Gary M. Shaw

All Publications

• Strategies for Equitable Recruitment to Engage Underrepresented Youth and Their Families into Clinical Research: Findings from the BEAD-T1D Pilot Study. Hormone research in paediatrics Medina Peñaranda, R., Figg, L. E., Hanes, S. J., Shaw, G. M., Chamberlain, L. J., Raymond, J., Naranjo, D., Maahs, D. M., Hood, K. K., Addala, A. 2024: 1-9

  Abstract

  To address disparities in clinical research, we present strategies to optimize recruitment of underrepresented families into the Building the Evidence to Address Disparities in Type 1 Diabetes (BEAD-T1D) study.A bilingual/bicultural Latino research assistant (RA) was hired to facilitate culturally congruent recruitment for pediatric type 1 diabetes families. The RA screened, approached, and consented families using their preferred language, time of contact, and answered personal concerns around research. Families were given the option to consent during outpatient clinic visits (in-person, or virtually via video/phone call) at a pace set by the parent/guardian to ensure understanding.Sixty-four families (Hispanic-65%, Non-Hispanic White [NHW]-17%, Non-Hispanic Black-1%, and Other-4%) were eligible. Of 49 approached, 32 consented (39 ± 7.9 years; female-81%; Hispanic-72%, NHW-28%, <50K income-69%, Spanish-speaking-50%). Clinic approaches were important to successful consent: 87% of the clinic approaches resulted in consent. Barriers to clinic approaches for RA included late/no response from clinicians, care team ending visit, and bandwidth/connectivity issues. Facilitators to clinic approaches included collaborative clinic care teams, flexible RA hours, and patient screening days in advance. We exceeded our recruitment goals for surveys (31/30), focus groups/interviews (26/20), and advisory board (22/10).We identified that culturally and linguistically congruent staff, flexible recruitment practices, and prioritizing participant availability were solutions to recruit a diverse study cohort resulting exceeding recruitment goals. Cultural interpersonal relationships formed with families addressed barriers to research participation within and outside of the medical system. These strategies suggest equitable clinical trial recruitment is feasible in diabetes research.

  View details for DOI 10.1159/000541774

  View details for PubMedID 39369697

• Genome-wide study of gene-by-sex interactions identifies risks for cleft palate. Human genetics Robinson, K., Parrish, R., Adeyemo, W. L., Beaty, T. H., Butali, A., Buxo, C. J., Gowans, L. J., Hecht, J. T., Moreno Uribe, L., Murray, J. C., Shaw, G. M., Weinberg, S. M., Brand, H., Marazita, M. L., Cutler, D. J., Epstein, M. P., Yang, J., Leslie, E. J. 2024

  Abstract

  Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (G*S) interaction testing. There were 13 loci significant for G*S interactions, with the top finding in LTBP1 (RR=3.37 [2.04-5.56], p=1.93*10-6). LTBP1 plays a role in regulating TGF-beta bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant G*S interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p=0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.

  View details for DOI 10.1007/s00439-024-02704-y

  View details for PubMedID 39361040

• Generating pregnant patient biological profiles by deconvoluting clinical records with electronic health record foundation models. Briefings in bioinformatics Seong, D., Mataraso, S., Espinosa, C., Berson, E., Reincke, S. M., Xue, L., Kashiwagi, C., Kim, Y., Shu, C. H., Chung, P., Ghanem, M., Xie, F., Wong, R. J., Angst, M. S., Gaudilliere, B., Shaw, G. M., Stevenson, D. K., Aghaeepour, N. 2024; 25 (6)

  Abstract

  Translational biology posits a strong bi-directional link between clinical phenotypes and a patient's biological profile. By leveraging this bi-directional link, we can efficiently deconvolute pre-existing clinical information into biological profiles. However, traditional computational tools are limited in their ability to resolve this link because of the relatively small sizes of paired clinical-biological datasets for training and the high dimensionality/sparsity of tabular clinical data. Here, we use state-of-the-art foundation models (FMs) for electronic health record (EHR) data to generate proteomics profiles of pregnant patients, thereby deconvoluting pre-existing clinical information into biological profiles without the cost and effort of running large-scale traditional omics studies. We show that FM-derived representations of a patient's EHR data coupled with a fully connected neural network prediction head can generate 206 blood protein expression levels. Interestingly, these proteins were enriched for developmental pathways, while proteins not able to be generated from EHR data were enriched for metabolic pathways. Finally, we show a proteomic signature of gestational diabetes that includes proteins with established and novel links to gestational diabetes. These results showcase the power of FM-derived EHR representations in efficiently generating biological states of pregnant patients. This capability can revolutionize disease understanding and therapeutic development, offering a cost-effective, time-efficient, and less invasive alternative to traditional methods of generating proteomics.

  View details for DOI 10.1093/bib/bbae574

  View details for PubMedID 39545787

  View details for PubMedCentralID PMC11565587

• Sociodemographic Trends and Perinatal Outcomes in Fathers 50 Years and Older. JAMA network open Ha, A. S., Scott, M., Zhang, C. A., Li, S., Langroudi, A. P., Glover, F., Basran, S., Del Giudice, F., Shaw, G. M., Eisenberg, M. L. 2024; 7 (8): e2425269

  Abstract

  The age of fathers at childbirth is rising, with an increasing number of births attributed to older fathers. While the impact of advanced paternal age has been documented, sociodemographic data about fathers aged 50 years and older remain scarce.To explore sociodemographic and temporal trends among the oldest US fathers (age ≥50 years) and their associations with perinatal outcomes.This retrospective cross-sectional study included data from all US births from 2011 to 2022 using the National Vital Statistics System. Data were analyzed from August 2023 and May 2024.Reported paternal age at childbirth.Outcomes of interest were sociodemographic factors, temporal trends in older fatherhood, and perinatal outcomes, including preterm birth, low birth weight, gestational diabetes, gestational hypertension, assisted reproductive technology (ART), rates of maternal primiparity, and the infant sex ratio.From 2011 to 2022, the US recorded 46 195 453 births, with an overall mean (SD) paternal age of 31.5 (6.8) years and 484 507 (1.1%) involving fathers aged 50 years or older, 47 785 (0.1%) aged 60 years or older, and 3777 (0.008%) aged 70 years or older. Births to fathers aged 50 years or older increased from 1.1% in 2011 to 1.3% in 2022 (P for trend < .001). Fathers aged 50 years or older were more diverse, with variations in educational achievement and race and ethnicity. Marital status and maternal racial and ethnic and educational backgrounds also varied by paternal age and race. Despite controlling for maternal age and other sociodemographic and perinatal factors, every 10-year increase in paternal age was consistently associated with greater use of ART (eg, age 50-59 years: adjusted odds ratio [aOR], 2.23; 95% CI, 2.19-2.27), higher likelihood of first maternal birth (eg, age 50-59 years: aOR, 1.16; 95% CI, 1.15-1.17), and increased risks of preterm birth (eg, age 50-59 years: aOR, 1.16; 95% CI, 1.15-1.18) and low birth weight (eg, age 50-59 years: aOR, 1.14; 95% CI, 1.13-1.15) compared with fathers aged 30 to 39 years. No significant changes in the infant sex ratio were observed, except among fathers aged 70 years or older (aOR, 0.92; 95% CI, 0.86-0.99) and 75 years or older (aOR, 0.84; 95% CI, 0.73-0.97), who showed a decreased likelihood of having male offspring.In this cross-sectional study of all US births from 2011 to 2022, the percentage attributed to older fathers, while small, increased. Notable variations in paternal and maternal race and education were identified. Older fatherhood was associated with increased ART use, first-time maternal births, adverse perinatal outcomes, and altered sex ratio. Further research of this population is crucial for improving patient counseling and family planning.

  View details for DOI 10.1001/jamanetworkopen.2024.25269

  View details for PubMedID 39088214

• 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

• Increased Risk of Preterm Delivery Subtypes and Hypertensive Disorders of Pregnancy in First Deliveries of Patients With Systemic Vasculitis. ACR open rheumatology Horomanski, A., Mayo, J., Shaw, G. M., Simard, J. F. 2024

  Abstract

  The goal of this study was to investigate the risk of preterm birth subtypes and hypertensive disorders of pregnancy in patients with systemic vasculitis using large, statewide databases.Births to nulliparous patients with prevalent systemic vasculitides (Takayasu arteritis [TAK], Behçet disease [BD], antineutrophil cytoplasmic antibody-associated vasculitis [AAV], and Kawasaki disease [KD]) were identified using International Classification of Diseases, Ninth Revision codes in linked administrative data and birth records from the California Department of Health Care Access and Information and California Vital Statistics from 1991 to 2012. Hypertensive disorders of pregnancy and preterm delivery (PTD) subtypes were identified. Multivariable-adjusted Poisson models estimated risk ratios (RRs) of these outcomes compared with the general birthing population without history of rheumatic disease.A total of 96 births to nulliparous patients with systemic vasculitis were identified (TAK, 14; AAV, 31; BD, 26; KD, 15) and compared with 4,191,900 births of the nulliparous general population. Adjusted RRs for all PTD types were elevated in patients with vasculitis (RR 3.21, 95% confidence interval [CI] 2.15-4.79), as were the RRs of all PTD subtypes including preterm premature rupture of membranes (RR 4.30, 95% CI 2.05-9.01) and spontaneous PTD (RR 4.99, 95% CI 3.01-8.28). Of the spontaneous PTDs among patients with vasculitis, 16.7% were early PTDs (20-31 weeks), with the remaining 83.3% occurring between 32 to 36 weeks. Patients with vasculitis also had an elevated risk of hypertensive disorders of pregnancy (RR 2.96, 95% CI 1.72-5.10).Among first-time births, we found that patients with systemic vasculitis have an elevated risk of PTD subtypes as well as hypertensive disorders of pregnancy.

  View details for DOI 10.1002/acr2.11702

  View details for PubMedID 38970474

• Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study. Birth defects research Blue, E. E., Moore, K. J., North, K. E., Desrosiers, T. A., Carmichael, S. L., White, J. J., Chong, J. X., Bamshad, M. J., Jenkins, M. M., Almli, L. M., Brody, L. C., Freedman, S. F., Reefhuis, J., Romitti, P. A., Shaw, G. M., Werler, M., Kay, D. M., Browne, M. L., Feldkamp, M. L., Finnell, R. H., Nembhard, W. N., Pangilinan, F., Olshan, A. F. 2024; 116 (7): e2384

  Abstract

  Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI.Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2).Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

  View details for DOI 10.1002/bdr2.2384

  View details for PubMedID 38990107

  View details for PubMedCentralID PMC11245170

• Hydroxychloroquine and Preeclampsia in a Diverse Cohort of Women with SLE. Arthritis care & research Simard, J. F., Liu, E. F., Rector, A., Cantu, M., Chakravarty, E., Druzin, M., Kuo, D. Z., Shaw, G. M., Weisman, M., Hedderson, M. 2024

  Abstract

  Patients with systemic lupus erythematosus (SLE) are at risk for pregnancy complications such as preeclampsia and eclampsia. These clinically important complications are associated with maternal morbidity, mortality and postpartum cardiovascular disease. Some studies suggest that hydroxychloroquine (HCQ) may reduce preeclampsia risk in lupus pregnancy. Using a cohort of pregnancies in prevalent SLE patients at Kaiser Permanente Northern California (KPNC), we investigated whether HCQ use in early pregnancy reduced the risk of preeclampsia/eclampsia.Among SLE pregnancies from 2011-2020, we assessed HCQ use from three months before pregnancy through the first trimester. HCQ exposure was defined multiple ways to account for adherence and duration of use. Propensity scores accounted for multiple confounders and modified Poisson models estimated risk ratios (RR) and 95% confidence intervals of the association between HCQ and preeclampsia/eclampsia. Effect modification by pregestational hypertension, history of nephritis, and antiphospholipid antibody status was investigated through stratified analysis.There were 399 pregnancies among 324 patients with SLE at KPNC between 2011 and 2020. Considering multiple exposure definitions, we consistently found a null association between HCQ and preeclampsia/eclampsia. The RRs were consistently lower among the nullipara pregnancies, and RRs were consistently protective but not statistically significant among the high-risk subgroup of those with history of nephritis, aPL positivity, or pregestational hypertension (both nullipara and multipara).Although this study found no reduced risk of HCQ on preeclampsia/eclampsia, residual confounding may be attenuating the effect despite an integrated health care delivery system setting with detailed clinical data.

  View details for DOI 10.1002/acr.25386

  View details for PubMedID 38926748

• 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

• Ambient Environment and the Epidemiology of Preterm Birth. Clinics in perinatology Shaw, G. M., Gonzalez, D. J., Goin, D. E., Weber, K. A., Padula, A. M. 2024; 51 (2): 361-377

  Abstract

  Preterm birth (PTB) is associated with substantial mortality and morbidity. We describe environmental factors that may influence PTB risks. We focus on exposures associated with an individual's ambient environment, such as air pollutants, water contaminants, extreme heat, and proximities to point sources (oil/gas development or waste sites) and greenspace. These exposures may further vary by other PTB risk factors such as social constructs and stress. Future examinations of risks associated with ambient environment exposures would benefit from consideration toward multiple exposures - the exposome - and factors that modify risk including variations associated with the structural genome, epigenome, social stressors, and diet.

  View details for DOI 10.1016/j.clp.2024.02.004

  View details for PubMedID 38705646

• 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

• 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

• Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits. Genetics in medicine open Nicoletti, P., Zafer, S., Matok, L., Irron, I., Patrick, M., Haklai, R., Evangelista, J. E., Marino, G. B., Ma'ayan, A., Sewda, A., Holmes, G., Britton, S. R., Lee, W. J., Wu, M., Ru, Y., Arnaud, E., Botto, L., Brody, L. C., Byren, J. C., Caggana, M., Carmichael, S. L., Cilliers, D., Conway, K., Crawford, K., Cuellar, A., Di Rocco, F., Engel, M., Fearon, J., Feldkamp, M. L., Finnell, R., Fisher, S., Freudlsperger, C., Garcia-Fructuoso, G., Hagge, R., Heuzé, Y., Harshbarger, R. J., Hobbs, C., Howley, M., Jenkins, M. M., Johnson, D., Justice, C. M., Kane, A., Kay, D., Gosain, A. K., Langlois, P., Legal-Mallet, L., Lin, A. E., Mills, J. L., Morton, J. E., Noons, P., Olshan, A., Persing, J., Phipps, J. M., Redett, R., Reefhuis, J., Rizk, E., Samson, T. D., Shaw, G. M., Sicko, R., Smith, N., Staffenberg, D., Stoler, J., Sweeney, E., Taub, P. J., Timberlake, A. T., Topczewska, J., Wall, S. A., Wilson, A. F., Wilson, L. C., Boyadjiev, S. A., Wilkie, A. O., Richtsmeier, J. T., Jabs, E. W., Romitti, P. A., Karasik, D., Birnbaum, R. Y., Peter, I. 2024; 2

  Abstract

  The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown.We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model.Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E-12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence.Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

  View details for DOI 10.1016/j.gimo.2024.101851

  View details for PubMedID 39345948

  View details for PubMedCentralID PMC11434253

• Neighborhood Sociodemographic Characteristics and Prevalence of Congenital Anomalies in Texas Schraw, J. M., Jaime, E., Rathod, R., Shumate, C. J., Hughes, A. E., Pruitt, S. L., Shaw, G. M., Lupo, P. J. WILEY. 2024: S28

  View details for Web of Science ID 001290631200007

• Neighborhood sociodemographic characteristics and prevalence of congenital anomalies in Texas Schraw, J. M., Jaime, E., Rathod, R., Shumate, C. J., Hughes, A. E., Pruitt, S. L., Shaw, G. M., Lupo, P. J. PERGAMON-ELSEVIER SCIENCE LTD. 2024

  View details for Web of Science ID 001295309300015

• 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

• A search for factors associated with reduced carbohydrate intake and NTD risk in two population-based studies. Birth defects research Shaw, G. M., Yang, W., Weber, K. A., Olshan, A. F., Desrosiers, T. A., National Birth Defects Prevention Study 2024; 116 (3): e2328

  Abstract

  BACKGROUND: Two population-based case-control studies have reported an increased risk of neural tube defect (NTD)-affected pregnancies among women with low carbohydrate diet in the periconceptional period. Given that only two studies have investigated this association, it is unclear to what degree the findings could be impacted by residual confounding. Here, we further interrogated both studies that observed this association with the objective to identify factors from a much larger number of factors that might explain the association.METHODS: By employing a machine learning algorithm (random forest), we investigated a baseline set of over 200 variables. These analyses produced the top 10 variables in each data set for cases and controls that predicted periconceptional low carbohydrate intake.RESULTS: Examining those prediction variables with logistic regression modeling, we did not observe any particular variable that substantially contributed to the NTD-low carbohydrate association in either data set.CONCLUSIONS: If there are underlying factors that explain the association, our findings suggest that none of the 200+ variables we examined were sufficiently correlated with what that true explanatory exposure may be. Alternatively, our findings may suggest that there are other unidentified factor(s) at play, or the association observed in two independent data sets is directly related to low carbohydrate intake.

  View details for DOI 10.1002/bdr2.2328

  View details for PubMedID 38450884

• 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

• Air Pollution and Pregnancy: Insights into Immune Response, Histone Modifications, and Cytokine Signatures Jung, Y., Ha, J., Aguilera, J., Kaushik, A., Cansdale, S., Yang, E., Dermadi, D., Lurmann, F., Lutzker, L., Hammond, K., Balmes, J., Noth, E., Eisen, E., Aghaeepour, N., Shaw, G., Waldrop, A., Khatri, P., Utz, P., Rosenburg-Hasson, Y., Maecker, H., Burt, T., Johnson, M., Nadeau, K. MOSBY-ELSEVIER. 2024: AB370

  View details for Web of Science ID 001267526000850

• 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

• Hydroxychloroquine in lupus pregnancy and risk of preeclampsia. Arthritis & rheumatology (Hoboken, N.J.) Rector, A., Maric, I., Chaichian, Y., Chakravarty, E., Cantu, M., Weisman, M. H., Shaw, G. M., Druzin, M., Simard, J. F. 2024

  Abstract

  OBJECTIVE: Systemic lupus (SLE) disproportionately affects females during childbearing years, and hydroxychloroquine (HCQ) is the standard first-line treatment. Preeclampsia complicates up to one-third of lupus pregnancies, although reports vary by parity and multi-fetal gestation. We investigated whether HCQ use early in pregnancy may reduce the risk of preeclampsia.METHODS: We studied 1068 livebirth singleton pregnancies among 1020 privately insured patients with SLE (2007-2016). HCQ use was defined as 3 months preconception through the first trimester and prescription fills were a proxy for use. Modified Poisson regression estimated risk ratios (RRs) and 95% confidence intervals (95% CI) stratified by parity. Propensity scores accounted for confounders and stratified analyses examined effect modification.RESULTS: Approximately 15% of pregnancies were diagnosed with preeclampsia. 52% of pregnancies had ≥1 HCQ fill. HCQ-exposed pregnancies had more comorbidities, SLE activity, and azathioprine use. We found no evidence of a statistical association between HCQ and preeclampsia among nulliparous (RR=1.26, 95% CI 0.82, 1.93) and multiparous pregnancies (RR=1.20, 95% CI 0.80, 1.70). Additional control for confounding decreased the RRs towards the null (nulliparous: PS-adj RR=1.09, 95% CI 0.68, 1.76 and multiparous: PS-adj RR=1.01, 95% CI 0.66, 1.53).CONCLUSION: Using a large insurance-based database, we did not observe a decreased risk of preeclampsia associated with HCQ use in pregnancy, although we cannot rule out residual and unmeasured confounding and misclassification. Further studies leveraging large population-based data and prospective collection could characterize how HCQ influences preeclampsia risk in SLE pregnancy and among persons at greater risk of hypertensive disorders of pregnancy.

  View details for DOI 10.1002/art.42793

  View details for PubMedID 38272838

• 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

• Pregnancy outcomes in a diverse US Lupus Cohort. Arthritis care & research Simard, J. F., Liu, E. F., Chakravarty, E., Rector, A., Cantu, M., Kuo, D. Z., Shaw, G. M., Druzin, M. L., Weisman, M. H., Hedderson, M. M. 2024

  Abstract

  OBJECTIVE: Although the systemic lupus (SLE) patient population is racially and ethnically diverse, many study populations are homogeneous. Further, data are often lacking on critical factors such as antiphospholipid (aPL) antibodies. We investigated livebirth rates in patients with SLE at Kaiser Permanente Northern California including race/ethnicity and aPL data.METHODS: Electronic health records of pregnancies with outcomes observed from 2011-2020 were identified among patients with SLE. Prevalent SLE was defined as ≥2 ICD coded visits ≥7days apart before the last menstrual period (LMP). We summarized patient characteristics, medication orders, and healthcare utilization, and medication use. Pregnancy outcomes (livebirth, stillbirth, spontaneous abortion, ectopic, molar) were presented overall, and stratified by race/ethnicity, aPL status, and nephritis history.RESULTS: We identified 657 pregnancies among 453 patients with SLE. The cohort was diverse reflecting the Northern California population (27% Asian, 26% Hispanic, 26% Non-Hispanic (NH) White, 13% NH Black, 5% Multiracial, about 2% Islander, Native American). Approximately 74% of observed pregnancies ended in livebirth, 23% resulted in spontaneous abortion, 2% were ectopic or molar pregnancies, and <1% were stillbirths. There was limited variability in livebirths by race/ethnic group (72%-79%), aPL (69.5%-77%), and nephritis (71%-75%) CONCLUSION: Our findings are consistent with previous studies, however, some methodologic differences may yield a range of livebirth rates. We found that approximately 74% of pregnancies in SLE ended in livebirth, with modest variability in spontaneous abortion by race/ethnicity, nephritis, and aPL.

  View details for DOI 10.1002/acr.25279

  View details for PubMedID 38221659

• Factors associated with infant sex and preterm birth status for selected birth defects from the National Birth Defects Prevention Study, 1997-2011. Birth defects research Williford, E. M., Yang, W., Howley, M. M., Ma, C., Collins, R. T., Weber, K. A., Heinke, D., Petersen, J. M., Agopian, A. J., Archer, N. P., Olshan, A. F., Williams, L. A., Browne, M. L., Shaw, G. M. 2023

  Abstract

  Birth defects and preterm birth co-occur, with some overlapping risk factors. Many birth defects and preterm births tend to have a male preponderance. We explored potential risk factors impacting sex and preterm (<37 weeks of gestation) birth differences among infants with selected birth defects delivered from 1997 to 2011 using data from the National Birth Defects Prevention Study (NBDPS).The NBDPS was a large multisite, population-based case-control study. Using random forests, we identified important predictors of male preterm, female preterm, and male term, each compared with female term births for each birth defect. Using logistic regression, we estimated odds ratios for associations between important predictors and sex-preterm birth status by birth defect.We examined 11,379 infants with nine specific birth defects. The top 10 most important predictors of sex-preterm birth status from the random forests varied greatly across the birth defects and sex-preterm comparisons within a given defect group, with several being novel factors. However, one consistency was that short interpregnancy interval was associated with sex-preterm birth status for many of the studied birth defects. Although obesity has been identified as a risk factor for preterm birth and birth defects in other research, it was not associated with sex-preterm birth status for any of the examined defects.We confirmed expected associations for sex-preterm birth status differences and found new potential risk factors for further exploration among the studied birth defects.

  View details for DOI 10.1002/bdr2.2294

  View details for PubMedID 38155422

• Bias analyses to investigate the impact of differential participation: Application to a birth defects case-control study. Paediatric and perinatal epidemiology Petersen, J. M., Kahrs, J. C., Adrien, N., Wood, M. E., Olshan, A. F., Smith, L. H., Howley, M. M., Ailes, E. C., Romitti, P. A., Herring, A. H., Parker, S. E., Shaw, G. M., Politis, M. D. 2023

  Abstract

  Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking.To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS.We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR.Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02).Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research.

  View details for DOI 10.1111/ppe.13026

  View details for PubMedID 38102868

• Preconception dietary glycemic index and risk for large-for-gestational age births. Nutrition (Burbank, Los Angeles County, Calif.) Darling, A. M., Yazdy, M. M., Garcia, M. H., Carmichael, S. L., Shaw, G. M., Nestoridi, E., National Birth Defects Prevention Study 2023; 119: 112322

  Abstract

  OBJECTIVES: Diets with a high glycemic index (GI) leading to elevated postprandial glucose levels and hyperinsulinemia during pregnancy have been inconsistently linked to an increased risk for large-for-gestational-age (LGA) births. The effects of prepregnancy dietary GI on LGA risk are, to our knowledge, unknown. We examined the association of prepregnancy dietary GI with LGA births and joint associations of GI and maternal overweight/obesity and infant sex with LGA births among 10 188 infants born without congenital anomalies from 1997 to 2011, using data from the National Birth Defects Prevention Study (NBDPS). The aim of this study was to investigate this association among infants without major congenital anomalies (controls) who participated in the NBDPS and to evaluate how prepregnancy BMI and infant sex may modify this association on the additive scale.METHODS: Dietary intake was ascertained using a 58-item food frequency questionnaire. We dichotomized dietary GI into high and low categories using spline regression models. Infants with a birth weight at or above the 90th percentile for gestational age and sex, according to a U.S. population reference, were considered LGA. We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs).RESULTS: Of the infants, 859 (9%) had a high dietary GI (cut-point: 59), and 1244 infants (12%) were born LGA. Unadjusted analysis suggested an inverse association between high dietary GI and LGA (OR, 0.79; 95% CI, 0.62-0.99). No association was observed in multivariable models when comparing high dietary GI intake between LGA births and all other births (OR, 0.94; 95% CI, 0.74-1.20) or when excluding small-for-gestational-age (SGA) births (OR, 0.94; 95% CI, 0.73-1.19). No joint associations with maternal overweight/obesity or infant sex were observed.CONCLUSION: High prepregnancy maternal GI was not associated with LGA births independently of or jointly with other factors.

  View details for DOI 10.1016/j.nut.2023.112322

  View details for PubMedID 38199030

• Neighborhood Deprivation and Neural Tube Defects. Epidemiology (Cambridge, Mass.) Pruitt Evans, S., Ailes, E. C., Kramer, M. R., Shumate, C. J., Reefhuis, J., Insaf, T. Z., Yazdy, M. M., Carmichael, S. L., Romitti, P. A., Feldkamp, M. L., Neo, D. T., Nembhard, W. N., Shaw, G. M., Palmi, E., Gilboa, S. M. 2023; 34 (6): 774-785

  Abstract

  Individual measures of socioeconomic status (SES) have been associated with an increased risk of neural tube defects (NTDs); however, the association between neighborhood SES and NTD risk is unknown. Using data from the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we investigated the association between measures of census tract SES and NTD risk.The study population included 10,028 controls and 1829 NTD cases. We linked maternal addresses to census tract SES measures and used these measures to calculate the neighborhood deprivation index. We used generalized estimating equations to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) estimating the impact of quartiles of census tract deprivation on NTDs adjusting for maternal race-ethnicity, maternal education, and maternal age at delivery.Quartiles of higher neighborhood deprivation were associated with NTDs when compared with the least deprived quartile (Q2: aOR = 1.2; 95% CI = 1.0, 1.4; Q3: aOR = 1.3, 95% CI = 1.1, 1.5; Q4 (highest): aOR = 1.2; 95% CI = 1.0, 1.4). Results for spina bifida were similar; however, estimates for anencephaly and encephalocele were attenuated. Associations differed by maternal race-ethnicity.Our findings suggest that residing in a census tract with more socioeconomic deprivation is associated with an increased risk for NTDs, specifically spina bifida.

  View details for DOI 10.1097/EDE.0000000000001655

  View details for PubMedID 37757869

• Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome. HGG advances Blue, E. E., White, J. J., Dush, M. K., Gordon, W. W., Wyatt, B. H., White, P., Marvin, C. T., Helle, E., Ojala, T., Priest, J. R., Jenkins, M. M., Almli, L. M., Reefhuis, J., Pangilinan, F., Brody, L. C., McBride, K. L., Garg, V., Shaw, G. M., Romitti, P. A., Nembhard, W. N., Browne, M. L., Werler, M. M., Kay, D. M., Mital, S., Chong, J. X., Nascone-Yoder, N. M., Bamshad, M. J. 2023; 4 (4): 100232

  Abstract

  Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.

  View details for DOI 10.1016/j.xhgg.2023.100232

  View details for PubMedID 37663545

  View details for PubMedCentralID PMC10474499

• 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

• Pregnancy Outcomes Among Patients with Vasculitis Using Administrative Claims Data Rector, A., Simard, J., Shaw, G., Horomanski, A. WILEY. 2023: 4801-4803

  View details for Web of Science ID 001190014305027

• Hydroxychloroquine and Preeclampsia Risk in Lupus Pregnancy: Results from a Large Regional Integrated Health Network Simard, J., Liu, E., Rector, A., Cantu, M., Kuo, D., Chakravarty, E., Druzin, M., Shaw, G., Weisman, M., Hedderson, M. WILEY. 2023: 912-913

  View details for Web of Science ID 001190014300470

• Is gastroschisis associated with county-level socio-environmental quality during pregnancy? Birth defects research Krajewski, A. K., Patel, A., Gray, C. L., Messer, L. C., Keeler, C. Y., Langlois, P. H., Reefhuis, J., Gilboa, S. M., Werler, M. M., Shaw, G. M., Carmichael, S. L., Nembhard, W. N., Insaf, T. Z., Feldkamp, M. L., Conway, K. M., Lobdell, D. T., Desrosiers, T. A. 2023

  Abstract

  Gastroschisis prevalence more than doubled between 1995 and 2012. While there are individual-level risk factors (e.g., young maternal age, low body mass index), the impact of environmental exposures is not well understood.We used the U.S. Environmental Protection Agency's Environmental Quality Index (EQI) as a county-level estimate of cumulative environmental exposures for five domains (air, water, land, sociodemographic, and built) and overall from 2006 to 2010. Adjusted odds ratios (aOR) and 95% confidence interval (CI) were estimated from logistic regression models between EQI tertiles (better environmental quality (reference); mid; poorer) and gastroschisis in the National Birth Defects Prevention Study from births delivered between 2006 and 2011. Our analysis included 594 cases with gastroschisis and 4105 infants without a birth defect (controls).Overall EQI was modestly associated with gastroschisis (aOR [95% CI]: 1.29 [0.98, 1.71]) for maternal residence in counties with poorer environmental quality, compared to the reference (better environmental quality). Within domain-specific indices, only the sociodemographic domain (aOR: 1.51 [0.99, 2.29]) was modestly associated with gastroschisis, when comparing poorer to better environmental quality.Future work could elucidate pathway(s) by which components of the sociodemographic domain or possibly related psychosocial factors like chronic stress potentially contribute to risk of gastroschisis.

  View details for DOI 10.1002/bdr2.2250

  View details for PubMedID 37772934

• 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

• Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population-based case-control study of women meeting the folic acid recommendations. The American journal of clinical nutrition Petersen, J. M., Smith-Webb, R. S., Shaw, G. M., Carmichael, S. L., Desrosiers, T. A., Nestoridi, E., Darling, A. M., Parker, S. E., Politis, M. D., Yazdy, M. M., Werler, M. M. 2023; 118 (3): 720-728

  Abstract

  Neural tube defects (NTDs) still occur among some women who consume 400 μg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs.To investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations.Data were from the National Birth Defects Prevention Study (United States population-based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 μg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center.NTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake.Our findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

  View details for DOI 10.1016/j.ajcnut.2023.05.034

  View details for PubMedID 37661108

• Exome sequencing findings in children with annular pancreas. Molecular genetics & genomic medicine Pitsava, G., Pankratz, N., Lane, J., Yang, W., Rigler, S., Shaw, G. M., Mills, J. L. 2023: e2233

  Abstract

  Annular pancreas (AP) is a congenital defect of unknown cause in which the pancreas encircles the duodenum. Theories include abnormal migration and rotation of the ventral bud, persistence of ectopic pancreatic tissue, and inappropriate fusion of the ventral and dorsal buds before rotation. The few reported familial cases suggest a genetic contribution.We conducted exome sequencing in 115 affected infants from the California birth defects registry.Seven cases had a single heterozygous missense variant in IQGAP1, five of them with CADD scores >20; seven other infants had a single heterozygous missense variant in NRCAM, five of them with CADD scores >20. We also looked at genes previously associated with AP and found two rare heterozygous missense variants, one each in PDX1 and FOXF1.IQGAP1 and NRCAM are crucial in cell polarization and migration. Mutations result in decreased motility which could possibly cause the ventral bud to not migrate normally. To our knowledge, this is the first study reporting a possible association for IQGAP1 and NRCAM with AP. Our findings of rare genetic variants involved in cell migration in 15% of our population raise the possibility that AP may be related to abnormal cell migration.

  View details for DOI 10.1002/mgg3.2233

  View details for PubMedID 37635636

• Maternal physical activity, sitting, and risk of non-cardiac birth defects. Pediatric research Evenson, K. R., Mowla, S., Olshan, A. F., Shaw, G. M., Ailes, E. C., Reefhuis, J., Joshi, N., Desrosiers, T. A., National Birth Defects Prevention Study and Birth Defects Study To Evaluate Pregnancy exposureS 2023

  Abstract

  BACKGROUND: The relationship between maternal physical activity (PA)/sitting and birth defects is largely unexplored. We examined whether pre-pregnancy PA/sitting were associated with having a pregnancy affected by a birth defect.METHODS: We used data from two United States population-based case-control studies: 2008-2011 deliveries from the National Birth Defects Prevention Study (NBDPS; 9 states) and 2014-2018 deliveries from the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS; 7 states). Cases with one of 12 non-cardiac birth defects (n=3798) were identified through population-based registries. Controls (n=2682) were live-born infants without major birth defects randomly sampled using vital/hospital records. Mothers self-reported pre-pregnancy PA/sitting. Unconditional logistic regression models estimated associations between PA/sitting categories and the 12 birth defects.RESULTS: Mothers engaging in pre-pregnancy PA was associated with a reduced odds of five (spina bifida, cleft palate, anorectal atresia, hypospadias, transverse limb deficiency) and a higher odds of two (anencephaly, gastroschisis) birth defects. Mothers spending less time sitting in pre-pregnancy was associated with a reduced odds of two (anorectal atresia, hypospadias) and a higher odds of one (cleft lip with or without cleft palate) birth defect.CONCLUSIONS: Reasonable next steps include replication of these findings, improved exposure assessment, and elucidation of biologic mechanisms.IMPACT: Using data from two population-based case-control studies, we found that mothers engaging in different types of physical activity in the 3 months before pregnancy had an infant with a reduced odds of five and a higher odds of two birth defects. Mothers spending less time sitting in the 3 months before pregnancy had an infant with a reduced odds of two and a higher odds of one birth defect. Clarification and confirmation from additional studies are needed using more precise exposure measures, distinguishing occupational from leisure-time physical activity, and elucidation of mechanisms supporting these associations.

