin mesoporphyrin in mice. DeSandre, G. H., Wong, R. J., Morioka, I., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2005: S125–S125

  View details for Web of Science ID 000226539700280

• Effects of metalloporphyrins on survival of mice following oral Salmonella infection. Burns, S. M., Wong, R. J., Contag, C. F., Stevenson, D. K. B C DECKER INC. 2005: S125

  View details for Web of Science ID 000226539700281

• Oral administration of metalloporphyrins and its systemic effects on heme oxygenase expression. Morioka, Wong, R. J., Abate, A., Vreman, H. J., Contag, C. H., Stevenson, D. K. B C DECKER INC. 2005: S125

  View details for Web of Science ID 000226539700282

• Apigenin decreases hemin-mediated heme oxygenase-1 induction. Abate, A., Yang, G., Wong, R. J., Schroder, H., Stevenson, D. K., Dennery, P. A. B C DECKER INC. 2005: S125

  View details for Web of Science ID 000226539700283

• Internal capsule abnormalities on neonatal brain MRI are associated with later gait disorders in very low birth weight preterm children at 4 years. Rose, J., Mirmiran, M., Butler, E. E., Lin, C., Barnes, P. D., Kermoian, R., Stevenson, D. K., Ariagno, R. L. LIPPINCOTT WILLIAMS & WILKINS. 2005: S126–S126

  View details for Web of Science ID 000226539700286

• Phototherapy and photo-oxidation in premature neonates BIOLOGY OF THE NEONATE Kaplan, M., Gold, V., Hammerman, C., Hochman, A., Goldschmidt, D., Vreman, H. J., Stevenson, D. K. 2005; 87 (1): 44-50

  Abstract

  The potential for photo-oxidation during phototherapy in premature neonates was assessed by measuring parameters reflective of photo-oxidation.Blood was sampled from premature neonates prior to, and after 4 and 24 h of phototherapy, respectively. Total plasma bilirubin (TPB), blood carboxyhemoglobin corrected for inspired carbon monoxide (COHbc) (a sensitive index of heme catabolism), blood thiobarbituric acid reacting substances (TBARS) (a measure of lipid peroxidation), and plasma protein carbonyls (representative of protein oxidation) were determined. Study measurements were compared with baseline values both for the entire study group, and also individually for subgroups < and > or = 1.5 kg birthweight, respectively. The percentage difference (%delta) between baseline and the 24-hour measurement was calculated for each parameter.Forty-one premature neonates (mean [+/- SD] gestational age 30.5 +/- 2.7 weeks and birthweight 1,499 +/- 448 g) were studied. Mean TPB values decreased from a baseline of 9.1 +/- 2.3 to one of 7.2 +/- 2.8 mg/dl, p < 0.01, during the first 24 h of phototherapy. For the entire patient sample, neither COHbc, TBARS or protein carbonyl values increased significantly over baseline measurements: COHbc: 0.90 +/- 0.26% vs. 0.92 +/- 0.32%; TBARS: 19.0 +/- 5.6 vs. 18.0 +/- 4.5 nmol/ml, and protein carbonyls 7.73 +/- 3.78 vs. 7.63 +/- 3.56 U/ml (baseline and 24-hour samples only are shown in the abstract). Similarly, for the entire group, %delta (mean, interquartile range) were not significantly different between COHbc [-3.77 (-15.89-17.65)%], TBARS [-7.47 (-17.37-7.38)%], and protein carbonyls [-1.47 (-28.51-43.48)%], respectively. For subgroup analysis of neonates < or > or = 1.5 kg birthweight, respectively, no significant increases in COHbc, TBARS or protein carbonyls were documented. A significant increase in %delta for COHbc in the <1.5 kg birthweight subgroup compared with those > or =1.5 kg, possibly indicative of hemolysis, was not matched by similar changes in %delta for TBARS or protein carbonyls, and may therefore not be a result of photo-oxidation.Except for changes in %delta in COHbc alone and in the smallest babies only, overall, short term phototherapy in premature infants was effective in reducing TPB concentrations without associated evidence reflective of photo-oxidation.

  View details for DOI 10.1159/000081085

  View details for Web of Science ID 000226010200010

  View details for PubMedID 15467291

• NICHD Conference on Kernicterus: Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: Bench-to-Bedside--Diagnostic Methods and Prevention and Treatment Strategies. Journal of perinatology Stevenson, D. K., Wong, R. J., Vreman, H. J., McDonagh, A. F., Maisels, M. J., Lightner, D. A. 2004; 24 (8): 521-525

  Abstract

  In July 2003, the National Institute of Child Health and Human Development (NICHD) organized a consensus conference, where a group of experts were invited to review and discuss the current state of knowledge regarding neonatal hyperbilirubinemia and identify areas in which where future research should be directed. This paper summarizes the presentations addressing the current methodologies for direct and noninvasive assessments of serum total bilirubin concentrations as well as prevention and treatment strategies for the management of neonatal hyperbilirubinemia.

  View details for PubMedID 15129227

• Hyperbilirubinemia among African American, glucose-6-phosphate dehydrogenase-deficient neonates Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Kaplan, M., Herschel, M., Hammerman, C., Hoyer, J. D., Stevenson, D. K. AMER ACAD PEDIATRICS. 2004: 213–19

  View details for Web of Science ID 000223040000054

• Cesarean delivery rates and neonatal morbidity in a low-risk population OBSTETRICS AND GYNECOLOGY Gould, J. B., Danielsen, B., Korst, L. M., Phibbs, R., Chance, K., Main, E., Wirtschafter, D. D., Stevenson, D. K. 2004; 104 (1): 11-19

  Abstract

  To estimate the relationship between case-mix adjusted cesarean delivery rates and neonatal morbidity and mortality in infants born to low-risk mothers.This retrospective cohort study used vital and administrative data for 748,604 California singletons born without congenital abnormalities in 1998-2000. A total of 282 institutions was classified as average-, low-, or high-cesarean delivery hospitals based on their cesarean delivery rate for mothers without a previous cesarean delivery, in labor at term, with no evidence of maternal, fetal, or placental complications. Neonatal mortality, diagnoses, and therapeutic interventions determined by International Classification of Diseases, 9th Revision, Clinical Modification codes, and neonatal length of stay were compared across these hospital groupings.Compared with average-cesarean delivery-rate hospitals, infants born to low-risk mothers at low-cesarean delivery hospitals had increased fetal hemorrhage, birth asphyxia, meconium aspiration syndrome, feeding problems, and electrolyte abnormalities (P <.02). Infused medication, pressors, transfusion for shock, mechanical ventilation, and length of stay were also increased (P <.001). This suggests that some infants born in low-cesarean delivery hospitals might have benefited from cesarean delivery. Infants delivered at high-cesarean delivery hospitals demonstrated increased fetal hemorrhage, asphyxia, birth trauma, electrolyte abnormalities, and use of mechanical ventilation (P <.001), suggesting that high cesarean delivery rates themselves are not protective.Neonatal morbidity is increased in infants born to low-risk women who deliver at both low- and high-cesarean delivery-rate hospitals. The quality of perinatal care should be assessed in these outlier hospitals.III

  View details for DOI 10.1097/01.AOG.0000127035.64602.97

  View details for PubMedID 15228995

• Continuous, noninvasive, and localized microvascular tissue oximetry using visible light spectroscopy ANESTHESIOLOGY Benaron, D. A., Parachikov, I. H., Friedland, S., Soetikno, R., Brock-Utne, J., van der Starre, P. J., Nezhat, C., Terris, M. K., Maxim, P. G., Carson, J. J., Razavi, M. K., Gladstone, H. B., Fincher, E. F., Hsu, C. P., Clark, F. L., Cheong, W. F., Duckworth, J. L., Stevenson, D. K. 2004; 100 (6): 1469-1475

  Abstract

  The authors evaluated the ability of visible light spectroscopy (VLS) oximetry to detect hypoxemia and ischemia in human and animal subjects. Unlike near-infrared spectroscopy or pulse oximetry (SpO2), VLS tissue oximetry uses shallow-penetrating visible light to measure microvascular hemoglobin oxygen saturation (StO2) in small, thin tissue volumes.In pigs, StO2 was measured in muscle and enteric mucosa during normoxia, hypoxemia (SpO2 = 40-96%), and ischemia (occlusion, arrest). In patients, StO2 was measured in skin, muscle, and oral/enteric mucosa during normoxia, hypoxemia (SpO2 = 60-99%), and ischemia (occlusion, compression, ventricular fibrillation).In pigs, normoxic StO2 was 71 +/- 4% (mean +/- SD), without differences between sites, and decreased during hypoxemia (muscle, 11 +/- 6%; P < 0.001) and ischemia (colon, 31 +/- 11%; P < 0.001). In patients, mean normoxic StO2 ranged from 68 to 77% at different sites (733 measures, 111 subjects); for each noninvasive site except skin, variance between subjects was low (e.g., colon, 69% +/- 4%, 40 subjects; buccal, 77% +/- 3%, 21 subjects). During hypoxemia, StO2 correlated with SpO2 (animals, r2 = 0.98; humans, r2 = 0.87). During ischemia, StO2 initially decreased at -1.3 +/- 0.2%/s and decreased to zero in 3-9 min (r2 = 0.94). Ischemia was distinguished from normoxia and hypoxemia by a widened pulse/VLS saturation difference (Delta < 30% during normoxia or hypoxemia vs. Delta > 35% during ischemia).VLS oximetry provides a continuous, noninvasive, and localized measurement of the StO2, sensitive to hypoxemia, regional, and global ischemia. The reproducible and narrow StO2 normal range for oral/enteric mucosa supports use of this site as an accessible and reliable reference point for the VLS monitoring of systemic flow.

  View details for Web of Science ID 000221551300018

  View details for PubMedID 15166566

• Transcutaneous bilirubin measurements and serum total bilirubin levels in indigenous African infants PEDIATRICS Slusher, T. M., Angyo, I. A., Bode-Thomas, F., Akor, F., Pam, S. D., Adetunji, A. A., McLaren, D. W., Wong, R. J., Vreman, H. J., Stevenson, D. K. 2004; 113 (6): 1636-1641

  Abstract

  The objective of this study was to determine whether transcutaneous bilirubin (TcB) measurements correlate with serum total bilirubin (STB) levels in indigenous, darkly pigmented African newborns with varying degrees of skin pigmentation, some of which had developed kernicterus.Jaundiced infants who were < or =2 weeks of age and admitted to Baptist Medical Center-Eku (Eku; n = 29) and Jos University Teaching Hospital (Jos; n = 98) in Nigeria were studied. TcB measurements using the BiliChek were made simultaneously with blood sampling for STB measurements by spectrophotometry before phototherapy.Using linear regression analysis, we found that measurements of TcB correlated well with those of STB with r values of.90 and.88 for Eku and Jos, respectively. Mean bias and imprecision of TcB measurements as compared with STB measurements for the total population was 0.5 +/- 7.6 mg/dL using the method of Bland and Altman. At STB > or 12 mg/dL, correlation (r =.84) and bias and imprecision (-1.2 +/- 8.6 mg/dL) of measurements were only slightly poorer. Furthermore, when infants were grouped by degree of skin pigmentation, correlations of TcB and STB measurements remained strong.From these results, we can conclude that TcB measurements are a useful and reliable index for estimating STB levels in pigmented neonates, including those with hyperbilirubinemia and kernicterus. In the absence of reliable STB measurements, the relatively simple and noninvasive TcB measurements can be an important adjunct in directing phototherapy and exchange transfusions, thereby preventing bilirubin-induced morbidity and mortality in low-technology clinical environments.

  View details for Web of Science ID 000221781500012

  View details for PubMedID 15173484

• Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants Annual Meeting of the Pediatric-Academic-Societies Poindexter, B. B., Ehrenkranz, R. A., Stoll, B. J., Wright, L. L., Poole, W. K., Oh, W., Bauer, C. R., Papile, L. A., TYSON, J. E., Carlo, W. A., Laptook, A. R., Narendran, V., Stevenson, D. K., Fanaroff, A. A., Korones, S. B., Shankaran, S., Finer, N. N., Lemons, J. A. AMER ACAD PEDIATRICS. 2004: 1209–15

  Abstract

  Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions. Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults. Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known.We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants. Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital. The primary outcome was death or late-onset sepsis.Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97-1.17). Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth. No significant adverse events were observed with glutamine supplementation.Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants. Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population.

  View details for Web of Science ID 000221169200006

  View details for PubMedID 15121931

• To tap or not to tap: High likelihood of meningitis without sepsis among very low birth weight infants PEDIATRICS Stoll, B. J., Hansen, N., Fanaroff, A. A., Wright, L. L., Carlo, W. A., Ehrenkranz, R. A., Lemons, J. A., Donovan, E. F., Stark, A. R., TYSON, J. E., Oh, W., Bauer, C. R., Korones, S. B., Shankaran, S., Laptook, A. R., Stevenson, D. K., Papile, L. A., Poole, W. K. 2004; 113 (5): 1181-1186

  Abstract

  Neonatal meningitis is associated with significant morbidity and mortality. We speculated that meningitis may be underdiagnosed among very low birth weight (VLBW) infants because of the failure to perform lumbar punctures (LPs) in infants with suspected sepsis.This study was undertaken to review the epidemiology of late-onset meningitis in VLBW (401-1500 g) infants and to evaluate the concordance of cerebrospinal fluid (CSF) and blood culture (BC) results.VLBW infants (excluding those with intraventricular shunts) born at centers of the National Institute of Child Health and Human Development Neonatal Research Network from September 1, 1998, through December 31, 2001, were studied. Late-onset meningitis was defined by culture-based criteria and classified as meningitis with or without associated sepsis. Unadjusted comparisons were made using chi2 tests and adjusted comparisons using regression models.Of 9641 VLBW infants who survived >3 days, 2877 (30%) had > or = 1 LPs, and 6056 (63%) had > or = 1 BC performed after day 3. One hundred thirty-four infants had late-onset meningitis (1.4% of all patients; 5% of those with an LP). Pathogens associated with meningitis were similar to those associated with sepsis. One third (45 of 134) of the infants with meningitis had negative BCs. Lower gestational age and prior sepsis increased risk for meningitis. Compared with uninfected infants, those with meningitis had a longer time on mechanical ventilation (28 vs 18 days), had longer hospitalizations (91 vs 79 days), were more likely to have seizures (25% vs 2%), and were more likely to die (23% vs 2%).Meningitis is a serious complication among VLBW infants, associated with increased severity of illness and risk of death. Of note, one third of the infants with meningitis had meningitis in the absence of sepsis. Because CSF cultures were performed only half as often as BCs, this discordance in blood and CSF culture results suggests that meningitis may be underdiagnosed among VLBW infants.

  View details for Web of Science ID 000221169200002

  View details for PubMedID 15121927

• End tidal carbon monoxide levels are lower in women with gestational hypertension and pre-eclampsia. Journal of perinatology Kreiser, D., Baum, M., Seidman, D. S., Fanaroff, A., Shah, D., Hendler, I., Stevenson, D. K., Schiff, E., Druzin, M. L. 2004; 24 (4): 213-217

  Abstract

  The possible role of heme oxygenase and its byproduct carbon monoxide (CO) in the regulation of blood pressure is under investigation. The aim of this study was to compare end tidal breath CO (ETCO) levels in women with gestational hypertension (GH) or pre-eclampsia to the levels in healthy pregnant and nonpregnant women.We prospectively performed ETCO measurements corrected for ambient CO (ETCOc) in two medical centers (Stanford, CA and Cleveland, OH). A Natus CO-Stat End Tidal Breath Analyzer (Natus Medical Inc., San Carlos, CA) was used. The study group included a convenience sample of 31 women with GH/pre-eclampsia (PE). Control groups included 46 nonpregnant healthy women, 44 first-trimester and 48 third-trimester pregnant healthy women.Mean+/-SD ETCOc measurements were significantly lower in the GH/PE group compared to first-trimester (p=0.004) and third-trimester (p=0.001) normotensive pregnant and nonpregnant women (p=0.002) (1.36+/-0.30 vs 1.76+/-0.47, 1.72+/-0.42 and 1.78+/-0.54 ppm, respectively). The ETCOc values were < or =1.6 ppm in 89% of GH/PE women compared with, respectively, only 45, 54, and 46% of nonpregnant, first- and third-trimester normotensive pregnant women (p<0.05). ETCO measurements were not influenced by maternal age, parity, ethnicity, body mass index, gestational age or presence of household smokers. In the two centers, the controls had a similar mean ETCOc and the differences found remained significant when results for each center were analyzed separately.ETCOc levels were found to be significantly lower in women with GH/PE. Further investigation is required to determine if the lower CO levels reflect a deficient compensatory response to the increase in blood pressure or whether these are primary changes of significance to our understanding of the pathogenesis of GH/PE.

  View details for PubMedID 15014533

• Does decreasing G6PD enzyme activity level affect hemolysis and hyperbilirubinemia in G6PD deficient neonates? Kaplan, M., Herschel, M., Hoyer, J. D., Hammerman, C., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2004: 459A

  View details for Web of Science ID 000220591102673

• Hyperbilirubinemia in G6PD deficient African American neonates: A potential public health concern Kaplan, M., Herschel, M., Hammerman, C., Hoyer, J. D., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2004: 460A

  View details for Web of Science ID 000220591102674

• Can end tidal CO predict hyperbilirubinemia in G6PD deficient neonates? Herschel, M., Kaplan, M., Hammerman, C., Hoyer, J. D., Karrison, T., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2004: 460A

  View details for Web of Science ID 000220591102675

• Early measurement of ErC0c to identify neonates with hemolysis at birth who are at risk for hyperbilirubinemia in the first 24 hours Herschel, M. I., Karrison, T., Kaplan, M., Hammerman, C., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2004: 543A

  View details for Web of Science ID 000220591103160

• Dynamics of heme oxygenase-1 expression in infection of young mice Annual Meeting of the Pediatric-Academic-Societies Burns, S. M., Wong, R. J., Contag, C. H., Stevenson, D. K. NATURE PUBLISHING GROUP. 2004: 472A–472A

  View details for Web of Science ID 000220591102744

• Tissue-specific effects of dexamethasone on heme oxygenase-1 expression in mice Annual Meeting of the Pediatric-Academic-Societies Mizobuchi, M., Wong, R. J., Zhao, H., Abate, A., Vreman, H. J., Contag, H., Stevenson, D. K. NATURE PUBLISHING GROUP. 2004: 459A–459A

  View details for Web of Science ID 000220591102672

• Role of CpG island methylation in the developmental regulation of heme oxygenase-1 expression in the developing mouse brain Annual Meeting of the Pediatric-Academic-Societies Zhao, H., Wong, R. J., Mizobuchi, M., Contag, C. H., Stevenson, D. K. NATURE PUBLISHING GROUP. 2004: 422A–422A

  View details for Web of Science ID 000220591102464

• Phototherapy devices for the treatment of patients with type 1 Crigler-Najjar syndrome Annual Meeting of the Pediatric-Academic-Societies Vreman, H. J., Strauss, K. A., Morton, D. H., Robinson, D. L., Puffenberger, E. G., Martin, F., Martin, K., Carmichael, A., Wong, R. J., Stevenson, D. K. NATURE PUBLISHING GROUP. 2004: 561A–561A

  View details for Web of Science ID 000220591103259

• Induction of heme oxygenase-1 in transgenic mouse fibroblast cells following successive exposures to heme Annual Meeting of the Pediatric-Academic-Societies DeSandre, G. H., Wong, R. J., Vreman, H. J., Stevenson, D. K. NATURE PUBLISHING GROUP. 2004: 473A–473A

  View details for Web of Science ID 000220591102746

• Characterization of coelenterazine analogs for measurements of Renilla luciferase activity in live cells and living animals. Molecular imaging Zhao, H., Doyle, T. C., Wong, R. J., Cao, Y., Stevenson, D. K., Piwnica-Worms, D., Contag, C. H. 2004; 3 (1): 43-54

  Abstract

  In vivo imaging of bioluminescent reporters relies on expression of light-emitting enzymes, luciferases, and delivery of chemical substrates to expressing cells. Coelenterazine (CLZN) is the substrate for a group of bioluminescent enzymes obtained from marine organisms. At present, there are more than 10 commercially available CLZN analogs. To determine which analog is most suitable for activity measurements in live cells and living animals, we characterized 10 CLZN analogs using Renilla luciferase (Rluc) as the reporter enzyme. For each analog, we monitored enzyme activity, auto-oxidation, and efficiency of cellular uptake. All CLZN analogs tested showed higher auto-oxidation signals in serum than was observed in phosphate buffer or medium, mainly as a result of auto-oxidation by binding to albumin. CLZN-f, -h, and -e analogs showed 4- to 8-fold greater Rluc activity, relative to CLZN-native, in cells expressing the enzyme from a stable integrant. In studies using living mice expressing Rluc in hepatocytes, administration of CLZN-e and -native produced the highest signal. Furthermore, distinct temporal differences in signal for each analog were revealed following intravenous or intraperitoneal delivery. We conclude that the CLZN analogs that are presently available vary with respect to hRluc utilization in culture and in vivo, and that the effective use of CLZN-utilizing enzymes in living animals depends on the selection of an appropriate substrate.

  View details for PubMedID 15142411

• Induction of heme oxygenase-1 in mouse fibroblast cells after successive exposures to heme. Western Regional Meeting of the American-Federation-for-Medical-Research DeSandre, G. H., Wong, R. J., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2004: S122–S122

  View details for Web of Science ID 000188254600268

• Gestational pattern of heme oxygenase expression in the rat PEDIATRIC RESEARCH Kreiser, D., Kelly, D. K., Seidman, D. S., Stevenson, D. K., Baum, M., Dennery, P. A. 2003; 54 (2): 172-178

  Abstract

  Fetal growth is influenced by many intrinsic and extrinsic factors. Our objective was to determine the pattern of heme oxygenase (HO) expression in the pregnant rat and to study its association with fetal growth and growth factors. Uterine tissues were obtained from nonpregnant and from time-mated rats at 7, 13, 16, 19, and 21 d of pregnancy. Placental tissue was obtained on d 13, 16, 19 and 21 of pregnancy. Tissues were evaluated for HO activity, HO-1, HO-2, leptin and vascular endothelial growth factor protein, and HO-1 and HO-2 mRNA. HO activity in both the uterus and placenta peaked on d 21 of pregnancy. In the uterus, HO-1 and HO-2 protein and total mRNA levels peaked on d 16 of pregnancy, whereas, in the placenta, HO-1 and HO-2 protein levels peaked on d 19. Additionally, placental HO-1 mRNA peaked on d 16, but placental HO-2 mRNA declined toward the end of pregnancy. Placental leptin and vascular endothelial growth factor protein levels followed a similar pattern to placental HO-1 and peaked on d 16. We conclude that there is a clear uterine and placental gestational pattern of HO expression in the rat. This pattern is comparable to that of vascular endothelial growth factor and leptin.

  View details for DOI 10.1203/01.PDR.0000072516.83498.07

  View details for PubMedID 12736392

• Avertin: A mixed function oxidase substrate for the production of endogenous carbon monoxide Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Min, S. Y., Vreman, H. J., Wong, R. J., Stevenson, D. K. NATURE PUBLISHING GROUP. 2003: 560A–560A

  View details for Web of Science ID 000181897903166

• Increased hemolysis in G6PD deficient African American neonates Herschel, M., Kaplan, M., Hammerman, C., Hoyer, J. D., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2003: 399A

  View details for Web of Science ID 000181897902259

• Gene interaction: UGT promoter polymorphism and mechanism of jaundice in G6PD deficient neonates Kaplan, M., Muraca, M., Vreman, H. J., Hammerman, C., Renbaum, P., Levy-Lahad, E., Vilei, M. T., Rubaltelli, F. F., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2003: 399A–400A

  View details for Web of Science ID 000181897902260

• Intestinal absorption of metalloporphyrins and systemic effects on heme oxygenase Wong, R. J., Abate, A., Dennery, P. A., Vreman, H. J., Contag, C. H., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2003: 400A

  View details for Web of Science ID 000181897902263

• Identifying key mediators of age-related susceptibility to gastrointestinal infections utilizing microarray analyses guided by bioluminescent imaging Burns, S. M., Shinde, R. R., Stevenson, D. K., Contag, C. H. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2003: 373A–374A

  View details for Web of Science ID 000181897902120

• Antioxidant levels in rat and mouse tissues as indexed by measurements of carbon monoxide in vitro Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Wong, R. J., Vreman, H. J., Stevenson, D. K. NATURE PUBLISHING GROUP. 2003: 65A–65A

  View details for Web of Science ID 000181897900368

• An expandable, portable blue LED-based phototherapy system Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Vreman, H. J., Wong, R. J., Deese, R. E., Zimmerman, L. W., Hampton, B. H., Stevenson, D. K. NATURE PUBLISHING GROUP. 2003: 512A–512A

  View details for Web of Science ID 000181897902892

• In vitro efficacy of an LED-based phototherapy device (neoBlue (TM)) compared to traditional light sources Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Vreman, H. J., Wong, R. J., Murdock, J. R., Stevenson, D. K. NATURE PUBLISHING GROUP. 2003: 400A–400A

  View details for Web of Science ID 000181897902265

• Effect of dexamethasone on heme oxygenase-1 expression of NIH3T3 cells Annual Meeting of the Pediatric-Academic-Societies/Society-for-Pediatric-Research Mizobuchi, M., Zhao, H., Wong, R. J., Vreman, H. J., Stevenson, D. K., Contag, C. H. NATURE PUBLISHING GROUP. 2003: 366A–367A

  View details for Web of Science ID 000181897902083

• Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants AMERICAN JOURNAL OF CLINICAL NUTRITION Poindexter, B. B., Ehrenkranz, R. A., Stoll, B. J., Koch, M. A., Wright, L. L., Oh, W., Papile, L. A., Bauer, C. R., Carlo, W. A., Donovan, E. F., Fanaroff, A. A., Korones, S. B., Laptook, A. R., Shankaran, S., Stevenson, D. K., TYSON, J. E., Lemons, J. A. 2003; 77 (3): 737-743

  Abstract

  Glutamine is one of the most abundant amino acids in both plasma and human milk and may be conditionally essential in premature infants. However, glutamine is not provided by standard intravenous amino acid solutions.We assessed the effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants receiving parenteral nutrition (PN).A total of 141 infants with birth weights of 401-1000 g were randomly assigned to receive a standard intravenous amino acid solution that did not contain glutamine or an isonitrogenous amino acid solution with 20% of the total amino acids as glutamine. Blood samples were obtained just before initiation of study PN and again after the infants had received study PN (mean intake: 2.3 +/- 1.0 g amino acids x kg(-1) x d(-1)) for approximately 10 d.Infants randomly assigned to receive glutamine had mean plasma glutamine concentrations that increased significantly and were approximately 30% higher than those in the control group in response to PN (425 +/- 182 and 332 +/- 148 micromol/L for the glutamine and control groups, respectively). There was no significant difference between the 2 groups in the relative change in plasma glutamate concentration between the baseline and PN samples. In both groups, there were significant decreases in plasma phenylalanine and tyrosine between the baseline and PN samples; the decrease in tyrosine was greater in the group that received glutamine.In extremely low-birth-weight infants, parenteral glutamine supplementation can increase plasma glutamine concentrations without apparent biochemical risk. Currently available amino acid solutions are likely to be suboptimal in their supply of phenylalanine, tyrosine, or both for these infants.

  View details for Web of Science ID 000181210600034

  View details for PubMedID 12600870

• Direct intestinal administration of metalloporphyrins and heme oxygenase expression. Western Regional Meeting of the American-Federation-for-Medical-Research Wong, R. J., Abate, A., Dennery, P. A., Vreman, H. J., Contag, C. H., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2003: S140–S141

  View details for Web of Science ID 000180569600291

• Ethical considerations in neuroimaging and its impact on decision-making for neonates BRAIN AND COGNITION Stevenson, D. K., Goldworth, A. 2002; 50 (3): 449-454

  Abstract

  Neuroimaging can now provide information about structure and function. Despite new and improved neuroimaging technologies applicable to the newborn, predictions about later cognition, learning, social and emotional behavior, and neuromuscular capabilities, based on images of a fetus inside or a newborn outside the womb, are fraught with difficulties that go beyond technical ones. The interpretation of neuroimages may be necessary but it is not sufficient for decision-making related to the withholding or withdrawing of medical support for neonates. As the explanatory reach of neuroimaging increases, there will still need to be consideration of ethical issues as they relate to the best interests of the neonate and the neonate's parents, the quality of life of the neonate and non-beneficial treatment. Once this is appreciated, the boundary between the technical and the ethical will be less often disputed.

  View details for PubMedID 12480489

• Interim analysis of a phase II study of the safety and efficacy of gemtuzumab ozogamicin (Mylotarg (R)) given in combination with cytarabine and daunorubicin to patients < 60 years old with untreated acute myeloid leukemia. De Angelo, D. J., Schiffer, C., Stone, R., Amrein, P., Fernandez, H., Bradstock, K., Tallman, M., Foran, J., Juliusson, G., Liu, D., Paul, C., Russo, D., Stenke, L., Leopold, L., Stevenson, D., Richie, M., Berger, M. AMER SOC HEMATOLOGY. 2002: 198A–199A

  View details for Web of Science ID 000179184700746

• A portable phototherapy bed. Vreman, H. J., Wong, R. J., Stevenson, D. K. SPRINGERNATURE. 2002: 783

  View details for Web of Science ID 000178977200052

• The jaundiced newborn. Understanding and managing transitional hyperbilirubinemia. Minerva pediatrica Stevenson, D. K., Wong, R. J., Hintz, S. R., Vreman, H. J. 2002; 54 (5): 373-382

  Abstract

  Neonatal jaundice is one of the most common conditions diagnosed by the pediatrician. This normally benign transitional phenomenon is a dynamic balance between the production and elimination of bilirubin. These processes can be exacerbated by a number of pathophysiologic conditions, which cause either an increase in bilirubin production rates, such as hemolysis, or a decrease in bilirubin elimination rates, such as bilirubin conjugation defects. The most dangerous circumstance for an infant is the combination of increased bilirubin production with impaired elimination. These infants are at considerable risk for developing excessive and potentially dangerous hyperbilirubinemia and subsequent kernicterus. Therefore, the importance of early recognition of the imbalance is paramount. In this review, we will discuss the various risk factors associated with hyperbilirubinemia and describe strategies for the diagnosis and management of transitional hyperbilirubinemia.

  View details for PubMedID 12244276

• Hemolysis in Gilbert's syndrome - Reply HEPATOLOGY Kaplan, M., Hammerman, C., Stevenson, D. K., Vreman, H. J., Muraca, M. 2002; 36 (3): 764–65

  View details for DOI 10.1053/jhep.2002.34854

  View details for Web of Science ID 000177722500030

• Late-onset sepsis in very low birth weight neonates: The experience of the NICHD Neonatal Research Network PEDIATRICS Stoll, B. J., Hansen, N., Fanaroff, A. A., Wright, L. L., Carlo, W. A., Ehrenkranz, R. A., Lemons, J. A., Donovan, E. F., Stark, A. R., TYSON, J. E., Oh, W., Bauer, C. R., Korones, S. B., Shankaran, S., Laptook, A. R., Stevenson, D. K., Papile, L. A., Poole, W. K. 2002; 110 (2): 285-291

  Abstract

  Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401-1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998-2000).The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998.Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%).Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.

  View details for Web of Science ID 000177274800021

  View details for PubMedID 12165580

• Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants NEW ENGLAND JOURNAL OF MEDICINE Stoll, B. J., Hansen, N., Fanaroff, A. A., Wright, L. L., Carlo, W. A., Ehrenkranz, R. A., Lemons, J. A., Donovan, E. F., Stark, A. R., TYSON, J. E., Oh, W., Bauer, C. R., Korones, S. B., Shankaran, S., Laptook, A. R., Stevenson, D. K., Papile, L. A., Poole, W. K. 2002; 347 (4): 240-247

  Abstract

  It is uncertain whether the rates and causes of early-onset sepsis (that occurring within 72 hours after birth) among very-low-birth-weight infants have changed in recent years, since antibiotics have begun to be used more widely during labor and delivery.We studied 5447 very-low-birth-weight infants (those weighing between 401 and 1500 g) born at centers of the Neonatal Research Network of the National Institute of Child Health and Human Development between 1998 and 2000 who had at least one blood culture in the first three days of life and compared them with 7606 very-low-birth-weight infants born at centers in the network between 1991 and 1993.Early-onset sepsis (as confirmed by positive blood cultures) was present in 84 infants in the more recent birth cohort (1.5 percent). As compared with the earlier birth cohort, there was a marked reduction in group B streptococcal sepsis (from 5.9 to 1.7 per 1000 live births of infants weighing 401 to 1500 g, P<0.001) and an increase in Escherichia coli sepsis (from 3.2 to 6.8 per 1000 live births, P=0.004); the overall rate of early-onset sepsis was not significantly changed. Most E. coli isolates from the recent birth cohort (85 percent) were resistant to ampicillin, and mothers of infants with ampicillin-resistant E. coli infections were more likely to have received intrapartum ampicillin than were those with ampicillin-sensitive strains (26 of 28 with sensitivity data vs. 1 of 5, P=0.01). Infants with early-onset sepsis were more likely to die than uninfected infants (37 percent vs. 13 percent, P<0.001), especially if they were infected with gram-negative organisms.Early-onset sepsis remains an uncommon but potentially lethal problem among very-low-birth-weight infants. The change in pathogens over time from predominantly gram-positive to predominantly gram-negative requires confirmation by ongoing surveillance.

  View details for Web of Science ID 000177665800003

  View details for PubMedID 12140299

• Heme oxygenase-1 modulates fetal growth in the rat LABORATORY INVESTIGATION Kreiser, D., Nguyen, X., Wong, R., Seidman, D., Stevenson, D., Quan, S., Abraham, N., Dennery, P. A. 2002; 82 (6): 687-692

  Abstract

  Intrauterine growth restriction is associated with increased perinatal morbidity and mortality as well as with lifelong cardiovascular and metabolic complications. Deficiency of heme oxygenase 1 (HO-1) is associated with growth restriction in mice and in humans, suggesting a role for HO-1 in fetal growth and maintenance of pregnancy. We hypothesized that modulation of HO-1 in the pregnant rat would alter fetal growth. In pregnant dams, placental HO activity was significantly inhibited with zinc deuteroporphyrin IX 2,4 bis glycol, and HO-1 protein was increased by transducing adenoviral human HO-1. Inhibition of HO-1 by zinc deuteroporphyrin IX 2,4 bis glycol resulted in a significant decrease in pup size, whereas transfection with hHO-1 resulted in increased pup size. Furthermore, the expression of IGF binding protein-1 and its receptor paralleled the expression of HO-1 in the placenta and were significantly modulated by modification of HO-1 along with the expression of vascular endothelial growth factor. These observations demonstrate that HO-1 modulates fetal growth by its effects on placental growth factors.

  View details for DOI 10.1097/01.LAB.0000017167.26718.F2

  View details for PubMedID 12065678

• Failure to detect elevated levels of carboxyhemoglobin in infants dying from SIDS JOURNAL OF FORENSIC SCIENCES Meny, R. G., Vreman, H. J., Stevenson, D. K., Hauck, F. R., Donoghue, E. R., Smialek, J. E., Fowler, D. R., Zielke, H. R. 2002; 47 (3): 660-662

  Abstract

  Carboxyhemoglobin (COHb) levels were determined in stored blood samples from 91 infants diagnosed to have died from the sudden infant death syndrome (SIDS) (0.59+/-0.41%, excluding one outlying value of 10.83%); 48 age-matched controls (0.53+/-0.38%); and three individuals who died from fire related causes (41+/-20%). No statistical differences in COHb levels were detected between blood from SIDS and control infants (p = 0.43).

  View details for Web of Science ID 000175734800039

  View details for PubMedID 12051358

• Risk factors for early death among extremely low-birth-weight infants AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Shankaran, S., Fanaroff, A. A., Wright, L. L., Stevenson, D. K., Donovan, E. F., Ehrenkranz, R. A., Langer, J. C., Korones, S. B., Stoll, B. J., TYSON, J. E., Bauer, C. R., Lemons, J. A., Oh, W., Papile, L. A. 2002; 186 (4): 796-802

  Abstract

  The purposes of this study were to compare the clinical characteristics of extremely low birth-weight infants (501-1000 g birth weight) who die early (<12 hours of age) with those of infants who die >12 hours after birth and infants who survive to neonatal intensive care unit discharge and to develop a model of risk for early death.Perinatal data were prospectively collected on 5986 infants in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from March 1993 through December 1997. Maternal and neonatal characteristics of infants who died early were compared with infants who survived and infants who died beyond 12 hours of age. A model for risk for early death was developed by logistic regression analysis, with results expressed as odds ratio with 95% CI.Mothers of infants who died early were more likely to be delivered in an inborn setting and experience labor and were less likely to have hypertension or preeclampsia, to receive antenatal corticosteroids, or to be delivered by cesarean birth than mothers of infants who died >12 hours after birth or infants who survived. Infants who died early were more likely to have lower Apgar scores and lower gestational age/birth weight and were less likely to be intubated at birth and to receive mechanical ventilation and surfactant therapy than infants who died >12 hours after birth or infants who survived. Greater risk for early death versus survival to neonatal intensive care unit discharge was associated with the lack of surfactant administration (odds ratio, 8.6; 95% CI, 6.3-11.9), lack of delivery room intubation (odds ratio, 5.3; 95% CI, 3.5-8.1), lack of antenatal corticosteroid use (odds ratio, 2.3; 95% CI, 1.6-3.2), lower 1-minute Apgar score (odds ratio, 2.0; 95% CI, 1.8-2.2), male sex (odds ratio, 1.7; 95% CI, 1.3-2.3), multiple gestation (odds ratio, 1.7; 95% CI, 1.2-2.5), no tocolytics (odds ratio, 1.7; 95% CI, 1.2-2.3), lower gestational age per week (odds ratio, 1.4; 95% CI, 1.3-1.6), and lower birth weight per 50 g (95% CI, 1.2-1.4).Early death (<12 hours of age) among extremely low-birth-weight infants may reflect an assessment of non-viability by obstetricians and neonatologists.

  View details for DOI 10.1067/mob.2002.121651

  View details for Web of Science ID 000175545300033

  View details for PubMedID 11967510

• A portable phototherapy bed Vreman, H. J., Wong, R. J., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2002: 341A

  View details for Web of Science ID 000174714601977

• Glucuronosyltransferase promoter polymorphism (Gilbert's syndrome): A determinant of hemolysis in G-6-PD deficient neonates Kaplan, M., Hammerman, C., Vreman, H. J., Levy-Lahad, E., Renbaum, P., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2002: 342A–343A

  View details for Web of Science ID 000174714601987

• Does phototherapy exacerbate hemolysis in G-6-PD deficient neonates? Kaplan, M., Hammerman, C., Goldschmidt, D., Hochman, A., Vreman, H. J., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2002: 342A

  View details for Web of Science ID 000174714601985

• Reduction in RBC transfusions among preterm infants: Results of randomized trial utilizing an in-line point-of-care blood gas and electrolyte monitor Widness, J. A., Madan, A., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2002: 376A

  View details for Web of Science ID 000174714602186

• Comparing the host response of neonatal and adult mice to gastrointestinal infections utilizing microarrays Burns, S. M., Stevenson, D. K., Contag, C. H. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2002: 298A

  View details for Web of Science ID 000174714601734

• Imbalance between bilirubin production and conjugation: The basis of hyperbilirubinemia in G-6-PD deficient neonates Kaplan, M., Mauraca, M., Vreman, H. J., Hammerman, C., Levy-Lahad, E., Renbaum, P., Rubaltelli, F. F., Vilei, M. T., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2002: 342A

  View details for Web of Science ID 000174714601986

• Developmentally regulated pattern of heme oxygenase-1 expression in the mouse brain Wong, R. J., Nguyen, X. N., Zhao, H., Vreman, H. J., Contag, C. H., Stevenson, D. K. NATURE PUBLISHING GROUP. 2002: 328A–328A

  View details for Web of Science ID 000174714601906

• Rapid in vivo assessment of heme oxygenase-1 gene transcription: Involvement of regulatory regions in metalloporphyrin-mediated activation Kazerounizadeh, H. R., Gruber, C. A., Burns, S. M., Hardy, J. W., Wong, R. J., Vreman, H. J., Stevenson, D. K., Contag, C. H. NATURE PUBLISHING GROUP. 2002: 327A–328A

  View details for Web of Science ID 000174714601904

• Azalanstat (RS-1607): Evidence for a novel class of potential heme oxygenase inhibitors Vreman, H. J., Wong, R. J., Stevenson, D. K., Clark, J. D. NATURE PUBLISHING GROUP. 2002: 341A–341A

  View details for Web of Science ID 000174714601978

• Concentration of carbon monoxide (CO) in postmortem human tissues: Effect of environmental CO exposure Vreman, H. J., Wong, R. J., Stevenson, D. K., Smialek, J. E., Fowler, D., Li, L., Zielke, H. R. NATURE PUBLISHING GROUP. 2002: 468A–468A

  View details for Web of Science ID 000174714602725

• Effects of high fat diet with or without orlistat on heme degradation, heme oxygenase activity, and antioxidant levels in mice Verkade, H., Wong, R. J., Vreman, H. I., Stevenson, D. K. NATURE PUBLISHING GROUP. 2002: 138A–139A

  View details for Web of Science ID 000174714600806

• End tidal carbon monoxide measurements in relation to height in healthy subjects Terheggen, S. W., Snepyangers, Y., Stevenson, D. K., Wong, R. J., Vreeman, H. J., van der Ent, C. K. NATURE PUBLISHING GROUP. 2002: 476A–476A

  View details for Web of Science ID 000174714602773

• Role of carbon monoxide and nitric oxide in newborn infants with postasphyxial hypoxic-ischemic encephalopathy PEDIATRICS Vreman, H. J., Wong, R. J., Stevenson, D. K., Engel, R. R. 2002; 109 (4): 715-715

  View details for Web of Science ID 000174704000047

  View details for PubMedID 11927721

• In vivo patterns of heme oxygenase-1 transcription. Journal of perinatology Contag, C. H., Stevenson, D. K. 2001; 21: S119-24

  Abstract

  Gene fusions composed of specific promoters and bioluminescent reporter genes can be used to assess gene expression patterns using whole-body imaging in living animal models. A transgenic mouse model was developed using the regulatory elements of the heme oxygenase promoter to drive luciferase as the reporter gene. In these transgenic mice, heme oxygenase (HO)-1 expression was apparent in neuronal tissues of neonates but not adults as measured by whole-body imaging, and in adults transcription of the reporter gene was inducible by known inducers of HO-1 transcription. Whole-body imaging of luciferase activity was then used to evaluate the effects of metalloporphyrins (Mps) on the transcription of the reporter gene. Some of the Mps, which are potent inhibitors of HO activity, did not activate the reporter gene above background. These Mps are ideally suited as chemotherapeutics that may target bilirubin production rates by inhibiting HO activity, but not result in a net increase in output from the HO gene. In contrast, known inducers of HO transcription did increase luciferase activity as did some of the other Mps that have been examined. Using whole-body in vivo transcriptional assays may facilitate rapid screening of potential therapeutic compounds for both desired and untoward effects.

  View details for PubMedID 11803432

• Aspirin administration during pregnancy enhances placental heme oxygenase-1 expression in spontaneously hypertensive rats Elran, E., Alesker, M., Baum, M., Hendler, Kreiser, D., Sivan, E., Schiff, E., Dennery, P., Stevenson, D., Rosenthal, T., Peleg, E., Seidman, D. MOSBY, INC. 2001: S171

  View details for DOI 10.1016/S0002-9378(01)80356-2

  View details for Web of Science ID 000172921000322

• Understanding newborn jaundice. Journal of perinatology Stevenson, D. K., Dennery, P. A., Hintz, S. R. 2001; 21: S21-4

  View details for PubMedID 11803411

• The biology of bilirubin production. Journal of perinatology Dennery, P. A., Weng, Y. H., Stevenson, D. K., Yang, G. 2001; 21: S17-20

  Abstract

  Heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, has been identified from the late 1960s. This enzyme has been shown to have many other roles in recent years. The inducible form is regulated by oxidative stress, inflammation, and heavy metals, among others, and is cytoprotective in many instance. Nonetheless, there are instances when HO-1 can be deleterious due to the release of iron from the reaction. Another important by-product, carbon monoxide, is a vasodilator and a neurotransmitter and has been implicated in signal transduction pathways. More recently, nonenzymatic, signaling roles of HO have been suggested. This may serve to regulate the endogenous activity of this enzyme when cellular heme levels are low.

  View details for PubMedID 11803410

• Just when you thought it was safe... PEDIATRIC RESEARCH Hintz, S. R., Stevenson, D. K. 2001; 50 (6): 676-677

  View details for PubMedID 11726720

• Alternative metalloporphyrins for the treatment of neonatal jaundice. Journal of perinatology Vreman, H. J., Wong, R. J., Stevenson, D. K. 2001; 21: S108-13

  View details for PubMedID 11803430

• Prediction of hyperbilirubinemia in near-term and term infants. Journal of perinatology Stevenson, D. K., Fanaroff, A. A., Maisels, M. J., Young, B. W., Wong, R. J., Vreman, H. J., MacMahon, J. R., Yeung, C. Y., Seidman, D. S., Gale, R., Oh, W., Bhutani, V. K., Johnson, L. H., Kaplan, M., Hammerman, C., Nakamura, H. 2001; 21: S63-72

  Abstract

  The purpose of this study was to determine whether end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), as a single measurement or in combination with serum total bilirubin (STB) measurements, can predict the development of hyperbilirubinemia during the first 7 days of life.From nine multinational clinical sites, 1370 neonates completed this cohort study from February 20, 1998 through February 22, 1999. Measurements of both ETCOc and STB were performed at 30+/-6 hours of life; STB also was measured at 96+/-12 hours and subsequently following a flow diagram based on a table of hours of age-specific STB. An infant was defined as hyperbilirubinemic if the hours of age-specific STB was greater than or equal to the 95th percentile as defined by the table at any time during the study.A total of 120 (8.8%) of the enrolled infants became hyperbilirubinemic. Mean STB in breast-fed infants was 8.92+/-4.37 mg/dl at 96 hours versus 7.63+/-3.58 mg/dl in those fed formula only. The mean ETCOc at 30+/-6 hours for the total population was 1.48+/-0.49 ppm, whereas those of nonhyperbilirubinemic and hyperbilirubinemic infants were 1.45+/-0.47 and 1.81+/-0.59 ppm, respectively. Seventy-six percent (92 of 120) of hyperbilirubinemic infants had ETCOc greater than the population mean. An ETCOc greater than the population mean at 30+/-6 hours yielded a 13.0% positive predictive value (PPV) and a 95.8% negative predictive value (NPV) for STB > or =95th percentile. When infants with STB > or =95th percentile at <36 hours of age were excluded, the STB at 30+/-6 hours yielded a 16.7% PPV and a 98.1% NPV for STB >75th percentile. The combination of these two measurements at 30+/-6 hours (either ETCOc more than the population mean or STB >75th percentile) had a 6.4% PPV with a 99.0% NPV.This prospective cohort study supports previous observations that measuring STB before discharge may provide some assistance in predicting an infant's risk for developing hyperbilirubinemia. The addition of an ETCOc measurement provides insight into the processes that contribute to the condition but does not materially improve the predictive ability of an hours of age-specific STB in this study population. The combination of STB and ETCOc as early as 30+/-6 hours may identify infants with increased bilirubin production (eg, hemolysis) or decreased elimination (conjugation defects) as well as infants who require early follow-up after discharge for jaundice or other clinical problems such as late anemia. Depending on the incidence of hyperbilirubinemia within an institution, the criteria for decision making should vary according to its unique population.

  View details for PubMedID 11803421

• Endogenous carbon monoxide formation by chorionic villi of term human placenta PLACENTA McLaughlin, B. E., Lash, G. E., Graham, C. H., Smith, G. N., Vreman, H. J., Stevenson, D. K., Marks, G. S., Nakatsu, K., Brien, J. F. 2001; 22 (10): 886-888

  Abstract

  Carbon monoxide (CO) is a novel messenger that is proposed to play a complementary role with nitric oxide in the regulation of placental haemodynamics. In a previous study, CO formation from exogenous haem has been measured in the microsomal fraction of chorionic villi as an index of haem oxygenase activity. The objective of the present study was to determine whether endogenous CO is formed by dissected chorionic villi of term human placenta, to which no exogenous substrate or co-factor had been added. Each sample of freshly isolated chorionic villi (approximately 0.4 g) of term human placenta from caesarean delivery was incubated in a sealed vial containing 1 ml of Krebs' solution (pH 7.4) at 37 degrees C. CO formation was determined by quantitating, using a gas-chromatographic method, the amount of CO released into the headspace gas of the incubation vial. There was time-dependent formation of endogenous CO in chorionic villi incubated at 37 degrees C during a 60-min time course. CO formation was found to be minimal in chorionic villi samples incubated at 4 degrees C and was increased relative to tissue weight. The data demonstrate that there is endogenous CO formation by chorionic villi of term human placenta.

  View details for Web of Science ID 000172592500014

  View details for PubMedID 11718578

• Differing pathogenesis of perinatal bilirubinemia in glucose-6-phosphate dehydrogenase-deficient versus -normal neonates PEDIATRIC RESEARCH Kaplan, M., Hammerman, C., Renbaum, P., Levy-Lahad, E., Vreman, H. J., Stevenson, D. K. 2001; 50 (4): 532-537

  Abstract

  The objective was to compare the contribution to perinatal bilirubinemia of hemolysis and UDP-glucuronosyltransferase (UGT) gene promoter polymorphism, seen in Gilbert's syndrome, between glucose-6-phosphate dehydrogenase (G-6-PD)-deficient and -normal neonates. Serum total bilirubin (STB) values from 52 G-6-PD-deficient and 166 G-6-PD-normal term, male neonates, sampled within 3 h of delivery (first sample) and on d 3 (second sample), were analyzed in relation to blood carboxyhemoglobin corrected for inspired CO (COHbc), an accurate index of hemolysis, and UGT promoter genotype. COHbc values (% total Hb) were greater in G-6-PD-deficient neonates than controls: first sample 1.00 +/- 0.25% versus 0.84 +/- 0.24%, p < 0.0001; second sample 0.83 +/- 0.20% versus 0.76 +/- 0.19%, p = 0.002. First sample COHbc and STB values did not correlate in either the G-6-PD-deficient or control groups, whereas second sample COHbc values correlated significantly with corresponding STB values in the control population only (r = 0.28, p = 0.0007). At second sampling, there was a higher allele frequency of the variant UGT promoter among those with STB values > or =75th percentile than those <75th among the G-6-PD-deficient neonates (0.60 versus 0.33, respectively, p = 0.025), but not controls (0.31 versus 0.40, respectively, p = 0.24). Among those infants with at least one variant UGT promoter allele, STB values were higher in the G-6-PD-deficient neonates than controls at second sampling only (181 +/- 56 microM versus 149 +/- 46 microM, respectively, p = 0.03). Both within and between the G-6-PD-deficient and control groups, our data demonstrate changing and differing contributions of hemolysis and UGT promoter polymorphism to bilirubinemia during the first 3 d of life.

  View details for Web of Science ID 000171092600018

  View details for PubMedID 11568299

• Prediction of hyperbilirubinemia in near-term and term infants PEDIATRICS Stevenson, D. K., Fanaroff, A. A., Maisels, M. J., Young, B. W., Wong, R. J., Vreman, H. J., MacMahon, J. R., Yeung, C. Y., Seidman, D. S., Gale, R., Oh, W., Bhutani, V. K., Johnson, L. H., Kaplan, M., Hammerman, C., Nakamura, H. 2001; 108 (1): 31-39

  Abstract

  The purpose of this study was to determine whether end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), as a single measurement or in combination with serum total bilirubin (STB) measurements, can predict the development of hyperbilirubinemia during the first 7 days of life.From 9 multinational clinical sites, 1370 neonates completed this cohort study from February 20, 1998, through February 22, 1999. Measurements of both ETCOc and STB were performed at 30 +/- 6 hours of life; STB also was measured at 96 +/- 12 hours and subsequently following a flow diagram based on a table of hours of age-specific STB. An infant was defined as hyperbilirubinemic if the hours of age-specific STB was greater than or equal to the 95th percentile as defined by the table at any time during the study.A total of 120 (8.8%) of the enrolled infants became hyperbilirubinemic. Mean STB in breastfed infants was 8.92 +/- 4.37 mg/dL at 96 hours versus 7.63 +/- 3.58 mg/dL in those fed formula only. The mean ETCOc at 30 +/- 6 hours for the total population was 1.48 +/- 0.49 ppm, whereas those of nonhyperbilirubinemic and hyperbilirubinemic infants were 1.45 +/- 0.47 ppm and 1.81 +/- 0.59 ppm, respectively. Seventy-six percent (92 of 120) of hyperbilirubinemic infants had ETCOc greater than the population mean. An ETCOc greater than the population mean at 30 +/- 6 hours yielded a 13.0% positive predictive value (PPV) and a 95.8% negative predictive value (NPV) for STB >/=95th percentile. When infants with STB >95th percentile at <36 hours of age were excluded, the STB at 30 +/- 6 hours yielded a 16.7% PPV and a 98.1% NPV for STB >75th percentile. The combination of these 2 measurements at 30 +/- 6 hours (either ETCOc more than the population mean or STB >75th percentile) had a 6.4% PPV with a 99.0% NPV. Conclusions. This prospective cohort study supports previous observations that measuring STB before discharge may provide some assistance in predicting an infant's risk for developing hyperbilirubinemia. The addition of an ETCOc measurement provides insight into the processes that contribute to the condition but does not materially improve the predictive ability of an hours of age-specific STB in this study population. The combination of STB and ETCOc as early as 30 +/- 6 hours may identify infants with increased bilirubin production (eg, hemolysis) or decreased elimination (conjugation defects) as well as infants who require early follow-up after discharge for jaundice or other clinical problems such as late anemia. Depending on the incidence of hyperbilirubinemia within an institution, the criteria for decision making should vary according to its unique population.

  View details for Web of Science ID 000169571400025

  View details for PubMedID 11433051

• Acute hemolysis and severe neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes JOURNAL OF PEDIATRICS Kaplan, M., Hammerman, C., Vreman, H. J., Stevenson, D. K., Beutler, E. 2001; 139 (1): 137-140

  Abstract

  Two premature female infants had severe hyperbilirubinemia caused by hemolysis. Both neonates were heterozygotes for the glucose-6-phosphate dehydrogenase Mediterranean mutation as determined by DNA analysis. Glucose-6-phosphate dehydrogenase-deficient heterozygotes may be susceptible to the complications of this enzyme deficiency.

  View details for DOI 10.1067/mpd.2001.115312

  View details for Web of Science ID 000169877100029

  View details for PubMedID 11445808

• Serum bilirubin levels at 72 hours by selected characteristics in breastfed and formula-fed term infants delivered by cesarean section ACTA PAEDIATRICA Hintz, S. R., Gaylord, T. D., Oh, W., Fanaroff, A. A., Mele, L., Stevenson, D. K. 2001; 90 (7): 776-781

  Abstract

  The present multicenter study analysed the relative impact of maternal and infant factors on serum bilirubin levels at 72 +/- 12 h in exclusively breastfed vs formula-fed term infants. End-tidal carbon monoxide levels corrected for ambient air (ETCOc), an index of bilirubin production, were measured in exclusively breastfed (B = 66) or formula-fed (F = 210) term infants at 2-8 h of age. Inclusion criteria included cesarean section to ensure a 3 d hospitalization, birthweight > or = 2,500 g, gestational age >37 wk and absence of any illness. The ETCOc for B infants and F infants did not differ significantly (1.3 +/- 0.7 ppm vs 1.3 +/- 0.8 ppm). The serum bilirubin level at 72 +/- 12 h was significantly higher in B infants than in F infants (8.5 +/- 3.4mg dl(-1) vs 6.7 +/- 3.4mg dl(-1) p < 0.001), as was the percentage weight loss from birthweight. Serum bilirubin levels were significantly higher in infants who were male, who did not have meconium-stained amniotic fluid, and in those whose mothers were insulin-dependent diabetics or hypertensive. There was no difference between groups in the need for phototherapy or exchange transfusion.Although higher bilirubin levels were observed in group B at 72 +/- 12 h compared with group F, this finding was not of clinical or therapeutic consequence in this study. The lack of difference in ETCOc between the groups may be a factor of the timing of ETCOc measurement in this study, or may suggest that early increased bilirubin production is not a significant contributor to jaundice observed in exclusively breastfed infants. Key words: bilirubin, breastfeeding, jaundice

  View details for Web of Science ID 000170367700013

  View details for PubMedID 11519981

• Detection of heme oxygenase activity by measurement of CO. Current protocols in toxicology / editorial board, Mahin D. Maines (editor-in-chief) ... [et al.] Vreman, H. J., Stevenson, D. K. 2001; Chapter 9: Unit 9 2-?

