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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• "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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 PubMedID 25651820

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

  View details for DOI 10.1542/peds.2014-0529

  View details for PubMedID 25049338

• 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

• 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

• 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 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

• 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

• 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

• 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

• 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

• 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

• 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

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