  View details for DOI 10.1038/s41390-023-02768-y

  View details for PubMedID 37543708

• 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

• 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

• Are individual-level risk factors for gastroschisis modified by neighborhood-level socioeconomic factors? Birth defects research Neo, D. T., Martin, C. L., Carmichael, S. L., Gucsavas-Calikoglu, M., Conway, K. M., Evans, S. P., Feldkamp, M. L., Gilboa, S. M., Insaf, T. Z., Musfee, F. I., Shaw, G. M., Shumate, C., Werler, M. M., Olshan, A. F., Desrosiers, T. A. 2023

  Abstract

  Two strong risk factors for gastroschisis are young maternal age (<20 years) and low/normal pre-pregnancy body mass index (BMI), yet the reasons remain unknown. We explored whether neighborhood-level socioeconomic position (nSEP) during pregnancy modified these associations.We analyzed data from 1269 gastroschisis cases and 10,217 controls in the National Birth Defects Prevention Study (1997-2011). To characterize nSEP, we applied the neighborhood deprivation index and used generalized estimating equations to calculate odds ratios and relative excess risk due to interaction.Elevated odds of gastroschisis were consistently associated with young maternal age and low/normal BMI, regardless of nSEP. High-deprivation neighborhoods modified the association with young maternal age. Infants of young mothers in high-deprivation areas had lower odds of gastroschisis (adjusted odds ratio [aOR]: 3.1, 95% confidence interval [CI]: 2.6, 3.8) than young mothers in low-deprivation areas (aOR: 6.6; 95% CI: 4.6, 9.4). Mothers of low/normal BMI had approximately twice the odds of having an infant with gastroschisis compared to mothers with overweight/obese BMI, regardless of nSEP (aOR range: 1.5-2.3).Our findings suggest nSEP modified the association between gastroschisis and maternal age, but not BMI. Further research could clarify whether the modification is due to unidentified biologic and/or non-biologic factors.

  View details for DOI 10.1002/bdr2.2224

  View details for PubMedID 37439400

• 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

• Oxidative balance scores and neural crest cell-related congenital anomalies. Birth defects research Carmichael, S. L., Yang, W., Ma, C., Desrosiers, T. A., Weber, K., Collins, R. T., Nestoridi, E., Shaw, G. M. 2023

  Abstract

  Oxidative stress and redox imbalance adversely affect embryonic development. We developed two oxidative balance scores (OBS) that include dietary and nondietary exposures. We hypothesized that higher scores (i.e., lower oxidative stress) would be associated with lower risk of neural tube defects, orofacial clefts, conotruncal heart defects, and limb deficiencies. We used data from the National Birth Defects Prevention Study to create a dietary OBS based on intake of 13 nutrients and an overall OBS that included the 13 nutrients and eight additional nondietary factors related to oxidative balance (e.g., smoking). We used logistic regression to examine odds ratios associated with having low or high scores (i.e., <10th or >90th percentiles). Continuous models indicated reduced odds associated with high versus low scores (i.e., comparing odds at the 90th versus 10th percentile values of the distribution) on the overall OBS for cleft lip with or without cleft palate [adjusted odds ratio (aOR) 0.72, 95% confidence interval (CI) 0.63-0.82], longitudinal limb deficiency (aOR 0.73, CI 0.54-0.99), and transverse limb deficiency (aOR 0.74, CI 0.58-0.95); increased odds for anencephaly (aOR 1.40, CI 1.07-1.84); and primarily nonsignificant associations with conotruncal heart defects. Results for the dietary OBS were similar. This study provides some evidence that oxidative stress contributes to congenital anomalies related to neural crest cell development.

  View details for DOI 10.1002/bdr2.2211

  View details for PubMedID 37309307

• 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

• 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

• Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate. medRxiv : the preprint server for health sciences Robinson, K., Mosley, T. J., Rivera-González, K. S., Jabbarpour, C. R., Curtis, S. W., Adeyemo, W. L., Beaty, T. H., Butali, A., Buxó, C. J., Cutler, D. J., Epstein, M. P., Gowans, L. J., Hecht, J. T., Murray, J. C., Shaw, G. M., Uribe, L. M., Weinberg, S. M., Brand, H., Marazita, M. L., Lipinski, R. J., Leslie, E. J. 2023

  Abstract

  Orofacial clefts (OFCs) are the most common craniofacial birth defects and are often categorized into two etiologically distinct groups: cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP). CP is highly heritable, but there are still relatively few established genetic risk factors associated with its occurrence compared to CL/P. Historically, CP has been studied as a single phenotype despite manifesting across a spectrum of defects involving the hard and/or soft palate. We performed GWAS using transmission disequilibrium tests using 435 case-parent trios to evaluate broad risks for any cleft palate (ACP, n=435), as well as subtype-specific risks for any cleft soft palate (CSP, n=259) and any cleft hard palate (CHP, n=125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p=4.24×10 -8 ) associated with CHP. One gene at this locus, angiopoietin-like 2 ( ANGPTL2 ), plays a role in osteoblast differentiation. It is expressed in craniofacial tissue of human embryos, as well as in the developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p<5×10 -6 ), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios (ORs) for each of the 20 loci were most similar across all three groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either the CSP or CHP groups. We also found nominal evidence of replication (p<0.05) for 22 SNPs previously associated with cleft palate (including CL/P). Interestingly, most SNPs associated with CL/P cases were found to convey the opposite effect in those replicated in our dataset for CP only. Ours is the first study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.

  View details for DOI 10.1101/2023.03.01.23286642

  View details for PubMedID 37066311

  View details for PubMedCentralID PMC10104215

• 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

• Neighborhood-level socioeconomic position during early pregnancy and risk of gastroschisis. Epidemiology (Cambridge, Mass.) Neo, D. T., Desrosiers, T. A., Martin, C. L., Carmichael, S. L., Gucsavas-Calikoglu, M., Conway, K. M., Evans, S. P., Feldkamp, M. L., Gilboa, S. M., Insaf, T. Z., Musfee, F. I., Shaw, G. M., Shumate, C. J., Werler, M. M., Olshan, A. F. 2023

  Abstract

  Neighborhood-level socioeconomic position has been shown to influence birth outcomes, including selected birth defects. This study examines the understudied association between neighborhood-level socioeconomic position during early pregnancy and risk of gastroschisis, an abdominal birth defect of increasing prevalence.We conducted a case-control study of 1,269 gastroschisis cases and 10,217 controls using data from the National Birth Defects Prevention Study (1997 - 2011). To characterize neighborhood-level socioeconomic position, we conducted principal component analysis to construct two indices - Neighborhood Deprivation Index (NDI) and Neighborhood Socioeconomic Position Index (nSEPI). We created neighborhood-level indices using census socioeconomic indicators corresponding to census tracts associated with addresses where mothers lived the longest during the periconceptional period. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with multiple imputation for missing data and adjustment for maternal race-ethnicity, household income, education, birth year, and duration of residence.Mothers residing in moderate (NDI Tertile 2 aOR: 1.2; 95% CI: 1.0, 1.5 and nSEPI Tertile 2 aOR: 1.2; 95% CI: 1.0, 1.5) or low socioeconomic neighborhoods (NDI Tertile 3 aOR: 1.3; 95% CI: 1.01, 1.6 and nSEPI Tertile 3 aOR: 1.3, 95% CI: 1.1, 1.6) were more likely to deliver an infant with gastroschisis compared with mothers residing in high socioeconomic neighborhoods.Our findings suggest that lower neighborhood-level socioeconomic position during early pregnancy is associated with elevated odds of gastroschisis. Additional epidemiologic studies may aid in confirming this finding and evaluating potential mechanisms linking neighborhood-level socioeconomic factors and gastroschisis.

  View details for DOI 10.1097/EDE.0000000000001621

  View details for PubMedID 36976718

• 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

• Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants. American journal of medical genetics. Part A Sok, P., Sabo, A., Almli, L. M., Jenkins, M. M., Nembhard, W. N., Agopian, A. J., Bamshad, M. J., Blue, E. E., Brody, L. C., Brown, A. L., Browne, M. L., Canfield, M. A., Carmichael, S. L., Chong, J. X., Dugan-Perez, S., Feldkamp, M. L., Finnell, R. H., Gibbs, R. A., Kay, D. M., Lei, Y., Meng, Q., Moore, C. A., Mullikin, J. C., Muzny, D., Olshan, A. F., Pangilinan, F., Reefhuis, J., Romitti, P. A., Schraw, J. M., Shaw, G. M., Werler, M. M., Harpavat, S., Lupo, P. J. 2023

  Abstract

  The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.

  View details for DOI 10.1002/ajmg.a.63185

  View details for PubMedID 36942736

• 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

• 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

• Congenital male genital malformations and paternal health: an analysis of US claims data. Andrology Yu, B., Zhang, C. A., Chen, T., Mulloy, E., Shaw, G. M., Eisenberg, M. L. 2023

  Abstract

  OBJECTIVE: To investigate the potential association between paternal health and male genital malformations in the offspring.MATERIALS AND METHODS: We analyzed data from 2007 to 2016 derived from the IBM MarketScan Research database, which reports on reimbursed private healthcare claims in the United States. The association between paternal comorbidities (defined as individual and combined measures) and genital malformations in male offspring was analyzed.RESULTS: Of 376,362 male births, 22% of fathers had at least one component of the metabolic syndrome (MetS ≥1) prior to conception. Totals of 2880 cases of cryptorchidism (0.77%) and 2651 cases of hypospadias (0.70%) were identified at birth. While 0.76% of sons born to fathers with no MetS components were diagnosed with cryptorchidism, 0.82% of sons with fathers with multiple MetS components had cryptorchidism. Similarly, 0.69% vs 0.88% of sons had hypospadias when fathers had 0 or 2+ components of MetS. After adjusting for maternal and paternal factors, the odds of a son diagnosed with hypospadias increased with two or more paternal MetS components (Odds ratio [95% confidence interval]: 1.27 [1.10 - 1.47]). Specific components of paternal MetS were not generally more associated with a son's genital malformations. When we performed a subgroup analysis where genital malformations were defined based on surgical correction, the association with hypospadias persisted.CONCLUSIONS: Fathers with multiple components of the metabolic syndrome in the preconception period were observed to be at increased risks for having sons born with hypospadias. The results support the association between a man's andrological and overall health. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/andr.13404

  View details for PubMedID 36727635

• The impacts of ambient air pollution exposure during pregnancy on maternal and neonatal inflammatory biomarkers Ha, J., Aguilera, J., Jung, Y., Cansdale, S., Lurmann, F., Lutzker, L., Hammond, K., Balmes, J., Noth, E., Eisen, E., Aghaeepour, N., Shaw, G., Waldrop, A., Khatri, P., Utz, P. J., Rosenburg-Hasson, Y., Maecker, H., Burt, T., Nadeau, K., Prunicki, M. MOSBY-ELSEVIER. 2023: AB119

  View details for Web of Science ID 000991651900367

• 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

• Antenatal wildfire smoke exposure and hypertensive disorders of pregnancy Waldrop, A. R., Blumenfeld, Y. J., Mayo, J. A., Panelli, D. M., Heft-Neal, S., Burke, M., Leonard, S. A., Shaw, G. M. MOSBY-ELSEVIER. 2023: S59-S60

  View details for Web of Science ID 000909337400072

• Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate. HGG advances Robinson, K., Mosley, T. J., Rivera-Gonzalez, K. S., Jabbarpour, C. R., Curtis, S. W., Adeyemo, W. L., Beaty, T. H., Butali, A., Buxo, C. J., Cutler, D. J., Epstein, M. P., Gowans, L. J., Hecht, J. T., Murray, J. C., Shaw, G. M., Uribe, L. M., Weinberg, S. M., Brand, H., Marazita, M. L., Lipinski, R. J., Leslie, E. J. 2023; 4 (4): 100234

  Abstract

  Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n= 435), and subtype-specific risks for any cleft soft palate (CSP), (n= 259) and any cleft hard palate (CHP) (n= 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p= 4.24*10-8) associated with CHP. One gene at this locus, angiopoietin-like 2 (ANGPTL2), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p<5*10-6), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p<0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.

  View details for DOI 10.1016/j.xhgg.2023.100234

  View details for PubMedID 37719664

• The association of preconception paternal metabolic syndrome on early childhood emergency department visits and hospitalizations. Andrology Chen, T., Zhang, C. A., Li, S., Schroeder, A. R., Shaw, G. M., Eisenberg, M. L. 2022

  Abstract

  Increasing preconception paternal comorbidity has been associated with adverse pregnancy outcomes. However, whether the father's health impacts the child after birth is uncertain.In the present study, we examined the association of preconception paternal metabolic syndrome status with childhood emergency department (ED) visits and hospitalizations.This is a longitudinal cohort study of children (295,355 boys and 278,735 girls) born to linked pairs of fathers and mothers in the United States between 2009 to 2016 within the IBM MarketScan® Research database. Associations between paternal and maternal metabolic syndrome (MetS) component diagnoses and subsequent hospitalizations and emergency department visits for offspring within the first two years of life were determined.35.5% (203,617/574,090) of children had at least one emergency room visit and 6.1% (35,141/574,090) of children had an inpatient admission. After adjustment, the odds of inpatient admission and emergency department visits increased in a dose-dependent fashion among fathers with higher comorbidities. Similar trends were seen for emergency department visit utilization.Increasing paternal preconception comorbidity is associated with a higher risk that a child requires emergency department and inpatient care in the first years of life. An opportunity exists to engage men in preconception counseling to optimize theirs and their offspring's health. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/andr.13370

  View details for PubMedID 36542456

• 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

• 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

• Assessing associations between residential proximity to greenspace and birth defects in the National Birth Defects Prevention Study. Environmental research Weber, K. A., Yang, W., Carmichael, S. L., Collins, R. T., Luben, T. J., Desrosiers, T. A., Insaf, T. Z., Le, M. T., Evans, S. P., Romitti, P. A., Yazdy, M. M., Nembhard, W. N., Shaw, G. M., National Birth Defects Prevention Study 2022: 114760

  Abstract

  BACKGROUND: Residential proximity to greenspace is associated with various health outcomes.OBJECTIVES: We estimated associations between maternal residential proximity to greenspace (based on an index of vegetation) and selected structural birth defects, including effect modification by neighborhood-level factors.METHODS: Data were from the National Birth Defects Prevention Study (1997-2011) and included 19,065 infants with at least one eligible birth defect (cases) and 8925 without birth defects (controls) from eight Centers throughout the United States. Maternal participants reported their addresses throughout pregnancy. Each address was systematically geocoded and residences around conception were linked to greenspace, US Census, and US Department of Agriculture data. Greenspace was estimated using the normalized difference vegetation index (NDVI); average maximum NDVI was estimated within 100 m and 500 m concentric buffers surrounding geocoded addresses to estimate residential NDVI. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals comparing those in the highest and lowest quartiles of residential NDVI and stratifying by rural/urban residence and neighborhood median income.RESULTS: After multivariable adjustment, for the 500 m buffer, inverse associations were observed for tetralogy of Fallot, secundum atrial septal defects, anencephaly, anotia/microtia, cleft lip ± cleft palate, transverse limb deficiency, and omphalocele, (aORs: 0.54-0.86). Results were similar for 100 m buffer analyses and similar patterns were observed for other defects, though results were not significant. Significant heterogeneity was observed after stratification by rural/urban for hypoplastic left heart, coarctation of the aorta, and cleft palate, with inverse associations only among participants residing in rural areas. Stratification by median income showed heterogeneity for atrioventricular and secundum atrial septal defects, anencephaly, and anorectal atresia, with inverse associations only among participants residing in a high-income neighborhood (aORs: 0.45-0.81).DISCUSSION: Our results suggest that perinatal residential proximity to more greenspace may contribute to a reduced risk of certain birth defects, especially among those living in rural or high-income neighborhoods.

  View details for DOI 10.1016/j.envres.2022.114760

  View details for PubMedID 36356662

• Reconciling Between Medication Orders and Medication Fills for Lupus in Pregnancy. ACR open rheumatology Simard, J. F., Liu, E. F., Chakravarty, E., Rector, A., Cantu, M., Kuo, D. Z., Shaw, G. M., Druzin, M., Weisman, M. H., Hedderson, M. M. 2022

  Abstract

  OBJECTIVE: Most studies consider either medications ordered or filled, but not both. Medication underuse based on filling data cannot necessarily be ascribed to patient nonadherence. Using both data sources, we quantified primary medication adherence in a cohort of prevalent systemic lupus erythematosus (SLE) pregnancies.METHODS: We identified 419 pregnancies in Kaiser Permanente Northern California in patients with prevalent SLE from 2011 to 2020. We calculated the number of physician-initiated orders or pharmacy-initiated reorders during pregnancy and a comparable 9-month window the year before (prepregnancy) and the proportion of orders ever filled and filled within 30days for hydroxychloroquine (HCQ), azathioprine, and corticosteroids. For pregnancies without an order or reorder, we identified the proportion with previous prescription fills overlapping into the respective study period.RESULTS: New orders for lupus medications were usually filled. HCQ was prescribed most often (45.8% pregnancies) and usually filled (89.7% in prepregnancy, 93.2% during pregnancy). The majority filled within 30days (80.5% prepregnancy, 83.3% pregnancy). Some pregnancies without new HCQ orders had continuous refills from prior orders; 53% of 2011-2015 pregnancies either had a new order or fill coverage from a previous period, compared to 63.2% of pregnancies delivering in 2016-2019. Corticosteroid fill frequencies were 90.6% in prepregnancy and 83.6% during pregnancy. Fewer patients used azathioprine; however, most new orders were filled (94.3% prepregnancy, 91.7% pregnancy). For azathioprine and corticosteroids, fill rates were modestly higher in prepregnancy compared to pregnancy.CONCLUSION: We observed that patients have high adherence to filling new orders for lupus medications, such as HCQ and azathioprine, in pregnancy.

  View details for DOI 10.1002/acr2.11501

  View details for PubMedID 36252776

• Differential newborn DNA methylation among individuals with complex congenital heart defects and childhood lymphoma. Birth defects research Richard, M. A., Yang, W., Sok, P., Li, M., Carmichael, S. L., von Behren, J., Reynolds, P., Fisher, P. G., Collins, R. T., Hobbs, C. A., Luke, B., Shaw, G. M., Lupo, P. J. 2022

  Abstract

  BACKGROUND: There is emerging evidence that children with complex congenital heart defects (CHDs) are at increased risk for childhood lymphoma, but the mechanisms underlying this association are unclear. Thus, we sought to evaluate the role of DNA methylation patterns on "CHD-lymphoma" associations.METHODS: From >3 million live births (1988-2004) in California registry linkages, we obtained newborn dried bloodspots from eight children with CHD-lymphoma through the California BioBank. We performed case-control epigenome-wide association analyses (EWAS) using two comparison groups with reciprocal discovery and validation to identify differential methylation associated with CHD-lymphoma.RESULTS: After correction for multiple testing at the discovery and validation stages, individuals with CHD-lymphoma had differential newborn methylation at six sites relative to two comparison groups. Our top finding was significant in both EWAS and indicates PPFIA1 cg25574765 was hypomethylated among individuals with CHD-lymphoma (mean beta=0.04) relative to both unaffected individuals (mean beta=0.93, p=1.5*10-12 ) and individuals with complex CHD (mean beta=0.95, p=3.8*10-8 ). PPFIA1 encodes a ubiquitously expressed liprin protein in one of the most commonly amplified regions in many cancers (11q13). Further, cg25574765 is a proposed marker of pre-eclampsia, a maternal CHD risk factor that has not been fully evaluated for lymphoma risk in offspring, and the tumor microenvironment that may drive immune cell malignancies.CONCLUSIONS: We identified associations between molecular changes present in the genome at birth and risk of childhood lymphoma among those with CHD. Our findings also highlight novel perinatal exposures that may underlie methylation changes in CHD predisposing to lymphoma.

  View details for DOI 10.1002/bdr2.2105

  View details for PubMedID 36226634

• 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

• Preconception paternal comorbidities and offspring birth defects: Analysis of a large national data set. Birth defects research Yu, B., Zhang, C. A., Li, S., Chen, T., Mulloy, E., Shaw, G. M., Eisenberg, M. L. 2022

  Abstract

  BACKGROUND: Despite the fact that the father contributes half the genome to a child, associations between paternal factors and birth defects are poorly understood.OBJECTIVES: To investigate the association between preconception paternal health and birth defects in the offspring.MATERIALS AND METHODS: We conducted analysis of a national cohort study utilizing the IBM Marketscan Research Database, which includes data on reimbursed private healthcare claims in the United States from 2007 to 2016. The potential association between paternal comorbidities, as measured by the components of metabolic syndrome (MetS), and any birth defect in the offspring was analyzed.RESULTS: Of the 712,774 live births identified, 21.2% of children were born to fathers with at least one component of the metabolic syndrome (MetS ≥1) prior to conception. Compared to infants born to fathers with no components of the metabolic syndrome, a modestly higher percentage of infants with cardiac birth defects were born to fathers with more components of MetS (MetS=1, OR [95% CI]: 1.07 [1.01-1.13]; MetS ≥2, 1.17 [1.08-1.26], in comparison to MetS=0) after adjusting for maternal and paternal factors. Similarly, a higher percentage of infants with respiratory defects were born to fathers with two or more components of metabolic syndrome (MetS ≥2, OR [95% CI]: 1.45 [1.22-1.71]).DISCUSSION AND CONCLUSION: In this private insurance claims-based study, we found that fathers with metabolic syndrome-related diseases before conception were at increased risk for having a child affected by birth defects, especially cardiac and respiratory defects, and this association was not influenced by paternal age or assessed maternal factors.

  View details for DOI 10.1002/bdr2.2082

  View details for PubMedID 36106720

• Hospital variation in extremely preterm birth. Journal of perinatology : official journal of the California Perinatal Association Goldstein, G. P., Kan, P., Phibbs, C. S., Main, E., Shaw, G. M., Lee, H. C. 2022

  Abstract

  Given that regionalization of extremely preterm births (EPTBs) is associated with improved infant outcomes, we assessed between-hospital variation in EPTB stratified by hospital level of neonatal care, and determined the proportion of variance explained by differences in maternal and hospital factors.We assessed 7,046,253 births in California from 1997 to 2011, using hospital discharge, birth, and death certificate data. We estimated the association between maternal and hospital factors and EPTB using multivariable regression, calculated hospital-specific EPTB frequencies, and estimated between-hospital variances and median odds ratios, stratified by hospital level of care.Hospital frequencies of EPTB ranged from 0% to 2.5%. Between-hospital EPTB frequencies varied substantially, despite stratifying by hospital level of care and accounting for confounding factors.Our results demonstrate differences in EPTBs among hospitals with level 1 and 2 neonatal care, an area to target for future research and quality improvement.

  View details for DOI 10.1038/s41372-022-01505-3

  View details for PubMedID 36104499

• CIC missense variants contribute to susceptibility for spina bifida. Human mutation Han, X., Cao, X., Aguiar-Pulido, V., Yang, W., Karki, M., Ramirez, P. A., Cabrera, R. M., Lin, Y. L., Wlodarczyk, B. J., Shaw, G. M., Ross, M. E., Zhang, C., Finnell, R. H., Lei, Y. 2022

  Abstract

  Neural Tube Defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to the cerebral folate deficiency syndrome by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased risk for NTDs by depressing embryonic folate concentrations. In this study, we examined CIC variants from whole genome sequencing (WGS) data of 140 isolated spina bifida cases and identified 8 missense variants of CIC gene. We tested the pathogenicity of the observed variants through multiple in vitro experiments. We determined that CIC variants decreased FOLR1 protein level and planar cell polarity (PCP) pathway signaling in a human cell line (HeLa). In a murine cell line (NIH3T3), CIC loss of function variants down regulated PCP signaling. Taken together, this study provides evidence supporting CIC as a risk gene for human NTD. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/humu.24460

  View details for PubMedID 36054333

• Primary hydroxychloroquine adherence in lupus pregnancy Simard, J. F., Liu, E. F., Chakravarty, E., Rector, A., Cantu, M., Kuo, D., Shaw, G., Druzin, M., Weisman, M., Hedderson, M. WILEY. 2022: 125

  View details for Web of Science ID 000859084400242

• Pregnancy Outcomes in a Diverse Lupus Cohort Simard, J., Liu, E., Chakravarty, E., Rector, A., Cantu, M., Kuo, D., Shaw, G., Druzin, M., Weisman, M., Hedderson, M. WILEY. 2022: 1905-1906

  View details for Web of Science ID 000877386501479

• Increased Risk of Preterm Delivery Phenotypes and Hypertensive Disorders of Pregnancy in First Deliveries of Patients with Systemic Vasculitis Horomanski, A., Shaw, G., Mayo, J., Simard, J. WILEY. 2022: 1880-1881

  View details for Web of Science ID 000877386501467

• Assessing the Association Between Hydroxychloroquine and Preeclampsia Risk in SLE Pregnancies Using Administrative Claims Data Rector, A., Maric, I., Chaichian, Y., Chakravarty, E., Cantu, M., Weisman, M., Shaw, G., Druzin, M., Simard, J. WILEY. 2022: 1890-1893

  View details for Web of Science ID 000877386501473

• 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

• Exome sequencing identifies genetic variants in anophthalmia and microphthalmia. American journal of medical genetics. Part A Li, J., Yang, W., Wang, Y. J., Ma, C., Curry, C. J., McGoldrick, D., Nickerson, D. A., Chong, J. X., Blue, E. E., Mullikin, J. C., Reefhuis, J., Nembhard, W. N., Romitti, P. A., Werler, M. M., Browne, M. L., Olshan, A. F., Finnell, R. H., Feldkamp, M. L., Pangilinan, F., Almli, L. M., Bamshad, M. J., Brody, L. C., Jenkins, M. M., Shaw, G. M., NISC Comparative Sequencing Program, University of Washington Center for Mendelian Genomics, National Birth Defects Prevention Study 2022

  Abstract

  Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

  View details for DOI 10.1002/ajmg.a.62874

  View details for PubMedID 35716026

• 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

• 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

• Distance from home to birth hospital, transfer, and mortality in neonates with hypoplastic left heart syndrome in California. Birth defects research Purkey, N. J., Ma, C., Lee, H. C., Hintz, S. R., Shaw, G. M., McElhinney, D. B., Carmichael, S. L. 2022

  Abstract

  BACKGROUND: Prior studies report a lower risk of mortality among neonates with hypoplastic left heart syndrome (HLHS) who are born at a cardiac surgical center, but many neonates with HLHS are born elsewhere and transferred for repair. We investigated the associations between the distance from maternal home to birth hospital, the need for transfer after birth, sociodemographic factors, and mortality in infants with HLHS in California from 2006 to 2011.METHODS: We used linked data from two statewide databases to identify neonates for this study. Three groups were included in the analysis: "lived close/not transferred," "lived close/transferred," and "lived far/not transferred." We defined "lived close" versus "lived far" as 11miles, the median distance from maternal residence to birth hospital. Log-binomial regression models were used to identify the association between sociodemographic variables, distance to birth hospital and transfer. Cox proportional hazards models were used to identify the association between mortality and distance to birth hospital and transfer. Models were adjusted for sociodemographic variables.RESULTS: Infants in the lived close/not transferred and the lived close/transferred groups (vs. the lived far/not transferred group) were more likely to live in census tracts above the 75th percentile for poverty with relative risks 1.94 (95% confidence interval [CI] 1.41-2.68) and 1.21 (95% CI 1.05-1.40), respectively. Neonatal mortality was higher among the lived close/not transferred group compared with the lived far/not transferred group (hazard ratio 1.77, 95% CI 1.17-2.67).CONCLUSIONS: Infants born to mothers experiencing poverty were more likely to be born close to home. Infants with HLHS who were born close to home and not transferred to a cardiac center had a higher risk of neonatal mortality than infants who were delivered far from home and not transferred. Future studies should identify the barriers to delivery at a cardiac center for mothers experiencing poverty.

  View details for DOI 10.1002/bdr2.2020

  View details for PubMedID 35488460

• 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

• A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study. American journal of medical genetics. Part A Rashkin, S. R., Cleves, M., Shaw, G. M., Nembhard, W. N., Nestoridi, E., Jenkins, M. M., Romitti, P. A., Lou, X., Browne, M. L., Mitchell, L. E., Olshan, A. F., Lomangino, K., Bhattacharyya, S., Witte, J. S., Hobbs, C. A., National Birth Defects Prevention Study 2022

  Abstract

  Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery =3978; Nreplication =2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT =440; Nreplication_TDT =275) and case-control analyses separately in infants (Ndiscovery_CCI =1635; Nreplication_CCI =990) and mothers (case status defined by infant; Ndiscovery_CCM =1703; Nreplication_CCM =1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery =4.08*10-9 ; preplication =2.44*10-4 ). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery =1.61*10-7 ; preplication =0.0016). Two other SNPs were suggestively associated (p<1*10-6 ) with OHD in only the discovery sample. In the case-control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds (*discovery <1*10-5 and preplication <0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery =1.42*10-6 ; preplication =0.04). Additional SNPs with pdiscovery <1*10-5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings.

  View details for DOI 10.1002/ajmg.a.62759

  View details for PubMedID 35451555

• 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

• 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

• Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study. Annals of internal medicine Wensink, M. J., Lu, Y., Tian, L., Shaw, G. M., Rizzi, S., Jensen, T. K., Mathiesen, E. R., Skakkebæk, N. E., Lindahl-Jacobsen, R., Eisenberg, M. L. 2022

  Abstract

  Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.Nationwide prospective registry-based cohort study.Denmark from 1997 to 2016.All liveborn singletons from mothers without histories of diabetes or essential hypertension.Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings.Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073).Information on underlying disease status was limited.Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation.National Institutes of Health.

  View details for DOI 10.7326/M21-4389

  View details for PubMedID 35344380

• Exome sequencing identifies variants in infants with sacral agenesis. Birth defects research Pitsava, G., Feldkamp, M. L., Pankratz, N., Lane, J., Kay, D. M., Conway, K. M., Hobbs, C., Shaw, G. M., Reefhuis, J., Jenkins, M. M., Almli, L. M., Moore, C., Werler, M., Browne, M. L., Cunniff, C., Olshan, A. F., Pangilinan, F., Brody, L. C., Sicko, R. J., Finnell, R. H., Bamshad, M. J., McGoldrick, D., Nickerson, D. A., Mullikin, J. C., Romitti, P. A., Mills, J. L., UW Center for Mendelian Genomics, N. C. 2022

  Abstract

  BACKGROUND: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA.METHODS: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced.RESULTS: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N=1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N=2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children.CONCLUSIONS: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies.

  View details for DOI 10.1002/bdr2.1987

  View details for PubMedID 35274497

• 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

• Upstream oil and gas production and ambient air pollution in California. The Science of the total environment Gonzalez, D. J., Francis, C. K., Shaw, G. M., Cullen, M. R., Baiocchi, M., Burke, M. 2022; 806 (Pt 1): 150298

  Abstract

  Prior studies have found that residential proximity to upstream oil and gas production is associated with increased risk of adverse health outcomes. Emissions of ambient air pollutants from oil and gas wells in the preproduction and production stages have been proposed as conferring risk of adverse health effects, but the extent of air pollutant emissions and resulting nearby pollution concentrations from wells is not clear.We examined the effects of upstream oil and gas preproduction (count of drilling sites) and production (total volume of oil and gas) activities on concentrations of five ambient air pollutants in California.We obtained data on approximately 1 million daily observations from 314 monitors in the EPA Air Quality System, 2006-2019, including daily concentrations of five routinely monitored ambient air pollutants: PM2.5, CO, NO2, O3, and VOCs. We obtained data on preproduction and production operations from Enverus and the California Geographic Energy Management Division (CalGEM) for all wells in the state. For each monitor and each day, we assessed exposure to upwind preproduction wells and total oil and gas production volume within 10 km. We used a panel regression approach in the analysis and fit adjusted fixed effects linear regression models for each pollutant, controlling for geographic, seasonal, temporal, and meteorological factors.We observed higher concentrations of PM2.5 and CO at monitors within 3 km of preproduction wells, NO2 at monitors at 1-2 km, and O3 at 2-4 km from the wells. Monitors with proximity to increased production volume observed higher concentrations of PM2.5, NO2, and VOCs within 1 km and higher O3 concentrations at 1-2 km. Results were robust to sensitivity analyses.Adjusting for geographic, meteorological, seasonal, and time-trending factors, we observed higher concentrations of ambient air pollutants at air quality monitors in proximity to preproduction wells within 4 km and producing wells within 2 km.

  View details for DOI 10.1016/j.scitotenv.2021.150298

  View details for PubMedID 34844318

• Upstream oil and gas production and ambient air pollution in California SCIENCE OF THE TOTAL ENVIRONMENT Gonzalez, D. X., Francis, C. K., Shaw, G. M., Cullen, M. R., Baiocchi, M., Burke, M. 2022; 806

  View details for DOI 10.1016/j.scitotenv.2021.150298

  View details for Web of Science ID 000709731100002

• 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

• 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

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

  Abstract

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

  View details for DOI 10.3389/fped.2022.933266

  View details for PubMedID 36582513

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

  Abstract

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

  View details for DOI 10.1055/a-1798-1602

  View details for PubMedID 35292943

• HOSPITAL VARIATION IN EXTREMELY PRETERM BIRTH Goldstein, G. P., Kan, P., Phibbs, C., Main, E., Shaw, G. M., Lee, H. BMJ PUBLISHING GROUP. 2022: 215

  View details for DOI 10.1136/jim-2022-WRMC.205

  View details for Web of Science ID 000737295900226

• Systems biology analysis of human genomes points to key pathways conferring spina bifida risk. Proceedings of the National Academy of Sciences of the United States of America Aguiar-Pulido, V., Wolujewicz, P., Martinez-Fundichely, A., Elhaik, E., Thareja, G., Abdel Aleem, A., Chalhoub, N., Cuykendall, T., Al-Zamer, J., Lei, Y., El-Bashir, H., Musser, J. M., Al-Kaabi, A., Shaw, G. M., Khurana, E., Suhre, K., Mason, C. E., Elemento, O., Finnell, R. H., Ross, M. E. 1800; 118 (51)

  Abstract

  Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance, and environmental influences that hamper genome-wide association studies approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases versus controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation, and essential transcriptional regulation consistent with their having impact on the pathogenesis of human SB. Additionally, an interrogation of conserved noncoding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to the interrogation of coding and noncoding sequence variant contributions to rare complex genetic disorders.

  View details for DOI 10.1073/pnas.2106844118

  View details for PubMedID 34916285

• Modeling complex effects of exposure to particulate matter and extreme heat during pregnancy on congenital heart defects: A U.S. population-based case-control study in the National Birth Defects Prevention Study. The Science of the total environment Simmons, W., Lin, S., Luben, T. J., Sheridan, S. C., Langlois, P. H., Shaw, G. M., Reefhuis, J., Romitti, P. A., Feldkamp, M. L., Nembhard, W. N., Desrosiers, T. A., Browne, M. L., Stingone, J. A., National Birth Defects Prevention Study 2021: 152150

  Abstract

  BACKGROUND/OBJECTIVE: Research suggests gestational exposure to particulate matter ≤2.5 mum (PM2.5) and extreme heat may independently increase risk of birth defects. We investigated whether duration of gestational extreme heat exposure modifies associations between PM2.5 exposure and specific congenital heart defects (CHDs). We also explored nonlinear exposure-outcome relationships.METHODS: We identified CHD case children (n = 2824) and non-malformed live-birth control children (n = 4033) from pregnancies ending between 1999 and 2007 in the National Birth Defects Prevention Study, a U.S. population-based multicenter case-control study. We assigned mothers 6-week averages of PM2.5 exposure during the cardiac critical period (postconceptional weeks 3-8) using the closest monitor within 50 km of maternal residence. We assigned a count of extreme heat days (EHDs, days above the 90th percentile of daily maximum temperature for year, season, and weather station) during this period using the closest weather station. Using generalized additive models, we explored logit-nonlinear exposure-outcome relationships, concluding logistic models were reasonable. We estimated joint effects of PM2.5 and EHDs on six CHDs using logistic regression models adjusted for mean dewpoint and maternal age, education, and race/ethnicity. We assessed multiplicative and additive effect modification.RESULTS: Conditional on the highest observed EHD count (15) and at least one critical period day during spring/summer, each 5 mug/m3 increase in average PM2.5 exposure was significantly associated with perimembranous ventricular septal defects (VSDpm; OR: 1.54 [95% CI: 1.01, 2.41]). High EHD counts (8+) in the same population were positively, but non-significantly, associated with both overall septal defects and VSDpm. Null or inverse associations were observed for lower EHD counts. Multiplicative and additive effect modification estimates were consistently positive in all septal models.CONCLUSIONS: Results provide limited evidence that duration of extreme heat exposure modifies the PM2.5-septal defects relationship. Future research with enhanced exposure assessment and modeling techniques could clarify these relationships.