  Abstract

  Heme oxygenase (HO) is the first and rate-limiting step in degradation of heme, and in the presence of NADPH-cytochrome P-450 reductase it produces equimolar amounts of biliverdin and CO. CO produced in a closed system can be quantified as described in this unit by gas chromatography as a measure of HO activity in tissue slices, tissue homogenates, and tissue fractions.

  View details for DOI 10.1002/0471140856.tx0902s00

  View details for PubMedID 23045068

• Formation of endogenous carbon monoxide by chorionic villi of term human placenta McLaughlin, B. E., Smith, G. N., Graham, C. H., Marks, G. S., Nakatsu, K., Vreman, H. J., Stevenson, D. K., Brien, J. F. FEDERATION AMER SOC EXP BIOL. 2001: A935

  View details for Web of Science ID 000167454201274

• Unique effects of zinc protoporphyrin on HO-1 induction and apoptosis BLOOD Yang, G., Nguyen, X., Ou, J., Rekulapelli, P., Stevenson, D. K., Dennery, P. A. 2001; 97 (5): 1306-1313

  Abstract

  Zinc protoporphyrin (ZnPP), a naturally occurring molecule, is increased in iron deficiency and lead intoxication. ZnPP can also induce heme oxygenase (HO-1), the enzyme it competitively inhibits. In cultured cells (HA-1), ZnPP was the strongest HO-1 inducer of any metalloporphyrin (MP) tested. This was not due to increased oxidative stress, enhanced binding at metal response element, nor increased binding at activator protein-1 (AP-1) or SP-1 sites on HO-1. Only ZnPP, however, increased binding of nuclear proteins to early growth response-1 (Egr-1) protein consensus sequence. Pretreatment of HA-1 with cycloheximide inhibited ZnPP-induced HO-1 messenger RNA (mRNA) by 55%. Incubation with antisense Egr-1 oligomers decreased ZnPP-induced HO-1 expression by 47%. Furthermore, the level of HO-1 mRNA induction by ZnPP was 2-fold less in Egr-1-deficient fibroblasts than in wild-type cells. Because no Egr-1 binding site was previously identified on the HO-1 promoter, HA-1 cells were transfected with HO-1 CAT constructs containing segments of a 12.5-kb enhancer region of HO-1. A 196-bp fragment (RH) located approximately 9.5 kb upstream of the transcription start site mediated HO-1 induction by ZnPP alone. DNase I footprinting analysis further revealed that nuclear proteins bound to a 50-bp sequence in the RH. Within this sequence, a novel 9-bp region with 78% homology to the Egr-1 consensus sequence was identified further suggesting that Egr-1 partially mediates HO-1 induction by ZnPP. Lastly, increased apoptosis and nuclear localization were only seen with ZnPP, suggesting that increased ZnPP in disease states may serve as a cellular signaling mechanism.

  View details for PubMedID 11222374

• Drug therapy: Neonatal hyperbilirubinemia. NEW ENGLAND JOURNAL OF MEDICINE Dennery, P. A., Seidman, D. S., Stevenson, D. K. 2001; 344 (8): 581-590

  View details for Web of Science ID 000167044600007

• Neonatal hyperbilirubinemia. The New England journal of medicine Dennery, P. A., Seidman, D. S., Stevenson, D. K. 2001; 344 (8): 581-90

  View details for DOI 10.1056/NEJM200102223440807

  View details for PubMedID 11207355

• Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression TRANSGENIC RESEARCH Zhang, W. S., Feng, J. Q., Harris, S. E., Contag, P. R., Stevenson, D. K., Contag, C. H. 2001; 10 (5): 423-434

  Abstract

  The use of transgenic animals in biomedical research is increasing rapidly and may be the best means of determining gene function. Generating transgenic animals typically requires time-consuming screening processes, and gene function is assessed by an array of difficult phenotypic and biochemical assays performed ex vivo. To address the unmet need in transgenic research for functional assays performed with ease in living animals, we demonstrate here that in vivo detection of luciferase enzyme as a transcriptional reporter facilitates rapid screening for both the presence and function of transgenes in intact living mice. Using this approach we identified three bioluminescent transgenic founders where the transgene consisted of the heme oxygenase promoter fused to the modified coding sequence of the luciferase gene. These founders were identified from 183 pups and confirmed by PCR analysis. Identification of HO-1-luc homozygotes from back- crossed F2 littermates was then accelerated by in vivo imaging. In another transgenic mouse line, where the transgene was comprised of the bone morphogenic-4 (BMP4) promoter fused to the modified luciferase gene, we were able to identify transgenic animals and in each line we were able to visualize patterns of expression in living animals over time. The light production from these transgenic mice indicated that the desired DNA fragment was functional and different expression profiles apparent at different ages and after gene induction.

  View details for PubMedID 11708652

• Term infants with fetal growth restriction are not at increased risk for low intelligence scores at age 17 years JOURNAL OF PEDIATRICS Paz, I., Laor, A., Gale, R., Harlap, S., Stevenson, D. K., Seidman, D. S. 2001; 138 (1): 87-91

  Abstract

  To assess the long-term cognitive outcome of small for gestational age (SGA) compared with appropriate for gestational age (AGA) infants.Data from the Jerusalem Perinatal Study was matched with information from the army draft medical board. SGA and severe SGA were defined as birth weight below the 10th and 3rd percentiles for gestational age, respectively. A multiple linear regression analysis was performed to control for clinical, perinatal, and socio-demographic confounding variables.A cohort of 13,454 consecutive singleton term infants born between 1974 and 1976.IQ at age 17 years.SGA infants had lower adjusted mean +/- SE IQ scores compared with their AGA peers: 102.2 +/- 0.9 versus 105.1 +/- 0.7 (P <.0001) for males and 102.5 +/- 0.9 versus 103.9 +/- 0.7 (P <.015) for females. SGA was not associated with lower academic achievements compared with AGA.After controlling for multiple confounders, being born SGA at term is associated with slightly lower intelligence test scores at age 17 years. However, the clinical significance of the small difference is not evident in academic achievements.

  View details for DOI 10.1067/mpd.2001.110131

  View details for Web of Science ID 000166478700016

  View details for PubMedID 11148518

• Bedside functional imaging of the premature infant brain during passive motor activation JOURNAL OF PERINATAL MEDICINE Hintz, S. R., Benaron, D. A., Siegel, A. M., Zourabian, A., Stevenson, D. K., Boas, D. A. 2001; 29 (4): 335-343

  Abstract

  Changes in regional brain blood flow and hemoglobin oxygen saturation occur in the human cortex in response to neural activation. Traditional functional radiologic methods cannot provide continuous, portable measurements. Imaging methods, which use near-infrared light allow for non-invasive measurements by taking advantage of the fact that hemoglobin is a strong absorber at these wavelengths.To test the feasibility of a new optical functional imaging system in premature infants, and to obtain preliminary brain imaging of passive motor activation in this population.A new optical imaging system, the Diffuse Optical Tomography System (DOTS), was used to provide real-time, bedside assessments. Custom-made soft flexible fiberoptic probes were placed on two extremely ill, mechanically ventilated 24 week premature infants, and three healthier 32 week premature infants. Passive motor stimulation protocols were used during imaging.Specific movement of the arm resulted in reproducible focal, contralateral changes in cerebral absorption. The data suggest an overall increase in blood volume to the imaged area, as well as an increase in deoxyhemoglobin concentration. These findings in premature infants differ from those expected in adults.In the intensive care setting, continuous non-invasive optical functional imaging could be critically important and, with further study, may provide a bedside monitoring tool for prospectively identifying patients at high risk for brain injury.

  View details for PubMedID 11565203

• Exhaled carbon monoxide in asthma JOURNAL OF PEDIATRICS Vreman, H. J., Wong, R. J., Stevenson, D. K. 2000; 137 (6): 889-890

  View details for Web of Science ID 000165876300029

  View details for PubMedID 11113853

• Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage ARCHIVES OF DISEASE IN CHILDHOOD Stevenson, D. K., Verter, J., Fanaroff, A. A., Oh, W., Ehrenkranz, R. A., Shankaran, S., Donovan, E. F., Wright, L. L., Lemons, J. A., TYSON, J. E., Korones, S. B., Bauer, C. R., Stoll, B. J. 2000; 83 (3): F182-F185

  Abstract

  To determine the differences in short term outcome of very low birthweight infants attributable to sex.Boys and girls weighing 501-1500 g admitted to the 12 centres of the National Institute of Child Health and Human Development Neonatal Research Network were compared. Maternal information and perinatal data were collected from hospital records. Infant outcome was recorded at discharge, at 120 days of age if the infant was still in hospital, or at death. Best obstetric estimate based on the last menstrual period, standard obstetric factors, and ultrasound were used to assign gestational age in completed weeks. Data were collected on a cohort that included 3356 boys and 3382 girls, representing all inborn births from 1 May 1991 to 31 December 1993.Mortality for boys was 22% and that for girls 15%. The prenatal and perinatal data indicate few differences between the sex groups, except that boys were less likely to have been exposed to antenatal steroids (odds ratio (OR) = 0.80) and were less stable after birth, as reflected in a higher percentage with lower Apgar scores at one and five minutes and the need for physical and pharmacological assistance. In particular, boys were more likely to have been intubated (OR = 1.16) and to have received resuscitation medication (OR = 1.40). Boys had a higher risk (OR > 1.00) for most adverse neonatal outcomes. Although pulmonary morbidity predominated, intracranial haemorrhage and urinary tract infection were also more common.Relative differences in short term morbidity and mortality persist between the sexes.

  View details for Web of Science ID 000165126200005

  View details for PubMedID 11040165

• End-tidal carbon monoxide measurements in women with pregnancy-induced hypertension and preeclampsia AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Baum, M., Schiff, E., Kreiser, D., Dennery, P. A., Stevenson, D. K., Rosenthal, T., Seidman, D. S. 2000; 183 (4): 900-903

  Abstract

  We sought to compare the end-tidal carbon monoxide breath levels in pregnant women with and without pregnancy-induced hypertension and preeclampsia.We prospectively performed end-tidal carbon monoxide measurements corrected for ambient carbon monoxide in nonsmoking women during late gestation (>31 weeks). The study group included 22 women with pregnancy-induced hypertension or symptoms of preeclampsia and a control group of 20 normotensive pregnant women.The carbon monoxide measurements corrected for ambient carbon monoxide (mean +/- SD) were significantly lower (P <.01) in the hypertensive group than in the control group (1.17 +/- 0.35 vs 1.70 +/- 0.54 ppm). The study group had a significantly higher number of low (<1.2 ppm) end-tidal carbon monoxide measurements corrected for ambient carbon monoxide (13 [59.1%] vs 1 [5.0%]; P <.001). The end-tidal carbon monoxide measurements corrected for ambient carbon monoxide remained significantly lower in comparison with those found in the control group when the study group was divided into women with pregnancy-induced hypertension only (n = 11) and those with preeclampsia (n = 11) (1.19 +/- 0.37 ppm; P <.01; and 1.15 +/- 0.41 ppm; P <.01; respectively).Our findings suggest that carbon monoxide formation may be significantly lower in women with pregnancy-induced hypertension and preeclampsia. These data suggest that carbon monoxide could have a contributory role in the apparent paradox of the seemingly protective effect of smoking to decrease the risk of preeclampsia.

  View details for DOI 10.1067/mob.2000.109047

  View details for Web of Science ID 000089983200021

  View details for PubMedID 11035334

• Reduction of the NO-mediated response in the rat aorta by metalloporphyrins CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Vreman, H. J., Haenen, G. R., Stevenson, D. K., Bast, A. 2000; 78 (6): 457-461

  Abstract

  Metalloporphyrins (MPs) have been found to affect the production of carbon monoxide (CO) and nitric oxide (NO). Unlike that for CO, little is known about the mechanism of action of MPs on the NO system. We determined the in vitro ability of ferrous protoporphyrin (heme, FePP), zinc protoporphyrin (ZnPP), and bilirubin (BR) to scavenge NO. Heme and ZnPP were studied in the rat aortic ring system for their ability to affect phenylephrine-induced contraction and methacholine-stimulated relaxation. Heme was found to be a good NO scavenger with a ks = 0.53 +/- 0.19 x 10(4) M(-1)xs(-1) (n = 6). ZnPP and BR did not scavenge NO. Neither heme nor ZnPP treatment affected the phenylephrine response as measured by -logEC50 and the maximal effect. However, heme and ZnPP treatments decreased the -logEC50 and the maximal effects of methacholine, therefore decreasing vasorelaxation. We conclude that when ZnPP is administered in vivo blood pressure should be carefully monitored.

  View details for Web of Science ID 000087770700003

  View details for PubMedID 10914634

• Association of fetal and maternal carboxyhemoglobin levels in normal and Rh-alloimmune pregnancies EARLY HUMAN DEVELOPMENT Hayde, M., Pollak, A., Bernaschek, G., Weiner, C. P., Vreman, H. J., Stevenson, D. K., Widness, J. A. 2000; 58 (3): 205-212

  Abstract

  To compare paired antepartum fetal/maternal COHb ratios in whole blood from control and alloimmunized pregnancies and to examine the relationships between fetal and maternal COHb.COHb levels were measured in paired fetal and maternal blood samples obtained at cordocentesis in 47 control and 16 Rh-alloimmunized pregnancies. COHb was determined by gas chromatography. Results were analyzed by t-test, regression and analysis of covariance.Although fetal/maternal COHb ratios for control and alloimmunized pregnancies were not statistically significantly different, i.e. 1. 11+/-0.04 and 1.26+/-0.09, respectively (P=0.09), fetal COHb levels were higher in Rh-alloimmunized fetuses (P=0.0002). Fetal COHb levels were also higher than paired maternal levels among the alloimmunized group (P=0.011), but not among the control group (1. 04+/-0.04, P=ns). In univariate regression analysis, fetal and maternal COHb levels were significantly correlated with one another in both control (r=0.52, P=0.0002) and alloimmunized pregnancy groups (r=0.52, P=0.05). Comparison of the slopes of the fetal versus maternal COHb plots for the two groups showed a significant difference (P=0.02), with the alloimmunized group having the steeper slope.Differences in the antepartum fetal-maternal COHb relationships in control and alloimmunized groups likely reflect increased endogenous CO production among alloimmunized fetuses as a result of pathologic hemolysis.

  View details for Web of Science ID 000088889200004

  View details for PubMedID 10936440

• Haem oxygenase activity in human umbilical cord and rat vascular tissues PLACENTA Vreman, H. J., Wong, R. J., Kim, E. C., Nabseth, D. C., Marks, G. S., Stevenson, D. K. 2000; 21 (4): 337-344

  Abstract

  Carbon monoxide (CO) has been shown to affect vascular tone in smooth muscle cells and thus, may regulate regional or systemic blood pressure as well as fetoplacental vascular tone and fetal blood delivery. To assess the potential of vascular tissue to produce CO, we determined haem oxygenase (HO) activity through in vitro quantitation of CO production with gas chromatography and its inhibition by 33-66 microm of chromium mesoporphyrin (CrMP) in homogenate preparations of rat aorta and vena cava and human umbilical cord tissues. We compared these results to HO activity in rat heart and liver. We also discuss normalization of HO activity on a per mg protein as well as per g fresh weight (FW) tissue basis. We found that both rat vascular tissue HO activities (per g FW) were equal, but greater than that of heart (x3) and less than that of liver (x0.2). For human cord tissues, HO activities of artery and vein were equal, but greater than that of Wharton's jelly. Also, HO activity in rat vascular tissues was 3x greater than that of the human cord tissues. HO activity was completely inhibited by CrMP in rat heart (90 per cent) and liver (96 per cent), but incompletely (50-66 per cent) in both rat and human vascular tissues. We established that it is unlikely that other non-haem CO-generating processes account for this unique insensitivity of HO to CrMP inhibition. In fact, high concentrations of other potent metalloporphyrin inhibitors affected vascular tissue HO even less. We found that the degree of in vitro HO inhibition appeared to be related to the concentration of haem in the reaction medium. We conclude that the presence of HO activity in cord tissues supports the possibility that CO plays a role in fetoplacental blood flow regulation.

  View details for Web of Science ID 000087666000006

  View details for PubMedID 10833368

• Dermal carbon monoxide (CO) production and excretion in neonatal rats during light exposure Vreman, H. J., Wong, R. J., Chan, M. L., Young, B. W., Stevenson, D. K. NATURE PUBLISHING GROUP. 2000: 79A–79A

  View details for Web of Science ID 000086155300464

• Gilbert's syndrome mediates hyperbilirubinemia in direct Coombs negative ABO incompatible neonates Kaplan, M., Hammerman, C., Renbaum, P., Levy-Lahad, E. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2000: 406A

  View details for Web of Science ID 000086155302400

• The ontogeny of heme oxygenase activity in the mouse Vreman, H. J., Wong, R. J., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2000: 79A

  View details for Web of Science ID 000086155300465

• Does phototherapy induce hemolysis in premature neonates? Kaplan, M., Gold, Hammerman, C., Goldschmidt, D., Vreman, H. J., Hochberg, A., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2000: 406A

  View details for Web of Science ID 000086155302397

• Shining a new light on metalloporphyrins and heme oxygenase Hajdena-Dawson, M., Contag, C., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2000: 401A

  View details for Web of Science ID 000086155302366

• Bilirubin percentiles predict hyperbilirubinemia in G-6-PD deficient neonates and facilitate discharge planning Kaplan, M., Hammerman, C. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2000: 406A

  View details for Web of Science ID 000086155302398

• (Metallo)porphyrin inhibitors of heme oxygenase also inhibit lipid peroxidation (LP) Wong, R. J., Vreman, H. J., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2000: 79A

  View details for Web of Science ID 000086155300466

• Noninvasive functional imaging of human brain using light JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Benaron, D. A., Hintz, S. R., Villringer, A., Boas, D., Kleinschmidt, A., Frahm, J., Hirth, C., Obrig, H., van Houten, J. C., Kermit, E. L., Cheong, W. F., Stevenson, D. K. 2000; 20 (3): 469-477

  Abstract

  Analysis of photon transit time for low-power light passing into the head, and through both skull and brain, of human subjects allowed for tomographic imaging of cerebral hemoglobin oxygenation based on photon diffusion theory. In healthy adults, imaging of changes in hemoglobin saturation during hand movement revealed focal, contralateral increases in motor cortex oxygenation with spatial agreement to activation maps determined by functional magnetic resonance imaging; in ill neonates, imaging of hemoglobin saturation revealed focal regions of low oxygenation after acute stroke, with spatial overlap to injury location determined by computed tomography scan. Because such slow optical changes occur over seconds and co-localize with magnetic resonance imaging vascular signals whereas fast activation-related optical changes occur over milliseconds and co-localize with EEG electrical signals, optical methods offer a single modality for exploring the spatio-temporal relationship between electrical and vascular responses in the brain in vivo, as well as for mapping cortical activation and oxygenation at the bedside in real-time for clinical monitoring.

  View details for PubMedID 10724111

• What can we learn from STOP-ROP and earlier studies? PEDIATRICS Gaynon, M. W., Stevenson, D. K. 2000; 105 (2): 420-422

  View details for Web of Science ID 000085106500032

  View details for PubMedID 10654965

• Carbon monoxide detection and biological investigations. Transactions of the American Clinical and Climatological Association Stevenson, D. K., Vreman, H. J., Wong, R. J., Dennery, P. A., Contag, C. H. 2000; 111: 61-75

  Abstract

  Even though the heme degradation pathway consists of only two reactions, it and its major enzyme (i.e. HO), nonetheless, impact other processes not only through the removal of excess heme, but also through the production of several metabolically active compounds. Thus CO and biliverdin along with reactive iron, Fe2, are the primordial products of this ancient, highly conserved reaction. That every component of the heme catabolic pathway is directly or indirectly related to other reactions involving oxygen or light is, perhaps, no accident of nature. That a fundamentally destructive event can be linked with a multiplicity of synthetic events and various biological effects, depending on the timing and location of the HO activity, is testament to the economy and the ultimate beauty of nature. Furthermore, the interaction of the heme catabolic pathway with that of the NOS system may lead to even more exciting avenues of research. It may be shown that the integrity of the heme catabolic pathway, which is ever present and plays a role in every tissue, is central to the existence of most complex organisms.

  View details for PubMedID 10881332

• Dermal carbon monoxide (CO) production and excretion in neonatal rats during blue light exposure. Vreman, H. J., Wong, R. J., Chan, M. L., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2000: 23A

  View details for Web of Science ID 000086346600132

• Noninvasive monitoring of gene delivery using Salmonella vaccines. Bachmann, M. H., Burns, S. M., Gruber, C., Stevenson, D. K., Contag, C. H. LIPPINCOTT WILLIAMS & WILKINS. 2000: 43A

  View details for Web of Science ID 000086346600243

• Validation of the natus CO-Stat (TM) end tidal breath analyzer in children and adults JOURNAL OF CLINICAL MONITORING AND COMPUTING Vreman, H. J., Wong, R. J., Harmatz, P., Fanaroff, A. A., Berman, B., Stevenson, D. K. 1999; 15 (7-8): 421-427

  Abstract

  The performance of a point-of-care, noninvasive end tidal breath carbon monoxide analyzer (CO-Stat End Tidal Breath Analyzer, Natus Medical Inc.) that also reports end tidal carbon dioxide (ETCO2) and respiratory rate (RR), was compared to established, marketed (predicate) devices in children (n = 39) and adults (n = 48) who are normal or at-risk of elevated CO excretion.Concentrations of end tidal breath CO (ETCO), room air CO, ETCO corrected for inhaled CO (ETCOc), ETCO2, and RR were measured with the CO-Stat analyzer and the data compared to those obtained from the same subjects using the Vitalograph BreathCO monitor (Vitalograph, Inc.) for ETCOc and the Pryon CO2 monitor (SC210 and SC300, Pryon Corp) for ETCO2 and RR. Adults and children were studied at three medical centers. The data were analyzed by paired t-tests and linear regression. Bias and imprecision between the CO-Stat analyzer and the predicate devices was calculated by the method of Bland and Altman.Paired t-tests, performed on the three parameters measured with the CO-Stat analyzer and predicate devices showed that only the ETCOc values in the adults and the ETCO2 values in the children were significantly different (lower, p < or = 0.0001, and higher, p < or = 0.0001, respectively). The mean bias and imprecision of the CO-Stat analyzer for adult ETCOc and children ETCO2 measurements were -0.9 +/- 1.2 ppm and 0.4 +/- 0.6%, respectively. Linear regression analysis for the ETCOc results in children and adults had a high degree of correlation (r = 0.91 and 0.98, respectively).We conclude that in a clinical environment the Natus CO-Stat End Tidal Breath Analyzer performs at least as well as predicate devices for the measurements of ETCOc, ETCO2, and RR.

  View details for Web of Science ID 000086962600004

  View details for PubMedID 12578038

• Zinc protoporphyrin: A metabolite with a mission CLINICAL CHEMISTRY Labbe, R. F., Vreman, H. J., Stevenson, D. K. 1999; 45 (12): 2060-2072

  Abstract

  Zinc protoporphyrin (ZnPP) is a normal metabolite that is formed in trace amounts during heme biosynthesis. The final reaction in the biosynthetic pathway of heme is the chelation of iron with protoporphyrin. During periods of iron insufficiency or impaired iron utilization, zinc becomes an alternative metal substrate for ferrochelatase, leading to increased ZnPP formation. Evidence suggests that this metal substitution is one of the first biochemical responses to iron depletion, causing increased ZnPP to appear in circulating erythrocytes. Because this zinc-for-iron substitution occurs predominantly within the bone marrow, the ZnPP/heme ratio in erythrocytes reflects iron status in the bone marrow. In addition, ZnPP may regulate heme catabolism through competitive inhibition of heme oxygenase, the rate-limiting enzyme in the heme degradation pathway that produces bilirubin and carbon monoxide. Physiological roles, especially relating to carbon monoxide and possibly nitric oxide production, have been suggested for ZnPP. Clinically, ZnPP quantification is valuable as a sensitive and specific tool for evaluating iron nutrition and metabolism. Diagnostic determinations are applicable in a variety of clinical settings, including pediatrics, obstetrics, and blood banking. ZnPP analytical methodologies for clinical studies are discussed. In addition to diagnostic tests and metabolic studies, ZnPP has a potential therapeutic application in controlling bilirubin formation in neonates as a preventive measure for hyperbilirubinemia. Biochemical research techniques, both in vivo and in vitro, are described for further studies into the role of ZnPP in metabolism and physiology.

  View details for Web of Science ID 000084071400003

  View details for PubMedID 10585337

• Selective inhibition of heme oxygenase, without inhibition of nitric oxide synthase or soluble guanylyl cyclase, by metalloporphyrins at low concentrations DRUG METABOLISM AND DISPOSITION Appleton, S. D., Chretien, M. L., McLlaughlin, B. E., Vreman, H. J., Stevenson, D. K., Brien, J. F., Nakatsu, K., Maurice, D. H., Marks, G. S. 1999; 27 (10): 1214-1219

  Abstract

  Studies on the physiological role of heme oxygenase (HO) require an inhibitor that will selectively inhibit HO activity without inhibiting the activity of either nitric oxide synthase (NOS) or soluble guanylyl cyclase (sGC). The objective of this study was to test a series of metalloporphyrins that have previously been shown to inhibit HO activity, for their ability to inhibit HO without inhibiting NOS or sGC activities. Measurement of activity of HO in rat brain microsomes and NOS in rat brain cytosol was made for samples incubated with metalloporphyrins (0.15-50 microM), including zinc protoporphyrin IX, zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG), chromium mesoporphyrin IX (CrMP), tin protoporphyrin IX, and zinc N-methylprotoporphyrin IX. CrMP and ZnBG were found to be the most selective inhibitors of HO activity (i.e., caused the greatest inhibition of HO activity, 89 and 80%, respectively, without inhibition of NOS activity). Based on these results, sGC activity in rat lung cytosol incubated with CrMP or ZnBG (0.15-15 microM) was measured. ZnBG did not affect basal sGC activity but did potentiate S-nitroso-N-acetylpenicillamine (SNAP)-induced sGC activity. CrMP did not affect either basal or SNAP-induced activity. It was concluded that of the five metalloporphyrins studied, CrMP, at a concentration of 5 microM, was a selective inhibitor of HO activity and was the most useful metalloporphyrin for the conditions tested. Thus, CrMP would appear to be a valuable chemical probe in elucidating the physiological role of HO.

  View details for Web of Science ID 000082861700017

  View details for PubMedID 10497150

• Effects of skin-to-skin holding on general movements of preterm infants CLINICAL PEDIATRICS Constantinou, J. C., Adamson-Macedo, E. N., Stevenson, D. K., Mirmiran, M., Fleisher, B. E. 1999; 38 (8): 467-471

  Abstract

  The study objective was to test the hypothesis that the effect of skin-to-skin (STS) holding increases the ratio of rest to activity in low birth weight preterm infants. Ten infants with birthweight < 2,000 grams were videotaped before and after STS holding. Video recordings were analyzed to determine the number of general movements. We found no statistically significant difference between the percentage of general movements over the two periods. We conclude that the ratio of rest-activity before and after STS holding does not change as measured by occurrence of general movements.

  View details for Web of Science ID 000081864400005

  View details for PubMedID 10456242

• Neonatal bilirubin production, reflected by carboxyhaemoglobin concentrations, in Down's syndrome ARCHIVES OF DISEASE IN CHILDHOOD Kaplan, M., Vreman, H. J., Hammerman, C., Stevenson, D. K. 1999; 81 (1): F56-F60

  Abstract

  To determine whether increased bilirubin production, reflected by blood carboxyhaemoglobin (COHb) values, is responsible for hyperbilirubinaemia in cases of Down's syndrome with no obvious cause for excessive jaundice.Blood was sampled on the third day of life for COHb, total haemoglobin (tHb), and serum total bilirubin, from 19 consecutively born neonates with Down's syndrome (a subset of 34 term babies), who had developed hyperbilirubinaemia (serum bilirubin >/= 256 micromol), and from 32 term controls. COHb, measured by gas chromatography, was corrected for inspired CO (COHbc) and expressed as a percentage of tHb.Significantly more of the Down's syndrome subset developed hyperbilirubinaemia than the controls (10/19 (52%) vs 7/32 (22%), relative risk 2.4, 95% confidence intervals (CI) 1.10 to 5.26). Third day serum bilirubin values (mean (SD)) were higher in the Down's syndrome neonates than in controls (214 +- 63 micromol/l vs 172 +- 54 micromol/l, respectively, p=0.015). Mean (SD) COHbc values were significantly higher in the Down's syndrome neonates than in controls (0.92 +- 0. 24% vs 0.63 +- 0.17%; p<0.0001). However, Down's syndrome neonates who became hyperbilirubinaemic had similar COHbc values to those who did not (0.87 +- 0.26% and 0.95 +- 0.23%, respectively). These values contrast with those of the controls, in whom a significant increase in COHbc was associated with hyperbilirubinaemia (0.74 +- 0. 15% vs 0.60 +- 0.16%, respectively; p<0.05). tHb values were similar in both groups.Down's syndrome neonates had a greater risk of hyperbilirubinaemia, and higher COHbc values, than controls. However, excessive bilirubin production could not be exclusively responsible for the hyperbilirubinaemia. By inference, decreased bilirubin elimination probably plays a greater part in its pathogenesis than in controls. Down's syndrome neonates may have abnormal erythropoiesis, leading to increased haem turnover.

  View details for Web of Science ID 000081283900012

  View details for PubMedID 10375364

  View details for PubMedCentralID PMC1720958

• Vitamin A supplementation for extremely-low-birth-weight infants NEW ENGLAND JOURNAL OF MEDICINE TYSON, J. E., Wright, L. L., Oh, W. O., Kennedy, K. A., Mele, L., Ehrenkranz, R. A., Stoll, B. J., Lemons, J. A., Stevenson, D. K., Bauer, C. R., Korones, S. B., Fanaroff, A. A. 1999; 340 (25): 1962-1968

  Abstract

  Vitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials.We performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks.By 36 weeks' postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome - death or chronic lung disease at 36 weeks' postmenstrual age - occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 microg per deciliter (0.70 micromol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001).Intramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants.

  View details for Web of Science ID 000081088500005

  View details for PubMedID 10379020

• Untitled PEDIATRIC RESEARCH Hintz, S. R., Stevenson, D. K., Benaron, D. A. 1999; 45 (5): 737-738

  View details for Web of Science ID 000080086700023

• Bilirubin toxicity and differentiation of cultured astrocytes. Journal of perinatology Rhine, W. D., SCHMITTER, S. P., Yu, A. C., Eng, L. F., Stevenson, D. K. 1999; 19 (3): 206-211

  Abstract

  To study the toxicity of bilirubin in primary cultures of newborn rat cerebral cortical astrocytes.Primary cultures of newborn rat astrocytes were incubated at bilirubin concentrations of 0, 1, 5, 10, 25, 50, 100, 200, and 2000 microM, at a bilirubin:albumin molar ratio of 1.7. Bilirubin toxicity was determined by changes in cellular morphology, trypan blue staining, and lactate dehydrogenase (LDH) release into the culture medium at various times of incubation. To determine if differentiation of astrocytes affects bilirubin toxicity, cultures were treated with dibutyryl cyclic adenosine monophosphate.All three indices of toxicity showed a bilirubin concentration dependence. LDH release in experimental cultures was significantly elevated (p < 0.05) above that of control cultures by 24 hours at bilirubin concentrations of > or = 100 microM. The absolute amount of LDH release differed significantly between the 200 and 2000 microM cultures from 1.5 to 24 hours, after which duration of exposure appeared to take over and all cultures approached maximum. LDH release for the lower concentrations all reached maximum by 120 hours, except for the 1 microM cultures, which showed no significant elevation above control throughout the study period. At 100 and 200 microM bilirubin, LDH release by untreated cells was significantly higher (p < 0.05) than release by treated cells by 36 hours.Undifferentiated astrocytes appeared to be more sensitive to bilirubin toxicity, which may correlate with the greater susceptibility of newborns to kernicteric injury. Studies with primary astrocyte culture may provide insight into how bilirubin sensitivity changes with brain development as well as the cellular and biochemical mechanisms of bilirubin encephalopathy.

  View details for PubMedID 10685223

• Socio-demographic factors and the risk for asthma at 17 years of age Paz, Laor, A., Gale, R., Stevenson, D. K., Seidman, D. S. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1999: 106A

  View details for Web of Science ID 000079476700613

• Real-time functional imaging of the premature infant brain during passive motor activation Hintz, Benaron, D. A., Siegel, A. M., Stevenson, D. K., Boas, D. A. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1999: 343A

  View details for DOI 10.1203/00006450-199904020-02037

  View details for Web of Science ID 000079476702021

• Serum bilirubin levels in an international, multiracial newborn population Maisels, M. J., Fanaroff, A. A., Stevenson, D. K., Young, B. W., Vreman, H. J. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1999: 167A

  View details for DOI 10.1203/00006450-199904020-00994

  View details for Web of Science ID 000079476700978

• Transcriptional regulation of heme oxygenase-1 by metalloporphyrins Zhang, W. S., Contag, P. R., Contag, C. H., Stevenson, D. K. NATURE PUBLISHING GROUP. 1999: 72A–72A

  View details for Web of Science ID 000079476700418

• Carbon monoxide production and upregulation of heme oxygenase activity in mice after heme administration Vreman, H. J., Zentner, A. R., Wong, R. J., Stevenson, D. K. NATURE PUBLISHING GROUP. 1999: 231A–231A

  View details for Web of Science ID 000079476701359

• In vivo efficacy of light-emitting diodes (LEDs) as a light source for phototherapy in neonatal jaundiced rats Chan, M. L., Vreman, H. J., Wong, R. J., Young, B. W., Stevenson, D. K. NATURE PUBLISHING GROUP. 1999: 189A–189A

  View details for Web of Science ID 000079476701105

• Prediction of hyperbilirubinemia in healthy term and near-term Chinese newborns Chan, M. L., Ho, H. T., Ip, K. S., Chen, H., Young, B. W., Lo, Y. C., Wong, R. J., Vreman, H. J., Stevenson, D. K. NATURE PUBLISHING GROUP. 1999: 188A–188A

  View details for Web of Science ID 000079476701104

• Transcutaneous bilirubinometry: A new tool for studying neonatal jaundiced rats Wong, R. J., Chan, M. L., Vreman, H. J., Young, B. W., Stevenson, D. K. NATURE PUBLISHING GROUP. 1999: 233A–233A

  View details for Web of Science ID 000079476701374

• Do hemolysis and jaundice associated with G6PD deficiency commence in utero? Kaplan, M., Hammerman, C., Vreman, H. J., Stevenson, D. K., Beutler, E. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1999: 204A

  View details for DOI 10.1203/00006450-199904020-01211

  View details for Web of Science ID 000079476701195

• Fetal growth restriction in full-term infants and height at 17 years of age Paz, Stevenson, D. K., Laor, A., Gale, R., Seidman, D. S. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1999: 106A

  View details for Web of Science ID 000079476700614

• Ethnic origin should be considered when end-tidal breath carbon monoxide measurements are used to predict the development of hyperbilirubinemia in healthy term infants Braun, J., Seidman, D. S., Stevenson, D. K., Vreman, H. J., Gur, Gale, R. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1999: 187A

  View details for DOI 10.1203/00006450-199904020-01111

  View details for Web of Science ID 000079476701095

• The incidence of increased bilirubin production in hyperbilirubinemic neonates as indexed by breath carbon monoxide (CO) Stevenson, D. K., Young, B. W., Maisels, M. J., Fanaroff, A. A., Vreman, H. J. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1999: 227A

  View details for DOI 10.1203/00006450-199904020-01352

  View details for Web of Science ID 000079476701336

• HIF-1 alpha protein is increased in the retina of a neonatal rat model of retinopathy Madan, A., Bergeron, M., Stevenson, D. K., Penn, J. S. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 1999: S975

  View details for Web of Science ID 000079269205130

• Antepartum fetal and maternal carboxyhemoglobin and cotinine levels among cigarette smokers ACTA PAEDIATRICA Hayde, M., Bernaschek, G., Stevenson, D. K., Knight, G. J., Haddow, J. E., Widness, J. A. 1999; 88 (3): 327-331

  Abstract

  The objective of this study was to examine the association of carboxyhemoglobin (COHb) and plasma cotinine levels among pregnant women who smoke cigarettes and their fetuses. Fifteen pregnant women who smoked and their fetuses undergoing cordocentesis had blood samples analysed simultaneously for COHb and cotinine. Linear regression was used to test for associations among study variables. Significant maternal-fetal associations were observed both with COHb (r = 0.72, p = 0.003) and with cotinine (r = 0.96, p = 0.003). Maternal cotinine levels were correlated with maternal and fetal COHb levels (r = 0.96, p = 0.003; r = 0.99, p = 0.0003, respectively). Fetal cotinine levels were correlated with COHb in maternal and in fetal blood (r = 0.81, p = 0.0003; r = 0.88, p<0.0001, respectively). The strong direct associations of maternal and fetal levels of COHb and cotinine indicate that maternal COHb and cotinine measurements may be interpreted as surrogates of fetal COHb levels. However, the specificity, ex vivo stability and ease of measurement of cotinine offer advantages over using COHb in quantifying fetal CO exposure following maternal cigarette smoking.

  View details for Web of Science ID 000079338200018

  View details for PubMedID 10229047

• Commentary: Neonatal viability in the 1990s: Held hostage by technology CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS Stevenson, D. K., Goldworth, A. 1999; 8 (2): 170–72

  View details for DOI 10.1017/S0963180199222050

  View details for Web of Science ID 000078778300005

  View details for PubMedID 11645146

• Bedside functional imaging of the premature infant brain during passive motor activation Hintz, Benaron, D. A., Siegel, A. M., Stevenson, D. K., Boas, D. A. SLACK INC. 1999: 60A

  View details for Web of Science ID 000078137600322

• Carbon monoxide production and upregulation of heme oxygenase activity in mice after heme administration. Vreman, H. J., Zentner, A. R., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 1999: 27A–27A

  View details for Web of Science ID 000078137600145

• Transcutaneous bilirubinometry: A new tool for studying neonatal jaundiced rats. Chan, M. L., Wong, R. J., Vreman, H. J., Young, B. W., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 1999: 96A–96A

  View details for Web of Science ID 000078137600511

• In vivo efficacy of light-emitting diodes (LEDs) as a light source for phototherapy in neonatal jaundiced rats. Chan, M. L., Vreman, H. J., Wong, R. J., Young, B. W., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 1999: 56A–56A

  View details for Web of Science ID 000078137600299

• Effects of metalloporphyrins on heme oxygenase-1 expression Zhang, W., Contag, P. R., Contag, C. H., Stevenson, D. K. SLACK INC. 1999: 6A

  View details for Web of Science ID 000078137600032

• Bedside imaging of intracranial hemorrhage in the neonate using light: Comparison with ultrasound, computed tomography, and magnetic resonance imaging PEDIATRIC RESEARCH Hintz, S. R., Cheong, W. F., van Houten, J. P., Stevenson, D. K., Benaron, D. A. 1999; 45 (1): 54-59

  Abstract

  Medical optical imaging (MOI) uses light emitted into opaque tissues to determine the interior structure. Previous reports detailed a portable time-of-flight and absorbance system emitting pulses of near infrared light into tissues and measuring the emerging light. Using this system, optical images of phantoms, whole rats, and pathologic neonatal brain specimens have been tomographically reconstructed. We have now modified the existing instrumentation into a clinically relevant headband-based system to be used for optical imaging of structure in the neonatal brain at the bedside. Eight medical optical imaging studies in the neonatal intensive care unit were performed in a blinded clinical comparison of optical images with ultrasound, computed tomography, and magnetic resonance imaging. Optical images were interpreted as correct in six of eight cases, with one error attributed to the age of the clot, and one small clot not seen. In addition, one disagreement with ultrasound, not reported as an error, was found to be the result of a mislabeled ultrasound report rather than because of an inaccurate optical scan. Optical scan correlated well with computed tomography and magnetic resonance imaging findings in one patient. We conclude that light-based imaging using a portable time-of-flight system is feasible and represents an important new noninvasive diagnostic technique, with potential for continuous monitoring of critically ill neonates at risk for intraventricular hemorrhage or stroke. Further studies are now underway to further investigate the functional imaging capabilities of this new diagnostic tool.

  View details for PubMedID 9890608

• Simultaneous production of carbon monoxide and thiobarbituric acid reactive substances in rat tissue preparations by an iron-ascorbate system CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Vreman, H. J., Wong, R. J., Sanesi, C. A., Dennery, P. A., Stevenson, D. K. 1998; 76 (12): 1057-1065

  Abstract

  Most of the carbon monoxide (CO) produced by mammals is a product of the heme oxygenase (HO) reaction, the rate-limiting step in the heme degradation pathway leading to the generation of bilirubin in man. However, some CO is derived from other sources. We studied the association of CO production with lipid peroxidation in tissue preparations from adult male Wistar rats. Supernatants, from 20% tissue homogenates in potassium phosphate buffer, centrifuged for 1 min at 13,000 x g, were incubated for 30 min at 37 degrees C in septum-sealed vials in the dark with ascorbate (100 microM) and Fe(II) (6 microM) and (or) Fe(III) (60 microM). Butylated hydroxytoluene (BHT, 100 microM) was added for the blank reaction. CO produced into the headspace was quantitated by gas chromatography. Thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD), and lipid hydroperoxides (LOOH) in the reaction medium were quantitated by spectrophotometry. Of the tissues studied, CO and TBARS formation was greatest for brain, followed by kidney, lung, spleen, and blood, but no CO or TBARS formation was detected for testes, intestine, liver, and heart. Cell fractionation studies indicated that these differences might be due to the presence of endogenous soluble antioxidants in the latter tissues. Furthermore, these studies demonstrated that CO was exclusively generated by subcellular fractions that contained membranes. The magnitude of the rate of product formation in brain supernatants depended on the concentration of Fe(II) and (or) Fe(III). The formation of CO, TBARS, CD, and LOOH increased linearly with time for up to 30 min, but the rates of product formation were different. Product formation was completely inhibited by BHT (100 microM), biliverdin (50 microM), bilirubin (50 microM), citrate (100 microM), and the Fe(II) chelators, desferrioxamine mesylate (100 microM) and diethylenetriaminepentaacetate, but not by 10 microM of the HO inhibitor, zinc deuteroporphyrin bis glycol. We conclude that CO generation is associated with the process of in vitro lipid peroxidation in tissues with limited antioxidant reserves.

  View details for Web of Science ID 000079780100001

  View details for PubMedID 10326826

• Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December 1994 AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Stevenson, D. K., Wright, L. L., Lemons, J. A., Oh, W., Korones, S. B., Papile, L. A., Bauer, C. R., Stoll, B. J., TYSON, J. E., Shankaran, S., Fanaroff, A. A., Donovan, E. F. 1998; 179 (6): 1632-1639

  Abstract

  Our purpose was to determine the mortality and morbidity rates for infants weighing 501 to 1500 g according to gestational age, birth weight, and gender.Perinatal data were collected prospectively on an inborn cohort from January 1993 through December 1994 by 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network and were compared with the corresponding data from previous reports. Sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death were evaluated.Eighty-three percent of infants survived until discharge to home or to a long- term care facility (compared with 74% in 1988). Survival to discharge was 49% for infants weighing 501 to 750 g at birth, 85% for those 751 to 1000 g, 93% for those 1001 to 1250 g, and 96% for those 1251 to 1500 g. The majority of deaths occurred within the first 3 days of life. Mortality rates were greater for male than for female infants. Respiratory distress syndrome was the most frequent pulmonary disease (52%). Chronic lung disease (defined as an oxygen requirement at 36 weeks after conception) developed in 19%. Thirty-two percent of infants had evidence of intracranial hemorrhage. Periventricular leukomalacia was noted in 6% of infants who had ultrasonography after 2 weeks. The average duration of hospitalization for survivors was 68 days (122 days for surviving infants weighing 501 to 750 g, compared with an average of 43 days for surviving infants 1251 to 1500 g). Among infants who died, the average length of stay was 19 days.The mortality rate for infants weighing between 501 and 1500 g at birth continues to decline. This increase in survival is not accompanied by an increase in medical morbidity. There are interactions between birth weight, gestational age, sex, and survival rates.

  View details for PubMedID 9855609

• Light-emitting diodes: A novel light source for phototherapy PEDIATRIC RESEARCH Vreman, H. J., Wong, R. J., Stevenson, D. K., Route, R. K., Reader, S. D., Fejer, M. M., Gale, R., Seidman, D. S. 1998; 44 (5): 804-809

  Abstract

  High intensity light-emitting diodes (LEDs) are being studied as possible light sources for the phototherapy of hyperbilirubinemic neonates. These power-efficient, low heat-producing light sources have the potential to deliver high intensity light of narrow wavelength band in the blue-green portion of the visible light spectrum, which overlaps the absorption spectrum of bilirubin (BR). We compared the efficacy between single LEDs of different color and then constructed a prototype phototherapy device using 300 blue LEDs. The efficacy of this device was compared with that of conventional phototherapy devices by measuring the in vitro photodegradation of BR in human serum albumin. When blue, blue-green, green, and white LEDs were compared, the blue light was the most effective in degrading BR by 28% of dark control, followed by blue-green (18% of control), and then white light (14% of control). Green light was the least effective (11% of control). The prototype device with three focused arrays, each with 100 blue LEDs, generated greater irradiance (> 200 microW.cm-2.nm-1) than any of the conventional devices tested. It also supported the greatest rate of BR photodegradation. We conclude that light from LEDs should be considered a more effective treatment for hyperbilirubinemia than light from presently used phototherapy devices. Furthermore, the unique characteristics of this light source may make it especially suitable for use in safe and lightweight home phototherapy devices.

  View details for PubMedID 9803466

• Strategy for lipid suppression in lactate imaging using STIR-DQCT: A study of hypoxic-ischemic brain injury MAGNETIC RESONANCE IN MEDICINE Nakai, T., Rhine, W. D., Okada, T., Stevenson, D. K., Spielman, D. M. 1998; 40 (4): 629-632

  Abstract

  In vivo lactate detection using gradient enhanced double quantum coherence transfer (DQCT) was significantly improved by addition of short-time-inversion-recovery (STIR). Phantom studies demonstrated lipid suppression down to the background noise level with 33% loss of lactate signal. In vivo studies using a rabbit model of hypoxic and unilateral-ischemic brain injury showed reduction down to 29 +/- 11% in lipids with inversion times between 140 and 170 ms. Lactate signals on the ischemic side were 51 +/- 53% higher than the nonischemic side at the peak of hypoxia. STIR-DQCT can be a useful robust method of obtaining metabolic maps of lactate in vivo.

  View details for PubMedID 9771580

• Stationary headband for clinical time-of-flight optical imaging at the bedside PHOTOCHEMISTRY AND PHOTOBIOLOGY Hintz, S. R., Benaron, D. A., van Houten, J. P., Duckworth, J. L., Liu, F. W., Spilman, S. D., Stevenson, D. K., Cheong, W. F. 1998; 68 (3): 361-369

  Abstract

  Conventional brain-imaging modalities may be limited by high cost, difficulty of bedside use, noncontinuous operation, invasiveness or an inability to obtain measurements of tissue function, such as oxygenation during stroke. Our goal was to develop a bedside clinical device able to generate continuous, noninvasive, tomographic images of the brain using low-power nonionizing optical radiation. We modified an existing stage-based time-of-flight optical tomography system to allow imaging of patients under clinical conditions. First, a stationary head-band consisting of thin, flexible optical fibers was constructed. The headband was then calibrated and tested, including an assessment of fiber lengths, the existing system software was modified to collect headband data and to perform simultaneous collection of data and image reconstruction, and the existing hardware was modified to scan optically using this headband. The headband was tested on resin models and allowed for the generation of tomographic images in vitro; the headband was tested on critically ill infants and allowed for optical tomographic images of the neonatal brain to be obtained in vivo.

  View details for PubMedID 9747590

• Outcomes of very low birth weight twins cared for in the National Institute of Child Health and Human Development Neonatal Research Network's intensive care units AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Donovan, E. F., Ehrenkranz, R. A., Shankaran, S., Stevenson, D. K., Wright, L. L., Younes, N., Fanaroff, A. A., Korones, S. B., Stoll, B. J., TYSON, J. E., Bauer, C. R., Lemons, J. A., Oh, W., Papile, L. A. 1998; 179 (3): 742-749

  Abstract

  The study's aim was to compare outcomes of very low birth weight twins with those of matched singletons.With data from the Neonatal Research Network registry (May 1991 to December 1994), univariable and multivariable comparisons of very low birth weight twin pairs and singletons were performed in 2 subgroups: (1) all paired twins and singletons with birth weights between 401 and 1500 g and (2) all paired twins and singletons born at <28 weeks' gestation.Twins constituted 19% of infants admitted with very low birth weight. Mothers of twins were more likely to receive prenatal care, have labor, have cesarean delivery, and receive antenatal glucocorticoids. Twins were more likely to have respiratory disease and to receive surfactant. Second-born twins had more early respiratory disease but similar longer-term outcomes. The risks of death, chronic lung disease, and grade III or IV intracranial hemorrhage were similar in twins and singletons.Although very low birth weight twins compose a sizable proportion of admissions, in National Institute of Child Health and Human Development Neonatal Research Network intensive care units, twins and singletons have similar outcomes.

  View details for Web of Science ID 000076085500031

  View details for PubMedID 9757982

• Diffusion and perfusion magnetic resonance imaging of the evolution of hypoxic ischemic encephalopathy in the neonatal rabbit JOURNAL OF MAGNETIC RESONANCE IMAGING D'Arceuil, H. E., de Crespigny, A. J., Rother, J., Seri, S., Moseley, M. E., Stevenson, D. K., Rhine, W. 1998; 8 (4): 820-828

  Abstract

  Hypoxic-ischemic encephalopathy (HIE) can result from neonatal asphyxia, the pathophysiology of which is poorly understood. We studied the acute evolution of this disease, using magnetic resonance imaging in an established animal model. HIE was induced in neonatal rabbits by a combination of common carotid artery (CCA) ligation and hypoxia. Serial diffusion and perfusion-weighted magnetic resonance images were acquired before, during, and after the hypoxic interval. Focal areas of decreased apparent diffusion coefficient (ADC) were detected initially in the cortex ipsilateral to CCA ligation within 62 +/- 48 min from the onset of hypoxia. Subsequently, these areas of decreased ADC spread to the subcortical white matter, basal ganglia (ipsilateral side), and then to the contralateral side. Corresponding perfusion-weighted images showed relative cerebral blood volume deficits which closely matched those regions of ADC change. Our results show that MRI diffusion and perfusion-weighted imaging can detect acute cell swelling post-hypoxia in this HIE model.

  View details for Web of Science ID 000080143600010

  View details for PubMedID 9702883

• Ethical dilemmas in the delivery room SEMINARS IN PERINATOLOGY Stevenson, D. K., Goldworth, A. 1998; 22 (3): 198-206

  Abstract

  The decision to withhold or withdraw life support in the neonatal intensive care unit (NICU) is common but is never routine. Often, moral demands make such decisions difficult and emotionally exhausting. But, what is perhaps more challenging from the moral point of view is the transition from the delivery room to the NICU. A satisfactory analysis of the moral issues of delivery room practices must include a discussion of quality of life, the best interest of the infant, the best interests of the family members, and futile treatment. Although these topics are relevant in any discussion of the moral justification of the omission, withdrawal, or use of treatment for patients, they are especially telling when entertained in the context of the transition of the fetus to a newborn. This article uses these four topics as a moral compass for certain decisions made in the delivery room.

  View details for PubMedID 9650227

• A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants NEW ENGLAND JOURNAL OF MEDICINE Papile, L. A., TYSON, J. E., Stoll, B. J., Wright, L. L., Donovan, E. F., Bauer, C. R., Krause-Steinrauf, H., Verter, J., Korones, S. B., Lemons, J. A., Fanaroff, A. A., Stevenson, D. K. 1998; 338 (16): 1112-1118

  Abstract

  Ventilator-dependent premature infants are often treated with dexamethasone. However, the optimal timing of therapy is unknown.We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants (501 to 1500 g) who had respiratory index scores (mean airway pressure x the fraction of inspired oxygen) of 52.4 at two weeks of age. One hundred eighty-two infants received dexamethasone for two weeks followed by placebo for two weeks, and 189 infants received placebo for two weeks followed by either dexamethasone (those with a respiratory-index score of > or =2.4 on treatment day 14) or additional placebo for two weeks. Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days, and the dose was then tapered.The median time to ventilator independence was 36 days in the dexamethasone-placebo group and 37 days in the placebo-dexamethasone group. The incidences of chronic lung disease (defined as the need for oxygen supplementation at 36 weeks' postconceptional age) were 66 percent and 67 percent, respectively. Dexamethasone was associated with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95 percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9; 95 percent confidence interval, 1.2 to 3.0) in the dexamethasone-placebo group, elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2 to 6.9) in the placebo-dexamethasone group, and diminished weight gain and head growth (P< 0.001) in both groups.Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of ages.

  View details for Web of Science ID 000073070100004

  View details for PubMedID 9545359

• Combination of ABO blood group incompatibility and glucose-6-phosphate dehydrogenase deficiency: effect on hemolysis and neonatal hyperbilirubinemia ACTA PAEDIATRICA Kaplan, M., Vreman, H. J., Hammerman, J., Leiter, C., Rudensky, B., MacDonald, M. G., Stevenson, D. K. 1998; 87 (4): 455-457

  Abstract

  The incidence (%) of hyperbilirubinemia (serum bilirubin > or = 257 micromol/l) was similar in neonates with a combination of ABO incompatibility and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (45%), with ABO incompatibility (54%) or G-6-PD deficiency (37%), alone (ns). Carboxyhemoglobin values, corrected for inspired CO, were similarly elevated in all three groups (0.87 +/- 0.32%, 0.82 +/- 0.29%, 0.76 +/- 0.18%, respectively, ns), but correlated with bilirubin only in those with ABO incompatibility alone. ABO-incompatible/G-6-PD-deficient neonates, compared with those with either condition alone, are not at increased risk for hemolysis or hyperbilirubinemia.

  View details for Web of Science ID 000073985400023

  View details for PubMedID 9628306

• Bioluminescent indicators in living mammals NATURE MEDICINE Contag, P. R., Olomu, I. N., Stevenson, D. K., Contag, C. H. 1998; 4 (2): 245-247

  View details for Web of Science ID 000072249800043

  View details for PubMedID 9461201

• Neonatal hypoglycemia, part II: Pathophysiology and therapy International Symposium on Neonatal Hypoglycemia Halamek, L. P., Stevenson, D. K. SAGE PUBLICATIONS INC. 1998: 11–16

  Abstract

  Contemporary research is elucidating both the molecular mechanisms of hypoglycemia-induced neuronal injury and its corresponding clinical manifestations. Recognizing and screening those neonates at highest risk of hypoglycemia-induced injury is an important skill for all physicians responsible for the care of newborns. Appropriate therapy, consisting of either oral or intravenous glucose, should never be delayed while one is awaiting laboratory confirmation of a "low" glucose level.

  View details for PubMedID 9475694

• Calibration of time-of-flight optical spectroscopy Conference on Photon Propagation in Tissues III Duckworth, J. L., Benaron, D. A., Hintz, S. R., Liu, F. W., Stevenson, D. K., Cheong, W. F. SPIE - INT SOC OPTICAL ENGINEERING. 1998: 73–82

  View details for Web of Science ID 000072611700009

• Automated quantitation of tissue components using real-time spectroscopy Conference on Photon Propagation in Tissues III Benaron, D. A., Rubinski, B., Hintz, S. R., Duckworth, J. L., Murphy, A. L., Price, J. W., Liu, F. W., Otten, D. M., Stevenson, D. K., Cheong, W. F., Kermit, E. L. SPIE - INT SOC OPTICAL ENGINEERING. 1998: 500–511

  View details for Web of Science ID 000072611700060

• Brain functional imaging using time-of-flight optical spectroscopy Conference on Photon Propagation in Tissues III Hintz, S. R., Benaron, D. A., Robbins, R., Duckworth, J. L., Murphy, A. L., Price, J. W., Liu, F. W., Stevenson, D. K., Cheong, W. F. SPIE - INT SOC OPTICAL ENGINEERING. 1998: 176–183

  View details for Web of Science ID 000072611700021

• Visualizing tumor dynamics in vivo. Olomu, A. B., Sweeney, T. J., Mailander, V., Eames, B. F., Negrin, R. S., Stevenson, D. K., Benaron, D. A., Contag, C. H. LIPPINCOTT WILLIAMS & WILKINS. 1998: 169A–169A

  View details for Web of Science ID 000071684700907

• In vivo monitoring of antitumor therapies in intact mice. Sweeney, T. J., Olomu, A. B., Mailander, V., Stevenson, D. K., Contag, C. H., Negrin, R. S. LIPPINCOTT WILLIAMS & WILKINS. 1998: 91A–91A

  View details for Web of Science ID 000071684700479

• Inhibition of in vitro lipid peroxidation by heme degradation pathway products, bilirubin and biliverdin. Williams, S. A., Wong, R. J., Vreman, H. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 1998: 94A–94A

  View details for Web of Science ID 000071684700495

• Metalloporphyrin inhibition of in vitro heme oxygenase isoenzyme activity. Wong, R. J., Breman, H. J., Williams, S. A., Stevenson, D. K. SLACK INC. 1998: 94A

  View details for Web of Science ID 000071684700496

• Construction of a red-emitting firefly luciferase. Eames, B. F., Benaron, D. A., Stevenson, D. K., Contag, C. H. SLACK INC. 1998: 94A

  View details for Web of Science ID 000071684700497

• Developmental ontogeny of HIF-1 mRNA and protein in the mouse eye. Balsubramanian, S., Varma, S., Stevenson, D. K., Madan, A. SLACK INC. 1998: 94A

  View details for Web of Science ID 000071684700500

• Changes in spontaneous general movements of very low birthweight infants over time. Constantinou, J. C., Fleisher, B. E., Mirmiran, M., Stevenson, D. K. SLACK INC. 1998: 105A

  View details for Web of Science ID 000071684700556

• Does heart transplantation in the very young effect growth and neurodevelopment? Fleisher, B. E., Baum, D., Duckworth, J., Brudos, G., Klein, P., Constantinou, J., Bernstein, D., Stevenson, D. K. SLACK INC. 1998: 73A

  View details for Web of Science ID 000071684700384

• Involvement of a global regulator in Salmonella virulence. Contag, P. R., Pham, H. H., Olomu, I. N., Stevenson, D. K., Contag, C. H., Falkow, S. SLACK INC. 1998: 116A

  View details for Web of Science ID 000071684700614

• Noninvasive monitoring of acute susceptibility and host response to Salmonella infection in living neonatal mice. Olomu, I. N., Contag, C. H., Spilman, S. D., Benaron, D. A., Stevenson, D. K., Contag, P. R. SLACK INC. 1998: 116A

  View details for Web of Science ID 000071684700615

• The effects of potential therapeutic agents on transcription of heme oxygenase. Zhang, W., Contag, P. R., Contag, C. H., Hajdena-Dawson, M., Stevenson, D. K. SLACK INC. 1998: 132A

  View details for Web of Science ID 000071684700705

• Viral selection during transmission of HIV-1 to infants. Basile, A., Batra, M., Bachmann, M., Zhang, W., Stevenson, D. K., Contag, C. H., Kliks, S. SLACK INC. 1998: 142A

  View details for Web of Science ID 000071684700758

• Kernicteric findings at autopsy in two sick near term infants PEDIATRICS Halamek, L. P., Stevenson, D. K. 1998; 101 (1): 158–59

  View details for DOI 10.1542/peds.101.1.158a

  View details for Web of Science ID 000071331400045

  View details for PubMedID 11345982

• Macrosomia does not predict overweight in late adolescence in infants of diabetic mothers ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA Seidman, D. S., Laor, A., Stevenson, D. K., Sivan, E., Gale, R., Shemer, J. 1998; 77 (1): 58-62

  Abstract

  To determine the predictive value of macrosomia for overweight later in adult life in infants of diabetic mothers.Data from the computerized records of the Jerusalem Perinatal Study were matched to measurements made at age 17 obtained from the military draft medical examination records.10,891 infants born in Jerusalem between November 1974 and February 1976.Macrosomia based on 90th percentile birth weight for gestational age and overweight defined as the 90th percentile for body mass index at age 17.Diabetes was diagnosed in 87 (0.8%) of the mothers. Thirty-one (35.6%) of the infants of the diabetic mothers were macrosomic compared to 1012 (9.4%) of the siblings of nondiabetic mothers (p < 0.001). At 17 years of age 10.3% vs. 9.4% of the siblings of diabetic vs. nondiabetic mothers were overweight (p > 0.05). The rate of adolescent overweight in macrosomic vs. nonmacrosomic subjects was 12.3% vs. 9.7% (p < 0.01) in siblings of nondiabetic mothers, and 16.1% vs. 7.1% (p > 0.05) for diabetic mothers. The sensitivity and specificity, in diabetic mothers, of macrosomia for overweight at age 17 was 44.4% and 66.7%, respectively. The positive and negative predictive value of macrosomia for overweight at age 17 was 16.1% and 92.9%, respectively.The risk of adolescent overweight was significantly increased among macrosomic infants, although this trend did not reach statistical significance in the smaller group of infants born to diabetic mothers. Macrosomia among infants of diabetic mothers had little predictive value for overweight in late adolescence.

  View details for Web of Science ID 000071812100013

  View details for PubMedID 9492720

• Neonatal hypoglycemia .1. Background and definition International Symposium on Neonatal Hypoglycemia Halamek, L. P., Benaron, D. A., Stevenson, D. K. SAGE PUBLICATIONS INC. 1997: 675–80

  Abstract

  Hypoglycemia in the neonate remains a common problem. The association of low blood glucose concentrations and abnormal development has prompted extensive research into the anticipation, evaluation, and treatment of neonatal hypoglycemia. Glucose homeostasis in the fetus and neonate is a developmentally regulated dynamic process involving a number of intricate physiologic mechanisms. In addition, the determination of glucose concentrations is dependent upon both the type of tissue analyzed and the limitations of the specific method employed. The complexity of glucose metabolism makes it difficult to precisely define "normal" and "abnormal" glucose levels in preterm and term neonates.

  View details for PubMedID 9415833

• Supplemental oxygen may decrease progression of prethreshold disease to threshold retinopathy of prematurity. Journal of perinatology Gaynon, M. W., Stevenson, D. K., Sunshine, P., Fleisher, B. E., Landers, M. B. 1997; 17 (6): 434-438

  Abstract

  The optimum level of oxygen saturation for infants with prethreshold retinopathy of prematurity (ROP) is unknown. We reviewed our conversion rate from prethreshold to threshold ROP between 1985 and 1993 during which time target levels of oxygen saturation rose in a stepwise fashion. A retrospective study of 153 infants with prethreshold ROP was performed at Stanford University between 1985 and 1993 that showed that target minimum oxygen saturation rose from 92% (1985-1987) to 95% (1988) to 96% (1989) to 99% (1990-1993). In addition, we looked at 26 infants between 1994 and 1996 who were excluded from the STOP-ROP study and who were not receiving supplemental oxygen in an effort to maintain equipoise for that study. Infant characteristics were tabulated, and rates of progression from prethreshold to threshold ROP were calculated. Rates of progression to threshold varied little between 1985 and 1989 (average 37%), but dropped to 7% for the period between 1990 and 1993. From 1994 through 1996 the rate of progression to threshold disease rose again, to 38%. Moderate supplemental oxygen (target saturation 99% with PO2 no higher than 100 mm Hg) was associated with regression of prethreshold ROP, without appearing to arrest retinal vascular maturation.

  View details for PubMedID 9447528

• Visualizing gene expression in living mammals using a bioluminescent reporter PHOTOCHEMISTRY AND PHOTOBIOLOGY Contag, C. H., Spilman, S. D., Contag, P. R., Oshiro, M., Eames, B., Dennery, P., Stevenson, D. K., Benaron, D. A. 1997; 66 (4): 523-531

  Abstract

  Control of gene expression often involves an interwoven set of regulatory processes. As information regarding regulatory pathways may be lost in ex vivo analyses, we used bioluminescence to monitor gene expression in living mammals. Viral promoters fused to firefly luciferase as transgenes in mice allowed external monitoring of gene expression both superficially and in deep tissues. In vivo bioluminescence was detectable using either intensified or cooled charge-coupled device cameras, and could be detected following both topical and systemic delivery of substrate. In vivo control of the promoter from the human immunodeficiency virus was demonstrated. As a model for DNA-based therapies and vaccines, in vivo transfection of a luciferase expression vector (SV-40 promoter and enhancer controlling expression) was detected. We conclude that gene regulation, DNA delivery and expression can now be noninvasively monitored in living mammals using a luciferase reporter. Thus, real-time, noninvasive study of gene expression in living animal models for human development and disease is possible.

  View details for PubMedID 9337626

• Size at birth, maternal nutritional status in pregnancy, and blood pressure at age 17: population based analysis BRITISH MEDICAL JOURNAL Laor, A., Stevenson, D. K., Shemer, J., Gale, R., Seidman, D. S. 1997; 315 (7106): 449-453

  Abstract

  To assess the effect of size at birth, maternal nutrition, and body mass index on blood pressure in late adolescence.Population based analysis of birth weight corrected for gestational age, mother's weight before pregnancy and weight gain in pregnancy, obtained from the Jerusalem perinatal study, and blood pressure and body mass index at age 17, available from military draft records.Jerusalem, Israel.10,883 subjects (6684 men and 4199 women) born in Jerusalem during 1974-6 and subsequently drafted to the army.Systolic and diastolic blood pressures measured at age 17 and their correlation with birth weight, size at birth, mother's body mass index and weight gain during pregnancy, and height and weight at age 17.Systolic and diastolic blood pressures were significantly and positively correlated with body weight, height, body mass index at age 17, and with mother's body weight and body mass index before pregnancy, but not with birth weight or mother's weight gain in pregnancy.Variables reflecting poor intrauterine nutrition, including low maternal body mass index before pregnancy, poor maternal weight gain in pregnancy, and being born small for gestational age, were not associated with a higher blood pressure in late adolescence.

  View details for Web of Science ID A1997XT71400014

  View details for PubMedID 9284660

  View details for PubMedCentralID PMC2127333

• The effect of antenatal phenobarbital therapy on neonatal intracranial hemorrhage in preterm infants NEW ENGLAND JOURNAL OF MEDICINE Shankaran, S., Papile, L. A., Wright, L. L., Ehrenkranz, R. A., Mele, L., Lemons, J. A., Korones, S. B., Stevenson, D. K., Donovan, E. F., Stoll, B. J., Fanaroff, A. A., Oh, W. 1997; 337 (7): 466-471

  Abstract

  The administration of phenobarbital to pregnant women before delivery has been thought to decrease the frequency of intracranial hemorrhage in preterm infants. To evaluate this potential neuroprotective therapy further, we determined the effect of antenatal administration of phenobarbital on the frequency of neonatal intracranial hemorrhage and early death.We studied 610 women who were 24 to 33 weeks pregnant and who were expected to deliver their infants within 24 hours. The women were randomly assigned to receive either phenobarbital (10 mg per kilogram of body weight) or placebo intravenously, followed by maintenance doses until delivery or 34 weeks of gestation. The infants born to these women underwent cranial ultrasonography to detect the presence of intracranial hemorrhage.There were 309 women in the phenobarbital group and 301 in the placebo group. A total of 247 women (80 percent) in the phenobarbital group and 235 (78 percent) in the placebo group delivered within 24 hours after infusion of the study drug or administration of the last maintenance dose. Intracranial hemorrhage or early death occurred in 83 of the 344 infants born to the women in the phenobarbital group (24 percent) and in 74 of the 324 born to the women in the placebo group (23 percent; risk ratio for the infants in the phenobarbital group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Among infants born before 34 weeks' gestation in whom ultrasonographic studies were performed, intracranial hemorrhage was diagnosed in 70 of 311 infants in the phenobarbital group (23 percent) and 64 of 279 in the placebo group (23 percent; risk ratio, 1.0; 95 percent confidence interval, 0.8 to 1.4).Antenatal administration of phenobarbital does not decrease the risk of intracranial hemorrhage or early death in preterm infants.

  View details for Web of Science ID A1997XQ49900005

  View details for PubMedID 9250849

• Carbon monoxide and bilirubin production in neonates Japan-Society-for-Premature-and-Newborn-Medicine Stevenson, D. K., Vreman, H. J. AMER ACAD PEDIATRICS. 1997: 252–54

  View details for PubMedID 9240808

• Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: Has the dose been too low? EARLY HUMAN DEVELOPMENT Kennedy, K. A., Stoll, B. J., Ehrenkranz, R. A., Oh, W., Wright, L. L., Stevenson, D. K., Lemons, J. A., Sowell, A., Mele, L., TYSON, J. E., Verter, J. 1997; 49 (1): 19-31

  Abstract

  Inconsistent effects of vitamin A supplementation on prevention of bronchopulmonary dysplasia have been reported. Meta-analysis of these reports resulted in a relative risk of 0.69-1.02 for death or bronchopulmonary dysplasia associated with vitamin A supplementation. Effective dosage regimens or serum retinol concentrations have not been determined in previous reports. The purpose of this pilot study was to define a vitamin A regimen that produces serum retinol concentrations of 25-55 micrograms/dl.In this three-phase study, 91 infants (mean birth weight 799-864 g) were enrolled. Vitamin A was administered three times/week for 4 weeks at an average daily dose of 986-2143 IU/day. Physical examinations were performed and serum retinol specimens were collected weekly to assess clinical signs of toxicity.The majority of serum retinol concentrations remained < 25 micrograms/dl until an intramuscular vitamin A dose of 5000 IU/dose three times/week was used. No clinical signs of toxicity were associated with the higher dosage and higher serum concentrations of vitamin A.A large clinical trial of vitamin A supplementation with 5000 IU/dose three times/week (25-114% more than the dose used in the three published clinical trials) is needed to assess whether vitamin A supplementation safely reduces the risk of bronchopulmonary dysplasia in very-low-birth-weight infants.

  View details for Web of Science ID A1997XC43800003

  View details for PubMedID 9179535

• Carbon monoxide formation in the guinea pig hippocampus: Ontogeny and effect of in vitro ethanol exposure DEVELOPMENTAL BRAIN RESEARCH Cook, M. N., Marks, G. S., Vreman, H. J., McLaughlin, B. E., Nakatsu, K., Stevenson, D. K., Brien, J. F. 1997; 101 (1-2): 283-286

  Abstract

  Carbon monoxide (CO) is considered to be a novel neuronal messenger in the brain, similar to nitric oxide. The ontogeny of CO formation in transverse hippocampal slices of the guinea pig was elucidated at selected prenatal and postnatal ages, and the effect of in vitro ethanol exposure on hippocampal CO formation was determined. There was a higher rate of hippocampal CO formation in the fetus at gestational day (GD) 50 and GD 62 (term, about GD 68) compared with the adult. In vitro ethanol exposure (50 and 100 mM) decreased hippocampal CO formation in the GD 62 fetus, which was prevented by incubation with 500 microM L-glutamate.

  View details for Web of Science ID A1997XP15200030

  View details for PubMedID 9263603

• Heme oxygenase activity and immunohistochemical localization in bovine pulmonary artery and vein JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Marks, G. S., McLaughlin, B. E., Vreman, H. J., Stevenson, D. K., Nakatsu, K., Brien, J. F., Pang, S. C. 1997; 30 (1): 1-6

  Abstract

  Recent studies suggest that carbon monoxide (CO) derived from heme oxygenase (HO)-catalyzed metabolism of heme plays a role in the regulation of cell function and communication. In blood vessels, CO may regulate vascular smooth-muscle tone through the activation of soluble guanylyl cyclase, in a manner similar to that of nitric oxide. The objective of this study was to determine the relation between HO enzymatic activity and localization of HO protein in bovine pulmonary blood vessels. HO enzymatic activity was determined by quantitating the rate of CO formation in the microsomal fraction of homogenates of bovine pulmonary artery (BPA) and vein (BPV). HO protein was localized by immunohistochemical analysis of paraformaldehyde-fixed tissue by using polyclonal antibodies to inducible HO (HO-1) and noninducible HO (HO-2). HO enzymatic activity was measured in BPA and BPV, which correlated with the presence of HO protein. In BPA, HO enzymatic activity was found in the adventitia and medial layer; HO protein was localized in the nerves and vasa vasorum of the adventitia and was found throughout the smooth-muscle cells in the medial layer. The data clearly demonstrate the presence of HO enzymatic activity for the formation of CO in blood vessels that contain HO protein.

  View details for Web of Science ID A1997YK70100001

  View details for PubMedID 9268214

• Imaging - Tissue optics SCIENCE Benaron, D. A., Cheong, W. F., Stevenson, D. K. 1997; 276 (5321): 2002-2003

  View details for Web of Science ID A1997XG74800051

  View details for PubMedID 9221510

• Development of jaundice in Korean neonates after Cesarean section ACTA PAEDIATRICA JAPONICA Lee, C. S., Vreman, H. J., Choi, J. H., Yun, C. K., Stevenson, D. K. 1997; 39 (3): 309-311

  Abstract

  The aim of the project was to determine the physiologic mechanisms of later- and higher-peak transitional plasma bilirubin levels in Korean infants. Blood carboxyhemoglobin, corrected for inhaled CO (COHbc), as an index of bilirubin production, and plasma total bilirubin levels in 40 healthy term Korean infants delivered by Cesarean section were measured throughout the first week of life. The COHbc levels were significantly higher in the Korean neonates than in previously studied Caucasian neonates. Moreover, COHbc levels decreased by 28% during the first 7 days of life from 0.85 +/- 0.20 to 0.61 +/- 0.34% (P < 0.025). This pattern parallels a 15% decrease in total hemoglobin from 181 +/- 23 to 154 +/- 53 g/L (P < 0.05). In contrast, plasma bilirubin concentrations more than doubled from 80 +/- 32 to 172 +/- 48 mumol/L (4.7 +/- 1.8 to 10.0 +/- 2.8 mg/dL; P < 0.001), remaining unchanged between days 4 and 7. Both increased production and decreased elimination of bilirubin contribute to physiologic jaundice in Korean infants.

  View details for PubMedID 9241890

• Hypoxia-ischemia, but not hypoxia alone, induces the expression of heme oxygenase-1 (HSP32) in newborn rat brain JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Bergeron, M., Ferriero, D. M., Vreman, H. J., Stevenson, D. K., Sharp, F. R. 1997; 17 (6): 647-658

  Abstract

  Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme to produce bile pigments and carbon monoxide. The HO-1 isozyme is induced by a variety of agents such as heat, heme, and hydrogen peroxide. Evidence suggests that the bile pigments serve as antioxidants in cells with compromised defense mechanisms. Because hypoxia-ischemia (HI) increases the level of oxygen free radicals, the induction of HO-1 expression in the brain during ischemia could modulate the response to oxidative stress. To study the possible involvement of HO-1 in neonatal hypoxia-induced ischemic tolerance, we examined the brains of newborn rat pups exposed to 8% O2 (for 2.5 to 3 hours), and the brain of chronically hypoxic rat pups with congenital cardiac defects (Wistar Kyoto; WKY/ NCr). Heme oxygenase-1 immunostaining did not change after either acute or chronic hypoxia, suggesting that HO-1 is not a good candidate for explaining hypoxia preconditioning in newborn rat brain. To study the role of HO-1 in neonatal HI, 1-week-old rats were subjected to right carotid coagulation and exposure to 8% O2/92% N2 for 2.5 hours. Whereas HO enzymatic activity was unchanged in ipsilateral cortex and subcortical regions compared with the contralateral hemisphere or control brains, immunocytochemistry and Western blot analysis showed increased HO-1 staining in ipsilateral cortex, hippocampus, and striatum at 12 to 24 hours up to 7 days after HI. Double fluorescence immunostaining showed that HO-1 was expressed mostly in ED-1 positive macrophages. Because activated brain macrophages have been associated with the release of several cytotoxic molecules, the presence of HO-1 positive brain macrophages may determine the tissue vulnerability after HI injury.

  View details for Web of Science ID A1997XL36800006

  View details for PubMedID 9236721

• Rhesus isoimmunization: Increased hemolysis during early infancy PEDIATRIC RESEARCH Hayde, M., Widness, J. A., Pollak, A., KohlhauserVollmuth, C., Vreman, H. J., Stevenson, D. K. 1997; 41 (5): 716-721

  Abstract

  The objective of the present study was to determine whether whole blood carboxyhemoglobin (COHb) and plasma bilirubin, two indicators of hemolysis, are elevated in infants with severe Rh isoimmune hemolytic disease during the first months of life. Beginning at 2 wk of age and continuing monthly for 3 mo, serial blood samples were obtained for COHb, plasma bilirubin, Hb, reticulocyte count, plasma erythropoietin, plasma enzymes, and plasma iron. Because control infants (n = 13) and infants with ABO hemolytic disease (n = 5) did not differ from one another in any of the study parameters, these two groups were combined and compared with infants with the Rh isoimmunization. Infants with severe Rh isoimmune hemolytic disease (n = 13) were found to have significantly lower Hb and significantly higher bilirubin, the COHb fraction divided by the Hb concentration (COHb/Hb), and plasma erythropoietin levels at 2 and 6 wk of age, and reticulocyte counts at 6 wk. The remaining parameters were not different between the control-ABO group and Rh-isoimmune group at any of the study intervals. The study's two primary indicators of hemolysis, plasma bilirubin and COHb/Hb, were significantly correlated with one another in the Rh-immunized group (r = 0.66, p < 0.0001), but not in the combined control-ABO group. Serial Rh antibody concentrations measured in the serum of four neonates with Rh isoimmunization demonstrated a mean half-life of 14.3 d. We speculate that, among infants with severe Rh isoimmune hemolytic disease, elevated total bilirubin levels and COHb/Hb ratios identified in the early weeks of life indicate continuing hemolysis due to persistence of maternal Rh antibodies.

  View details for Web of Science ID A1997WV66300018

  View details for PubMedID 9128296

• The value of neurophysiologic approaches in the anticipation and evaluation of neonatal hypoglycemia. Acta paediatrica Japonica; Overseas edition Halamek, L. P., Benaron, D. A., Stevenson, D. K. 1997; 39: S33-43

  Abstract

  The association of low blood glucose with central nervous system (CNS) injury was first described in 1937 by Hartmann and Jaudon. In the early 60 years since publication of these observations the effects of hypoglycemia upon the brain remain poorly understood. Technology capable of accurately determining plasma glucose concentrations has been developed. Investigators have sought to establish critical values below which glucose levels should not be allowed to fall. Despite these efforts the definitive level of glucose capable of producing brain injury in any particular patient remains unknown. Glucose homeostasis within the neonatal CNS represents a dynamic process consisting of many interrelated variables including gestational and chronologic age, genotype, relative health, blood flow, metabolic rate and availability of other suitable substrates. New technique for assessing the glucose delivery: consumption ratio and directly monitoring the cellular consequences of glucose deprivation within discrete regions of the brain will help to answer the question 'How long is too low and how long is too long?'

  View details for PubMedID 9200877

• Neonatal severity of illness scoring systems: A comparison CLINICAL PEDIATRICS Fleisher, B. E., Murthy, L., Lee, S., Constantinou, J. C., Benitz, W. E., Stevenson, D. K. 1997; 36 (4): 223-227

  Abstract

  Several different scoring systems have been developed to predict neonatal morbidity and mortality. In this investigation we compared the utility of four severity of illness scoring systems (SISS) as predictors of days on ventilatory (DOV), length of hospital stay (LOS), and mortality in very-low-birth weight (VLBW) premature infants who required mechanical ventilation. The SISS assessed were the Score for Neonatal Acute Physiology (SNAP); the Score for Neonatal Acute Physiology-Perinatal Extension (SNAP + PE); Clinical Risk Index for Babies (CRIB), and the Sinkin Score at 12 hours (SS12). Results revealed significant correlations among the SS12, SNAP, SNAP + PE, CRIB, birth weight (BW), DOV, and LOS. However, none of the systems we assessed offered striking advantage over BW in a VLBW ventilated group.

  View details for PubMedID 9114994

• Heme oxygenase activity and acute and chronic ethanol exposure in the hippocampus, frontal cerebral cortex, and cerebellum of the near-term fetal guinea pig ALCOHOL Cook, M. N., Marks, G. S., Vreman, H. J., Nakatsu, K., Stevenson, D. K., Brien, J. F. 1997; 14 (2): 117-124

  Abstract

  Heme oxygenase (HO) catalyzes the oxidation of heme to produce carbon monoxide, which is considered to be a novel neuronal messenger in the brain and may play a role in neuronal development. The objective of this study was to determine the effects of in vitro, acute in vivo, and chronic in vivo ethanol exposure on HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the near-term fetal guinea pig. HO activity was determined using a gas chromatographic method to quantitate CO formation in the microsomal fraction of the homogenate of each selected brain region, incubated with saturating concentrations of heme, NADPH, and O2. Fetal body, brain, hippocampal, and cerebellar weights were recorded. In vitro ethanol exposure (25-100 mM) did not affect hippocampal, cerebral cortical, or cerebellar HO activity of the fetal guinea pig at gestational day (GD) 62 (term, about GD 68). Acute maternal oral administration of 4 g ethanol/kg maternal body weight at GD 62 did not affect HO activity in these three fetal brain areas compared with control fetuses (maternal administration of isocaloric sucrose or water). For chronic daily maternal oral administration of 4 g ethanol/kg maternal body weight throughout gestation, fetal body, brain, hippocampal, and cerebellar weights were decreased at GD 62 compared with isocaloric-sucrose/pair-fed and water treatment control groups. Furthermore, isocaloric-sucrose/pair-feeding treatment decreased fetal body and brain weights compared with water treatment. Chronic in vivo ethanol exposure did not alter HO activity in the near-term fetal hippocampus, frontal cerebral cortex, or cerebellum. This is the first study of the effect of ethanol exposure on HO activity in the developing brain of any species. The data demonstrate, for ethanol CNS teratogenesis in the guinea pig manifesting as fetal brain growth restriction, there is no associated change in HO activity in the hippocampus, frontal cerebral cortex, or cerebellum.

  View details for Web of Science ID A1997WP44200003

  View details for PubMedID 9085711

• Carbon monoxide formation in the ductus arteriosus in the lamb: Implications for the regulation of muscle tone BRITISH JOURNAL OF PHARMACOLOGY Coceani, F., Kelsey, L., Seidlitz, E., Marks, G. S., McLaughlin, B. E., Vreman, H. J., Stevenson, D. K., RABINOVITCH, M., Ackerley, C. 1997; 120 (4): 599-608

  Abstract

  1. We have previously shown that carbon monoxide (CO) potently relaxes the lamb ductus arteriosus and have ascribed this response to inhibition of a cytochrome P450-based mono-oxygenase reaction controlling the formation of endothelin-1 (ET-1). In the present study, we have examined whether CO is formed naturally in the vessel. 2. The CO-forming enzyme, haem oxygenase (HO), was identified in ductal tissue in its constitutive (HO-2) and inducible (HO-1) isoforms by Western immunoblotting and immunological staining procedures (both light and electron microscopy). HO-1 was localized to endothelial and muscle cells, while HO-2 was found only in muscle cells. Inside the muscle cells, HO-1 and HO-2 immunoreactivity was limited to the perinuclear region, and the Golgi apparatus in particular. However, upon exposure to endotoxin, HO-1 became more abundant, and both HO isoforms migrated towards the outer region of the cytoplasm close to the sarcolemma. 3. CO was formed enzymatically from added substrate (hemin, 50 microM) in the 10,000 g supernatant of the ductus and its formation was inhibited by zinc protoporphyrin IX (ZnPP, 200 microM). 4. ZnPP (10 microM) had no effect on the tone of the ductus under normal conditions (2.5 to 95% O2), but it contracted the endotoxin-treated ductus (at 2.5% O2). At the same concentration, ZnPP also tended to contract the hypoxic vessel (zero O2). 5. ZnPP (10 microM) curtailed the relaxant response of the oxygen (30%)/indomethacin (2.8 microM)-contracted ductus to bradykinin (35 nM), while it left the sodium nitroprusside (35 nM) relaxation unchanged. 6. We conclude that CO is formed in the ductus and may exert a relaxing influence when its synthesis is upregulated by an appropriate stimulus.

  View details for Web of Science ID A1997WJ00500011

  View details for PubMedID 9051297

  View details for PubMedCentralID PMC1564507

• Does vitamin C cause hemolysis in premature newborn infants? Results of a multicenter double-blind, randomized, controlled trial JOURNAL OF PEDIATRICS Doyle, J., Vreman, H. J., Stevenson, D. K., Brown, E. J., Schmidt, B., Paes, B., Ohlsson, A., Boulton, J., Kelly, E., Gillie, P., Lewis, N., Merko, S., Shaw, D., Zipursky, A. 1997; 130 (1): 103–9

  Abstract

  We tested the hypothesis that vitamin C supplementation of premature neonates is associated with hemolysis.A double-blind, randomized, controlled trial of vitamin C supplementation (50 mg/day) was undertaken in premature neonates (birth weight, 1000 to 1500 gm). Infants were randomly assigned to receive vitamin C (Ce-Vi-Sol) (n = 32) or placebo (n = 24) for 14 days. Twenty-three subjects per group were required to detect a difference of 1 SD in corrected carboxyhemoglobin values (alpha = 0.05, beta = 0.10).Day 14 vitamin C levels were lower in control subjects than in supplemented neonates (62 +/- 24 vs 125 +/- 62 micromol/L, p = 0.005). There was no difference in corrected blood carboxyhemoglogin concentrations (0.72 +/- 0.44 vs 0.72 +/- 0.23%; p = 0.95), other parameters of hemolysis, weight gain, blood sampled, presumed septic episodes, necrotizing enterocolitis, feeding intolerance, or transfusion. On day 14, bilirubin values were higher in control subjects than in the supplemented group (77 +/- 37 vs 55 +/- 33 micromol/L; p = 0.04). When a distant outlier in the nonsupplemented group was excluded (163 micromol/L), statistical significance was lost (73 +/- 32 vs 55 +/- 33 micromol/L; p = 0.09).Oral supplementation of premature infants with vitamin C is not associated with evidence of increased erythrocyte destruction, hyperbilirubinemia, or other morbidity.

  View details for DOI 10.1016/S0022-3476(97)70317-2

  View details for Web of Science ID A1997WD71800019

  View details for PubMedID 9003858

• Automated classification of tissue by type using real-time spectroscopy Conference on Optical Biopsies and Microscopic Techniques II Benaron, D. A., Cheong, W. F., Duckworth, J. L., Noles, K., Nezhat, C., Seidman, D., Hintz, S. R., Levinson, C. J., Murphy, A. L., Price, J. W., Liu, F. W., Stevenson, D. K., Kermit, E. L. SPIE - INT SOC OPTICAL ENGINEERING. 1997: 99–107

  View details for Web of Science ID 000071861300013

• The risk of carbon monoxide poisoning after prolonged laparoscopic surgery OBSTETRICS AND GYNECOLOGY Nezhat, C., Seidman, D. S., Vreman, H. J., Stevenson, D. K., Nezhat, F., Nezhat, C. 1996; 88 (5): 771-774

  Abstract

  To evaluate whether thermal energy produced by laser and bipolar electrosurgery during laparoscopic procedures significantly elevates blood carboxyhemoglobin levels.We prospectively studied 27 healthy nonsmoking patients, mean +/- standard deviation (SD) age 39.1 +/- 8.0 years (range 22-56), scheduled for laparoscopic procedures in which smoke was generated. Prolonged operative laparoscopy involved high-flow carbon dioxide insufflation, intensive evacuation of intra-abdominal smoke, and controlled hyperventilation with 50-100% oxygen. Laser and bipolar electrosurgery were used in all cases. Blood samples were drawn before and after surgery. Carboxyhemoglobin concentrations were measured using a highly accurate gas chromatography method.The mean +/- SD duration of surgery was 141 +/- 72 minutes (range 45-300). The mean +/- SD carboxyhemoglobin levels were 0.70 +/- 0.15% (range 0.44-1.20%) before surgery and 0.58 +/- 0.20% (range 0.30-1.33%) after surgery. A significant decrease (P < .001) in carboxyhemoglobin concentrations occurred during surgery (mean +/- SD, 20 +/- 11%; range 3-46%). The carboxyhemoglobin level was increased at the end of surgery in only one woman. In only one patient did the levels exceed 1% (1.33%), still well below the human threshold tolerance level of 2%. The Spearman correlation coefficient between carboxyhemoglobin concentrations and duration of surgery was r = 0.308 (P = .12).Carbon monoxide (CO) poisoning is not associated with even prolonged laparoscopic surgical procedures. This may be attributed to aggressive smoke evacuation that minimizes exposure to CO, and to active elimination of CO by ventilation with high oxygen concentrations.

  View details for PubMedID 8885911

• Maternal smoking and fetal carboxyhaemoglobin and blood gas levels BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY Vreman, H. J., Stevenson, D. K., Seidman, D. S., Widness, J. A. 1996; 103 (11): 1171–72

  View details for DOI 10.1111/j.1471-0528.1996.tb09607.x

  View details for Web of Science ID A1996VR35300039

  View details for PubMedID 8917012

• Intravenous immune globulin in neonatal immune hemolytic disease: Does it reduce hemolysis? ACTA PAEDIATRICA Hammerman, C., Vreman, H. J., Kaplan, M., Stevenson, D. K. 1996; 85 (11): 1351-1353

  Abstract

  We studied the effect of intravenous immune globulin (IVIG) on hemolysis in term, hyperbilirubinemic, Coomb's positive infants utilizing measurement of carboxyhemoglobin fraction corrected for inhaled carbon monoxide (COHbc), a sensitive indicator of hemolysis. COHbc values were determined before and after IVIG infusion. In those babies who responded with a decrease in serum total bilirubin (n = 19), no exchange transfusions were required and COHbc levels decreased significantly by 24 h post-IVIG from 1.37 +/- 0.31 to 1.12 +/- 0.26% tHb (p < 0.0001). There were no corresponding decreases in COHbc levels (1.989 +/- 0.54 to 1.82 +/- 0.48% tHb; p > 0.05) among those whose serum bilirubin levels did not decrease in response in to IVIG (n = 7), and all of these infants required exchange transfusions. Furthermore, the extent of the decrease in COHbc was related to the degree of decrease in serum bilirubin levels, such that the percentage decrease of bilirubin at 24 h was directly correlated with the percentage decrease of COHbc at 24 h (p = 0.007). We conclude that IVIG, when successful, inhibits hemolysis in these infants.

  View details for Web of Science ID A1996VT95200017

  View details for PubMedID 8955465

• Nitrovasodilator therapy for severe respiratory distress syndrome. Journal of perinatology Benitz, W. E., Rhine, W. D., Van Meurs, K. P., Stevenson, D. K. 1996; 16 (6): 443-448

  Abstract

  Improved gas exchange in infants with severe respiratory distress syndrome has been reported in association with infusion of nitroprusside and during inhalation of nitric oxide. To evaluate the association between nitrovasodilator therapy and clinical improvement in premature neonates with severe respiratory distress syndrome, we reviewed the courses of 22 infants with severe respiratory distress syndrome who were treated with sodium nitroprusside for at least 24 hours. These infants had birth weights of 2049 +/- 828 gm (range 720 to 3430 gm), gestational ages of 32.5 +/- 3.5 weeks (range 25 to 38 weeks), high ventilator settings before treatment (FIO2 of 100%, peak inspiratory pressures of 37.8 +/- 6.1 cm H2O [range 30 to 50 cm H2O], and mean airway pressures of 18.0 +/- 3.3 cm H2O [range 12.3 to 26 cm H2O]), and low pretreatment PaO2 of 49.3 +/- 9.4 mm Hg (range 27 to 69 mm Hg). Baseline oxygenation indexes were 39.4 +/- 12.1 (range 18.6 to 66.7). Nitroprusside infusion was temporally associated with increased PaO2, decreased PaCO2, and reduced oxygenation index. Potentially beneficial changes were inconsistent in infants with pulmonary interstitial emphysema and were greatest in infants treated with end-expiratory pressures of at least 4 cm H2O. These observations provide a basis for the hypothesis that nitrovasodilator therapy produces improvement in gas exchange in premature infants with severe respiratory distress syndrome.

  View details for PubMedID 8979182

• Varicella vaccine in pregnancy. BMJ (Clinical research ed.) Seidman, D. S., Stevenson, D. K., Arvin, A. M. 1996; 313 (7059): 701-702

  View details for PubMedID 8819427

  View details for PubMedCentralID PMC2352106

• Carbon monoxide poisoning is unlikely during laparoscopic surgical procedures BrockUtne, J. G., Seidman, D. S., Nezhat, F., Vreman, H. J., Stevenson, D. K., Nezhat, C. H., Nezhat, C. LIPPINCOTT-RAVEN PUBL. 1996: A5

  View details for Web of Science ID A1996VM46600005

• Hepatic heme oxygenase is inducible in neonatal rats during the early postnatal period PEDIATRIC RESEARCH Tom, D. J., Rodgers, P. A., Shokoohi, V., Stevenson, D. K., Dennery, P. A. 1996; 40 (2): 288-293

  Abstract

  Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to bilirubin. Cobalt chloride (CoCl2) and many other agents that generate oxidant stresses induce the HO-1 isoform. Furthermore, HO-1 has been shown to protect against oxidant stress in vitro and in vivo by mechanisms involving increased ferritin synthesis. However, little is known about the inducibility of hepatic HO-1 during the very early postnatal period, and whether HO-1 induction is associated with increased ferritin synthesis in neonates. Therefore, we studied hepatic HO-1 mRNA, HO-1 protein concentration, total HO activity, and ferritin protein levels in neonatal rats. Neonatal rats 0-5 d of age were injected with 250 mumol/kg body weight of CoCl2. 6H2O in saline or with an equal volume of saline in age-matched controls. Liver samples were collected 4 h after injection for HO-1 mRNA analysis and 20 h after injection for analysis of HO-1 protein concentration, total HO activity, and ferritin protein levels. In CoCl2-treated rats, hepatic HO-1 mRNA was 3-10 times the levels in control rats (p < 0.05), HO-1 protein concentration was 2-5 times the levels in control rats (p < 0.05), and total HO activity was higher by 20-80% than in control rats (p < 0.05). There were no differences in hepatic ferritin protein levels between CoCl2-treated neonatal rats and controls; however, in CoCl2-treated adult rats, hepatic ferritin protein levels were 1.6 times the levels in controls (p < 0.05). Thus, neonatal rats can up-regulate hepatic HO-1 mRNA, HO-1 protein concentration, and total HO activity in response to CoCl2; however, no upregulation of hepatic ferritin protein levels was observed in neonatal rats after CoCl2 administration or subsequent HO-1 induction. We speculate that neonatal rats induce hepatic HO-1 and up-regulate ferritin by different mechanisms than do adult rats.

  View details for PubMedID 8827779

• Intravenous immune globulin in neonatal ABO isoimmunization: Factors associated with clinical efficacy BIOLOGY OF THE NEONATE Hammerman, C., Kaplan, M., Vreman, H. J., Stevenson, D. K. 1996; 70 (2): 69-74

  Abstract

  Intravenous immune globulin (IVIG) reduces jaundice in many but not all cases of neonatal isoimmunization. We sought to elucidate the type of infant most likely to benefit from IVIG administration by attempting to define pretreatment parameters associated with both clinical symptomatology and therapeutic responsiveness to IVIG.Term, healthy Coombs-positive infants were studied prospectively. IVIG was administered if, despite phototherapy, serum bilirubin reached > or = 222 mumol/l (13 mg/dl) at < or = 24 h of age and/or > or = 274 mumol/l (16 mg/dl) at > 24 h of age. Clinical data including serial serum total bilirubin levels, rate of bilirubin rise on day 1 of life, serial corrected carboxyhemoglobin levels (a sensitive indicator of hemolysis) and total hemoglobin (tHb) levels were collected.Infants were classified as IVIG responders (n = 18), those in whom total serum bilirubin levels either remained stable or decreased following IVIG administration; IVIG nonresponders (n = 5), those who developed a total serum bilirubin of > or = 2 mg/dl greater than pre-IVIG bilirubin levels within the first 24 h after IVIG administration, or nontreated, those not meeting IVIG treatment criteria (n = 13). Four of the five nonresponders proceeded to require exchange transfusion vs. none of the others (p < 0.001). Four of the five nonresponders had a pretreatment rate of bilirubin rise of > or = 1 mg/dl/h as compared with only 1 of 18 responders and none of the nontreated (p < 0.001). Pretreatment tHb levels were also different (13.2 +/- 1.3 vs. 15.5 +/- 2.3 vs. 17.7 +/- 2.4 g/dl for nonresponders vs. responders vs. nontreated infants, respectively; p < 0.005). The highest pretreatment COHbc levels were seen in the nonresponders (1.8 +/- 0.7 vs. 1.4 +/- 0.3 vs. 0.9 +/- 0.3% tHb, respectively).Our 3 groups represent a spectrum of hemolysis, ranging from severe to moderate to mild. This spectrum appears to relate not only to the severity of hemolysis, but also to the therapeutic responsiveness to IVIG. We speculate that some or all of the factors identified can be used prospectively to predict the subsequent clinical course of ABO-incompatible infants and to facilitate optimal management.

  View details for Web of Science ID A1996VD14700001

  View details for PubMedID 8864425

• Is Carbon Monoxide Poisoning a Risk During Prolonged Laparoscopic Surgery? The Journal of the American Association of Gynecologic Laparoscopists Seidman, D. S., Nezhat, C. R., Vreman, H. J., Stevenson, D. K., Brock-Une, J. G. 1996; 3 (4, Supplement): S45

  Abstract

  We evaluated whether prolonged laparoscopic procedures performed with high-flow carbon dioxide (CO2) insufflation, intensive evacuation of intraabdominal smoke, and controlled hyperventilation with 50% to 90% oxygen results in significant elevation in blood carboxyhemoglobin levels. Twenty-seven healthy, nonsmoking women (mean ± SD age 39.1 ± 8.0 yrs, range 22-56 yrs) undergoing laparoscopic procedures in which smoke was generated participated. In all cases both the CO2 laser and bipolar electrosurgery were used extensively. The mean ± SD duration of surgery was 141 ± 72 minutes (range 45-300 min). Blood samples were drawn before and after surgery. Carboxyhemoglobin concentrations were measured using a highly accurate gas chromatography method. The mean ± SD carboxyhemoglobin levels were 0.70% ± 0.15% (range 0.44-1.20%) before and 0.58% ± 0.20% (range 0.30-1.33%) after surgery. The concentrations decreased significantly during surgery (mean ± SD 20% ± 11%, range 3-46%, p <0.001). In only one woman the level increased at the end of surgery. This also occurred when levels exceeded 1% (1.33%). The correlation coefficient (r) between carboxyhemoglobin concentrations and duration of surgery was 0.324. We concluded that carbon monoxide poisoning is not associated with prolonged laparoscopic surgical procedures. This may be attributed to aggressive smoke evacuation that minimized exposure and to elimination of CO2 through hyperventilation.

  View details for PubMedID 9074233

• Early-onset sepsis in very low birth weight neonates. A report from the National Institute of Child Health and Human Development Neonatal Research Network JOURNAL OF PEDIATRICS Stoll, B. J., Gordon, T., Korones, S. B., Shankaran, S., TYSON, J. E., Bauer, C. R., Fanaroff, A. A., Lemons, J. A., Donovan, E. F., Oh, W., Stevenson, D. K., Ehrenkranz, R. A., Papile, L. A., Verter, J., Wright, L. L. 1996; 129 (1): 72-80

  Abstract

  Early-onset sepsis (occurring within 72 hours of birth) is included in the differential diagnosis of most very low birth weight (VLBW) neonates. To determine the current incidence of early-onset sepsis, risk factors for disease, and the impact of early-onset sepsis on subsequent hospital course, we studied a cohort of 7861 VLBW neonates (401 to 1500 gm) admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991-1993).The NICHD Neonatal Research Network maintains a prospectively collected registry on all VLBW neonates born or cared for at participating centers. Data from this registry were analyzed retrospectively.Blood culture-proven early-onset sepsis was uncommon, occurring in only 1.9% of VLBW neonates. Group B streptococcus was the most frequent pathogen associated with early-onset sepsis (31%), followed by Escherichia coli (16%) and Haemophilus influenzae (12%). Decreasing gestational age was associated with increased rates of infection. Antibiotic therapy for suspected sepsis is frequently initiated at birth in VLBW neonates. Almost half of the infants in this cohort were considered to have clinical sepsis and continued to receive antibiotics for 5 or more days, despite a negative blood culture result in 98% of cases. These findings underscore the difficulty of ruling out sepsis in the symptomatic immature neonate and the special concern for culture-negative clinical sepsis in the face of maternal antibiotic use. Neonates with early-onset sepsis were significantly more likely to have subsequent comorbidities, including severe intraventricular hemorrhage, patent ductus arteriosus, and prolonged assisted ventilation. Although 26% of VLBW neonates with early-onset sepsis died, only 4% of the 950 deaths that occurred in the first 72 hours of life were attributed to infection. For those infants discharged alive, early-onset sepsis was associated with a significantly prolonged hospital stay (86 vs 69 days; p <0.02).Early-onset sepsis remains an important but uncommon problem among VLBW preterm infants. Improved diagnostic strategies are needed to enable the clinician to distinguish between the infected and the uninfected VLBW neonate with symptoms and to target continued antibiotic therapy to those who are truly infected.

  View details for Web of Science ID A1996UY27200011

  View details for PubMedID 8757565

• Late-onset sepsis in very low birth weight neonates: A report from the National Institute of Child Health and Human Development Neonatal Research Network JOURNAL OF PEDIATRICS Stoll, B. J., Gordon, T., Korones, S. B., Shankaran, S., TYSON, J. E., Bauer, C. R., Fanaroff, A. A., Lemons, J. A., Donovan, E. F., Oh, W., Stevenson, D. K., Ehrenkranz, R. A., Papile, L. A., Verter, J., Wright, L. L. 1996; 129 (1): 63-71

  Abstract

  Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 7861 VLBW (401 to 1500 gm) neonates admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991 to 1993).The NICHD Neonatal Research Network maintains a prospectively collected registry of all VLBW neonates cared for at participating centers. Data from this registry were analyzed retrospectively.Of 6911 infants who survived beyond 3 days, 1696 (25%) had one or more episodes of blood culture-proven sepsis. The vast majority of infection (73%) were caused by gram-positive organisms, with coagulase-negative staphylococci accounting for 55% of all infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of infection included intubation, respiratory distress syndrome, prolonged ventilation, bronchopulmonary dysplasia, patent ductus arteriosus, severe intraventricular hemorrhage, and necrotizing enterocolitis. Among infants with bronchopulmonary dysplasia, those with late-onset sepsis had a significantly longer duration of mechanical ventilation (45 vs 33 days; p <0.01). Late-onset sepsis prolonged hospital stay: the mean number of days in the hospital for VLBW neonates with and without late-onset sepsis was 86 and 61 days, respectively (p <0.001). Even after adjustment for other complications of prematurity, including intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia, infants with late-onset sepsis had a significantly longer hospitalization (p <0.001). Moreover, neonates in whom late-onset sepsis developed were significantly more likely to die than those who were uninfected (17% vs 7%; p <0.000 1), especially if they were infected with gram-negative organisms (40%) or fungi (28%). Deaths attributed to infection increased with increasing chronologic age. Whereas only 4% of deaths in the first 3 days of life were attributed to infection, 45% of deaths after 2 weeks were related to infection.Late-onset sepsis is a frequent and important problem among VLBW preterm infants. Successful strategies to decrease late-onset sepsis should decrease VLBW mortality rates, shorten hospital stay, and reduce costs.

  View details for Web of Science ID A1996UY27200010

  View details for PubMedID 8757564

• Interlaboratory variability of bilirubin measurements CLINICAL CHEMISTRY Vreman, H. J., Verter, J., Oh, W., Fanaroff, A. A., Wright, L. L., Lemons, J. A., Shankaran, S., TYSON, J. E., Korones, S. B., Bauer, C. R., Stoll, B. J., Papile, L. A., Donovan, E. F., Ehrenkranz, R. A., Stevenson, D. K. 1996; 42 (6): 869-873

  Abstract

  During an 8-month study, 14 laboratories used automated analytical systems to measure total bilirubin concentrations in lyophilized bovine specimens containing 38, 169, and 253 micromol/L bilirubin (2.2, 9.9, and 14.8 mg/dL, respectively). The measured mean +/- SD (n, range) were: 39 +/- 7 micromol/L (n = 90, 31-53) [2.3 +/- 0.4 mg/dL (1.8-3.1)]; 176 +/- 29 micromol/L (n = 89, 146-222) [10.3 +/- 1.7 mg/dL (8.5-13.0)]; and 260 +/- 43 micromol/L (n = 103, 208-316) [15.2 +/- 2.5 mg/dL (12.1-18.5)]. In comparison with target values, measurements were consistently lower at 4, higher at 6, and within +/- 4% at 4 laboratories for each of the three concentrations. The measured values for each concentration remained fairly constant during the study at each laboratory. We conclude that bilirubin measurements differed significantly from the established target values at most of the participating laboratories.

  View details for PubMedID 8665677

• Contribution of haemolysis to jaundice in Sephardic Jewish glucose-6-phosphate dehydrogenase deficient neonates BRITISH JOURNAL OF HAEMATOLOGY Kaplan, M., Vreman, H. J., Hammerman, C., Leiter, C., Abramov, A., Stevenson, D. K. 1996; 93 (4): 822-827

  Abstract

  We determined the contribution of haemolysis to the development of hyperbilirubinaemia in glucose-6-phosphate dehydrogenase (G-6-PD) deficient neonates and G-6-PD normal controls. Blood carboxyhaemoglobin (COHb), sampled on the third day of life, was measured by gas chromatography, corrected for inhaled carbon monoxide (COHbC), and expressed as a percentage of total haemoglobin concentration (Hb). Serum bilirubin was tested as clinically necessary. 37 non-jaundiced (peak serum total bilirubin (PSTB) < or = 255 mumol/l) and 20 jaundiced (PSTB > or = 257 mumol/l) G-6-PD-deficient neonates were compared to 31 non-jaundiced and 24 jaundiced controls with comparable PSTB values, respectively. COHbC values for the entire G-6-PD deficient group were higher than in the controls (0.75 +/- 0.17% v 0.62 +/- 0.19%, P < 0.001). COHbC and PSTB values did not correlate in the G-6-PD-deficient group (r = 0.15, P > 0.05) but did in the controls (r = 0.58, P < 0.001). COHbC values were increased to a similar extent in the G-6-PD-deficient, non-jaundiced (0.72 +/- 0.16%), the G-6-PD-deficient, jaundiced (0.80 +/- 0.19%) and the control, jaundiced (0.75 +/- 0.18%) subgroups, compared to the control, non-jaundiced subgroup (0.53 +/- 0.13%) (P < 0.05). Although present in G-6-PD deficient neonates, increased haemolysis was not directly related to the PSTB.

  View details for Web of Science ID A1996UU82400013

  View details for PubMedID 8703811

• Duration of action and tissue distribution of zinc protoporphyrin in neonatal rats PEDIATRIC RESEARCH Rodgers, P. A., Seidman, D. S., Wei, P. L., Dennery, P. A., Stevenson, D. K. 1996; 39 (6): 1041-1049

  Abstract

  Zinc protoporphyrin IX (ZnPP) has been shown to inhibit heme oxygenase (HO) activity effectively in vivo and has potential in the treatment of neonatal jaundice. Because this is a transitional or temporary condition lasting only several days, an effective chemopreventive agent with a relatively short duration of action would be desirable for the treatment of severe neonatal jaundice. To determine the effective duration of action of ZnPP, we administered either 40 nmol/g of body weight ZnPP or 5 microL/g body weight diluent intraperitoneally to neonatal rats 24-36 h after birth. Between 0 and 21 d after ZnPP dosing, the duration of action was investigated through measurements of serum bilirubin and hepatic and splenic HO inhibition, which were correlated to measurements of ZnPP distribution. Significant (p < 0.05) hepatic HO inhibition, ranging from 27 to 51%, was observed in the liver between 1 and 4 d after dosing, concurrent with a 23-28% reduction in serum bilirubin levels, and was associated with ZnPP tissue concentrations of 27-38 nmol/g. Splenic HO was not inhibited measurably by the much lower concentrations of ZnPP found in the spleen (2.8-20.1 nmol/g) between 0 and 21 d after dosing. Furthermore, HO isoform 1 (HO-1) induction was apparently not a confounding factor in the duration of action of ZnPP, because the modest increases in HO-1 protein levels were not sustained longer than 24 h after ZnPP administration. Our findings demonstrated that the duration of action of ZnPP in neonatal rats is less than 1 wk. The reduction in serum bilirubin levels, the short duration of action and minimal confounding effects suggest that ZnPP may be an effective chemopreventive agent for the treatment of severe neonatal jaundice.

  View details for PubMedID 8725267

• A model for detecting early metabolic changes in neonatal asphyxia by 1H-MRS JOURNAL OF MAGNETIC RESONANCE IMAGING Nakai, T., Rhine, W. D., Enzmann, D. R., Stevenson, D. K., Spielman, D. M. 1996; 6 (3): 445-452

  Abstract

  In newborn rabbits, the early cerebral metabolic changes caused by hypoxic-ischemic (H-I) insult was examined by using volume localized 1H-MRS (STEAM). Partial ischemia was caused by unilateral carotid artery ligation, and hypoxia was induced by 10% oxygen inspiration for 150 minutes. Lactate immediately increased after hypoxia induction and almost disappeared 120 to 150 minutes after removal of hypoxia in both H-I and hypoxia-only experiments. Lactate production correlated well with decrease of the blood oxygen saturation. More lactate was produced on ischemic side 50 minutes post-hypoxia induction in H-I study. Ischemia alone did not cause any significant lactate production. Lactate caused by hypoxia can be dynamically monitored by localized 1H-MRS. Existence of regional ischemia can induce greater anaerobic glycolysis and may affect the pattern of brain injury under hypoxia. 1H-MRS is a sensitive tool to detect the acute metabolic change caused by H-I insult.

  View details for Web of Science ID A1996UM58400004

  View details for PubMedID 8724409

• Evaluation of neonatal jaundice: monitoring the transition in bilirubin metabolism. Journal of perinatology Stevenson, D. K., Vreman, H. J., Benaron, D. A. 1996; 16 (3): S62-7

  View details for PubMedID 8817441

• Neonatal intracranial ischemia and hemorrhage: Diagnosis with US, CT, and MR imaging RADIOLOGY Blankenberg, F. G., Norbash, A. M., Lane, B., Stevenson, D. K., Bracci, P. M., Enzmann, D. R. 1996; 199 (1): 253-259

  Abstract

  To assess the usefulness of ultrasound (US), computed tomography (CT), and magnetic resonance (MR) imaging in the detection of intracranial hemorrhage and ischemia in newborns.Seventy-six neonates who underwent US within 72 hours of CT or MR examination were studied. Four observers rated images for the presence of germinal matrix hemorrhage (GMH), intraventricular hemorrhage (IPH), extraaxial hemorrhage, and hypoxic-ischemic encephalopathy.In 39% of neonates, CT and MR imaging provided greater confidence than US for the diagnosis or exlusion of neonatal ischemia or hemorrhage. Kappa analysis revealed significantly better interobserver agreement with CT than with US for the detection of GMH, IVH, IPH, and cortical infarction or ischemia (P <.005). Interobserver agreement was significantly better with MR imaging than with US for the detection of GMH, IVH, and cortical infarction or ischemia (P < .005).Sensitivity and interobserver agreement are better with MR imaging and CT than with US for the detection of neonatal cortical ischemia or infarction.

  View details for PubMedID 8633155

• Ontogeny of heme oxygenase activity in the hippocampus, frontal cerebral cortex, and cerebellum of the guinea pig DEVELOPMENTAL BRAIN RESEARCH Cook, M. N., Marks, G. S., Vreman, H. J., Nakatsu, K., Stevenson, D. K., Brien, J. F. 1996; 92 (1): 18-23

  Abstract

  Heme oxygenase (HO) catalyzes the oxidation of heme to produce carbon monoxide (CO), biliverdin and iron. CO is considered to function as a novel neuronal messenger in the brain analogous to nitric oxide. The ontogeny of microsomal HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the immature fetal, mature fetal and adult guinea pig was determined using an optimized assay which quantitated heme-derived CO formation by a gas chromatographic method. There was a distinct developmental profile of HO activity that was similar for all three brain regions. In particular, HO activity was maximal in the mature fetus compared with the immature fetus and the adult. These data demonstrate that HO activity is developmentally regulated and that there is similar ontogeny of HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the guinea pig.