  View details for DOI 10.1016/j.scitotenv.2021.152150

  View details for PubMedID 34864029

• 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

• Trends in eclampsia in the United States, 2009-2017: a population-based study. Journal of hypertension Xiao, M. Z., Whitney, D., Guo, N., Bentley, J., Shaw, G. M., Druzin, M. L., Butwick, A. J. 2021

  Abstract

  BACKGROUND: Reducing the prevalence of eclampsia, a major cause of maternal and perinatal morbidity, is a maternal health priority. However, sparse data exist examining trends in the USA prevalence of eclampsia.OBJECTIVE: The aim of this study was to assess temporal trends in the prevalence of eclampsia among live births in the United States from 2009 to 2017.STUDY DESIGN: This population-based cross-sectional study included live births in 41 USA states and the District of Columbia between 2009 and 2017. The prevalence of eclampsia among all women, women with chronic hypertension and hypertensive disorders of pregnancy were reported by 1000 live births. Risk ratios adjusted for maternal characteristics were used to assess temporal trends.RESULTS: Of 27 866 714 live births between 2009 and 2017, 83 000 (0.30%) were associated with eclampsia. The adjusted risk of eclampsia decreased 10% during the 7 most recent years of the cohort, with an adjusted risk ratio of 0.90 [95% confidence interval (95% CI): 0.87-0.93] in 2017 relative to 2009. Relative to 2009, the adjusted risk of eclampsia in 2017 was substantially lower among women with chronic hypertension (adjusted risk ratio: 0.51; 95% CI: 0.46-0.57) and women with hypertensive pregnancy disorders (adjusted risk ratio: 0.43; 95% CI: 0.40-0.47). Among nonhypertensive women, there was a slight increase in the adjusted risk of eclampsia in 2017 relative to 2009 (adjusted risk ratio: 1.14; 95% CI: 1.10-1.17).CONCLUSION: Despite reductions in the eclampsia prevalence among women with chronic hypertension and hypertensive disorders of pregnancy, public health initiatives are needed to reduce the overall eclampsia prevalence, especially in nonhypertensive women.

  View details for DOI 10.1097/HJH.0000000000003037

  View details for PubMedID 34751169

• 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

• 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

• THE ASSOCIATION OF PRECONCEPTION PATERNAL METABOLIC SYNDROME ON EARLY CHILDHOOD EMERGENCY DEPARTMENT VISITS AND HOSPITALIZATION: ANALYSIS OF US CLAIMS DATA Chen, T., Zhang, C., Li, S., Shaw, G., Schroeder, A., Eisenberg, M. LIPPINCOTT WILLIAMS & WILKINS. 2021: E526

  View details for Web of Science ID 000693688500311

• Homelessness in pregnancy: perinatal outcomes. Journal of perinatology : official journal of the California Perinatal Association St Martin, B. S., Spiegel, A. M., Sie, L., Leonard, S. A., Seidman, D., Girsen, A. I., Shaw, G. M., El-Sayed, Y. Y. 2021

  Abstract

  OBJECTIVE: Investigate the association between maternal homelessness at the time of delivery and perinatal outcomes, with a focus on neonatal health outcomes.STUDY DESIGN: Population-based cohort using California's statewide database included 1,520,253 women with linked birth and maternal discharge data, 2008-2012. Multivariable analysis assessed homelessness at time of delivery on perinatal outcomes, preterm delivery, and neonatal intensive care unit admission.RESULT: A total of 672 women (0.05%) were homeless at the time of delivery. Homelessness was associated with premature delivery at multiple gestational age cutoffs (34w0d-36w6d; 32w0d-33w6d; 28w0d-31w6d; <28w0d) (range of aORs:1.62-2.19), and neonatal intensive care unit admission (aOR=1.66, 95% CI:1.31-2.09). Among term infants, homelessness remained associated with increased odds of neonatal intensive care unit admission (aOR=1.84, 95% CI:1.34-2.53), low birthweight (aOR=1.99, 95% CI:1.36-2.90), neonatal abstinence syndrome (aOR=2.13, 95% CI:1.35-2.53), hypoxic-ischemic encephalopathy (aOR=14.38, 95% CI:3.90-53.01), and necrotizing enterocolitis (aOR=14.94, 95% CI:2.68-83.20).CONCLUSION: Homelessness in pregnancy was associated with adverse perinatal outcomes including increased odds of preterm delivery across all gestational ages, and increased risk of neonatal intensive care unit admission and low birth weight independent of preterm delivery.

  View details for DOI 10.1038/s41372-021-01187-3

  View details for PubMedID 34404925

• Associations between wildfire smoke exposure during pregnancy and risk of preterm birth in California. Environmental research Heft-Neal, S., Driscoll, A., Yang, W., Shaw, G., Burke, M. 2021: 111872

  Abstract

  There is limited population-scale evidence on the burden of exposure to wildfire smoke during pregnancy and its impacts on birth outcomes. In order to investigate this relationship, data on every singleton birth in California 2006-2012 were combined with satellite-based estimates of wildfire smoke plume boundaries and high-resolution gridded estimates of surface PM2.5 concentrations and a regression model was used to estimate associations with preterm birth risk. Results suggest that each additional day of exposure to any wildfire smoke during pregnancy was associated with an 0.49 % (95 % CI: 0.41-0.59 %) increase in risk of preterm birth (<37 weeks). At sample median smoke exposure (7 days) this translated to a 3.4 % increase in risk, relative to an unexposed mother. Estimates by trimester suggest stronger associations with exposure later in pregnancy and estimates by smoke intensity indicate that observed associations were driven by higher intensity smoke-days. Exposure to low intensity smoke-days had no association with preterm birth while an additional medium (smoke PM2.5 5-10 mug/m3) or high (smoke PM2.5 > 10 mug/m3) intensity smoke-day was associated with an 0.95 % (95 % CI: 0.47-1.42 %) and 0.82 % (95 % CI: 0.41-1.24 %) increase in preterm risk, respectively. In contrast to previous findings for other pollution types, neither exposure to smoke nor the relative impact of smoke on preterm birth differed by race/ethnicity or income in our sample. However, impacts differed greatly by baseline smoke exposure, with mothers in regions with infrequent smoke exposure experiencing substantially larger impacts from an additional smoke-day than mothers in regions where smoke is more common. We estimate 6,974 (95 % CI: 5,513-8,437) excess preterm births attributable to wildfire smoke exposure 2007-2012, accounting for 3.7 % of observed preterm births during this period. Our findings have important implications for understanding the costs of growing wildfire smoke exposure, and for understanding the benefits of smoke mitigation measures.

  View details for DOI 10.1016/j.envres.2021.111872

  View details for PubMedID 34403668

• Exome sequencing of child-parent trios with bladder exstrophy: Findings in 26 children. American journal of medical genetics. Part A Pitsava, G., Feldkamp, M. L., Pankratz, N., Lane, J., Kay, D. M., Conway, K. M., Shaw, G. M., Reefhuis, J., Jenkins, M. M., Almli, L. M., Olshan, A. F., Pangilinan, F., Brody, L. C., Sicko, R. J., Hobbs, C. A., Bamshad, M., McGoldrick, D., Nickerson, D. A., Finnell, R. H., Mullikin, J., Romitti, P. A., Mills, J. L., University of Washington Center for Mendelian Genomics, N. C. 2021

  Abstract

  Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency≤0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.

  View details for DOI 10.1002/ajmg.a.62439

  View details for PubMedID 34355505

• Stillbirth as left truncation for early neonatal death in California, 1989-2015: a time-series study. BMC pregnancy and childbirth Bruckner, T. A., Gailey, S., Das, A., Gemmill, A., Casey, J. A., Catalano, R., Shaw, G. M., Zeitlin, J. 2021; 21 (1): 478

  Abstract

  BACKGROUND: Some scholars posit that attempts to avert stillbirth among extremely preterm gestations may result in a live birth but an early neonatal death. The literature, however, reports no empirical test of this potential form of left truncation. We examine whether annual cohorts delivered at extremely preterm gestational ages show an inverse correlation between their incidence of stillbirth and early neonatal death.METHODS: We retrieved live birth and infant death information from the California Linked Birth and Infant Death Cohort Files for years 1989 to 2015. We defined the extremely preterm period as delivery from 22 to <28weeks of gestation and early neonatal death as infant death at less than 7days of life. We calculated proportions of stillbirth and early neonatal death separately by cohort year, race/ethnicity, and sex. Our correlational analysis controlled for well-documented declines in neonatal mortality over time.RESULTS: California reported 89,276 extremely preterm deliveries (live births and stillbirths) to Hispanic, non-Hispanic (NH) Black, and NH white mothers from 1989 to 2015. Findings indicate an inverse correlation between stillbirth and early neonatal death in the same cohortyear (coefficient: -0.27, 95% CI of -0.11; -0.42). Results remain robust to alternative specifications and falsification tests.CONCLUSIONS: Findings support the notion that cohorts with an elevated risk of stillbirth also show a reduced risk of early neonatal death among extremely preterm deliveries. Results add to the evidence base that selection in utero may influence the survival characteristics of live-born cohorts.

  View details for DOI 10.1186/s12884-021-03852-z

  View details for PubMedID 34215208

• 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

• Association of Gestational Age with Postpartum Hemorrhage: An International Cohort Study ANESTHESIOLOGY Butwick, A. J., Liu, C., Guo, N., Bentley, J., Main, E. K., Mayo, J. A., Shaw, G. M., Stephansson, O. 2021; 134 (6): 874-886

  Abstract

  Risk factors for postpartum hemorrhage, such as chorioamnionitis and multiple gestation, have been identified in previous epidemiologic studies. However, existing data describing the association between gestational age at delivery and postpartum hemorrhage are conflicting. The aim of this study was to assess the association between gestational age at delivery and postpartum hemorrhage.The authors conducted a population-based retrospective cohort study of women who underwent live birth delivery in Sweden between 2014 and 2017 and in California between 2011 and 2015. The primary exposure was gestational age at delivery. The primary outcome was postpartum hemorrhage, classified using International Classification of Diseases, Ninth Revision-Clinical Modification codes for California births and a blood loss greater than 1,000 ml for Swedish births. The authors accounted for demographic and obstetric factors as potential confounders in the analyses.The incidences of postpartum hemorrhage in Sweden (23,323/328,729; 7.1%) and in California (66,583/2,079,637; 3.2%) were not comparable. In Sweden and California, the incidence of postpartum hemorrhage was highest for deliveries between 41 and 42 weeks' gestation (7,186/75,539 [9.5%] and 8,921/160,267 [5.6%], respectively). Compared to deliveries between 37 and 38 weeks, deliveries between 41 and 42 weeks had the highest adjusted odds of postpartum hemorrhage (1.62 [95% CI, 1.56 to 1.69] in Sweden and 2.04 [95% CI, 1.98 to 2.09] in California). In both cohorts, the authors observed a nonlinear (J-shaped) association between gestational age and postpartum hemorrhage risk, with 39 weeks as the nadir. In the sensitivity analyses, similar findings were observed among cesarean deliveries only, when postpartum hemorrhage was classified only by International Classification of Diseases, Tenth Revision-Clinical Modification codes, and after excluding women with abnormal placentation disorders.The postpartum hemorrhage incidence in Sweden and California was not comparable. When assessing a woman's risk for postpartum hemorrhage, clinicians should be aware of the heightened odds in women who deliver between 41 and 42 weeks' gestation.

  View details for DOI 10.1097/ALN.0000000000003730

  View details for Web of Science ID 000648691100012

  View details for PubMedID 33760074

• 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

• 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

• Nitrate in Drinking Water during Pregnancy and Spontaneous Preterm Birth: A Retrospective Within-Mother Analysis in California. Environmental health perspectives Sherris, A. R., Baiocchi, M., Fendorf, S., Luby, S. P., Yang, W., Shaw, G. M. 2021; 129 (5): 57001

  Abstract

  BACKGROUND: Nitrate is a widespread groundwater contaminant and a leading cause of drinking water quality violations in California. Associations between nitrate exposure and select adverse birth outcomes have been suggested, but few studies have examined gestational exposures to nitrate and risk of preterm birth (before 37 wk gestation).OBJECTIVE: We investigated the association between elevated nitrate in drinking water and spontaneous preterm birth through a within-mother retrospective cohort study of births in California.METHODS: We acquired over 6 million birth certificate records linked with Office of Statewide Health Planning and Development hospital discharge data for California births from 2000-2011. We used public water system monitoring records to estimate nitrate concentrations in drinking water for each woman's residence during gestation. After exclusions, we constructed a sample of 1,443,318 consecutive sibling births in order to conduct a within-mother analysis. We used separate conditional logistic regression models to estimate the odds of preterm birth at 20-31 and 32-36 wk, respectively, among women whose nitrate exposure changed between consecutive pregnancies.RESULTS: Spontaneous preterm birth at 20-31 wk was increased in association with tap water nitrate concentrations during pregnancy of 5 to <10mg/L [odds ratio (OR)=1.47; 95% confidence interval (CI): 1.29, 1.67] and ≥10mg/L (OR=2.52; 95% CI: 1.49, 4.26) compared with <5mg/L (as nitrogen). Corresponding estimates for spontaneous preterm birth at 32-36 wk were positive but close to the null for 5 to <10mg/L nitrate (OR=1.08; 95% CI: 1.02, 1.15) and for ≥10mg/L nitrate (OR=1.05; 95% CI: 0.85, 1.31) vs. <5mg/L nitrate. Our findings were similar in several secondary and sensitivity analyses, including in a conventional individual-level design.DISCUSSION: The results suggest that nitrate in drinking water is associated with increased odds of spontaneous preterm birth. Notably, we estimated modestly increased odds associated with tap water nitrate concentrations of 5 to <10mg/L (below the federal drinking water standard of 10mg/L) relative to <5mg/L. https://doi.org/10.1289/EHP8205.

  View details for DOI 10.1289/EHP8205

  View details for PubMedID 33949893

• 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

• The relationship between air pollutants and maternal socioeconomic factors on preterm birth in California urban counties. Journal of exposure science & environmental epidemiology Mekonnen, Z. K., Oehlert, J. W., Eskenazi, B., Shaw, G. M., Balmes, J. R., Padula, A. M. 2021

  Abstract

  BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality in the U.S. and disparities among racial and ethnic groups persist. While etiologies of preterm birth have not been fully elucidated, it is probable that environmental and social factors play a role.OBJECTIVE: We hypothesized that there is an interactive association between exposure to fine particulate matter (PM2.5) or ozone (O3) and neighborhood socioeconomic factors that increase the risk of preterm birth.METHODS: We conducted a retrospective study using geocoded birth certificate data between 2007 and 2011, daily ambient air quality data on PM2.5 and O3, and American Community Survey (2007-2011 5-year estimates) data to assess census tract-level socioeconomic factors in California urban counties.RESULTS: Our study found a small positive association between maternal exposures to PM2.5 and O3 and preterm birth that varied by gestational exposure period. In mixed-effects models, we found an increase in the risk of preterm birth for a one-unit change in PM2.5 averaged across the entire pregnancy (AOR=1.02, 95% CI: 1.01, 1.02) and O3 during 3-months pre-pregnancy (AOR=1.03, 95% CI: 1.02, 1.04). Interaction between census tract-level factors and air pollutants showed an increase in the risk of preterm birth among mothers living in higher socioeconomic areas, though, a fixed cohort bias sensitivity analysis showed these associations were not significant.SIGNIFICANCE: These findings substantiate previous studies that showed associations between air pollution and preterm birth, even as pollution levels have decreased. This study has important implications for policy decisions and may help inform research on potential mechanisms of preterm birth.

  View details for DOI 10.1038/s41370-021-00323-7

  View details for PubMedID 33859340

• African American Unemployment and the Disparity in Periviable Births. Journal of racial and ethnic health disparities Catalano, R., Karasek, D., Bruckner, T., Casey, J. A., Saxton, K., Ncube, C. N., Shaw, G. M., Elser, H., Gemmill, A. 2021

  Abstract

  Periviable infants (i.e., born before 26 complete weeks of gestation) represent fewer than .5% of births in the US but account for 40% of infant mortality and 20% of billed hospital obstetric costs. African American women contribute about 14% of live births in the US, but these include nearly a third of the country's periviable births. Consistent with theory and with periviable births among other race/ethnicity groups, males predominate among African American periviable births in stressed populations. We test the hypothesis that the disparity in periviable male births among African American and non-Hispanic white populations responds to the African American unemployment rate because that indicator not only traces, but also contributes to, the prevalence of stress in the population. We use time-series methods that control for autocorrelation including secular trends, seasonality, and the tendency to remain elevated or depressed after high or low values. The racial disparity in male periviable birth increases by 4.45% for each percentage point increase in the unemployment rate of African Americans above its expected value. We infer that unemployment-a population stressor over which our institutions exercise considerable control-affects the disparity between African American and non-Hispanic white periviable births in the US.

  View details for DOI 10.1007/s40615-021-01022-7

  View details for PubMedID 33783756

• 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

• Interdisciplinary Data Science to Advance Environmental Health Research and Improve Birth Outcomes. Environmental research Stingone, J. A., Triantafillou, S., Larsen, A., Kitt, J. P., Shaw, G. M., Marsillach, J. 2021: 111019

  Abstract

  Rates of preterm birth and low birthweight continue to rise in the United States and pose a significant public health problem. Although a variety of environmental exposures are known to contribute to these and other adverse birth outcomes, there has been a limited success in developing policies to prevent these outcomes. A better characterization of the complexities between multiple exposures and their biological responses can provide the evidence needed to inform public health policy and strengthen preventative population-level interventions. In order to achieve this, we encourage the establishment of an interdisciplinary data science framework that integrates epidemiology, toxicology and bioinformatics with biomarker-based research to better define how population-level exposures contribute to these adverse birth outcomes. The proposed interdisciplinary research framework would 1) facilitate data-driven analyses using existing data from health registries and environmental monitoring programs; 2) develop novel algorithms with the ability to predict which exposures are driving, in this case, adverse birth outcomes in simultaneous exposures; and 3) refine biomarker-based research, ultimately leading to new policies and interventions to reduce the incidence of adverse birth outcomes.

  View details for DOI 10.1016/j.envres.2021.111019

  View details for PubMedID 33737076

• Genome-wide investigation identifies a rare copy-number variant burden associated with human spina bifida. Genetics in medicine : official journal of the American College of Medical Genetics Wolujewicz, P., Aguiar-Pulido, V., AbdelAleem, A., Nair, V., Thareja, G., Suhre, K., Shaw, G. M., Finnell, R. H., Elemento, O., Ross, M. E. 2021

  Abstract

  PURPOSE: Next-generation sequencing has implicated some risk variants for human spina bifida (SB), but the genome-wide contribution of structural variation to this complex genetic disorder remains largely unknown. We examined copy-number variant (CNV) participation in the genetic architecture underlying SB risk.METHODS: A high-confidence ensemble approach to genome sequences (GS) was benchmarked and employed for systematic detection of common and rare CNVs in two separate ancestry-matched SB case-control cohorts.RESULTS: SB cases were enriched with exon disruptive rare CNVs, 44% of which were under 10 kb, in both ancestral populations (P=6.75 * 10-7; P=7.59 * 10-4). Genes containing these disruptive CNVs fall into molecular pathways, supporting a role for these genes in SB. Our results expand the catalog of variants and genes with potential contribution to genetic and gene-environment interactions that interfere with neurulation, useful for further functional characterization.CONCLUSION: This study underscores the need for genome-wide investigation and extends our previous threshold model of exonic, single-nucleotide variation toward human SB risk to include structural variation. Since GS data afford detection of CNVs with greater resolution than microarray methods, our results have important implications toward a more comprehensive understanding of the genetic risk and mechanisms underlying neural tube defect pathogenesis.

  View details for DOI 10.1038/s41436-021-01126-9

  View details for PubMedID 33686259

• Gene-environment interactions between air pollution and biotransformation enzymes and risk of birth defects. Birth defects research Padula, A. M., Yang, W., Schultz, K., Lee, C., Lurmann, F., Hammond, S. K., Shaw, G. M. 2021

  Abstract

  Genetic and environmental factors have been observed to influence risks for birth defects, though few studies have investigated gene-environment interactions. Our aim was to examine the interaction terms of gene variants in biotransformation enzyme pathways and air pollution exposures in relation to risk of several structural birth defects. We evaluated the role of ambient air pollutant exposure (nitrogen dioxide [NO2 ], nitrogen oxide, carbon monoxide, particulate matter <10 [PM10 ] and <2.5 [PM2.5 ] microns) during pregnancy and 104 gene variants of biotransformation enzymes from infant bloodspots or buccal cells in a California population-based case-control study in 1997-2006. Cases included cleft lip with or without cleft palate (N = 206), gastroschisis (N = 94), tetralogy of Fallot (N = 69), and dextro-transposition of the great arteries (d-TGA; N = 40) and were compared to 208 nonmalformed controls. Overall, the results were not consistent, though did highlight some associations for further investigation as indicated by Wald chi-square test p value <.1. Increased risk of cleft lip was associated with exposure to high PM10 and two CYP gene variants. High PM2.5 and the variant of SLCO1B1 was associated with increased risk of teratology of Fallot. Higher NO2 and two gene variants, CYP2A6 and SLC01B1, were associated with increased risk of d-TGA. Results for gastroschisis were inconsistent in direction and across pollutants. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of air pollution.

  View details for DOI 10.1002/bdr2.1880

  View details for PubMedID 33569925

• Timing of Transfer and Mortality in Neonates with Hypoplastic Left Heart Syndrome in California. Pediatric cardiology Purkey, N. J., Ma, C., Lee, H. C., Hintz, S. R., Shaw, G. M., McElhinney, D. B., Carmichael, S. L. 2021

  Abstract

  Maternal race/ethnicity is associated with mortality in neonates with hypoplastic left heart syndrome (HLHS). We investigated whether maternal race/ethnicity and other sociodemographic factors affect timing of transfer after birth and whether timing of transfer impacts mortality in infants with HLHS. We linked two statewide databases, the California Perinatal Quality Care Collaborative and records from the Office of Statewide Health Planning and Development, to identify cases of HLHS born between 1/1/06 and 12/31/11. Cases were divided into three groups: birth at destination hospital, transfer on day of life 0-1 ("early transfer"), or transfer on day of life≥2 ("late transfer"). We used log-binomial regression models to estimate relative risks (RR) for timing of transfer and Cox proportional hazard models to estimate hazard ratios (HR) for mortality. We excluded infants who died within 60days of life without intervention from the main analyses of timing of transfer, since intervention may not have been planned in these infants. Of 556 cases, 107 died without intervention (19%) and another 52 (9%) died within 28days. Of the 449 included in analyses of timing of transfer, 28% were born at the destination hospital, 49% were transferred early, and 23% were transferred late. Late transfer was more likely for infants of low birthweight (RR 1.74) and infants born to US-born Hispanic (RR 1.69) and black (RR 2.45) mothers. Low birthweight (HR 1.50), low 5-min Apgar score (HR 4.69), and the presence of other major congenital anomalies (HR 3.41), but not timing of transfer, predicted neonatal mortality. Late transfer was more likely in neonates born to US-born Hispanic and black mothers but was not associated with higher mortality.

  View details for DOI 10.1007/s00246-021-02561-w

  View details for PubMedID 33533967

• 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

• Interpregnancy intervals and adverse birth outcomes in high-income countries: An international cohort study. PloS one Tessema, G. A., Marinovich, M. L., Haberg, S. E., Gissler, M., Mayo, J. A., Nassar, N., Ball, S., Betran, A. P., Gebremedhin, A. T., de Klerk, N., Magnus, M. C., Marston, C., Regan, A. K., Shaw, G. M., Padula, A. M., Pereira, G. 2021; 16 (7): e0255000

  Abstract

  BACKGROUND: Most evidence for interpregnancy interval (IPI) and adverse birth outcomes come from studies that are prone to incomplete control for confounders that vary between women. Comparing pregnancies to the same women can address this issue.METHODS: We conducted an international longitudinal cohort study of 5,521,211 births to 3,849,193 women from Australia (1980-2016), Finland (1987-2017), Norway (1980-2016) and the United States (California) (1991-2012). IPI was calculated based on the time difference between two dates-the date of birth of the first pregnancy and the date of conception of the next (index) pregnancy. We estimated associations between IPI and preterm birth (PTB), spontaneous PTB, and small-for-gestational age births (SGA) using logistic regression (between-women analyses). We also used conditional logistic regression comparing IPIs and birth outcomes in the same women (within-women analyses). Random effects meta-analysis was used to calculate pooled adjusted odds ratios (aOR).RESULTS: Compared to an IPI of 18-23 months, there was insufficient evidence for an association between IPI <6 months and overall PTB (aOR 1.08, 95% CI 0.99-1.18) and SGA (aOR 0.99, 95% CI 0.81-1.19), but increased odds of spontaneous PTB (aOR 1.38, 95% CI 1.21-1.57) in the within-women analysis. We observed elevated odds of all birth outcomes associated with IPI ≥60 months. In comparison, between-women analyses showed elevated odds of adverse birth outcomes for <12 month and >24 month IPIs.CONCLUSIONS: We found consistently elevated odds of adverse birth outcomes following long IPIs. IPI shorter than 6 months were associated with elevated risk of spontaneous PTB, but there was insufficient evidence for increased risk of other adverse birth outcomes. Current recommendations of waiting at least 24 months to conceive after a previous pregnancy, may be unnecessarily long in high-income countries.

  View details for DOI 10.1371/journal.pone.0255000

  View details for PubMedID 34280228

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

  Abstract

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

  View details for DOI 10.3389/frph.2021.684207

  View details for PubMedID 36303973

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

  Abstract

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

  View details for DOI 10.3389/fped.2021.680201

  View details for PubMedID 33903851

  View details for PubMedCentralID PMC8065098

• 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

• 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

• Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach. PLoS genetics Patel, J. n., Bircan, E. n., Tang, X. n., Orloff, M. n., Hobbs, C. A., Browne, M. L., Botto, L. D., Finnell, R. H., Jenkins, M. M., Olshan, A. n., Romitti, P. A., Shaw, G. M., Werler, M. M., Li, J. n., Nembhard, W. N. 2021; 17 (3): e1009413

  Abstract

  Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.

  View details for DOI 10.1371/journal.pgen.1009413

  View details for PubMedID 33684136

• 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

• Maternal Exposure to Disinfection By-Products and Risk of Hypospadias in the National Birth Defects Prevention Study (2000-2005). International journal of environmental research and public health Zaganjor, I., Luben, T. J., Desrosiers, T. A., Keil, A. P., Engel, L. S., Michalski, A. M., Carmichael, S. L., Nembhard, W. N., Shaw, G. M., Reefhuis, J., Yazdy, M. M., Langlois, P. H., Feldkamp, M. L., Romitti, P. A., Olshan, A. F., The National Birth Defects Prevention Study 2020; 17 (24)

  Abstract

  The purpose of this study was to estimate the association between 2nd and 3rd degree hypospadias and maternal exposure to disinfection by-products (DBPs) using data from a large case-control study in the United States. Concentration estimates for total trihalomethanes (TTHMs), the sum of the five most prevalent haloacetic acids (HAA5), and individual species of each were integrated with data on maternal behaviors related to water use from the National Birth Defects Prevention Study (NBDPS) to create three different exposure metrics: (1) household DBP concentrations; (2) estimates of DBP ingestion; (3) predicted uptake (i.e., internal dose) of trihalomethanes (THMs) via ingestion, showering, and bathing. The distribution of DBP exposure was categorized as follows: (Q1/referent) < 50%; (Q2) ≥ 50% to < 75%; and (Q3) ≥ 75%. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Generally, null associations were observed with increasing TTHM or HAA5 exposure. An increased risk was observed among women with household bromodichloromethane levels in the second quantile (aOR: 1.8; 95% CI: 1.2, 2.7); however, this association did not persist after the inclusion of individual-level water-use data. Findings from the present study do not support the hypothesis that maternal DBP exposures are related to the occurrence of hypospadias.

  View details for DOI 10.3390/ijerph17249564

  View details for PubMedID 33371304

• 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

• 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

• Infant Allergy Testing and Food Allergy Diagnoses Before and After Guidelines for Early Peanut Introduction. The journal of allergy and clinical immunology. In practice Lo, R. M., Purington, N., McGhee, S. A., Mathur, M. B., Shaw, G. M., Schroeder, A. R. 2020

  Abstract

  BACKGROUND: A landmark 2015 trial on early exposure to peanuts led to expert recommendations for screening and early peanut introduction in high-risk (severe eczema and/or egg allergy) infants, but the impact of this paradigm shift on allergy testing and diagnosis is unknown.OBJECTIVE: We assessed the effects of the Learning Early About Peanut Allergy (LEAP) trial and guideline publications on allergy testing and food allergy diagnoses in infants.METHODS: In this retrospective cohort study, de-identified administrative health claims from a commercial and Medicare advantage claims database were used. Infants with at least one year of continuous coverage were selected using newborn codes for birth hospitalizations from January 2010 to June 2018. Interrupted time series models were used to compare the prevalence of allergy testing before and after LEAP publication in February 2015 and formal guideline publication in January 2017.RESULTS: For 487,533 included infants, allergy testing increased after LEAP (risk ratio [RR]: 1.11 [95% CI, 1.07-1.15]) and guidelines (1.21 [1.18-1.23]). This increase of testing was also seen in infants not considered high-risk, both after LEAP (1.12 [1.08-1.17]) and guidelines (1.20 [1.16, 1.23]). For first-time allergy tests, post-guideline median number of allergens tested was 9 for serum tests and 10 for skin tests. Post-guidelines there was a significant increase in diagnosis of peanut (RR: 1.08 [1.00, 1.16]), egg (1.12 [1.05, 1.20]), and other food allergies (excluding milk) (1.22 [1.14, 1.31]).CONCLUSION: Allergy testing has increased, including in non-high-risk infants. Multi-allergen testing may be contributing to an increase in the diagnosis of other food allergies.

  View details for DOI 10.1016/j.jaip.2020.10.060

  View details for PubMedID 33186769

• 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

• 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

• Congenital diaphragmatic hernia and maternal dietary nutrient pathways and diet quality. Birth defects research Carmichael, S. L., Ma, C., Witte, J. S., Yang, W., Rasmussen, S. A., Brunelli, L., Nestoridi, E., Shaw, G. M., Feldkamp, M. L., National Birth Defects Prevention Study 2020

  Abstract

  INTRODUCTION: We examined the association of congenital diaphragmatic hernia (CDH) with maternal dietary intake, using semi-Bayes hierarchical models and principal components analysis to consider intake of nutrients that contribute to one-carbon metabolism and oxidative stress pathways, and a diet quality index.METHODS: We included data on 825 cases and 11,108 nonmalformed controls born from 1997-2011 whose mother participated in the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study. Exposure data were from maternal telephone interviews, which included a food frequency questionnaire. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were generated from logistic regression models that included nutritional factors as continuous variables and were adjusted for maternal energy intake, race-ethnicity, parity, and vitamin supplement intake.RESULTS: In the semi-Bayes hierarchical model that included all nutrients and confounders, riboflavin was the only nutrient for which the 95% CI excluded 1.0; the aOR for a 1SD increase was 0.83. The aORs were 0.79 (95% CI 0.69-0.91) for the one-carbon metabolism pathway score, 0.90 (95% CI 0.80-1.01) for oxidative stress, and 0.85 (95% CI 0.77-0.93) for diet quality (the aORs correspond to a 1 SD increase).CONCLUSIONS: The findings from this study provide some support for the hypothesis that better prepregnancy nutrition is associated with reduced risk for CDH. These results provide etiologic clues but should be interpreted with caution given the novelty of the investigation.

  View details for DOI 10.1002/bdr2.1770

  View details for PubMedID 32744808

• Newborn Iodine Status Is Not Related to Congenital Hypothyroidism. The Journal of nutrition Mills, J. L., Reische, E. C., Kannan, K., Gao, C., Shaw, G. M., Sundaram, R. 2020

  Abstract

  BACKGROUND: Severe iodine deficiency or excess during pregnancy can cause congenital hypothyroidism (CH). Iodine deficiency is common in pregnant women in the United States.OBJECTIVES: We conducted a nested case-control study in a cohort of 2.5 million births in California to determine whether iodine status is related to CH in a US population.METHODS: Dried blood spots from 907 newborns with CH identified by newborn screening and 909 unaffected controls matched by month of birth were obtained from the California Newborn Screening Program to measure whole-blood iodine concentration. Iodine status was compared between cases and controls, and logistic regression was used to assess the association between CH status and blood iodine concentrations. Iodine status was also compared between cases and controls among infants treated in a neonatal intensive care unit (NICU) because CH has been reported in infants exposed to high levels of iodine in the NICU.RESULTS: Blood iodine concentrations did not differ significantly between cases (median: 20.0 ng/mL; IQR: 12.1-29.8 ng/mL) and controls (median: 20.3 ng/mL; IQR: 12.5-30.9 ng/mL; P=0.59). Neither extremely high nor extremely low blood iodine concentrations (1st, 5th, 95th, and 99th percentiles of the distribution) were more common in cases. Among infants treated in NICUs, however, cases had significantly (P=0.01) higher iodine (median: 22.7 ng/mL; IQR: 16.4-32.1 ng/mL) compared with controls (median: 17.3 ng/mL; IQR: 8.3-26.6 ng/mL).CONCLUSIONS: CH cases did not have significantly higher or lower iodine in this population, which is reassuring given that maternal iodine deficiency is common in the United States. Among newborns in the NICU, CH cases had higher blood iodine concentrations compared with controls, suggesting that excess iodine exposure in the NICU could be causing CH. It may be beneficial to monitor iodine exposure from surgical procedures, imaging, and iodine-containing disinfectants and to consider non-iodine alternatives.