  View details for Web of Science ID A1996UG30200003

  View details for PubMedID 8861718

• Characterization of porphyrin heme oxygenase inhibitors CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY Vreman, H. J., Cipkala, D. A., Stevenson, D. K. 1996; 74 (3): 278-285

  Abstract

  Synthetic metalloporphyrin derivatives of heme have been identified as competitive inhibitors of heme oxygenase, the rate-limiting enzyme in the heme degradation pathway that produces equimolar quantities of carbon monoxide, biliverdin, and bilirubin. Therefore, administration of metalloporphyrin has been proposed as one means to prevent excessive hyperbilirubinemia in human neonates. Tin proto- and meso-porphyrin have been studied for the suppression of neonatal jaundice. However, these compounds are also photosensitizers. This property may limit the clinical use of these compounds, particularly in infants being exposed simultaneously to phototherapy. Via measurements of carbon monoxide, we have studied the photooxidative, metabolic, and inhibitory characteristics of metalloporphyrins that have not yet been studied for this purpose: deuteroporphyrin bisglycol (DBG), iron deuteroporphyrin bisglycol (FeBG), tin deuteroporphyrin bisglycol (SnBG),tin deuteroporphyrin (SnDP), chromium deuteroporphyrin (CrDP), and zinc deuteroporphyrin (ZnDP). Of the six compounds, SnDP, SnBG, and DBG were significantly photoreactive in vitro. Furthermore, in vitro measurements of brain, liver, and spleen heme oxygenase activity inhibition indicated that, of the nonphotoreactive compounds, CrDP and ZnDP were the most potent inhibitors. Only FeBG served as a substrate for the heme oxygenase reaction. The concentration for 50% inhibition with the three tissues ranged from 0.6 to 1.3 microM for CrDP and from 11.0 to 13.5 microM for ZnDP. When 25 mumol CrDP and 50 mumol ZnDP per kilogram body weight were administered to rats given a heme load of 30 mumol/kg body weight, the total body carbon monoxide excretion due to the administered heme load was reduced by 46 and 32%, respectively, at t = 7.5 h, when the experiment was terminated in order to measure heme oxygenase activity. Brain heme oxygenase activity was not affected by the metalloporphyrin treatment. However, both CrDP and ZnDP inhibited liver tissue heme oxygenase activity to 5 and 20%, respectively, whereas only CrDP inhibited spleen tissue heme oxygenase, to 7% of untreated control. Thus, CrDP appears to be the most attractive of the six compounds and deserves further study.

  View details for PubMedID 8773407

• Imaging brain injury using time-resolved near infrared light scanning PEDIATRIC RESEARCH VANHOUTEN, J. P., Benaron, D. A., Spilman, S., Stevenson, D. K. 1996; 39 (3): 470-476

  Abstract

  Conventional brain imaging modalities are limited in that they image only secondary physical manifestations of brain injury, which may occur well after the actual insult to the brain and represent irreversible structural changes. A real-time continuous bedside monitor that images functional changes in cerebral blood flow or oxygenation might allow for recognition of brain tissue ischemia or hypoxia before the development of irreversible injury. Visible and near infrared light pass through human bone and tissue in small amounts, and the emerging light can be used to form images of the interior structure of the tissue and measure tissue blood flow and oxygen utilization based on light absorbance and scattering. We developed a portable time-of-flight and absorbance system which emits pulses of near infrared light into tissue and measures the transit time of photons through the tissue. Images can then be reconstructed mathematically using either absorbance or scattering information. Pathologic brain specimens from adult sheep and human newborns were studied with this device using rotational optical tomography. Images generated from these optical scans show that neonatal brain injuries such as subependymal and intraventricular hemorrhages can be successfully identified and localized. Resolution of this system appears to be better than 1 cm at a tissue depth of 5 cm, which should be sufficient for imaging some brain lesions as well as for detection of regional changes in cerebral blood flow and oxygenation. We conclude that light-based imaging of cerebral structure and function is feasible and may permit identification of patients with impending brain injury as well as monitoring of the efficacy of intervention. Construction of real-time images of brain structure and function is now underway using a fiber optic headband and nonmechanical rotational scanner allowing comfortable, unintrusive monitoring over extended periods of time.

  View details for PubMedID 8929868

• Evaluation of a fully automated end-tidal carbon monoxide instrument for breath analysis CLINICAL CHEMISTRY Vreman, H. J., Baxter, L. M., Stone, R. T., Stevenson, D. K. 1996; 42 (1): 50-56

  Abstract

  We evaluated a novel, portable breath sampler/CO-quantifying instrument [Baby's Breath Carbon Monoxide Analyzer (BB); Natus Medical], developed for use at the bedside or with gas samples collected into bags. Bench tests demonstrated that the CO measurements were linear, accurate, and precise when compared with gas chromatography (GC) results. In vivo tests (n = 30) performed with adults showed excellent correlation between end-tidal breath CO measurements (ETCO) corrected for inhaled CO (ETCOc) as determined by BB and GC. Breath sampling efficiency was 96%. ETCOc measurements and blood carboxyhemoglobin fractions (% of total hemoglobin) corrected for inhaled CO (COHbc) correlated strongly: COHbc = 0.25 ETCOc--0.01 microL/L CO (r2 = 0.97, Sy/x = 0.47, SE slope = 0.01, n = 30). The imprecision, assessed by the mean of the population's CV for triplicate determinations, was 11%. Measurements with healthy and hemolytic term newborns showed that ETCOc values of > 3 microL/L correlated with known hemolytic conditions. We conclude that this instrument is clinically reliable and can be used to noninvasively measure ETCO in neonates and adults.

  View details for PubMedID 8565232

• Bilirubin-related mortality and morbidity in Nigerian neonates Slusher, T. M., Vreman, H. J., McLaren, D. W., CLARDY, C. W., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 1996: A189–A189

  View details for Web of Science ID A1996TP69001009

• Evaluation of efficacy of various metalloporphyrins in cultured hamster fibroblasts. Dennery, P. A., Rodgers, P. A., Sullivan, T. M., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 1996: A114–A114

  View details for Web of Science ID A1996TP69000608

• Measurement of brain oxygenation and function using light-based optical tomography vanHouten, J. P., Benaron, D. A., Cheong, W. F., Kermit, E. L. SLACK INC. 1996: A95

  View details for Web of Science ID A1996TP69000509

• Evaluating gene expression using a bioluminescent reporter system in living animals Contag, C. H., Spilman, S. D., Stevenson, D. K., Benaron, D. A. SLACK INC. 1996: A106

  View details for Web of Science ID A1996TP69000565

• Ontogeny of lung heme oxygenase in the neonatal Wistar rat. Rodgers, P. A., Lee, C. S., Stevenson, D. K., Dennery, P. A. SLACK INC. 1996: A114

  View details for Web of Science ID A1996TP69000609

• Effect of starvation on hepatic heme oxygenase (HO) in adult rats. Rodgers, P. A., Pramanik, S., Dennery, P. A., Stevenson, D. K. SLACK INC. 1996: A145

  View details for Web of Science ID A1996TP69000778

• Is the natural heme oxygenase inhibitor, zinc protoporphyrin, a photosensitizer? Kim, E. C., Vreman, H. J., Stevenson, D. K. SLACK INC. 1996: A149

  View details for Web of Science ID A1996TP69000796

• Pilot comparison of light-based optical tomography versus ultrasound for real-time imaging of neonatal intraventricular hemorrhage Benaron, D. A., vanHouten, J. P., Cheong, W. F., Kermit, E. L., MacHold, T. R., Stevenson, D. K. SLACK INC. 1996: A161

  View details for Web of Science ID A1996TP69000860

• Induction of kidney heme oxygenase by indium, gallium, and arsenic Imai, R., Vreman, H. J., Stevenson, D. K., Akkerman, M., Fowler, B. A., Squibb, K. S. SLACK INC. 1996: A168

  View details for Web of Science ID A1996TP69000898

• Is laparoscopic surgery safe during pregnancy? Seidman, D. S., Nezhat, C., Nezhat, F., Nezhat, C., Yuval, Y., Oelsner, G., Vreman, H. J., Stevenson, D. K. SLACK INC. 1996: A196

  View details for Web of Science ID A1996TP69001048

• The potential for carbon monoxide production in vascular tissues Vreman, H. J., Nabseth, D. E., Kim, E. C., Stevenson, D. K., Marks, G. S. SLACK INC. 1996: A149

  View details for Web of Science ID A1996TP69000799

• Photonic detection of bacterial pathogens in living hosts MOLECULAR MICROBIOLOGY Contag, C. H., Contag, P. R., Mullins, J. I., Spilman, S. D., Stevenson, D. K., Benaron, D. A. 1995; 18 (4): 593-603

  Abstract

  The study of pathogenic processes is often limited to ex vivo assays and cell-culture correlates. A greater understanding of infectious diseases would be facilitated by in vivo analyses. Therefore, we have developed a method for detecting bacterial pathogens in a living host and used this method to evaluate disease processes for strains of Salmonella typhimurlum that differ in their virulence for mice. Three strains of Salmonella were marked with bioluminescence through transformation with a plasmid conferring constitutive expression of bacterial luciferase. Detection of photons transmitted through tissues of animals infected with bioluminescent Salmonella allowed localization of the bacteria to specific tissues. In this manner progressive infections were distinguished from those that were persistent or abortive. We observed patterns of bioluminescence that suggested the caecum may play a pivotal role in Salmonella pathogenesis. In vivo efficacy of an antibiotic was monitored using this optical method. This study demonstrates that real time non-invasive analyses of pathogenic events and pharmacological monitoring can be performed in vivo.

  View details for PubMedID 8817482

• ROLE OF HEMOLYSIS IN NEONATAL JAUNDICE ASSOCIATED WITH GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY JOURNAL OF PEDIATRICS SEIDMAN, D. S., SHILOH, M., STEVENSON, D. K., VREMAN, H. J., PAZ, GALE, R. 1995; 127 (5): 804–6

  Abstract

  End-tidal carbon monoxide was measured in 108 newborn infants who had been screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency. The mean +/- SD end-tidal carbon monoxide did not differ significantly between the G6PD-deficient and the normal neonates, 2.1 +/- 0.6 microliters/L and 2.0 +/- 0.5 microliters/L, respectively, within 12 hours of birth and 1.9 +/- 1.4 microliters/L and 1.5 +/- 0.7 microliters/L, respectively, at 48 to 72 hours after birth. On the basis of these measurements, hemolysis is not a sufficient explanation for jaundice in G6PD-deficient newborn infants in the transitional period.

  View details for DOI 10.1016/S0022-3476(95)70177-X

  View details for Web of Science ID A1995TD93100026

  View details for PubMedID 7472840

• VERY-LOW-BIRTH-WEIGHT OUTCOMES OF THE NATIONAL-INSTITUTE-OF-CHILD-HEALTH-AND-HUMAN-DEVELOPMENT NEONATAL RESEARCH NETWORK, MAY 1991 THROUGH DECEMBER 1992 AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Fanaroff, A. A., Wright, L. L., Stevenson, D. K., Shankaran, S., Donovan, E. F., EHRENKRANS, R. A., Younes, N., Korones, S. B., Stoll, B. J., TYSON, J. E., Bauer, C. R., Oh, W., Lemons, J. A., Papile, L. A., Verter, J. 1995; 173 (5): 1423-1431

  Abstract

  Our goals were to determine the mortality risk for infants weighing 501 to 1500 gm according to gestational age, birth weight, and gender and to document birth weight-related changes in mortality and morbidity over a 5-year time period.In this observational study perinatal data were prospectively collected by the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from May 1991 through December 1992 and compared with the corresponding data from 1987 through 1990. Standard definitions were used to record sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death.The 1991 and 1992 cohort included 4279 in-born infants. Among their mothers 10% were < 18 years old; 55% were black, 31% were white, and 11% were Hispanic; 14% had received no prenatal care; and 20% had received antenatal corticosteroids. Multiple gestations accounted for 20% of the births. Fifty percent of the infants were delivered by cesarean section. During 1991 and 1992 the overall survival for infants weighing 501 to 1500 gm at birth was 81%, compared with 74% in 1987 and 1988. Survival at birth weight 501 to 750 gm was 44%; it was 81% at 751 to 1000 gm, 92% at 1001 to 1250 gm, and 95% between 1251 and 1500 gm. Female infants had a significantly greater chance of surviving than male infants at similar birth weights and gestational ages. At any given gestational age, smaller infants were less likely to survive. Survival in all birth weight categories increased between 1987 and 1992, without accompanying increases in medical morbidity. Major morbidity increased with decreasing birth weight and included late-onset septicemia 22%, chronic lung disease (oxygen dependence at 36 weeks' corrected age) 18%, severe intraventricular hemorrhage (grades III and IV) 11%, and necrotizing enterocolitis 5%. Twelve percent of all infants were treated with corticosteroids for chronic lung disease, including 36% of infants who were oxygen dependent at age 28 days. The mean length of hospital stay was 69 days for survivors and 18 days for infants who died.Mortality for infants between 501 and 1500 gm at birth has declined over the past 5 years. There are interactions between birth weight, gestational age, gender, and survival rate. This increase in survival was not accompanied by an increase in medical morbidity.

  View details for Web of Science ID A1995TH56000014

  View details for PubMedID 7503180

• HYPERBILIRUBINEMIA RESULTS IN REDUCED OXIDATIVE INJURY IN NEONATAL GUNN-RATS EXPOSED TO HYPEROXIA FREE RADICAL BIOLOGY AND MEDICINE Dennery, P. A., McDonagh, A. F., Spitz, D. R., Rodgers, P. A., Stevenson, D. K. 1995; 19 (4): 395-404

  Abstract

  Bilirubin is a potent antioxidant in vitro. To determine whether bilirubin also is an antioxidant in vivo, we studied markers of oxidative injury in the Gunn rat model exposed to hyperoxia. Homozygous jaundiced males were mated with heterozygous nonjaundiced females to obtain both jaundiced and nonjaundiced pups within a litter. Once delivered, the pups and their mother were placed in air (21% O2) or hyperoxia (> 95% O2) for 3 d. Both jaundiced and nonjaundiced pups were removed from the chambers daily. Animals were sacrificed and blood was drawn for determination of serum bilirubin, blood thiobarbituric acid-reactive substances (TBARS) by fluorescence assay, serum hydroperoxides, and serum protein oxidation. Tissues (liver, lung, and brain) were assayed for lipid peroxides (TBARS, conjugated dienes [CD], loss of polyunsaturated fatty acid content [PUFA]). We also measured a wide range of serum antioxidants including superoxide dismutase, catalase, glutathione, vitamins A, C, and E, and uric acid. Blood TBARS were significantly decreased in the jaundiced pups compared to the nonjaundiced pups on day 3 of hyperoxia, and blood TBARS were inversely correlated to serum bilirubin on day 3 of hyperoxia (R2 +/- .89). Similar decreases in serum lipid hydroperoxides and serum protein carbonyl content were detected in the jaundiced pups as compared to their nonjaundiced littermates. Other serum antioxidants were not increased in jaundiced animals compared to nonjaundiced animals. Relative lung weight was lower in jaundiced pups exposed to hyperoxia compared to similarly exposed nonjaundiced pups, suggesting a reduction in hyperoxia-induced lung edema. We detected no significant effects of bilirubin on parameters of lipid peroxidation in solid tissues. We conclude that serum bilirubin protects against serum oxidative damage in the first days of life in neonatal Gunn rats exposed to hyperoxia. We speculate that bilirubin is a functionally important transitional antioxidant in the circulation of human neonates and that it may be involved in modulation of injury due to hyperoxia.

  View details for PubMedID 7590389

• INDIVIDUALIZED DEVELOPMENTAL CARE FOR VERY-LOW-BIRTH-WEIGHT PREMATURE-INFANTS CLINICAL PEDIATRICS Fleisher, B. E., Vandenberg, K., Constantinou, J., Heller, C., Benitz, W. E., Johnson, A., Rosenthal, A., Stevenson, D. K. 1995; 34 (10): 523-529

  Abstract

  Forty very-low-birth-weight neonatal intensive care unit (NICU) infants with birth weights < or = 1,250 g were randomly assigned to treatment or control groups. Behavior of the treatment infants was systematically evaluated, and individualized developmentally oriented care plans were implemented to enhance stability. Treatment babies required fewer days of intermittent mandatory ventilation and continuous positive airway pressure and achieved full enteral feedings sooner. Length of hospital stay and hospital charges were less for treatment than control infants. There were favorable effects on treatment infants' behavioral performance at 42 weeks' postconceptional age. These results support the hypothesis that behaviorally sensitive, developmentally oriented care improves medical and neurodevelopmental outcome in the NICU.

  View details for Web of Science ID A1995RZ28800003

  View details for PubMedID 8591679

• HOSPITAL READMISSION DUE TO NEONATAL HYPERBILIRUBINEMIA PEDIATRICS Seidman, D. S., Stevenson, D. K., Ergaz, Z., Gale, R. 1995; 96 (4): 727-729

  Abstract

  Severe neonatal hyperbilirubinemia can occur without apparent reason in term healthy breast-fed infants and some develop kernicterus. The aim of our study was to assess the incidence of severe hyperbilirubinemia in term healthy newborns discharged from the hospital. From January 1 through December 31, 1994, 6705 infants were delivered at Bikur-Cholim and Misgav-Ladach Community Hospitals. All 1448 newborns discharged with a serum bilirubin level > 10.0 mg/dL were instructed to return to the hospital within 3 days for follow-up, as well as bilirubin determination. Twenty-one newborns with a bilirubin level > 18.0 mg/dL were identified and readmitted at mean +/- standard deviation (SD) 5.5 +/- 1.8 (range, 5 to 10 days of life). This represents 1.7% of the 1220 infants who returned for follow-up examination. Mean +/- SD serum bilirubin levels at readmission were 19.6 +/- 2.5 mg/dL. All but one of the infants were breast-fed. No cases of ABO incompatibility were found and two newborns were glucose-6-phosphate dehydrogenase (G6PD)-deficient. Sepsis work-up and direct Coomb's tests were negative in all cases. None had hemolysis or were found to have any cause for hyperbilirubinemia other than breast-feeding. Phototherapy was provided in all but two cases, and an exchange transfusion was performed in one case. Three additional infants, with bilirubin levels < 10 mg/dL at discharge, were readmitted due to hyperbilirubinemia. One was diagnosed with neonatal hepatitis. We conclude that, based on our study population, 0.36% of term infants may subsequently develop severe neonatal hyperbilirubinemia in the first postnatal week.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for PubMedID 7567338

• ADVERSE REPRODUCTIVE OUTCOMES AND YOUNG MATERNAL AGE NEW ENGLAND JOURNAL OF MEDICINE SEIDMAN, D. S., STEVENSON, D. K. 1995; 333 (12): 800–801

  View details for Web of Science ID A1995RU80900018

  View details for PubMedID 7643894

• ADVANCES IN THE DIAGNOSIS AND TREATMENT OF NEONATAL HYPERBILIRUBINEMIA CLINICS IN PERINATOLOGY Yao, T. C., Stevenson, D. K. 1995; 22 (3): 741-?

  Abstract

  Many controversies remain regarding the role of bilirubin in the developing human. Although kernicterus and cognitive impairment have been linked to hyperbilirubinemia, more recent studies have suggested that there might actually be beneficial effects of bilirubin at a cellular level; thus, the need to better understand the molecular and cellular physiology of this molecule is important. The attempted management of serum or tissue levels of bilirubin may either have implications for long-term neurologic development or interfere with normal body stress responses. Production of CO via heme catabolism also warrants further investigation regarding its role in cell to cell communication or in other important cellular reactions. New methods are being developed to better detect CO under a variety of experimental conditions, as well as to estimate total bilirubin production by measuring the COHb level of pulmonary excretion of CO. The development of new drugs to modulate bilirubin production is the subject of ongoing research. Although some metalloporphyrins already have been used clinically, the advantages and disadvantages of each drug still require further study. These new drugs are not only raising fascinating research questions about heme and bilirubin metabolism, but they may soon revolutionize the way we approach the diagnosis and management of neonatal jaundice, and provide new pharmacologic tools for exploring other aspects of metabolism.

  View details for PubMedID 8521691

• THE ISSUES OF HYPERBILIRUBINEMIA PEDIATRICS SEIDMAN, D. S., STEVENSON, D. K. 1995; 96 (3): 543

  View details for Web of Science ID A1995RT95400030

  View details for PubMedID 7651796

• ANTENATAL STEROIDS AND NEONATAL OUTCOMES IN CONTROLLED CLINICAL-TRIALS OF SURFACTANT REPLACEMENT Consensus Development Conference - Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes White, A., Marcucci, G., Andrews, E., Edwards, K., Long, W., Watts, J., Finer, N., Peliowski, A., McMillan, D., Shukla, A., Smyth, J., Chernick, V., Sankaran, K., Allen, A., MACMURRAY, B., Schiff, D., Mackenzie, W., Bard, H., Stevenson, D., Goldman, S., Walther, F., Boros, S., Mammel, M., Thompson, T., Bucciarelli, R., Burchfield, D., CORBET, A., Mullett, M., Cotton, R., Sundell, H., Vaughn, R., LeBlanc, M., Bose, C., Walter, D., Pauley, T., Schumacher, R., Soll, M., Courtney, S., Gerdes, J., DERLETH, D., Anday, E., VOLBERG, F. MOSBY-ELSEVIER. 1995: 286–90

  View details for Web of Science ID A1995RL64600056

• RECOMBINANT-HUMAN-ERYTHROPOIETIN (RHUEPO) INCREASES TOTAL BILIRUBIN PRODUCTION IN PREMATURE-INFANTS CLINICAL PEDIATRICS Baxter, L. M., Vreman, H. J., Ball, B., Stevenson, D. K. 1995; 34 (4): 213-216

  View details for Web of Science ID A1995QR60000007

  View details for PubMedID 7789015

• HEME OXYGENASE ACTIVITY IN THE ADULT-RAT AORTA AND LIVER AS MEASURED BY CARBON-MONOXIDE FORMATION CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY COOK, M. N., NAKATSU, K., MARKS, G. S., MCLAUGHLIN, B. E., VREMAN, H. J., STEVENSON, D. K., BRIEN, J. F. 1995; 73 (4): 515–18

  Abstract

  Rat aorta was homogenized and the 13000 x g supernatant fraction was tested for heme oxygenase (HO) activity by using a sensitive gas chromatographic method to measure carbon monoxide (CO), one of the products of the HO reaction. The rate of NADPH-dependent CO formation, an index of HO activity, was 1.41 +/- 0.40 nmol CO.mg(-1)protein. h(-1) in the rat aorta supernatant fraction and 2.05 +/- 0.55 nmol CO.mg(-1) protein.h(-1) in the rat liver 13000 x g supernatant fraction, a tissue known to contain HO activity. Chromium mesoporphyrin (0.05 mM), an inhibitor of rat liver HO, significantly decreased HO activity by 26% in the aorta supernatant fraction and 50% in the liver supernatant fraction. On the basis of the results of this study, which demonstrated HO-catalyzed CO formation in aortic tissue, and previous observations that CO relaxes vascular smooth muscle, we suggest that a physiological role for CO in vascular smooth muscle relaxation should be further investigated.

  View details for DOI 10.1139/y95-065

  View details for Web of Science ID A1995RC05800012

  View details for PubMedID 7671194

• THE COGNITIVE OUTCOME OF FULL-TERM SMALL-FOR-GESTATIONAL-AGE INFANTS AT LATE ADOLESCENCE OBSTETRICS AND GYNECOLOGY Paz, I., Gale, R., Laor, A., Danon, Y. L., Stevenson, D. K., Seidman, D. S. 1995; 85 (3): 452-456

  Abstract

  To assess the cognitive and academic performance of adolescents who were born small for gestational age (SGA) at term.A 17-year historical prospective study was done by matching neonatal data of 1758 infants to the results of the medical and intelligence assessment performed at age 17 years at the army draft board medical examination in Israel. The results of children born SGA (weight at term birth below the third percentile) were compared to those of children who were born appropriate for gestational age (AGA).After adjustment by a multiple linear regression analysis, the mean (+/- standard error of the mean) intelligence test scores were 103.1 +/- 2.9 versus 105.8 +/- 1.5 (P = 0.3) for the males and 100.3 +/- 2.5 versus 104.7 +/- 1.6 (P < .03) for the females. Males born SGA at term were found to have lower educational achievements (having less than 12 years of schooling or attending a vocational school) compared with the AGA group. The odds ratio for this finding after adjustment by a logistic regression analysis was 2.40 (95% confidence interval 1.07-5.39; P < .03). Intranatal events were not found to have an effect on the measured neurodevelopmental outcome.Infants born SGA at term have an increased risk for lower cognitive performance and schooling achievements than those born AGA; this result seems to be unrelated to their intranatal course.

  View details for Web of Science ID A1995QH30500027

  View details for PubMedID 7862391

• END-TIDAL CARBON-MONOXIDE IN NEWBORN-INFANTS - OBSERVATIONS DURING THE 1ST WEEK OF LIFE BIOLOGY OF THE NEONATE Balaraman, V., Pelke, S., DiMauro, S., Cheung, S., Stevenson, D. K., Easa, D. 1995; 67 (3): 182-185

  Abstract

  Serial end-tidal carbon monoxide corrected for ambient CO (ETCOc) levels were measured in an ethnically diverse population of 87 normal newborn infants during the first 5 days of life. The results demonstrate a progressive reduction in ETCOc from 1.6 +/- 0.4 to 0.8 +/- 0.2 ppm. These levels were unrelated to ethnicity, but were inversely related to serum bilirubin levels. We conclude that ETCOc is not a useful indicator for predicting the course of transitional hyperbilirubinemia in the normal newborn infant.

  View details for Web of Science ID A1995RF69400006

  View details for PubMedID 7640317

• NEONATAL JAUNDICE - WHAT NOW CLINICAL PEDIATRICS Dennery, P. A., Rhine, W. D., Stevenson, D. K. 1995; 34 (2): 103-107

  View details for Web of Science ID A1995QH23900007

  View details for PubMedID 7729104

• Carbon monoxide and carboxyhemoglobin. Advances in pediatrics Vreman, H. J., Mahoney, J. J., Stevenson, D. K. 1995; 42: 303-334

  View details for PubMedID 8540431

• RECOMBINANT-HUMAN-ERYTHROPOIETIN STIMULATES ERYTHROPOIESIS AND REDUCES ERYTHROCYTE TRANSFUSIONS IN VERY-LOW-BIRTH-WEIGHT PRETERM INFANTS PEDIATRICS Shannon, K. M., Keith, J. F., Mentzer, W. C., Ehrenkranz, R. A., BROWN, M. S., Widness, J. A., Gleason, C. A., Bifano, E. M., Millard, D. D., Davis, C. B., Stevenson, D. K., Alverson, D. C., Simmons, C. F., Brim, M., Abels, R. I., Phibbs, R. H. 1995; 95 (1): 1-8

  Abstract

  We hypothesized that treatment with recombinant human erythropoietin (r-HuEPO) would stimulate erythropoiesis and would thereby reduce the need for erythrocyte transfusions in preterm infants. We treated 157 preterm infants born at 26.9 +/- 1.6 weeks of gestation who weighed 924 +/- 183 g at birth with either subcutaneous r-HuEPO (100 U/kg/d, 5 days per week) or placebo for 6 weeks in a randomized, double-blind, controlled clinical trial. All patients received oral iron and were managed according to uniform conservative transfusion guidelines.Treatment with r-HuEPO was associated with fewer erythrocyte transfusions (1.1 +/- 1.5 per infant in the r-HuEPO group versus 1.6 +/- 1.7 per infant in the placebo group; P = .046) and with a reduction in the volume of packed erythrocytes transfused (16.5 +/- 23.0 mL versus 23.9 +/- 25.7 mL per infant; P = .023). Overall, 43% of the infants in the r-HuEPO group and 31% of placebo-treated infants were transfusion-free during the study (P = .18). The volume of blood removed for laboratory tests and the need for respiratory support at the start of treatment had major effects on transfusion requirements independent of r-HuEPO. Reticulocyte counts were higher during treatment in the r-HuEPO group (P = .0001), and r-HuEPO-treated infants had higher hematocrit values at the end of the study (32% versus 27.3% in the placebo group; P = .0001). We found no differences in the incidence of major complications of prematurity between the treatment groups.We conclude that treatment with r-HuEPO at a weekly dose of 500 U/kg stimulates erythropoiesis, moderates the course of anemia, is associated with a reduction in erythrocyte transfusions, and appears safe in very low birth weight preterm infants who are receiving iron supplements. Conservative transfusion criteria, minimization of phlebotomy losses, and treatment with r-HuEPO are complementary strategies to reduce erythrocyte transfusions in these infants.

  View details for Web of Science ID A1995PZ72900001

  View details for PubMedID 7770284

• GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY AND CARBOXYHEMOGLOBIN CONCENTRATIONS ASSOCIATED WITH BILIRUBIN-RELATED MORBIDITY AND DEATH IN NIGERIAN INFANTS JOURNAL OF PEDIATRICS Slusher, T. M., Vreman, H. J., McLaren, D. W., LEWISON, L. J., Brown, A. K., Stevenson, D. K. 1995; 126 (1): 102-108

  Abstract

  Our objective was to determine whether glucose-6-phosphate dehydrogenase (G6PD) deficiency and elevated carboxyhemoglobin (COHb) levels correlated with bilirubin-related morbidity and mortality rates. For this purpose, we studied 55 clinically jaundiced infants admitted to a rural mission hospital in southern Nigeria. Total serum bilirubin levels (range, 80 to 1016 mumol/L (4.7 to 59.4 mg/dl)) correlated with the percentage COHb concentrations (COHb = 0.45 + 0.08 Total serum bilirubin; r = 0.72). Infants were divided into two groups of equal size around the median COHb concentration (COHb range, 0.43% to 5.93% (median = 1.40%), with ambient carbon monoxide of 0.65 +/- 0.03 microL/L). The COHb levels > or = 1.40% were associated with the need for exchange transfusion (15/28, or 54%, vs 5/27, or 19%; p < 0.01) and with an increased incidence of clinical findings compatible with kernicterus (9/28, or 32%, vs 0/27, or 0%; p < 0.01). Mortality rate was 29% (8/29) among infants with higher COHb levels, and 7% (2/28) in those with lower levels (p = 0.08). Thirty-one percent (14/45) of the clinically jaundiced infants tested had G6PD deficiency. Thirty-six percent of the infants with G6PD deficiency died with presumed kernicterus, compared with only 3% (1/31) of the infants with a normal G6PD screening test result (p < 0.01). These data suggest that G6PD deficiency and increased bilirubin production, as indexed by COHb, are associated with jaundice-related morbidity and death in Nigerian infants.

  View details for Web of Science ID A1995QB18400020

  View details for PubMedID 7815196

• WITHHOLDING AND WITHDRAWING LIFE-SUSTAINING TREATMENT IN NEONATAL INTENSIVE-CARE - ISSUES FOR THE 1990S ARCHIVES OF DISEASE IN CHILDHOOD Lantos, J. D., TYSON, J. E., Allen, A., Frader, J., Hack, M., Korones, S., Merenstein, G., Paneth, N., Poland, R. L., Saigal, S., Stevenson, D., Truog, R. D., VANMARTER, L. J. 1994; 71 (3): F218-F223

  View details for Web of Science ID A1994PR93100018

  View details for PubMedID 7820723

  View details for PubMedCentralID PMC1061132

• SEMIPORTABLE ELECTROCHEMICAL INSTRUMENT FOR DETERMINING CARBON-MONOXIDE IN BREATH CLINICAL CHEMISTRY Vreman, H. J., Stevenson, D. K., Oh, W., Fanaroff, A. A., Wright, L. L., Lemons, J. A., Wright, E., Shankaran, S., TYSON, J. E., Korones, S. B., Bauer, C. R., Stoll, B. J., Papile, L. A., Donovan, E. F., Ehrenkranz, R. A. 1994; 40 (10): 1927-1933

  Abstract

  Measurements of carbon monoxide (CO) in breath can be used for the diagnosis of hemolytic disease. A small, semiportable, easy-to-operate CO instrument was developed at Stanford University and tested at 12 Neonatal Research Network Centers of the National Institute of Child Health and Human Development. A syringe pump delivers 7.7 mL of sample per minute through an activate carbon filter to an electrochemical (EC) sensor having a sensitivity of 0.10 +/- 0.01 V per 1 microL/L CO in air. The electronically processed sensor signal is displayed on a digital multimeter. For a typical end-tidal CO measurement, corrected for inhaled CO, three 10- to 12-mL breath and room air samples are manually or mechanically collected and analyzed. CO determination in breath samples from 108 healthy, 1-day-old infants of nonsmoking mothers compared favorably with determinations by gas chromatography (GC), 1.3 +/- 0.8 vs 1.2 +/- 0.8 (mean +/- SD), respectively, with a regression equation of EC = 0.95 GC+0.13 (r2 = 0.98). The results demonstrate that the EC-CO instrument yields results that are comparable with those obtained by the more difficult to perform GC assay.

  View details for PubMedID 7923774

• ARE MULTIPLE CESAREAN-SECTIONS SAFE EUROPEAN JOURNAL OF OBSTETRICS GYNECOLOGY AND REPRODUCTIVE BIOLOGY Seidman, D. S., Paz, I., Nadu, A., Dollberg, S., Stevenson, D. K., Gale, R., Mashiach, S., Barkai, G. 1994; 57 (1): 7-12

  Abstract

  To assess the maternal and neonatal risk associated with high-order cesarean sections, a case-control study was carried out in two university affiliated maternity wards. The outcome of 154 pregnancies of women undergoing cesarean section for the 4th time or more was compared with 148 women sectioned for the 2nd or 3rd time and 132 women of similar age and parity after spontaneous birth. The main outcome measures were maternal operative and postoperative morbidity and neonatal prematurity and its complications, Apgar scores, and the need for intensive care. Women undergoing multiple (> or = 4) cesarean sections had significantly more intra-abdominal adhesions (P < 0.0001) than women sectioned for the 2nd or 3rd time. However, the time interval from incision to delivery and the total duration of operation were similar. The postoperative course was not adversely affected by multiple cesarean sections. A high incidence (16.2%) of preterm cesarean deliveries was noted in the study group. This was due to non-elective repeat cesarean delivery rather than to poor timing of scheduled cesarean sections. The significantly increased (P < 0.05) need for neonatal intensive care was explained by the higher occurrence of prematurity. Low Apgar scores (< or = 7) at 1 and 5 min were significantly (P < 0.01) related to multiple cesarean sections, even after controlling for the effect of gestational age. We conclude that multiple cesarean sections pose little risk for the mother, but may be associated with increased neonatal risk, attributed mainly to preterm non-elective cesarean sections.

  View details for Web of Science ID A1994PM22200002

  View details for PubMedID 7821507

• BILIRUBIN PRODUCTION IN HEALTHY TERM INFANTS AS MEASURED BY CARBON-MONOXIDE IN BREATH CLINICAL CHEMISTRY Stevenson, D. K., Vreman, H. J., Oh, W., Fanaroff, A. A., Wright, L. L., Lemons, J. A., Verter, J., Shankaran, S., TYSON, J. E., Korones, S. B., Bauer, C. R., Stoll, B. J., Papile, L. A., OKAH, F., Ehrenkranz, R. A. 1994; 40 (10): 1934-1939

  Abstract

  To describe total bilirubin production in healthy term infants, we measured the end-tidal breath CO, corrected for ambient CO (ETCOc), with an automated sampler and electrochemical (EC) CO instrument. For infants of mothers with a negative Coombs' test, the ETCOc was 1.3 +/- 0.7 microL/L (n = 397) and the serum bilirubin on day 3 postpartum was 73 +/- 35 mg/L (n = 381). In contrast, the ETCOc for infants with ABO or Rh incompatibility, a positive direct Coombs' test, and bilirubin > 130 mg/L (n = 9) was significantly higher, 1.8 +/- 0.8 microL/L, than for those who had a positive Coombs' test result but whose bilirubin was < or = 130 mg/L (n = 12), 1.0 +/- 0.5 microL/L (P < 0.05). At 2 to 8 h postpartum seven term babies from mothers with insulin-dependent diabetes had ETCOc of 1.8 +/- 0.7 microL/L, significantly higher than that in the other term infants [1.3 +/- 0.7 microL/L (n = 390), P < 0.04]. Their bilirubin concentration at 72 +/- 12 h was also higher: 121 +/- 45 mg/L (n = 7) vs 73 +/- 34 mg/L (n = 374; P = 0.03). We conclude that ETCOc measurements may be helpful in understanding the mechanisms of jaundice in healthy term infants in a variety of conditions.

  View details for PubMedID 7923775

• CARBOXYHEMOGLOBIN DETERMINED IN NEONATAL BLOOD WITH A COOXIMETER UNAFFECTED BY FETAL OXYHEMOGLOBIN CLINICAL CHEMISTRY Vreman, H. J., Stevenson, D. K. 1994; 40 (8): 1522-1527

  Abstract

  Measurements of carboxyhemoglobin (COHb) for clinical purposes are routinely made with CO-oximeters. However, fetal hemoglobin (HbF) interferes with this spectrophotometric method. The manufacturer (Ciba Corning Diagnostics) of a new CO-oximeter (CCD 270) claims that COHb measurements with this instrument are insignificantly affected by HbF. We examined this claim through CO-oximeter analysis of cord blood/adult blood mixtures and compared the results with those obtained by gas chromatography (GC). We also studied the influence of oxygen and bilirubin concentrations. Measurements of COHb with CCD 270 were significantly lower than the GC measurements, but the differences were not clinically important. Linear regression analysis of HbF and COHb measurements (n = 68) showed significant correlation (P < 0.0001) between the two factors for the older CCD 2500 CO-oximeter (R2 = 0.56), but not for the CCD 270 (R2 = 0.06) or GC (R2 = 0.02). Bilirubin concentrations, which affected COHb measurements with CCD 2500, did not significantly affect CCD 270 measurements. We conclude that COHb measurements with CCD 270 CO-oximeter are not affected by HbF or bilirubin concentrations.

  View details for PubMedID 7519133

• Maternal transmission of human immunodeficiency virus-1. Obstetrical & gynecological survey Paz, I., Seidman, D. S., Mashiach, S., Stevenson, D. K. 1994; 49 (8): 577-584

  Abstract

  The dramatic increase in the number of women of childbearing age infected with human immunodeficiency virus (HIV) has led to the revelation of another terrible consequence of the human immunodeficiency virus (HIV) pandemic; maternal transmission of HIV to the fetus. Over 90 per cent of the children who are infected with HIV contract the virus from their mother. Viral transmission may occur in utero, during labor when the newborn is exposed to maternal blood and body fluids or postnatally, mainly via breast-feeding. However, the risk of infection for a baby whose mother is an HIV carrier is not yet clear. The determination of the HIV status of the newborn remains a major diagnostic problem as the routine test, which detects antibodies to HIV, is of limited value in evaluating newborns. A summary of all of the large prospective long-term follow-up studies reported to date, shows an overall transmission rate of 22.4 per cent, with a 95 per cent confidence interval of 20.5 to 24.0 per cent. However, it is difficult to refer to the wide range of reported transmission rates, from 9.1 to 55.0 per cent, as they are confounded by the differing distribution of risk factors. The risk of maternal to newborn transmission must, therefore, be determined according to the specific characteristics of each parturient population.

  View details for PubMedID 7970451

• KERNICTERUS IN A FULL-TERM INFANT PEDIATRICS Penn, A. A., Enzmann, D. R., Hahn, J. S., Stevenson, D. K. 1994; 93 (6): 1003-1006

  View details for Web of Science ID A1994NP67800024

  View details for PubMedID 7794295

• THE EFFECT OF NUTRITIONAL ADDITIVES ON ANTIINFECTIVE FACTORS IN HUMAN-MILK CLINICAL PEDIATRICS Quan, R., Yang, C., Rubinstein, S., LEWISTON, N. J., Stevenson, D. K., Kerner, J. A. 1994; 33 (6): 325-328

  Abstract

  It has become a common practice to supplement human milk with a variety of additives to improve the nutritive content of the feeding for the premature infant. Twenty-two freshly frozen human milk samples were measured for lysozyme activity, total IgA, and specific IgA to Escherichia coli serotypes 01, 04, and 06. One mL aliquots were mixed with the following: 1 mL of Similac, Similac Special Care, Enfamil, Enfamil Premature Formula, and sterile water; 33 mL of Poly-Vi-Sol, 33 mg of Moducal, and 38 mg of breast-milk fortifier, and then reanalyzed. Significant decreases (41% to 74%) in lysozyme activity were seen with the addition of all formulas; breast-milk fortifier reduced activity by 19%, while no differences were seen with Moducal, sterile water, or Poly-Vi-Sol. No differences were seen in total IgA content, but some decreases were seen in specific IgA to E. coli serotypes 04 and 06. E. coli growth was determined after 3 1/2 hours of incubation at 37 degrees C after mixing. All cow-milk formulas enhanced E. coli growth; soy formulas and other additives preserved inhibition of bacterial growth. Nutritional additives can impair anti-infective properties of human milk, and such interplay should be considered in the decision on the feeding regimen of premature infants.

  View details for Web of Science ID A1994NR58100002

  View details for PubMedID 8200164

• DIRECT RELATIONSHIP OF FETAL CARBOXYHEMOGLOBIN WITH HEMOLYSIS IN ALLOIMMUNIZED PREGNANCIES PEDIATRIC RESEARCH Widness, J. A., Lowe, L. S., Stevenson, D. K., Vreman, H. J., Weiner, C. P., Hayde, M., Pollak, A. 1994; 35 (6): 713-719

  Abstract

  Because carbon monoxide (CO) is a byproduct of heme degradation and because placental diffusing capacity of CO is limited, we hypothesized that the concentration of CO transported in fetal blood as carboxyhemoglobin (HbCO) would correlate with the severity of fetal hemolytic disease. Fetal blood was obtained by cordocentesis and HbCO was measured by gas chromatography. The two primary study groups included control fetuses (n = 26) and fetuses of Coombs-positive mothers before in utero transfusion (n = 15). Compared with controls, fetuses with hemolytic disease had higher HbCO levels (0.0111 +/- 0.0014 versus 0.0159 +/- 0.0072 fraction of total Hb, mean +/- SD, p < 0.002). In contrast, HbCO levels in simultaneously sampled maternal blood samples were not different in the control and alloimmune groups [0.0110 +/- 0.0025 (n = 20) versus 0.0115 +/- 0.0021 (n = 11)]. There was a significant inverse correlation observed between fetal HbCO and Hb concentrations in the group with hemolytic disease (r = -0.73, p < 0.002) but not in controls. In fetuses with hemolytic disease, HbCO and bilirubin were highly correlated (r = 0.88, p < 0.0001). Data from four anemic fetuses who were Coombs negative, three of whom had no evidence of hemolysis, indicated normal HbCO and normal plasma bilirubin levels. A fourth fetus with anemia had viral sepsis and elevated HbCO and plasma bilirubin levels. We conclude that elevated HbCO levels detected in fetuses of nonsmoking mothers with erythrocyte alloimmunization are likely the result of accelerated hemolysis.

  View details for Web of Science ID A1994NM43800016

  View details for PubMedID 7936824

• MAGNETIC-RESONANCE (MR) DIFFUSION AND PERFUSION IMAGING STUDIES OF IMMATURE RABBIT HYPOXIC-ISCHEMIC ENCEPHALOPATHY (HIE) RHINE, W. D., DECRESPIGNY, A., PELC, L. R., MOSELEY, M. E., STEVENSON, D. K. WILLIAMS & WILKINS. 1994: A386

  View details for Web of Science ID A1994NG77902292

• IMAGING NEONATAL BRAIN INJURY USING LIGHT-BASED OPTICAL TOMOGRAPHY BENARON, D. A., VANHOUTEN, J., HO, D. C., SPILMAN, S. D., STEVENSON, D. K. WILLIAMS & WILKINS. 1994: A378

  View details for Web of Science ID A1994NG77902246

• INDIVIDUALIZED DEVELOPMENTAL CARE FOR THE VERY-LOW-BIRTH-WEIGHT PREMATURE IMPROVES MEDICAL OUTCOME IN THE NEONATAL INTENSIVE-CARE UNIT FLEISHER, B. E., VANDENBERG, K., CONSTANTINOU, J., JOHNSON, A., STEVENSON, D. K. WILLIAMS & WILKINS. 1994: A20

  View details for Web of Science ID A1994NG77900108

• BEHAVIORAL ASSESSMENTS OF VERY-LOW-BIRTH-WEIGHT COCAINE-EXPOSED PREMATURES DIFFERENTIATED THEM FROM NONEXPOSED COUNTERPARTS - SOCIAL INTERVENTIONS HELPED IMPROVE SOCIAL OUTCOMES VANDENBERG, K., SWEET, N., WESTON, D., FLEISHER, B. E., JOHNSON, A., STEVENSON, D. K. WILLIAMS & WILKINS. 1994: A28

  View details for Web of Science ID A1994NG77900153

• HEPATIC HEME OXYGENASE IS INDUCIBLE IN NEONATAL RATS DURING THE EARLY TRANSITIONAL PERIOD TOM, D. J., RODGERS, P. A., STEVENSON, D. K., DENNERY, P. A. WILLIAMS & WILKINS. 1994: A78

  View details for Web of Science ID A1994NG77900453

• TOTAL BILIRUBIN PRODUCTION DECREASES WITH AGE IN NEONATES BALARAMAN, PELKE, S., DIMAURO, S., CHEUNG, S., STEVENSON, D., EASA, D. WILLIAMS & WILKINS. 1994: A214

  View details for Web of Science ID A1994NG77901264

• THE USE OF PERCUTANEOUS CENTRAL CATHETERS IN THE NICU BAXTER, L. M., STEVENSON, D. K. WILLIAMS & WILKINS. 1994: A215

  View details for Web of Science ID A1994NG77901271

• IS THE NEONATAL JAUNDICE ASSOCIATED WITH GLUCOSE-6-PHOSPHATE-DEHYDROGENASE (G-6-PD) DEFICIENCY DUE TO ACUTE HEMOLYSIS GALE, R., SHILOH, M., PAZ, STEVENSON, D. K., SEIDMAN, D. S. WILLIAMS & WILKINS. 1994: A225

  View details for Web of Science ID A1994NG77901332

• CHILDREN BORN SMALL-FOR-GESTATIONAL-AGE ARE AT INCREASED RISK OF SHORT STATURE INDEPENDENT OF THE EFFECT OF BIRTH-WEIGHT LAOR, A., SEIDMAN, D. S., STEVENSON, D. K., GALE, R. WILLIAMS & WILKINS. 1994: A236

  View details for Web of Science ID A1994NG77901397

• END-TIDAL CARBON-MONOXIDE LEVELS ARE NOT INCREASED IN ASIAN NEWBORN-INFANTS BALARAMAN, PELKE, S., DIMAURO, S., CHEUNG, S., STEVENSON, D., EASA, D. WILLIAMS & WILKINS. 1994: A263

  View details for Web of Science ID A1994NG77901562

• IMAGING OF PULMONARY PATHOPHYSIOLOGY USING OPTICAL TOMOGRAPHY IN MODEL SYSTEMS BENARON, D. A., HO, D. C., SPILMAN, S. D., STEVENSON, D. K. WILLIAMS & WILKINS. 1994: A325

  View details for Web of Science ID A1994NG77901932

• SOURCES OF CARBON-MONOXIDE (CO) IN BIOLOGICAL-SYSTEMS AND APPLICATIONS OF CO DETECTION TECHNOLOGIES 12th Meeting of the International-Perinatal-Collegium Rodgers, P. A., Vreman, H. J., Dennery, P. A., Stevenson, D. K. W B SAUNDERS CO. 1994: 2–10

  Abstract

  Carbon monoxide is produced from a variety of sources in biological systems. Heme oxygenase and heme oxygenase-like activity is the predominant source in mammals, and may be equally important in plants and lower animals. The enzyme appears to be ubiquitous, highly conserved throughout phylogeny, and tightly regulated during development. This and other evidence suggests that heme oxygenase has an important physiological role, of which CO production may be a part. Other minor sources of CO include the oxidation of organic molecules. This includes the following: (1) auto-oxidation of phenols, flavenoids, and halomethanes; (2) photo-oxidation of organic compounds; and (3) lipid peroxidation of membrane lipids. No longer thought of as a waste product only, recent studies suggest that in the central nervous system cellular CO production can influence cGMP levels through effects on soluble guanylyl cyclase activity. Cellular CO production may also be linked to cell-cell interactions, and may be important in the cell's response to environmental changes. Whether CO will have a place similar to nitric oxide in cellular metabolism is still unclear, but it is apparent that these metabolic relationships will become increasingly complex. Cellular heme oxygenase activity results in the equimolar production of CO and bilirubin for each molecule of heme degraded. The CO thus formed diffuses into the blood, is carried via hemoglobin, and is excreted in the lungs. Therefore, CO production can be assessed clinically by measuring the rate of total body CO excretion, blood COHb levels, and end-tidal CO concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for PubMedID 8209283

• EARLY INDUCTION OF HEPATIC HEME OXYGENASE IN NEONATAL RATS TOM, D. J., RODGERS, P. A., STEVENSON, D. K., DENNERY, P. A. SLACK INC. 1994: A8

  View details for Web of Science ID A1994MR21400043

• IMAGING NEONATAL BRAIN INJURY USING LIGHT BENARON, D. A., HO, D. C., SPILMAN, S. D., STEVENSON, D. K. SLACK INC. 1994: A28

  View details for Web of Science ID A1994MR21400150

• BEHAVIORAL ASSESSMENTS OF VERY-LOW-BIRTH-WEIGHT COCAINE-EXPOSED PREMATURES DIFFERENTIATED THEM FROM NON-EXPOSED COUNTERPARTS - SOCIAL INTERVENTIONS HELPED IMPROVE SOCIAL OUTCOMES VANDENBERG, K., SWEET, N., WESTON, D., FLEISHER, B., JOHNSON, A., STEVENSON, D. K. SLACK INC. 1994: A69

  View details for Web of Science ID A1994MR21400372

• INDIVIDUALIZED DEVELOPMENTAL CARE FOR THE VERY-LOW-BIRTH-WEIGHT PREMATURE IMPROVES MEDICAL OUTCOME IN THE NEONATAL INTENSIVE-CARE UNIT FLEISHER, B., VANDENBERG, K., CONSTANTINOU, J., JOHNSON, A., STEVENSON, D. K. SLACK INC. 1994: A69

  View details for Web of Science ID A1994MR21400371

• THE EFFECT OF METALLOPORPHYRINS ON PT AND PTT IN RAT PLASMA RODGERS, P. A., SHOKOOHI, STEVENSON, D. K. SLACK INC. 1994: A78

  View details for Web of Science ID A1994MR21400421

• TOTAL BILIRUBIN PRODUCTION DECREASES WITH AGE IN NEONATES BALARAMAN, PELKE, S., DIMAURO, S., CHEUNG, S., STEVENSON, D. K., EASA, D. SLACK INC. 1994: A91

  View details for Web of Science ID A1994MR21400490

• END-TIDAL CARBON-MONOXIDE LEVELS ARE NOT INCREASED IN ASIAN NEWBORN-INFANTS BALARAMAN, PELKE, S., DIMAURO, S., CHEUNG, S., STEVENSON, D. K., EASA, D. SLACK INC. 1994: A108

  View details for Web of Science ID A1994MR21400572

• CAN END-TIDAL CARBON-MONOXIDE MEASUREMENT PREDICT THE DEVELOPMENT OF HEMOLYTIC JAUNDICE IN GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENT NEONATES GALE, R., SHILEH, M., PAZ, SEIDMAN, D. S., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1994: A108

  View details for Web of Science ID A1994MR21400574

• IMAGING PULMONARY PATHOPHYSIOLOGY IN-VIVO USING OPTICAL TOMOGRAPHY BENARON, D. A., HO, D. C., SPILMAN, S. D., STEVENSON, D. K. SLACK INC. 1994: A33

  View details for Web of Science ID A1994MR21400177

• RESOLUTION OF NEAR-INFRARED TIME-OF-FLIGHT BRAIN OXYGENATION IMAGING 20th Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue Benaron, D. A., Stevenson, D. K. PLENUM PRESS DIV PLENUM PUBLISHING CORP. 1994: 609–617

  View details for Web of Science ID A1994BA42S00081

  View details for PubMedID 8079765

• PRETERM MEDICAL COMPLICATIONS DIFFERENTIALLY AFFECT NEUROBEHAVIORAL FUNCTIONS - RESULTS FROM A NEW NEONATAL MEDICAL INDEX INFANT BEHAVIOR & DEVELOPMENT Korner, A. F., Stevenson, D. K., Forrest, T., Constantinou, J. C., DiMiceli, S., Brown, B. W. 1994; 17 (1): 37-43

  View details for Web of Science ID A1994NN43500005

• TOMOGRAPHIC TIME-OF-FLIGHT OPTICAL IMAGING DEVICE 21st Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue Benaron, D. A., Ho, D. C., Spilman, S., VANHOUTEN, J. P., Stevenson, D. K. PLENUM PRESS DIV PLENUM PUBLISHING CORP. 1994: 207–214

  Abstract

  Time-resolved optical imaging has been used to image phantoms, animals, and humans, and offers the potential for the production of functional images of human tissues, such as the oxygenation of brain during stroke. We had previously reported a transmission scanner, and now give an early report on conversion to a rotational tomographic scanner with a non-parallel ray geometry similar to early CAT scanners. Initial scans show that 1) spatial imaging in turbid media using time-of-flight measurements, non-recursive algorithms, and standard tomographic geometry is possible, 2) separation of absorbance and scattering as an image is attainable, a key step in performing spatially-resolved chemometric analysis, 3) imaging of multiple objects buried within scattering material is feasible, demonstrating that equations derived for homogeneous media can be applied in at least some cases to inhomogeneous media such as tissue-like phantoms, and 4) imaging of brain pathology produces recognizable images with sufficient resolution for diagnostic decisions. We conclude that optical tomography is feasible for clinical use and that conversion of the present mechanically scanning device to a clinical scanner should be possible with retention of the current processing algorithms. Such a clinical scanner should ultimately be able to generate images in a few minutes with centimeter resolution at the center of living human brain.

  View details for Web of Science ID A1994BC72H00025

  View details for PubMedID 7597945

• NON-RECURSIVE LINEAR ALGORITHMS FOR OPTICAL IMAGING IN DIFFUSIVE MEDIA 21st Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue Benaron, D. A., Ho, D. C., Spilman, S., VANHOUTEN, J. P., Stevenson, D. K. PLENUM PRESS DIV PLENUM PUBLISHING CORP. 1994: 215–222

  Abstract

  Optical imaging has been used to image phantoms, animals, and humans. It offers the potential for the production of functional images of tissues, such as oxygenation of brain during stroke. Fast algorithms are needed to allow diagnostically useful images to be generated under realistic conditions, including the likelihood that transmission geometries will not be possible. We proposed a linear algorithm, while less than ideal, may allow rapid reconstruction of images and avoid the pitfalls of recursive, nonlinear solutions. Such techniques may also facilitate the use of varied but physiologic imaging geometries. We found that linear backprojection tomography is feasible for clinical use. Conversion of the present mechanically scanning device to a clinical scanner should be possible with retention of the current processing algorithms. Such a clinical scanner should ultimately be able to generate images in less than one minute with centimeter resolution at the center of living human brain.

  View details for Web of Science ID A1994BC72H00026

  View details for PubMedID 7597946

• Effect of phototherapy for neonatal jaundice on cognitive performance. Journal of perinatology Seidman, D. S., Paz, I., Stevenson, D. K., Laor, A., Danon, Y. L., Gale, R. 1994; 14 (1): 23-28

  Abstract

  Phototherapy for neonatal hyperbilirubinemia was introduced to our medical center in March 1971. To assess the influence of phototherapy on subsequent cognitive outcome, we compared the intelligence test scores at 17 years of age of subjects born 4 months before and 10 months after the introduction of phototherapy. The intelligence quotient score (mean +/- SE) at 17 years for 84 subjects with severe neonatal hyperbilirubinemia was 108 +/- 2 for those treated by phototherapy and 107 +/- 2 for controls matched for gestational age and birth weight. The confounding effect on intelligence quotient scores of perinatal factors (bilirubin concentrations, gestational age, birth weight, Apgar score) and demographic characteristics (ethnic origin, socioeconomic status, paternal education) was taken into account in a multiple logistic regression analysis by using a General Linear Models procedure. Phototherapy was found to have no independent effect on intelligence quotient scores after adjustment for the effect of confounding factors. We conclude that for full-term newborn infants with neonatal hyperbilirubinemia, phototherapy had neither a beneficial nor an adverse effect on intellectual ability in late adolescence.

  View details for PubMedID 8169674

• IS THE ASSOCIATION BETWEEN BIRTH-WEIGHT AND HEIGHT ATTAINMENT INDEPENDENT OF THE CONFOUNDING EFFECT OF ETHNIC AND SOCIOECONOMIC-FACTORS ISRAEL JOURNAL OF MEDICAL SCIENCES Seidman, D. S., Gale, R., Stevenson, D. K., Laor, A., BETTANE, P. A., Danon, Y. L. 1993; 29 (12): 772-776

  Abstract

  The association between birthweight and body height attainment at 17 years of age was investigated by studying a sample of 30,083 subjects born in Jerusalem between 1964 and 1971. Birthweights obtained from the computerized records of the Jerusalem Perinatal Study were matched with demographic and medical examination results available from the military draft boards. Linear regression models for standing height by birthweight were fitted for the data in order to adjust for the possible confounding effect of ethnic origin, socioeconomic status (as determined by parental education level), birth order and maternal age. Separate models were constructed for each sex. A significant (P < 0.0001) linear increase in standing height by birthweight of 3.33 cm/1,000 g was observed for the males (mean +/- SE height 174.5 +/- 0.1 cm) and 2.85 cm/1,000 g for the females (mean +/- SE height 163.5 +/- 0.1 cm). This positive linear association between body height at 17 years of age and birthweight was also demonstrated after stratification according to various categories of social class and ethnic origin. Adult body height was thus found to be strongly related to birthweight in both sexes, regardless of ethnic and socioeconomic influences.

  View details for Web of Science ID A1993MP13800004

  View details for PubMedID 8300385

• DOES VITAMIN-C CAUSE HEMOLYSIS IN PREMATURE NEWBORNS - RESULTS OF A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, CONTROLLED TRIAL DOYLE, J., VREMAN, H., STEVENSON, D., BROWN, E., SCHMIDT, B., PAES, B., OHLSSON, A., BOULTON, J., KELLY, E., GILLIE, P., LEWIS, N., MERKO, S., SHAW, D., VEGH, P., ZIPURSKY, A. W B SAUNDERS CO. 1993: A96

  View details for Web of Science ID A1993MJ68200369

• ELECTROCHEMICAL MEASUREMENT OF CARBON-MONOXIDE IN BREATH - INTERFERENCE BY HYDROGEN ATMOSPHERIC ENVIRONMENT PART A-GENERAL TOPICS Vreman, H. J., Mahoney, J. J., Stevenson, D. K. 1993; 27 (14): 2193-2198

  View details for Web of Science ID A1993MD96800011

• MEASUREMENT OF CARBOXYHEMOGLOBIN AND TOTAL HEMOGLOBIN BY 5 SPECIALIZED SPECTROPHOTOMETERS (CO-OXIMETERS) IN COMPARISON WITH REFERENCE METHODS CLINICAL CHEMISTRY Mahoney, J. J., Vreman, H. J., Stevenson, D. K., VanKessel, A. L. 1993; 39 (8): 1693-1700

  Abstract

  We measured total hemoglobin (CtHb) and carboxyhemoglobin (COHb) in 100 patients' blood samples by using five specialized spectrophotometers (CO-oximeters)--IL 482 CO-Oximeter, Corning 2500 CO-oximeter, Radiometer OSM 3 Hemoximeter, Corning 270 CO-oximeter, and the AVL 912 CO-Oxylite--and compared the results with those obtained with the manual cyanmethemoglobin method and a gas-chromatographic (GC) method, respectively. For the CtHb measurements, the differences between the cyanmethemoglobin method and the CO-oximeters were not clinically important for any model. For the blood COHb measurements, the direction of the bias relative to GC was dependent on COHb concentration. In general, the CO-oximeters underestimated COHb concentration for COHb > 2.5% of total hemoglobin but overestimated COHb concentration for COHb < or = 2.5%. We conclude that all five CO-oximeters compared favorably with the reference methods for CtHb and for high concentrations of COHb. However, the inaccuracy of CO-oximeters for low-concentration (< or = 2.5%) COHb measurements may make these instruments unsuitable for some applications.

  View details for PubMedID 8353959

• GD-DTPA MR DETECTION OF BLOOD-BRAIN-BARRIER OPENING IN RATS AFTER HYPEROSOMOTIC SHOCK JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Rhine, W. D., Benaron, D. A., Enzmann, D. R., Chung, C., GONZALESMENDEZ, R., Sayre, J. R., Stevenson, D. K. 1993; 17 (4): 563-566

  Abstract

  Detection of blood-brain barrier (BBB) opening in neonates has required invasive methods not clinically applicable. We set out to develop a noninvasive approach to detect such opening.Wistar rats were studied using MRI with Gd-DTPA contrast before and after injection of hyperosmotic solutions known to produce barrier opening. Arabinose was given via right carotid artery to produce unilateral barrier opening; urea was given via tail vein to produce bilateral opening; controls received normal saline. Next, all animals received Gd-DTPA via tail vein.Animals receiving carotid hyperosmotic injections showed increased signal in the ipsilateral brain hemisphere; those receiving venous hyperosmotic injections showed increased signal bilaterally. Similar increases were not found prior to administration of hyperosmotic agent or in saline controls. In both cases, barrier opening was detectable using the relative partitioning of Gd-DTPA between intrabarrier and extrabarrier structures, even in the absence of a hemispheric control.We conclude that MRI with Gd-DTPA contrast allows noninvasive detection of BBB opening in the rat.

  View details for Web of Science ID A1993LM74900008

  View details for PubMedID 8331226

• TARGETING ZINC PROTOPORPHYRIN LIPOSOMES TO THE SPLEEN USING RETICULOENDOTHELIAL BLOCKADE WITH BLANK LIPOSOMES PEDIATRIC RESEARCH HAMORI, C. J., Lasic, D. D., Vreman, H. J., Stevenson, D. K. 1993; 34 (1): 1-5

  Abstract

  Metalloporphyrin inhibitors of heme oxygenase have been studied for use in the prevention of hyperbilirubinemia of the neonate. One report has suggested that incorporation of these drugs into liposomes can increase their localization to the spleen, dramatically reducing heme oxygenase activity in that important heme-degrading organ. We sought to further increase porphyrin delivery to the spleen by using reticuloendothelial blockade with blank liposomes 2 h before injection of 0.3 microns extruded zinc protoporphyrin liposomes (L-ZnPP). Control adult rats without hemolysis had splenic heme oxygenase activity of 1.07 +/- 0.09 nmol carbon monoxide (CO)/h/mg protein. Rats treated with L-ZnPP alone had splenic heme oxygenase activity of 0.53 +/- 0.16 nmol CO/h/mg protein 6 h after L-ZnPP dosing. However, rats treated with 1000 mumol of blank liposomes per kg to saturate the reticuloendothelial system 2 h before L-ZnPP administration had splenic heme oxygenase activity of 0.25 +/- 0.16 nmol CO/h/mg protein at t = 6 h, which is significantly less than that of the L-ZnPP alone group (p < 0.05). In adult rats treated with heat-damaged red blood cells (RBC) to simulate hemolysis, treatment with 10 mumol of aqueous ZnPP per kg or 10 mumol of untargeted L-ZnPP per kg did not produce a difference from control in total body bilirubin production as estimated by CO excretion. However, RBC-treated rats given 1000 mumol of blank liposomes per kg 2 h before L-ZnPP administration produced significantly less CO than control, aqueous ZnPP-treated, and untargeted L-ZnPP-treated rats from 8 to 12 h after RBC treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993LJ67900001

  View details for PubMedID 8356009

• ENHANCEMENT OF HEME OXYGENASE EXPRESSION AND ACTIVITY IN A431 SQUAMOUS CARCINOMA MULTICELLULAR TUMOR SPHEROIDS CANCER RESEARCH MURPHY, B. J., LADEROUTE, K. R., VREMAN, H. J., GRANT, T. D., GILL, N. S., STEVENSON, D. K., SUTHERLAND, R. M. 1993; 53 (12): 2700–2703

  Abstract

  We have investigated the effects of the growth of A431 human squamous carcinoma cells as three-dimensional aggregates (multicellular tumor spheroids) on the expression and enzyme activity of heme oxygenase (HO). We demonstrate that A431 squamous carcinoma cells grown as day 4 spheroids selectively increase the expression of heme oxygenase 1 (HO-1), caused, directly or indirectly, by three-dimensional cell-cell contact effects. Steady-state levels of both mRNA and protein are significantly enhanced in spheroids compared with day 4 monolayers (approximately 13-fold). Because of the similarity of apparent half-lives between monolayers (2.7 h) and spheroids (2.1 h), it appears that the increases are caused at least partly by altered transcriptional rates. Total HO enzyme activity, measured by carbon monoxide production, is also up-regulated (2.6-fold) in spheroids, compared to that in monolayers. This increase indicates that the up-regulation in HO-1 protein expression corresponds to an increase in functional enzyme levels. We propose that HO may play a more complex role in cellular metabolism than would be evident from studies using two-dimensional monolayer cultures.

  View details for Web of Science ID A1993LG35400002

  View details for PubMedID 8504407

• ABRUPTIO PLACENTAE AND VERY HIGH PARITY AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY SEIDMAN, D. S., MASHIACH, S., STEVENSON, D. K. 1993; 168 (5): 1641–42

  View details for DOI 10.1016/S0002-9378(11)90813-8

  View details for Web of Science ID A1993LD67200053

  View details for PubMedID 8347201

• PREDICTION OF THE DEVELOPMENT OF LOW-BIRTH-WEIGHT PRETERM INFANTS BY A NEW NEONATAL MEDICAL INDEX JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Korner, A. F., Stevenson, D. K., Kraemer, H. C., Spiker, D., Scott, D. T., Constantinou, J., DiMiceli, S. 1993; 14 (2): 106-111

  Abstract

  A new neonatal medical index (NMI) was used to predict the mental and motor development of low birth weight, preterm infants up to 3-years-old. The NMI is a summary score of only a few clinically salient items that are readily available on brief chart review. The sample consisted of 512 of 608 infants randomly assigned to the control group of the eight-site Infant Health and Development Program and on whom the complete set of developmental outcome measures was available. The developmental tests administered were the Bayley Scales at 12 and 24 months and the Stanford-Binet at 3 years. The findings indicated the NMI was predictive of later cognitive and motor development, and in infants born weighing less than 1500 g, the effects of neonatal medical complications continued to adversely influence these children's development to at least 3 years of age. In the heavier babies the developmental effects of sociodemographic factors predominated by 24 months and beyond.

  View details for PubMedID 8473525

• METALLOPORPHYRINS AND LIGHT - EVALUATION OF SAFETY IN NEONATAL RATS DENNERY, P. A., RODGERS, P. A., LUM, M. A., STEVENSON, D. K. SLACK INC. 1993: A297

  View details for Web of Science ID A1993KW76101010

• OPTICAL TIME-OF-FLIGHT AND ABSORBENCY IMAGING OF BIOLOGIC MEDIA SCIENCE Benaron, D. A., Stevenson, D. K. 1993; 259 (5100): 1463-1466

  Abstract

  Imaging the interior of living bodies with light may assist in the diagnosis and treatment of a number of clinical problems, which include the early detection of tumors and hypoxic cerebral injury. An existing picosecond time-of-flight and absorbance (TOFA) optical system has been used to image a model biologic system and a rat. Model measurements confirmed TOFA principles in systems with a high degree of photon scattering; rat images, which were constructed from the variable time delays experienced by a fixed fraction of early-arriving transmitted photons, revealed identifiable internal structure. A combination of light-based quantitative measurement and TOFA localization may have applications in continuous, noninvasive monitoring for structural imaging and spatial chemometric analysis in humans.

  View details for PubMedID 8451643

• ARE CHILDREN BORN SMALL-FOR-GESTATIONAL-AGE AT INCREASED RISK OF SHORT STATURE AMERICAN JOURNAL OF DISEASES OF CHILDREN Paz, I., Seidman, D. S., Danon, Y. L., Laor, A., Stevenson, D. K., Gale, R. 1993; 147 (3): 337-339

  Abstract

  To assess the height outcome of newborns born small for gestational age.A historical prospective study.A cohort of 1758 newborns born at a single university hospital maternity ward and subsequently examined at the military draft medical board at age 17 years.Newborns whose weight at birth was below the third percentile were defined as small for gestational age. Their body measurements at age 17 years were compared with those of their peers who were appropriate for gestational age.The adjusted mean +/- SEM height for boys born small for gestational age vs peers born appropriate for gestational age was 169.9 +/- 1.5 vs 175.4 +/- 0.8 cm (P < .0001); and for girls, 159.4 +/- 1.3 vs 163.1 +/- 0.8 cm (P < .0005). In addition, the risk for height attainment below the 10th percentile was significantly increased for newborns born small for gestational age. The adjusted odds ratio was 4.13 for boys (95% confidence interval, 1.66 to 10.25; P < .0006) and 3.32 for girls (95% confidence interval, 1.38 to 8.05; P < .0005).Infants born small for gestational age may be at increased risk for short stature in late adolescence.

  View details for Web of Science ID A1993KQ56100026

  View details for PubMedID 8438822

• BREATH HYDROGEN EXCRETION IN INFANCY JOURNAL OF PEDIATRICS STEVENSON, D. K., DENNERY, P. A. 1993; 122 (3): 502–3

  View details for DOI 10.1016/S0022-3476(05)83466-3

  View details for Web of Science ID A1993KQ59200042

  View details for PubMedID 8441117

• SELECTION OF METALLOPORPHYRIN HEME OXYGENASE INHIBITORS BASED ON POTENCY AND PHOTOREACTIVITY PEDIATRIC RESEARCH Vreman, H. J., Ekstrand, B. C., Stevenson, D. K. 1993; 33 (2): 195-200

  Abstract

  The heme oxygenase inhibitor, tin protoporphyrin, is being studied for the prevention of neonatal jaundice. This potential drug, however, is also a photosensitizer that could cause serious and unknown side effects when administered to newborns. Therefore, we have developed in vitro and in vivo procedures for the screening and further characterization of potentially safe heme oxygenase inhibitors. The ideal inhibitor: 1) contains a biocompatible metal, 2) is not degraded in tissues, 3) is a highly potent inhibitor of heme oxygenase, and 4) does not participate in photochemical reactions. Proto- and mesoporphyrin derivatives with the tin, zinc, manganese, chromium, nickel, and magnesium were screened in vitro for suitability. Chromium protoporphyrin and mesoporphyrin were further studied in vitro and in vivo and were found to meet the ideal criteria. Chromium mesoporphyrin appeared to be the most potent in vitro inhibitor of adult Wistar rat tissue heme oxygenase. Four mumol of chromium protoporphyrin or chromium mesoporphyrin/kg body weight, administered intraperitoneally to adult male Wistar rats given a heme load through intraperitoneal administration of 30 mumol heme/kg body weight, caused significant suppression of hemolysis-induced increase in carbon monoxide production to 72 and 44% of control, respectively, 5.5 h after treatment. At t = 6 h, the tissue heme oxygenase activity, measured in vitro, was significantly reduced to 33 and < 5% in liver and to 22 and < 5% in spleen after the administration of chromium protoporphyrin and mesoporphyrin, respectively, but was not reduced in brain. The results show that there exist effective metalloporphyrin heme oxygenase inhibitors without photosensitizing properties.

  View details for PubMedID 8433895

• THE EFFECTS OF BILIRUBIN ON NEURITE OUTGROWTH IN PC-12 CELLS IN THE PRESENCE OF NERVE GROWTH-FACTOR Rhine, W. D., Chung, C. E., AARONS, R. D., Stevenson, D. K. SLACK INC. 1993: A49–A49

  View details for Web of Science ID A1993KH41000262

• DOES INSURANCE STATUS INFLUENCE RESOURCE-ALLOCATION IN THE NICU Seidman, D. S., Wang, T. H., Baxter, L., Ferguson, J. E., Stevenson, D. K. SLACK INC. 1993: A88–A88

  View details for Web of Science ID A1993KH41000483

• DETERMINATION OF END-TIDAL CARBON-MONOXIDE AND BILIRUBIN PRODUCTION WITH A SEMIPORTABLE BREATH ANALYZER VREMAN, H. J., STEVENSON, D. K., OH, W., FANAROFF, A. A., LEMONS, J. A., WRIGHT, E., WRIGHT, L. SLACK INC. 1993: A23

  View details for Web of Science ID A1993KH41000118

• DETERMINATION OF COHB IN NEONATAL BLOOD WITH A COOXIMETER NOT AFFECTED BY HBF VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1993: A71

  View details for Web of Science ID A1993KH41000390

• METALLOPORPHYRINS AND LIGHT - EVALUATION OF SAFETY IN NEONATAL RATS DENNERY, P. A., RODGERS, P. A., LUM, M. A., STEVENSON, D. K. SLACK INC. 1993: A22

  View details for Web of Science ID A1993KH41000117

• BILIRUBIN PRODUCTION IN HEALTHY TERM INFANTS WITHOUT HEMOLYSIS STEVENSON, D. K., VREMAN, H. J., OH, W., FANAROFF, A. A., LEMONS, J. A., WRIGHT, E., WRIGHT, L. SLACK INC. 1993: A72

  View details for Web of Science ID A1993KH41000391

• AN AUTOMATED END-TIDAL CARBON-MONOXIDE (ETCOC) ANALYZER FOR INFANT BREATH ANALYSIS STONE, R. T., STEVENSON, D. K., VREMAN, H. J. SLACK INC. 1993: A96

  View details for Web of Science ID A1993KH41000524

• ROLE OF LIPID-PEROXIDATION IN METALLOPORPHYRIN-MEDIATED PHOTOTOXIC REACTIONS IN NEONATAL RATS PEDIATRIC RESEARCH Dennery, P. A., Vreman, H. J., Rodgers, P. A., Stevenson, D. K. 1993; 33 (1): 87-91

  Abstract

  Our group previously demonstrated dose-dependent mortality in neonatal rats treated with tin protoporphyrin and light. We hypothesize that lipid peroxidation may be responsible for the toxic effects of photosensitizing metalloporphyrins. Neonatal rat blood samples with or without metalloporphyrins (40 mM) were exposed to cool white light (20 microW/cm2/nm) for 30 min at 37 degrees C. In the in vivo model, neonatal rat pups were given injections of 40 mumol of either tin protoporphyrin (4 mM), zinc protoporphyrin/kg body weight, or saline and placed over cool white light. The control animals were similarly treated but kept in the dark. After 3 h, the animals were killed, and their tissues were analyzed for malondialdehyde, conjugated dienes, and disappearance of polyunsaturated fatty acids as indices of lipid peroxidation. In all cases, the known photosensitizer tin protoporphyrin was associated with increased conjugated dienes in the liver and disappearance of polyunsaturated fatty acids and increased malondialdehyde in the liver and brain when animals were exposed to light. Zinc protoporphyrin was not associated with increased lipid peroxidation in the light except in the case of blood in vitro where malondialdehyde levels increased. We conclude that lipid peroxidation plays a role in metalloporphyrin-mediated phototoxicity in neonatal rat tissues.

  View details for PubMedID 8433867

• INHIBITION OF HEME OXYGENASE AFTER ORAL VS INTRAPERITONEAL ADMINISTRATION OF CHROMIUM PORPHYRINS LIFE SCIENCES Vallier, H. A., Rodgers, P. A., Stevenson, D. K. 1993; 52 (10): PL79-PL84

  Abstract

  The effects of chromium porphyrins on suckling rat heme oxygenase activity were compared following oral vs intraperitoneal dosing. Chromium protoporphyrin (CrPP), chromium mesoporphyrin (CrMP), or chromium deuteroporphyrin 2,4 bis glycol (CrBG) were administered at 40 mumol/kg to 2-week old suckling rats either orally or intraperitoneally. Six hours after intraperitoneal dosing, CrPP and CrMP had significantly reduced hepatic and splenic heme oxygenase activity by more than 55%. CrBG effectively reduced hepatic heme oxygenase activity by 42%. More importantly, only CrMP was an effective inhibitor of hepatic heme oxygenase activity 6 hr after oral administration. In the first reported comparison of chromium porphyrin efficacy in vivo, our data suggest that chromium porphyrins, and particularly CrMP, may be effective in chemopreventive strategies for the treatment of neonatal jaundice.

  View details for PubMedID 8445977

• RACE, ETHNICITY, AND THE PROPENSITY FOR NEONATAL JAUNDICE - INTRODUCTION CLINICAL PEDIATRICS Stevenson, D. K., Brown, A. K. 1992; 31 (12): 706-707

  View details for Web of Science ID A1992KD27700001

  View details for PubMedID 1360343

• LABORATORY EVALUATION OF JAUNDICE IN NEWBORNS - CORRECTIONS AMERICAN JOURNAL OF DISEASES OF CHILDREN Newman, T. B., EASTERLING, M. J., Goldman, E. S., Stevenson, D. K. 1992; 146 (12): 1420-1421

  View details for Web of Science ID A1992KC11800009

  View details for PubMedID 1456248

• THE CARBOXYHEMOGLOBIN METHOD FOR ESTIMATING BILIRUBIN PRODUCTION IN NEONATES - JAPANESE STUDIES CLINICAL PEDIATRICS Stevenson, D. K. 1992; 31 (12): 708-711

  View details for Web of Science ID A1992KD27700002

  View details for PubMedID 1451376

• DELAYED COMPLIANCE INCREASE IN INFANTS WITH RESPIRATORY-DISTRESS SYNDROME FOLLOWING SYNTHETIC SURFACTANT PEDIATRIC PULMONOLOGY ARMSBY, D. H., Bellon, G., Carlisle, K., Rector, D., Baldwin, R., Long, W., Stevenson, D. K., Ariagno, R. L. 1992; 14 (4): 206-213

  Abstract

  Recent research has demonstrated that Exosurf (EXSF), a newly synthesized artificial surfactant, increases survival when administered endotracheally to premature infants with RDS. This study examines the effects of EXSF on static respiratory system compliance (Crs). Thirty-four patients received two doses of EXSF in this rescue protocol. Crs (mL/cmH2O/kg) did not significantly change within the first 4 hours after either dose. However, Crs values did increase significantly (paired Student's t-test, P = 0.005) when data collected after the second dose (0.36 +/- 0.13 mL/cmH2O/kg) were compared to first week follow-up data (0.51 +/- 0.21 mL/cmH2O/kg). Crs data collected between 2 and 4 weeks after treatments were again not significantly different from non-concurrent control data collected at 3-4 weeks of life. The measurement of Crs in infants receiving EXSF may have been affected by an increase in lung inflation, which could mask an increase in Crs. We speculate that improved lung inflation may occur with less barotrauma in the first week of life due to surfactant replacement treatment and may in part explain the improved Crs seen at 1 week of age. Many investigators using different surfactants, dosing schedules, and pulmonary function methodologies to evaluate lung mechanics have reported that the improvement in compliance after surfactant treatment usually follows the clinical improvement in gas exchange. Additional studies are needed to explain the mechanism of early improvement following surfactant replacement in infants with RDS.

  View details for Web of Science ID A1992KD24300002

  View details for PubMedID 1484754

• MATURATION OF JEJUNOILEAL GRADIENTS IN RAT INTESTINE - THE ROLE OF INTRALUMINAL NUTRIENTS BIOLOGY OF THE NEONATE Castillo, R. O., Feng, J. J., Stevenson, D. K., Kwong, L. K. 1992; 62 (5): 351-362

  Abstract

  Jejunoileal gradients of intestinal function are thought to be established during the third week of life in the rat when postnatal intestinal maturation occurs. In order to investigate the normal development of jejunoileal gradients and whether either the absence of intraluminal nutrients or the form in which they are provided affected the development of jejunoileal gradients, gradients for mucosal DNA, protein, lactase and sucrase were studied in suckling rats undergoing normal weaning and compared to gradients in rats receiving no intraluminal nutrients or rats receiving nutrients in elemental form. In suckling animals, preexisting jejunoileal gradients for DNA and protein persisted through the weaning period, gradients for lactase formed by rapid decline of ileal function and sucrase gradients formed by rapid increase in jejunal activities. Intraluminal nutrients in elemental form resulted in the formation of jejunoileal gradients similar to those in intestines of normally weaned rats. The lack of intraluminal nutrients resulted in no qualitative differences in the expression of jejunoileal gradients for sucrase, but provision of elemental nutrients resulted in increased jejunoileal differences for this enzyme. The lack of intraluminal nutrients resulted in no gradients for DNA, less pronounced jejunoileal differences for protein and delayed maturational decline of ileal lactase which prevented development of jejunoileal gradients for the enzyme. These studies indicate that the formation of jejunoileal gradients in the maturing rat intestine for the parameters investigated require intraluminal nutrients regardless of the form in which they are provided for their normal expression.

  View details for PubMedID 1467373

• IMMUNE HEMOLYTIC-DISEASE IN THE FETUS - INVERSE CORRELATION OF CARBOXYHEMOGLOBIN LEVELS WITH HEMOGLOBIN LOWE, L. S., WIDNESS, J. A., WEINER, C. P., ESTLE, L. C., STEVENSON, D. K., VREMAN, H. J., POLLAK, A., HAYDE, M. SLACK INC. 1992: A679

  View details for Web of Science ID A1992JQ52100168

• OPTIMIZING GROWTH-POTENTIAL OF CHILDREN JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION SEIDMAN, D. S., STEVENSON, D. K. 1992; 268 (5): 600

  View details for DOI 10.1001/jama.1992.03490050048010

  View details for Web of Science ID A1992JF47300009

  View details for PubMedID 1629979

• NONINVASIVE METHODS FOR ESTIMATING INVIVO OXYGENATION CLINICAL PEDIATRICS Benaron, D. A., Benitz, W. E., Ariagno, R. L., Stevenson, D. K. 1992; 31 (5): 258-273

  Abstract

  Clinical signs of hypoxia and hyperoxia are nonspecific and unreliable, yet both are potentially injurious. Noninvasive methods of oxygen assessment fill the gap between clinical observation and invasive tests, helping physicians deliver sufficient oxygen with minimum toxicity. Potential sites for oxygen measurement vary between the blood and the mitochondria; each method measures at a different site and detects different types of hypoxia and hyperoxia. Thus, values obtained by two different methods are not equivalent, giving each method unique strengths and weaknesses. We review two clinical methods (pulse oximetry and transcutaneous oximetry), as well as four experimental methods (near-infrared spectrophotometry, magnetic resonance spectroscopy, magnetic resonance saturation imaging, and time-of-flight absorbance spectrophotometry). The principles of each method and the clinical situations in which each succeeds or fails are discussed. A fundamental understanding of each method can help in deciding which methods, if any, are appropriate for a given patient and how best to correct observed oxygenation problems once they are discovered.

  View details for Web of Science ID A1992HU95600001

  View details for PubMedID 1582091

• JAUNDICE IN HEALTHY, TERM NEONATES - DO WE NEED NEW ACTION LEVELS OR NEW APPROACHES PEDIATRICS BROWN, A. K., SEIDMAN, D. S., STEVENSON, D. K. 1992; 89 (5): 827–29

  View details for Web of Science ID A1992HT16800008

  View details for PubMedID 1579387

• NICOTINE REPLACEMENT THERAPY DURING PREGNANCY JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION SEIDMAN, D. S., STEVENSON, D. K. 1992; 267 (14): 1922

  View details for DOI 10.1001/jama.267.14.1922

  View details for Web of Science ID A1992HL67700020

  View details for PubMedID 1548823

• EFFECTS OF MICROWAVE-RADIATION ON ANTIINFECTIVE FACTORS IN HUMAN-MILK PEDIATRICS Quan, R., Yang, C., Rubinstein, S., LEWISTON, N. J., Sunshine, P., Stevenson, D. K., Kerner, J. A. 1992; 89 (4): 667-669

  Abstract

  In intensive care nurseries it has become common practice to use microwave thawing of frozen human milk for more rapid accessibility. Twenty-two freshly frozen human milk samples were tested for lysozyme activity, total IgA, and specific secretory IgA to Escherichia coli serotypes 01, 04, and 06. The samples were heated by microwave for 30 seconds at a low- or high-power setting and then reanalyzed. One-mL aliquots of 10 additional human milk samples were microwaved at low (20 degrees C to 25 degrees C), medium (60 degrees C to 70 degrees C), and high (greater than or equal to 98 degrees C) setting before the addition to each of 1 mL of diluted E coli suspension. E coli growth was determined after 3 1/2 hours of incubation at 37 degrees C. Microwaving at high temperatures (72 degrees C to 98 degrees C) caused a marked decrease in activity of all the tested antiinfective factors. E coli growth at greater than or equal to 98 degrees C was 18 times that of control human milk. Microwaving at low temperatures (20 degrees C to 53 degrees C) had no significant effect on total IgA, specific IgA to E coli serotypes 01 and 04, but did significantly decrease lysozyme and specific IgA to E coli serotype 06. Even at 20 degrees C to 25 degrees C, E coli growth was five times that of control human milk. Microwaving appears to be contraindicated at high temperatures, and questions regarding its safety exist even at low temperatures.

  View details for Web of Science ID A1992HM25100018

  View details for PubMedID 1557249

• ROLE OF LIPID-PEROXIDATION IN METALLOPORPHYRIN-MEDIATED PHOTOTOXIC REACTIONS IN NEONATAL RATS DENNERY, P. A., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1992: A128

  View details for Web of Science ID A1992HA10300699

• HOW LONG IS THE DURATION OF ACTION OF ZINC PROTOPORPHYRIN IN NEONATAL RATS Rodgers, P. A., Wei, P. L., Stevenson, D. K. SLACK INC. 1992: A22–A22

  View details for Web of Science ID A1992HA10300119

• MULTIPLE CESAREAN SECTIONS - A NEONATAL RISK FACTOR SEIDMAN, D. S., PAZ, NADOO, A., BARKAI, G., MASHIACH, S., GALE, R., STEVENSON, D. K. SLACK INC. 1992: A8

  View details for Web of Science ID A1992HA10300044

• CHROMIUM PORPHYRINS INHIBIT HEME OXYGENASE IN NEONATAL RATS VALLIER, H. A., RODGERS, P. A., STEVENSON, D. K. SLACK INC. 1992: A23

  View details for Web of Science ID A1992HA10300122

• THE OUTCOME OF FULL-TERM SMALL-FOR-GESTATIONAL-AGE INFANTS IN LATE ADOLESCENCE SEIDMAN, D. S., PAZ, DANON, Y. L., LAOR, A., MASHIACH, S., STEVENSON, D. K., GALE, R. SLACK INC. 1992: A98

  View details for Web of Science ID A1992HA10300541

• NEONATAL BILIRUBIN LANCET SEIDMAN, D. S., STEVENSON, D. K. 1992; 339 (8784): 65–66

  View details for DOI 10.1016/0140-6736(92)90197-B

  View details for Web of Science ID A1992GY04300058

  View details for PubMedID 1345995

• Anthropometry and bilirubin production. Journal of perinatology Stevenson, D. K., Ochikubo, C. G., Rodgers, P. A., Kerner, J. A. 1991; 11 (4): 340-342

  Abstract

  Anthropometric measurements and total bilirubin formation (TBF) estimates were performed on infants born to normal and diabetic mothers. Although we do not exclude the theoretical possibility of a low-frequency occurrence of increased TBF in macrosomic infants of normal mothers, we can conclude that infants of mothers whose diabetes is well managed may have normal TBF.

  View details for PubMedID 1770390

• INVITRO AND INVIVO CHARACTERISTICS OF A HEME OXYGENASE INHIBITOR - ZNBG AMERICAN JOURNAL OF THE MEDICAL SCIENCES Vreman, H. J., Lee, O. K., Stevenson, D. K. 1991; 302 (6): 335-341

  Abstract

  The authors evaluated the in vitro and in vivo efficacy and photosensitizing effects of zinc deuteroporphyrin 2,4-bis glycol (ZnBG) as an inhibitor of adult Wistar rat tissue heme oxygenase (HO) activity and bilirubin production. Concentrations of 0.02-0.05 microM ZnBG inhibited the HO activity in postmitochondrial supernatants of liver, spleen, brain, and kidney by at least 50%. Administration of 4 mumole ZnBG/kg body weight to adult rats significantly reduced the total body carbon monoxide (CO) excretion, an index of bilirubin formation, from 1 to 6 hours posttreatment. At 6 hours posttreatment, the HO activity in postmitochondrial supernatants of the liver and spleen, but not of the brain, was significantly lowered. ZnBG also behaved as an in vitro photooxidizer by degrading, in the presence of cool white light, the reduced form of nicotinamide adenine dinucleotide phosphate and histidine to CO and other nonidentified products. ZnBG also enhanced the natural photodegradation of bilirubin. Furthermore, administration of ZnBG to 1-day-old neonatal rats caused mortality within 12 hours in light-exposed animals, with a lethal dose 50 of 23 microM/kg body weight.

  View details for Web of Science ID A1991GU87600002

  View details for PubMedID 1772116

• OBSERVATIONS ON NEONATAL HYPERBILIRUBINEMIA NEW YORK STATE JOURNAL OF MEDICINE Stevenson, D. K., Brown, A. K. 1991; 91 (11): 477-478

  View details for Web of Science ID A1991GN36000003

  View details for PubMedID 1771041

• DIRECT BILIRUBIN MEASUREMENTS IN JAUNDICED TERM NEWBORNS - A REEVALUATION AMERICAN JOURNAL OF DISEASES OF CHILDREN NEWMAN, T. B., HOPE, S., STEVENSON, D. K. 1991; 145 (11): 1305–9

  Abstract

  To investigate the usefulness of measuring direct bilirubin in jaundiced term newborns, we reviewed the outcome of 5255 such measurements on 2877 term (37 weeks' gestation) newborns in two hospitals. Direct bilirubin tests were ordered 15 times as often per infant at the University of California, San Francisco, as at Stanford (Calif) University, and the reported results were more than twice as high. In most of the 149 infants with high (greater than 95th percentile) direct bilirubin levels, the high levels remained unexplained (52% of cases) or were due to apparent laboratory errors (21% of cases). Forty infants (27%) had conditions sometimes associated with high direct bilirubin levels. Elevation of direct bilirubin levels contributed to the diagnosis in only four of these infants. All had minor laboratory abnormalities that resolved spontaneously. Because of their low yield and poor specificity, direct bilirubin tests are seldom helpful in evaluating jaundice in term newborns.

  View details for DOI 10.1001/archpedi.1991.02160110097029

  View details for Web of Science ID A1991GN26000027

  View details for PubMedID 1951226

• NEONATAL HYPERBILIRUBINEMIA AND PHYSICAL AND COGNITIVE PERFORMANCE AT 17 YEARS OF AGE PEDIATRICS Seidman, D. S., Paz, I., Stevenson, D. K., Laor, A., Danon, Y. L., Gale, R. 1991; 88 (4): 828-833

  Abstract

  To estimate the effect of neonatal hyperbilirubinemia on long-term cognitive ability in full-term newborns with a negative Coombs test, we performed a 17-year historical prospective study of 1948 subjects. Intelligence tests and medical examinations performed at the military draft board were stratified according to serum bilirubin concentration. A logistic regression analysis was used to adjust for the confounding effects of gestational age, birth weight, Apgar score, ethnic origin, socioeconomic class, paternal education, birth order, and the administration of phototherapy and exchange transfusion. No direct linear association was shown between neonatal bilirubin levels and intelligence test scores or school achievement at 17 years of age. However, the risk for low intelligence test scores (IQ score less than 85) was found to be significantly higher (P = .014) among full-term male subjects with serum bilirubin levels above 342 mumol/L (20 mg/dL) (odds ratio, 2.96; 95% confidence interval, 1.29-6.79). This association was not observed among female subjects. We conclude that severe neonatal hyperbilirubinemia, among full-term male newborns with a negative Coombs test, could be associated with lower IQ scores at 17 years of age.

  View details for Web of Science ID A1991GY80100030

  View details for PubMedID 1896294

• A LONGITUDINAL-STUDY OF BIRTH-WEIGHT AND BEING OVERWEIGHT IN LATE ADOLESCENCE AMERICAN JOURNAL OF DISEASES OF CHILDREN Seidman, D. S., Laor, A., Gale, R., Stevenson, D. K., Danon, Y. L. 1991; 145 (7): 782-785

  Abstract

  A total of 33,413 infants born in Jerusalem between 1964 and 1971 were followed up at 17 years of age by matching computerized database files. A logistic regression model was used to estimate the odds ratios for being overweight at 17 years of age for 500-g birth weight categories from less than 2500 g to 4500 g or greater. Information on the ethnic origin, paternal education, birth order, maternal age, and area of residence at birth was available, and these factors were used as possible confounders. The adjusted odds ratios for being overweight (greater than or equal to 90th percentile; body mass index greater than 24.6 kg/m2) and severely overweight (greater than or equal to 97th percentile; body mass index greater than 27.8 kg/m2) at 17 years of age was elevated for the three birth weight categories above the normal reference category of 3000 to 3499 g, with an estimate of 2.16 and 2.30 for male subjects with a birth weight greater than 4500 g and 2.95 and 4.39 for female subjects. The data suggest that higher birth weights correlate strongly with being overweight in late adolescence independently of other factors considered. However, the predictive power of this association is poor.

  View details for Web of Science ID A1991FV10800026

  View details for PubMedID 2058611

• APGAR SCORES AND COGNITIVE PERFORMANCE AT 17 YEARS OF AGE OBSTETRICS AND GYNECOLOGY Seidman, D. S., Paz, I., Laor, A., Gale, R., Stevenson, D. K., Danon, Y. L. 1991; 77 (6): 875-878

  Abstract

  The association between low Apgar scores (7 or less) at 1 and 5 minutes and cognitive performance in late adolescence was assessed. A 17-year follow-up of 1942 subjects was performed. The intelligence test scores at 17 years of age were matched with 1- and 5-minutes Apgar scores. A multiple linear regression analysis was used to control for the possible confounding effect of perinatal factors (birth weight, gestational age, serum bilirubin levels, birth order) and demographic characteristics (ethnic origin, paternal education, social class). The sensitivity and positive predictive value of a low 1-minute Apgar score were 8 and 8% and of a low 5-minute Apgar score 1.5 and 5%, respectively. Low Apgar scores are poorly correlated with long-term intellectual outcome.

  View details for Web of Science ID A1991FN40100015

  View details for PubMedID 2030860

• IS LOW-BIRTH-WEIGHT A RISK FACTOR FOR ASTHMA DURING ADOLESCENCE ARCHIVES OF DISEASE IN CHILDHOOD Seidman, D. S., Laor, A., Gale, R., Stevenson, D. K., Danon, Y. L. 1991; 66 (5): 584-587

  Abstract

  The effect of low birth weight on the incidence of asthma by 17 years of age was investigated by studying medical draft examination records of 20,312 male subjects born in Jerusalem between January 1967 and December 1971. Additional information on birth weight and other demographic factors was abstracted from the Jerusalem Perinatal Study computerised database. A stepwise multiple logistic regression was used to estimate the odds ratios for developing asthma by 17 years of age in 500 g birthweight categories from less than 2000 g to 4500 g. The odds ratios were adjusted for the confounding effects of ethnic origin, social class (determined by area of residence), paternal education, maternal age, and birth order. The group with low birth weights (less than 2500 g, n = 1004) had a significantly increased risk of developing asthma by 17 years of age, with an adjusted odds ratio of 1.44 (95% confidence interval (CI) 0.79 to 2.66) for birthweight group less than 2000 g and 1.49 (95% CI 1.05 to 2.12) for birthweight group 2000-2499 g compared with the reference group of 3000-3499 g. We conclude that infants with birth weights of less than 2500 g may have a higher risk of asthma during childhood and adolescence than infants who were heavier at birth.

  View details for Web of Science ID A1991FL46500006

  View details for PubMedID 2039246

  View details for PubMedCentralID PMC1792927

• VIGINTIPHOBIA OR REAL DANGER - NEONATAL JAUNDICE AND COGNITIVE PERFORMANCE AT 17 YEARS OF AGE SEIDMAN, D. S., PAZ, STEVENSON, D. K., LAOR, A., DANON, Y. L., GALE, R. WILLIAMS & WILKINS. 1991: A265

  View details for Web of Science ID A1991FE03801570

• THE EFFECT OF PHOTOTHERAPY FOR NEONATAL HYPERBILIRUBINEMIA ON LONG-TERM COGNITIVE PERFORMANCE SEIDMAN, D. S., PAZ, STEVENSON, D. K., LAOR, A., DANON, Y. L., GALE, R. WILLIAMS & WILKINS. 1991: A265

  View details for Web of Science ID A1991FE03801571

• APGAR SCORES AND COGNITIVE PERFORMANCE AT 17-YEARS-OF-AGE SEIDMAN, D. S., PAZ, LAOI, A., STEVENSON, D. K., DANON, Y. L., GALE, R. WILLIAMS & WILKINS. 1991: A265

  View details for Web of Science ID A1991FE03801569

• ZINC DEUTEROPORPHYRIN 2,4 BIS GLYCOL IS ABSORBED BY THE SMALL-INTESTINE IN NEONATAL RATS Vallier, H. A., Rodgers, P. A., Stevenson, D. K., Castillo, R. O. NATURE PUBLISHING GROUP. 1991: A67–A67

  View details for Web of Science ID A1991FE03800386

• A NEW GENERATION OF POTENT HEME OXYGENASE (HO) INHIBITORS VREMAN, H. J., STEVENSON, D. K. WILLIAMS & WILKINS. 1991: A67

  View details for Web of Science ID A1991FE03800387

• BIRTH-WEIGHT BODY-MASS AND BLOOD-PRESSURE IN LATE ADOLESCENCE SEIDMAN, D. S., LAOR, A., GALE, R., STEVENSON, D. K., BETTANE, P. A., DANON, Y. L. WILLIAMS & WILKINS. 1991: A6

  View details for Web of Science ID A1991FE03800019

• A STUDY OF NEPHROTOXIN-INDUCED ACUTE TUBULAR-NECROSIS WITH P-31 MAGNETIC-RESONANCE SPECTROSCOPY MAGNETIC RESONANCE IN MEDICINE Schutz, T., GONZALEZMENDEZ, R., Nabseth, D. C., Tune, B. M., Jardetzky, O., Stevenson, D. K. 1991; 18 (1): 159-168

  Abstract

  Phosphorus magnetic resonance spectroscopy (31P MRS) was used to obtain in vivo spectra from rat kidneys undergoing acute tubular necrosis induced by a nephrotoxic dose of cephaloridine (CLD). Spectra were obtained 0, 24, and 48 h after injection of CLD (experimental group, n = 6) or saline vehicle (control group, n = 6). The nephrotoxicity of CLD was demonstrated by severely increased serum creatinine levels and the development of extensive proximal tubular necrosis in the CLD-injected rats, and the lack of such changes in the controls. 31P MRS showed an increase in the inorganic phosphate region signal (Pi, p = 0.004) and a decrease in the phosphodiester region signal (PDE, p = 0.01) in the experimental group by 48 h, whereas these parameters did not vary significantly in the control group during the experiment. Significant correlations were found between serum creatinine and the same two 31P MRS parameters. In summary, rat kidneys which have developed severe CLD-induced proximal tubular necrosis exhibit changes in the 31P spectrum 48 h after administration of the drug. The causes of these changes were not determined.

  View details for Web of Science ID A1991EZ54700015

  View details for PubMedID 2062227

• ALTERED MATURATION OF SMALL INTESTINAL FUNCTION IN THE ABSENCE OF INTRALUMINAL NUTRIENTS - RAPID NORMALIZATION WITH REFEEDING AMERICAN JOURNAL OF CLINICAL NUTRITION Castillo, R. O., Feng, J. J., Stevenson, D. K., Kwong, L. K. 1991; 53 (2): 558-561

  Abstract

  The absence of intraluminal nutrients during weaning in rats was shown to result in altered intestinal growth and maturation. In this study intestinal length, mucosal weight, DNA, protein, and total disaccharidase activities were significantly lower in animals sustained by intravenous nutrients over the normal weaning age than were normally weaned controls but were greater than preweaning values. Absorptive capacity for sucrose (assessed by hydrogen-gas production) was diminished, directly linking incomplete maturation of sucrase to diminished intestinal function. To determine whether these alterations were permanent, rats previously deprived of intraluminal nutrients over the weaning period were refed. Eight days after refeeding, all variables except total lactase had attained values found in normally weaned age-matched controls, including absorptive capacity for sucrose. Although intestinal growth and maturation is abnormal in the absence of intraluminal nutrients during weaning, the abnormalities are not permanent and are rapidly corrected upon refeeding.

  View details for Web of Science ID A1991EU94600027

  View details for PubMedID 1899174

• BIRTH-WEIGHT, BODY-MASS AND BLOOD-PRESSURE IN LATE ADOLESCENCE SEIDMAN, D. S., LAOR, A., GALE, R., STEVENSON, D. K., BETTANE, P. A., DANON, Y. L. SLACK INC. 1991: A2

  View details for Web of Science ID A1991ET78600009

• ZINC DEUTEROPORPHYRIN 2,4 BIS GLYCOL IS ABSORBED BY THE SMALL-INTESTINE IN NEONATAL RATS VALLIER, H. A., RODGERS, P. A., STEVENSON, D. K., CASTILLO, R. O. SLACK INC. 1991: A18

  View details for Web of Science ID A1991ET78600102

• 2 RESCUE DOSES OF EXOSURF IMPROVE RESPIRATORY SYSTEM STATIC COMPLIANCE (CST) AT ONE WEEK ARMSBY, D. H., BELLON, G., CARLISLE, K., RECTOR, D., BALDWIN, R., STEVENSON, D. K., LONG, W. A., ARIAGNO, R. L. SLACK INC. 1991: A41

  View details for Web of Science ID A1991ET78600227

• PLASMA DISAPPEARANCE AND TISSUE DISTRIBUTION OF ZINC PROTOPORPHYRIN AND ZINC DEUTEROPORPHYRIN 2,4 BIS GLYCOL IN ADULT-RATS RODGERS, P. A., VALLIER, H. A., STEVENSON, D. K. SLACK INC. 1991: A51

  View details for Web of Science ID A1991ET78600282

• A NEW GENERATION OF POTENT HEME OXYGENASE (HO) INHIBITORS VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1991: A50

  View details for Web of Science ID A1991ET78600274

• VIGINTIPHOBIA OR REAL DANGER - NEONATAL JAUNDICE AND COGNITIVE PERFORMANCE AT 17 YEARS OF AGE SEIDMAN, D. S., PAZ, STEVENSON, D. K., LAOR, A., DANON, Y. L., GALE, R. SLACK INC. 1991: A71

  View details for Web of Science ID A1991ET78600393

• CARBON-MONOXIDE (CO) AS AN INDEX OF LIPID-PEROXIDATION VREMAN, H. J., SANESI, C. A., DENNERY, P. A., STEVENSON, D. K. SLACK INC. 1991: A109

  View details for Web of Science ID A1991ET78600598

• ORAL-ADMINISTRATION OF ZINC DEUTEROPORPHYRIN IX 2,4 BIS GLYCOL INHIBITS HEME OXYGENASE IN NEONATAL RATS DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS Vallier, H. A., Rodgers, P. A., Stevenson, D. K. 1991; 17 (3-4): 220-222

  Abstract

  Zinc deuteroporphyrin IX 2,4 bis glycol (ZnBG) has been shown to be a potent inhibitor of heme oxygenase (HO) in vitro. Oral administration, which has been minimally effective with other metalloporphyrins, could be clinically advantageous for prevention of neonatal hyperbilirubinemia. Therefore, we examined the effect of oral administration of ZnBG on tissue HO activity and tissue ZnBG concentrations. Suckling rats at 2 weeks of age received ZnBG at 40 mumol/kg BW via gastric gavage. Rats were killed with anesthetic over-dose after 60 min. ZnBG was detected in the portal and systemic circulation (n = 12), and the liver, kidney, spleen, and intestine (n = 8). ZnBG concentrations of 7.9 nmol/g liver and 1.7 nmol/g spleen corresponded to 67 and 72% inhibition of control HO activity (n = 9; p less than 0.0005) respectively.

  View details for Web of Science ID A1991JJ26500017

  View details for PubMedID 1841841

• THE EFFECTS OF HIGH PARITY AND SOCIOECONOMIC-STATUS ON OBSTETRIC AND NEONATAL OUTCOME ARCHIVES OF GYNECOLOGY AND OBSTETRICS Seidman, D. S., Dollberg, S., Stevenson, D. K., Gale, R. 1991; 249 (3): 119-127

  Abstract

  We studied the interaction of social status and high parity in 15,102 consecutive births in one inner-city hospital, of which 1874 (12.4%) occurred in mothers who had given birth to seven or more infants (Grand multiparae). Group 1 consisted of 1258 grand multiparae from a socioeconomically stable and homogeneous ultra-orthodox Jewish community in Jerusalem, and group 2, included all other grand multiparae of relatively greater age and lower socioeconomic status. A significantly higher rate of small for gestational age, low birth weight and preterm infants was found in group 2 compared with group 1. The results suggest that grand multiparity is not of itself a risk factor, but reflects the confounding effect of environmental conditions.

  View details for Web of Science ID A1991GK60300002

  View details for PubMedID 1772264

• ABSORPTION OF ZINC DEUTEROPORPHYRIN-IX 2,4-BIS-GLYCOL BY THE NEONATAL RAT SMALL-INTESTINE INVIVO DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS Vallier, H. A., Rodgers, P. A., Castillo, R. O., Stevenson, D. K. 1991; 17 (1-2): 109-115

  Abstract

  Zinc deuteroporphyrin IX 2,4-bis-glycol (ZnBG) is a potent inhibitor of heme oxygenase and may be useful in the prevention of neonatal jaundice. Enteral administration could be advantageous clinically, but it has been only minimally effective with other metalloporphyrins in rats and humans. Thus, the absorption of ZnBG by the small intestine in vivo was examined. ZnBG was administered enterally at 40 mumol/kg to 2-week-old suckling rats via in situ catheterization of the small intestine. Within 15 min ZnBG was absorbed by the small intestine, as it was measured in portal and systemic venous plasma, intestine, kidney, liver, and spleen. Concentrations exceeding 5.0 microM were found in plasma within 30 min, and 9.4 microM was found in the liver after 30 min. A total of 4.6% of the administered ZnBG dose was measured in plasma and tissues.

  View details for Web of Science ID A1991HK86500014

  View details for PubMedID 1811916

• METALLOPORPHYRIN PHOTOTOXICITY JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY Scott, J., Quirke, J. M., Vreman, H. J., Stevenson, D. K., Downum, K. R. 1990; 7 (2-4): 149-157

  Abstract

  The phototoxicities of six metalloporphyrin dimethylesters (i.e. cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), tin (Sn) and zinc (Zn) were investigated. Hemolysis of human erythrocytes and inactivation of two enzymes (acetylcholinesterase and beta-galactosidase) were used to assess the phototoxic efficacy of these metal chelates. Tin protoporphyrin (SnPP), the only porphyrin found to hemolyze erythrocytes at a concentration of 40 microM (radiation dose, 230 kJ m-2), was much less efficient than either free protoporphyrin IX or hematoporphyrin. SnPP completely inactivated beta-galactosidase at concentrations above 15 microM (radiation dose, 75 kJ m-2) and drastically interfered with acetylcholinesterase activity at a concentration of 150 microM (radiation dose, 75 kJ m-2). CoPP, CuPP, MnPP, NiPP and ZnPP were ineffective photohemolytic agents at 40 microM (radiation dose, 230 kJ m-2), but inactivated acetylcholinesterase and beta-galactosidase activity to varying degrees. These results suggest that (i) metal ions reduce the phototoxicity of protoporphyrin IX, (ii) different metal ions reduce the phototoxic activity of protoporphyrin IX to different degrees and (iii) the biological activities of the various metal complexes vary in different assay systems.

  View details for Web of Science ID A1990EG30500002

  View details for PubMedID 2128321

• ZINC PROTOPORPHYRIN ADMINISTRATION FOR SUPPRESSION OF INCREASED BILIRUBIN PRODUCTION BY IATROGENIC HEMOLYSIS IN RHESUS NEONATES JOURNAL OF PEDIATRICS Vreman, H. J., Rodgers, P. A., Stevenson, D. K. 1990; 117 (2): 292-297

  Abstract

  We studied the effect of intravenous zinc protoporphyrin (ZnPP) administration on total body carbon monoxide excretion (VeCO), (an index of heme degradation), blood carboxyhemoglobin level, plasma bilirubin level, and tissue homogenate heme oxygenase activity 24 hours after delivery of rhesus neonates treated at 12 hours of age with heat-damaged erythrocytes (32 mumol heme/kg birth weight). All neonates were delivered by cesarean section and received ampicillin and gentamicin to suppress intestinal flora. The control group (n = 4) was treated with saline solution and ZnPP solvent; the erythrocyte-treated control group (n = 4) received erythrocytes and ZnPP solvent; and two experimental groups received erythrocytes and one dose of 10 (n = 3) or 40 (n = 4) mumol ZnPP/kg body weight, respectively. At 24 hours, administration of erythrocytes alone doubled the VeCO (p less than 0.05), carboxyhemoglobin level, (p less than 0.05), and plasma total bilirubin level (p less than 0.05). Treatment with ZnPP, 40 mumol/kg body weight, caused a significant decrease in VeCO (p less than 0.05), carboxyhemoglobin (p less than 0.05), bilirubin (p less than 0.05), and spleen heme oxygenase (p less than 0.05). Treatment of the erythrocyte-loaded animals with ZnPP, 10 mumol/kg body weight, also significantly (p less than 0.05) lowered VeCO and spleen heme oxygenase activity but did not cause a significant lowering of blood carboxyhemoglobin or plasma bilirubin concentration. We conclude that ZnPP is an effective, dose-dependent in vivo inhibitor of heme oxygenase in the newborn rhesus with latrogenic hemolysis, and that it suppresses both bilirubin production and subsequent accumulation.

  View details for Web of Science ID A1990DU14800025

  View details for PubMedID 2380831

• A COMPARISON OF TOCOLYSIS WITH NIFEDIPINE OR RITODRINE - ANALYSIS OF EFFICACY AND MATERNAL, FETAL, AND NEONATAL OUTCOME AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Ferguson, J. E., Dyson, D. C., Schutz, T., Stevenson, D. K. 1990; 163 (1): 105-111

  Abstract

  Nifedipine, a dihydropyridone calcium entry blocker, has been used with increasing frequency in the treatment of preterm labor. We studied 66 patients in this prospective, randomized trial to evaluate the efficacy and maternal, fetal, and neonatal outcome associated with tocolysis with nifedipine or ritodrine. Delivery was delayed for 48 hours, 7 days, and until the thirty-sixth week of gestation in 84%, 70%, and 41%, respectively, of patients in the nifedipine group, compared with 72%, 63%, and 52% of patients in the ritodrine group (difference not significant). Maternal side effects were more common and more serious in the group of patients who received ritodrine compared with those who received nifedipine (18 of 38 versus 5 of 38, p less than 0.01); however, fetal and neonatal outcome appeared to be similar when the groups were compared. On the basis of this study, it appears that tocolysis with either nifedipine or ritodrine is equally efficacious; however, maternal side effects are less common with nifedipine treatment. We conclude that nifedipine may have a role in the treatment of preterm labor but suggest further careful evaluation of this agent before it is considered for routine clinical use.

  View details for Web of Science ID A1990DR23400027

  View details for PubMedID 2197860

• DEVELOPMENTAL BIOLOGY OF HEME OXYGENASE CLINICS IN PERINATOLOGY Rodgers, P. A., Stevenson, D. K. 1990; 17 (2): 275-291

  Abstract

  The regulation of heme oxygenase activity in the developing neonate is essential to the control of bilirubin production as well as intracellular heme and hemoprotein metabolism. The coordinated activity of the microsomal enzymes, heme oxygenase and NADPH-cytochrome c (P450) reductase, and the cytosolic enzyme biliverdin reductase is responsible for the degradation of heme. The complete reaction sequence requires oxygen and NADPH, and produces bilirubin and carbon monoxide in equimolar amounts. Although heme oxygenase expresses a rather broad range of substrate affinities, the oxidative degradation of heme is exclusively alpha-specific. Heme oxygenase is found in several tissues, with significant activity levels in the liver, spleen, and erythropoeitic tissue. Heme oxygenase activity is inducible by heme and other metalloporphyrins, hormones, starvation, stress, toxins, and xenobiotics. Heme oxygenase induction is generally considered to be the result of an increased protein synthesis and gene transcription. This hypothesis is supported by recent studies of the heme oxygenase gene that identified inducer element binding sites responsive to metal administration, heat shock, and nutrient availability. In the developing fetus and neonate, hepatic heme oxygenase activity and mRNA levels are elevated above that of the adult. This suggests that the elevated heme catabolism observed in neonates may be associated with an increased transcription of the heme oxygenase gene. The apparent induction of hepatic heme oxygenase during the neonatal period is probably the result of tissue-specific and time-dependent transcriptional regulating factors including potentially hormones and heme. Several metalloporphyrins, such as the tin and zinc porphyrin complexes, inhibit heme oxygenase activity and thus have therapeutic potential for the treatment of neonatal jaundice. Recent studies suggest that the meso- and bis-glycol derivatives of these metalloporphyrins may be more potent inhibitors of heme oxygenase activity in vitro and in vivo than the protoporphyrin structures. As structural analogues of heme, however, these compounds may also have other less desirable effects on the regulation of heme and hemoprotein metabolism, particularly in the developing neonate.