  View details for DOI 10.1093/jn/nxaa178

  View details for PubMedID 32633779

• 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

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

  View details for Web of Science ID 000554572900377

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

  Abstract

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

  View details for DOI 10.1016/j.ajogmf.2020.100100

  View details for PubMedID 33345966

• 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

• 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

• Maternal occupational exposure to polycyclic aromatic hydrocarbons and the risk of isolated congenital heart defects among offspring. Environmental research Patel, J., Nembhard, W. N., Politis, M. D., Rocheleau, C. M., Langlois, P. H., Shaw, G. M., Romitti, P. A., Gilboa, S. M., Desrosiers, T. A., Insaf, T., Lupo, P. J., National Birth Defects Prevention Study 2020; 186: 109550

  Abstract

  BACKGROUND: Although there is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) is linked with congenital heart defects (CHDs), few studies have examined the association in humans. We conducted a case-control study to examine the association between maternal exposure to PAHs and CHDs in offspring using data from the National Birth Defects Prevention Study (NBDPS) (1997-2011).METHODS: We obtained detailed information on maternal occupation during the month before to three months after conception. Expert raters, masked to case-control status, assessed job descriptions to assign categorical levels of exposure. Categories were quantitatively mapped to estimate cumulative exposure to PAHs, incorporating exposure intensity, frequency, work duration, and work hours. Quartiles were generated for cumulative maternal exposure to PAHs. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression for quartiles of PAH exposure and six CHD groupings (e.g. conotruncal) and specific subtypes (e.g. tetralogy of Fallot [ToF]). Final models were adjusted for maternal age, race/ethnicity, education, smoking, anticonvulsant use, folic acid supplementation, and study center.RESULTS: There were 4,775 case and 7,734 control infants eligible for the study. The prevalence of occupational exposure to PAHs was 10.2% among both case and control mothers. In adjusted analysis, compared to mothers with no occupational PAH exposure, those in the highest quartile of exposure were more likely to have offspring in the conotruncal heart defects group (OR 1.41; 95% CI 1.00-2.00), and with ToF (OR 1.83; 95% CI 1.21-2.78).CONCLUSIONS: Women in the highest quartile of estimated cumulative occupational PAH exposure during early pregnancy were more likely to have offspring with conotruncal heart defects, specifically ToF, compared to women with no occupational PAH exposure. Other comparisons between PAHs and other CHDs subgroups did not show any statistically precise associations.

  View details for DOI 10.1016/j.envres.2020.109550

  View details for PubMedID 32335433

• Quantification of selection bias in studies of risk factors for birth defects among livebirths. Paediatric and perinatal epidemiology Heinke, D., Rich-Edwards, J. W., Williams, P. L., Hernandez-Diaz, S., Anderka, M., Fisher, S. C., Desrosiers, T. A., Shaw, G. M., Romitti, P. A., Canfield, M. A., Yazdy, M. M., National Birth Defects Prevention Study 2020

  Abstract

  BACKGROUND: Risk factors for birth defects are frequently investigated using data limited to liveborn infants. By conditioning on survival, results of such studies may be distorted by selection bias, also described as "livebirth bias." However, the implications of livebirth bias on risk estimation remain poorly understood.OBJECTIVES: We sought to quantify livebirth bias and to investigate the conditions under which it arose.METHODS: We used data on 3994 birth defects cases and 11829 controls enrolled in the National Birth Defects Prevention Study to compare odds ratio (OR) estimates of the relationship between three established risk factors (antiepileptic drug use, smoking, and multifetal pregnancy) and four birth defects (anencephaly, spina bifida, omphalocele, and cleft palate) when restricted to livebirths as compared to among livebirths, stillbirths, and elective terminations. Exposures and birth defects represented varying strengths of association with livebirth; all controls were liveborn. We performed a quantitative bias analysis to evaluate the sensitivity of our results to excluding terminated and stillborn controls.RESULTS: Cases ranged from 33% liveborn (anencephaly) to 99% (cleft palate). Smoking and multifetal pregnancy were associated with livebirth among anencephaly (crude OR [cOR] 0.61 and cOR 3.15, respectively) and omphalocele cases (cOR 2.22 and cOR 5.22, respectively). For analyses of the association between exposures and birth defects, restricting to livebirths produced negligible differences in estimates except for anencephaly and multifetal pregnancy, which was twofold higher among livebirths (adjusted OR [aOR] 4.93) as among all pregnancy outcomes (aOR 2.44). Within tested scenarios, bias analyses suggested that results were not sensitive to the restriction to liveborn controls.CONCLUSIONS: Selection bias was generally limited except for high mortality defects in the context of exposures strongly associated with livebirth. Findings indicate that substantial livebirth bias is unlikely to affect studies of risk factors for most birth defects.

  View details for DOI 10.1111/ppe.12650

  View details for PubMedID 32249969

• 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

• Maternal dietary fat intake and the risk of congenital heart defects in offspring. Pediatric research Collins, R. T., Yang, W., Carmichael, S. L., Bolin, E. H., Nembhard, W. N., Shaw, G. M., National Birth Defects Prevention Study 2020

  Abstract

  BACKGROUND: Fatty acids are crucial in embryologic development, including cardiogenesis. The impact of maternal periconceptional dietary fat intake on the risk of congenital heart defects (CHDs) has not been clearly elucidated. We hypothesized that maternal dietary fat intake during pregnancy is associated with risk of CHDs in offspring.METHODS: We analyzed CHD cases and nonmalformed controls from the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. We used multivariable logistic regression to analyze the association between maternal periconceptional dietary fat intake and occurrence of CHDs.RESULTS: We examined 11,393 infants with CHDs (cases) and 11,029 infants without birth defects (controls). Multivariable analysis of maternal dietary fat intake adjusted for maternal energy intake demonstrated modest change in risk for 2 of the 25 CHDs analyzed; otherwise there was no association. Maternal dietary fat intake unadjusted for total energy was associated with increased risk for several CHDs.CONCLUSIONS: After adjusting for total energy intake, maternal periconceptional dietary fat intake has a modest association with risk of a few specific CHDs. If maternal dietary fat intake does impact CHD risk, the effect is minimal.IMPACT: In this large, case-control study, after adjusting for total caloric intake, maternal periconceptional dietary fat intake was not associated with increased odds of congenital heart defects.This study investigates the hypothesis that women's periconceptional fat intake alters the risk of congenital heart defects in offspring.Our results raise questions about the role maternal fat intake may play in cardiogenesis and risk of congenital heart defects. Additionally, they raise the question about whether maternal lipid metabolism, as opposed to fat intake, may influence cardiac development.

  View details for DOI 10.1038/s41390-020-0813-x

  View details for PubMedID 32120376

• 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

• 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

• Racial/ethnic disparities and human milk use in necrotizing enterocolitis. Pediatric research Goldstein, G. P., Pai, V. V., Liu, J. n., Sigurdson, K. n., Vernon, L. B., Lee, H. C., Sylvester, K. G., Shaw, G. M., Profit, J. n. 2020; 88 (Suppl 1): 3–9

  Abstract

  The impact of human milk use on racial/ethnic disparities in necrotizing enterocolitis (NEC) incidence is unknown.Trends in NEC incidence and human milk use at discharge were evaluated by race/ethnicity among 47,112 very low birth weight infants born in California from 2008 to 2017. We interrogated the association between race/ethnicity and NEC using multilevel regression analysis, and evaluated the effect of human milk use at discharge on the relationship between race/ethnicity and NEC using mediation analysis.Annual NEC incidence declined across all racial/ethnic groups from an aggregate average of 4.8% in 2008 to 2.6% in 2017. Human milk use at discharge increased over the time period across all racial groups, and non-Hispanic (NH) black infants received the least human milk each year. In multivariable analyses, Hispanic ethnicity (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.02-1.57) and Asian or Pacific Islander race (OR 1.35, 95% CI 1.01-1.80) were each associated with higher odds of NEC, while the association of NH black race with NEC was attenuated after adding human milk use at discharge to the model. Mediation analysis revealed that human milk use at discharge accounted for 22% of the total risk of NEC in non-white vs. white infants, and 44% in black vs. white infants.Although NEC incidence has declined substantially over the past decade, a sizable racial/ethnic disparity persists. Quality improvement initiatives augmenting human milk use may further reduce the incidence of NEC in vulnerable populations.

  View details for DOI 10.1038/s41390-020-1073-5

  View details for PubMedID 32855505

• Associations between interpregnancy interval and preterm birth by previous preterm birth status in four high-income countries: a cohort study. BJOG : an international journal of obstetrics and gynaecology Marinovich, M. L., Regan, A. K., Gissler, M. n., Magnus, M. C., Håberg, S. E., Mayo, J. A., Shaw, G. M., Bell, J. n., Nassar, N. n., Ball, S. n., Gebremedhin, A. T., Marston, C. n., de Klerk, N. n., Betrán, A. P., Padula, A. M., Pereira, G. n. 2020

  Abstract

  To investigate the effect of interpregnancy interval (IPI) on preterm birth (PTB) according to whether the previous birth was preterm or term.Cohort study.USA (California), Australia, Finland, Norway (1980-2017).Women who gave birth to first and second (N=3,213,855) singleton livebirths.Odds ratios (ORs) for PTB according to IPIs were modelled using logistic regression with prognostic score stratification for potential confounders. Within-site ORs were pooled by random-effects meta-analysis.PTB (gestational age<37 weeks).Absolute risk of PTB for each IPI ranged from 3-6% after previous term and 17-22% after previous PTB. ORs for PTB differed between previous term and preterm births in all countries (P-for-interaction≤0.001). For women with a previous term birth, pooled ORs were increased for IPI <6months (1.50, 95%CI 1.43-1.58); 6-11months (1.10, 95%CI 1.04-1.16); 24-59months (1.16, 95%CI 1.13-1.18); and ≥60months (1.72, 95%CI 1.60-1.86), compared to 18-23months. For previous PTB, ORs were increased for <6months (1.30, 95%CI 1.18-1.42) and ≥60months (1.29, 95%CI 1.17-1.42), but were less than ORs among women with a previous term birth (P<0.05).Associations between IPI and PTB are modified by whether the previous pregnancy was preterm. ORs for short and long IPIs were higher among women with a previous term birth than a previous PTB, which for short IPI is consistent with the maternal depletion hypothesis. Given high risk of recurrence and assuming a causal association between IPI and PTB, IPI remains a potentially modifiable risk factor for women with previous PTB.

  View details for DOI 10.1111/1471-0528.16606

  View details for PubMedID 33232573

• 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

• Male-to-female ratios among NTDs and women's periconceptional intake of folic acid. Birth defects research Shaw, G. M., Yang, W. n., Finnell, R. H. 2020

  Abstract

  About a decade ago, a hypothesis was put forward to explain the preponderance of females among neural tube defect (NTD) fetuses. That hypothesis predicts that a woman's higher levels of early gestational intake of methyl groups, such as folic acid, will be associated with lesser male-to-female ratio differences in NTD-affected births, specifically less preponderance of females. We explored this hypothesis in four distinct studies that investigated human NTDs, obtained information on folic acid, and capitalized on timing of folic acid fortification by investigating data that were collected both prior to and after the 1998 initiation of U.S. mandatory folic acid fortification of grains.We analyzed data from four population-based case control studies conducted in California for birth years spanning 1987-2011. Two studies were conducted before folic acid fortification of the U.S. food supply. Each of the four studies included interviews of women who either had NTD-affected pregnancies (cases) or who did not have a pregnancy affected by a birth defect (controls). In each study, information on periconceptional supplement use was elicited. We explored male-to-female ratios and 95% binomial confidence limits in each data set.Our analyses of two case-control studies performed prior to and two performed post mandatory folate fortification in the United States showed that more NTD-affected fetuses were female in the first two studies. In the studies done before fortification, the frequency of females was even greater among those pregnancies without folic acid supplementation.Our findings suggest folic acid may differentially reduce risk of NTDs among female fetuses.

  View details for DOI 10.1002/bdr2.1708

  View details for PubMedID 32415919

• 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

• 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

• Periconceptional stressors and social support and risk for adverse birth outcomes. BMC pregnancy and childbirth Weber, K. A., Carmichael, S. L., Yang, W. n., Tinker, S. C., Shaw, G. M. 2020; 20 (1): 487

  Abstract

  The prevalence of preterm birth and low birth weight has been increasing slightly in recent years. A few studies have suggested that psychosocial stress during pregnancy may increase risk for these adverse birth outcomes. To extend those observations, we analyzed various major life event stressors separately and cumulatively as potential risk factors for preterm birth and low birth weight using granular categories of each outcome in a large, population-based study. Additionally, we assessed if greater social support buffered any effects.Data were from a nested prevalence study of 4395 women in the National Birth Defects Prevention Study who delivered live-born non-malformed infants (controls) between 2006 and 2011. Participants completed a standardized, computer-assisted interview between 6 weeks and 24 months after delivery that included questions on stress and social support from 3 months before pregnancy to the 3rd month of pregnancy. Cumulative stress and support indices were also calculated. Preterm birth was divided into "early preterm" (< 32 weeks), "late preterm" (32-36 weeks) and "term." Low birthweight was divided into "very low birth weight" (< 1500 g), "low birth weight" (1500-2499 g) and "normal birth weight" (≥2500 g). Relative risks and 95% confidence intervals (95% CI) were calculated using Poisson regression.For women reporting relationship difficulties, there was a suggestive risk of early preterm birth (RR: 1.9, 95%CI: 0.9-3.9) and very low birthweight (RR: 2.0, 95%CI: 0.9-4.4). For women reporting that they or someone close to them were victims of abuse, violence, or crime, there was an increased risk of low birthweight (RR: 1.8, 95%CI: 1.1-2.7) and late preterm birth (RR: 1.5, 95%CI: 1.0-2.2). There were no strong associations observed between social support questions and the various outcomes.Our results add some support to prior evidence that certain stressors may be associated with increase selected adverse birth outcomes risk. We did not find strong evidence that social support buffered the observed risks in our study.

  View details for DOI 10.1186/s12884-020-03182-6

  View details for PubMedID 32831042

• 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

• FKBP8 variants are risk factors for spina bifida. Human molecular genetics Tian, T. n., Cao, X. n., Kim, S. E., Lin, Y. L., Steele, J. W., Cabrera, R. M., Karki, M. n., Yang, W. n., Marini, N. J., Hoffman, E. N., Han, X. n., Hu, C. n., Wang, L. n., Wlodarczyk, B. J., Shaw, G. M., Ren, A. n., Finnell, R. H., Lei, Y. n. 2020

  Abstract

  Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although extensively investigated, the genetic etiology of NTDs remains poorly understood. FKBP8 is critical for proper mammalian neural tube closure. Fkbp8-/- mouse embryos showed posterior NTDs consistent with a diagnosis of spina bifida (SB). To date, no publication has reported any association between FKBP8 and human NTDs. Using Sanger sequencing on genomic DNA samples from 472 SB and 565 control samples, we identified 5 rare (MAF < =0.001) deleterious variants in SB patients, while no rare deleterious variant was identified in the controls (p = 0.0191). p.Glu140* affected FKBP8 localization to the mitochondria and created a truncated form of the FKBP8 protein, thus impairing its interaction with BCL2 and ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein levels. p.Lys315Asn further increased the cellular apoptosis. RNA sequencing on anterior and posterior tissues isolated from Fkbp8-/- and wildtype mice at E9.5 and E10.5 showed that Fkbp8-/- embryos have an abnormal expression profile within tissues harvested at posterior sites, thus leading to a posterior NTD. Moreover, we found that Fkbp8 knockout mouse embryos have abnormal expression of Wnt3a and Nkx2.9 during the early stage of neural tube development, perhaps also contributing to caudal specific NTDs. These findings provide evidence that functional variants of FKBP8 are risk factors for SB, which may involve a novel mechanism by which Fkbp8 mutations specifically cause SB in mice.

  View details for DOI 10.1093/hmg/ddaa211

  View details for PubMedID 32969478

• Defining critical factors in multi-country studies of assisted reproductive technologies (ART): data from the US and UK health systems. Journal of assisted reproduction and genetics Eisenberg, M. L., Luke, B. n., Cameron, K. n., Shaw, G. M., Pacey, A. A., Sutcliffe, A. G., Williams, C. n., Gardiner, J. n., Anderson, R. A., Baker, V. L. 2020

  Abstract

  As the worldwide use of assisted reproductive technologies (ART) continues to grow, there is a critical need to assess the safety of these treatment parameters and the potential adverse health effects of their use in adults and their offspring. While key elements remain similar across nations, geographic variations both in treatments and populations make generalizability challenging. We describe and compare the demographic factors between the USA and the UK related to ART use and discuss implications for research. The USA and the UK share some common elements of ART practice and in how data are collected regarding long-term outcomes. However, the monitoring of ART in these two countries each brings strengths that complement each other's limitations.

  View details for DOI 10.1007/s10815-020-01951-y

  View details for PubMedID 32995971

• 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

• 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

• Evaluation of US State-Level Variation in Hypertensive Disorders of Pregnancy. JAMA network open Butwick, A. J., Druzin, M. L., Shaw, G. M., Guo, N. n. 2020; 3 (10): e2018741

  Abstract

  Hypertensive disorders of pregnancy are important causes of maternal and perinatal morbidity in the US. However, the extent of statewide variation in the prevalence of chronic hypertension, pregnancy-induced hypertension or preeclampsia, and eclampsia in the US remains unknown.To examine the extent of statewide variation in the prevalence of chronic hypertension, hypertensive disorders of pregnancy (including pregnancy-induced hypertension or preeclampsia), and eclampsia in the US.A cross-sectional study using 2017 US birth certificate data was conducted from September 1, 2019, to February 1, 2020. A population-based sample of 3 659 553 women with a live birth delivery was included.State-specific prevalence of chronic hypertension, hypertensive disorders of pregnancy, and eclampsia was assessed using multilevel multivariable logistic regression, with the median odds ratio (MOR) to evaluate statewide variation.Of the 3 659 553 women, 185 932 women (5.1%) were younger than 20 years, 727 573 women (19.9%) were aged between 20 and 24 years, 1 069 647 women (29.2%) were aged between 25 and 29 years, 1 037 307 women (28.3%) were aged between 30 and 34 years, 523 607 women (14.3%) were aged between 35 and 39 years, and 115 487 women (3.2%) were 40 years or older. Most women had Medicaid (42.8%) or private insurance (49.4%). Hawaii had the lowest adjusted prevalence of chronic hypertension (1.0%; 95% CI, 0.9%-1.2%), and Alaska had the highest (3.4%; 95% CI, 3.0%-3.9%). Massachusetts had the lowest adjusted prevalence of hypertensive disorders of pregnancy (4.3%; 95% CI, 4.1%-4.6%), and Louisiana had the highest (9.3%; 95% CI, 8.9%-9.8%). Delaware had the lowest adjusted prevalence of eclampsia (0.03%; 95% CI, 0.01%-0.09%), and Hawaii had the highest (2.8%; 95% CI, 2.2%-3.4%). The degree of statewide variation was high for eclampsia (MOR, 2.36; 95% CI, 1.88-2.82), indicating that the median odds of eclampsia were 2.4-fold higher if the same woman delivered in a US state with a higher vs lower prevalence of eclampsia. Modest variation between states was observed for chronic hypertension (MOR, 1.27; 95% CI, 1.20-1.33) and hypertensive disorders of pregnancy (MOR, 1.17; 95% CI, 1.13-1.21).The findings of this study suggest that after accounting for patient-level and state-level variables, substantial state-level variation exists in the prevalence of eclampsia. These data can inform future public-health inquiries to identify reasons for the eclampsia variability.

  View details for DOI 10.1001/jamanetworkopen.2020.18741

  View details for PubMedID 33001203

• 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

• Survival of infants with congenital diaphragmatic hernia in California: impact of hospital, clinical, and sociodemographic factors. Journal of perinatology : official journal of the California Perinatal Association Carmichael, S. L., Ma, C. n., Lee, H. C., Shaw, G. M., Sylvester, K. G., Hintz, S. R. 2020

  Abstract

  To understand factors associated with care and survival among babies with congenital diaphragmatic hernia (CDH).We used data on California births (2006-2011) to examine birth hospital level of care, hospital transfer before repair, and survival.Among 577 infants, 25% were born at lower-level hospitals, 62% were transferred, and 31% died during infancy. Late or no prenatal care had the strongest association with birth at lower-level hospitals (adjusted relative risk (ARR) = 1.9, 95% confidence interval (CI) = 1.0-3.6). Birth at lower-level hospitals was associated with transfer (ARR = 1.2, CI = 1.1-1.4), and transferred infants tended to be less clinically complex. Infants with low birthweight, other birth defects, low Apgar scores, and late or no prenatal care had two- to fourfold higher risk of mortality than their comparison groups.These data support the importance of prenatal care and delivery planning into higher-level hospitals for optimal care and outcomes for newborns with CDH.

  View details for DOI 10.1038/s41372-020-0612-6

  View details for PubMedID 32086437

• Loss of RAD9B impairs early neural development and contributes to the risk for human spina bifida. Human mutation Cao, X. n., Tian, T. n., Steele, J. W., Cabrera, R. M., Aguiar-Pulido, V. n., Wadhwa, S. n., Bhavani, N. n., Bi, P. n., Gargurevich, N. H., Hoffman, E. N., Cai, C. Q., Marini, N. J., Yang, W. n., Shaw, G. M., Elizabeth Ross, M. n., Finnell, R. H., Lei, Y. n. 2020

  Abstract

  DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells (NPC). To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing (WGS) and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs 0 /298, p=0.0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells (hESCs) profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/humu.23969

  View details for PubMedID 31898828

• 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

• 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

• Associations between fine particulate matter, extreme heat events, and congenital heart defects. Environmental epidemiology (Philadelphia, Pa.) Stingone, J. A., Luben, T. J., Sheridan, S. C., Langlois, P. H., Shaw, G. M., Reefhuis, J., Romitti, P. A., Feldkamp, M. L., Nembhard, W. N., Browne, M. L., Lin, S., National Birth Defects Prevention Study 2019; 3 (6): e071

  Abstract

  Previous research reports associations between air pollution measured during pregnancy and the occurrence of congenital heart defects (CHDs) in offspring. The objective of this research was to assess if exposure to extreme heat events (EHEs) during pregnancy may modify this association.Methods: The study population consisted of 4,033 controls and 2,632 cases with dates of delivery between 1999 and 2007 who participated in the National Birth Defects Prevention Study, a multi-site case-control study in the United States. Daily data from the closest stationary fine particulate matter (PM2.5) monitor within 50 km from the maternal residence were averaged across weeks 3-8 post-conception. EHEs were defined as maximum ambient temperature in the upper 95th percentile for at least 2 consecutive days or the upper 90th percentile for 3 consecutive days. Logistic regression models were adjusted for maternal age, ethnicity, education, and average humidity. Relative excess risks due to interaction (RERI) were calculated.Results: Compared with women with low PM2.5 exposure and no exposure to an EHE, the odds of a ventricular septal defect in offspring associated with high PM2.5 exposure was elevated only among women who experienced an EHE (odds ratio [OR] 2.14 95% confidence interval [CI] 1.19, 3.38 vs. OR 0.97 95% CI 0.49, 1.95; RERI 0.82 95% CI -0.39, 2.17). The majority of observed associations and interactions for other heart defects were null and/or inconclusive due to lack of precision.Conclusions: This study provides limited evidence that EHEs may modify the association between prenatal exposure to PM2.5 and CHD occurrence.

  View details for DOI 10.1097/EE9.0000000000000071

  View details for PubMedID 32091506

• 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

• 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

• Associations between PM2.5 and risk of preterm birth among liveborn infants. Annals of epidemiology Alman, B. L., Stingone, J. A., Yazdy, M., Botto, L. D., Desrosiers, T. A., Pruitt, S., Herring, A. H., Langlois, P. H., Nembhard, W. N., Shaw, G. M., Olshan, A. F., Luben, T. J., National Birth Defects Prevention Study 2019

  Abstract

  PURPOSE: Studies suggest exposure to ambient particulate matter less than 2.5mug/m3 in aerodynamic diameter (PM2.5) may be associated with preterm birth (PTB), but few have evaluated how this is modified by ambient temperature. We investigated the relationship between PM2.5 exposure during pregnancy and PTB in infants without birth defects (1999-2006) and enrolled in the National Birth Defects Prevention Study and how it is modified by concurrent temperature.METHODS: PTB was defined as spontaneous or iatrogenic delivery before 37weeks. Exposure was assigned using inverse distance weighting with up to four monitors within 50kilometers of maternal residence. To account for state-level variations, a Bayesian two-level hierarchal model was developed.RESULTS: PTB was associated with PM2.5 during the third and fourth months of pregnancy (range: (odds ratio (95% confidence interval)=1.00 (0.35, 2.15) to 1.49 (0.82, 2.68) and 1.31 (0.56, 2.91) to 1.62 (0.7, 3.32), respectively); no week of exposure conveyed greater risk. Temperature may modify this relationship; higher local average temperatures during pregnancy yielded stronger positive relationships between PM2.5 and PTB compared to nonstratified results.CONCLUSIONS: Results add to literature on associations between PM2.5 and PTB, underscoring the importance of considering co-exposures when estimating effects of PM2.5 exposure during pregnancy.

  View details for DOI 10.1016/j.annepidem.2019.09.008

  View details for PubMedID 31678056

• Air Pollution, Maternal Hypertensive Disorders, and Preterm Birth. Environmental epidemiology (Philadelphia, Pa.) Weber, K. A., Yang, W., Lurmann, F., Hammond, S. K., Shaw, G. M., Padula, A. M. 2019; 3 (5)

  Abstract

  Background: Air pollution has been associated with hypertension and preterm birth. We examined if prenatal exposure to air pollutants was associated with gestational hypertension and if its association with preterm birth was modified by maternal hypertension.Methods: Data were from birth certificates and hospital discharge records of 252,205 women in San Joaquin Valley of California from 2000-2006. Air quality data were assigned from 24-hour averages of nitrogen dioxide (NO2), particulate matter <10mum (PM10) and <2.5mum (PM2.5), and carbon monoxide (CO) for different averaging periods over pregnancy. We estimated odds of preterm birth and multiplicative interaction between each pollutant and hypertensive disorder.Results: Among normotensive women, odds of preterm birth were slightly higher for higher exposure to all pollutants over the entire pregnancy. Patterns were similar among women with a hypertensive disorder. Among 32-36 week births there was effect modification for exposure to NO2 and CO during the first trimester with higher odds among hypertensive women, and PM2.5 and CO during the last six weeks with higher odds among normotensive women. For 28-31 week births, there was effect modification by hypertensive status for PM10 exposure for entire pregnancy, first, and second trimester with hypertensive women consistently having lower odds of preterm birth than normotensive.Conclusion: There was some evidence of effect modification in the direction counter to our hypothesis for exposure to PM10 and early preterm birth, and CO and PM2.5 at the end of pregnancy, but overall, hypertension did not modify the relationship between pollution and preterm birth.

  View details for DOI 10.1097/ee9.0000000000000062

  View details for PubMedID 32051927

• 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

• Maternal exposure to outdoor air pollution and congenital limb deficiencies in the National Birth Defects Prevention Study. Environmental research Choi, G., Stingone, J. A., Desrosiers, T. A., Olshan, A. F., Nembhard, W. N., Shaw, G. M., Pruitt, S., Romitti, P. A., Yazdy, M. M., Browne, M. L., Langlois, P. H., Botto, L., Luben, T. J., National Birth Defects Prevention Study 2019; 179 (Pt A): 108716

  Abstract

  BACKGROUND: Congenital limb deficiencies (CLDs) are a relatively common group of birth defects whose etiology is mostly unknown. Recent studies suggest maternal air pollution exposure as a potential risk factor.AIM: To investigate the relationship between ambient air pollution exposure during early pregnancy and offspring CLDs.METHODS: The study population was identified from the National Birth Defects Prevention Study, a population-based multi-center case-control study, and consisted of 615 CLD cases and 5,701 controls with due dates during 1997 through 2006. Daily averages and/or maxima of six criteria air pollutants (particulate matter <2.5 mum [PM2.5], particulate matter <10 mum [PM10], nitrogen dioxide [NO2], sulfur dioxide [SO2], carbon monoxide [CO], and ozone [O3]) were averaged over gestational weeks 2-8, as well as for individual weeks during this period, using data from EPA air monitors nearest to the maternal address. Logistic regression was used to estimate odds ratios (aORs) and 95% confidence intervals (CIs) adjusted for maternal age, race/ethnicity, education, and study center. We estimated aORs for any CLD and CLD subtypes (i.e., transverse, longitudinal, and preaxial). Potential confounding by co-pollutant was assessed by adjusting for one additional air pollutant. Using the single pollutant model, we further investigated effect measure modification by body mass index, cigarette smoking, and folic acid use. Sensitivity analyses were conducted restricting to those with a residence closer to an air monitor.RESULTS: We observed near-null aORs for CLDs per interquartile range (IQR) increase in PM10, PM2.5, and O3. However, weekly averages of the daily average NO2 and SO2, and daily max NO2, SO2, and CO concentrations were associated with increased odds of CLDs. The crude ORs ranged from 1.03 to 1.12 per IQR increase in these air pollution concentrations, and consistently elevated aORs were observed for CO. Stronger associations were observed for SO2 and O3 in subtype analysis (preaxial). In co-pollutant adjusted models, associations with CO remained elevated (aORs: 1.02-1.30); but aORs for SO2 and NO2 became near-null. The aORs for CO remained elevated among mothers who lived within 20 km of an air monitor. The aORs varied by maternal BMI, smoking status, and folic acid use.CONCLUSION: We observed modest associations between CLDs and air pollution exposures during pregnancy, including CO, SO2, and NO2, though replication through further epidemiologic research is warranted.

  View details for DOI 10.1016/j.envres.2019.108716

  View details for PubMedID 31546130

• 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

• Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data. Birth defects research Jenkins, M. M., Almli, L. M., Pangilinan, F., Chong, J. X., Blue, E. E., Shapira, S. K., White, J., McGoldrick, D., Smith, J. D., Mullikin, J. C., Bean, C. J., Nembhard, W. N., Lou, X., Shaw, G. M., Romitti, P. A., Keppler-Noreuil, K., Yazdy, M. M., Kay, D. M., Carter, T. C., Olshan, A. F., Moore, K. J., Nascone-Yoder, N., Finnell, R. H., Lupo, P. J., Feldkamp, M. L., NISC Comparative Sequencing Program, University of Washington Center for Mendelian Genomics, Nickerson, D. A., Bamshad, M. J., Brody, L. C., Reefhuis, J., National Birth Defects Prevention Study 2019

  Abstract

  BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens.METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA.RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol.CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.

  View details for DOI 10.1002/bdr2.1554

  View details for PubMedID 31328417

• Factors Associated with Timeliness of Surgical Repair among Infants with Myelomeningocele: California Perinatal Quality Care Collaborative, 2006 to 2011. American journal of perinatology Kancherla, V., Ma, C., Grant, G., Lee, H. C., Shaw, G. M., Hintz, S. R., Carmichael, S. L. 2019

  Abstract

  OBJECTIVE: To examine factors associated with timely (0-2 days after birth) myelomeningocele surgical repair.STUDY DESIGN: We examined 2006 to 2011 births from the California Perinatal Quality Care Collaborative, linking to hospital discharge and vital records. Selected maternal, infant, and delivery hospital characteristics were evaluated to understand disparities in timely repair. Poisson regression was used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs).RESULTS: Overall, 399 of the 450 (89%) infants had a timely repair and approximately 80% of them were delivered in level III/IV hospitals. Infants with hydrocephalus were significantly less likely to have a delayed myelomeningocele repair compared with those without (aRR=0.22; 95% CI=0.13, 0.39); infants whose medical care was paid by Medi-Cal or other nonprivate insurance were 2.2 times more likely to have a delayed repair compared with those covered by a private insurance (aRR=2.23; 95% CI=1.17, 4.27). Low birth weight was a significant predictor for delayed repair (aRR=2.06; 95% CI=1.10, 3.83).CONCLUSION: There was a significant disparity in myelomenigocele repair based on medical care payer. Families and hospitals should work together for timely repair in hospitals having specialized multidisciplinary teams. Findings from the study can be used to follow best clinical practices for myelomeningocele repair.

  View details for DOI 10.1055/s-0039-1693127

  View details for PubMedID 31307103

• Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY Ryan, M. A., Olshan, A. F., Canfield, M. A., Hoyt, A. T., Scheuerle, A. E., Carmichael, S. L., Shaw, G. M., Werler, M. M., Fisher, S. C., Desrosiers, T. A., Natl Birth Defects Prevention Stud 2019; 122: 18–26

  View details for DOI 10.1016/j.ijporl.2019.03.026

  View details for Web of Science ID 000471738900004

• Preterm Delivery Phenotypes in Systemic Lupus Erythematosus Pregnancies AMERICAN JOURNAL OF PERINATOLOGY Simard, J. F., Chaichian, Y., Rossides, M., Wikstrom, A., Shaw, G. M., Druzin, M. L. 2019; 36 (9): 964–68

  View details for DOI 10.1055/s-0038-1675648

  View details for Web of Science ID 000477661000014

• 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

• Risk factors associated with the development of double-inlet ventricle congenital heart disease BIRTH DEFECTS RESEARCH Paige, S. L., Yang, W., Priest, J. R., Botto, L. D., Shaw, G. M., Collins, R., Natl Birth Defects Prevention 2019; 111 (11): 640–48

  View details for DOI 10.1002/bdr2.1501

  View details for Web of Science ID 000473561000003

• Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate AMERICAN JOURNAL OF MEDICAL GENETICS PART A Marini, N. J., Asrani, K., Yang, W., Rine, J., Shaw, G. M. 2019; 179 (7): 1260–69

  View details for DOI 10.1002/ajmg.a.61183

  View details for Web of Science ID 000471068000019

• 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

• 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

• Developing evidence-based recommendations for optimal interpregnancy intervals in high-income countries: protocol for an international cohort study BMJ OPEN Marinovich, M., Regan, A. K., Gissler, M., Magnus, M. C., Haberg, S., Padula, A. M., Mayo, J. A., Shaw, G. M., Ball, S., Malacova, E., Gebremedhin, A. T., Nassar, N., Marston, C., de Klerk, N., Betran, A., Pereira, G. F. 2019; 9 (1)

  View details for DOI 10.1136/bmjopen-2018-027941

  View details for Web of Science ID 000471116800279

• Maternal genetic markers for risk of celiac disease and their potential association with neural tube defects in offspring MOLECULAR GENETICS & GENOMIC MEDICINE Hoang, T. T., Lei, Y., Mitchell, L. E., Sharma, S., Swartz, M. D., Waller, D., Finnell, R. H., Benjamin, R. H., Browne, M. L., Canfield, M. A., Lupo, P. J., McKenzie, P., Shaw, G. M., Agopian, A. J., Natl Birth Defects Prevention Stud 2019; 7 (6)

  View details for DOI 10.1002/mgg3.688

  View details for Web of Science ID 000476745400037

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

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

  View details for Web of Science ID 000468895300010

• The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation HUMAN MOLECULAR GENETICS Kousa, Y. A., Zhu, H., Fakhouri, W. D., Lei, Y., Kinoshita, A., Roushangar, R. R., Patel, N. K., Agopian, A. J., Yang, W., Leslie, E. J., Busch, T. D., Mansour, T. A., Li, X., Smith, A. L., Li, E. B., Sharma, D. B., Williams, T. J., Chai, Y., Amendt, B. A., Liao, E. C., Mitchell, L. E., Bassuk, A. G., Gregory, S., Ashley-Koch, A., Shaw, G. M., Finnell, R. H., Schutte, B. C. 2019; 28 (10): 1726–37

  View details for DOI 10.1093/hmg/ddz010

  View details for Web of Science ID 000475882600012

• Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate. American journal of medical genetics. Part A Marini, N. J., Asrani, K., Yang, W., Rine, J., Shaw, G. M. 2019

  Abstract

  Cleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 nonmalformed controls. Our findings indicated that rare, protein-altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss-of-function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p = 0.01). Second, in gene-level analyses, the burden of rare alleles showed greater case-association for several genes previously implicated in cleft risk. For example, BHMT displayed a 10-fold increase in protein-altering variants in CLP cases (p = .03), including multiple case occurrences of a rare frameshift mutation (K400fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B, BMP4, BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP.