  View details for Web of Science ID A1990DM55000003

  View details for PubMedID 2196131

• LIMITING TREATMENT FOR EXTREMELY PREMATURE, LOW-BIRTH-WEIGHT INFANTS (500 TO 750-G) AMERICAN JOURNAL OF DISEASES OF CHILDREN Young, E. W., Stevenson, D. K. 1990; 144 (5): 549-552

  Abstract

  Despite impressive recent advances in neonatology, outcomes for extremely premature, very-low-birth-weight infants (500 to 750 g) remain uneven. In a situation of inherent uncertainty, treating patients vigorously could do violence to the moral principles of nonmaleficence and (distributive) justice. Equally, failing to treat patients vigorously because of concerns about nonmaleficence and (distributive) justice could violate the principle of patient-centered beneficence. Compounding this dilemma is the legacy of the "Baby Doe Regulations." International perspectives on this particular quandary are provided. We assert that at Stanford (Calif) University the "individualized prognostic strategy" rather than the "wait until certainty" approach prevails. Four concluding questions are posed: Why is prevention not encouraged more than after-the-fact heroic intervention? Is it possible to develop a more rational view of stopping aggressive therapy once having started? Can we ignore the finitude of our medical resources? Is there a need to redefine the nature of autonomy?

  View details for Web of Science ID A1990DB96200021

  View details for PubMedID 2330921

• METALLOPORPHYRIN-ENHANCED PHOTODEGRADATION OF BILIRUBIN INVITRO AMERICAN JOURNAL OF DISEASES OF CHILDREN Vreman, H. J., Stevenson, D. K. 1990; 144 (5): 590-594

  Abstract

  Solutions of bilirubin containing human serum albumin were exposed in vitro in the presence of 10 mumols/L of tin and zinc metalloporphyrins at 37 degrees C for 30 minutes to light sources used clinically for phototherapy of neonates. Bilirubin in the model solutions was photodegraded to approximately 60% of dark control in cool white light (17 microW/cm2 per nanometer). The presence of zinc protoporphyrin and zinc mesoporphyrin further reduced the bilirubin concentration slightly, but the tin analogues caused a significant enhancement of degradation to 35% and 25% of dark control, respectively. The results provide evidence that the zinc and tin metalloporphyrins are photosensitizers capable of enhancing the native photodegradation of bilirubin in biologic matrices, but that the tin compounds are more potent. The metalloporphyrin time course, dose-response curve, oxygen effects, and efficacy of phototherapy light sources were also studied.

  View details for Web of Science ID A1990DB96200030

  View details for PubMedID 2330928

• IS LOW-BIRTH-WEIGHT A RISK FACTOR FOR BRONCHIAL-ASTHMA DURING ADOLESCENCE SEIDMAN, D. S., LAOR, A., GALE, R., STEVENSON, D. K., DANON, Y. WILLIAMS & WILKINS. 1990: A256

  View details for Web of Science ID A1990CW36201513

• INTELLECTUAL-PERFORMANCE BY LOW-BIRTH-WEIGHT INFANTS AT 17 YEARS OF AGE SEIDMAN, D. S., LAOR, A., GALE, R., STEVENSON, D. K., DANON, Y. WILLIAMS & WILKINS. 1990: A256

  View details for Web of Science ID A1990CW36201514

• BIRTH-WEIGHT AND OBESITY AT 17 YEARS OF AGE SEIDMAN, D. S., DANON, Y., LAOR, A., STEVENSON, D. K., GALE, R. WILLIAMS & WILKINS. 1990: A256

  View details for Web of Science ID A1990CW36201512

• THE ASSOCIATION OF BIRTH-WEIGHT AND ADULT BODY HEIGHT SEIDMAN, D. S., LAOR, A., STEVENSON, D. K., GALE, R., DANON, Y. WILLIAMS & WILKINS. 1990: A256

  View details for Web of Science ID A1990CW36201515

• SELECTION OF HEME OXYGENASE INHIBITORS BASED ON POTENCY AND PHOTOREACTIVITY EKSTRAND, B. C., VREMAN, H. J., STEVENSON, D. K. WILLIAMS & WILKINS. 1990: A59

  View details for Web of Science ID A1990CW36200334

• ZINC DEUTEROPORPHYRIN BIS GLYCOL - A POTENT HEME OXYGENASE INHIBITOR VREMAN, H. J., LEE, O. K., STEVENSON, D. K. WILLIAMS & WILKINS. 1990: A66

  View details for Web of Science ID A1990CW36200380

• ZINC PROTOPORPHYRIN ADMINISTRATION SUPPRESSES HEMOLYTIC HYPERBILIRUBINEMIA IN RHESUS NEONATES VREMAN, H. J., RODGERS, P. A., STEVENSON, D. K. WILLIAMS & WILKINS. 1990: A230

  View details for Web of Science ID A1990CW36201359

• CARBON-MONOXIDE PRODUCTION BY NONBACTERIAL SOURCES AFTER HEME FEEDING OF NEONATAL RATS BIOLOGY OF THE NEONATE Stevenson, D. K., HAMORI, C. J., Carlton, R. R., Castillo, R. O., Kerner, J. A., Vreman, H. J. 1990; 57 (3-4): 238-242

  Abstract

  We determined the relative potential for nonbacterial CO production after oral heme feeding of 12-hour-old rats. The intestinal flora was eliminated by treatment with kanamycin, ampicillin, and neomycin. CO excretion (VeCO) was measured after oral administration of heme (0.64 mumol/animal). Antibiotic treatment alone did not significantly affect the VeCO of rats gavaged with saline. Heme administration increased (p less than 0.05) the VeCO during t = 1-11 h with a peak at 3 h. Antibiotic treatment reduced this VeCO (p less than 0.05) during t = 2-8 h, but its level (peak at t = 2-3 h) was still significantly (p less than 0.05) above its nonheme control. The results confirm that bacterial degradation of heme is an important source of CO in suckling rats not pretreated with broad-spectrum antibiotics. However, oral heme feeding of gut-sterilized animals yielded transiently significantly increased VeCO. HO-mediated degradation of enteral heme is a likely nonbacterial source of CO and possibly bilirubin in the neonate.

  View details for Web of Science ID A1990CR41700015

  View details for PubMedID 2322605

• LABORATORY EVALUATION OF JAUNDICE IN NEWBORNS - FREQUENCY, COST, AND YIELD AMERICAN JOURNAL OF DISEASES OF CHILDREN Newman, T. B., EASTERLING, M. J., Goldman, E. S., Stevenson, D. K. 1990; 144 (3): 364-368

  Abstract

  Neonates with hyperbilirubinemia commonly undergo a battery of laboratory tests. We used a computerized database and medical records to study the frequency, cost, and yield of these tests in 2443 infants born at the University of California, San Francisco, between 1980 and 1982. Four hundred forty-seven (18%) of the infants met standard criteria for "nonphysiologic" hyperbilirubinemia; the incidence varied from 9% in blacks to 31% in Asian infants. About 55% of these 447 infants received a $125 "hyperbilirubinemia workup." Hospital discharge diagnoses on all 447 hyperbilirubinemic infants were reviewed. In 214 (48%), no cause of the jaundice was identified. An additional 145 (32%) had a possible cause apparent from history, physical examination, or initial hematocrit determination. The only diagnosis made as a result of routine investigations of hyperbilirubinemia was possible ABO or Rh isoimmunization in 75 infants (17%). Nonphysiologic hyperbilirubinemia may be more common than previously reported. The recommended tests are expensive and rarely lead to diagnoses other than ABO or Rh isoimmunization. Their routine use should be reevaluated.

  View details for Web of Science ID A1990CR02200036

  View details for PubMedID 2106258

• REGULATION OF INTESTINAL ONTOGENY BY INTRALUMINAL NUTRIENTS JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Castillo, R. O., Feng, J. J., Stevenson, D. K., Kerner, J. A., Kwong, L. K. 1990; 10 (2): 199-205

  Abstract

  Major events in gastrointestinal ontogeny occur in the infant rat in association with weaning, resulting in striking alterations in small intestinal structure and function. Although the dietary changes attendant to weaning are not essential for the initiation of these events, dietary nutrients have been shown to participate in the maturation of some intestinal parameters. In order to define more precisely the role of intraluminal nutrients in the regulation of small intestinal ontogeny, a longitudinal study was conducted using a unique animal model in which intraluminal nutrients were excluded from the intact maturing intestine in vivo throughout the entire weaning period without major compromise in nutritional status. The absence of intraluminal nutrients over the weaning period resulted in diminished lengthening and accretion of mucosal mass, suggesting a slower rate of intestinal growth. Lower mucosal DNA, protein, and mitotic indices in intestines of animals receiving no intraluminal nutrients suggested that the lack of intraluminal nutrients resulted in the blunting of the striking increases in cellular proliferation normally exhibited by the developing intestinal mucosa at this time. Maturation of intestinal lactase-phlorizin hydrolase and maltase-glucoamylase was not affected by the absence of intraluminal nutrients. Although the appearance of sucrase-isomaltase was not altered by the absence of intraluminal nutrients, activity levels rose to only 50% of control levels. These data suggest that during this period of rapid intestinal maturation, intestinal growth is more dependent upon intraluminal nutrients than are the characteristic enzymic alterations normally expressed during this period.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1990CM93700010

  View details for PubMedID 2303970

• THE USE OF ANTIBIOTICS IN NEONATES WEIGHING LESS THAN 1200 GRAMS PEDIATRIC INFECTIOUS DISEASE JOURNAL Prober, C. G., Stevenson, D. K., Benitz, W. E. 1990; 9 (2): 111-121

  View details for Web of Science ID A1990CT73000009

  View details for PubMedID 2179837

• HEME CATABOLISM IN RHESUS NEONATES INHIBITED BY ZINC PROTOPORPHYRIN DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS Rodgers, P. A., Vreman, H. J., Stevenson, D. K. 1990; 14 (4): 216-222

  Abstract

  The effect of zinc (II) protoporphyrin IX (ZnPP) administration (40 mumol/kg, i.v.) on neonatal heme catabolism and the associated bilirubin production was investigated in rhesus (Macaca mulatta) neonates. Carbon monoxide excretion rates (VECO), tissue heme oxygenase activity, and plasma bilirubin concentrations were measured during a 26-hour postnatal period. In ZnPP-treated neonates (n = 4), VECO values were significantly (p = 0.002) diminished by 24% within 24 h. When compared to controls (n = 3), tissue heme oxygenase activity in ZnPP-treated neonates was greatly reduced in both liver (94% inhibition, p = 0.047) and spleen (48% inhibition, p = 0.077), but essentially unaffected in the kidney and brain. Although not statistically significant, peak (24-hour) neonatal plasma bilirubin concentrations tended to be lower (23%). These results suggest ZnPP may be efficacious in reducing heme catabolism associated with neonatal jaundice.

  View details for Web of Science ID A1990DV23600004

  View details for PubMedID 2397675

• ZINC DEUTEROPORPHYRIN BIS GLYCOL - A POTENT HEME OXYGENASE INHIBITOR VREMAN, H. J., LEE, O. K., STEVENSON, D. K. SLACK INC. 1990: A199

  View details for Web of Science ID A1990CF63601155

• HEME OXYGENASE ACTIVITY AS MEASURED BY CO PRODUCTION - EFFECTS OF METALLOPORPHYRINS AND LIGHT VREMAN, H. J., STEVENSON, D. K. PERGAMON-ELSEVIER SCIENCE LTD. 1990: 35–36

  View details for Web of Science ID A1990AY75000035

• SELECTION OF HEME OXYGENASE INHIBITORS BASED ON POTENCY AND PHOTOREACTIVITY EKSTRAND, B. C., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1990: A194

  View details for Web of Science ID A1990CF63601124

• A RANDOMIZED CONTROLLED APPLICATION OF THE WALLABY PHOTOTHERAPY SYSTEM COMPARED TO STANDARD PHOTOTHERAPY GALE, R., DRANITZKI, Z., DOLLBERG, S., STEVENSON, D. K. SLACK INC. 1990: A194

  View details for Web of Science ID A1990CF63601126

• FETAL HEMOGLOBIN IN TRANSFUSED NEONATES MAHONEY, J. J., WONG, R. J., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1990: A196

  View details for Web of Science ID A1990CF63601138

• ANTHROPOMETRY DOES NOT PREDICT INCREASED BILIRUBIN FORMATION AMONG INFANTS WITH NORMAL MOTHERS OCHIKUBO, C. G., INGUILLO, D., MARTIN, D. M., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1990: A197

  View details for Web of Science ID A1990CF63601142

• ZINC PROTOPORPHYRIN ADMINISTRATION SUPPRESSES HEMOLYTIC HYPERBILIRUBINEMIA IN RHESUS NEONATES VREMAN, H. J., RODGERS, P. A., STEVENSON, D. K. SLACK INC. 1990: A199

  View details for Web of Science ID A1990CF63601156

• EPIDEMIOLOGY OF NEONATAL JAUNDICE IN THE JERUSALEM POPULATION JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Gale, R., Seidman, D. S., Dollberg, S., Stevenson, D. K. 1990; 10 (1): 82-86

  Abstract

  Of 10,122 singleton babies born from January 1, 1984 to March 31, 1988, we compared 1,154 term infants with high serum bilirubin levels (greater than 12.9 mg/dl) to 1,154 infants with low serum bilirubin levels (less than or equal to 12.9 mg/dl) randomly selected from the remaining 8,968 subjects. We found that a high bilirubin level was significantly associated with male sex; maternal diabetes (chronic and gestational); pregnancy-induced hypertension; previous sibling with neonatal jaundice; delivery by cesarean section, vacuum, or forceps; epidural anesthesia; mother with blood type O; first delivery; cephalohematoma; short gestation; lower birth weight; and lower birth order (p less than 0.01); and older maternal age, low percentile for birth weight, and the percentage of weight loss during hospitalization (p less than 0.05). Variables with significantly different frequencies in control and study groups were used in a multivariate analysis, thus further refining the data by the use of logistic regression. Teenage mothers (less than or equal to 19 years old) had the lowest risk, whereas older mothers (greater than 35 years old) had the highest risk of all age groups for having an infant with neonatal jaundice. First delivery and previous sibling with neonatal jaundice were also risk factors. Male sex, short gestation, and delivery by vacuum extraction were other notable risk factors. Our results suggest that, even among industrialized Western societies, risk factors may interact differently to produce higher neonatal serum bilirubin levels. The importance of a risk factor may also be dependent upon its relative prevalence in a parturient population.

  View details for Web of Science ID A1990CG06200016

  View details for PubMedID 2324884

• INVITRO GENERATION OF CARBON-MONOXIDE FROM ORGANIC-MOLECULES AND SYNTHETIC METALLOPORPHYRINS MEDIATED BY LIGHT DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS Vreman, H. J., GILLMAN, M. J., Downum, K. R., Stevenson, D. K. 1990; 15 (2): 112-124

  Abstract

  Tin protoporphyrin (SnPP) and analogs are being studied as possible agents for the prevention of neonatal hyperbilirubinemia through inhibition of heme oxygenase. Because SnPP is a photosensitizer, we studied its role in the photogeneration of carbon monoxide (CO) from organic compounds in vitro. Generation of CO occurred in the presence of 5 microM SnPP and cool white light (19 muW/cm2/nm or 29 W/m2) from SnPP alone, human serum albumin, glucose, histidine, ethanolamine, medium-chain triglycerides, the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH), and human plasma. More detailed studies with human serum albumin and NADPH established that the photogeneration of CO is nearly linear with time and irradiance. It is curvilinear with respect to the SnPP concentration at the concentrations tested, and it is dependent on the presence of O2 in the reactor headspace. Cool white light generated less CO from human serum albumin and NADPH than equidistantly placed blue and green phototherapy light sources. Comparison of SnPP with other metalloporphyrin heme oxygenase inhibitors indicates that tin mesoporphyrin is most and zinc protoporphyrin least photoreactive.

  View details for Web of Science ID A1990EV12100009

  View details for PubMedID 2078972

• MORTALITY OF METALLOPORPHYRIN-TREATED NEONATAL RATS AFTER LIGHT EXPOSURE DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS Hintz, S. R., Vreman, H. J., Stevenson, D. K. 1990; 14 (3): 187-192

  Abstract

  Tin protoporphyrin (SnPP) has been used to suppress hyperbilirubinemia in human neonates through inhibition of heme oxygenase. Some of the subjects exhibited mild erythema upon receiving phototherapy. SnPP and three proposed alternatives, tin mesoporphyrin (SnMP), zinc protoporphyrin (ZnPP) and zinc mesoporphyrin (ZnMP) are potential photosensitizers. We therefore studied the phototoxic effects of these compounds in the neonatal rat model. Fed Wistar rats (24-36 h old) were injected intraperitoneally with up to 40 mumol SnPP/kg body weight, 30 mumol SnMP/kg body weight, 60 mumol ZnPP/kg body weight, or 45 mumol ZnMP/kg body weight. The animals were placed over cool white light (20 microW/cm2/nm) for 12 h. Light exposure resulted in SnPP dose-dependent mortality, and the LD50 was determined to be 11.7 mumol/kg body weight. No deaths were observed in pups treated with up to 20 mumol SnMP/kg; treatment with 30 mumol SnMP/kg resulted in a 40% mortality rate. No fatalities were observed among the light-exposed ZnPP- or ZnMP-treated pups. No deaths were observed among control pups treated with the highest metalloporphyrin doses and kept in the dark; similarly, no mortality was observed in untreated light-exposed control animals. We conclude that (1) SnPP and SnMP are potentially fatal phototoxic substances in the neonatal rat; (2) ZnPP and ZnMP may be safer drugs for neonatal rats receiving light exposure, and (3) further studies are needed to fully assess the photobiological hazards of metalloporphyrin administration to humans.

  View details for Web of Science ID A1990DG27100006

  View details for PubMedID 2364856

• CONTINUOUS PARENTERAL INFUSION OF VITAMIN-E PHARMACOKINETICS AND BILIRUBIN PRODUCTION IN PREMATURE NEONATES ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Stevenson, D. K., Vreman, H. J., Ferguson, J. E., Lenert, L. A., Leonard, M. B., Gale, R. 1989; 570: 352-357

  Abstract

  We conclude that 5 mg/kg of vitamin E, administered intra-arterially as an 8-hour continuous infusion, significantly and predictably raises serum vitamin E levels into the supraphysiologic range with no apparent side effects. In a group of premature infants whose initial serum vitamin E levels were generally greater than or equal to 0.5 mg/dL, no decrease in bilirubin production was observed. Thus, vitamin E deficiency probably does not play a prominent role in jaundice of prematurity.

  View details for Web of Science ID A1989CV07100032

  View details for PubMedID 2629604

• The education of scientific physicians. Journal of perinatology Stevenson, D. K. 1989; 9 (4): 442-443

  View details for PubMedID 2593019

• NIFEDIPINE PHARMACOKINETICS DURING PRETERM LABOR TOCOLYSIS AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Ferguson, J. E., Schutz, T., PERSHE, R., Stevenson, D. K., Blaschke, T. 1989; 161 (6): 1485-1490

  Abstract

  Nifedipine, a calcium entry blocker, has known relaxing effects on the myometrium. Thirteen women in preterm labor received nifedipine for tocolysis. Blood samples obtained serially during treatment and at the time of delivery were assayed for maternal and neonatal nifedipine concentrations. The peak concentration of nifedipine during sublingual therapy ranged from 23.4 to 197.9 ng/ml and reflected substantial interpatient variability. The mean (+/- SD) measurable trough value in patients who received 20 mg of nifedipine orally every 6 hours was 7.2 +/- 5.5 ng/ml. The maternal mean half-life of nifedipine was 81 minutes (range 49 to 137 minutes). At delivery, neonatal nifedipine levels were nondetectable in 6 of the 11 neonates available for study; in 5, values ranged from 29.5 to 1.8 ng/ml. From these results we conclude that both sublingual and oral nifedipine treatment results in variable but usually measurable maternal plasma concentrations and that placental transfer of nifedipine occurs.

  View details for Web of Science ID A1989CG73300010

  View details for PubMedID 2603904

• THE EFFECT OF ABORTION ON THE INCIDENCE OF PRE-ECLAMPSIA EUROPEAN JOURNAL OF OBSTETRICS GYNECOLOGY AND REPRODUCTIVE BIOLOGY Seidman, D. S., EVERHADANI, P., Stevenson, D. K., Gale, R. 1989; 33 (2): 109-114

  Abstract

  The incidence of pre-eclampsia was studied in 9771 women that were pregnant for the first or second time. The protection offered by a previous pregnancy which ended in abortion was compared to that provided by a first pregnancy that proceeded to term. The rate of pre-eclampsia was 2.9% for primigravid women and was significantly lower (1.5%, p less than 0.001) for women giving birth for the second time. Adjusting by multiple regression for confounding factors (e.g., maternal age, social class, ethnic origin and smoking), the incidence of pre-eclampsia was also significantly lower (p = 0.038) following an induced abortion, but not following a spontaneous abortion.

  View details for Web of Science ID A1989CA69700002

  View details for PubMedID 2583336

• BREATH HYDROGEN IN PRETERM INFANTS AMERICAN JOURNAL OF DISEASES OF CHILDREN STEVENSON, D. K. 1989; 143 (11): 1262–63

  View details for DOI 10.1001/archpedi.1989.02150230020012

  View details for Web of Science ID A1989AX98900012

  View details for PubMedID 2624654

• INVITRO INHIBITION OF ADULT-RAT INTESTINAL HEME OXYGENASE BY METALLOPORPHYRINS PEDIATRIC RESEARCH Vreman, H. J., GILLMAN, M. J., Stevenson, D. K. 1989; 26 (4): 362-365

  Abstract

  We determined the inhibitory effects of concentrations of tin- and zinc protoporphyrin (1-100 microM) and mesoporphyrin (0.1-10 microM) on the in vitro heme oxygenase (HO) (E.C.1.14.99.3) activity in liver, spleen, and intestine 13,000 x g tissue supernatants from fasted adult male Wistar rats through measurement of carbon monoxide by gas chromatography. All four metalloporphyrins inhibited intestinal HO, under the light-limited conditions of these experiments. The zinc porphyrins showed a clear concentration dependency over the entire range, reducing activity to near zero levels at their highest concentrations. The tin porphyrins reduced HO activity to 26% of initial levels, but the inhibition was not clearly concentration dependent. Liver and spleen supernatants exhibited concentration dependent inhibition by all four metalloporphyrins. We also assessed the effect of light on HO activity measurements. HO determinations in the light (8 microW/cm2/nm) yielded higher HO activity than for reactions performed in the dark. The presence of light and SnPP appeared to stimulate the HO activity of intestinal preparations thus overcoming the observed inhibition. Light and SnPP also decreased to a lesser degree the inhibition for the spleen preparation, but not for the liver. We conclude that heme oxygenase activity measurements via CO determination need to be conducted in the absence of light, in particular when photosensitizers are present. Furthermore, it appears that intestinal HO behaves in a quantitatively different way from other tissues, under varying conditions of metalloporphyrin inhibition and light exposure.

  View details for Web of Science ID A1989AR78400015

  View details for PubMedID 2797950

• BREAST-FEEDING OF TERM INFANTS - 3-HOUR VS 4-HOUR NON-DEMAND - A RANDOMIZED CONTROLLED REAPPRAISAL OF HOSPITAL-BASED FEEDING SCHEDULES CLINICAL PEDIATRICS Gale, R., Dollberg, S., BRANSKI, D., Stevenson, D. K., Seidman, D. S. 1989; 28 (10): 458-460

  Abstract

  On those maternity wards where "rooming in" is not practiced, infants are fed according to fixed schedules. The purpose of this study was to investigate possible differences between two common feeding regimens, three-hourly vs. four-hourly feeds during the first 3 days of life. A group of 152 singleton, full-term infants with birth weights 2,500-2,990 g, born at Bikur Cholim Hospital in Jerusalem from February 1988, to August 1988, were randomly assigned to one of two breast-feeding groups and followed prospectively. The study group (62 infants) was breast-fed every 4 hours, and the control group (90 infants) every 3 hours. The two groups were statistically similar for mean maternal age, parity, ethnic origin, social class, neonatal Apgar scores, birth percentile, and mean birth weights. Infants who breast-fed every 4 hours did not have greater transitional weight loss or higher serum bilirubin levels compared to infants fed at 3 hour intervals.

  View details for Web of Science ID A1989AV10200005

  View details for PubMedID 2676312

• CARDIOVASCULAR AND METABOLIC EFFECTS ASSOCIATED WITH NIFEDIPINE AND RITODRINE TOCOLYSIS AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Ferguson, J. E., Dyson, D. C., Holbrook, R. H., Schutz, T., Stevenson, D. K. 1989; 161 (3): 788-795

  Abstract

  Recent investigations have indicated that nifedipine, a calcium channel entry blocker, may be useful in the treatment of preterm labor. This prospective, randomized study compares cardiovascular and metabolic effects measured in association with sublingual and oral administration of nifedipine with those noted with the intravenous and oral administration of the beta-adrenergic agent ritodrine. Serial measurements of cardiovascular parameters, hematocrit, electrolytes, glucose, blood urea nitrogen, creatinine, calcium, and serum glutamic-oxaloacetic and glutamic-pyruvic transaminase were compared between groups. Sublingual and oral nifedipine caused minimal cardiovascular alterations. At doses sufficient to achieve tocolysis, ritodrine caused more pronounced cardiovascular changes than nifedipine. Both agents had a hemodilutional effect, but nifedipine was not associated with alterations in serum electrolytes or a dramatic hyperglycemia. On the basis of this study, it appears that the use of nifedipine for preterm labor management is associated with hemodilutional changes but not the adverse cardiovascular or metabolic effects often associated with ritodrine tocolysis.

  View details for Web of Science ID A1989AR60600059

  View details for PubMedID 2782362

• IS TEENAGE PREGNANCY A NEONATAL RISK FACTOR JOURNAL OF ADOLESCENT HEALTH GALE, R., SEIDMAN, D. S., DOLLBERG, S., ARMON, Y., STEVENSON, D. K. 1989; 10 (5): 404–8

  Abstract

  Maternal characteristics and neonatal outcome of 421 primiparas aged 15-19 years who delivered at Bikur Cholim Hospital in Jerusalem were examined. The study group included 190 teenage mothers from the Mea Shearim community who marry young and who receive extensive social and economic support. The control group included 231 teenage mothers from other areas of Jerusalem, characterized by a predominantly low social class, Oriental ethnic origin, and a high rate of out-of-wedlock births (28.6%). The Mea Shearim mothers had a significantly lower incidence of low birth weight (less than 2500 g) infants compared to the control group (6.3% vs. 14.7%, p less than 0.01). The differences could not be explained by maternal age distribution, ethnicity, smoking, or marital status. These results suggest that in a community that provides extensive social and economic support and good access to free prenatal care of high standard, teenage pregnancy is not a neonatal risk factor.

  View details for DOI 10.1016/0197-0070(89)90219-2

  View details for Web of Science ID A1989AP08300009

  View details for PubMedID 2808085

• VANCOMYCIN PHARMACOKINETICS IN VERY LOW BIRTH-WEIGHT NEONATES PEDIATRIC INFECTIOUS DISEASE JOURNAL Leonard, M. B., Koren, G., Stevenson, D. K., Prober, C. G. 1989; 8 (5): 282-286

  Abstract

  The pharmacokinetics of vancomycin hydrochloride was studied in 12 very low birth weight infants. The gestational age (mean +/- SD) was 25.9 +/- 1.3 weeks and body weight was 769.2 +/- 151.5 g at the time of initiation of the study. Vancomycin was infused over a period of 60 minutes in a dosage of 14.2 +/- 3.2 mg/kg once daily in 10 patients, twice daily in 1 patient and every 36 hours in 1 patient for a mean of 10.5 +/- 4.9 days. Serial blood samples were obtained and the concentration time data were fitted to a one-compartment open model using the ADAPT computer program. A significant positive correlation was found between postconceptional age and vancomycin clearance (P less than 0.005) and between vancomycin elimination half-life and plasma creatinine (P less than 0.01). A negative correlation existed between plasma creatinine and vancomycin clearance (P less than 0.005), between postconceptional age and plasma creatinine (P less than 0.005) and between vancomycin half-life and postconceptional age (P less than 0.01). On the basis of these findings a vancomycin dosage of 15 mg/kg every 24 hours for infants less than 1000 g should yield concentrations within the accepted therapeutic range. This susceptible population requires frequent monitoring of vancomycin concentrations because of the high degree of interpatient variability and the continuous maturation of renal function.

  View details for Web of Science ID A1989U613900006

  View details for PubMedID 2657617

• STABLE INDIVIDUAL-DIFFERENCES IN DEVELOPMENTALLY CHANGING PRETERM INFANTS - A REPLICATED STUDY CHILD DEVELOPMENT Korner, A. F., Brown, B. W., DiMiceli, S., Forrest, T., Stevenson, D. K., Lane, N. M., Constantinou, J., Thom, V. A. 1989; 60 (2): 502-513

  Abstract

  In a longitudinal study with the Neurobehavioral Maturity Assessment (NB-MAP), developmental changes and stability of individual differences were assessed in 2 independent samples of preterm infants ranging from 32 weeks conceptional age to term. Individual stability of response was assessed using regression analysis with repeated measures on subjects. The large majority of the functions tested showed highly significant developmental gains with age and highly significant individual stability of performance across age. These findings replicated well across the 2 cohorts. The results are discussed in the light of the neurobiological stage of development of preterm infants during the last 8 weeks prior to term.

  View details for Web of Science ID A1989T356100020

  View details for PubMedID 2924664

• MORTALITY AFTER LIGHT EXPOSURE IN METALLOPORPHYRIN-TREATED NEONATAL RATS HINTZ, VREMAN, H. J., STEVENSON, D. K. WILLIAMS & WILKINS. 1989: A218

  View details for Web of Science ID A1989T947101293

• IS TEENAGE PREGNANCY A NEONATAL RISK FACTOR GALE, R., SEIDMAN, D. S., DOLLBERG, S., ARMON, Y., STEVENSON, D. K. WILLIAMS & WILKINS. 1989: A5

  View details for Web of Science ID A1989T947100017

• EPIDEMIOLOGY OF NEONATAL JAUNDICE IN THE JERUSALEM POPULATION GALE, R., SEIDMAN, D. S., DOLLBERG, S., STEVENSON, D. K. WILLIAMS & WILKINS. 1989: A99

  View details for Web of Science ID A1989T947100582

• HEME OXYGENASE ACTIVITY AS MEASURED BY CO PRODUCTION - EFFECTS OF METALLOPORPHYRINS AND LIGHT VREMAN, H. J., GILLMAN, M. J., STEVENSON, D. K. WILLIAMS & WILKINS. 1989: A73

  View details for Web of Science ID A1989T947100422

• MAGNETIC-RESONANCE STUDIES OF BILIRUBIN ENCEPHALOPATHY RHINE, W. D., GONZALEZMENDEZ, R. R., SAYRE, ENZMANN, D. R., STEVENSON, D. K. WILLIAMS & WILKINS. 1989: A228

  View details for Web of Science ID A1989T947101354

• ACUTE TUBULAR-NECROSIS ASSESSED BY MAGNETIC-RESONANCE SCHUTZ, T. E., GONZALEZMENDEZ, R., NABSETH, D. C., TUNE, B., STEVENSON, D. K. WILLIAMS & WILKINS. 1989: A348

  View details for Web of Science ID A1989T947102067

• THE USE OF METALLOPORPHYRINS FOR THE CHEMOPREVENTION OF NEONATAL JAUNDICE AMERICAN JOURNAL OF DISEASES OF CHILDREN Stevenson, D. K., Rodgers, P. A., Vreman, H. J. 1989; 143 (3): 353-356

  Abstract

  Decreasing bilirubin formation is an important strategy for the prevention of neonatal jaundice. The stannic porphyrins, in particular tin protoporphyrin and tin mesoporphyrin, have been proposed for this purpose because these compounds competitively inhibit heme oxygenase, the rate-limiting enzyme in the heme-degrading pathway. However, these compounds are not only potent inhibitors of heme oxygenase but are also photosensitizers, which can generate cytotoxic oxygen species, such as singlet oxygen. Therapeutic regimens designed to avoid the phototoxicity caused by these and other metalloporphyrins have been suggested. An alternative approach would be the development of derivatives of tin protoporphyrin or other heme analogs that are less phototoxic and are stronger inhibitors of heme oxygenase. However, our understanding of the molecular basis of heme oxygenase inhibition is still limited. The response of heme oxygenase to specific inhibitors varies a great deal and depends on the organ and stage of development. This may be a result of the differing proportions of heme oxygenase isoenzymes in different organs. These questions and others need to be systematically answered so we may better understand and treat disturbances in heme homeostasis. In addition, administration of these compounds may have other metabolic consequences directly and indirectly related to their potent, long-lasting inhibition of heme oxygenase. The significance of such effects, whether transient or permanent, needs to be elucidated.

  View details for Web of Science ID A1989T561300024

  View details for PubMedID 2644817

• THE REAL CHALLENGE OF BABY DOE - CONSIDERING THE SANCTITY AND QUALITY OF LIFE CLINICAL PEDIATRICS Stevenson, D. K. 1989; 28 (3): 119-122

  View details for Web of Science ID A1989T798500002

  View details for PubMedID 2920487

• INTERPRETING THE CARBOXYHEMOGLOBIN CONCENTRATION IN FETAL CORD BLOOD JOURNAL OF DEVELOPMENTAL PHYSIOLOGY Leonard, M. B., Vreman, H. J., Ferguson, J. E., Smith, D. W., Stevenson, D. K. 1989; 11 (2): 73-76

  Abstract

  We calculated the fetal-to-maternal carboxyhaemoglobin concentration ratio in 19 mother-infant pairs at the time of term delivery. Mothers, who had a less than 10% drop in their carboxyhaemoglobin concentration during labour, had an average ratio of 1.40 +/- 0.19. For mothers whose carboxyhaemoglobin concentrations dropped by 10% or more during labour, the average fetal-to-maternal carboxyhaemoglobin concentration ratio was 1.83 +/- 0.48. There was a strong correlation (r = 0.82) between the percent change in maternal carboxyhaemoglobin concentration during labour and the fetal-to-maternal carboxyhaemoglobin concentration ratio at the time of delivery. We conclude that increased CO elimination during labour may be accompanied by rapid changes in the maternal carboxyhaemoglobin concentration, leading to a spuriously high fetal-to-maternal carboxyhemoglobin concentration ratio at the time of delivery.

  View details for Web of Science ID A1989AJ93800003

  View details for PubMedID 2778293

• NEONATAL-PERINATAL MEDICINE - A MODEL SUBSPECIALTY WESTERN JOURNAL OF MEDICINE STEVENSON, D. K. 1989; 150 (2): 213–14

  View details for Web of Science ID A1989T582300030

  View details for PubMedID 2728447

  View details for PubMedCentralID PMC1026356

• A CONCURRENT EPIDEMIC OF RESPIRATORY SYNCYTIAL VIRUS AND ECHOVIRUS-7 INFECTIONS IN AN INTENSIVE-CARE NURSERY PEDIATRIC INFECTIOUS DISEASE JOURNAL Wilson, C. W., Stevenson, D. K., Arvin, A. M. 1989; 8 (1): 24-29

  Abstract

  We describe concurrent outbreaks of respiratory syncytial virus (RSV) and Echovirus 7 (Echo 7) infections in a neonatal intensive care unit, including infants who had dual infections. Seventy-three infants were identified as having RSV from January through June, 1984. During the same surveillance period Echo 7 was cultured from 20 infants, and 6 infants had concurrent RSV and Echo 7 and RSV were isolated, but not concurrently. This dual outbreak of RSV and Echo 7 infections persisted for months despite infection control measures. Control procedures were complicated by: (1) cases of RSV infection at less than 72 hours of age, which had not previously been reported and which led to the reintroduction of RSV into "clean" areas; (2) the lack of a rapid diagnostic test for enterovirus infection; (3) the number of infants who were asymptomatic with each infection; and (4) the logistical problems of handling a dual pathogen outbreak in a confined setting. These problems were compounded by the many risk factors associated with nosocomial infections found in neonatal intensive care settings such as prolonged hospitalizations, endotracheal or nasogastric tubes and contact with many ancillary care personnel.

  View details for Web of Science ID A1989R833000007

  View details for PubMedID 2922234

• IS TEENAGE PREGNANCY A NEONATAL RISK FACTOR GALE, R., SEIDMAN, D. S., DOLLBERG, S., ARMON, Y., STEVENSON, D. K. SLACK INC. 1989: A167

  View details for Web of Science ID A1989R585100977

• INVITRO INHIBITION OF INTESTINAL HEME OXYGENASE ACTIVITY BY ZINC PROTOPORPHYRIN (ZNPP) GILLMAN, M. J., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1989: A182

  View details for Web of Science ID A1989R585101062

• ZINC PROTOPORPHYRIN INHIBITS INVIVO LIVER AND SPLEEN HEME OXYGENASE ACTIVITY IN THE NEONATAL RAT CARLTON, R. R., HAMORI, C. J., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1989: A201

  View details for Web of Science ID A1989R585101177

• MAGNETIC-RESONANCE STUDIES OF BILIRUBIN ENCEPHALOPATHY RHINE, W. D., GONZALEZMENDEZ, R. R., SAYRE, ENZMANN, D. R., STEVENSON, D. K. SLACK INC. 1989: A207

  View details for Web of Science ID A1989R585101216

• ZINC PROTOPORPHYRIN INHIBITION OF TISSUE HEME OXYGENASE ACTIVITY IN RHESUS NEONATES RODGERS, P. A., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1989: A208

  View details for Web of Science ID A1989R585101218

• CARBON-MONOXIDE EXCRETION AS AN INDEX OF BILIRUBIN PRODUCTION IN RHESUS-MONKEYS JOURNAL OF MEDICAL PRIMATOLOGY Vreman, H. J., Rodgers, P. A., Gale, R., Stevenson, D. K. 1989; 18 (6): 449-460

  Abstract

  The role of increased heme catabolism in neonatal hyperbilirubinemia was investigated in rhesus (Macaca mulatta) neonates through the measurement of carbon monoxide excretion rates (VECO), blood carboxyhemoglobin content (HbCO), and plasma bilirubin concentrations. Neonatal values were compared to those of adult rhesus monkeys. These indices of bilirubin production responded appropriately to administration of NEM-damaged erythrocytes and tin protoporphyrin. Our results indicate that VECO measurements are a valid index of changes in bilirubin production in the newborn rhesus monkey.

  View details for Web of Science ID A1989CG06100003

  View details for PubMedID 2614809

• ZINC PROTOPORPHYRIN INHIBITS CO PRODUCTION IN RATS JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION HAMORI, C. J., Vreman, H. J., Rodgers, P. A., Stevenson, D. K. 1989; 8 (1): 110-115

  Abstract

  We studied the effect of zinc protoporphyrin (ZnPP) on in vivo total bilirubin production, as measured by the excretion rate of carbon monoxide (VeCO), in adult rats. A single subcutaneous dose of ZnPP (40 mumol/kg) suppressed the VeCO between 2-12 h posttreatment, with maximum suppression of approximately 20% by 4 h. The heme oxygenase activity in the liver and spleen of the ZnPP-treated rats was significantly inhibited at 12 h compared with that of the controls. The in vitro inhibition of heme oxygenase activity by the addition of exogenous ZnPP to native rat liver and spleen tissue preparations was observed, as evidenced by suppressed CO production. This in vitro inhibition of heme oxygenase activity by ZnPP was further confirmed by finding decreased bilirubin formation, as measured directly by high-performance liquid chromatography. This study demonstrates that ZnPP can inhibit in vivo liver and spleen heme oxygenase activity and suppress CO production in the rat, as well as inhibit in vitro heme oxygenase activity in native rat tissues.

  View details for Web of Science ID A1989T010800020

  View details for PubMedID 2732855

• NEONATAL BILIRUBIN PRODUCTION AFTER PRETERM LABOR TOCOLYSIS WITH NIFEDIPINE DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS Ferguson, J. E., SCHUTZ, T. E., Stevenson, D. K. 1989; 12 (3): 113-117

  Abstract

  We studied the in vivo total bilirubin production, as indexed by the carboxyhemoglobin level (HbCO), of infants whose mothers had ritodrine (RIT) tocolysis or underwent tocolysis with the calcium channel blocker, nifedipine (NIF). No difference in HbCO between the infant groups was detected: NIF 0.67 +/- 0.31% saturation and RIT 0.88 +/- 0.47% saturation. We conclude that NIF is unlikely to cause a clinically important increase in total bilirubin production when used at doses sufficient for tocolysis.

  View details for Web of Science ID A1989U271600001

  View details for PubMedID 2721333

• CARBOXYHEMOGLOBIN AS MEASURED BY GAS-CHROMATOGRAPHY AND WITH THE IL-282 AND IL-482 CO-OXIMETERS CLINICAL CHEMISTRY Vreman, H. J., Mahoney, J. J., VanKessel, A. L., Stevenson, D. K. 1988; 34 (12): 2562-2566

  Abstract

  We measured the concentration of carboxyhemoglobin (HbCO) in original and CO-tonometered blood samples from 53 intensive-care patients with IL 282 and IL 482 CO-Oximeters and by gas chromatography (GC), finding very strong correlations among the three methods for HbCO concentrations greater than 2.5%. For concentrations within the normal reference interval (less than or equal to 2.5%), however, the correlation between CO-Oximetry and GC is poor (r2 less than 0.26). The capillary mode of the IL 482 has a consistently lower correlation with any other method or mode. The correlations of measurements between the CO-Oximeters for total hemoglobin and oxyhemoglobin were excellent (r2 greater than or equal to 0.98). Correlations for methemoglobin were lower, owing to its low concentrations in the samples. We conclude that the IL 482 and the IL 282 are analytically equivalent for all analytes measured, but that both instruments differentiate poorly between HbCO values that fall within the reference interval.

  View details for Web of Science ID A1988R284000043

  View details for PubMedID 3197302

• OXYTOCIN-INDUCED LABOR CHARACTERISTICS AND UTERINE ACTIVITY AFTER PREINDUCTION CERVICAL PRIMING WITH PROSTAGLANDIN-E2 INTRACERVICAL GEL OBSTETRICS AND GYNECOLOGY Ferguson, J. E., Ueland, F. R., Stevenson, D. K., UELAND, K. 1988; 72 (5): 739-745

  Abstract

  Labor characteristics and quantitation of uterine activity resulting from oxytocin induction of labor after intracervical prostaglandin E2 (PGE2) gel priming have not been previously reported. Forty-seven women with modified Bishop scores of 5 or less received preinduction priming with 0.5 mg of intracervical PGE2 gel. Oxytocin was used to induce labor after priming, and uterine activity was quantitated. A matched group of control patients was managed identically but did not receive PGE2 gel. In the gel group, modified Bishop scores improved significantly and in two patients (4%), priming alone induced labor. No uterine hyperstimulation or fetal heart rate abnormalities occurred during priming. Cesarean sections for all indications and those for failed induction were less common in the gel group. The length of the active phase and the second stage of labor were significantly shorter in the gel group. Uterine activity was similar in both groups. The data suggest a primary cervical action of the gel.

  View details for Web of Science ID A1988Q648700012

  View details for PubMedID 3173925

• EFFECTS OF ORAL-ADMINISTRATION OF TIN AND ZINC PROTOPORPHYRIN ON NEONATAL AND ADULT-RAT TISSUE HEME OXYGENASE ACTIVITY JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Vreman, H. J., Hintz, S. R., Kim, C. B., Castillo, R. O., Stevenson, D. K. 1988; 7 (6): 902-906

  Abstract

  The purpose of this study was to investigate if oral metalloporphyrin treatment could suppress intestinal heme oxygenase (HO) activity and thus prevent HO-mediated heme degradation in this organ. Six hours after a single 40 mumol/kg oral dose of tin protoporphyrin (TP), zinc protoporphyrin (ZP), or heme to adult rats, no significant difference in the HO activity of the intestine was observed relative to control tissues. Moreover, the activity was not inhibited by in vitro exposure to 40 microM TP or ZP. Liver and spleen HO activity was also not significantly inhibited in vivo after oral administration of metalloporphyrins; however, in vitro exposure to TP or ZP decreased the HO activity of preparations from these organs significantly. Like adults, the intestinal HO activity of neonates was not inhibited effectively by oral administration of either metalloporphyrin. The results of subsequent in vitro exposure of control neonatal tissue preparations to ZP or TP was similar to those using adult tissue preparations. Even at 100 microM, only ZP seemed to have some in vitro inhibitory effect on the intestinal HO of suckling rats. We conclude that intestinal HO is less inhibitable by TP or ZP reaching the intestine via the stomach in concentrations at least 30-fold greater than those achieved after parenteral 40 mumol/kg doses, which cause significant hepatic and splenic HO inhibition. Intestinal absorption and enterohepatic circulation of heme, TP, and ZP do not seem to occur in amounts sufficient to consistently and significantly affect HO activity in liver or spleen.

  View details for Web of Science ID A1988Q638900019

  View details for PubMedID 3199276

• SUPPRESSION OF CARBON-MONOXIDE EXCRETION BY ZINC MESOPORPHYRIN IN ADULT WISTAR RATS - EVIDENCE FOR POTENT INVIVO INHIBITION OF BILIRUBIN PRODUCTION RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY HAMORI, C. J., Vreman, H. J., Stevenson, D. K. 1988; 62 (1): 41-48

  Abstract

  We studied the effect of zinc mesoporphyrin on the CO excretion rate (VeCO) and liver heme oxygenase activity of adult rats. A subcutaneous dose of 4 mumol/kg significantly lowered the VeCO between 4 and 12 hours after injection. The liver heme oxygenase activity of treated animals was significantly lower 12 hours after treatment. These findings demonstrate that zinc mesoporphyrin is a potent inhibitor of in vivo total bilirubin production, as measured by the VeCO.

  View details for Web of Science ID A1988Q715300004

  View details for PubMedID 3205979

• PLASMA PRORENIN AND RENIN IN CHILDHOOD AND ADOLESCENCE AMERICAN JOURNAL OF DISEASES OF CHILDREN Wilson, D. M., Stevenson, D. K., LUETSCHER, J. A. 1988; 142 (10): 1070-1072

  Abstract

  We studied 108 subjects (age range, 4 to 76 years) to determine the effect of age on prorenin (inactive renin), active renin, and plasma renin activity in normal children, adolescents, and adults. Children and adolescents had lower prorenin concentrations and higher plasma renin activity and active renin concentrations than did adults. Prorenin concentrations were positively correlated with age over the range of 4 to 76 years, while plasma renin activity and active renin concentration were negatively correlated with age. Plasma prorenin and active renin concentrations from umbilical cord blood samples obtained from 11 newborns and arterial samples obtained from five infants were higher than those in samples obtained from children or adults.

  View details for PubMedID 3052031

• END-STAGE PERIVENTRICULAR LEUKOMALACIA - MR EVALUATION RADIOLOGY Baker, L. L., Stevenson, D. K., Enzmann, D. R. 1988; 168 (3): 809-815

  Abstract

  A prospective study was performed to assess the capabilities of magnetic resonance (MR) imaging in evaluation of end-stage periventricular leukomalacia (PVL) in six children, aged 31-54 months, in whom PVL had been documented by neurologic ultrasonography during the neonatal period. Eight children of similar age (four premature infants and four full-term infants) with normal neurologic development served as controls. A characteristic triad of PVL abnormalities was seen on MR images: (a) abnormally increased periventricular white-matter signal intensity on the first and second echo images of a T2-weighted sequence (repetition time = 2,000-2,400 msec, echo times = 20 or 30 and 80 msec), most commonly observed in the trigone regions of the lateral ventricles bilaterally; (b) marked loss of periventricular white matter in these regions of abnormal signal intensity, predominantly in the periatrial regions; and (c) compensatory focal ventricular enlargement adjacent to regions of abnormal signal intensity. In patients with the classic periatrial distribution of PVL lesions, general correlation between the degree of neurologic impairment and the severity of MR abnormalities was demonstrated. MR imaging was useful in detecting subtle forms of PVL in cases in which neurologic damage was subclinical.

  View details for Web of Science ID A1988P738600041

  View details for PubMedID 3406411

• CHILDBEARING AFTER INDUCED-ABORTION - REASSESSMENT OF RISK JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH Seidman, D. S., EVERHADANI, P., Slater, P. E., Harlap, S., Stevenson, D. K., Gale, R. 1988; 42 (3): 294-298

  Abstract

  We reviewed 1791 singleton pregnancies of women with a history of previous induced abortion and compared them with 14,857 pregnancies in mothers with no previous induced abortions. Therapeutic termination of pregnancy was associated with a statistically significant increase in the incidence of low birth weight infants and bleeding in the first trimester of pregnancy. When other variables were examined, no significant differences were found between the two groups, except for a significantly higher rate of stillbirths among women who had not had a prior induced abortion. There were no increases in major or minor congenital malformations.

  View details for Web of Science ID A1988P899300016

  View details for PubMedID 3251012

  View details for PubMedCentralID PMC1052742

• BIRTH-ORDER AND BIRTH-WEIGHT REEXAMINED OBSTETRICS AND GYNECOLOGY Seidman, D. S., EVERHADANI, P., Stevenson, D. K., Slater, P. E., Harlap, S., Gale, R. 1988; 72 (2): 158-162

  Abstract

  We studied the longitudinal association of birth order and birth weight in two series of very large sibships, each consisting of at least seven children, and compared the findings with those based on analysis of cross-sectional data from a large population-based survey, the Jerusalem Perinatal Study. The birth weights of the cross-sectional sample were adjusted by multiple linear regression for a number of factors known to confound cross-sectional studies, including maternal age, education, marital status, religion, smoking, height and prepregnant weight, gestational age, and sex of the newborn. Birth weight increased with increasing birth order in both adjusted cross-sectional and socioeconomically homogeneous longitudinal data.

  View details for Web of Science ID A1988P381400003

  View details for PubMedID 3260664

• RELATIONSHIP BETWEEN BREATH AND TOTAL-BODY HYDROGEN EXCRETION RATES IN NEONATES JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Modler, S., Kerner, J. A., Castillo, R. O., Vreman, H. J., Stevenson, D. K. 1988; 7 (4): 554-558

  Abstract

  Our study examined the relationship of H2 excreted in breath to total body H2 excreted by neonates. We report simultaneously measured end-tidal H2 concentrations, plus breath H2 and total body H2 (breath H2 plus flatus H2) excretion rates in 10 neonates. End-tidal H2 concentrations varied from 2.4 to 192 ppm. Breath H2 excretion rates ranged from 0.20 to 6.5 and total body H2 excretion rates from 0.29 to 15.0 ml/h. The fractional breath H2 excretion in these infants was 48% (range 33-69%), compared with 21% reported in adults. The correlation coefficient for end-tidal derived H2 excretion and directly measured breath H2 excretion rates was 0.95 (p less than 0.001). We conclude that the proportion of total H2 excreted in the breath of neonates is increased compared with adults, suggesting that caution must be exercised when interpreting newborn breath H2 measurements and using adult norms.

  View details for Web of Science ID A1988N975500013

  View details for PubMedID 3397846

• BIRTH OUT OF WEDLOCK AND THE RISK OF INTRAUTERINE GROWTH-RETARDATION AMERICAN JOURNAL OF PERINATOLOGY Gale, R., ZENGEN, S., Harlap, S., Fischer, A. F., Stevenson, D. K. 1988; 5 (3): 278-282

  Abstract

  Birth out of wedlock has been associated with maternal and neonatal problems, especially low birthweight, attributed mainly to the young maternal age of the unmarried mothers. We surveyed a cohort of 300 first-born infants delivered in Israel to unwed mothers, matched for parity, maternal age, and ethnic origin. No maternal complications were found among the unwed mothers. However, the incidence of intrauterine growth retardation among infants of the out of wedlock mothers was 53 of 293, compared with 20 of 297 among the control population (p less than 0.001). This difference in the incidence of intrauterine growth retardation may not be associated with young maternal age.

  View details for Web of Science ID A1988P033700020

  View details for PubMedID 3382487

• EFFECT OF BUPIVACAINE HYDROCHLORIDE ON BILIRUBIN PRODUCTION IN NEONATAL RATS BIOLOGY OF THE NEONATE Gale, R., Vreman, H. J., Ferguson, J. E., Stevenson, D. K. 1988; 54 (1): 45-48

  Abstract

  The rate of bilirubin production was studied in 12-hour-old rats exposed to bupivacaine HCl by subcutaneous injection. The bilirubin production was estimated by measuring the excretion rate of carbon monoxide (VeCO) using an open flow-through system. No significant difference was found between the VeCO of bupivacaine HCl-treated and control animals, or between the levels of bilirubin in the pooled blood of treated (0.92 +/- 0.32 SE mg/dl) and control (1.0 +/- 0.28 SE mg/dl) animals. These negative findings support the clinical studies which have not demonstrated an association between epidural anesthesia with bupivacaine HCl and neonatal jaundice.

  View details for Web of Science ID A1988P486300005

  View details for PubMedID 3207780

• CORRELATION OF CARBON-MONOXIDE AND BILIRUBIN PRODUCTION BY TISSUE-HOMOGENATES JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS Vreman, H. J., Stevenson, D. K., HENTON, D., Rosenthal, P. 1988; 427 (2): 315-319

  View details for Web of Science ID A1988N905000013

  View details for PubMedID 3410913

• SN-PROTOPORPHYRIN - A CONSIDERATION OF THE 1ST CLINICAL-TRIAL IN HUMAN NEONATES PEDIATRICS Stevenson, D. K., Vreman, H. J. 1988; 81 (6): 881-882

  View details for Web of Science ID A1988N642600026

  View details for PubMedID 3285317

• INVITRO CARBON-MONOXIDE PRODUCTION BY THE SMALL-INTESTINE OF SUCKLING AND ADULT WISTAR RATS - EFFECT OF PARENTERAL TIN-PROTOPORPHYRIN DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS Kim, C. B., Hintz, S. R., Vreman, H. J., Stevenson, D. K. 1988; 11 (3): 166-172

  Abstract

  Single subcutaneous doses (25 mumol/kg body weight) of tin-protoporphyrin (TP), a potent competitive inhibitor or heme oxygenase (HO), were administered to both suckling and adult Wistar rats. The effect of TP on the carbon monoxide excretion rate (VeCO), an index of total bilirubin formation, and on in vitro carbon monoxide (CO) production by the small intestine were evaluated. Whereas the VeCO of the adult group was decreased (p less than 0.0005) after TP, that of the suckling rat was unchanged. Gradients of CO production along the small intestine were observed in sucklings as well as adults; however, these gradients were in opposite directions. Intestinal CO production was greatest in the adult duodenum, decreasing distally; conversely, the CO production was greatest in the suckling ileum, decreasing proximally. No significant difference in CO production between control and TP-treated adult intestinal mucosa was observed. In sucklings, a significant reduction of intestinal CO production in the TP-treated rats was detected in the duodenum only (p less than 0.05). The results suggest that suckling rats differ from adults in terms of the capacity to produce CO and the direction of the gradient of CO production along the intestine. We conclude that (1) TP may not substantially decrease the in vivo production of CO by the small intestine at a dose which inhibits hepatic and splenic heme oxygenase, and (2) because after a heme load, heme is excreted into the intestine after TP administration, heme-degrading, CO-producing processes in the intestine may contribute to an animal's VeCO under such conditions.

  View details for Web of Science ID A1988N081100006

  View details for PubMedID 3383729

• EFFECTS OF NUTRITIONAL SUPPLEMENTS ON ANTI-INFECTIVE FACTORS IN HUMAN-MILK (HM) KERNER, J. A., YANG, C. C., STEVENSON, D. K. W B SAUNDERS CO. 1988: A223

  View details for Web of Science ID A1988M939400885

• HOW TO BECOME A PRACTICAL PHYSICIAN CLINICAL PEDIATRICS STEVENSON, D. K., BENITZ, W. E. 1988; 27 (5): 260–61

  View details for DOI 10.1177/000992288802700512

  View details for Web of Science ID A1988N468000012

  View details for PubMedID 3365909

• GRAND MULTIPARITY - AN OBSTETRIC OR NEONATAL RISK FACTOR AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Seidman, D. S., Armon, Y., Roll, D., Stevenson, D. K., Gale, R. 1988; 158 (5): 1034-1039

  Abstract

  Grand multiparity has been considered to be a factor in maternal and neonatal morbidity. In addition, families with seven or more children have been associated with low socioeconomic status. To minimize the confounding effect of the socioeconomic status, the outcome of grand multiparity has been investigated in a mostly homogeneous, ultraorthodox Jewish community in Jerusalem, Israel. A total of 5916 deliveries in one community hospital (Bikur Cholim) were studied, of which 893 (13%) occurred in mothers who had given birth to seven or more infants. There was a significant decrease in the incidence of small for gestational age infants among the grand multiparous women (3.6% as opposed to 5.8% in the control population). This difference was independent of maternal age. Moreover, grand multiparous women gave birth to significantly more large for gestational age infants. No increase in obstetric complications or neonatal morbidity and mortality was found among the offspring of the grand multiparous mothers. Having taken socioeconomic status into account, we conclude that grand multiparity does not carry an increased risk of perinatal morbidity or mortality.

  View details for Web of Science ID A1988N458400004

  View details for PubMedID 3369480

• NEPHROLITHIASIS FOLLOWING INUTERO DIURETIC EXPOSURE - AN UNUSUAL CASE PEDIATRICS Fischer, A. F., Parker, B. R., Stevenson, D. K. 1988; 81 (5): 712-714

  View details for Web of Science ID A1988N207600021

  View details for PubMedID 3282218

• INTERFERENCE OF FETAL HEMOGLOBIN WITH THE SPECTROPHOTOMETRIC MEASUREMENT OF CARBOXYHEMOGLOBIN CLINICAL CHEMISTRY Vreman, H. J., RONQUILLO, R. B., Ariagno, R. L., Schwartz, H. C., Stevenson, D. K. 1988; 34 (5): 975-977

  Abstract

  We measured the concentration of carboxyhemoglobin (HbCO) in blood samples from 32 neonates by spectrophotometry (IL282 CO-Oximeter) and gas chromatography, finding a strong positive correlation (r = 0.89) between the concentration of fetal hemoglobin (Hb F) and HbCO as measured by spectrophotometry, but not by gas chromatography. Thus, Hb F interferes with the determination of HbCO by spectrophotometric techniques by falsely increasing apparent HbCO in direct proportion to Hb F. We conclude that, when Hb F is known or suspected to be present, blood HbCO cannot be reliably determined by methods based on spectrophotometry.

  View details for Web of Science ID A1988N563700035

  View details for PubMedID 2453310

• COMPARISON OF THE IL282 AND IL482 CO-OXIMETERS MAHONEY, J. J., VANKESSEL, A. L., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1988: A508

  View details for Web of Science ID A1988M818001517

• Outcome of neonates with birth weights of less than 801 grams. Journal of perinatology Stevenson, D. K., Petersen, K. R., Yates, B. L., Benitz, W. E., Gale, R. 1988; 8 (2): 82-87

  Abstract

  The follow-up results of intensive care for 68 infants with birth weights less than 801 g treated at Stanford University Hospital were reviewed. The overall survival rate for these infants was 35%, but was 50% for those infants who had been successfully resuscitated in the delivery room and were admitted to the Intensive Care Nursery. Infants under 601 g in weight or less than 25 weeks gestation were more likely to die in the delivery room, but survival among those admitted to the Intensive Care Nursery did not depend on birth weight or gestational age. One-minute and 5-minute Apgar scores less than 5 and interstitial emphysema were associated with increased risk of neonatal death. Only two of 22 survivors (9%) were severely handicapped and another eight (36%) had remediable disabilities at 2 years of age. No infant developed hydrocephalus and only one infant had spasticity. We suggest that the low incidence of major handicaps among survivors encourages the vigorous resuscitation of infants weighing less than 801 g at birth, yet strategies must be developed that will minimize both prolonged dying and the cost of intensive care for nonviable infants.

  View details for PubMedID 2461442

• COMPARISON OF BILIRUBIN PRODUCTION IN JAPANESE AND CAUCASIAN INFANTS JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Fischer, A. F., Nakamura, H., Uetani, Y., Vreman, H. J., Stevenson, D. K. 1988; 7 (1): 27-29

  Abstract

  Bilirubin production, as indexed by serum carboxyhemoglobin (HbCOc), was studied in a group of normal term Japanese infants and Caucasian controls during the second to third day of life. Stringent entry criteria were employed in order to eliminate infants with hemolysis or other known causes of increased bilirubin production. The mean HbCOc of the Japanese infants (0.69 +/- 0.15% sat) was significantly higher than that of the Caucasian infant (0.58 +/- 0.17% sat). The serum total bilirubin was also significantly higher in Japanese infants (11.1 +/- 3.0 mg/dl versus 8.0 +/- 2.2 mg/dl). This difference may be attributable to environmental and/or genetic factors.

  View details for Web of Science ID A1988L212500007

  View details for PubMedID 3335981

• HBF AND HBCO DETERMINATION BY SPECTROPHOTOMETRY AND GAS-CHROMATOGRAPHY VREMAN, H. J., RONQUILO, R., ARIAGNO, R. L., BALL, B., SCHWARTZ, H. C., STEVENSON, D. K. SLACK INC. 1988: A237

  View details for Web of Science ID A1988L516801387

• STATE BEHAVIOR OF PRETERM INFANTS AS A FUNCTION OF DEVELOPMENT, INDIVIDUAL AND SEX-DIFFERENCES INFANT BEHAVIOR & DEVELOPMENT KORNER, A. F., BROWN, B. W., READE, E. P., STEVENSON, D. K., FERNBACH, S. A., THOM, V. A. 1988; 11 (1): 111–24

  View details for DOI 10.1016/S0163-6383(88)80020-1

  View details for Web of Science ID A1988P316500009

• Postnatal somatic growth in very low birth weight infants on supplemental peripheral parenteral nutrition. Journal of pediatric & perinatal nutrition Kerner, J. A., HATTNER, J. A., Trautman, M. S., Stevenson, D. K. 1988; 2 (1): 27-34

  View details for PubMedID 3145974

• EFFECT OF BUPIVACAINE HYDROCHLORIDE ON BILIRUBIN PRODUCTION IN NEONATAL RATS Gale, R., Vreman, H. J., Ferguson, J. E., Stevenson, D. K. SLACK INC. 1988: A229–A229

  View details for Web of Science ID A1988L516801341

• PLASMA PRORENIN AND RENIN IN CHILDHOOD AND ADOLESCENCE Wilson, D. M., Stevenson, D. K., LUETSCHER, J. A. SLACK INC. 1988: A202–A202

  View details for Web of Science ID A1988L516801182

• ZINC-PROTOPORPHYRIN INHIBITS BILIRUBIN PRODUCTION IN ADULT-RATS HAMORI, C. J., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1988: A230

  View details for Web of Science ID A1988L516801344

• BILIRUBIN PRODUCTION-RATES IN RHESUS-MONKEYS VREMAN, H. J., GALE, R., STEVENSON, D. K. SLACK INC. 1988: A237

  View details for Web of Science ID A1988L516801386

• HEME OXYGENASE ACTIVITY AS MEASURED BY CARBON-MONOXIDE PRODUCTION ANALYTICAL BIOCHEMISTRY Vreman, H. J., Stevenson, D. K. 1988; 168 (1): 31-38

  Abstract

  A method is described for the in vitro determination of heme oxygenase (HO) activity in animal tissue preparations through determination of carbon monoxide production. Tissue homogenates were centrifuged and the 13,000g supernatants were incubated in septum-sealed vials with methemalbumin in the presence and absence of NADPH at 37 degrees C for 15 min. The reaction was terminated by quick-freezing to -78 degrees C and the amount of carbon monoxide released into the headspace was determined by gas chromatography with a reduction gas detector. The CO produced through mediation of NADPH is used as a measure of HO activity and is expressed as nanomoles of CO produced per hour per milligram protein. The method permits analysis of as little as 2 microliter normal rat tissue homogenate representing 0.4 mg liver tissue (approx 40 micrograms total protein). The assay rate is 10-15 duplicate samples per hour with a precision of 3% for sample (4.47 +/- 0.13 SD nmol CO/h/mg protein) and 6% for blank reactions (0.59 +/- 0.10 nmol CO/h/mg protein) for 10 microliter liver supernatant. Various reaction parameters were studied. The method was used to compare HO activity in several tissue homogenates from normal rats and rats treated with COCl2.

  View details for Web of Science ID A1988L731600005

  View details for PubMedID 3364715

• REFRACTORY NEONATAL HYPOXEMIA - DIAGNOSTIC EVALUATION AND PHARMACOLOGIC MANAGEMENT RESUSCITATION Benitz, W. E., Stevenson, D. K. 1988; 16 (1): 49-64

  Abstract

  Hypoxemia refractory to oxygen administration and assisted ventilation is found in many clinical conditions and results from a variety of pathophysiologic disorders. Recent clinical and laboratory experience has demonstrated that the choice of therapy for an infant with refractory hypoxemia depends upon identification of the underlying etiologic and pathophysiologic conditions. The ideal therapies for many of these conditions have not yet been defined. We have provided, based on our experience, guidelines for selection of the most appropriate of the currently available therapies for many of these patients.

  View details for Web of Science ID A1988M299000005

  View details for PubMedID 2831603

• LACK OF INHIBITION OF INTESTINAL HEME OXYGENASE BY ANTIBIOTICS AND TIN-PROTOPORPHYRIN PEDIATRIC RESEARCH Hintz, S. R., Kim, C. B., Vreman, H. J., Stevenson, D. K. 1988; 23 (1): 50-53

  Abstract

  We assessed the in vivo and in vitro effects of antibiotics and tin-protoporphyrin (TP) on intestinal heme oxygenase (HO) activity using a gas chromatographic assay. This method measures the carbon monoxide produced from heme in the presence of NADPH. After in vivo administration of kanamycin (10 mg/kg body weight), ampicillin (200 mg/kg body weight) or neomycin (60 mg/kg body weight) with or without TP (65 mumol/kg body weight) to suckling rats, no significant difference in HO activity along the small intestine was observed. In vitro exposure of adult rat intestinal preparations to the antibiotics showed no significant decrease in HO activity between control and experimental tissue preparations. A concentration-dependent stimulatory effect of neomycin was observed. Subcutaneous administration of TP (25 mumol/kg body weight) to adult male Wistar rats revealed no significant inhibition of the intestine. However, in vitro addition of TP (12.5 microM) to the control tissue preparations of adult Wistar rats revealed highly significant inhibition in liver and spleen when compared to the unexposed control tissues. In contrast, when TP was added to control intestinal preparations no inhibition was observed. These findings suggest that suckling rat intestinal heme oxygenase is not inhibited by in vivo treatment with high concentrations of kanamycin, ampicillin, or neomycin. Furthermore, these antibiotics are not in vitro inhibitors of adult rat intestinal HO. Finally, adult rat intestinal HO is not inhibited either in vivo or in vitro by a concentration of TP that significantly inhibits liver and spleen activity.

  View details for Web of Science ID A1988L542200010

  View details for PubMedID 3340445

• EFFECT OF EPIDURAL ANALGESIA WITH BUPIVACAINE HYDROCHLORIDE ON NEONATAL BILIRUBIN PRODUCTION OBSTETRICS AND GYNECOLOGY Gale, R., Ferguson, J. E., Stevenson, D. K. 1987; 70 (5): 692-695

  Abstract

  We evaluated the rate of bilirubin production in vivo in newborns whose mothers received an epidural block with bupivacaine hydrochloride during labor and delivery. Bilirubin production was estimated in 23 full-term newborns whose mothers were treated with bupivacaine and in 20 controls by determining the end-tidal carbon monoxide concentration and the blood carboxyhemoglobin level corrected for ambient carbon monoxide. No significant difference was found between the mean end-tidal carbon monoxide concentrations for the bupivacaine-treated and the control groups (1.3 +/- 0.5 and 1.4 +/- 0.7 microL/kg/hour, respectively), or between the mean blood carboxyhemoglobin levels corrected for ambient carbon monoxide (0.54 +/- 0.17 and 0.52 +/- 0.18% saturation, respectively). These negative findings support the clinical studies, which have failed to demonstrate a causative connection between bupivacaine and neonatal jaundice.

  View details for Web of Science ID A1987K565800005

  View details for PubMedID 3116476

• A TECHNIQUE FOR THE ADMINISTRATION OF RIBAVIRIN TO MECHANICALLY VENTILATED INFANTS WITH SEVERE RESPIRATORY SYNCYTIAL VIRUS-INFECTION CRITICAL CARE MEDICINE Frankel, L. R., Wilson, C. W., Demers, R. R., Parker, J. R., LEWISTON, N. J., Stevenson, D. K., Smith, D. W. 1987; 15 (11): 1051-1054

  Abstract

  Fifteen infants with respiratory syncytial virus pulmonary infection admitted to our pediatric ICU from December 1, 1985 through April 30, 1986, required mechanical ventilation. These patients were placed on an open trial of ribavirin therapy. We describe a technique for the safe delivery of aerosolized ribavirin to these infants while on the ventilator. The agent was delivered for 16 h/day for 7 days. Modifications of the ventilator circuit were needed to prevent the condensation of the drug in the ventilator tubing and to allow for the safe and effective operation of the ventilator. A common ventilator strategy was used for all patients. The highest positive inspiratory pressure generated was 42 +/- 9.5 (SD) cm H2O, the highest PEEP was 5.9 +/- 3.2 cm H2O, the duration of ventilation was 10.7 +/- 8.5 days, and exposure to fraction of inspired oxygen was greater than or equal to 0.6 for 55.3 h. Ribavirin levels were measurable in two patients, thereby demonstrating that the drug was in fact delivered and absorbed. Our preliminary results demonstrate that ribavirin can be delivered to the patients with respiratory syncytial viral infections who require mechanical ventilation; however, further studies are indicated to evaluate the efficacy and dose responsiveness, alterations in pulmonary dynamics, and safety of ribavirin in delivery to infants requiring ventilation.

  View details for Web of Science ID A1987K928100012

  View details for PubMedID 3677748

• CARBON-MONOXIDE GENERATION FROM TIN-PROTOPORPHYRIN AND ZINC-PROTOPORPHYRIN BY TISSUE-HOMOGENATES BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vreman, H. J., Stevenson, D. K. 1987; 148 (1): 417-421

  Abstract

  Both heme and tin-protoporphyrin (TP), but not zinc-protoporphyrin (ZP), supported significant NADPH-stimulated, concentration-dependent CO production in all tissues. These rates, for 400 microM substrate, ranged: for heme 0.52 (intestine) to 4.18 (spleen); for TP 0.08 (kidney) to 0.71 (liver); and for ZP 0.01 (liver) to 0.25 (kidney) nmoles CO/hr/mg protein. All three metalloporphyrins (400 microM) supported concentration-dependent CO production in the absence of NADPH. The rates ranged: for heme 0.31 (kidney) to 0.80 (spleen); for TP 0.41 (kidney) to 1.04 (intestine); and for ZP 0.12 (kidney) to 0.51 (spleen) nmoles/hr/mg protein. We conclude that both TP and ZP are subject to in vitro degradation by 13,000 x g supernatants of adult rat organs via CO-producing reactions.

  View details for Web of Science ID A1987K353100060

  View details for PubMedID 3675588

• THE CONSEQUENCES OF UNCERTAINTY - AN EMPIRICAL-APPROACH TO MEDICAL DECISION-MAKING IN NEONATAL INTENSIVE-CARE JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Fischer, A. F., Stevenson, D. K. 1987; 258 (14): 1929-1931

  View details for Web of Science ID A1987K235300026

  View details for PubMedID 3309387

• CARBON-MONOXIDE PRODUCTION IN VENTILATED PREMATURE-INFANTS WEIGHING LESS THAN 1500-G ARCHIVES OF DISEASE IN CHILDHOOD Fischer, A. F., Ochikubo, C. G., Vreman, H. J., Stevenson, D. K. 1987; 62 (10): 1070-1072

  Abstract

  Mean pulmonary excretion rate of carbon monoxide in 13 premature babies on ventilators was significantly higher (p less than 0.001) than that of 19 healthy infants born at full term. This correlated with carboxyhaemoglobin concentrations in blood, indicating that the premature infants on ventilators produced abnormally large amounts of bilirubin.

  View details for Web of Science ID A1987K271300022

  View details for PubMedID 3674926

• Metabolic emergencies of the newborn: hypoxemia and hypoglycemia. Comprehensive therapy Frankel, L., Stevenson, D. K. 1987; 13 (10): 14-19

  View details for PubMedID 3315406

• TIN-PROTOPORPHYRIN INHIBITS CARBON-MONOXIDE PRODUCTION IN ADULT MALE WISTAR RATS WITH COMMON BILE-DUCT LIGATION JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION MCMILLAN, J. J., Vreman, H. J., Stevenson, D. K. 1987; 6 (5): 795-798

  Abstract

  The excretion rate of CO (VeCO), an index of total bilirubin production, and the total plasma bilirubin level are significantly elevated by 72 h after ligation of the common bile duct in adult male Wistar rats. At 72 and 96 h, rats prepared in this manner were subcutaneously injected with 50 mumol/kg body weight of tin-protoporphyrin IX (TP) (n = 5) or saline (n = 6). At 120 h after surgery, the VeCO had fallen from the pretreatment level in the TP-treated animals by 22% (P less than 0.025) compared with no significant change in the saline-treated controls. The plasma total bilirubin level of the experimental animals had also declined by 32% (p less than 0.0005) compared with their pretreatment level. The hyperbilirubinemia of the saline-treated controls was not significantly modified. These results suggest that TP reduces bilirubin production and plasma total bilirubin levels in adult rats with surgically created obstructive jaundice.

  View details for Web of Science ID A1987J694100024

  View details for PubMedID 3694375

• CARBOXYHEMOGLOBIN CONCENTRATION AS AN INDEX OF BILIRUBIN PRODUCTION IN NEONATES WITH BIRTH WEIGHTS LESS THAN 1,500 GRAMS - A RANDOMIZED DOUBLE-BLIND COMPARISON OF SUPPLEMENTAL ORAL VITAMIN-E AND PLACEBO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Fischer, A. F., Inguillo, D., Martin, D. M., Ochikubo, C. G., Vreman, H. J., Stevenson, D. K. 1987; 6 (5): 748-751

  Abstract

  A randomized double-blind study of the efficacy of oral vitamin E supplementation as a prophylactic treatment for hyperbilirubinemia was undertaken in preterm infants weighing less than 1,500 g. Hemoglobin (Hb) levels, blood carboxyhemoglobin saturation (HbCOc), end-tidal carbon monoxide concentration (ETCO), and serum total bilirubin levels were determined in each subject on the first and third days of the study. We found no differences between the vitamin E-treated and placebo-treated groups with respect to Hb, HbCOc, ETCO, or serum bilirubin levels on day 1 or 3. In addition, we reanalyzed our data to compare those infants who had low vitamin E levels at birth with those who had vitamin E levels greater than 0.4 mg/dl on day 1. We still observed no differences in Hb, HbCOc, ETCO, or serum bilirubin levels on day 1 or 3. The results of our study suggest that supplemental oral vitamin E therapy has no major effect on bilirubin production during the first 3 days of life in premature infants weighing less than 1,500 g at birth.

  View details for Web of Science ID A1987J694100015

  View details for PubMedID 3320325

• A PRACTICAL APPROACH TO DIAGNOSIS AND IMMEDIATE CARE OF THE CYANOTIC NEONATE - STABILIZATION AND PREPARATION FOR TRANSFER TO LEVEL-III NURSERY CLINICAL PEDIATRICS Stevenson, D. K., Benitz, W. E. 1987; 26 (7): 325-331

  Abstract

  The diagnostic and therapeutic strategies described above have been presented sequentially for the sake of clarity, but in practice should be performed as quickly as possible in any infant who remains cyanotic despite receiving 100% oxygen. The practitioner must proceed with emergent stabilization of the infant with specific therapies for identified problems and nonspecific therapies for suspected problems, recognizing that the coexistence of two or more pathophysiologic entities is not uncommon. By the time of transport, the practitioner may have laid the groundwork for further diagnostic procedures and therapies by having already classified the infant into one of four primary pathophysiologic categories, as outlined in Table 4. Although congenital heart disease may be highly suspected, confirmation may not be possible without echocardiography. The practitioner, however, should not be discouraged by failure to achieve a specific etiologic diagnosis, despite careful analysis of all the information obtained from diagnostic evaluations prior to transport. Hypoxemia refractory to oxygen administration and assisted ventilation is found in many clinical conditions and results from a variety of pathophysiological disorders. The pediatrician caring for such an infant has primary responsibility for stabilization and preparation for transport of the infant to a Level III facility, and for communicating information about diagnostic procedures and therapeutic maneuvers that might facilitate extended resuscitative efforts by the neonatologist accepting responsibility for the transport and subsequent care of the infant.

  View details for Web of Science ID A1987J242000001

  View details for PubMedID 3595037

• CORRELATION OF ECHOENCEPHALOGRAPHIC FINDINGS AND NEURODEVELOPMENTAL OUTCOME - INTRACRANIAL HEMORRHAGE AND VENTRICULOMEGALY IN INFANTS OF BIRTH-WEIGHT 1,000 GRAMS OR LESS JOURNAL OF CLINICAL MONITORING Salomon, W. L., Benitz, W. E., Enzmann, D. R., BRAVO, R. H., MURPHYIRWIN, K., Stevenson, D. K. 1987; 3 (3): 178-186

  Abstract

  Echoencephalograms were obtained for 118 of 121 successive infants who were admitted to the Stanford intensive care nursery, weighed 1,000 g or less at birth, and survived long enough for at least one study to be performed. Eighty-eight of these infants survived and were followed up for 1 to 3 years; psychometric testing (Bayley Scales of Infant Development, Stanford-Binet Intelligence Scale, or both) was performed on 81% of these infants. Subependymal-intraventricular hemorrhages or intraparenchymal hemorrhages were associated with impaired development, but ventriculomegaly was not. The absence of echoencephalographic abnormalities did not exclude the possibility of impaired development in many infants. Periventricular leukomalacia was not observed. These data support independent scoring of subependymal-intraventricular hemorrhages, intraparenchymal hemorrhages, and ventriculomegaly, rather than use of combined scales for prognostic purposes.

  View details for Web of Science ID A1987K089700005

  View details for PubMedID 3612216

• Immediate management of the asphyxiated infant: facilitating the cardiorespiratory transition from fetus to newborn. Journal of perinatology Stevenson, D. K., Frankel, L. R., Benitz, W. E. 1987; 7 (3): 221-225

  Abstract

  The authors discuss the possible ways of managing the asphyxiated infant by considering the respiratory circumstances of the fetus and newborn. However, they conclude that further multicenter clinical trials are required to evaluate the efficacy of the various methods of management of delayed transition in cardiorespiratory function after birth.

  View details for PubMedID 3504458

• ANALYSIS FOR CARBOXYHEMOGLOBIN BY GAS-CHROMATOGRAPHY AND MULTICOMPONENT SPECTROPHOTOMETRY COMPARED CLINICAL CHEMISTRY Vreman, H. J., Stevenson, D. K., Zwart, A. 1987; 33 (5): 694-697

  Abstract

  Measurements of carboxyhemoglobin (HbCO) by gas chromatography (GC) were compared with those obtained by multicomponent spectrophotometric analysis (MCA). Correlation was good for HbCO ranges (proportion of total hemoglobin) of 1.5 to less than or equal to 5% (GC = 0.94 MCA + 0.37%, n = 25, r = 0.98); 5.0 to less than or equal to 10.0% (GC = 0.89 MCA + 0.63%, n = 19, r = 0.93); greater than 10% (GC = 1.01 MCA - 0.02%, n = 22, r = 0.99); and greater than 0% (GC = 1.01 MCA - 0.10%, n = 95, r = 1.00). The correlation is lower for the clinically normal range of 0 to less than or equal to 1.5% (GC = 0.65 MCA + 0.24%, n = 29, r = 0.87). The gas-chromatographic method is linear for HbCO proportions of 30% to as little as 0.15%. Re-analysis of blood samples after two-month storage at 4 degrees C showed that samples remained stable under these conditions.

  View details for Web of Science ID A1987H380800014

  View details for PubMedID 3568355

• HEME OXYGENASE ACTIVITY - COMPARISON OF DIRECT MEASUREMENT BY CARBON-MONOXIDE GENERATION WITH BILIRUBIN PRODUCTION ROSENTHAL, P., VREMAN, H., HENTON, D., STEVENSON, D. W B SAUNDERS CO. 1987: 1768

  View details for Web of Science ID A1987G966001914

• DIRECT MEASUREMENT OF HEME OXYGENASE ACTIVITY BY GAS-CHROMATOGRAPHY VREMAN, H. J., STEVENSON, D. K. WILLIAMS & WILKINS. 1987: A242

  View details for DOI 10.1203/00006450-198704010-00451

  View details for Web of Science ID A1987G700500413

• EFFECTS OF MICROWAVE THAWING (MT) ON ANTIINFECTIVE FACTORS IN HUMAN-MILK (HM) Kerner, J. A., Quan, R., Yang, C., LEWISTON, N., Sunshine, P., Stevenson, D. K. WILLIAMS & WILKINS. 1987: A430–A430

  View details for Web of Science ID A1987G700501539

• COMPARISON OF BILIRUBIN PRODUCTION IN JAPANESE AND CAUCASIAN INFANTS STEVENSON, D. K., VREMAN, H. J., FISCHER, A. F., UETANI, Y., NAKAMURA, H. WILLIAMS & WILKINS. 1987: A377

  View details for Web of Science ID A1987G700501223

• TIN-PROTOPORPHYRIN DECREASES BILIRUBIN PRODUCTION AND HYPERBILIRUBINEMIA IN OBSTRUCTIVE-JAUNDICE MCMILLAN, J. J., VREMAN, H. J., STEVENSON, D. K. WILLIAMS & WILKINS. 1987: A273

  View details for DOI 10.1203/00006450-198704010-00634

  View details for Web of Science ID A1987G700500596

• SOCIOECONOMIC-STATUS AND THE COST OF DYING IN THE INTENSIVE-CARE NURSERY FISCHER, A. F., STEVENSON, D. K. WILLIAMS & WILKINS. 1987: A394

  View details for Web of Science ID A1987G700501325

• THE CONSEQUENCES OF UNCERTAINTY - AN EMPIRICAL-APPROACH TO DECISION-MAKING IN NEONATAL INTENSIVE-CARE STEVENSON, D. K., FISCHER, A. F. WILLIAMS & WILKINS. 1987: A404

  View details for Web of Science ID A1987G700501382

• High serum vitamin E levels in premature infants receiving MVI-Pediatric. Journal of pediatric & perinatal nutrition Kerner, J. A., Poole, R. L., Sunshine, P., Stevenson, D. K. 1987; 1 (1): 75-82

  View details for PubMedID 3694523

• RECOVERY OF EXOGENOUS HEME AS CARBON-MONOXIDE AND BILIARY HEME IN ADULT-RATS AFTER TIN PROTOPORPHYRIN TREATMENT JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Hintz, S. R., Kwong, L. K., Vreman, H. J., Stevenson, D. K. 1987; 6 (2): 302-306

  Abstract

  We studied the effect of tin protoporphyrin (TP) on bilirubin production in adult Wistar rats by quantifying in vivo carbon monoxide (CO) excretion and the simultaneous excretion of biliary heme after common bile duct cannulation. A known amount of heme was injected intravenously as red blood cells (RBC) damaged with a sulfhydryl inhibitor, N-ethylmaleimide. The recovery of heme as CO or biliary heme in the cannulated animals was calculated as the molar percent of heme recovered over heme injected. For cannulated controls (n = 4), the recovery was 89 +/- 6% SD, and no heme appeared in bile. Cannulated rats treated with TP (n = 4) had 64 +/- 11% recovered as CO and 30 +/- 11% as heme in bile. Our findings suggest that TP is an effective in vivo inhibitor of exogenous heme catabolism and bilirubin production in adult rats. Furthermore, this inhibition results in increased excretion of heme into the bile proportional to the degree of inhibition.

  View details for Web of Science ID A1987G188100025

  View details for PubMedID 3694354

• CLINICAL USES, COLLECTION, AND BANKING OF HUMAN-MILK CLINICS IN PERINATOLOGY ASQUITH, M. T., PEDROTTI, P. W., Stevenson, D. K., Sunshine, P. 1987; 14 (1): 173-185

  Abstract

  The Mothers' Milk Bank (MMB) of San Jose, CA, has provided banked human milk to clinicians and researchers since its founding in 1974. This article briefly acknowledges the many and varied reasons for the use of human milk. Its primary focus however, is to review the protocol followed by the MMB for collection, banking, and distribution of human milk.

  View details for Web of Science ID A1987G133400010

  View details for PubMedID 3829570

• ELEVATION OF BILIRUBIN PRODUCTION IN NEONATAL RATS TREATED WITH NICARDIPINE HYDROCHLORIDE DEVELOPMENTAL PHARMACOLOGY AND THERAPEUTICS Ochikubo, C. G., SUNSHINE, S. E., Vreman, H. J., Ferguson, J. E., Stevenson, D. K. 1987; 10 (2): 118-124

  Abstract

  Administration of nicardipine hydrochloride, a dihydropyridine calcium entry blocker, caused a 30% rise in the rate of bilirubin formation in neonatal rats. Plasma bilirubin concentrations also increased from 0.83 +/- 0.05 to 1.06 +/- 0.10 mg/100 ml (p less than 0.05). We conclude that maternal administration of nicardipine hydrochloride for tocolysis could affect bilirubin production in the neonate.

  View details for Web of Science ID A1987H536600006

  View details for PubMedID 3608742

• RESUMPTION OF INTESTINAL MATURATION UPON REINTRODUCTION OF INTRALUMINAL NUTRIENTS (ILN) - FUNCTIONAL AND BIOCHEMICAL CORRELATIONS Feng, J. J., Kwong, L. K., Kerner, J. A., Stevenson, D. K., Castillo, R. O. SLACK INC. 1987: A228–A228

  View details for Web of Science ID A1987F528501319

• THE FETAL TO MATERNAL CARBOXYHEMOGLOBIN (HBCO) RATIO AS A PREDICTOR OF NEONATAL JAUNDICE Leonard, M. B., Vreman, H. J., Ferguson, J. E., Stevenson, D. K. SLACK INC. 1987: A235–A235

  View details for Web of Science ID A1987F528501362

• CARE OF THE EXTREMELY SMALL INFANT (LESS-THAN 800 GM) - THE MORTALITY, MORBIDITY AND COST OF UNCERTAINTY STEVENSON, D. K., PETERSEN, K. R., YATES, B. L. SLACK INC. 1987: A214

  View details for Web of Science ID A1987F528501237

• CARBON-MONOXIDE PRODUCTION IN VENTILATED LOW-BIRTH-WEIGHT INFANTS FISCHER, A. F., OCHIKUBO, C. G., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1987: A233

  View details for Web of Science ID A1987F528501349

• TIN-PROTOPORPHYRIN-IX (TP) INHIBITS CARBON MONOXIDE(CO) PRODUCTION IN ADULT MALE-RATS WITH COMMON BILE-DUCT LIGATION MCMILLAN, J. J., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1987: A236

  View details for Web of Science ID A1987F528501364

• INVITRO INTESTINAL CO PRODUCTION IN SUCKLING RATS AFTER ANTIBIOTICS AND TIN-PROTOPORPHYRIN (TP) HINTZ, KIM, C. B., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1987: A208

  View details for Web of Science ID A1987F528501197

• ADJUNCTIVE MAGNESIUM-SULFATE INFUSION DOES NOT ALTER METABOLIC CHANGES ASSOCIATED WITH RITODRINE TOCOLYSIS AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Ferguson, J. E., Holbrook, R. H., Stevenson, D. K., Hensleigh, P. A., Kredentser, D. 1987; 156 (1): 103-107

  Abstract

  Magnesium sulfate, an agent whose cellular actions might cause metabolic disturbances, has been used concomitantly with ritodrine hydrochloride for preterm labor tocolysis. Although the profound metabolic effects of beta-adrenergic agents have been well described, the possibility that adjunctive magnesium might cause further or unexpected alterations in maternal metabolic parameters has not been fully evaluated. To investigate this question, we prospectively randomized patients, in a blinded fashion, to receive ritodrine plus placebo or ritodrine plus adjunctive magnesium sulfate for preterm labor tocolysis. Serial measurements of potassium, glucose, blood urea nitrogen, and hematocrit were obtained and compared between tocolytic treatment groups. The metabolic changes found were similar in each group and appear to result predominantly from beta-adrenergic stimulation with no apparent perturbations caused by the direct cellular actions of magnesium sulfate. From the metabolic standpoint, it appears that the clinician may use adjunctive magnesium sulfate without fear of accentuating or obscuring the expected beta-adrenergic-induced alterations in the above-mentioned maternal metabolic parameters.

  View details for Web of Science ID A1987F713600024

  View details for PubMedID 3541613

• TIN PROTOPORPHYRIN INHIBITS CARBON-MONOXIDE PRODUCTION IN SUCKLING MICE BIOLOGY OF THE NEONATE Stevenson, D. K., Watson, E. M., Hintz, S. R., Kim, C. B., Vreman, H. J. 1987; 51 (1): 40-44

  Abstract

  The carbon monoxide excretion rate (VeCO) of groups of 1-day-old mice was measured after administration of two separate doses of 50 nmol of tin protoporphyrin (TP) per gram of body weight. The mean VeCO of the saline-treated control groups over the study period was 1.50 +/- 0.26 nmol/g/h, and that of the TP-treated groups was 1.35 +/- 0.29 nmol/g/h. Tin protoporphyrin treatment reduced the CO excretion by approximately 14% in 2-day-old mice over 24-48 h.

  View details for Web of Science ID A1987G021800007

  View details for PubMedID 3828416

• CLINICAL OBSERVATIONS ON MECHANICAL VENTILATION FOR RESPIRATORY-FAILURE IN BRONCHIOLITIS PEDIATRIC PULMONOLOGY Frankel, L. R., LEWISTON, N. J., Smith, D. W., Stevenson, D. K. 1986; 2 (5): 307-311

  Abstract

  An unusually large number of infants (82) were admitted to Stanford University Hospital from November 1, 1983, through May 31, 1985, with a diagnosis of bronchiolitis requiring oxygen therapy. A larger percentage of these infants (17/82 = 21%) than generally expected required mechanical ventilation for respiratory failure. Fourteen infants had respiratory syncytial virus (RSV) infections, and three had parainfluenza virus infections. Ten patients had respiratory difficulties as neonates. The mechanical ventilation of the children requiring respiratory assistance was characterized by high minute ventilation with high tidal volumes (15 to 20 ml/kg) and slow respiratory rates (16 to 22 breaths/min). Peak inspiratory pressure averaged (mean +/- SD) 35 +/- 6 cm H2O in the RSV group and 34 +/- 6 cm H2O in the parainfluenza group. The mean number of days on the ventilator was 9.7 +/- 3.1 for the RSV group and 8.3 +/- 2.9 for the parainfluenza group. All were extubated within 17 days of presentation and discharged within 28 days. The complications encountered included pneumothorax and acute pulmonary hypertension.

  View details for Web of Science ID A1986E394600009

  View details for PubMedID 3022224

• RED-CELL DESTRUCTION AND BILIRUBIN PRODUCTION IN ADULT-RATS WITH SHORT-TERM BILIARY OBSTRUCTION JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Salomon, W. L., Vreman, H. J., Kwong, L. K., Stevenson, D. K. 1986; 5 (5): 806-810

  Abstract

  The rate of total bilirubin production and the concomitant relative rate of early-labeled bilirubin (ELB) formation were studied in adult Wistar rats with short-term common bile duct ligation. The pulmonary excretion rate of CO (VeCO), an index of total bilirubin production, was measured preoperatively and postoperatively on day 3 and on day 5 or 6. While the VeCO measurements of control and experimental animals were similar preoperatively, the postoperative VeCO measurements of the experimental animals averaged 30% higher than those of control animals. On postoperative day 3, the relative rate of ELB formation was measured by the recovery of excreted 14CO after the administration of 14C-labeled delta-aminolevulinic acid (ALA) or glycine as nonerythropoietic or total heme synthesis precursor, respectively. No significant differences were found in the 14CO recovered from either compound during the study period between the experimental and control animals. The half-life of 51Cr-labeled transfused red blood cells was decreased by nearly 50% in bile duct ligated rats compared to that in the sham operated ones. We conclude that hemolysis is a major factor contributing to the increase in total bilirubin production even after short-term biliary obstruction in the rat.

  View details for Web of Science ID A1986D717700024

  View details for PubMedID 3761112

• NEONATAL ASPERGILLOSIS - A CASE-REPORT AND REVIEW OF THE LITERATURE CLINICAL PEDIATRICS Rhine, W. D., Arvin, A. M., Stevenson, D. K. 1986; 25 (8): 400-403

  Abstract

  Neonatal aspergillosis is a rare, usually overwhelming multisystem infection diagnosed postmortem. We present a neonate who had a brain abscess diagnosed by CT scan that was found at surgical exploration to contain aspergillus. Treatment included prolonged antifungal medication and several surgical interventions. The child has neurologic sequelae, including a seizure disorder and hemiplegia. There are no previously reported survivors of neonatal aspergillosis.

  View details for Web of Science ID A1986D516900004

  View details for PubMedID 3731668

• THE PHARMACOLOGY OF NEONATAL RESUSCITATION AND CARDIOPULMONARY INTENSIVE-CARE .2. EXTENDED INTENSIVE-CARE WESTERN JOURNAL OF MEDICINE Benitz, W. E., Frankel, L. R., Stevenson, D. K. 1986; 145 (1): 47-51

  Abstract

  An optimal outcome for a distressed newborn infant can be achieved only if immediate resuscitation is followed by appropriate cardiopulmonary intensive care. In the preceding article in this series, we provided recommendations for drug therapy during the initial resuscitation. When an infant is stable enough for transfer to an intensive care nursery, extended cardiopulmonary intensive care should be initiated. If the infant remains distressed, this may require drug therapy to improve cardiac output, either by enhancing cardiac performance (dopamine, dobutamine or epinephrine) or by reducing afterload (nitroprusside). Drugs that alter the distribution of the circulation may be required for infants with persistent hypoxemia due to pulmonary hypertension or congenital heart disease (tolazoline, nitroprusside, prostaglandin E(1)), or with pulmonary congestion due to persistent patency of the ductus arteriosus (indomethacin). Infants with pulmonary disease may benefit from administration of agents that alter pulmonary function (furosemide, nitroprusside or neuromuscular blockers). Finally, treatment of the underlying disorder, with antibiotics or naloxone, for example, must not be neglected.

  View details for Web of Science ID A1986D218900003

  View details for PubMedID 3529631

  View details for PubMedCentralID PMC1306814

• THE PHARMACOLOGY OF NEONATAL RESUSCITATION AND CARDIOPULMONARY INTENSIVE-CARE .1. IMMEDIATE RESUSCITATION WESTERN JOURNAL OF MEDICINE Benitz, W. E., Frankel, L. R., Stevenson, D. K. 1986; 144 (6): 704-709

  Abstract

  Resuscitation of a neonate requires both immediate cardiopulmonary resuscitation and extended intensive care. Initial resuscitation of the neonate, as for adults, must include support of the airway, breathing and circulation. Because of the unique physiology of a newborn infant, some aspects of drug therapy differ significantly from their counterparts in the resuscitation of adults, and hypoglycemia and hypothermia pose special threats to a distressed neonate. Epinephrine and atropine can be administered via an endotracheal tube, but vascular access, which is most easily obtained by cannulating an umbilical vessel, is required for administering other drugs. Initial drug therapy, including glucose, oxygen and bicarbonate, is intended to restore metabolic homeostasis. Bicarbonate administration must be preceded by adequate alveolar ventilation. Drugs used to increase cardiac output early in resuscitation include those that increase heart rate, increase preload or improve myocardial function. Other drugs used in extended intensive care may also improve cardiac output, alter the distribution of the circulation or alter pulmonary function or gas exchange. These agents will be reviewed in a subsequent article.

  View details for Web of Science ID A1986C700700004

  View details for PubMedID 3727530

  View details for PubMedCentralID PMC1306753

• THE BABY-DOE RULE JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Stevenson, D. K., Ariagno, R. L., Kutner, J. S., Raffin, T. A., Young, E. W. 1986; 255 (14): 1909-1912

  View details for Web of Science ID A1986A718900029

  View details for PubMedID 3951118

• CARBOXYHEMOGLOBIN (HBCO) AFTER RANDOMIZED DOUBLE-BLIND CONTROLLED TRIAL OF ORAL VITAMIN-E (E) OR PLACEBO IN BABIES WITH BIRTH WEIGHTS LESS-THAN 1.5 KG FISCHER, A. F., INGUILLO, D. R., MARTIN, D. M., YANG, C. C., STEVENSON, D. K. WILLIAMS & WILKINS. 1986: A347

  View details for Web of Science ID A1986A712001166

• CARBON-MONOXIDE (CO) PRODUCTION BY THE SMALL-INTESTINE OF THE ADULT WISTAR RAT AFTER TIN PROTOPORPHYRIN (TP) Kim, C. B., Vreman, H. J., Kwong, L. K., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1986: A352–A352

  View details for Web of Science ID A1986A712001193

• PREDICTING OUTCOME IN LOW-BIRTH-WEIGHT INFANTS PEDIATRICS FISCHER, A. F., FRANKEL, L. R., STEVENSON, D. K. 1986; 77 (4): 615–16

  View details for Web of Science ID A1986A761000032

  View details for PubMedID 3960630

• CARBOXYHEMOGLOBIN ANALYSIS BY GAS-CHROMATOGRAPHY - CORRELATION WITH HEMOGLOBINOMETRY USING A SPECTROPHOTOMETER VREMAN, H. J., ZWART, A., STEVENSON, D. K. WILLIAMS & WILKINS. 1986: A364

  View details for Web of Science ID A1986A712001265

• SUPPRESSION OF CARBON-MONOXIDE EXCRETION RATE BY TIN PROTOPORPHYRIN AMERICAN JOURNAL OF DISEASES OF CHILDREN Posselt, A. M., Kwong, L. K., Vreman, H. J., Stevenson, D. K. 1986; 140 (2): 147-150

  Abstract

  The effect of a single prophylactic dose of tin protoporphyrin on the carbon monoxide (CO) excretion rate of antibiotic-treated neonatal rats before and after hematoma formation was evaluated. The CO excretion rate, reflecting the rate of bilirubin production, of tin protoporphyrin-treated (TP-H) rats 24 hours after injection of 65 mole of tin protoporphyrin per kilogram (time [t] = 0 hours) was approximately 18% lower than those of the saline-control (S-C) and saline-hematoma (S-H) rats, but this difference was no longer evident at t = 43 hours. After hematoma formation at t = 44 hours, the CO excretion rate of the S-H rats increased rapidly; this increase was delayed and lessened in the TP-H rats. At eight hours posthematoma (t = 52 hours), the CO excretion rate of the TP-H rats was significantly lower than that of the S-H rats, 53 +/- 2 vs 73 +/- 3 microL/kg/hr, respectively. A maximal rate of 89 +/- 5 microL/kg/hr was reached 25 hours posthematoma in the S-H rats (t = 69 hours), as compared with 80 +/- 3 microL/kg/hr at 44 hours posthematoma in the TP-H rats (t = 88 hours). The recovery of injected blood as CO over a 68-hour study period was approximately 90% for the S-H rats and approximately 65% for the TP-H rats. At t = 112 hours, hepatic heme oxygenase activity of the TP-H rats was still significantly lower than that of the S-H and S-C rats; however, plasma bilirubin concentrations of all three groups were similar. These studies demonstrate that tin protoporphyrin is an effective in vivo inhibitor of endogenous heme catabolism as measured by the CO excretion rate in antibiotic-treated neonatal rats with and without artificially created hematomas.

  View details for Web of Science ID A1986AYW9200032

  View details for PubMedID 3753817

• ABO HEMOLYTIC-DISEASE CLINICAL PEDIATRICS SMITH, D. W., STEVENSON, D. K. 1986; 25 (2): 116

  View details for Web of Science ID A1986AZE8100015

  View details for PubMedID 3943260

• THE EFFECT OF RITODRINE HYDROCHLORIDE ON BILIRUBIN PRODUCTION IN NEONATAL RATS PEDIATRIC PHARMACOLOGY Ochikubo, C. G., SUNSHINE, S. E., Vreman, H. J., Ferguson, J. E., Stevenson, D. K. 1986; 5 (4): 247-252

  Abstract

  The effect of ritodrine hydrochloride (RH) on bilirubin metabolism in newborn Wistar rats was studied. Wistar rat pups were given two 35-mg/kg injections of RH, and total bilirubin formation (TBF) was determined from the whole body excretion rate of carbon monoxide (VeCO). Early labeled bilirubin formation (ELB), plasma bilirubin levels, and hepatic heme oxygenase (HO) activity were also determined. We found significant increases in TBF, ELB, and HO in the RH-treated animals over the control animals. These increases, however, were small, considering the high doses of RH administered. Our findings suggest that at clinically administered doses, the potential for RH to exacerbate neonatal jaundice is minimal.

  View details for Web of Science ID A1986D232200005

  View details for PubMedID 3755522

• PRODUCTION OF CARBON-MONOXIDE (CO) FROM HEME IN HOMOGENATES OF THE SMALL-INTESTINE OF ADULT WISTAR RATS Kim, C. B., Vreman, H. J., Kwong, L. K., Stevenson, D. K. SLACK INC. 1986: A145–A145

  View details for Web of Science ID A1986C748300848

• HIGH VITAMIN-E LEVELS IN PREMATURE-INFANTS ON MVIR PEDIATRIC KERNER, J. A., POOLE, R., INGUILLO, D., MARTIN, D., YANG, C., STEVENSON, D. K. SLACK INC. 1986: A138

  View details for Web of Science ID A1986C748300809

• INCREASED IMMUNOREACTIVE ERYTHROPOIETIN IN CORD PLASMA AND NEONATAL BILIRUBIN PRODUCTION IN NORMAL TERM INFANTS AFTER LABOR OBSTETRICS AND GYNECOLOGY Stevenson, D. K., BUCALO, L. R., Cohen, R. S., Vreman, H. J., Ferguson, J. E., Schwartz, H. C. 1986; 67 (1): 69-73

  Abstract

  The purpose of this investigation was to compare immunoreactive erythropoietin levels in umbilical cord plasma and neonatal bilirubin production in infants born of normal women who delivered with or without labor. Two groups of term (38 to 42 weeks) singleton pregnancies were compared: 1) those delivered by repeat elective cesarean section without prior labor (N = 17), and 2) those delivered vaginally or by cesarean section after labor (N = 24). None of the infants was asphyxiated, and there was no difference in Apgar scores between the no-labor and labor groups. The cord plasma erythropoietin levels were lower in the infants of women who had repeat elective cesarean section without labor than in those whose mothers had labor before delivery (Wilcoxon rank sum test, P less than .025). The median erythropoietin for the no-labor group was 22.9 mU/mL compared with 38.8 mU/mL for the labor group. The pulmonary excretion rate of carbon monoxide (VeCO), an index of bilirubin production, for the no-labor group was 14.3 +/- 6.2 SD microL/kg per hour compared with 18.0 +/- 4.9 SD microL/kg per hour for the labor group (P less than .05). The hemoglobin concentration for the no-labor group was 16.0 +/- 1.5 SD g/dL compared with 17.7 +/- 2.2 SD g/dL for the labor group (P less than .05). The VeCO correlated with the hemoglobin concentration (N = 32, r = 0.37, P less than .05). The results of the present study suggest that labor is normally associated with increases in the cord plasma erythropoietin level.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1986AWU2300013

  View details for PubMedID 3940341

• THE NATURE OF MATURATIONAL DECLINE OF INTESTINAL LACTASE ACTIVITY BIOCHIMICA ET BIOPHYSICA ACTA TSUBOI, K. K., Kwong, L. K., DHARLINGUE, A. E., Stevenson, D. K., Kerner, J. A., Sunshine, P. 1985; 840 (1): 69-78

  Abstract

  We have examined the nature of the decline of lactase (EC 3.2.1.23) activity in the maturing rat intestine. It was established in an initial study that the activity decline reflected a proportional reduction in the concentration of the enzyme protein. Accumulation patterns of label into lactase, total intestinal proteins and sucrase (EC 3.2.1.48)-isomaltase (EC 3.2.1.10) were compared, 4 h following administration of a tracer dose of [3H]leucine to weanling rats exhibiting a wide range of lactase decline. Accumulation of increasing amounts of label in total intestinal proteins and sucrase-isomaltase pools was found to accompany the lactase decline, in contrast to accumulation of a constant amount of label in the declining lactase pools. The pattern of increased label accumulation in total intestinal proteins was shown in a corollary study to reflect a corresponding acceleration of total protein synthesis. On this basis, the finding of a constant amount of label in the declining lactase pools suggested a constant synthesis of lactase. We proposed earlier that associated reductions in enterocyte life-span (leading to correspondingly less lactase accumulation) rather than suppressed synthesis may provide the primary causal basis of lactase decline in the postweaned mammal.

  View details for Web of Science ID A1985AKH8600011

  View details for PubMedID 3922428

• CEREBRO-COSTO-MANDIBULAR SYNDROME - A FAMILIAL CASE CONSISTENT WITH AUTOSOMAL RECESSIVE INHERITANCE JOURNAL OF PEDIATRICS TRAUTMAN, M. S., SCHELLEY, S. L., STEVENSON, D. K. 1985; 107 (6): 990–91

  View details for DOI 10.1016/S0022-3476(85)80219-5

  View details for Web of Science ID A1985AVU1100043

  View details for PubMedID 4067764

• THE EARLY ONSET EFFECT OF BILIARY OBSTRUCTION ON CO EXCRETION IN THE RAT Salomon, W. L., Vreman, H. J., Kwong, L. K., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1985: A319–A319

  View details for Web of Science ID A1985AEU1801254

• NONIMMUNE HYDROPS FETALIS IN ASSOCIATION WITH HEMANGIOMA OF THE UMBILICAL-CORD OBSTETRICS AND GYNECOLOGY Seifer, D. B., Ferguson, J. E., BEHRENS, C. M., Zemel, S., Stevenson, D. K., Ross, J. C. 1985; 66 (2): 283-286

  Abstract

  Nonimmune hydrops fetalis is becoming the predominant form of fetal hydrops due to the declining frequency of Rh isoimmunization. Reported is the preterm delivery of a hydropic twin with umbilical cord and cutaneous hemangiomata. The unusual umbilical angiomatous malformation was associated with marked edema of the cord. This produced an ultrasonographic abnormality detected antenatally as a multicystic mass in close approximation to the fetal abdomen. The hydropic twin responded to aggressive neonatal management. It appears that hemangiomata of the umbilical cord may be causally related to fetal hydrops and may represent another entry in the differential diagnosis of this disorder.

  View details for Web of Science ID A1985AMX7100030

  View details for PubMedID 3895076

• NEUROMUSCULAR OUTCOME IN INFANTS UNDER 1001 GM STUDIED PROSPECTIVELY WITH ECHOENCEPHALOGRAPHY (ECHO) FOR INTRACRANIAL HEMORRHAGE (ICH) SALOMON, W. L., STEVENSON, D. K., ENZMAN, D. R. WILLIAMS & WILKINS. 1985: A362

  View details for DOI 10.1203/00006450-198504000-01531

  View details for Web of Science ID A1985AEU1801506

• BILIRUBIN PRODUCTION AFTER SUPPLEMENTAL ORAL VITAMIN-E THERAPY IN PRETERM INFANTS JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Smith, D. W., Cohen, R. S., Vreman, H. J., Yeh, A., SHARRON, S., Stevenson, D. K. 1985; 4 (1): 38-44

  Abstract

  The purpose of this investigation was to determine the influence of early vitamin E supplementation on the rate of heme catabolism (bilirubin production) in healthy preterm infants. Bilirubin production was estimated from the concentration of carbon monoxide in "end-tidal" gas. Serum vitamin E, hemoglobin, and bilirubin levels were determined by standard techniques. Thirty infants received supplementation with vitamin E or placebo in a double-blind, randomized fashion. Infants were studied on day 1 of life prior to therapy, and on days 3 and 7 postnatally. Results showed that in both placebo-supplemented and vitamin E-supplemented groups, vitamin E levels were significantly higher on days 3 and 7 compared with day 1. Bilirubin production was not significantly different on day 3 compared with day 1 in either group, but was significantly lower in both groups by day 7 compared with day 1. There were no significant differences in hemoglobin and serum bilirubin levels between the two groups at any point in time. In conclusion, although vitamin E supplementation significantly raises vitamin E levels, placebo-supplemented premature infants also achieve vitamin E sufficiency and a decrease in bilirubin production by day 7 of age.

  View details for Web of Science ID A1985ABS3400008

  View details for PubMedID 3981366

• EFFECT OF TIN PROTOPORPHYRIN ON THE EXCRETION RATE OF CARBON-MONOXIDE IN NEWBORN RATS AFTER HEMATOMA FORMATION JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Posselt, A. M., Cowan, B. E., Kwong, L. K., Vreman, H. J., Stevenson, D. K. 1985; 4 (4): 650-654

  Abstract

  This study evaluated the efficacy of tin protoporphyrin (TP), a competitive inhibitor of heme oxygenase, in suppressing the total body excretion rate of carbon monoxide (CO), an index of total bilirubin formation, in neonatal rats with artificially created hematomas. Wistar rat litters less than 12 h old were each divided into three groups of similar weight and treated as follows: (a) saline control (S); (b) hematoma, 80 microliter blood (H); (c) TP, 65 mumol/kg, and hematoma (TP-H). CO excretion of the H group increased rapidly after hematoma formation, reaching a maximum value of 79 +/- 4 SE microliter/kg/h 25 h later. Treatment with TP did not affect the pattern of CO excretion or its magnitude (78 +/- 2 SE microliter/kg/h, 25 h posthematoma). The S group showed no increase in CO excretion at this time (40 +/- 2 SE microliter/kg/h). At the conclusion of the experiment (45 h posthematoma), the plasma total bilirubin levels were slightly lower in the TP-H rats (1.0 +/- 0.1 SE mg/dl) than in H rats (1.2 +/- 0.1 SE mg/dl). The S rats had a plasma total bilirubin concentration of 0.8 +/- 0.1 SE mg/dl. The hepatic and splenic heme oxygenase activities were decreased by 61% (p less than 0.001) and 48% (p less than 0.05), respectively, in the TP-H rats as compared to the H rats. The S and H rats had similar enzyme activities. The results of this study suggest that though single-dose TP decreased tissue heme oxygenase activity, it did not significantly affect total bilirubin formation.

  View details for Web of Science ID A1985ALA8000027

  View details for PubMedID 3839847

• TIN PROTOPORPHYRIN (TP) AND THE EXCRETION RATE OF CO (VECO) IN ANTIBIOTIC-TREATED NEONATAL RATS WITH ARTIFICIAL HEMATOMAS Posselt, A., Kwong, L., Cowan, B., Vreman, H., Stevenson, D. K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1985: A358–A358

  View details for Web of Science ID A1985AEU1801485

• USE OF NONINVASIVE TESTS TO PREDICT SIGNIFICANT JAUNDICE IN FULL-TERM INFANTS - PRELIMINARY STUDIES PEDIATRICS Smith, D. W., Inguillo, D., Martin, D., Vreman, H. J., Cohen, R. S., Stevenson, D. K. 1985; 75 (2): 278-280

  View details for Web of Science ID A1985ABK4100011

  View details for PubMedID 3969329

• INTESTINAL FLORA IN THE 2ND WEEK OF LIFE IN HOSPITALIZED PRETERM INFANTS FED STORED FROZEN BREAST-MILK OR A PROPRIETARY FORMULA CLINICAL PEDIATRICS Stevenson, D. K., Yang, C., Kerner, J. A., YEAGER, A. S. 1985; 24 (6): 338-341

  Abstract

  Twenty infants fed stored frozen breast milk or a proprietary formula only had both aerobic and anaerobic cultures performed at a chronologic age of 8 to 14 days. Nine out of 10 stools from the infants fed stored frozen breast milk contained Enterobacteriaceae and one stool was sterile. One contained a Pseudomonas species; one contained anaerobic gram-positive rods; one contained anaerobic gram-negative rods; and four contained anaerobic gram-positive cocci. No anaerobes were found in six stools. Six stools had aerobic gram-positive cocci, none of which was hemolytic. Nine out of 10 stools from infants fed a proprietary formula had Enterobacteriaceae. Six stools had anaerobic gram-positive rods, three had anaerobic gram-negative rods, and four had gram-positive cocci. Four stools had no anaerobic bacteria. All 10 stools had nonhemolytic aerobic gram-positive cocci. Enterobacteriaceae were predominant in the stools of the infants fed either stored frozen breast milk or a proprietary formula, and the colony counts of aerobic bacteria were similar in both groups. This pattern of intestinal flora in hospitalized preterm infants in the second week of life is very different from that of normal term infants and may contribute to their increased incidence of systemic and localized infections. The use of stored frozen breast milk for the purpose of suppressing coliform and other potentially pathogenic organisms may not be effective in hospitalized preterm infants who have been treated previously with broad-spectrum, parenteral antibiotics.