  View details for PubMedID 31063268

• Substantial Cardiovascular Morbidity in Adults With Lower-Complexity Congenital Heart Disease CIRCULATION Saha, P., Potiny, P., Rigdon, J., Morello, M., Tcheandjieu, C., Romfh, A., Fernandes, S. M., McElhinney, D. B., Bernstein, D., Lui, G. K., Shaw, G. M., Ingelsson, E., Priest, J. R. 2019; 139 (16): 1889–99

  View details for DOI 10.1161/CIRCULATIONAHA.118.037064

  View details for Web of Science ID 000469321500006

• 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

• Maternal genetic markers for risk of celiac disease and their potential association with neural tube defects in offspring. Molecular genetics & genomic medicine Hoang, T. T., Lei, Y., Mitchell, L. E., Sharma, S. V., Swartz, M. D., Waller, D. K., Finnell, R. H., Benjamin, R. H., Browne, M. L., Canfield, M. A., Lupo, P. J., McKenzie, P., Shaw, G. M., Agopian, A. J., National Birth Defects Prevention Study 2019: e688

  Abstract

  BACKGROUND: We examined the association between the maternal genotype for celiac disease-associated variants and risk of neural tube defects (NTDs).METHODS: We conducted a case-control study, using data from the National Birth Defects Prevention Study. We evaluated 667 cases (women with an offspring with NTD) and 743 controls (women with an offspring without a birth defect). We classified women as having low, intermediate, or high risk of celiac disease based on human leukocyte antigen (HLA) variants. We used logistic regression to assess the relationship between HLA celiac risk group (low, intermediate, high) and risk of NTDs. Fifteen non-HLA variants (identified from genome-wide association studies of celiac disease) were individually evaluated and modeled additively.RESULTS: There was no association between HLA celiac risk group and NTDs (intermediate vs. low risk: aOR, 1.0; 95% CI, 0.8-1.3; high vs. low risk: aOR, 0.8; 95% CI, 0.5-1.3). Of the fifteen non-HLA variants, we observed five significant associations after accounting for multiple comparisons. Three negative associations were observed with rs10903122, rs13314993, rs13151961 (aOR range: 0.69-0.81), and two positive associations were observed with rs13003464 and rs11221332 (aOR range: 1.27-1.73).CONCLUSION: If confirmed, our results suggest that the maternal variants related to celiac disease may be involved in the risk of NTDs.

  View details for PubMedID 30968606

• Variants identified in PTK7 associated with neural tube defects MOLECULAR GENETICS & GENOMIC MEDICINE Lei, Y., Kim, S., Chen, Z., Cao, X., Zhu, H., Yang, W., Shaw, G. M., Zheng, Y., Zhang, T., Wang, H., Finnell, R. H. 2019; 7 (4)

  View details for DOI 10.1002/mgg3.584

  View details for Web of Science ID 000465102200008

• 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

• Risk factors associated with the development of double-inlet ventricle congenital heart disease. Birth defects research Paige, S. L., Yang, W., Priest, J. R., Botto, L. D., Shaw, G. M., Collins, R. T., National Birth Defects Prevention Study 2019

  Abstract

  BACKGROUND: Congenital heart disease (CHD) is the most common birth defect group and a significant contributor to neonatal and infant death. CHD with single ventricle anatomy, including hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA), and various double-inlet ventricle (DIV) malformations, is the most complex with the highest mortality. Prenatal risk factors associated with HLHS have been studied, but such data for DIV are lacking.METHODS: We analyzed DIV cases and nonmalformed controls in the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. Random forest analysis identified potential predictor variables for DIV, which were included in multivariable models to estimate effect magnitude and directionality.RESULTS: Random forest analysis identified pre-pregnancy diabetes, history of maternal insulin use, maternal total lipid intake, paternal race, and intake of several foods and nutrients as potential predictors of DIV. Logistic regression confirmed pre-pregnancy diabetes, maternal insulin use, and paternal race as risk factors for having a child with DIV. Additionally, higher maternal total fat intake was associated with a reduced risk.CONCLUSIONS: Maternal pre-pregnancy diabetes and history of insulin use were associated with an increased risk of having an infant with DIV, while maternal lipid intake had an inverse association. These novel data provide multiple metabolic pathways for investigation to identify better the developmental etiologies of DIV and suggest that public health interventions targeting diabetes prevention and management in women of childbearing age could reduce CHD risk.

  View details for PubMedID 30920163

• Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study. International journal of pediatric otorhinolaryngology Ryan, M. A., Olshan, A. F., Canfield, M. A., Hoyt, A. T., Scheuerle, A. E., Carmichael, S. L., Shaw, G. M., Werler, M. M., Fisher, S. C., Desrosiers, T. A., National Birth Defects Prevention Study 2019; 122: 18–26

  Abstract

  OBJECTIVE: Anotia and microtia are congenital malformations of the external ear with few known risk factors. We conducted a comprehensive assessment of a wide range of potential risk factors using data from the National Birth Defects Prevention Study (NBDPS), a population-based case-control study of non-chromosomal structural birth defects in the United States.METHODS: Mothers of 699 infants with anotia or microtia (cases) and 11,797 non-malformed infants (controls) delivered between 1997 and 2011 were interviewed to obtain information about sociodemographic, health behavioral, and clinical characteristics. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated with logistic regression.RESULTS: Infants with anotia/microtia were more likely to be male (aOR, 1.29; 95% CI, 1.10-1.50) and from a multifetal pregnancy (aOR, 1.68; 95% CI, 1.16-2.42). Cases were also more likely to have parents of Hispanic ethnicity (maternal aOR, 3.19; 95% CI, 2.61-3.91; paternal aOR, 2.11; 95% CI, 1.54-2.88), and parents born outside the United States (maternal aOR, 1.29; 95% CI, 1.06-1.57; paternal aOR, 1.92; 95% CI, 1.53-2.41). Maternal health conditions associated with increased odds of anotia/microtia included obesity (aOR, 1.31; 95% CI, 1.06-1.61) and pre-pregnancy diabetes (type I aOR, 9.89; 95% CI, 5.46-17.92; type II aOR, 4.70; 95% CI, 2.56-8.63). Reduced odds were observed for black mothers (aOR, 0.57; 95% CI, 0.38-0.85) and mothers reporting daily intake of folic acid-containing supplements (aOR, 0.59; 95% CI, 0.46-0.76).CONCLUSION: We identified several risk factors for anotia/microtia, some which have been previously reported (e.g., diabetes) and others which we investigate for perhaps the first time (e.g., binge drinking) that warrant further investigation. Our findings point to some potentially modifiable risk factors and provide further leads toward understanding the etiology of anotia/microtia.

  View details for PubMedID 30928866

• Women's periconceptional lowered carbohydrate intake and NTD-affected pregnancy risk in the era of prefortification with folic acid BIRTH DEFECTS RESEARCH Shaw, G. M., Yang, W. 2019; 111 (5): 248–53

  View details for DOI 10.1002/bdr2.1466

  View details for Web of Science ID 000460569200002

• Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk. Epigenetics Gonseth, S., Shaw, G. M., Roy, R., Segal, M. R., Asrani, K., Rine, J., Wiemels, J., Marini, N. J. 2019: 1–16

  Abstract

  Cleft lip with or without cleft palate (CL/P) is a common human birth defect whose etiologies remain largely unknown. Several studies have demonstrated that periconceptional supplementation of folic acid can reduce risk of CL/P in offspring. In this study, we tested the hypothesis that the preventive effect of folic acid is manifested through epigenetic modifications by determining whether DNA methylation changes are associated with CL/P. To more readily observe the potential effects of maternal folate on the offspring epigenome, we focused on births prior to mandatory dietary folate fortification in the United States (i.e. birth year 1997 or earlier). Genomic DNA methylation levels were assessed from archived newborn bloodspots in a 182-member case-control study using the Illumina Human Beadchip 450K array. CL/P cases displayed striking epigenome-wide hypomethylation relative to controls: 63% of CpGs interrogated had lower methylation levels in case newborns, a trend which held up in racially stratified sub-groups. 28 CpG sites reached epigenome-wide significance and all were case-hypomethylated. The most significant CL/P-associated differentially methylated region encompassed the VTRNA2-1 gene, which was also hypomethylated in cases (FWER p =0.014). This region has been previously characterized as a nutritionally-responsive, metastable epiallele and CL/P-associated methylation changes, in general, were greater at or near putative metastable epiallelic regions. Gene Set Enrichment Analysis of CL/P-associated DMRs showed an over-representation of genes involved in palate development such as WNT9B, MIR140 and LHX8. CL/P-associated DNA methylation changes may partly explain the mechanism by which orofacial clefts are responsive to maternal folate levels.

  View details for PubMedID 30870065

• NEUROCOGNITIVE DEFICITS IN ADULT CONGENITAL HEART DISEASE: DOES CORONARY ARTERY DISEASE ADD INSULT TO INJURY? Morello, M. L., Beidelman, M., Saha, P., Ingelsson, E., Shaw, G., Lui, G., Priest, J. ELSEVIER SCIENCE INC. 2019: 566

  View details for Web of Science ID 000460565900566

• 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

• A machine learning approach to investigate potential risk factors for gastroschisis in California BIRTH DEFECTS RESEARCH Weber, K. A., Yang, W., Carmichael, S. L., Padula, A. M., Shaw, G. M. 2019; 111 (4): 212–21

  View details for DOI 10.1002/bdr2.1441

  View details for Web of Science ID 000461575000004

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

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

  View details for Web of Science ID 000460127000003

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

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

  View details for Web of Science ID 000459549600018

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

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

  View details for Web of Science ID 000459549600003

• 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

• 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

• Prenatal exposure to air pollution, maternal diabetes and preterm birth ENVIRONMENTAL RESEARCH Padula, A. M., Yang, W., Lurmann, F. W., Balmes, J., Hammond, S., Shaw, G. M. 2019; 170: 160–67

  View details for DOI 10.1016/j.envres.2018.12.031

  View details for Web of Science ID 000458710800020

• Comparing Usual Dietary Intakes Among Subgroups of Mothers in the Year Before Pregnancy PUBLIC HEALTH REPORTS Carmichael, S. L., Ma, C., Feldkamp, M. L., Shaw, G. M., Natl Birth Defects Prevention Stu 2019; 134 (2): 155–63

  View details for DOI 10.1177/0033354918821078

  View details for Web of Science ID 000460640500009

• Substantial Cardiovascular Morbidity in Adults with Lower-Complexity Congenital Heart Disease. Circulation Saha, P., Potiny, P., Rigdon, J., Morello, M., Tcheandjieu, C., Romfh, A., Fernandes, S. M., McElhinney, D. B., Bernstein, D., Lui, G. K., Shaw, G. M., Ingelsson, E., Priest, J. R. 2019

  Abstract

  BACKGROUND: Although lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors.METHODS: A multi-tiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison amongst >500,000 British adults in the UK Biobank (UKB). ACHD diagnoses were sub-classified as "isolated aortic valve (AoV)" and "non-complex" defects. Time-to-event analyses were conducted for primary endpoints of fatal or non-fatal acute coronary syndrome (ACS), ischemic stroke, heart failure (HF), and atrial fibrillation, and a secondary combined endpoint for major adverse cardiovascular event (MACE). Maximum follow-up time for the study period was 22 years using retrospectively and prospectively collected data from the UKB.RESULTS: We identified 2,006 individuals with lower-complexity ACHD and 497,983 unexposed individuals in the UKB (median [IQR] age at enrollment 58 [51,63]). Of the ACHD-exposed group, 59% were male; 51% were current or former smokers; 30% were obese; 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary endpoints, with hazard ratios (HR) ranging from 2.0 (95% confidence interval [CI] 1.5-2.8, p<0.001) for ACS to 13.0 (95% CI 9.4-18.1, p<0.001) for HF. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of MACE in contrast to 13% in non-ACHD individuals with ≥5 risk factors.CONCLUSIONS: Individuals with lower-complexity ACHD had higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.

  View details for PubMedID 30813762

• 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

• Projected Changes in Maternal Heat Exposure During Early Pregnancy and the Associated Congenital Heart Defect Burden in the United States. Journal of the American Heart Association Zhang, W., Spero, T. L., Nolte, C. G., Garcia, V. C., Lin, Z., Romitti, P. A., Shaw, G. M., Sheridan, S. C., Feldkamp, M. L., Woomert, A., Hwang, S., Fisher, S. C., Browne, M. L., Hao, Y., Lin, S., National Birth Defects Prevention Study 2019; 8 (3): e010995

  Abstract

  Background More intense and longer-lasting heat events are expected in the United States as a consequence of climate change. This study aimed to project the potential changes in maternal heat exposure during early pregnancy (3-8weeks post conception) and the associated burden of congenital heart defects ( CHD s) in the future. Methods and Results This study expanded on a prior nationwide case-control study that evaluated the association between CHD s and maternal heat exposure during early pregnancy in summer and spring. We defined multiple indicators of heat exposure, and applied published odds ratios obtained for the matching season of the baseline (1995-2005) into the projection period (2025-2035) to estimate potential changes in CHD burden throughout the United States. Increases in maternal heat exposure were projected across the United States and to be larger in the summer. The Midwest will potentially have the highest increase in summer maternal exposure to excessively hot days (3.42; 95% CI, 2.99-3.88 per pregnancy), heat event frequency (0.52; 95% CI, 0.44-0.60) and heat event duration (1.73; 95% CI, 1.49-1.97). We also found large increases in specific CHD subtypes during spring, including a 34.0% (95% CI, 4.9%-70.8%) increase in conotruncal CHD in the South and a 38.6% (95% CI , 9.9%-75.1%) increase in atrial septal defect in the Northeast. Conclusions Projected increases in maternal heat exposure could result in an increased CHD burden in certain seasons and regions of the United States.

  View details for PubMedID 30696385

• Projected Changes in Maternal Heat Exposure During Early Pregnancy and the Associated Congenital Heart Defect Burden in the United States JOURNAL OF THE AMERICAN HEART ASSOCIATION Zhang, W., Spero, T. L., Nolte, C. G., Garcia, V. C., Lin, Z., Romitti, P. A., Shaw, G. M., Sheridan, S. C., Feldkamp, M. L., Woomert, A., Hwang, S., Fisher, S. C., Browne, M. L., Hao, Y., Lin, S., Hobbs, C., Shaw, G., Carmichael, S., Reefhuis, J., Tinker, S., Romitti, P., Anderka, M., Druschel, C., Bell, E., Browne, M., Olshan, A., Meyer, R., Canfield, M., Langlois, P., Feldkamp, M., Botto, L., Natl Birth Defects Prevention Stud 2019; 8 (3)

  View details for DOI 10.1161/JAHA.118.010995

  View details for Web of Science ID 000460106400018

• Maternal Lactase Polymorphism (rs4988235) Is Associated with Neural Tube Defects in Offspring in the National Birth Defects Prevention Study JOURNAL OF NUTRITION Hoang, T. T., Lei, Y., Mitchell, L. E., Sharma, S. V., Swartz, M. D., Waller, D., Finnell, R. H., Benjamin, R. H., Browne, M. L., Canfield, M. A., Lupo, P. J., McKenzie, P., Shaw, G., Agopian, A. J., Natl Birth Defects Prevention 2019; 149 (2): 295–303

  View details for DOI 10.1093/jn/nxy246

  View details for Web of Science ID 000458632000015

• Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk EPIGENETICS Gonseth, S., Shaw, G. M., Roy, R., Segal, M. R., Asrani, K., Rine, J., Wiemels, J., Marini, N. J. 2019; 14 (2): 198–213

  View details for DOI 10.1080/15592294.2019.1581591

  View details for Web of Science ID 000463795900008

• Developing evidence-based recommendations for optimal interpregnancy intervals in high-income countries: protocol for an international cohort study. BMJ open Marinovich, M. L., Regan, A. K., Gissler, M., Magnus, M. C., Haberg, S. E., Padula, A. M., Mayo, J. A., Shaw, G. M., Ball, S., Malacova, E., Gebremedhin, A. T., Nassar, N., Marston, C., de Klerk, N., Betran, A. P., Pereira, G. F. 2019; 9 (1): e027941

  Abstract

  INTRODUCTION: Short interpregnancy interval (IPI) has been linked to adverse pregnancy outcomes. WHO recommends waiting at least 2years after a live birth and 6months after miscarriage or induced termination before conception of another pregnancy. The evidence underpinning these recommendations largely relies on data from low/middle-income countries. Furthermore, recent epidemiological investigations have suggested that these studies may overestimate the effects of IPI due to residual confounding. Future investigations of IPI effects in high-income countries drawing from large, population-based data sources are needed to inform IPI recommendations. We aim to assess the impact of IPIs on maternal and child health outcomes in high-income countries.METHODS AND ANALYSIS: This international longitudinal retrospective cohort study will include more than 18million pregnancies, making it the largest study to investigate IPI in high-income countries. Population-based data from Australia, Finland, Norway and USA will be used. Birth records in each country will be used to identify consecutive pregnancies. Exact dates of birth and clinical best estimates of gestational length will be used to estimate IPI. Administrative birth and health data sources with >99%coverage in each country will be used to identify maternal sociodemographics, pregnancy complications, details of labour and delivery, birth and child health information. We will use matched and unmatched regression models to investigate the impact of IPI on maternal and infant outcomes, and conduct meta-analysis to pool results across countries.ETHICS AND DISSEMINATION: Ethics boards at participating sites approved this research (approval was not required in Finland). Findings will be published in peer-reviewed journals and presented at international conferences, and will inform recommendations for optimal IPI in high-income countries. Findings will provide important information for women and families planning future pregnancies and for clinicians providing prenatal care and giving guidance on family planning.

  View details for PubMedID 30700492

• 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

• Variants identified in PTK7 associated with neural tube defects. Molecular genetics & genomic medicine Lei, Y., Kim, S., Chen, Z., Cao, X., Zhu, H., Yang, W., Shaw, G. M., Zheng, Y., Zhang, T., Wang, H., Finnell, R. H. 2019: e584

  Abstract

  BACKGROUND: Variants in planar cell polarity (PCP) pathway genes have been repeatedly implicated in the pathogenesis of NTDs in both mouse models and in human cohorts. Mouse models indicate that the homogenous disruption of the Ptk7 gene, a PCP regulator, results in craniorachischisis; while embryos that are doubly heterozygous for Ptk7XST87 and Vangl2Lp mutations present with spina bifida.METHODS: In this study, we initially sequenced exons of the human PTK7 gene in 192 spina bifida patients and 190 controls from a California population. A phase II validation study was performed in 343 Chinese NTD cohort. Functional assays including immunoblotting and immunoprecipitation were used to study identified variants effect on PTK7 function.RESULTS: We identified three rare (MAF <0.001) missense heterozygous PTK7 variants (NM_001270398.1:c.581C>T, p.Arg630Ser and p.Tyr725Phe) in the spina bifida patients. In our functional analyses, p.Arg630Ser affected PTK7 mutant protein stability and increased interaction with Dvl2, while the p.Thr186Met variant decreased PTK7 interactions with Dvl2. No novel predicted-to-be-damaging variant or function-disrupted PTK7 variant was identified among the control subjects. We subsequently re-sequenced the PTK7 CDS region in 343 NTDs from China to validate the association between PTK7 and NTDs. The frequency of PTK7 rare missense variants in the Chinese NTD samples is significantly higher than in gnomAD controls.CONCLUSION: Our study suggests that rare missense variants in PTK7 contribute to the genetic risk of NTDs.

  View details for PubMedID 30689296

• Women's periconceptional lowered carbohydrate intake and NTD-affected pregnancy risk in the era of prefortification with folic acid. Birth defects research Shaw, G. M., Yang, W. 2019

  Abstract

  BACKGROUND: A recent study observed women's restricted carbohydrate diet in the year before conception was associated with increased risk of neural tube defect (NTD)-affected pregnancies. That study corresponded to the era of postfortification of folic acid. Because folic acid and carbohydrate measures would derive from similar foods, investigators of that study could not determine whether the increased risk with restricted carbohydrate intake was a consequence of lower folate intake. We extend their novel observation by examining rigorous NTD data prior to folic acid fortification.METHODS: Data were derived from a population-based case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 449 NTD cases and with mothers of 458 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess macro- and micronutrient intakes based on reported intakes 3 months before conception.RESULTS: Case mothers were twice as likely to have consumed a low carbohydrate (≤5th percentile intake among controls) diet with a crude odds ratio of 2.0 (95% confidence interval, 1.2-3.4). Adjustment for race/ethnicity, education, alcohol intake, and folic acid use made very little difference on the odds ratio. Adjustment for total energy intake appeared to be the only factor to slightly attenuate the odds ratio.CONCLUSION: Our findings indicate that the association between low carbohydrate intake and NTD risk may not be wholly a function of low folic acid in the postfortification era. Such a finding offers new clues to pursue for the seemingly folate-insensitive NTDs that continue to occur.

  View details for PubMedID 30681289

• The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation. Human molecular genetics Kousa, Y. A., Zhu, H., Fakhouri, W. D., Lei, Y., Kinoshita, A., Roushangar, R. R., Patel, N. K., Agopian, A. J., Yang, W., Leslie, E. J., Busch, T. D., Mansour, T. A., Li, X., Smith, A. L., Li, E. B., Sharma, D. B., Williams, T. J., Chai, Y., Amendt, B. A., Liao, E. C., Mitchell, L. E., Bassuk, A. G., Gregory, S., Ashley-Koch, A., Shaw, G. M., Finnell, R. H., Schutte, B. C. 2019

  Abstract

  Mutations in IRF6, TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Over-expression of Irf6 caused exencephaly, a rostral neural tube defect, through suppression of Tfap2a and Grhl3 expression. Conversely, loss of Irf6 function caused a curly tail and coincided with a reduction of Tfap2a and Grhl3 expression in tail tissues. To test whether Irf6 function in neurulation was conserved, we sequenced samples obtained from human cases of spina bifida and anencephaly. We found two likely disease-causing variants in two samples from patients with spina bifida. Overall, these data suggest that the Tfap2a-Irf6-Grhl3 genetic pathway is shared by two embryologically distinct morphogenetic events that previously were considered independent during mammalian development. In addition, these data suggest new candidates to delineate the genetic architecture of neural tube defects and new therapeutic targets to prevent this common birth defect.

  View details for PubMedID 30689861

• Maternal Lactase Polymorphism (rs4988235) Is Associated with Neural Tube Defects in Offspring in the National Birth Defects Prevention Study. The Journal of nutrition Hoang, T. T., Lei, Y., Mitchell, L. E., Sharma, S. V., Swartz, M. D., Waller, D. K., Finnell, R. H., Benjamin, R. H., Browne, M. L., Canfield, M. A., Lupo, P. J., McKenzie, P., Shaw, G., Agopian, A. J., National Birth Defects Prevention Study 2019

  Abstract

  Background: The risk of neural tube defect (NTD)-affected pregnancies is reduced with adequate folic acid intake during early pregnancy. However, NTDs have been observed among offspring of women with adequate folic acid intake. Some of these women are possibly not absorbing enough folic acid. Because lactase deficiency can lead to poor nutrient absorption, we hypothesized that lactase-deficient women will be at increased risk of having offspring with NTDs.Objective: We examined the association between maternal rs4988235 (a lactase deficiency genetic marker) and NTDs in offspring.Methods: We conducted a case-control study using data from the National Birth Defects Prevention Study, United States, 1997-2009, restricting to non-Hispanic white (NHW) and Hispanic women. Cases were women with an offspring with an NTD (n = 378 NHW, 207 Hispanic), and controls were women with an offspring without a birth defect (n = 461 NHW, 165 Hispanic). Analyses were conducted separately by race/ethnicity, using logistic regression. Women with the CC genotype were categorized as being lactase deficient. To assess potential effect modification, analyses were stratified by lactose intake, folic acid supplementation, dietary folate, and diet quality.Results: Among NHW women, the odds of being lactase deficient were greater among cases compared with controls (OR: 1.37; 95% CI: 1.02, 1.82). Among Hispanic women, the odds of being lactase deficient were significantly lower among cases compared with controls (OR: 0.50, 95% CI: 0.33, 0.77). The association differed when stratified by lactose intake in NHW women (higher odds among women who consumed ≥12 g lactose/1000 kcal) and by dietary folate in Hispanic women (opposite direction of associations). The association did not differ when stratified by folic acid supplementation or diet quality.Conclusions: Our findings suggest that maternal lactase deficiency is associated with NTDs in offspring. However, we observed opposite directions of effect by race/ethnicity that could not be definitively explained.

  View details for PubMedID 30689919

• 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

• 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

• Dominant negative GPR161 rare variants are risk factors of human spina bifida HUMAN MOLECULAR GENETICS Kim, S., Lei, Y., Hwang, S., Wlodarczyk, B. J., Mukhopadhyay, S., Shaw, G. M., Ross, M., Finnell, R. H. 2019; 28 (2): 200–208

  Abstract

  Spina bifida (SB) is a complex disorder of failed neural tube closure during the first month of human gestation, with a suspected etiology involving multiple gene and environmental interactions. GPR161 is a ciliary G-protein coupled receptor that regulates Sonic Hedgehog (Shh) signaling. Gpr161 null and hypomorphic mutations cause neural tube defects (NTDs) in mouse models. Herein we show that several genes involved in Shh and Wnt signaling were differentially expressed in the Gpr161 null embryos using RNA-seq analysis. To determine whether there exists an association between GPR161 and SB in humans, we performed direct Sanger sequencing on the GPR161 gene in a cohort of 384 SB patients and 190 healthy controls. We identified six rare variants of GPR161 in six SB cases, of which two of the variants were novel and did not exist in any databases. Both of these variants were predicted to be damaging by SIFT and/or PolyPhen analysis. The novel GPR161 rare variants mislocalized to the primary cilia, dysregulated Shh and Wnt signaling and inhibited cell proliferation in vitro. Our results demonstrate that GPR161 mutations cause NTDs via dysregulation of Shh and Wnt signaling in mice, and novel rare variants of GPR161 can be risk factors for SB in humans.

  View details for PubMedID 30256984

• 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

• “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

• Re: Herpesvirus Infection in Infants with Gastroschisis Respond EPIDEMIOLOGY Francis, S. S., Shaw, G. M. 2019; 30 (1): E2-E3

  View details for DOI 10.1097/EDE.0000000000000935

  View details for Web of Science ID 000452754000004

• 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

• Preterm birth occurrence among Asian women relative to their place of birth Girsen, A., Mayo, J. A., Datoc, I., Karakash, S., El-Sayed, Y. Y., Shaw, G. M. MOSBY-ELSEVIER. 2019: S352

  View details for DOI 10.1016/j.ajog.2018.11.546

  View details for Web of Science ID 000454249402006

• 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

• "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

• 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

• Comparing Usual Dietary Intakes Among Subgroups of Mothers in the Year Before Pregnancy. Public health reports (Washington, D.C. : 1974) Carmichael, S. L., Ma, C., Feldkamp, M. L., Shaw, G. M. 2018: 33354918821078

  Abstract

  OBJECTIVE:: The quantity and quality of dietary intake among women of reproductive age has important public health implications for nutritional status during pregnancy. We described dietary intake during the year before pregnancy among a large, diverse group of US mothers.METHODS:: We examined data from 11109 mothers who gave birth from 1997 through 2011 and participated in a population-based case-control study, the National Birth Defects Prevention Study, as controls (mothers who had babies without major birth defects). We examined whether subgroups of mothers at elevated risk of adverse pregnancy outcomes were more likely than their reference groups to have high dietary intake (>90th percentile of intake) or low dietary intake (<10th percentile of intake). We examined dietary intake of 22 nutritional factors, which were estimated from responses to a food frequency questionnaire.RESULTS:: Participants who were aged <20, were nulliparous, had

  View details for PubMedID 30593261

• A machine learning approach to investigate potential risk factors for gastroschisis in California. Birth defects research Weber, K. A., Yang, W., Carmichael, S. L., Padula, A. M., Shaw, G. M. 2018

  Abstract

  BACKGROUND: To generate new leads about risk factors for gastroschisis, a birth defect that has been increasing in prevalence over time, we performed an untargeted data mining statistical approach.METHODS: Using data exclusively from the California Center of the National Birth Defects Prevention Study, we compared 286 cases of gastroschisis and 1,263 non-malformed, live-born controls. All infants had delivery dates between October 1997 and December 2011 and were stratified by maternal age at birth (<20 and ≥ 20years). Cases and controls were compared by maternal responses to 183 questions (219 variables) using random forest, a data mining procedure. Variables deemed important by random forest were included in logistic regression models to estimate odds ratios and 95% confidence intervals.RESULTS: Among women younger than 20, of variables deemed important, there were higher odds observed for higher consumption of chocolate, low intake of iron, acetaminophen use, and urinary tract infections during the beginning of pregnancy. After adjustment, the higher odds remained for low iron intake and a urinary tract infection in the first month of pregnancy. Among women aged 20 or older, of variables deemed important, higher odds were observed for US-born women of Hispanic ethnicity and for parental substance abuse. There were lower odds observed for obese women, women who ate any cereal the month before pregnancy, and those with higher parity.CONCLUSIONS: We did not discover many previously unreported associations, despite our novel approach to generate new hypotheses. However, our results do add evidence to some previously proposed risk factors.

  View details for PubMedID 30588769

• 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

• 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

• Prenatal exposure to air pollution, maternal diabetes and preterm birth. Environmental research Padula, A. M., Yang, W., Lurmann, F. W., Balmes, J., Hammond, S. K., Shaw, G. M. 2018; 170: 160–67

  Abstract

  Prenatal exposure to ambient air pollution has been associated with preterm birth in several studies. Associations between air pollution and gestational or pre-existing diabetes have been hypothesized but are not well established. We examined the association between air pollution exposure in pregnancy and gestational diabetes and whether the association between air pollution and preterm birth is modified by diabetes (gestational or pre-existing) in a highly polluted area of California. Birth certificates and hospital discharge data from all singleton births from 2000 to 2006 to women living in four counties in the San Joaquin Valley of California were linked to criteria air pollution and traffic density measurements at the geocoded maternal residence. Air pollutants were dichotomized at the highest quartile and compared to the lower three quartiles. Logistic regression models were adjusted for maternal race-ethnicity, age, education, payment of birth expenses, and prenatal care. There were consistent inverse associations between exposure to air pollution during the first two trimesters and gestational diabetes (statistically significant odds ratios (OR) less than 1). When stratified by any diabetes (gestational or pre-existing), associations between air pollution exposure during pregnancy and categories of preterm birth (20-27, 28-31, 32-33, 34-36 weeks) were generally similar with few exceptions of exposures to carbon monoxide (CO) and particulate matter < 2.5 m (PM2.5). Those with diabetes and exposure higher levels of CO (in first trimester or entire pregnancy) or PM2.5 (in first trimester) had higher risk of extremely preterm birth (20-27 weeks) compared with those without diabetes. The associations between traffic-related air pollution and gestational diabetes were in the unexpected ("protective") direction. Among those with any diabetes, associations were stronger between CO and PM2.5 and extremely preterm birth.

  View details for PubMedID 30579990

• Copy number variants in hypoplastic right heart syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Giannakou, A., Sicko, R. J., Kay, D. M., Zhang, W., Romitti, P. A., Caggana, M., Shaw, G. M., Jelliffe-Pawlowski, L. L., Mills, J. L. 2018; 176 (12): 2760-2767

  View details for DOI 10.1002/ajmg.a.40527

  View details for Web of Science ID 000454612700029

• Preterm Delivery Phenotypes in Systemic Lupus Erythematosus Pregnancies. American journal of perinatology Simard, J. F., Chaichian, Y., Rossides, M., Wikstrom, A., Shaw, G. M., Druzin, M. L. 2018

  Abstract

  OBJECTIVE: Women with systemic lupus erythematosus (SLE) are at a greater risk of preterm delivery, many of which may be medically indicated (iatrogenic). We investigated preterm delivery phenotypes in SLE and general population comparators and assessed the role of preeclampsia.STUDY DESIGN: We used population-based Swedish Register data (2001-2013) and defined maternal SLE as ≥2 SLE-coded discharge diagnoses from the Patient Register with ≥1 coded by an appropriate specialist. Women from the general population were identified using the Total Population Register. Preterm delivery was defined as <37 weeks and separated into spontaneous and iatrogenic, as well as later versus extremely preterm (32 to <37 weeks vs. <32 weeks). Maternal comorbidity was assessed, and the proportion mediated by preeclampsia was calculated examining first, subsequent, and all pregnancies.RESULTS: Preterm delivery was more common in SLE for the first (22 vs. 6%) and subsequent (15 vs. 4%) pregnancies among 781 SLE-exposed pregnancies and 11,271 non-SLE pregnancies. Of SLE-exposed first births, 27% delivered before 32 weeks, and 90% were iatrogenic (compared with 47% of non-SLE first births).CONCLUSION: Preterm delivery complicates a greater proportion of SLE pregnancies than general population pregnancies, and a considerable proportion of risk is mediated through preeclampsia.

  View details for PubMedID 30477035

• 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., 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

• Risk Factors Associated With the Development of Common Ventricle Congenital Heart Disease Paige, S. L., Yang, W., Priest, J. R., Botto, L., Shaw, G. M., Collins, R., Natl Birth Defects Prevention LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619402118

• 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

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

  Abstract

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

  View details for PubMedID 30396225

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

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

  View details for Web of Science ID 000450525400001

• An application of data mining to identify potential risk factors for anophthalmia and microphthalmia PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Weber, K. A., Yang, W., Carmichael, S. L., Lupo, P. J., Dukhovny, S., Yazdy, M. M., Lin, A. E., Van Bennekom, C. M., Mitchell, A. A., Shaw, G. M., Natl Birth Defects Prevention 2018; 32 (6): 545–55

  View details for DOI 10.1111/ppe.12509

  View details for Web of Science ID 000451452900007

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

  View details for DOI 10.1016/j.annepidem.2018.08.008

  View details for Web of Science ID 000450020400006

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

  Abstract

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

  View details for PubMedID 30381468

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

  View details for DOI 10.1136/bmj.k4372

  View details for Web of Science ID 000449564200004

• A population-based case-control study of the association between weather-related extreme heat events and orofacial clefts. Birth defects research Soim, A., Sheridan, S. C., Hwang, S., Hsu, W., Fisher, S. C., Shaw, G. M., Feldkamp, M. L., Romitti, P. A., Reefhuis, J., Langlois, P. H., Browne, M. L., Lin, S., National Birth Defects Prevention Study 2018: e1385

  Abstract

  BACKGROUND: Limited epidemiologic research exists on the association between weather-related extreme heat events (EHEs) and orofacial clefts (OFCs). We estimated the associations between maternal exposure to EHEs in the summer season and OFCs in offspring and investigated the potential modifying effect of body mass index on these associations.METHODS: We conducted a population-based case-control study among mothers who participated in the National Birth Defects Prevention Study for whom at least 1 day of their first two post-conception months occurred during summer. Cases were live-born infants, stillbirths, and induced terminations with OFCs; controls were live-born infants without major birth defects. We defined EHEs using the 95th and the 90th percentiles of the daily maximum universal apparent temperature distribution. We used unconditional logistic regression with Firth's penalized likelihood method to estimate adjusted odds ratios and 95% confidence intervals, controlling for maternal sociodemographic and anthropometric variables.RESULTS: We observed no association between maternal exposure to EHEs and OFCs overall, although prolonged duration of EHEs may increase the risk of OFCs in some study sites located in the Southeast climate region. Analyses by subtypes of OFCs revealed no associations with EHEs. Modifying effect by BMI was not observed.CONCLUSIONS: We did not find a significantly increased risk of OFCs associated with maternal exposure to EHEs during the relevant window of embryogenesis. Future studies should account for maternal indoor and outdoor activities and for characteristics such as hydration and use of air conditioning that could modify the effect of EHEs on pregnant women.