  View details for Web of Science ID A1985AHW9200008

  View details for PubMedID 3995864

• SEQUELAE OF ACQUIRED CYTOMEGALO-VIRUS INFECTION IN PREMATURE AND SICK TERM INFANTS JOURNAL OF PEDIATRICS PARYANI, S. G., YEAGER, A. S., HOSFORDDUNN, H., Johnson, S. J., MALACHOWSKI, N., Ariagno, R. L., Stevenson, D. K. 1985; 107 (3): 451-456

  Abstract

  To assess the risk of long-term sequelae after acquired cytomegalovirus (CMV) infection in premature and sick term infants, 55 CMV infected patients were matched prospectively with 55 control patients and these matched pairs were evaluated at 3 years of age. Sensorineural hearing losses were present in four of 43 CMV infected patients (all mild-moderate) and in two of 43 controls (one severe). The incidence of neurologic sequelae was not increased in CMV infected patients with birth weight greater than 2000 gm. Among patients with birth weight less than 2001 gm, moderately abnormal EEGs were found in four (17%) of 23 CMV infected patients and in one (4%) of 23 controls, and severe handicaps occurred in four (14%) of 29 CMV infected patients and in two (7%) of 29 controls. Severe handicaps in premature infants were significantly (P less than 0.05) associated with early onset of CMV excretion (less than 8 weeks of age) and severe cardiopulmonary disease. Among the premature infants who were documented early excretors, three of 13 had severe neuromuscular impairment, four of 13 had severe handicaps (DQ less than 70, severe neuromuscular impairment, or profound loss of vision or hearing), and an additional four had DQs of 70 to 79. Among their matched control subjects, none of 13 had severe neuromuscular impairment, two of 13 had severe handicaps, and an additional two had DQs between 70 and 79. None of the premature infants who were documented late excretors (greater than or equal to 8 weeks of age) had any neurologic sequelae. The risk of neurologic sequelae and handicap may be increased in premature infants with onset of CMV excretion in the first 2 months of life.

  View details for Web of Science ID A1985AQU3800028

  View details for PubMedID 2993576

• USE OF SODIUM-NITROPRUSSIDE IN NEONATES - EFFICACY AND SAFETY JOURNAL OF PEDIATRICS Benitz, W. E., MALACHOWSKI, N., Cohen, R. S., Stevenson, D. K., Ariagno, R. L., Sunshine, P. 1985; 106 (1): 102-110

  Abstract

  Sodium nitroprusside was administered to 58 neonates, including 11 with severe respiratory distress syndrome, 15 with persistent pulmonary hypertension of the newborn, 28 with clinical shock, three with systemic hypertension, and two with pulmonary hypoplasia, all refractory to conventional intensive therapy. Nitroprusside was infused at 0.2 to 6.0 micrograms/kg/min for periods of 10 minutes to 126 hours. Infants with severe respiratory distress syndrome had increased PaO2 and decreased PaCO2 or peak inspiratory pressure, and nearly all (82%) survived. Infants with persistent pulmonary hypertension of the newborn had variable responses; improvement did not correlate with survival, but survival (47%) was identical to that in an earlier series of infants given tolazoline. Infants in shock had improved perfusion, urine output, and serum bicarbonate levels, and these responses were significantly related to survival. Hypertension was controlled in all three hypertensive infants. Adverse effects were very uncommon. Toxic effects were not observed. Sodium nitroprusside is effective and can be used safely in circulatory disorders in the neonate.

  View details for Web of Science ID A1985AAH1500023

  View details for PubMedID 3917495

• SURVIVAL AND MORBIDITY OF OUR SMALLEST BABIES - IS THERE A LIMIT TO NEONATAL CARE PEDIATRICS Cohen, R. S., Stevenson, D. K., Ariagno, R. L., Sunshine, P. 1984; 73 (3): 415-416

  View details for Web of Science ID A1984SG26800040

  View details for PubMedID 6701075

• NO INCREASE IN BILIRUBIN PRODUCTION IN THE 2ND WEEK IN HEALTHY TERM INFANTS FED BREAST-MILK Meyers, C. H., Stevenson, D. K., Kwong, L. K., Vreman, H. J., DUKE, P. M., Smith, D. W. SLACK INC. 1984: A126–A126

  View details for Web of Science ID A1984RZ82200747

• THE EFFECT OF TIN PROTOPORPHYRIN ON THE BILIRUBIN PRODUCTION-RATE IN NEWBORN RATS Cowan, B. E., Kwong, L. K., Vreman, H. J., Stevenson, D. K. SLACK INC. 1984: A122–A122

  View details for Web of Science ID A1984RZ82200720

• PREDICTION OF HYPERBILIRUBINEMIA IN TERM INFANTS SMITH, D. W., EHLERS, D., INGUILLO, D., VREMAN, H. J., STEVENSON, D. K. SLACK INC. 1984: A103

  View details for Web of Science ID A1984RZ82200610

• OXYTOCIN AND NEONATAL HYPERBILIRUBINEMIA - STUDIES OF BILIRUBIN PRODUCTION AMERICAN JOURNAL OF DISEASES OF CHILDREN Johnson, J. D., Aldrich, M., Angelus, P., Stevenson, D. K., Smith, D. W., HERSCHEL, M. J., Papagaroufalis, C., Valaes, T. 1984; 138 (11): 1047-1050

  Abstract

  We studied the effect of oxytocin induction or augmentation of labor on rates of bilirubin production in newborns at three different institutions. Bilirubin production, assessed quantitatively by the pulmonary excretion rate of carbon monoxide or qualitatively by the blood carboxyhemoglobin concentration, was not elevated when compared with appropriately matched control groups. Previous studies have implicated administration of large volumes of electrolyte-free dextrose solutions together with oxytocin as an important factor contributing to hemolysis in the infant. The mothers in our studies received minimal amounts of free water. We conclude that oxytocin induction or augmentation of labor does not result in neonatal hemolysis and subsequent hyperbilirubinemia when it is administered without large volumes of sodium-free intravenous solutions.

  View details for Web of Science ID A1984TQ40400010

  View details for PubMedID 6496421

• LATERAL DECUBITUS POSITION AS THERAPY FOR PERSISTENT FOCAL PULMONARY INTERSTITIAL EMPHYSEMA IN NEONATES - A PRELIMINARY-REPORT JOURNAL OF PEDIATRICS Cohen, R. S., Smith, D. W., Stevenson, D. K., MOSKOWITZ, P. S., Graham, C. B. 1984; 104 (3): 441-443

  View details for Web of Science ID A1984SH24800023

  View details for PubMedID 6707799

• THE BACTERIAL CONTENT OF BREAST-MILK AFTER THE EARLY INITIATION OF EXPRESSION USING A STANDARD TECHNIQUE JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION ASQUITH, M. T., PEDROTTI, P. W., HARROD, J. R., Stevenson, D. K., Sunshine, P. 1984; 3 (1): 104-107

  Abstract

  This study was initiated to evaluate the effect of early expression on the bacterial colony count of human milk. Significant bacterial contamination (greater than or equal to 10,000 colony-forming units/ml milk) was more common in 11 mothers who delayed the onset of expression of their milk compared with mothers who began to express their milk in the immediate postpartum period (n = 15) or who began to nurse their own full-term infants soon after delivery (n = 9). These data suggest that mothers who are separated from their prematurely born or sick infants should begin to express milk for their own infants as soon after birth as possible to provide milk with low bacterial contamination for frozen storage and later use.

  View details for Web of Science ID A1984RW76000022

  View details for PubMedID 6694039

• PULMONARY EXCRETION RATE OF CARBON-MONOXIDE AS AN INDEX OF TOTAL BILIRUBIN FORMATION IN ADULT MALE WISTAR RATS WITH COMMON BILE-DUCT LIGATION JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Stevenson, D. K., Salomon, W. L., MOORE, L. Y., TRUDGEN, J. K., Cowan, B. E., Vreman, H. J., Kwong, L. K. 1984; 3 (5): 790-794

  Abstract

  Total bilirubin formation (TBF) in the rat after a short period of common bile duct ligation was studied by measuring the pulmonary excretion rate of CO (VECO). At postoperative day 3, the VECO of experimental animals was higher when compared with the preoperative VECO (p less than 0.005); whereas the VECO of control animals did not change. Also, on the 3rd postoperative day, the relative rate of early labeling of bilirubin following the administration of delta-aminolevulinic acid-5-14C, a preferential hepatic heme synthesis precursor, was similar between the experimental and control animals; only the experimental animals had an abnormal peroxide hemolysis test. We conclude that common bile duct ligation in the rat is associated with elevations in the VECO, indicating significant increases in TBF, and the source of the increase is probably of erythropoietic origin. This finding may be relevant to the understanding of the pathophysiology of obstructive jaundice in human neonates.

  View details for Web of Science ID A1984TN98700026

  View details for PubMedID 6438296

• HYDROGEN GAS EXCRETION AFTER SUCROSE GAVAGE IN THE FASTED RAT AMERICAN JOURNAL OF CLINICAL NUTRITION Griffin, G. C., Kwong, L. K., Morrill, J. S., Vreman, H. J., Stevenson, D. K. 1984; 40 (4): 758-762

  Abstract

  The effect of a 3-day fast on the functional ability of the adult rat to hydrolyze and absorb sucrose was determined. The evaluation was based on previous studies which have shown the total amount of hydrogen gas (H2) excreted by the animal to reflect the extent of undigested carbohydrate entering the colon from the small intestine. H2 excretion was measured using a gas chromatographic technique in experimental (72 h fasted) and control (12 h fasted) animals after administration of sucrose by gastric gavage. Total H2 excretion was 3-fold higher in the experimental animals (n = 5) than in the controls (n = 5) (p less than 0.005) indicating a significant increase of sucrose malabsorption in the experimental animals. Administration of a second dose of sucrose 8 to 9 h after the first dose (refeeding) resulted in markedly decreased malabsorption relative to the first administration in both experimental (n = 2) and control (n = 2) animals. These results suggest that a 3-day fast markedly impairs the ability of the intestine to hydrolyze and absorb sucrose and that refeeding rapidly restores the ability to utilize this substrate. H2 excretion was similar between experimental and control animals after the administration of lactulose, a nonabsorbed and nondigested carbohydrate, suggesting that the observed results of the sucrose studies were independent of any possible changes in the intestinal microflora.

  View details for Web of Science ID A1984TN99200004

  View details for PubMedID 6486082

• NEONATAL BILIRUBIN PRODUCTION ESTIMATED FROM END-TIDAL CARBON-MONOXIDE CONCENTRATION JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Smith, D. W., Hopper, A. O., SHAHIN, S. M., Cohen, R. S., OSTRANDER, C. R., Ariagno, R. L., Stevenson, D. K. 1984; 3 (1): 77-80

  Abstract

  The relationship between the pulmonary excretion rate of carbon monoxide (VECO) and the concentration of CO, in a sample of breath, drawn through a nasopharyngeal catheter at end-expiration, was assessed in 25 studies of nine preterm and 14 term infants. The VECO and this approximate end-tidal sample of CO (ETCO) correlated significantly over a wide range of CO elimination rates: VECO = 10.45 ETCO + 2.25 (n = 25, r = 0.95). The ETCO correctly predicted elevations in VECO greater than 2 SD of the mean VECO for normal infants (13.9 +/- 3.5 microliter/kg/h), with 90% sensitivity and 73% specificity (p less than 0.01). Three subjects with Rh isoimmune hemolytic disease were easily identified by the ETCO as well as the VECO. The ETCO is a simple, noninvasive measurement for rapidly identifying infants with significant hemolytic disease.

  View details for Web of Science ID A1984RW76000017

  View details for PubMedID 6537974

• THE ROLE OF BILIRUBIN PRODUCTION IN BREAST-FED INFANTS WITH ELEVATED SERUM BILIRUBIN CONCENTRATIONS AT 2 WEEKS OF LIFE CLINICAL PEDIATRICS Meyers, C. H., Kwong, L. K., Vreman, H. J., Stevenson, D. K. 1984; 23 (9): 480-482

  Abstract

  The carboxyhemoglobin level (COHb), an accepted qualitative index of bilirubin production, was measured in normal, full-term, breast-fed (n = 9) or formula-fed (n = 11) infants at 2 days and 2 weeks of life. The mean COHb did not differ significantly at 2 days and 2 weeks in either of the groups, nor did the mean COHb differ between the groups at 2 weeks. The mean serum bilirubin concentration was lower in the formula-fed infants compared to the breast-fed infants at 2 weeks (p less than 0.05). The mean serum bilirubin concentration decreased by only 14 percent among the breast-fed infants, and actually increased in three infants by 2 weeks. In comparison, the mean serum bilirubin concentration of the formula-fed infants decreased by 61 percent (p less than 0.05), with the serum bilirubin concentration decreasing in each infant by 2 weeks. These findings are consistent with the generally held belief that bilirubin production is not the primary etiology of elevated serum bilirubin concentrations associated with breast-feeding in the second week of life. However, continued high bilirubin production at 2 weeks may contribute to the potential for significant jaundice in some infants with impaired hepatic function or increased enterohepatic circulation of bilirubin.

  View details for Web of Science ID A1984TG73200005

  View details for PubMedID 6467779

• CARBON-MONOXIDE IN BLOOD - AN IMPROVED MICROLITER BLOOD-SAMPLE COLLECTION SYSTEM, WITH RAPID ANALYSIS BY GAS-CHROMATOGRAPHY CLINICAL CHEMISTRY Vreman, H. J., Kwong, L. K., Stevenson, D. K. 1984; 30 (8): 1382-1386

  Abstract

  We examined the sensitive assay for carboxyhemoglobin based on reaction with K3Fe(CN)6 and gas chromatography of the liberated CO. Our improvements included increased baseline stability, shorter analysis time, and simpler standardization. EDTA-containing Vacutainer Tubes (lavender-stoppered) increase the carboxyhemoglobin content of blood stored in them. The carboxyhemoglobin content of blood stored in capillary tubes containing solid heparin and saponin remained stable for two weeks. Using our improved procedures, we measured the carboxyhemoglobin content of blood from adults and neonates collected via venipuncture or heel or fingersticks. We observed no significant difference in carboxyhemoglobin content of blood obtained by venipuncture or heel stick for premature infants, 0.19 +/- 0.04 vs 0.18 +/- 0.03 mL of CO per 100 mL of blood, respectively (mean +/- SD). Nonsmoking adults (n = 19) had CO values (mean +/- SD) of 0.19 +/- 0.03 and 0.17 +/- 0.04 mL per 100 mL of blood, and smoking adults (n = 7) gave CO values of 0.96 +/- 0.49 and 0.91 +/- 0.49 mL/dL, for venipuncture and fingerstick, respectively.

  View details for Web of Science ID A1984TN07800025

  View details for PubMedID 6744592

• DETECTION OF GASTRIC CONTENTS IN TRACHEAL FLUID OF INFANTS BY LACTOSE ASSAY JOURNAL OF PEDIATRICS Hopper, A. O., Kwong, L. K., Stevenson, D. K., SHAHIN, S. M., DHARLINGUE, A., TSUBOI, K. K., Ariagno, R. L. 1983; 102 (3): 415-418

  Abstract

  We designed an in vitro assay to detect the presence of lactose in the tracheal aspirates of premature, ventilator-dependent infants. This method was employed to identify recurrent, unrecognized aspiration, which could prolong the requirements for ventilator support and contribute to the development of chronic lung disease. One hundred five determinations of lactose were performed on the tracheal fluid obtained from 42 ventilator-dependent infants who were receiving enteral feedings. There was a wide range of lactose levels (0 to 3,270 nmol lactose/ml tracheal aspirate). Six infants had samples that were highly suggestive of aspiration (greater than 200 nmol lactose/ml tracheal aspirate). Twenty infants had questionably positive samples (25 to 200 nmol lactose/ml tracheal aspirate), and 16 infants had samples that were considered negative for aspiration (less than 25 nmol lactose/ml tracheal aspirate).

  View details for Web of Science ID A1983QF66500023

  View details for PubMedID 6402576

• LIMITED VALUE OF NEPHELOMETRY IN MONITORING THE ADMINISTRATION OF INTRAVENOUS FAT IN NEONATES JOURNAL OF PARENTERAL AND ENTERAL NUTRITION DHARLINGUE, A., HOPPER, A. O., STEVENSON, D. K., SHAHIN, S. M., KERNER, J. A. 1983; 7 (1): 55–58

  Abstract

  To evaluate the usefulness of nephelometry in predicting hyperlipidemia in neonates receiving intravenous fat (IVF), 23 infants in our neonatal intensive care nursery had simultaneous measurements of the serum IVF level (as determined by nephelometry), triglyceride, cholesterol, and free fatty acid/albumin molar ratio. There was a positive correlation between the serum IVF level and triglycerides, but the IVF level did not reliably predict elevated triglycerides, cholesterol, or free fatty acid-albumin molar ratio. Thus, neonates receiving IVF emulsions cannot be monitored by nephelometry alone. Adequate monitoring requires measurement of specific lipid fractions.

  View details for DOI 10.1177/014860718300700155

  View details for Web of Science ID A1983QB56200011

  View details for PubMedID 6682158

• EFFECTS OF A COMMERCIAL STARCH BLOCKER PREPARATION ON CARBOHYDRATE DIGESTION AND ABSORPTION - INVIVO AND INVITRO STUDIES AMERICAN JOURNAL OF CLINICAL NUTRITION HOLLENBECK, C. B., COULSTON, A. M., QUAN, R., BECKER, T. R., VREMAN, H. J., STEVENSON, D. K., REAVEN, G. M. 1983; 38 (4): 498–503

  Abstract

  We have tested the effectiveness of a commercial starch blocker on the digestion and absorption of dietary carbohydrates in six normal, healthy volunteers. The effectiveness of the starch blocker to attenuate or block the digestion of carbohydrate was assessed against a placebo by the measurement of end tidal breath hydrogen, plasma glucose, and insulin responses to a constant test meal. There were no significant differences in breath hydrogen, or plasma glucose and insulin responses. In vitro enzyme inhibition studies assessed the ability of the brush border enzyme maltase/glucoamylase to degrade starch in the presence of the starch blockers. A highly purified solution of rat and human maltase/glucoamylase was capable of degrading a starch solution, while 40 mM Tris-HCl (a known maltase/glucoamylase inhibitor) completely abolished the enzyme activity. These data challenge the claims that starch blocker preparations are effective in reducing or attenuating the absorption of carbohydrates or calories from a mixed meal. The ineffectiveness in vivo could be explained, in part, by the ability of the brush border enzyme maltase/glucoamylase to hydrolyze starch in the presence of starch blockers.

  View details for Web of Science ID A1983RL60500001

  View details for PubMedID 6414283

• ELEVATIONS OF THE PULMONARY EXCRETION RATE OF CO (VECO) IN RATS WITH COMMON BILE-DUCT LIGATION TRUDGEN, J. K., Cowan, B. E., MOORE, L. Y., Smith, D. W., OSTRANDER, C. R., Kwong, L. K., Stevenson, D. K. SLACK INC. 1983: A139–A139

  View details for Web of Science ID A1983PU88600823

• PREDOMINANCE OF BRONCHOPULMONARY DYSPLASIA (BPD) IN INFANTS LESS-THAN-1500 GM AT BIRTH Smith, D. W., Stevenson, D. K., Sunshine, P., Northway, W., Ariagno, R. L. AMER THORACIC SOC. 1983: 212–12

  View details for Web of Science ID A1983QM03800591

• BREATH HYDROGEN ANALYSIS - A REVIEW OF THE METHODOLOGIES AND CLINICAL-APPLICATIONS JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION OSTRANDER, C. R., Cohen, R. S., Hopper, A. O., SHAHIN, S. M., Kerner, J. A., Johnson, J. D., Stevenson, D. K. 1983; 2 (3): 525-533

  Abstract

  Hydrogen gas (H2) is a product of the fermentation of dietary carbohydrate (CHO) by bacteria in the lumen of the gastrointestinal tract in man. Thus, H2 is actually an exogenously produced gas, which either is passed as flatus, or diffuses into the body and is exhaled. In the adult, a fairly constant fraction is expired, providing a reliable indicator of total colonic H2 production. Breath H2 analysis currently represents a useful clinical means of testing adults and older children for the malabsorption of CHO. Noninvasive and easy procedures for the collection of expired air have encouraged their increasingly widespread use in pediatrics. Evidence to date suggests that breath H2 analysis may provide the best available method for estimating semiquantitatively the degree of CHO malabsorption. The association of the results of breath H2 analysis with other clinical measures of CHO digestion and absorption is expected, but discrepancies can also be anticipated based on the nature of this particular trace gas method. The interpretation of the results of breath H2 analysis in neonates and young infants remains especially problematic because of confounding variables which are difficult to control and are measured infrequently.

  View details for Web of Science ID A1983RC94400022

  View details for PubMedID 6620060

• MATERNAL BETA-ADRENERGIC TOCOLYSIS AND NEONATAL BILIRUBIN PRODUCTION AMERICAN JOURNAL OF DISEASES OF CHILDREN Hopper, A. O., Cohen, R. S., OSTRANDER, C. R., BRICKMAN, F. S., UELAND, K., Stevenson, D. K. 1983; 137 (1): 58-60

  Abstract

  The potential for beta-adrenergic drugs to increase total bilirubin formation via cyclic adenosine monophosphate-mediated stimulation of hepatic microsomal heme oxygenase in the human neonate was evaluated. The pulmonary excretion rate of endogenously produced carbon monoxide (VeCO), an index of total bilirubin formation (TBF), was measured in 18 preterm neonates whose mothers received beta-adrenergic drugs for tocolysis and in 18 preterm neonates whose mothers were untreated. The mean VeCO of the neonates in the former group (17.2 +/- 7.3 microL/kg/hr) was the same as that in the latter group (17.4 +/- 6.2 microL/kg/hr); both values were elevated when compared with the mean VeCO of 20 term newborns (13.9 +/- 3.5 microL/kg/hr). Our findings indicate that TBF is not significantly increased in neonates whose mothers received beta-adrenergic drugs before delivery.

  View details for Web of Science ID A1983PV55800013

  View details for PubMedID 6128920

• USE OF END-TIDAL CARBON-MONOXIDE TO CORRECT END-TIDAL HYDROGEN IN NEONATES JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Hopper, A. O., Smith, D. W., OSTRANDER, C. R., Cohen, R. S., Stevenson, D. K. 1983; 2 (4): 659-662

  Abstract

  We evaluated the usefulness of end-tidal CO (ETCO) as an internal standard for reducing the error in end-tidal H2 (ETH2) measurements due to contamination of repeated breath samples with nonalveolar gas. Triplicate end-tidal samples were drawn from 12 healthy premature infants in small (less than 1 cc) increments through a posterior nasopharyngeal catheter at end-expiration, determined from the infant's chest wall movement. CO and H2 determinations were made on each sample by a reduction gas detector capable of determining CO and H2 concentrations to +/- 0.001 and 0.010 ppm, respectively. Respiratory breath samples were corrected for ambient CO and H2 concentrations. Since the alveolar gas fraction has the highest CO concentration of all tidal gases, the end-tidal sample with the highest CO peak was assumed to be most representative of uncontaminated alveolar gas. The other samples were "corrected" using a factor that was the ratio of the patient's highest CO peak to the given sample's CO value. The use of ETCO to correct ETH2 from samples deliberately contaminated with ambient air can significantly reduce the variability of ETH2 values. However, such correction is probably not necessary when comparing groups of infants using a standard collection technique. For individual infants, correction may reveal more marked short-term fluctuations in true alveolar H2 concentration.

  View details for Web of Science ID A1983RM46200015

  View details for PubMedID 6644447

• THE EFFECT OF TIN PROTOPORPHYRIN ON THE BILIRUBIN PRODUCTION-RATE IN NEWBORN RATS PEDIATRIC PHARMACOLOGY Cowan, B. E., Kwong, L. K., Vreman, H. J., Stevenson, D. K. 1983; 3 (2): 95-100

  Abstract

  Using a flow-through system, the pulmonary excretion rate of carbon monoxide (VECO) was determined by gas chromatography and used as an index of bilirubin production in newborn rats treated with tin protoporphyrin. Hepatic and splenic heme oxygenase activities were determined spectrophotometrically. No significant differences in the VECO were found between experimental and control animals despite significant decreases in hepatic heme oxygenase activity (P less than .0005) and splenic heme oxygenase activity (P less than .025). These results suggest that 1) there is no simple relation between heme oxygenase activity and bilirubin production; 2) heme oxygenase is present in excess amounts in neonatal rats; and 3) the lowering of serum bilirubin levels caused by tin protoporphyrin cannot be attributed to decreased bilirubin production and may be owing instead to increased uptake, conjugation, or excretion of bilirubin, or decreased enterohepatic circulation of bilirubin.

  View details for Web of Science ID A1983SJ33800006

  View details for PubMedID 6689532

• ON THE MECHANISM OF NORMAL INTESTINAL LACTASE DECLINE IN THE POSTWEANED MAMMAL TSUBOI, K. K., DHARLINGUE, A., Kwong, L. K., Stevenson, D. K., Kerner, J. A., Sunshine, P. SLACK INC. 1983: A106–A106

  View details for Web of Science ID A1983PU88600631

• INCIDENCE OF ACTIVE PROLIFERATIVE RETROLENTAL FIBROPLASIA (RLF) IN INFANTS LESS-THAN-OR-EQUAL-TO 1000 GRAMS DHARLINGUE, A. E., Gaynon, M., MALACHOWSKI, N., Stevenson, D. K., Sunshine, P. SLACK INC. 1983: A113–A113

  View details for Web of Science ID A1983PU88600671

• PREDICTING SURVIVAL AMONG VENTILATOR-DEPENDENT VERY LOW-BIRTH-WEIGHT INFANTS CRITICAL CARE MEDICINE KIMBLE, K. J., Ariagno, R. L., Stevenson, D. K., Sunshine, P. 1983; 11 (3): 182-185

  Abstract

  Ventilator-bound very low birth weight (VLBW) infants represent an increasing proportion of our nursery population. We reviewed the hospital course of 38 VLBW infants who required more than 1 month of intermittent mandatory ventilation (IMV) between 1976 and 1978. Twenty-eight infants survived; 10 died. There were no significant differences between survivors and nonsurvivors in estimated gestational age (EGA), Apgar scores, first pH, first mean arterial pressure (MAP), h of IMV required, or birth weight; nor did the incidence of patent ductus arteriosus (PDA), respiratory distress syndrome (RDS), or transport differ. Pneumothorax was significantly more common among those infants who died. When ventilator settings were reviewed, significant differences were found consistently between the 2 groups of 3, 5, and 7 days of age, but not at 1, 14, 21, or 28 days of age. A predictive model for estimating the probability of survival of such infants was developed based upon these data, employing birth weight, mean airway pressure (MAWP) at 7 days of age, and occurrence of pneumothorax, and was applied prospectively to a group of 29 such infants born in 1979 and 1980. Prediction of outcome was significantly more accurate than chance alone. We conclude that prolonged ventilator dependence is largely confined to VLBW infants; that it is the rule among infants less than 750 g; and that accurate, objective assessment of an individual infant's prognosis may lead to improved care.

  View details for Web of Science ID A1983QH45800007

  View details for PubMedID 6831887

• SEQUELAE OF MATERNALLY DERIVED CYTOMEGALOVIRUS INFECTIONS IN PREMATURE-INFANTS JOURNAL OF PEDIATRICS YEAGER, A. S., Palumbo, P. E., MALACHOWSKI, N., Ariagno, R. L., Stevenson, D. K. 1983; 102 (6): 918-922

  Abstract

  Eighteen of 106 (17%) infants of seropositive mothers, with birth weights less than 1500 gm, acquired cytomegalovirus from a maternal source. Neutropenia, lymphocytosis, thrombocytopenia, and hepatosplenomegaly developed in some infants concomitant with the onset of CMV excretion. Infected infants who excreted CMV at less than 7 weeks of age had longer oxygen requirements than infants who did not excrete CMV until they were older. Passively derived maternal antibody to CMV fell more rapidly over the first few months of life in sick premature infants than would be expected in term infants. Among six infected premature infants, five had undetectable antibody titers when CMV excretion began. Loss of passively acquired antibody and early excretion of virus appear to be associated with symptomatic CMV infections in premature infants of seropositive mothers.

  View details for Web of Science ID A1983QU32100022

  View details for PubMedID 6304275

• FAVORABLE RESULTS OF NEONATAL INTENSIVE-CARE FOR VERY LOW-BIRTH-WEIGHT INFANTS PEDIATRICS Cohen, R. S., Stevenson, D. K., MALACHOWSKI, N., Ariagno, R. L., KIMBLE, K. J., Hopper, A. O., Johnson, J. D., UELAND, K., Sunshine, P. 1982; 69 (5): 621-625

  Abstract

  From 1961 to 1976, 229 infants with birth weights ranging from 751 to 1,000 gm were admitted to the Stanford University Hospital Intensive Care Nursery. The overall neonatal mortality for these infants was 63% (144/229), and there were ten late deaths. Before 1967, no infant in this group who required mechanical ventilation survived; thereafter, 30% (34/114) of the ventilated patients survived. Of the 75 long-term survivors 60 participated in a high-risk infant follow-up program; these included 23 infants who had received mechanical ventilation. The mean birth weight of these infants was 928 +/- 67 (SD) gm. Seventeen children (28%) had significant morbidity: seven (12%) with severe handicaps and ten (17%) with moderate handicaps. During this same period, seven infants weighing less than 750 gm at birth were also observed. The three infants who had not required ventilatory support thrived; the other four infants had required respirators and were significantly handicapped. More recently, neonatal mortality for infants with birth weights from 751 to 1,000 gm has improved: for 1977 to 1980, it was 28% (33/118). Furthermore, neonatal mortality for ventilated infants in this weight group was 27% (26/95). These data indicate an improved prognosis for very low-birth-weight infants, even with ventilatory support.

  View details for Web of Science ID A1982NN58700022

  View details for PubMedID 7079021

• EVALUATION OF SERUM FREE-THYROXINE LEVELS IN TERM, PRETERM, AND SICK INFANTS HOPPER, A. O., WILSON, D. M., MCDOUGALL, I. R., BAYER, M. F., HINTZ, R. L., ROSENFELD, R. G., STEVENSON, D. K. SLACK INC. 1982: A113

  View details for Web of Science ID A1982MX91200665

• SERUM FREE-THYROXINE VALUES IN TERM, PREMATURE, AND SICK INFANTS JOURNAL OF PEDIATRICS Wilson, D. M., Hopper, A. O., McDougall, I. R., BAYER, M. F., Hintz, R. L., Stevenson, D. K., Rosenfeld, R. G. 1982; 101 (1): 113-117

  Abstract

  Free thyroxine concentrations were determined by radioimmunoassay in 96 infants within an intensive care nursery and in 32 healthy term infants. Sera for free T4 levels were drawn simultaneously with the filter paper specimens for T4 obtained to screen these infants for congenital hypothyroidism. The mean free T4 level in 20 adults was 1.38 +/- 0.03 ng/dl (mean +/- SEM). The mean in the ICN infants was 3.48 +/- 0.18 ng/dl and in healthy term infants, 4.24 +/- 0.23 ng/dl. Like T4, free T4 correlated positively with increasing gestational age and birth weight, and was lower in infants with RDS. Although 66% of the ICN infants had T4 levels below the statistically selected screening level (fifth percentile), all of these infants had free T4 levels greater than 0.8 ng/dl. Two additional infants with untreated congenital hypothyroidism has free T4 levels of 0.3 and 0.4 ng/dl. The measurement of free T4 appears to be an accurate indicator of thyroid function in these infants.

  View details for Web of Science ID A1982NX34400029

  View details for PubMedID 7086610

• EVIDENCE FOR THE POSSIBLE RELATIONSHIP OF NEONATAL SKINFOLD THICKNESS TO MATERNAL GLUCOSE-METABOLISM DURING THE 3RD TRIMESTER JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Kerner, J. A., Stevenson, D. K., HATTNER, J. A., Cohen, R. S., Schwartz, H. C., Sunshine, P. 1982; 1 (1): 59-62

  Abstract

  Forty-eight infants, including 14 premature infants who were appropriate size for gestational age (AGA), 10 full-term AGA infants, 18 full-term infants who were large for gestational age (LGA), and six premature LGA infants of diabetic mothers (IDMs), had measurements of skinfold thickness (SFT) in the first 72 h of life. For the 24 LGA infants, there was a significant positive correlation between maternal glycohemoglobin (Hb AIc) in the post-partum period and SFT (r = 0.42, p less than 0.05). Our observations in this study support those of others, demonstrating that SFT increases with increasing gestational age. In addition, they support the hypothesis that, in diabetic pregnancies, or pregnancies associated with an elevated Hb AIc, a reflection of the time-integrated blood glucose level over the weeks preceding parturition, fetal hyperglycemia and hyperinsulinemia stimulate increased triglyceride synthesis in adipose cells and lead to an increase in fetal subcutaneous fat.

  View details for Web of Science ID A1982PB96400012

  View details for PubMedID 6193261

• PAIRED DETERMINATIONS OF BLOOD CARBOXYHEMOGLOBIN CONCENTRATION AND CARBON-MONOXIDE EXCRETION RATE IN TERM AND PRETERM INFANTS JOURNAL OF LABORATORY AND CLINICAL MEDICINE OSTRANDER, C. R., Cohen, R. S., Hopper, A. O., Cowan, B. E., Stevens, G. B., Stevenson, D. K. 1982; 100 (5): 745-755

  Abstract

  Paired determinations of COHb and VeCO were performed on 30 term infants (38 to 42 weeks' gestation) and 26 preterm infants (28 to 37 weeks' gestation) during the first week of life. All subjects were breathing room air at the time of the study. Values of COHb were corrected for RAco by linear regression of COHb (percent saturation) vs RAco (ppm). Regression coefficients for term and preterm infants with no history of pulmonary impairment were nearly identical (COHb = 0.175 RAco + 0.45, r = 0.77, n = 25 for term infants; COHb = 0.168 RAco + 0.51, r = 0.82, n = 9 for preterm infants) and agreed well with theoretical values. For the group of term infants, linear regression of Veco (microliter/kg/hr) vs. COHbc, where COHbc = COHb - 0.17 RAco, resulted in VEco = 23.4 COHbc + 4.02, r = 0.75, n = 30. The corresponding relationship for preterm infants with no history of pulmonary impairment was VEco = 24.7 COHbc + 3.85, r = 0.61, n = 13. For a subpopulation of preterm infants with a history of pulmonary dysfunction, the correlation decreased significantly, with VEco = 4.34 COHbc + 17.6, r = 0.097, n = 11. These results demonstrate that (1) COHbc is a reasonable index of VEco and consequently of the heme catabolic rate in both term and preterm infants with no clinical history of pulmonary dysfunction and (2) inference of VEco from COHbc may be misleading in certain cases without a consideration of the factors relating these two variables.

  View details for Web of Science ID A1982PN66000009

  View details for PubMedID 7130831

• PULMONARY EXCRETION RATES OF CARBON-MONOXIDE USING A MODIFIED TECHNIQUE - DIFFERENCES BETWEEN PREMATURE AND FULL-TERM INFANTS BIOLOGY OF THE NEONATE Cohen, R. S., OSTRANDER, C. R., Cowan, B. E., Stevens, G. B., Hopper, A. O., Stevenson, D. K. 1982; 41 (5-6): 289-293

  Abstract

  The pathophysiology of the exaggerated hyperbilirubinemia in premature infants remains unclear. The relative contribution of bilirubin production may be estimated by measuring the pulmonary excretion rate of carbon monoxide (VeCO). We found that the mean VeCO of premature infants, 16.7 +/- 5.0 microliters/kg/h, was significantly elevated (p less than 0.05) compared with the mean VeCO of full-term infants, 13.9 +/- 3.5 microliters/kg/h. Premature infants who required phototherapy had a significantly (p less than 0.05) higher mean VeCO than those who did not. The VeCO did not correlate with gestational age, implying that factors which associate frequently but variably with gestational age may have an important influence on heme catabolism.

  View details for Web of Science ID A1982NV61400012

  View details for PubMedID 7104416

• GROWTH TO AGE 3 YEARS AMONG VERY LOW-BIRTH-WEIGHT SEQUELAE-FREE SURVIVORS OF MODERN NEONATAL INTENSIVE-CARE JOURNAL OF PEDIATRICS KIMBLE, K. J., Ariagno, R. L., Stevenson, D. K., Sunshine, P. 1982; 100 (4): 622-624

  View details for Web of Science ID A1982NK67300025

  View details for PubMedID 7062213

• A SENSITIVE ANALYTICAL APPARATUS FOR MEASURING HYDROGEN PRODUCTION-RATES .1. APPLICATION TO STUDIES IN SMALL ANIMALS - EVIDENCE OF THE EFFECTS OF AN ALPHA-GLUCOSIDEHYDROLASE INHIBITOR IN THE RAT ANALYTICAL BIOCHEMISTRY OSTRANDER, C. R., Stevenson, D. K., Neu, J., Kerner, J. A., Moses, S. W. 1982; 119 (2): 378-386

  View details for Web of Science ID A1982NE96700025

  View details for PubMedID 7041699

• MACROSOMIA - CAUSES AND CONSEQUENCES JOURNAL OF PEDIATRICS Stevenson, D. K., Cohen, R. S., Kerner, J. A. 1982; 100 (4): 515-520

  View details for Web of Science ID A1982NK67300001

  View details for PubMedID 7062199

• BREATH HYDROGEN IN PRETERM INFANTS - CORRELATION WITH CHANGES IN BACTERIAL-COLONIZATION OF THE GASTROINTESTINAL-TRACT JOURNAL OF PEDIATRICS Stevenson, D. K., SHAHIN, S. M., OSTRANDER, C. R., Kerner, J. A., Cohen, R. S., Hopper, A. O., YEAGER, A. S. 1982; 101 (4): 607-610

  View details for Web of Science ID A1982PK84200032

  View details for PubMedID 7119967

• A SENSITIVE ANALYTICAL APPARATUS FOR MEASURING HYDROGEN PRODUCTION-RATES .2. APPLICATION TO STUDIES IN HUMAN INFANTS JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Stevenson, D. K., Cohen, R. S., OSTRANDER, C. R., SHAHIN, S. M., Kerner, J. A., WETMORE, D. L., Werner, S. B., Tomczyk, M., Johnson, J. D. 1982; 1 (2): 233-237

  Abstract

  We estimated hydrogen (H2) production by determining simultaneously the end-tidal concentration (ETH2) and the direct pulmonary excretion rate (VeH2) in normal-sized, healthy, term and preterm neonates between 2 days and 7 weeks of life who were receiving all their calories enterally as breast milk or a proprietary formula. We found that there was no peak or pattern in H2 production during the first 3 postprandial hours (mean VeH2 = 1.00 +/- 0.97 SD ml/kg/h; mean ETH2 = 40.3 +/- 33.1 SD ppm). Frequently, there was marked short-term variability of the ETH2 in a given infant (coefficient of variation = 13.4% +/- 18.7%). H2 production was elevated in normal neonates without signs of malabsorption. We found that VeH2 correlated with ETH2 using both nasopharyngeal catheter (r = 0.63; p less than 0.001) and nasal prong (r = 0.71; p less than 0.001) collection techniques. We conclude that breath hydrogen determinations in neonates are not readily comparable to similar studies in older patients. Longitudinal studies of individual infants may reveal changes in breath H2 excretion of sufficient magnitude to be distinguishable from moment-to-moment variations, and correlatable with certain intercurrent clinical problems affecting intestinal H2 production or pulmonary H2 excretion. However, interpretation of breath H2 determinations in human infants will be difficult.

  View details for Web of Science ID A1982PB96500014

  View details for PubMedID 7186035

• TRANS-CUTANEOUS OXYGEN MONITORING, HYPOXIC RANGE AND CORRELATION WITH PROSTAGLANDIN-E1 KIMBLE, K. J., Ariagno, R. L., Stevenson, D. K., Sunshine, P. NATURE PUBLISHING GROUP. 1981: 666–66

  View details for Web of Science ID A1981LG15501359

• SIMULTANEOUS DETERMINATIONS OF BREATH CONCENTRATION AND PULMONARY EXCRETION RATE OF HYDROGEN IN NEWBORNS OSTRANDER, C. R., COWAN, B. E., KERNER, J. A., STEVENSON, D. K., JOHNSON, J. D. WILLIAMS & WILKINS. 1981: 543

  View details for DOI 10.1203/00006450-198104001-00627

  View details for Web of Science ID A1981LG15500618

• CALORIC DEPRIVATION QUESTIONED IN BREAST-MILK JAUNDICE - REPLY PEDIATRICS STEVENSON, D. K. 1981; 67 (5): 749–50

  View details for Web of Science ID A1981LP33300045

• PULMONARY EXCRETION OF CARBON-MONOXIDE AS AN INDEX OF BILIRUBIN PRODUCTION .2A. EVIDENCE FOR POSSIBLE DELAYED CLEARANCE OF BILIRUBIN IN INFANTS OF DIABETIC MOTHERS JOURNAL OF PEDIATRICS Stevenson, D. K., OSTRANDER, C. R., Hopper, A. O., Cohen, R. S., Johnson, J. D. 1981; 98 (5): 822-824

  View details for Web of Science ID A1981LQ51000034

  View details for PubMedID 7229770

• TRANS-CUTANEOUS OXYGEN MONITORING, HYPOXIC RANGE AND CORRELATION WITH PROSTAGLANDIN-E1 KIMBLE, K. J., Ariagno, R. L., Stevenson, D. K., Sunshine, P. SLACK INC. 1981: A142–A142

  View details for Web of Science ID A1981KY10800841

• EFFECTS OF ASPHYXIA AND ORAL GENTAMICIN ON INTESTINAL LACTASE IN THE SUCKLING RAT PEDIATRIC PHARMACOLOGY Neu, J., Masi, M., Stevenson, D. K., Kwong, L. K., Hurwitz, R., Sunshine, P. 1981; 1 (3): 215-220

  Abstract

  The effect of oral gentamicin on lactase, the major disaccharidase of the neonatal intestine, was studied using the suckling Wistar rat as a model. The jejunal lactase-specific activity of asphyxiated animals given oral gentamicin at a dose of 20 mg/kg/day for two days was significantly decreased compared to that of nonasphyxiated animals given oral saline (P less than 0.01). Although the intestinal lactase-specific activity of nonasphyxiated animals given oral gentamicin at a dose of 20 mg/kg/day for two days was not significantly different from that of animals given oral saline, a high dose of oral gentamicin (160 mg/kg/day) was associated with decreased lactase-specific activity in both the jejunum and ileum. Intramuscular administration of gentamicin was not associated with decreased intestinal lactase-specific activity. More information is needed regarding the mechanism of the biochemical injury associated with the oral use of aminoglycosides and its clinical significance, if any, in the human infant. Until this is known, the potential for such injury should be of special concern where prophylaxis against necrotizing enterocolitis is being considered, particularly in view of the increased tendency for treated infants to become colonized with gram negative organisms resistant to the antibiotic being used.

  View details for Web of Science ID A1981LQ63100005

  View details for PubMedID 6810292

• PULMONARY EXCRETION OF CARBON-MONOXIDE IN THE HUMAN INFANT AS AN INDEX OF BILIRUBIN PRODUCTION .26. EVIDENCE FOR THE POSSIBLE EFFECT OF MATERNAL PRENATAL GLUCOSE-METABOLISM ON POSTNATAL BILIRUBIN PRODUCTION IN A MIXED POPULATION OF INFANTS EUROPEAN JOURNAL OF PEDIATRICS Stevenson, D. K., OSTRANDER, C. R., Cohen, R. S., Johnson, J. D., Schwartz, H. C. 1981; 137 (3): 255-259

  View details for Web of Science ID A1981MU40700002

  View details for PubMedID 7318835

• LATE MORBIDITY AMONG SURVIVORS OF NECROTIZING ENTEROCOLITIS PEDIATRICS Stevenson, D. K., Kerner, J. A., MALACHOWSKI, N., Sunshine, P. 1980; 66 (6): 925-927

  Abstract

  Of 40 survivors of necrotizing enterocolitis 19 were completely normal children at the time of follow-up, one to three years later. Among the other 21 children, only six had moderate to severe neurologic impairment, representing 15% of all survivors. Despite the fact that intestinal injury is the main feature of the neonatal disease, only four children were symptomatic from gastrointestinal sequelae, and none of these suffered failure to thrive. Thus, 81% (17) of the children with late morbidity had problems unrelated to the gastrointestinal tract. The nongastrointestinal morbidity was associated with prematurity and the degree of perinatal stress.

  View details for Web of Science ID A1980KU96100021

  View details for PubMedID 7454483

• COMPLEMENT CONCENTRATIONS AND ACTIVATION IN NECROTIZING ENTEROCOLITIS (NEC) Stevenson, D. K., Hsu, Y. P., McMorrow, M., Berseth, C. L., Neu, J., Miller, J. J. NATURE PUBLISHING GROUP. 1980: 612–12

  View details for Web of Science ID A1980JL99401117

• CEREBRO-COSTO-MANDIBULAR SYNDROME JOURNAL OF PEDIATRICS SILVERMAN, F. N., STREFLING, A. M., Stevenson, D. K., Lazarus, J. 1980; 97 (3): 406-416

  Abstract

  The cerebro-costo-mandibular syndrome is characterized by cerebral maldevelopment or malfunction or both, costal deficiencies, and micrognathia. Cleft palate and glossoptosis are frequently present and contribute to the common presenting sign, neonatal respiratory distress. Intrauterine and postnatal growth retardation are common. Familial cases are rare and the mode of transmission is uncertain. The deficiencies in the posterior portion of affected ribs are the sine qua non for diagnosis; roentgenographic confirmation is required. Since the first description of this pattern of prenatal growth defect in 1966, 19 patients who fulfill the criteria for diagnosis have been reported. We present three additional cases, one of which includes roentgenographic-pathologic correlations, and summarize the combinations of features present in previously described cases. Pulmonary complications incident to lack of thoracic cage support result in poor prognosis for survival.

  View details for Web of Science ID A1980KH59600013

  View details for PubMedID 7411303

• EFFECT OF ORAL AMINOGLYCOSIDE ADMINISTRATION ON INTESTINAL LACTASE IN THE SUCKLING RAT Masi, M., Neu, J., Stevenson, D. K., Kwong, L. K., Sunshine, P. SLACK INC. 1980: A124–A124

  View details for Web of Science ID A1980JB49200732

• EFFECT OF FASTING ON BILIRUBIN PRODUCTION IN THE 1ST POSTNATAL WEEK STEVENSON, D. K., BARTOLETTI, A. L., OSTRANDER, C. R., JOHNSON, J. D. SLACK INC. 1980: A126

  View details for Web of Science ID A1980JB49200746

• COMPONENT CONCENTRATIONS AND ACTIVATION OF THE COMPLEMENT-SYSTEM IN NEONATAL ILLNESS - A PRELIMINARY-STUDY OF NECROTIZING ENTEROCOLITIS EUROPEAN JOURNAL OF PEDIATRICS Stevenson, D. K., Hsu, Y. P., McMorrow, M., Berseth, C. L., Neu, J., Miller, J. J. 1980; 134 (3): 255-259

  Abstract

  Determinations of C3, C4, and C5 concentrations by radial immunodiffusion, and assays for the activation products of C3, C3c and C3d by counterimmunoelectrophoresis, were performed on 80 infants. Seven nonbacteremic preterm infants with necrotizing enterocolitis (NEC) or probable NEC (PNEC) were found at the time of diagnosis to have a significantly lower mean concentration of C3 (P less than 0.05, 1-tailed) without C3 activation when compared to other noninfected preterm infants. Ten full-term and 63 preterm infants were studied prospectively during the first days of life, and were then followed for the postnatal development of localized or systemic infection. Assays for the detection of C3 activation products were negative in all these infants. Four preterm infants who developed PNEC after 5 or more days without clinical illness had low original concentrations of complement components. The pathogenesis of NEC may not involve primarily complement activation, and susceptibility to this condition may be related to pre-existing deficiencies in complement component concentrations relative to gestational age, or to defective activation of C3 in the presence of certain bacterial species and strains.

  View details for Web of Science ID A1980KG25200012

  View details for PubMedID 7053192

• LATE MORBIDITY AMONG SURVIVORS OF RESPIRATORY-FAILURE TREATED WITH TOLAZOLINE JOURNAL OF PEDIATRICS Cohen, R. S., Stevenson, D. K., MALACHOWSKI, N., Ariagno, R. L., Johnson, J. D., Sunshine, P. 1980; 97 (4): 644-647

  View details for Web of Science ID A1980KL58300030

  View details for PubMedID 6158564

• LIFE CHANGE AND THE POST-OPERATIVE COURSE OF DUODENAL-ULCER PATIENTS JOURNAL OF HUMAN STRESS Stevenson, D. K., Nabseth, D. C., Masuda, M., Holmes, T. H. 1979; 5 (1): 19-28

  View details for Web of Science ID A1979GM35000003

  View details for PubMedID 422836

• UNUSUAL ROENTGENOGRAPHIC PRESENTATION OF A CONGENITAL CYSTIC MALFORMATION OF THE LUNG EUROPEAN JOURNAL OF PEDIATRICS Stevenson, D. K., SILVERMAN, F. N., Churg, A. M., Shochat, S. J. 1979; 132 (2): 119-124

  Abstract

  We describe here an infant with a large, solitary, fluid-filled lung cyst and hyperinflation of adjacent lung tissue in the same lobe. The combination of a fluid-filled cyst and ectatic emphysema in the same lobe suggests bronchial collapse and airway obstruction as a contributory mechanism for this unusual roentgenographic presentation of a congenital cystic malformation of the lung.

  View details for Web of Science ID A1979HT75600008

  View details for PubMedID 499260

• PULMONARY EXCRETION OF CARBON-MONOXIDE IN THE HUMAN INFANT AS AN INDEX OF BILIRUBIN PRODUCTION .2. INFANTS OF DIABETIC MOTHERS JOURNAL OF PEDIATRICS STEVENSON, D. K., BARTOLETTI, A. L., OSTRANDER, C. R., JOHNSON, J. D. 1979; 94 (6): 956–58

  View details for DOI 10.1016/S0022-3476(79)80232-2

  View details for Web of Science ID A1979GX74400031

  View details for PubMedID 448545

• WHITE CELL RATIO IN THE VERY SMALL PREMATURE-INFANT PROBER, C. G., STEVENSON, D. K. SLACK INC. 1979: A128

  View details for Web of Science ID A1979GC72700754

• PULMONARY EXCRETION OF CARBON-MONOXIDE IN HUMAN NEWBORN-INFANTS OF DIABETIC MOTHERS (IDMS) AS AN INDEX OF BILIRUBIN PRODUCTION STEVENSON, D. K., BARTOLETTI, A. L., OSTRANDER, C. R., JOHNSON, J. D. SLACK INC. 1979: A129

  View details for Web of Science ID A1979GC72700760

• WHITE BLOOD-CELL RATIO AND PROLONGED RUPTURE OF MEMBRANES IN FULL-TERM INFANTS STEVENSON, D. K., PROBER, C. G., NEU, J. WILLIAMS & WILKINS. 1979: 469

  View details for Web of Science ID A1979GS68100860

• MEASUREMENT OF PULMONARY EXCRETION OF CARBON-MONOXIDE AS AN INDEX OF BILIRUBIN PRODUCTION IN THE PREMATURE HUMAN INFANT AFTER THE 1ST POSTNATAL WEEK STEVENSON, D. K., BARTOLETTI, A. L., OSTRANDER, C. R., JOHNSON, J. D. WILLIAMS & WILKINS. 1979: 507

  View details for Web of Science ID A1979GS68101087

• REFRACTORY HYPOXEMIA ASSOCIATED WITH NEONATAL PULMONARY-DISEASE - USE AND LIMITATIONS OF TOLAZOLINE JOURNAL OF PEDIATRICS Stevenson, D. K., KASTING, D. S., Darnall, R. A., Ariagno, R. L., Johnson, J. D., MALACHOWSKI, N., BEETS, C. L., Sunshine, P. 1979; 95 (4): 595-599

  Abstract

  Thirty-nine critically ill infants with pulmonary disease received tolazoline because of severe hypoxemia refractory to administration of 100% O2 and mechanical ventilation. Twenty-seven (69%) of the infants responded with an increase in PaO2 greater than or equal to 20 torr in the first umbilical arterial gas after completion of the initial ten-minute infusion (1 to 2 mg/kg) of the drug. A response was not correlated with survival. The overall survival was 46%, essentially unchanged from our previous report (44%). Infants with hyaline membrane disease had the poorest survival rate (33%). Complications associated with the use of tolazoline occurred in 82% of the infants. A hypotensive reaction, defined as a 25% decrease in mean arterial pressure from the pre-tolazoline level, occurred in 67% of the infants, and more commonly in the infants with RDS (87%). In 11 infants who did not respond to the initial dose of tolazoline, the dose was increased up to 10 mg/kg/hour; only one infant responded, and eight (73%) had a hypotensive reaction.

  View details for Web of Science ID A1979HN82900024

  View details for PubMedID 480041

• EFFECT OF ERYTHROCYTE DESTRUCTION ON THE PULMONARY EXCRETION RATE OF CARBON-MONOXIDE IN ADULT MALE WISTAR RATS JOURNAL OF LABORATORY AND CLINICAL MEDICINE Stevenson, D. K., OSTRANDER, C. E., Johnson, J. D. 1979; 94 (4): 649-654

  Abstract

  One of the major contributory factors to hyperbilirubinemia in the human infant is bilirubin production. Determination of the pulmonary excretion rate of carbon monoxide is used to measure indirectly the rate of bilirubin production by estimating the endogenous production of CO, which is formed in equimolar amounts with bilirubin in the catabolism of heme. There has been no study to confirm that complete recovery of CO produced in vivo from the catabolism of known amounts of heme occurs via pulmonary excretion. We report here quantitative determinations of the pulmonary excretion rate of CO in five adult male Wistar rats after injection of known amounts of heme in the form of red blood cells "damaged" by incubation in a solution containing a sulfhydryl inhibitor, NEM. The mean recovery of "extra" CO above baseline production represented as a molar ratio of extra CO to heme was 0.98 +/- 0.02 (S.E.). Control studies showed no extra CO production after starvation, injection of NEM in an amount comparable to that used in the experimental animals, or injection of undamaged red blood cells.

  View details for Web of Science ID A1979HN77300016

  View details for PubMedID 479672

• WHITE CELL RATIO IN THE VERY LOW BIRTH-WEIGHT INFANT CLINICAL PEDIATRICS Prober, C. G., Stevenson, D. K., Neu, J., Johnson, J. D. 1979; 18 (8): 481-?

  Abstract

  The purpose of this study was to assess the usefulness of the white cell ratio of immature neutrophils (PMNs) to total (immature plus mature) PMNs as an indication of infection in the very small premature infant. We retrospectively reviewed the charts of 59 premature infants less than or equal to 1,250 g admitted to our Newborn Intensive Care Unit over a one-year period who had at least one white count determined. Twenty-three were born after rupture of membranes for greater than or equal to 24 hours (PROM), 47 had a one-minute Apgar score less than or equal to 6 and 31 had a five-minute Apgar scores less than or equal to 6, 38 had respiratory distress syndrome (RDS), and 4 had confirmed infection. Thirty-one of the infants had a ratio greater than or equal to .15 in the first day of life, a value which has been suggested in the literature as being abnormal and an indication to suspect sepsis. This ratio bore no statistical relationship to PROM, low Apgar scores, or RDS. We analyzed these same relationships using a ratio greater than or equal to .25, another ratio derived from data in the literature which has been said to suggest infection. No statistical correlation was found for low Apgars or RDS, but there was a significant relationship between PROM and attainment of a ratio greater than or equal to .25 (p less than .005). It is notable that 2 out of the 4 infants with infection had a ratio less than .15. We wish to cast doubt on the applicability of the currently defined WBC ratios in the literature as they apply to the infant with birth weight less than 1,250 g and emphasize the apparent effect of PROM as a factor upon these ratios.

  View details for Web of Science ID A1979HG89000004

  View details for PubMedID 455879

• USE OF TOLAZOLINE IN INFANTS WITH SEVERE HYPOXEMIA ASSOCIATED WITH PULMONARY-DISEASE KASTING, D. S., Darnall, R. A., Stevenson, D. K., Ariagno, R. L., Johnson, J. D., MALACHOWSKI, N., Sunshine, P. INT PEDIATRIC RESEARCH FOUNDATION, INC. 1978: 528–28

  View details for Web of Science ID A1978EV11700984