  View details for PubMedID 30338937

• Congenital heart disease complexity and childhood cancer risk BIRTH DEFECTS RESEARCH Collins, R., Von Behren, J., Yang, W., Carmichael, S. L., Reynolds, P., Fisher, P. G., Shaw, G. M. 2018; 110 (17): 1314–21

  View details for DOI 10.1002/bdr2.1390

  View details for Web of Science ID 000448368300002

• An application of data mining to identify potential risk factors for anophthalmia and microphthalmia. Paediatric and perinatal epidemiology Weber, K. A., Yang, W., Carmichael, S. L., Lupo, P. J., Dukhovny, S., Yazdy, M. M., Lin, A. E., Van Bennekom, C. M., Mitchell, A. A., Shaw, G. M., National Birth Defects Prevention Study 2018

  Abstract

  BACKGROUND: We examined a large number of variables to generate new hypotheses regarding a wider range of risk factors for anophthalmia/microphthalmia using data mining.METHODS: Data were from the National Birth Defects Prevention Study, a multicentre, case-control study from 10 centres in the United States. There were 134 cases of "isolated" and 87 "nonisolated" (with other major birth defects) of anophthalmia/microphthalmia and 11052 nonmalformed controls with delivery dates October 1997-December 2011. Using random forest, a data mining procedure, we compared the two case types with controls for 201 variables. Variables considered important ranked by random forest were included in a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals.RESULTS: Predictors for isolated cases included paternal race/ethnicity, maternal intake of certain nutrients and foods, and childhood health problems in relatives. Using regression, inverse associations were observed with greater maternal education and with increasing intake of folate and potatoes. Odds were slightly higher with greater paternal education, for increased intake of carbohydrates and beans, and if relatives had a childhood health problem. For nonisolated cases, predictors included paternal race/ethnicity, maternal intake of certain nutrients, and smoking in the home the month before conception. Odds were higher for Hispanic fathers and smoking in the home and NSAID use the month before conception.CONCLUSIONS: Results appear to support previously hypothesised risk factors, socio-economic status, NSAID use, and inadequate folate intake, and potentially provide new areas such as passive smoking pre-pregnancy, and paternal education and ethnicity, to explore for further understanding of anophthalmia/microphthalmia.

  View details for PubMedID 30300919

• Copy number variants in hypoplastic right heart syndrome. American journal of medical genetics. Part A Giannakou, A., Sicko, R. J., Kay, D. M., Zhang, W., Romitti, P. A., Caggana, M., Shaw, G. M., Jelliffe-Pawlowski, L. L., Mills, J. L. 2018

  Abstract

  Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdeveloped and malformed structures of the right heart. Familial recurrence of HRHS indicates genetic factors contribute to its etiology. Our study investigates the presence of copy number variants (CNVs) in HRHS cases. We genotyped 42 HRHS cases identified from live births throughout California (2003-2010) using the Illumina HumanOmni2.5-8 array. We identified 14 candidate CNVs in 14 HRHS cases (33%) based on the genes included in the CNVs and their functions. Duplications overlapping part of ERBB4 were identified in two unrelated cases. ERBB4 is a neuregulin receptor with a pivotal role in cardiomyocyte differentiation and heart development. We also described a 7.5 Mb duplication at 16q11-12. Multiple genes in the duplicated region have previously been linked to heart defects and cardiac development, including RPGRIP1L, RBL2, SALL1, and MYLK3. Of the 14 validated CNVs, we identified four CNVs in close proximity to genes linked to the Wnt signaling pathway. This study expands on our previous work supporting the role of genetics in HRHS. We identified CNVs affecting crucial genes and signaling pathways involved in right heart development. ERBB4 and duplication of the 16q11-12 region are important areas for future investigation.

  View details for PubMedID 30289599

• The Authors Respond. Epidemiology (Cambridge, Mass.) Francis, S. S., Shaw, G. M. 2018

  View details for PubMedID 30299403

• 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

• 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

• 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

• Maternal ambient heat exposure during early pregnancy in summer and spring and congenital heart defects - A large US population-based, case-control study ENVIRONMENT INTERNATIONAL Lin, S., Lin, Z., Ou, Y., Soim, A., Shrestha, S., Lu, Y., Sheridan, S., Luben, T. J., Fitzgerald, E., Bell, E., Shaw, G. M., Reefhuis, J., Langlois, P. H., Romitti, P., Feldkamp, M. L., Malik, S., Pantea, C., Nayak, S., Hwang, S., Browne, M., Natl Birth Defects Prevention Stud 2018; 118: 211–21

  Abstract

  Few studies have assessed the effect of ambient heat during the fetal development period on congenital heart defects (CHDs), especially in transitional seasons. We examined and compared the associations between extreme heat and CHD phenotypes in summer and spring, assessed their geographical differences, and compared different heat indicators.We identified 5848 CHD cases and 5742 controls (without major structural defects) from the National Birth Defects Prevention Study, a US multicenter, population-based case-control study. Extreme heat events (EHEs) were defined by using the 95th (EHE95) or 90th (EHE90) percentile of daily maximum temperature and its frequency and duration during postconceptional weeks 3-8. We used a two-stage Bayesian hierarchical model to examine both regional and study-wide associations. Exposure odds ratios (ORs) were calculated using multivariate logistic regression analyses, while controlling for potential confounding factors.Overall, we observed no significant relationships between maternal EHE exposure and CHDs in most regions during summer. However, we found that 3-11 days of EHE90 during summer and spring was significantly associated with ventricular septal defects (VSDs) study-wide (ORs ranged: 2.17-3.24). EHE95 in spring was significantly associated with conotruncal defects and VSDs in the South (ORs: 1.23-1.78). Most EHE indicators in spring were significantly associated with increased septal defects (both VSDs and atrial septal defects (ASDs)) in the Northeast.While generally null results were found, long duration of unseasonable heat was associated with the increased risks for VSDs and ASDs, mainly in South and Northeast of the US. Further research to confirm our findings is needed.

  View details for PubMedID 29886237

• 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

• Change in Prevalence of Orofacial Clefts in California between 1987 and 2010 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Andrew, T., Yang, W., Bernstein, J. A., Shaw, G. M. 2018; 176 (9): 1910–16

  View details for DOI 10.1002/ajmg.a.40384

  View details for Web of Science ID 000445271900017

• Epidemiology of anophthalmia and microphthalmia: Prevalence and patterns in Texas, 1999-2009 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chambers, T. M., Agopian, A. J., Lewis, R. A., Langlois, P. H., Danysh, H. E., Weber, K. A., Shaw, G. M., Mitchell, L. E., Lupo, P. J. 2018; 176 (9): 1810–18

  Abstract

  Anophthalmia and microphthalmia are a set of rare, yet severe, birth defects considered to be part of a spectrum of developmental ocular malformations ranging from smaller than average to completely absent eyes. Despite their clinical significance, little is known about the etiologies of these conditions. The goal of this study was to expand our understanding of the epidemiology of anophthalmia and microphthalmia. Data for this population-based assessment were obtained from the Texas Birth Defects Registry (TBDR) and Center for Health Statistics for the period 1999-2009. Descriptive analyses and estimates of birth prevalence and prevalence ratios (PR) were determined for this defect. There were 1,262 definite anophthalmia and microphthalmia patients identified in the TBDR, with an overall combined prevalence of 3.0 per 10,000 live births. More than half (55.7%) of the patients had at least one chromosome abnormality or syndrome. In addition, 92.4% of nonsyndromic patients (i.e., have no recorded chromosome abnormalities or syndromes) had at least one additional birth defect. After adjustment for multiple factors, the prevalence of nonsyndromic anophthalmia and microphthalmia was higher among mothers who had ≥2 previous fetal deaths (PR = 1.43, 95% confidence interval [CI]: 1.03-1.97) and among mothers with any reported diabetes (PR = 2.08, 95% CI: 1.49-2.90). Our results confirm that children with anophthalmia and microphthalmia frequently have genetic syndromes or are born with other major birth defects. Our findings add to the limited body of literature on anophthalmia and microphthalmia as well as help define subgroups of women who are more likely to have children with this malformation.

  View details for PubMedID 30070760

• 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

• 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

• Change in Prevalence of Orofacial Clefts in California between 1987 and 2010. American journal of medical genetics. Part A Andrew, T., Yang, W., Bernstein, J. A., Shaw, G. M. 2018

  Abstract

  INTRODUCTION: To extend the knowledge base about possible prevalence declines of specific orofacial cleft phenotypes, here we examine prevalence in a population base from California over a two-decade period among numerous race/ethnic groups.METHODS: This population-based study used vital statistics and birth defects registry data. Its population involved all births (~1.5 million births) in central California counties from 1987 to 2010. Orofacial clefts were defined as cleft lip with or without cleft palate (CLP, n=1766), and cleft palate (CP, n=922) only. The slope of prevalence of each cleft phenotype over the period 1987-2010 was estimated using weighted least squares regression.RESULTS: Birth prevalence of CLP was 121/100,000 live births, and 63/100,000 live births for CP. The slope for CLP decreased by 1.2 (slope: -1.2; 95% CI: -1.9, -0.5), and for CP by 0.7 (slope: -0.7; 95% CI: -1.7, 0.2) for CP. Stratification by race/ethnicity or infant sex did not demonstrate a statistical difference in slopes.CONCLUSIONS: We observed a decline in the prevalence in CLP in all ethnic groups, however did not observe the same amount of decline in CP, perhaps due to antenatal screening.

  View details for PubMedID 30063089

• Women's periconceptional diet and risk of biliary atresia in offspring BIRTH DEFECTS RESEARCH Carmichael, S. L., Ma, C., Van Zutphen, A. R., Moore, C. A., Shaw, G. M., Natl Birth Defects Prevention Stud 2018; 110 (12): 994-1000

  View details for DOI 10.1002/bdr2.1340

  View details for Web of Science ID 000445630800004

• 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

• Herpesvirus Infection in Infants with Gastroschisis EPIDEMIOLOGY Francis, S. S., Wiemels, J. L., Yang, W., Shaw, G. M. 2018; 29 (4): 571–73

  Abstract

  Gastroschisis is a congenital malformation that has been shown to be more common in younger mothers and appears to be increasing in prevalence in the United States and elsewhere. Epidemiologic data suggest a potential role of infection and recent studies report an association between maternal antibodies to human herpesviruses (HHV) and development of gastroschisis.In this study, we examined newborn bloodspots from 50 children with gastroschisis and 50 healthy controls using a highly sensitive digital droplet polymerase chain reaction assay covering eight human herpesviruses [herpes simplex sirus 1/2, Epstein-Barr virus (HHV-4), cytomegalovirus (HHV-5), HHV-6A/B, HHV-7, and HHV-8], to examine the presence of herpesvirus DNA at birth, which would suggest in utero infection.One control tested positive for low-level cytomegalovirus infection. We found no evidence of an association between herpesvirus DNA in neonatal blood spots taken at birth and gastroschisis.Our results do not support direct involvement of herpesviruses in the etiology of gastroschisis. However, there are several limitations in our study, most notably the known induction of this congenital malformation early in pregnancy and our analysis of blood taken at birth. Therefore, we cannot conclude that herpesviruses play no role in the etiology of gastroschisis and further research is needed to better define this relationship.

  View details for PubMedID 29634591

• 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

• 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

  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

• 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

• Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring. Birth defects research Weber, K. A., Yang, W., Carmichael, S. L., Shaw, G. M., National Birth Defects Prevention Study 2018; 110 (10): 863–70

  Abstract

  BACKGROUND: We previously explored associations between nutrients including folate and other macro and micronutrients and risks of anophthalmia or microphthalmia in the National Birth Defects Prevention Study. In the current study, we expand those previous results with larger sample sizes and conduct analyses with an additional diet quality index using more recent data.METHODS: The National Birth Defects Prevention Study is a population-based, multicenter case-control study of over 30 major birth defects, with estimated due dates from October 1997 to December 2011. Cases were 224 infants diagnosed with anophthalmia or microphthalmia. Controls were 11,109 live-born, nonmalformed infants randomly selected by each study center. Mothers completed a standardized, computer-assisted telephone interview between 6 weeks and 24 months after delivery. Mothers responded to a shortened food frequency questionnaire, assessing their nutrient intake for the year before pregnancy, and questions about periconceptional (2 months before to 2 months after conception) vitamin supplement use. Nutrient intake quartiles were based on the intake among controls.RESULTS: Among vitamin supplement users, odds of anophthalmia/microphthalmia were decreased for women with intake levels in the highest quartile of folate (0.56, 95% confidence interval [CI] 0.32-0.98), magnesium (0.42, 95% CI 0.22-0.82), and vitamin E (0.50, 95% CI 0.29-0.89). Among women not reporting vitamin supplement use, the odds were significantly increased for beta-carotene (2.5, 95% CI 1.10-5.68) and decreased for retinol (0.37, 95% CI 0.19-0.73).CONCLUSIONS: In this expanded analysis, we observed associations for a few nutrients, specifically forms of vitamin A. However, the heterogeneity of results by form and vitamin use necessitates further inquiry.

  View details for PubMedID 29504274

• Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring BIRTH DEFECTS RESEARCH Weber, K. A., Yang, W., Carmichael, S. L., Shaw, G. M., Natl Birth Defects Prevention 2018; 110 (10): 863–70

  View details for DOI 10.1002/bdr2.1201

  View details for Web of Science ID 000434062300004

• Reproductive suppression, birth defects, and periviable birth. Evolutionary applications Catalano, R., Bruckner, T. A., Karasek, D., Yang, W., Shaw, G. M. 2018; 11 (5): 762-767

  Abstract

  We argue that reproductive suppression has clinical implications beyond its contribution to the burden of spontaneous abortion. We theorize that the incidence of births before the 28th week of gestation, which contribute disproportionately to infant morbidity and mortality, varies over time in part due to reproductive suppression in the form of selection in utero. We further theorize that the prevalence of structural birth defects among survivors to birth from conception cohorts gauges selection in utero. We based these theories on literature positing that natural selection conserved mechanisms that spontaneously abort "risky" pregnancies including those otherwise likely to yield infants with structural birth defects or small-for-gestational age males. We test our theory using high-quality birth defect surveillance data. We identify 479,885 male infants exposed to strong selection defined as membership in conception cohorts ranked in the lowest quartile of odds of a birth defect among live-born females. We estimate the risk of periviable birth among these infants as a function of selective pressure as well as of mother's race/ethnicity and age. We find that male infants from exposed conception cohorts exhibited 10% lower odds of periviable birth than males from other conception cohorts. Our findings support the argument that selection in utero has implications beyond its contribution to the burden of spontaneous abortion.

  View details for DOI 10.1111/eva.12585

  View details for PubMedID 29875817

  View details for PubMedCentralID PMC5979761

• Reproductive suppression, birth defects, and periviable birth EVOLUTIONARY APPLICATIONS Catalano, R., Bruckner, T. A., Karasek, D., Yang, W., Shaw, G. M. 2018; 11 (5): 762–67

  View details for DOI 10.1111/eva.12585

  View details for Web of Science ID 000433572400015

• Women's periconceptional diet and risk of biliary atresia in offspring. Birth defects research Carmichael, S. L., Ma, C., Van Zutphen, A. R., Moore, C. A., Shaw, G. M., National Birth Defects Prevention Study 2018

  Abstract

  INTRODUCTION: We examined the association of biliary atresia with maternal dietary intake, using National Birth Defects Prevention Study (NBDPS) data from 152 cases and 11,112 nonmalformed controls born 1997-2011.METHODS: NBDPS is a multisite, population-based case-control study. Exposure data were from maternal telephone interviews, which included a food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were generated from logistic regression models that included nutritional factors as continuous variables and were adjusted for energy intake only or energy intake plus covariates (maternal race-ethnicity, education, age, prepregnancy body mass index, vitamin/mineral supplement intake, conception during summer). Models included a quadratic term for the nutrient if p<0.10. ORs reflect odds of having biliary atresia for nutrient values at the 75th compared to 25th percentile values of each nutrient, based on distributions among controls.RESULTS: ORs for which the 95% CI excluded 1.00 were energy-adjusted ORs for calcium (0.63), protein (0.65), riboflavin (0.71), and diet quality index (0.69), and fully adjusted ORs for calcium (0.68) and vitamin E (0.72). ORs that were fully adjusted for covariates tended to be closer to 1.0 than ORs adjusted only for energy intake. ORs for the other studied nutrients had 95% CIs that included 1.00.CONCLUSIONS: NBDPS is the first study to include detailed information on maternal dietary intake and risk of biliary atresia. Our results suggest reduced risks associated with some nutrients, which may provide etiologic clues but should be interpreted with caution given the small number of cases and novelty of the investigation.

  View details for PubMedID 29762915

• 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

• Genetic variation in biotransformation enzymes, air pollution exposures, and risk of spina bifida AMERICAN JOURNAL OF MEDICAL GENETICS PART A Padula, A. M., Yang, W., Schultz, K., Lurmann, F., Hammond, S., Shaw, G. M. 2018; 176 (5): 1055–90

  Abstract

  Spina bifida is a birth defect characterized by incomplete closure of the embryonic neural tube. Genetic factors as well as environmental factors have been observed to influence risks for spina bifida. Few studies have investigated possible gene-environment interactions that could contribute to spina bifida risk. The aim of this study is to examine the interaction between gene variants in biotransformation enzyme pathways and ambient air pollution exposures and risk of spina bifida. We evaluated the role of air pollution exposure during pregnancy and gene variants of biotransformation enzymes from bloodspots and buccal cells in a California population-based case-control (86 cases of spina bifida and 208 non-malformed controls) study. We considered race/ethnicity and folic acid vitamin use as potential effect modifiers and adjusted for those factors and smoking. We observed gene-environment interactions between each of the five pollutants and several gene variants: NO (ABCC2), NO2 (ABCC2, SLC01B1), PM10 (ABCC2, CYP1A1, CYP2B6, CYP2C19, CYP2D6, NAT2, SLC01B1, SLC01B3), PM2.5 (CYP1A1 and CYP1A2). These analyses show positive interactions between air pollution exposure during early pregnancy and gene variants associated with metabolizing enzymes. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of pollution.

  View details for PubMedID 29681089

• 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

• 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

• Demographic Characteristics and Outcomes of Pregnancies among Homeless Women in California. Spiegel, A. M., Sie, L., Sherwin, K. B., St Martin, B. S., Girsen, A. I., Shaw, G. M., Lee, H. C., El-Sayed, Y. Y. SAGE PUBLICATIONS INC. 2018: 87A

  View details for Web of Science ID 000429928200091

• Neonatal Outcomes of Pregnancies Complicated by Maternal Homelessness in California. Spiegel, A. M., Sie, L., Sherwin, K. B., St Martin, B. S., Girsen, A. I., Shaw, G. M., Lee, H. C., El-Sayed, Y. Y. SAGE PUBLICATIONS INC. 2018: 135A

  View details for Web of Science ID 000429928200237

• 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

• 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

• 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

• 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

• Congenital heart disease complexity and childhood cancer risk. Birth defects research Collins, R. T., Von Behren, J. n., Yang, W. n., Carmichael, S. L., Reynolds, P. n., Fisher, P. G., Shaw, G. M. 2018; 110 (17): 1314–21

  Abstract

  Childhood cancer is increased in those with birth defects, including those with congenital heart disease (CHD). Lymphoma risk is increased in children with CHD. This study analyzes the effect of CHD and CHD severity on childhood cancer risk.We analyzed cancer risk in a population-based cohort of children with and without CHD born between 1988 and 2004 by linking data from the California Birth Defects Monitoring Program with data from the California Cancer Registry. We compared cancer risk in children with and without CHD, excluding children with chromosomal anomalies.Of >3 million children in the birth cohort, 65,585 had birth defects (2%), 25,981 with CHD. Cancer occurred in 4,781 (0.15%) children, 43 (0.17%) with CHD. Cancer risk in CHD was increased (hazard ratio [HR]) 2.63, 95% CI: 1.95, 3.55). Leukemia was the most common cancer in those without CHD (1,722/4,738, 36%), central nervous system tumors were second (1,073/4,738, 23%), and lymphoma third (410/4,738, 9%). Among children with CHD, lymphoma and leukemia occurred with the same frequency (12/43, 28% for each). HR for lymphoma was 8.37 (CI: 4.71, 14.86) with CHD versus without. HR for leukemia was 2.05 (CI: 1.16, 3.61) with CHD versus without. CHD complexity was higher in lymphoma (3, interquartile range [IQR]: 2-3) than those with leukemia (1, IQR, 1-2; p < .02).Cancer risk is increased in children with CHD. Lymphoma risk is increased in CHD and is correlated with more complex CHD. These results suggest a shared developmental origin for CHD and lymphoma may be present.

  View details for PubMedID 30328285

• Antioxidant Consumption is Associated with Decreased Odds of Congenital Limb Deficiencies PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Pace, N. D., Desrosiers, T. A., Carmichael, S. L., Shaw, G. M., Olshan, A. F., Siega-Riz, A., Natl Birth Defects Prevention Stud 2018; 32 (1): 90–99

  Abstract

  Approximately 1 in 2000 infants is born with a limb deficiency in the US. Research has shown that women's periconceptional diet and use of vitamin supplements can affect risk of birth defects. We investigated whether maternal consumption of nutritional antioxidants was associated with occurrence of transverse limb deficiency (TLD) and longitudinal limb deficiencies (LLD).We analysed case-control data from mothers and their singleton infants with TLD (n = 566), LLD (n = 339), or no malformation (controls; n = 9384) in the National Birth Defects Prevention Study (1997-2009). Using a modified food frequency, we estimated usual pre-pregnancy antioxidant consumption by total fruit and vegetable consumption (in grams) grouped into tertiles, and cumulative antioxidant score (ranging from 1 to 10) based on consumption of three antioxidants: beta-carotene, lycopene, and lutein. We estimated odds ratios (OR) adjusted for maternal age, race/ethnicity, education, smoking, alcohol use, body mass index, and total energy.Compared to women in the lowest tertile of fruit and vegetable consumption, women in the highest tertile were less likely to have infants with TLD (OR 0.74, 95% CI 0.57, 0.96) or LLD (OR 0.82, 95% CI 0.59, 1.13). Compared to the lowest antioxidant consumption score of 1, those with the highest score of 10 had ORs of 0.68 (95% CI 0.48, 0.95) for TLD and 0.77 (95% CI 0.50, 1.17) for LLD.Dietary intake of antioxidants was associated with reduced odds of limb deficiencies. These findings add further evidence for women's periconceptional diet reducing occurrence of some birth defects.

  View details for PubMedID 28869773

  View details for PubMedCentralID PMC5771883

• First Trimester Plasma Glucose Values in Women without Diabetes are Associated with Risk for Congenital Heart Disease in Offspring. The Journal of pediatrics Helle, E. I., Biegley, P. n., Knowles, J. W., Leader, J. B., Pendergrass, S. n., Yang, W. n., Reaven, G. R., Shaw, G. M., Ritchie, M. n., Priest, J. R. 2018; 195: 275–78

  Abstract

  In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes.

  View details for PubMedID 29254757

  View details for PubMedCentralID PMC5869072

• Copy number variants in Ebstein anomaly PLOS ONE Giannakou, A., Sicko, R. J., Zhang, W., Romitti, P., Browne, M. L., Caggana, M., Brody, L. C., Jelliffe-Pawlowski, L., Shaw, G. M., Kay, D. M., Mills, J. L. 2017; 12 (12): e0188168

  Abstract

  Ebstein anomaly (EA) is a rare congenital defect characterized by apical displacement of the septal tricuspid leaflets and atrialization of the right ventricle. The etiology of EA is unclear; however, recurrence in families and the association of EA with genetic syndromes and copy number variants (CNVs) suggest a genetic component.We performed a population-based study to search for recurrent and novel CNVs in a previously unreported set of EA cases.We genotyped 60 EA cases identified from all live births (2,891,076) from selected California counties (1991-2010) using the Illumina HumanOmni2.5-8 array. We identified 38 candidate CNVs in 28 (46%) cases and prioritized and validated 11 CNVs based on the genes included.Five CNVs (41%) overlapped or were close to genes involved in early myocardial development, including NODAL, PDLIM5, SIX1, ASF1A and FGF12. We also replicated a previous association of EA with CNVs at 1p34.1 and AKAP12. Finally, we identified four CNVs overlapping or in close proximity to the transcription factors HES3, TRIM71, CUX1 and EIF4EBP2.This study supports the relationship of genetic factors to EA and demonstrates that defects in cardiomyocytes and myocardium differentiation may play a role. Abnormal differentiation of cardiomyocytes and how genetic factors contribute should be examined for their association with EA.

  View details for PubMedID 29216221

• 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

• Population-based case-control study of the association between weather-related extreme heat events and neural tube defects BIRTH DEFECTS RESEARCH Soim, A., Lin, S., Sheridan, S. C., Hwang, S., Hsu, W., Luben, T. J., Shaw, G. M., Feldkamp, M. L., Romitti, P. A., Reefhuis, J., Langlois, P. H., Browne, M. L., Natl Birth Defects Prevention 2017; 109 (18): 1482–93

  Abstract

  Elevated body core temperature has been shown to have teratogenic effects in animal studies. Our study evaluated the association between weather-related extreme heat events (EHEs) in the summer season and neural tube defects (NTDs), and further investigated whether pregnant women with a high pregestational body mass index (BMI) have a greater risk of having a child with NTDs associated with exposure to EHE than women with a normal BMI.We conducted a population-based case-control study among mothers of infants with NTDs and mothers of infants without major birth defects, who participated in the National Birth Defects Prevention Study and had at least 1 day of the third or fourth week postconception during summer months. EHEs were defined using the 95th and the 90th percentiles of the daily maximum universal apparent temperature. Adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression models with Firth's penalized likelihood method while controlling for other known risk factors.Overall, we did not observe a significant association between EHEs and NTDs. At the climate region level, consistently elevated but not statistically significant estimates were observed for at least 2 consecutive days with daily universal apparent maximum temperature above the 95th percentile of the UATmax distribution for the season, year, and weather monitoring station in New York (Northeast), North Carolina and Georgia (Southeast), and Iowa (Upper Midwest). No effect modification by BMI was observed.EHEs occurring during the relevant developmental window of embryogenesis do not appear to appreciably affect the risk of NTDs. Future studies should refine exposure assessment, and more completely account for maternal activities that may modify the effects of weather exposure. Birth Defects Research 109:1482-1493, 2017.© 2017 Wiley Periodicals, Inc.

  View details for PubMedID 28766872

• 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

• Preterm Delivery Phenotypes in SLE Pregnancies Simard, J. F., Chaichian, Y., Rossides, M., Wikstrom, A., Shaw, G. M., Druzin, M. WILEY. 2017

  View details for Web of Science ID 000411824102208

• Maternal Exposure to Nitrogen Dioxide, Intake of Methyl Nutrients, and Congenital Heart Defects in Offspring AMERICAN JOURNAL OF EPIDEMIOLOGY Stingone, J. A., Luben, T. J., Carmichael, S. L., Aylsworth, A. S., Botto, L. D., Correa, A., Gilboa, S. M., Langlois, P. H., Nembhard, W. N., Richmond-Bryant, J., Shaw, G. M., Olshan, A. F., Natl Birth Defects Prevention 2017; 186 (6): 719–29

  Abstract

  Nutrients that regulate methylation processes may modify susceptibility to the effects of air pollutants. Data from the National Birth Defects Prevention Study (United States, 1997-2006) were used to estimate associations between maternal exposure to nitrogen dioxide (NO2), dietary intake of methyl nutrients, and the odds of congenital heart defects in offspring. NO2 concentrations, a marker of traffic-related air pollution, averaged across postconception weeks 2-8, were assigned to 6,160 nondiabetic mothers of cases and controls using inverse distance-squared weighting of air monitors within 50 km of maternal residences. Intakes of choline, folate, methionine, and vitamins B6 and B12 were assessed using a food frequency questionnaire. Hierarchical regression models, which accounted for similarities across defects, were constructed, and relative excess risks due to interaction were calculated. Relative to women with the lowest NO2 exposure and high methionine intake, women with the highest NO2 exposure and lowest methionine intake had the greatest odds of offspring with a perimembranous ventricular septal defect (odds ratio = 3.23, 95% confidence interval: 1.74, 6.01; relative excess risk due to interaction = 2.15, 95% confidence interval: 0.39, 3.92). Considerable departure from additivity was not observed for other defects. These results provide modest evidence of interaction between nutrition and NO2 exposure during pregnancy.

  View details for DOI 10.1093/aje/kwx139

  View details for Web of Science ID 000410728500012

  View details for PubMedID 28520847

  View details for PubMedCentralID PMC5610640

• 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

• A Multivariate Dynamic Spatial Factor Model for Speciated Pollutants and Adverse Birth Outcomes INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH Kaufeld, K. A., Fuentes, M., Reich, B. J., Herring, A. H., Shaw, G. M., Terres, M. A. 2017; 14 (9)

  Abstract

  Evidence suggests that exposure to elevated concentrations of air pollution during pregnancy is associated with increased risks of birth defects and other adverse birth outcomes. While current regulations put limits on total PM2.5 concentrations, there are many speciated pollutants within this size class that likely have distinct effects on perinatal health. However, due to correlations between these speciated pollutants, it can be difficult to decipher their effects in a model for birth outcomes. To combat this difficulty, we develop a multivariate spatio-temporal Bayesian model for speciated particulate matter using dynamic spatial factors. These spatial factors can then be interpolated to the pregnant women's homes to be used to model birth defects. The birth defect model allows the impact of pollutants to vary across different weeks of the pregnancy in order to identify susceptible periods. The proposed methodology is illustrated using pollutant monitoring data from the Environmental Protection Agency and birth records from the National Birth Defect Prevention Study.

  View details for PubMedID 28891988

• 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

• 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

• Cohort Variation in Selection During Pregnancy and Risk of Selected Birth Defects Among Males. Epidemiology Bruckner, T. A., Karasek, D., Yang, W., Shaw, G. M., Catalano, R. A. 2017; 28 (4): 580-586

  Abstract

  The literature theorizes, but does not test, that variation over time in selective loss in utero affects the observed count of live-born birth defects cases. We test the hypothesis that the risk of birth defects among live-born males varies inversely with the strength of selection against males in utero.We identified a subset of six birth defect phenotypes among males from the California Birth Defects Monitoring Program, an active surveillance system for over 490,000 male singletons born in eight California counties from 1986 to 2004. We assigned each birth defect case infant to a monthly conception cohort at risk of selection in utero. We used the monthly sex ratio at birth (M:F), derived from each conception cohort, as the indicator of selection against males. We analyzed the odds ratio of birth defects with both individual-level logistic regression and aggregate time-series methods.Consistent with selection in utero, male infants from conception cohorts with low outlying sex ratios (i.e., stronger selectivity) exhibit fewer than expected birth defects (adjusted odds ratio [OR] = 0.86; 95% confidence interval [CI] = 0.76, 0.98). Aggregate time-series tests also yield similar findings (OR = 0.81; 95% CI = 0.71, 0.90).Our findings among males indicate that variation in the strength of selectivity in utero accounts for a portion of observed cohort differences in morbidity due to birth defects. These findings suggest that "revealed prevalence" of morbidity across birth cohorts varies, at least in part, from selective loss in utero. See video abstract at, http://links.lww.com/EDE/B209.

  View details for DOI 10.1097/EDE.0000000000000661

  View details for PubMedID 28346269

• 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

• The association of maternal lymphatic markers and critical congenital heart defects in the fetus-A population based case-control study AMERICAN JOURNAL OF MEDICAL GENETICS PART A Steurer, M. A., Norton, M. E., Baer, R. J., Shaw, G. M., Keating, S., Moon-Grady, A. J., Chambers, C. D., Jelliffe-Pawlowski, L. L. 2017; 173 (5): 1231-1236

  Abstract

  The objective ot this study was to investigate whether lymphatic markers measured in women during the second trimester are associated with critical congenital heart defects (CCHDs) in offspring. This is a retrospective cohort study of pregnant women who participated in the California Prenatal Screening Program. CCHD data in the offspring was captured by linking birth certificate data with hospital patient discharge records. Second trimester samples were assayed for vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) AA/BB, and PDGF AB. Logistic models were used to evaluate the association between lymphatic biomarkers and CCHD. Models were adjusted for other serum biomarkers and maternal characteristics. Results are presented in odds ratios (OR) with 95% confidence intervals (CI). We identified 93 cases with CCHDs and 194 controls without CCHDs. The crude and adjusted OR for log (ln) VEGF was 1.07 (95%CI 0.94-1.22) and 1.08 (95%CI 0.94-1.24), respectively; for ln PDGF AB/BB was 0.93 (95%CI 0.6-1.35) and 0.58 (95%CI 0.32-1.05), respectively. There was a significant association between ln PDFG AA and CCHDs (crude OR 1.83 (95%CI 1.05-3.2); adjusted OR 2.41 (95%CI 1.06-5.44)). Levels of circulating PDGF AA were highest in cases with hypoplastic left heart syndrome (HLHS) (mean 8.78 +/- 1.54 pg/ml). In this study, increased mid-pregnancy maternal serum levels of PDGF AA were associated with CCHDs in offspring. The highest PDGF AA levels were found in mothers of fetuses with HLHS. These findings may be useful in screening for CCHDs and offer insight into their association with nuchal translucency.

  View details for DOI 10.1002/ajmg.a.38152

  View details for Web of Science ID 000399691500015

  View details for PubMedID 28323386

• . 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

• Air pollution, neighborhood acculturation factors, and neural tube defects among Hispanic women in California BIRTH DEFECTS RESEARCH Padula, A. M., Yang, W., Carmichael, S. L., Lurmann, F., Balmes, J., Hammond, S. K., Shaw, G. M. 2017; 109 (6): 403-422

  Abstract

  Neural tube defects (NTDs) are one of the most common types of birth defects. Environmental pollutants and acculturation have been associated with NTDs independently. The potential effect modification of acculturation in the relationship between ambient air pollution and risks of NTDs is not well understood.We investigated whether associations between traffic-related air pollutant exposure in early gestation and NTDs, and more specifically spina bifida, were modified by individual and neighborhood acculturation factors among 139 cases and 466 controls born in the San Joaquin Valley of California, 1997 to 2006. Five criteria pollutant exposures in tertiles, two outcomes, and seven neighborhood acculturation factors from the U.S. Census at the block group level were included for a total of 280 investigated associations. Estimates were adjusted for maternal education and multivitamin use in the first 2 months of pregnancy. Additional analyses were stratified by nativity.Increased odds of NTDs were observed for individuals who had high exposures to carbon monoxide, nitrogen oxide, or nitrogen dioxide and lived in neighborhoods that were more acculturated. Conversely, there were increased odds of NTDs for those who had high prenatal exposure to PM10 and lived in neighborhoods that were less acculturated. The results of spina bifida alone were generally stronger in magnitude. When stratified by individual nativity (U.S.- vs. foreign-born), carbon monoxide, nitrogen oxide, and nitrogen dioxide were more strongly associated with NTDs among U.S.-born Hispanic mothers.Neighborhood acculturation factors were modifiers of the relationship between air pollution and NTDs in California, though not in a consistent direction for all pollutants. Birth Defects Research 109:403-422, 2017. © 2017 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23602

  View details for Web of Science ID 000398804400001

  View details for PubMedID 28398703

• 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

• 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

• Acute Fatty Liver of Pregnancy and Risk of Preterm Birth. Foeller, M. E., Mayo, J., Yeaton-Massey, A., Girsen, A., Do, S., Ness, A., Shaw, G., El-Sayed, Y., Druzin, M. SAGE PUBLICATIONS INC. 2017: 246A–247A

  View details for Web of Science ID 000399043900621

• 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

• An Electronic Health Record Investigation of Lenticulostriate Vasculopathy Features. American journal of perinatology Frankovich, J., Egan, M., Mahony, T., Benitz, W., Shaw, G. 2017; 34 (3): 253-258

  Abstract

  Objective Lenticulostriate vasculopathy (LSV) is characterized by linear hyperechogenicities in the basal ganglia found on the head ultrasounds of infants. We reviewed electronic health records of infants with and without LSV to investigate whether physician dictations indicated symptoms which could reflect subtle basal ganglia injury. Study Design In a case-control study, we analyzed data from 46 infants with LSV and 127 controls. Infants were stratified between term and preterm birth. Odds ratios (ORs) and 95% confidence intervals were calculated for tone abnormalities, apnea, feeding difficulties, seizures, and movement abnormalities in the presence of LSV. Results Both term and preterm infants with LSV showed elevated risks for tone abnormalities (OR: 3.6 and 2.9, respectively). Term infants with LSV showed elevated risks for hypotonia (OR: 4.3), apnea (OR: 2.9), and feeding difficulties (OR: 4.1). Preterm infants with LSV showed elevated risks for truncal hypotonia (OR: 3.9) and hyperreflexia (OR: 3.9). Conclusion Our findings provide some evidence that LSV is associated with an increased risk of early signs of abnormal development, possibly relating to signs of subtle basal ganglia injury. Historically LSV has been considered incidental. The associations identified here suggest that LSV findings are worthy of further study.

  View details for DOI 10.1055/s-0036-1585417

  View details for PubMedID 27471823

• Maternal underweight and obesity and risk of orofacial clefts in a large international consortium of population-based studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Kutbi, H., Wehby, G. L., Uribe, L., Romitti, P. A., Carmichael, S., Shaw, G. M., Olshan, A. F., DeRoo, L., Rasmussen, S. A., Murray, J. C., Wilcox, A., Lie, R. T., Munger, R. G. 2017; 46 (1): 190–99

  Abstract

  Evidence on association of maternal pre-pregnancy weight with risk of orofacial clefts is inconsistent.Six large case-control studies of orofacial clefts from Northern Europe and the USA were included in analyses pooling individual-level data. Cases included 4943 mothers of children with orofacial clefts (cleft lip only: 1135, cleft palate with cleft lip: 2081, cleft palate only: 1727) and controls included 10 592 mothers of unaffected children. Association of orofacial cleft risk with pre-pregnancy maternal weight classified by level of body mass index (BMI, kg/m 2 ) was evaluated using logistic regression adjusting for multiple covariates.Cleft palate, both alone and with cleft lip (CP+/-CL), was associated with maternal class II+ pre-pregnancy obesity (≥ 35)compared with normal weight [adjusted odds ratio (aOR) = 1.36; 95% confidence interval (CI) = 1.16, 1.58]. CP+/-CL was marginally associated with maternal underweight (aOR = 1.16; 95% CI = 0.98, 1.36). Cleft lip alone was not associated with BMI.In this largest population-based study to date, we found an increased risk of cleft palate, with or without cleft lip, in class II+ obese mothers compared with normal-weight mothers; underweight mothers may also have an increased risk, but this requires further study. These results also suggest that extremes of weight may have a specific effect on palatal development.

  View details for PubMedID 27215617

  View details for PubMedCentralID PMC5837498

• 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

• 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

• An Investigation of Connections between Birth Defects and Cancers Arising in Adolescence and Very Young Adulthood. The Journal of pediatrics Von Behren, J. n., Fisher, P. G., Carmichael, S. L., Shaw, G. M., Reynolds, P. n. 2017; 185: 237–40

  Abstract

  This study investigated the relationship between birth defects and cancer in adolescents and very young adults using California's population-based registries. Although overall cancer risk was elevated among individuals with chromosomal birth defects, this was not observed in those with nonchromosomal birth defects, as was demonstrated previously in younger children.

  View details for PubMedID 28336146

• Maternal Stressors and Social Support and Risks of Delivering Babies With Gastroschisis or Hypospadias. American journal of epidemiology Carmichael, S. L., Ma, C. n., Tinker, S. n., Shaw, G. M. 2017; 185 (12): 1240–46

  Abstract

  We examined the association of maternal stressful life events and social support with risks of gastroschisis and hypospadias, using data from the National Birth Defects Prevention Study, a population-based case-control study of US births taking place in 2006-2011. We examined maternal self-reports of 7 life events and 3 sources of social support during the periconceptional period among mothers of 593 gastroschisis cases, 1,142 male hypospadias cases, and 4,399 nonmalformed controls. Responses to the questions on stressful life events were summed to form an index (higher is worse), as were responses to questions on social support (higher is better). We used logistic regression to estimate adjusted odds ratios and 95% confidence intervals. The adjusted odds ratios for gastroschisis for a 4-point increase in the stress index were 3.5 (95% confidence interval (CI): 2.6, 4.8) among nonteenage mothers (age ≥20 years) and 1.0 (95% CI: 0.5, 1.7) among teenage mothers (age <20 years). The odds ratio for hypospadias (among all mothers) was 0.8 (95% CI: 0.7, 1.1). Adjusted odds ratios for a social support score of 3 (versus 0) in the 3 respective groups were 0.6 (95% CI: 0.4, 1.0), 1.0 (95% CI: 0.5, 2.3), and 0.6 (95% CI: 0.4, 0.9). Given the lack of prior research on these outcomes and stress, results should be interpreted with caution.

  View details for PubMedID 28505275

• Maternal Smoking, Alcohol, and Caffeine Exposures and Risk of Hypospadias. Birth defects research Carmichael, S. L., Ma, C. n., Shaw, G. M. 2017; 109 (14): 1127–33

  Abstract

  We examined the association of hypospadias risk with maternal smoking and consumption of alcohol and caffeine.We analyzed data from mothers of 2437 moderate/severe cases and 5472 nonmalformed controls born from 1997 to 2011 who participated in the National Birth Defects Prevention Study (NBDPS). Exposures were assessed by maternal telephone interviews. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for mother's age, parity, race-ethnicity, education, vitamin/mineral supplement intake, obesity, and study center.Active smoking during the first month of pregnancy was associated with reduced risk, with smaller ORs for increasing quantity smoked; the OR for smoking >1/2 pack/day was 0.7 (95% CI, 0.5-0.9). Among nonsmokers, the OR for any secondhand smoke exposure was 0.8 (95% CI, 0.7-0.9). ORs for alcohol and caffeine consumption were near one and CIs included 1.0. In an analysis of joint exposures to smoking and alcohol and caffeine consumption, the only OR for which the 95% CI excluded 1.0 was for women who smoked, drank, and had low caffeine consumption (OR, 0.6; 95% CI, 0.4-0.8).Maternal exposure to cigarette smoke was associated with reduced risk, and women who smoked, drank, and had low caffeine intake were at lowest risk. We do not interpret these results to suggest that these exposures have overall benefit to a pregnant woman or developing fetus. They may, however, offer clues to help us understand mechanisms that lead to hypospadias. Birth Defects Research 109:1127-1133, 2017. © 2017 Wiley Periodicals, Inc.

  View details for PubMedID 28635116

• DNA Methylome Profiling on the Infinium HumanMethylation450 Array from Limiting Quantities of Genomic DNA from a Single, Small Archived Bloodspot. Genetic testing and molecular biomarkers Asrani, K. n., Shaw, G. M., Rine, J. n., Marini, N. J. 2017; 21 (8): 516–19

  Abstract

  Archived newborn bloodspots are valuable sample collections for genetic and epigenetic disease research. However, they have often been stored for long periods of time, under less than ideal circumstances, and nucleic acid yields can be low, particularly when samples become limiting. We wished to determine whether the quantity and quality of genomic DNA (gDNA) isolated from a single, surgical bloodspot punch (2 mm dia.) was adequate for accurate and reliable DNA methylome profiling on the Illumina HumanMethylation450 array.A total of 25-750 ng of archived bloodspot or Jurkat cell gDNA were bisulfite converted and analyzed on the array without any additional DNA amplification steps. Methylation profiles were assessed for call rate, call confidence (detection p-value), and reproducibility.Using 25 ng gDNA from either Jurkat cells or dried bloodspots, array-wide call rates (∼99.9%) and detection p-values (99.9% with p < 5 × 10-6) were excellent. There was good agreement between methylation profiles generated from 25 ng gDNA and those generated from 750 ng (ρ > 0.98), although a fraction of CpG sites (2-8% depending on experiment) exhibited quantitative differences. Genome-wide methylation levels were strikingly reproducible from 25 ng DNA in both replicate and interindividual samples (ρ > 0.98).Twenty-five nanograms of gDNA, isolated from a single, surgical punch (2 mm dia.) of an archived newborn bloodspot, generate a genome-wide methylation profile on the Illumina HumanMethylation450 array that is robust, reproducible, and suitable for differential methylation studies.

  View details for PubMedID 28609193

  View details for PubMedCentralID PMC5568181

• Selected birth defects among males following the United States terrorist attacks of 11 September 2001. Birth defects research Singh, P. n., Yang, W. n., Shaw, G. M., Catalano, R. n., Bruckner, T. A. 2017; 109 (16): 1277–83

  Abstract

  The terrorist attacks of 11 September 2001 (hereafter referred to as 9/11) preceded an increase in male fetal deaths and reduced male live births among exposed gestational cohorts across several geographic locations in the United States, including California. We analyze whether the extreme stressor of 9/11 may have selected against frail males in utero by testing if the prevalence of male births with selected defects in California fell among cohorts exposed to the stressor during gestation.We used data from the California Birth Defects Monitoring Program from July 1985 to January 2004 (223 conception cohorts). We included six birth defects that as a group of phenotypes disproportionately affect males. We applied time-series methods and defined as "exposed to 9/11" the cohorts conceived in February, March, April, May, June, July, and August 2001.Three of the seven monthly conception cohorts exposed to 9/11 in utero show lower than expected odds of live born males with the studied defects: February 2001 (odds ratio [OR] = 0.39; 95% confidence interval [CI], 0.21-0.71), May 2001 (OR = 0.36; 95% CI, 0.16-0.81), and August 2001 (OR = 0.51; 95% CI, 0.28-0.93).The population-wide stressor of 9/11 precedes a reduction in the risk of live born males with selected birth defects. Our analysis contributes to the understanding of adaptation to stress among pregnant women exposed to large and unexpected ambient stressors. Results further support the notion that the prevalence of live born defects may reflect temporal variation in cohort selection in utero against frail males. Birth Defects Research 109:1277-1283, 2017. © 2017 Wiley Periodicals, Inc.

  View details for PubMedID 28722355

• Vasa previa and extreme prematurity Yeaton-Massey, A., Girsen, A. I., Mayo, J., Blumenfeld, Y. J., El-Sayed, Y. Y., Shaw, G. M., March Dimes Prematurity Res Ctr MOSBY-ELSEVIER. 2017: S419

  View details for Web of Science ID 000414256403036

• 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

• 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

• 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

• 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 PubMedID 27718495

• 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. 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

• Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways HUMAN GENETICS Hagen, E. M., Sicko, R. J., Kay, D. M., Rigler, S. L., Dimopoulos, A., Ahmad, S., Doleman, M. H., Fan, R., Romitti, P. A., Browne, M. L., Caggana, M., Brody, L. C., Shaw, G. M., Jelliffe-Pawlowski, L. L., Mills, J. L. 2016; 135 (12): 1355-1364

  Abstract

  Classic heterotaxy consists of congenital heart defects with abnormally positioned thoracic and abdominal organs. We aimed to uncover novel, genomic copy-number variants (CNVs) in classic heterotaxy cases. A microarray containing 2.5 million single-nucleotide polymorphisms (SNPs) was used to genotype 69 infants (cases) with classic heterotaxy identified from California live births from 1998 to 2009. CNVs were identified using the PennCNV software. We identified 56 rare CNVs encompassing genes in the NODAL (NIPBL, TBX6), BMP (PPP4C), and WNT (FZD3) signaling pathways, not previously linked to classic heterotaxy. We also identified a CNV involving FGF12, a gene previously noted in a classic heterotaxy case. CNVs involving RBFOX1 and near MIR302F were detected in multiple cases. Our findings illustrate the importance of body patterning pathways for cardiac development and left/right axes determination. FGF12, RBFOX1, and MIR302F could be important in human heterotaxy, because they were noted in multiple cases. Further investigation into genes involved in the NODAL, BMP, and WNT body patterning pathways and into the dosage effects of FGF12, RBFOX1, and MIR302F is warranted.

  View details for DOI 10.1007/s00439-016-1727-x

  View details for Web of Science ID 000385345900004

  View details for PubMedID 27637763

  View details for PubMedCentralID PMC5065782

• Folic acid fortification and prevalences of neural tube defects, orofacial clefts, and gastroschisis in California, 1989 to 2010. Birth defects research. Part A, Clinical and molecular teratology Yang, W., Carmichael, S. L., Shaw, G. M. 2016; 106 (12): 1032-1041

  Abstract

  We examined whether prevalences of neural tube defects (NTDs), orofacial clefts, and gastroschisis changed more rapidly after than before folic acid fortification in California.This population-based study used vital statistics and birth defects registry data. The study population included all live births and stillbirths delivered in central California counties from 1989 to 2010. Cases included deliveries with NTDs, orofacial clefts, and gastroschisis. Weighted least squares regression was used to estimate slopes during prefortification (before 1997) and postfortification (after 1998), respectively. The difference of the two slopes with the 95% confidence interval (CI) was calculated.For all NTDs combined, slopes indicated that NTD prevalence was decreasing by 8.7 (slope: -8.7; 95% CI, -13.5--3.9) cases per 100,000 deliveries per year before fortification and by 1.7 (slope: -1.7; 95% CI, -3.7-0.3) after fortification; thus the decline had slowed by 7.0 (95% CI, 2.7-11.3) cases per 100,000 deliveries per year. For orofacial clefts, slopes for cleft lip with/without palate as well as for cleft palate alone indicated that the postfortification slope was lower than the prefortification slope suggesting a more accelerated decrease in the postfortification time period. For gastroschisis, the slope after fortification was lower compared with prefortification, indicating a less accelerated prevalence increase in the postfortification time period. Stratification by race/ethnicity did not substantially alter results.We observed a slower decline in prevalence of NTDs, an emergence of a decline in orofacial clefts, and a slower increase in gastroschisis, during the postfortification period in central California, relative to the prefortification period. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1032-1041, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23514

  View details for PubMedID 27191125

• 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

• Paternal and Joint Parental Occupational Pesticide Exposure and Spina Bifida in the National Birth Defects Prevention Study, 1997 to 2002 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Pettigrew, S. M., Bell, E. M., Van Zutphen, A. R., Rocheleau, C. M., Shaw, G. M., Romitti, P. A., Olshan, A., Lupo, P. J., Soim, A., Makelarski, J. A., Michalski, A. M., Sanderson, W. 2016; 106 (11): 963-971

  Abstract

  Because of persistent concerns over the association between pesticides and spina bifida, we examined the role of paternal and combined parental occupational pesticide exposures in spina bifida in offspring using data from a large population-based study of birth defects.Occupational information from fathers of 291 spina bifida cases and 2745 unaffected live born control infants with estimated dates of delivery from 1997 to 2002 were collected by means of maternal report. Two expert industrial hygienists estimated exposure intensity and frequency to insecticides, herbicides, and fungicides. Multivariable logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for exposure to any pesticide and to any class of pesticide (yes/no; and by median), and exposure to combinations of pesticides (yes/no) and risk of spina bifida. Adjusted odds ratios were also estimated by parent exposed to pesticides (neither, mother only, father only, both parents).Joint parental occupational pesticide exposure was positively associated with spina bifida (aOR, 1.5; 95% CI, 0.9-2.4) when compared with infants with neither maternal nor paternal exposures; a similar association was not observed when only one parent was exposed. There was a suggested positive association between combined paternal insecticide and fungicide exposures and spina bifida (aOR, 1.5; 95% CI, 0.8-2.8), however, nearly all other aORs were close to unity.Overall, there was little evidence paternal occupational pesticide exposure was associated with spina bifida. However, the small numbers make it difficult to precisely evaluate the role of pesticide classes, individually and in combination. Birth Defects Research (Part A) 106:963-971, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23551

  View details for Web of Science ID 000392817500013

  View details for PubMedID 27891778

• 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

• Sequence variation in folate pathway genes and risks of human cleft lip with or without cleft palate. American journal of medical genetics. Part A Marini, N. J., Yang, W., Asrani, K., Witte, J. S., Rine, J., Lammer, E. J., Shaw, G. M. 2016; 170 (11): 2777-2787

  Abstract

  In an effort to comprehensively interrogate genetic variation in the folate pathway for risk of cleft lip with or without cleft palate (CLP), we evaluated 504 common and rare variants in 35 folate-related genes in a panel of 330 infants with CLP and 367 non-malformed controls. Odds ratios (OR) with 95% confidence intervals were computed for common genotypes. A Case-Control Difference metric was calculated for rare variants to highlight differentially occurring alleles. Interactions between variants and a maternal folate intake variable were also evaluated. In gene-only results, significant odds ratios were observed for multiple variants in the BHMT/BHMT2/DMGDH gene cluster, particularly in Hispanic infants. Also in this cluster, rare variant analysis highlighted a substantial case-control difference in BHMT rs60340837 (synonymous Y284Y). In Hispanics, the ALDH1L1 I812V variant (rs4646750) was the most significant risk allele: OR = 3.8 (95%CI = 1.6-9.2) when heterozygous. In non-Hispanic white infants, we observed significant risk for AHCYL2 rs1095423 (homozygous OR = 3.0, 95%CI 1.1-7.8) and the 68 bp CBS insertion (c.844ins68; heterozygous OR = 2.4, 95%CI = 1.1-5.3). Rare variant analysis in this group revealed case-control differences in MTRR and several other methionine cycle genes, a process implicated previously in clefting risk. In women with low folate intake specifically, increased risks were observed for CBS rs2851391 (OR = 3.6, 95%CI = 1.3-9.6) and the R259P nonsynonymous variant of TCN2 (rs1801198; OR = 2.8, 95%CI = 1.2-6.3). This comprehensive study provides further direction on candidate loci to help disentangle the folate-related developmental phenomena in human clefting risk. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37874

  View details for PubMedID 27604992

• Gene variants as risk factors for gastroschisis. American journal of medical genetics. Part A Padula, A. M., Yang, W., Schultz, K., Tom, L., Lin, B., Carmichael, S. L., Lammer, E. J., Shaw, G. M. 2016; 170 (11): 2788-2802

  Abstract

  In a population-based case-control study in California of 228 infants, we investigated 75 genetic variants in 20 genes and risk of gastroschisis with regard to maternal age, race/ethnicity, vitamin use, and smoking exposure. We hypothesized that genes related to vascular compromise may interact with environmental factors to affect the risk of gastroschisis. Haplotypes were constructed for 75 gene variants using the HaploView program. Risk for gastroschisis associated with each gene variant was calculated for both the homozygotes and the heterozygotes, with the homozygous wildtypes as the referent. Risks were estimated as odds ratios (ORs) with 95% confidence intervals (CIs) by logistic regression. We found 11 gene variants with increased risk and four variants with decreased risk of gastroschisis for heterozygous (ORh ) or homozygous variants (ORv ) genotypes. These included NOS3 (rs1036145) ORh  = 0.4 (95% CI: 0.2-0.7); NOS3 (rs10277237) ORv  = 2.7 (95% CI: 1.3-6.0); ADD1 (rs12503220) ORh  = 2.9 (95% CI: 1.6-5.4), GNB3 (rs5443) ORh  = 0.2 (95% CI: 0.1-0.5), ORv  = 0.4 (95% CI: 0.2-0.9); ICAM1 (rs281428) ORv  = 6.9 (95% CI: 2.1-22.9), ICAM1 (rs3093030) ORv  = 2.6 (95% CI: 1.2-5.6); ICAM4 (rs281438) ORv  = 4.9 (95% CI: 1.4-16.6), ICAM5 (rs281417) ORh  = 2.1 (95% CI: 1.1-4.1), ORv  = 4.8 (95% CI: 1.7-13.6); ICAM5 (rs281440) ORh  = 23.7 (95% CI: 5.5-102.5), ORv  = 20.6 (95% CI: 3.4-124.3); ICAM5 (rs2075741) ORv  = 2.2 (95% CI: 1.1-4.4); NAT1 ORv  = 0.3 (95% CI: 0.1-0.9). There were additional associations between several gene variants and gastroschisis among women aged 20-24 and among mothers with and without vitamin use. NOS3, ADD1, ICAM1, ICAM4, and ICAM5 warrant further investigation in additional populations and with the interaction of additional environmental exposures. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37883

  View details for PubMedID 27616475

  View details for PubMedCentralID PMC5096035

• Genetic variation of FOXE1 and risk for orofacial clefts in a California population. American journal of medical genetics. Part A Lammer, E. J., Mohammed, N., Iovannisci, D. M., Ma, C., Lidral, A. C., Shaw, G. M. 2016; 170 (11): 2770-2776

  Abstract

  We investigated whether orofacial clefts are associated with polymorphic variation within and around FOXE1. This California population-based case control study focused on white Hispanic and white nonHispanic infants among which there were 262 infants with cleft lip with or without cleft palate (CL/P), 103 with cleft palate only (CPO), and 382 unaffected controls. These cases and controls were genotyped for 13 SNPs across 220 Kb at the FOXE1 Locus. We observed associations with multiple FOXE1 SNPs for CL/P and for CPO, especially for the Hispanic study population. Increased risks were associated with the more common allele for all SNPs tested. Our results implicate FOXE1 as an important locus whose polymorphic variation increases risks for all types of isolated clefts, and opens a new biological pathway to investigate in efforts to understand genetic factors underlying human clefting. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37871

  View details for PubMedID 27604706

• 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

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

  Abstract

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

  View details for DOI 10.1016/j.jpeds.2016.09.030

  View details for PubMedID 27742123

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

  Abstract

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

  View details for DOI 10.3109/14767058.2015.1124083

  View details for PubMedID 26700828

• Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index Confirms Known Associations but Provides No Biologic Explanation for 2/3 of All Preterm Births PLOS ONE Ferrero, D. M., Larson, J., Jacobsson, B., Di Renzo, G. C., Norman, J. E., Martin, J. N., D'alton, M., Castelazo, E., Howson, C. P., Sengpiel, V., Bottai, M., Mayo, J. A., Shaw, G. M., Verdenik, I., Tul, N., Velebil, P., Cairns-Smith, S., Rushwan, H., Arulkumaran, S., Howse, J. L., Simpson, J. L. 2016; 11 (9)

  Abstract

  Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice.We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors.Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6-6.0 and 2.8-5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25-50% and 11-16% of excess population attributable risk, respectively (p<0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted.We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions.

  View details for DOI 10.1371/journal.pone.0162506

  View details for Web of Science ID 000383681000035

  View details for PubMedID 27622562

  View details for PubMedCentralID PMC5021369

• Gastroschisis and maternal intake of phytoestrogens AMERICAN JOURNAL OF MEDICAL GENETICS PART A Wadhwa, E. L., Ma, C., Shaw, G. M., Carmichael, S. L. 2016; 170 (8): 2078-2082

  Abstract

  The prevalence of gastroschisis has increased significantly in the past few decades. The strongest risks have been observed for women <25 years old or of low body mass index, and maternal diet also been proposed to be associated with risk. The objective of this study was to evaluate whether the risk of gastroschisis is associated with maternal dietary intake of phytoestrogens. The analysis includes data on mothers of 409 gastroschisis cases and 3,007 controls who delivered their infants from 2005 to 2010 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. Detailed information was obtained from maternal telephone interviews that included a validated food frequency questionnaire. We conducted logistic regression analyses that included each phytoestrogen in its continuous form (to test for linearity) and quadratic form (to test for non-linearity), adjusted for maternal energy intake, age, BMI, race-ethnicity, and smoking in 1st trimester. Logistic regression analysis indicated that biochanin A, formonoetin, and coumestrol had a significant non-linear association with gastroschisis (P-value <0.05 for quadratic term). Lower intakes were associated with increased risk, with somewhat stronger but relatively modest associations at the lower end of the distribution; for example, the ORs for the 10th versus 50th percentiles ranged from 1.1 to 1.2. Associations were not significant for the other phytoestrogens. This study provides some evidence for association with certain phytoestrogens, after adjusting for covariates. The implications of our findings for clinical practice are uncertain pending other studies examining this association. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37659

  View details for Web of Science ID 000379948400016

  View details for PubMedID 27232448

• 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

• 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

• Joint effects of genetic variants and residential proximity to pesticide applications on hypospadias risk. Birth defects research. Part A, Clinical and molecular teratology Carmichael, S. L., Yang, W., Ma, C., Roberts, E., Kegley, S., English, P., Lammer, E. J., Witte, J. S., Shaw, G. M. 2016; 106 (8): 653-658

  Abstract

  We examined risks associated with joint exposure of gene variants and pesticides.Analyses included 189 cases and 390 male controls born from 1991 to 2003 in California's San Joaquin Valley. We used logistic regression to examine risks associated with joint exposures of gene variants and pesticides that our previous work identified as associated with hypospadias. Genetic variables were based on variants in DGKK, genes involved in sex steroid synthesis/metabolism, and genes involved in genital tubercle development. Pesticide exposure was based on residential proximity to commercial agricultural pesticide applications.Odds ratios (ORs) were highest among babies with joint exposures, who had two- to fourfold increased risks; for example, the OR was 3.7 (95% confidence interval [CI], 0.8-16.5) among subjects with the risk-associated DGKK haplotype and pesticide exposure; OR, 1.5 (95% CI, 0.7-3.1) among subjects with the haplotype and no pesticide exposure; and OR, 0.9 (95% CI, 0.5-1.6) among subjects without the haplotype but with pesticide exposure, relative to subjects with neither. However, results did not provide statistical evidence that these risks were significantly greater than expected on an additive scale, relative to risks associated with one exposure at a time.We observed elevated risks associated with joint exposures to selected pesticides and genetic variants but no statistical evidence for interaction. Birth Defects Research (Part A) 106:653-658, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23508

  View details for PubMedID 27098078

  View details for PubMedCentralID PMC4983249

• Obituary: Dr. Ed Lammer BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Finnell, R. H., Shaw, G. M. 2016; 106 (7): 515-516

  View details for DOI 10.1002/bdra.23524

  View details for Web of Science ID 000382840300001

• The genetic predisposition to bronchopulmonary dysplasia CURRENT OPINION IN PEDIATRICS Yu, K., Li, J., Snyder, M., Shaw, G. M., O'Brodovich, H. M. 2016; 28 (3): 318-323

  Abstract

  Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in premature infants. Twin studies have shown strong heritability underlying this disease; however, the genetic architecture of BPD remains unclear.A number of studies employed different approaches to characterize the genetic aberrations associated with BPD, including candidate gene studies, genome-wide association studies, exome sequencing, integrative omics analysis, and pathway analysis. Candidate gene studies identified a number of genes potentially involved with the development of BPD, but the etiological contribution from each gene is not substantial. Copy number variation studies and three independent genome-wide association studies did not identify genetic variations significantly and consistently associated with BPD. A recent exome-sequencing study pointed to rare variants implicated in the disease. In this review, we summarize these studies' methodology and findings, and suggest future research directions to better understand the genetic underpinnings of this potentially life-long lung disease.Genetic factors play a significant role in the development of BPD. Recent studies suggested that rare variants in genes participating in lung development pathways could contribute to BPD susceptibility.

  View details for DOI 10.1097/MOP.0000000000000344

  View details for Web of Science ID 000376387000010

  View details for PubMedID 26963946

  View details for PubMedCentralID PMC4853271

• 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

• Elevated body mass index and decreased diet quality among women and risk of birth defects in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Yang, W., Gilboa, S., Ailes, E., Correa, A., Botto, L. D., Feldkamp, M. L., Shaw, G. M. 2016; 106 (3): 164-171

  Abstract

  We examined whether risks of 32 birth defects were higher than expected in the presence of overweight or obese body mass index (BMI) and low diet quality, based on estimating individual and joint effects of these factors and calculating relative excess risk due to interaction.Analyses included mothers of 20,250 cases with birth defects and 8617 population-based controls without birth defects born from 1997 to 2009 and interviewed for the National Birth Defects Prevention Study. We used logistic regression to generate adjusted odds ratios (AORs) reflecting the combined effects of BMI and diet quality. We focused analyses on 16 birth defects (n = 11,868 cases, 8617 controls) for which initial results suggested an association with BMI or diet quality.Relative to the reference group (normal weight women with not low diet quality, i.e., >lowest quartile), AORs for low diet quality among normal weight women tended to be >1, and AORs for overweight and obese women tended to be stronger among women who had low diet quality than not low diet quality. For 9/16 birth defects, AORs for obese women who had low diet quality-the group we hypothesized to have highest risk-were higher than other stratum-specific AORs. Most relative excess risk due to interactions were positive but small (<0.5), with confidence intervals that included zero.These findings provide evidence for the hypothesis of highest birth defect risks among offspring to women who are obese and have low diet quality but insufficient evidence for an interaction of these factors in their contribution to risk. Birth Defects Research (Part A) 106:164-171, 2016. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23471

  View details for Web of Science ID 000372908700002

• 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

• Elevated body mass index and decreased diet quality among women and risk of birth defects in their offspring. Birth defects research. Part A, Clinical and molecular teratology Carmichael, S. L., Yang, W., Gilboa, S., Ailes, E., Correa, A., Botto, L. D., Feldkamp, M. L., Shaw, G. M. 2016; 106 (3): 164-171

  Abstract

  We examined whether risks of 32 birth defects were higher than expected in the presence of overweight or obese body mass index (BMI) and low diet quality, based on estimating individual and joint effects of these factors and calculating relative excess risk due to interaction.Analyses included mothers of 20,250 cases with birth defects and 8617 population-based controls without birth defects born from 1997 to 2009 and interviewed for the National Birth Defects Prevention Study. We used logistic regression to generate adjusted odds ratios (AORs) reflecting the combined effects of BMI and diet quality. We focused analyses on 16 birth defects (n = 11,868 cases, 8617 controls) for which initial results suggested an association with BMI or diet quality.Relative to the reference group (normal weight women with not low diet quality, i.e., >lowest quartile), AORs for low diet quality among normal weight women tended to be >1, and AORs for overweight and obese women tended to be stronger among women who had low diet quality than not low diet quality. For 9/16 birth defects, AORs for obese women who had low diet quality-the group we hypothesized to have highest risk-were higher than other stratum-specific AORs. Most relative excess risk due to interactions were positive but small (<0.5), with confidence intervals that included zero.These findings provide evidence for the hypothesis of highest birth defect risks among offspring to women who are obese and have low diet quality but insufficient evidence for an interaction of these factors in their contribution to risk. Birth Defects Research (Part A) 106:164-171, 2016. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23471

  View details for PubMedID 26663631

• 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

• Residential agricultural pesticide exposures and risks of selected birth defects among offspring in the San Joaquin Valley of California. Birth defects research. Part A, Clinical and molecular teratology Carmichael, S. L., Yang, W., Roberts, E., Kegley, S. E., Brown, T. J., English, P. B., Lammer, E. J., Shaw, G. M. 2016; 106 (1): 27-35

  Abstract

  We examined associations of birth defects with residential proximity to commercial agricultural pesticide applications in California. Subjects included 367 cases representing five types of birth defects and 785 nonmalformed controls born 1997 to 2006.Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for covariates. Overall, 46% of cases and 38% of controls were classified as exposed to pesticides within a 500 m radius of mother's address during a 3-month periconceptional window.We estimated odds ratios (ORs) for 85 groups and 95 chemicals with five or more exposed cases and control mothers. Ninety-five percent confidence intervals (CI) excluded 1.0 for 11 ORs for groups and 22 ORs for chemicals, ranging from 1.9 to 3.1 for groups and 1.8 to 4.9 for chemicals except for two that were <1 (noted below).For groups, these ORs were for anotia/microtia (n = 95 cases) and dichlorophenoxy acids/esters and neonicotinoids; anorectal atresia/stenosis (n = 77) and alcohol/ethers and organophosphates (these ORs were < 1.0); transverse limb deficiencies (n = 59) and dichlorophenoxy acids/esters, petroleum derivatives, and triazines; and craniosynostosis (n = 79) and alcohol/ethers, avermectins, neonicotinoids, and organophosphates. For chemicals, ORs were: anotia/microtia and five pesticides from the groups dichlorophenoxy acids/esters, copper-containing compounds, neonicotinoids, organophosphates, and triazines; transverse limb deficiency and six pesticides - oxyfluorfen and pesticides from the groups copper-containing compounds, 2,6-dinitroanilines, neonicotinoids, petroleum derivatives and polyalkyloxy compounds; craniosynostosis and 10 pesticides - oxyfluorfen and pesticides from the groups alcohol/ethers, avermectins, n-methyl-carbamates, neonicotinoids, ogranophosphates (two chemicals), polyalkyloxy compounds (two chemicals), and pyrethroids; and congenital diaphragmatic hernia (n = 62) and a copper-containing compound.

  View details for DOI 10.1002/bdra.23459

  View details for PubMedID 26689858

• Temporal and geographic patterns of home births in California 1991-2010 Girsen, A., Mayo, J. A., Blumenfeld, Y. J., Lyell, D. J., Druzin, M. L., El-Sayed, Y. Y., Shaw, G. M. MOSBY-ELSEVIER. 2016: S395

  View details for DOI 10.1016/j.ajog.2015.10.801

  View details for Web of Science ID 000367092800744

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

  View details for DOI 10.1016/j.ajog.2015.10.800

  View details for Web of Science ID 000367092800743

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

  View details for DOI 10.1016/j.ajog.2015.10.898

  View details for Web of Science ID 000367092800837

• 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

• 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

• Remembering Edward J. Lammer, MD. American journal of medical genetics. Part A Finnell, R. H., Shaw, G. M. 2016; 170 (11): 2767–68

  View details for PubMedID 27481654

• Lower rate of selected congenital heart defects with better maternal diet quality: a population-based study. Archives of disease in childhood. Fetal and neonatal edition Botto, L. D., Krikov, S., Carmichael, S. L., Munger, R. G., Shaw, G. M., Feldkamp, M. L. 2016; 101 (1): 43-49

  Abstract

  To evaluate whether better diet quality in mothers is associated with lower risk for major non-syndromic congenital heart defects in their children.Multicentre population-based case-control study, the National Birth Defects Prevention Study.Ten sites in the USA.Mothers of babies with major non-syndromic congenital heart defects (n=9885) and mothers with unaffected babies (n=9468) with estimated date of delivery from 1997 to 2009.Adjusted ORs for specific major congenital heart defects by quartiles of maternal diet quality in the year before pregnancy, assessed by the Diet Quality Index for pregnancy (DQI-P) and the Mediterranean Diet Score. Quartile 1 (Q1) reflecting the worst diet quality and Q4 the best diet quality.Better diet quality was associated with reduced risk for some conotruncal and atrial septal heart defects. For DQI-P, estimated risks reductions (Q4 vs Q1) for conotruncal defects were 37% for tetralogy of Fallot (OR 0.63, 95% CI 0.49 to 0.80) and 24% overall (OR 0.76, 95% CI 0.64 to 0.91); and for septal defects, 23% for atrial septal defects (OR 0.77, 95% CI 0.63 to 0.94) and 14% overall (OR 0.86, 95% CI 0.75 to 1.00). Risk reductions were weaker or minimal for most other major congenital heart defects.Better diet quality is associated with a reduced occurrence of some conotruncal and septal heart defects. This finding suggests that a reduction in certain cardiac malformations may be an additional benefit of improved maternal diet quality, reinforcing current preconception care recommendations.

  View details for DOI 10.1136/archdischild-2014-308013

  View details for PubMedID 26304461

• Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring JAMA PEDIATRICS Priest, J. R., Yang, W., Reaven, G., Knowles, J. W., Shaw, G. M. 2015; 169 (12): 1112-1116

  Abstract

  There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations.To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin.Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015.Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status.Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 μIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 μIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 μIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79).These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.

  View details for DOI 10.1001/jamapediatrics.2015.2831

  View details for Web of Science ID 000366334600014

  View details for PubMedID 26457543

  View details for PubMedCentralID PMC4996656

• 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)

  View details for DOI 10.1016/j.ajog.2015.07.005

  View details for Web of Science ID 000365763400027

  View details for PubMedID 26187451

• 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

• Air Pollution, Neighbourhood Socioeconomic Factors, and Neural Tube Defects in the San Joaquin Valley of California PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Padula, A. M., Yang, W., Carmichael, S. L., Tager, I. B., Lurmann, F., Hammond, S. K., Shaw, G. M. 2015; 29 (6): 536-545

  Abstract

  Environmental pollutants and neighbourhood socioeconomic factors have been associated with neural tube defects, but the potential impact of interaction between ambient air pollution and neighbourhood socioeconomic factors on the risks of neural tube defects is not well understood.We used data from the California Center of the National Birth Defects Study and the Children's Health and Air Pollution Study to investigate whether associations between air pollutant exposure in early gestation and neural tube defects were modified by neighbourhood socioeconomic factors in the San Joaquin Valley of California, 1997-2006. There were 5 pollutant exposures, 3 outcomes, and 9 neighbourhood socioeconomic factors included for a total of 135 investigated associations. Estimates were adjusted for maternal race-ethnicity, education, and multivitamin use.We present below odds ratios (ORs) that exclude 1 and a chi-square test of homogeneity P-value of <0.05. We observed increased odds of spina bifida comparing the highest to lowest quartile of particulate matter <10 μm (PM10 ) among those living in a neighbourhood with: (i) median household income of less than $30 000 per year [OR 5.1, 95% confidence interval (CI) 1.7, 15.3]; (ii) more than 20% living below the federal poverty level (OR 2.6, 95% CI 1.1, 6.0); and (iii) more than 30% with less than or equal to a high school education (OR 3.2, 95% CI 1.4, 7.4). The ORs were not statistically significant among those higher socioeconomic status (SES) neighbourhoods.Our results demonstrate effect modification by neighbourhood socioeconomic factors in the association of particulate matter and neural tube defects in California.

  View details for DOI 10.1111/ppe.12244

  View details for Web of Science ID 000362723900009

  View details for PubMedID 26443985

  View details for PubMedCentralID PMC4646169

• 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

• 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 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

• Periconceptional changes in weight and risk of delivering offspring with conotruncal heart defects. Birth defects research. Part A, Clinical and molecular teratology Carter, E. H., Carmichael, S. L., Birnie, K., Yang, W., Lammer, E. J., Shaw, G. M. 2015; 103 (10): 843-846

  Abstract

  Maternal nutritional status has been recognized as a contributor to conotruncal heart defects, but there is limited understanding of the specific nutrition-related factors involved. In this California case-control study of 296 conotruncal cases and 695 nonmalformed controls we explored whether weight loss during early pregnancy was associated with an increased risk of d-transposition of the great arteries (dTGA) and tetralogy of Fallot (TOF) conotruncal defects.During telephone interviews women were asked whether they were dieting to lose weight or using weight loss remedies during 2 months before or 2 months after conception, and how much weight they gained or lost in the first 2 months of pregnancy or during the year before pregnancy.Odds ratios for dieting to lose weight and use of weight loss remedies for dTGA and TOF were not substantially elevated and all had confidence intervals that included 1.0. Mothers who had a loss of >5 lbs in the first 2 months of pregnancy as well as mothers who lost and gained >5 lbs in the first 2 months of pregnancy also did not show a significant increased risk of delivering case infants when compared with women with no weight change in the year before pregnancy.Given current recommendations about limited weight gain for obese pregnant women, these data indicate that dieting may not substantially increase a fetus' risk of having a conotruncal defect.

  View details for DOI 10.1002/bdra.23381

  View details for PubMedID 26033835

• Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia. journal of pediatrics Gage, S., Kan, P., Lee, H. C., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 167 (4): 875-880 e1

  Abstract

  To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD).Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007-2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma.Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07).Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants.

  View details for DOI 10.1016/j.jpeds.2015.06.048

  View details for PubMedID 26254835

• Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia. journal of pediatrics Gage, S., Kan, P., Lee, H. C., Gould, J. B., Stevenson, D. K., Shaw, G. M., O'Brodovich, H. M. 2015; 167 (4): 875-880 e1

  Abstract

  To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD).Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007-2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma.Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07).Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants.

  View details for DOI 10.1016/j.jpeds.2015.06.048

  View details for PubMedID 26254835

• Heightened risk of preterm birth and growth restriction after a first-born son ANNALS OF EPIDEMIOLOGY Bruckner, T. A., Mayo, J. A., Gould, J. B., Stevenson, D. K., Lewis, D. B., Shaw, G. M., Carmichael, S. L. 2015; 25 (10): 743-747

  Abstract

  In Scandinavia, delivery of a first-born son elevates the risk of preterm delivery and intrauterine growth restriction of the next-born infant. External validity of these results remains unclear. We test this hypothesis for preterm delivery and growth restriction using the linked California birth cohort file. We examined the hypothesis separately by race and/or ethnicity.We retrieved data on 2,852,976 births to 1,426,488 mothers with at least two live births. Our within-mother tests applied Cox proportional hazards (preterm delivery, defined as less than 37 weeks gestation) and linear regression models (birth weight for gestational age percentiles).For non-Hispanic whites, Hispanics, Asians, and American Indian and/or Alaska Natives, analyses indicate heightened risk of preterm delivery and growth restriction after a first-born male. The race-specific hazard ratios for preterm delivery range from 1.07 to 1.18. Regression coefficients for birth weight for gestational age percentile range from -0.73 to -1.49. The 95% confidence intervals for all these estimates do not contain the null. By contrast, we could not reject the null for non-Hispanic black mothers.Whereas California findings generally support those from Scandinavia, the null results among non-Hispanic black mothers suggest that we do not detect adverse outcomes after a first-born male in all racial and/or ethnic groups.

  View details for DOI 10.1016/j.annepidem.2015.07.002

  View details for PubMedID 26265442

• 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

• 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

• 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; 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

• 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

• 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

• Maternal serum markers, characteristics and morbidly adherent placenta in women with previa JOURNAL OF PERINATOLOGY Lyell, D. J., Faucett, A. M., Baer, R. J., Blumenfeld, Y. J., Druzin, M. L., El-Sayed, Y. Y., Shaw, G. M., Currier, R. J., Jelliffe-Pawlowski, L. L. 2015; 35 (8): 570-574

  Abstract

  To examine associations with morbidly adherent placenta (MAP) among women with placenta previa.Women with MAP (cases) and previa alone (controls) were identified from a cohort of 236 714 singleton pregnancies with both first and second trimester prenatal screening, and live birth and hospital discharge records; pregnancies with aneuploidies and neural tube or abdominal wall defects were excluded. Logistic binomial regression was used to compare cases with controls.In all, 37 cases with MAP and 699 controls with previa alone were included. Risk for MAP was increased among multiparous women with pregnancy-associated plasma protein-A (PAPP-A) ⩾95th percentile (⩾2.63 multiple of the median (MoM); adjusted OR (aOR) 8.7, 95% confidence interval (CI) 2.8 to 27.4), maternal-serum alpha fetoprotein (MS-AFP) ⩾95th percentile (⩾1.79 MoM; aOR 2.8, 95% CI 1.0 to 8.0), and 1 and ⩾2 prior cesarean deliveries (CDs; aORs 4.4, 95% CI 1.5 to 13.6 and 18.4, 95% CI 5.9 to 57.5, respectively).Elevated PAPP-A, elevated MS-AFP and prior CDs are associated with MAP among women with previa.

  View details for DOI 10.1038/jp.2015.40

  View details for Web of Science ID 000358684100008

• The national birth defects prevention study: A review of the methods BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Reefhuis, J., Gilboa, S. M., Anderka, M., Browne, M. L., Feldkamp, M. L., Hobbs, C. A., Jenkins, M. M., Langlois, P. H., Newsome, K. B., Olshan, A. F., Romitti, P. A., Shapira, S. K., Shaw, G. M., Tinker, S. C., Honein, M. A. 2015; 103 (8): 656-669

  Abstract

  The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States.Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living).There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014.The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers. Birth Defects Research (Part A) 103:656-669, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23384

  View details for Web of Science ID 000359740800003

  View details for PubMedID 26033852

  View details for PubMedCentralID PMC4558899

• Detecting gene-environment interactions in human birth defects: Study designs and statistical methods BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Tai, C. G., Graff, R. E., Liu, J., Passarelli, M. N., Mefford, J. A., Shaw, G. M., Hoffmann, T. J., Witte, J. S. 2015; 103 (8): 692-702

  Abstract

  The National Birth Defects Prevention Study (NBDPS) contains a wealth of information on affected and unaffected family triads, and thus provides numerous opportunities to study gene-environment interactions (G×E) in the etiology of birth defect outcomes. Depending on the research objective, several analytic options exist to estimate G×E effects that use varying combinations of individuals drawn from available triads.In this study, we discuss important considerations in the collection of genetic data and environmental exposures.We will also present several population- and family-based approaches that can be applied to data from the NBDPS including case-control, case-only, family-based trio, and maternal versus fetal effects. For each, we describe the data requirements, applicable statistical methods, advantages, and disadvantages.A range of approaches can be used to evaluate potentially important G×E effects in the NBDPS. Investigators should be aware of the limitations inherent to each approach when choosing a study design and interpreting results. Birth Defects Research (Part A) 103:692-702, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23382

  View details for Web of Science ID 000359740800006

  View details for PubMedID 26010994

  View details for PubMedCentralID PMC4537677

• Developments in our understanding of the genetic basis of birth defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Webber, D. M., MacLeod, S. L., Bamshad, M. J., Shaw, G. M., Finnell, R. H., Shete, S. S., Witte, J. S., Erickson, S. W., Murphy, L. D., Hobbs, C. 2015; 103 (8): 680-691

  Abstract

  Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic birth defects is not well-understood. Although there is still much work to be done, we have many of the tools needed to accomplish the task. Advances in next-generation sequencing have introduced a sea of possibilities, from disease-gene discovery to clinical screening and diagnosis. These advances have been fruitful in identifying a host of candidate disease genes, spanning the spectrum of birth defects. With the advent of CRISPR-Cas9 gene editing, researchers now have a precise tool for characterizing this genetic variation in model systems. Work in model organisms has also illustrated the importance of epigenetics in human development and birth defects etiology. Here we review past and current knowledge in birth defects genetics. We describe genotyping and sequencing methods for the detection and analysis of rare and common variants. We remark on the utility of model organisms and explore epigenetics in the context of structural malformation. We conclude by highlighting approaches that may provide insight into the complex genetics of birth defects. Birth Defects Research (Part A) 103:680-691, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23385

  View details for Web of Science ID 000359740800005

  View details for PubMedID 26033863

  View details for PubMedCentralID PMC4537658

• Maternal Factors Associated with the Occurrence of Gastroschisis AMERICAN JOURNAL OF MEDICAL GENETICS PART A Baer, R. J., Chambers, C. D., Jones, K. L., Shew, S. B., MacKenzie, T. C., Shaw, G. M., Jelliffe-Pawlowski, L. L. 2015; 167A (7): 1534-1541

  Abstract

  We sought to identify age group specific maternal risk factors for gastroschisis. Maternal characteristics and prenatal factors were compared for 1,279 live born infants with gastroschisis and 3,069,678 without. Data were obtained using the California database containing linked hospital discharge, birth certificate and death records from 1 year prior to the birth to 1 year after the birth. Backwards-stepwise logistic regression models were used with maternal factors where initial inclusion was determined by a threshold of p < 0.10 on initial crude analyses. Due to the strong association of gastroschisis with young maternal age, models were stratified by age groups and odds ratios were calculated. These final models identified maternal infection as the only risk factor common to all age groups and a protective effect of obesity and gestational hypertension. In addition, age specific risk factors were identified. Although gestation at the time of infection was not available, a sexually transmitted disease complicating pregnancy was associated with increased risk in the less than 20 years of age grouping whereas viral infection was associated with increased risk only in the 20-24 and more than 24 years of age groupings. Urinary tract infection remained in the final logistic model for women less than 20 years. Short interpregnancy interval was not found to be a risk factor for any age group. Our findings support the need to explore maternal infection by type and gestational timing. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37016

  View details for Web of Science ID 000356676200063

• 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

• Maternal factors associated with the occurrence of gastroschisis. American journal of medical genetics. Part A Baer, R. J., Chambers, C. D., Jones, K. L., Shew, S. B., MacKenzie, T. C., Shaw, G. M., Jelliffe-Pawlowski, L. L. 2015; 167 (7): 1534-1541

  Abstract

  We sought to identify age group specific maternal risk factors for gastroschisis. Maternal characteristics and prenatal factors were compared for 1,279 live born infants with gastroschisis and 3,069,678 without. Data were obtained using the California database containing linked hospital discharge, birth certificate and death records from 1 year prior to the birth to 1 year after the birth. Backwards-stepwise logistic regression models were used with maternal factors where initial inclusion was determined by a threshold of p < 0.10 on initial crude analyses. Due to the strong association of gastroschisis with young maternal age, models were stratified by age groups and odds ratios were calculated. These final models identified maternal infection as the only risk factor common to all age groups and a protective effect of obesity and gestational hypertension. In addition, age specific risk factors were identified. Although gestation at the time of infection was not available, a sexually transmitted disease complicating pregnancy was associated with increased risk in the less than 20 years of age grouping whereas viral infection was associated with increased risk only in the 20-24 and more than 24 years of age groupings. Urinary tract infection remained in the final logistic model for women less than 20 years. Short interpregnancy interval was not found to be a risk factor for any age group. Our findings support the need to explore maternal infection by type and gestational timing. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37016

  View details for PubMedID 25913847

• Early-onset severe preeclampsia by first trimester pregnancy-associated plasma protein A and total human chorionic gonadotropin. American journal of perinatology Jelliffe-Pawlowski, L. L., Baer, R. J., Currier, R. J., Lyell, D. J., Blumenfeld, Y. J., El-Sayed, Y. Y., Shaw, G. M., Druzin, M. L. 2015; 32 (7): 703-712

  Abstract

  This study aims to evaluate the relationship between early-onset severe preeclampsia and first trimester serum levels of pregnancy-associated plasma protein A (PAPP-A) and total human chorionic gonadotropin (hCG).The association between early-onset severe preeclampsia and abnormal levels of first trimester PAPP-A and total hCG in maternal serum were measured in a sample of singleton pregnancies without chromosomal defects that had integrated prenatal serum screening in 2009 and 2010 (n = 129,488). Logistic binomial regression was used to estimate the relative risk (RR) of early-onset severe preeclampsia in pregnancies with abnormal levels of first trimester PAPP-A or total hCG as compared with controls.Regardless of parity, women with low first trimester PAPP-A or high total hCG were at increased risk for early-onset severe preeclampsia. Women with low PAPP-A (multiple of the median [MoM] ≤ the 10th percentile in nulliparous or ≤ the 5th percentile in multiparous) or high total hCG (MoM ≥ the 90th percentile in nulliparous or ≥ the 95th percentile in multiparous) were at more than a threefold increased risk for early-onset severe preeclampsia (RR, 4.2; 95% confidence interval [CI], 3.0-5.9 and RR, 3.3; 95% CI, 2.1-5.2, respectively).Routinely collected first trimester measurements of PAPP-A and total hCG provide unique risk information for early-onset severe preeclampsia.

  View details for DOI 10.1055/s-0034-1396697

  View details for PubMedID 25519199

• Early-Onset Severe Preeclampsia by First Trimester Pregnancy-Associated Plasma Protein A and Total Human Chorionic Gonadotropin AMERICAN JOURNAL OF PERINATOLOGY Jelliffe-Pawlowski, L. L., Baer, R. J., Currier, R. J., Lyell, D. J., Blumenfeld, Y. J., El-Sayed, Y. Y., Shaw, G. M., Druzin, M. L. 2015; 32 (7): 703-711

  Abstract

  This study aims to evaluate the relationship between early-onset severe preeclampsia and first trimester serum levels of pregnancy-associated plasma protein A (PAPP-A) and total human chorionic gonadotropin (hCG).The association between early-onset severe preeclampsia and abnormal levels of first trimester PAPP-A and total hCG in maternal serum were measured in a sample of singleton pregnancies without chromosomal defects that had integrated prenatal serum screening in 2009 and 2010 (n = 129,488). Logistic binomial regression was used to estimate the relative risk (RR) of early-onset severe preeclampsia in pregnancies with abnormal levels of first trimester PAPP-A or total hCG as compared with controls.Regardless of parity, women with low first trimester PAPP-A or high total hCG were at increased risk for early-onset severe preeclampsia. Women with low PAPP-A (multiple of the median [MoM] ≤ the 10th percentile in nulliparous or ≤ the 5th percentile in multiparous) or high total hCG (MoM ≥ the 90th percentile in nulliparous or ≥ the 95th percentile in multiparous) were at more than a threefold increased risk for early-onset severe preeclampsia (RR, 4.2; 95% confidence interval [CI], 3.0-5.9 and RR, 3.3; 95% CI, 2.1-5.2, respectively).Routinely collected first trimester measurements of PAPP-A and total hCG provide unique risk information for early-onset severe preeclampsia.

  View details for DOI 10.1055/s-0034-1396697

  View details for Web of Science ID 000355418600014

  View details for PubMedID 25519199

• Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation. American journal of medical genetics. Part A Tang, X., Cleves, M. A., Nick, T. G., Li, M., MacLeod, S. L., Erickson, S. W., Li, J., Shaw, G. M., Mosley, B. S., Hobbs, C. A. 2015; 167 (6): 1231-1242

  Abstract

  Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity.

  View details for DOI 10.1002/ajmg.a.36867

  View details for PubMedID 25846410

• 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

• Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation AMERICAN JOURNAL OF MEDICAL GENETICS PART A Tang, X., Cleves, M. A., Nick, T. G., Li, M., MacLeod, S. L., Erickson, S. W., Li, J., Shaw, G. M., Mosley, B. S., Hobbs, C. A. 2015; 167A (6): 1231-1242

  Abstract

  Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity.

  View details for DOI 10.1002/ajmg.a.36867

  View details for Web of Science ID 000355276700009

• Spatial analysis of gastroschisis in the national birth defects prevention study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yazdy, M. M., Werler, M. M., Feldkamp, M. L., Shaw, G. M., Mosley, B. S., Vieira, V. M. 2015; 103 (6): 544-553

  Abstract

  Gastroschisis is a birth defect where loops of bowel are protruding from the abdominal wall at birth. Previous research has suggested that gastroschisis cases can occur in clusters. The objective of this study was to identify if there were areas of elevated gastroschisis risk using data from the National Birth Defects Prevention Study (NBDPS), 1997 through 2007.We obtained data on cases (n = 371) through population-based birth defects surveillance systems in Arkansas, California, and Utah; controls (n = 2359) were selected from the same geographic areas as cases. Mothers were interviewed on demographic information and exposures during pregnancy, including residential history. We used first trimester maternal addresses and generalized additive models to create a continuous map surface of odds ratios (OR) by smoothing over latitude and longitude. Permutation tests were used to assess whether location of maternal residence was important and identify locations with statistically significant ORs.In Arkansas, adjusted ORs in the southwest corner were 2.0 and the global deviance was not statistically significant (p-value: 0.57). Adjusted ORs for California indicated areas of increased risk with ORs 1.3 (p-value: 0.34). In Utah, the adjusted ORs were elevated (OR: 2.4) in the south-eastern corner of the study area (p-value: 0.34).The results of this study, while not statistically significant, suggest there were spatial variations in gastroschisis births. We cannot rule out that these variations were due to edge effects or residual confounding. Birth Defects Research (Part A) 103:544-553, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23375

  View details for Web of Science ID 000356674800010

  View details for PubMedID 25850424

  View details for PubMedCentralID PMC4478213

• Genetic Polymorphisms in ESR1 and ESR2 Genes, and Risk of Hypospadias in a Multiethnic Study Population JOURNAL OF UROLOGY Choudhry, S., Baskin, L. S., Lammer, E. J., Witte, J. S., Dasgupta, S., Ma, C., Surampalli, A., Shen, J., Shaw, G. M., Carmichael, S. L. 2015; 193 (5): 1625-1631

  Abstract

  Estrogenic endocrine disruptors acting via estrogen receptors α (ESR1) and β (ESR2) have been implicated in the etiology of hypospadias, a common congenital malformation of the male external genitalia. We determined the association of single nucleotide polymorphisms in ESR1 and ESR2 genes with hypospadias in a racially/ethnically diverse study population of California births.We investigated the relationship between hypospadias and 108 ESR1 and 36 ESR2 single nucleotide polymorphisms in 647 cases and 877 population based nonmalformed controls among infants born in selected California counties from 1990 to 2003. Subgroup analyses were performed by race/ethnicity (nonHispanic white and Hispanic subjects) and by hypospadias severity (mild to moderate and severe).Odds ratios for 33 of the 108 ESR1 single nucleotide polymorphisms had p values less than 0.05 (p = 0.05 to 0.007) for risk of hypospadias. However, none of the 36 ESR2 single nucleotide polymorphisms was significantly associated. In stratified analyses the association results were consistent by disease severity but different sets of single nucleotide polymorphisms were significantly associated with hypospadias in nonHispanic white and Hispanic subjects. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and identified 6 haplotype blocks in ESR1 gene that had haplotypes significantly associated with an increased risk of hypospadias (OR 1.3 to 1.8, p = 0.04 to 0.00001). Similar to single nucleotide polymorphism analysis, different ESR1 haplotypes were associated with risk of hypospadias in nonHispanic white and Hispanic subjects. No significant haplotype association was observed for ESR2.The data provide evidence that ESR1 single nucleotide polymorphisms and haplotypes influence the risk of hypospadias in white and Hispanic subjects, and warrant further examination in other study populations.

  View details for DOI 10.1016/j.juro.2014.11.087

  View details for Web of Science ID 000353113200073

  View details for PubMedID 25463985

• Craniosynostosis and Risk Factors Related to Thyroid Dysfunction AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Ma, C., Rasmussen, S. A., Cunningham, M. L., Browne, M. L., Dosiou, C., Lammer, E. J., Shaw, G. M. 2015; 167A (4): 701-707

  View details for DOI 10.1002/ajmg.a.36953

  View details for Web of Science ID 000352019000007

• Craniosynostosis and risk factors related to thyroid dysfunction. American journal of medical genetics. Part A Carmichael, S. L., Ma, C., Rasmussen, S. A., Cunningham, M. L., Browne, M. L., Dosiou, C., Lammer, E. J., Shaw, G. M. 2015; 167A (4): 701-707

  Abstract

  Thyroid disease is a common problem among women of reproductive age but often goes undiagnosed. Maternal thyroid disease has been associated with increased risk of craniosynostosis. We hypothesized that known risk factors for thyroid disease would be associated with risk of craniosynostosis among women not diagnosed with thyroid disease. Analyses included mothers of 1,067 cases and 8,494 population-based controls who were interviewed for the National Birth Defects Prevention Study. We used multivariable logistic regression to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). After excluding women with diagnosed thyroid disease, younger maternal age (AOR 0.7, 95% CI 0.6-0.9, for <25 years versus 25-29), black or other race-ethnicity (AOR 0.3, 95% CI 0.2-0.4 and AOR 0.6, 95% CI 0.4-0.8, respectively, relative to non-Hispanic whites), fertility medications or procedures (AOR 1.5, 95% CI 1.2-2.0), and alcohol consumption (AOR 0.8, 95% CI 0.7-0.9) were associated with risk of craniosynostosis, based on confidence intervals that excluded 1.0. These associations with craniosynostosis are consistent with the direction of their association with thyroid dysfunction (i.e., younger age, black race-ethnicity and alcohol consumption are associated with reduced risk and fertility problems are associated with increased risk of thyroid disease). This study thus provides support for the hypothesis that risk factors associated with thyroid dysfunction are also associated with risk of craniosynostosis. Improved understanding of the potential association between maternal thyroid function and craniosynostosis among offspring is important given that craniosynostosis carries significant morbidity and that thyroid disease is under-diagnosed and potentially modifiable. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.36953

  View details for PubMedID 25655789

• Risk of critical congenital heart defects by nuchal translucency norms AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Jelliffe-Pawlowski, L. L., Norton, M. E., Shaw, G. M., Baer, R. J., Flessel, M. C., Goldman, S., Currier, R. J. 2015; 212 (4)

  Abstract

  The purpose of this study was to compare the performance of first-trimester nuchal translucency (NT) cutoff of ≥3.5 mm with NT percentiles that were calculated for crown-rump length to identify fetuses with critical congenital heart defects (CCHDs).This was a population-level study of singleton pregnancies in California with NT measurements performed between 11 and 14 weeks of gestation. Eligible cases were those that resulted in live births from 2009-2010 and had information about the presence or absence of CCHDs available in the hospital discharge records through age 1 year (n = 76,089). Logistic binomial regression methods were used to compare the rate of CCHDs by an NT percentile for crown-rump length and millimeter cutpoints.Compared with fetuses with an NT measurement of <90th percentile, fetuses with an NT of ≥99th percentile were >5 times as likely to have a CCHD (1.3% vs 0.2%; relative risk, 5.66; 95% confidence interval, 3.19-10.04) and fetuses with an NT measurement ≥3.5 mm were >12 times as likely to have a CCHD (2.8% vs 0.2%; relative risk, 12.28; 95% confidence interval, 5.11-29.51). NT ≥99th percentile had a sensitivity of 5.8% and a specificity of 98.9% for the detection of CCHDs compared with 2.6% and 99.8% for NT ≥3.5 mm.Results show that NT measurements of ≥99th percentile and ≥3.5 mm are not equivalent and that substantial risk for CCHD extends to the less restrictive ≥99th percentile cutpoint. Data suggest that the use of this cutpoint compared with the current standard could double the number of CCHDs that are identified based on NT risk.

  View details for DOI 10.1016/j.ajog.2014.10.1102

  View details for Web of Science ID 000352147100029

  View details for PubMedID 25448520

• Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis EUROPEAN JOURNAL OF HUMAN GENETICS Choi, A., Lao, R., Tang, P. L., Wan, E., Mayer, W., Bardakjian, T., Shaw, G. M., Kwok, P., Schneider, A., Slavotinek, A. 2015; 23 (3): 337-341

  Abstract

  We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and developmental delays. Sanger sequencing verified two Peroxidasin (PXDN) mutations in both sibs--a maternally inherited, nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional PXDN mutations in a sporadic male with bilateral microphthalmia, cataracts and anterior segment dysgenesis--a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in PXDN were previously reported in three families with congenital cataracts, microcornea, sclerocornea and developmental glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective peroxidasin has been shown to impair sulfilimine bond formation in collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that PXDN sequencing should be considered in microphthalmia with anterior segment dysgenesis.

  View details for DOI 10.1038/ejhg.2014.119

  View details for Web of Science ID 000349670900010

  View details for PubMedCentralID PMC4326713

• Factors Associated With Recurrent Preterm Birth Among Underweight Women Girsen, A. I., Mayo, J., Matthew, W. B., Gould, J. B., Carmichael, S. L., Lyell, D. J., Shaw, G. M. SAGE PUBLICATIONS INC. 2015: 150A

  View details for Web of Science ID 000351407201160

• Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. European journal of human genetics Choi, A., Lao, R., Ling-Fung Tang, P., Wan, E., Mayer, W., Bardakjian, T., Shaw, G. M., Kwok, P., Schneider, A., Slavotinek, A. 2015; 23 (3): 337-341

  Abstract

  We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and developmental delays. Sanger sequencing verified two Peroxidasin (PXDN) mutations in both sibs--a maternally inherited, nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional PXDN mutations in a sporadic male with bilateral microphthalmia, cataracts and anterior segment dysgenesis--a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in PXDN were previously reported in three families with congenital cataracts, microcornea, sclerocornea and developmental glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective peroxidasin has been shown to impair sulfilimine bond formation in collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that PXDN sequencing should be considered in microphthalmia with anterior segment dysgenesis.

  View details for DOI 10.1038/ejhg.2014.119

  View details for PubMedID 24939590

  View details for PubMedCentralID PMC4326713

• Rare LRP6 Variants Identified in Spina Bifida Patients HUMAN MUTATION Lei, Y., Fathe, K., McCartney, D., Zhu, H., Yang, W., Ross, M. E., Shaw, G. M., Finnell, R. H. 2015; 36 (3): 342-349

  Abstract

  Several single-nucleotide variants (SNVs) in low-density lipoprotein receptor-related protein 6 (Lrp6) cause neural tube defects (NTDs) in mice. We therefore examined LRP6 in 192 unrelated infants from California with the NTD, spina bifida, and found four heterozygous missense SNVs, three of which were predicted to be deleterious, among NTD cases and not in 190 ethnically matched nonmalformed controls. Parents and siblings could not be tested because of the study design. Like Crooked tail and Ringleschwanz mouse variants, the p.Tyr544Cys Lrp6 protein failed to bind the chaperone protein mesoderm development and impaired Lrp6 subcellular localization to the plasma membrane of MDCK II cells. Only the p.Tyr544Cys Lrp6 variant downregulated canonical Wnt signaling in a TopFlash luciferase reporter in vitro assay. In contrast, three Lrp6 mutants (p.Ala3Val, p.Tyr544Cys, and p.Arg1574Leu) increased noncanonical Wnt/planar cell polarity (PCP) signaling in an Ap1-luciferase assay. Thus, LRP6 variants outside of YWTD repeats could potentially predispose embryos to NTDs, whereas Lrp6 modulation of Wnt/PCP signaling would be more essential than its canonical pathway role in neural tube closure.

  View details for DOI 10.1002/humu.22750

  View details for Web of Science ID 000351399900010

  View details for PubMedID 25546815

  View details for PubMedCentralID PMC4361299

• 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

• Prevalence of Birth Defects among American-Indian Births in California, 1983-2010 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Aggarwal, D., Warmerdam, B., Wyatt, K., Ahmad, S., Shaw, G. M. 2015; 103 (2): 105-110

  Abstract

  Approximately 6.3 million live births and fetal deaths occurred during the ascertainment period in the California Birth Defects Monitoring Program registry. American-Indian and non-Hispanic white women delivered 40,268 and 2,044,118 births, respectively. While much information has been published about non-Hispanic white infants, little is known regarding the risks of birth defects among infants born to American-Indian women.This study used data from the California Birth Defects Monitoring Program to explore risks of selected birth defects in offspring of American-Indian relative to non-Hispanic white women in California. The study population included all live births and fetal deaths 20 weeks or greater from 1983 to 2010. Prevalence ratios and corresponding 95% confidence intervals (CI) were computed using Poisson regression for 51 groupings of birth defects.Prevalence ratios were estimated for 51 groupings of birth defects. Of the 51, nine had statistically precise results ranging from 0.78 to 1.85. The eight groups with elevated risks for American-Indian births were reduction deformities of brain, anomalies of anterior segments, specified anomalies of ear, ostium secundum type atrial septal defect, specified anomalies of heart, anomalies of the aorta, anomalies of great veins, and cleft lip with cleft palate.Our results suggest that American-Indian women having babies in California may be at higher risk for eight birth defect phenotypes compared with non-Hispanic whites. Further research is needed to determine whether these risks are observed among other populations of American-Indian women or when adjusted for potential covariates.

  View details for DOI 10.1002/bdra.23341

  View details for Web of Science ID 000350470500005

  View details for PubMedID 25721951

• Lower rate of selected congenital heart defects with better maternal diet quality: a population-based study ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Botto, L. D., Krikov, S., Carmichael, S. L., Munger, R. G., Shaw, G. M., Feldkamp, M. L. 2015; 101 (1): 43-49

  Abstract

  To evaluate whether better diet quality in mothers is associated with lower risk for major non-syndromic congenital heart defects in their children.Multicentre population-based case-control study, the National Birth Defects Prevention Study.Ten sites in the USA.Mothers of babies with major non-syndromic congenital heart defects (n=9885) and mothers with unaffected babies (n=9468) with estimated date of delivery from 1997 to 2009.Adjusted ORs for specific major congenital heart defects by quartiles of maternal diet quality in the year before pregnancy, assessed by the Diet Quality Index for pregnancy (DQI-P) and the Mediterranean Diet Score. Quartile 1 (Q1) reflecting the worst diet quality and Q4 the best diet quality.Better diet quality was associated with reduced risk for some conotruncal and atrial septal heart defects. For DQI-P, estimated risks reductions (Q4 vs Q1) for conotruncal defects were 37% for tetralogy of Fallot (OR 0.63, 95% CI 0.49 to 0.80) and 24% overall (OR 0.76, 95% CI 0.64 to 0.91); and for septal defects, 23% for atrial septal defects (OR 0.77, 95% CI 0.63 to 0.94) and 14% overall (OR 0.86, 95% CI 0.75 to 1.00). Risk reductions were weaker or minimal for most other major congenital heart defects.Better diet quality is associated with a reduced occurrence of some conotruncal and septal heart defects. This finding suggests that a reduction in certain cardiac malformations may be an additional benefit of improved maternal diet quality, reinforcing current preconception care recommendations.

  View details for DOI 10.1136/archdischild-2014-308013

  View details for Web of Science ID 000367479500010

• 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

• Maternal height and risk for spontaneous preterm birth across BMI categories Shachar, B., Mayo, J., Lee, H., Shaw, G., Gould, J. MOSBY-ELSEVIER. 2015: S83

  View details for DOI 10.1016/j.ajog.2014.10.178

  View details for Web of Science ID 000361140900134

• 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

• Spina bifida. Nature reviews. Disease primers Copp, A. J., Adzick, N. S., Chitty, L. S., Fletcher, J. M., Holmbeck, G. N., Shaw, G. M. 2015; 1: 15007

  Abstract

  Spina bifida is a birth defect in which the vertebral column is open, often with spinal cord involvement. The most clinically significant subtype is myelomeningocele (open spina bifida), which is a condition characterized by failure of the lumbosacral spinal neural tube to close during embryonic development. The exposed neural tissue degenerates in utero, resulting in neurological deficit that varies with the level of the lesion. Occurring in approximately 1 per 1,000 births worldwide, myelomeningocele is one of the most common congenital malformations, but its cause is largely unknown. The genetic component is estimated at 60-70%, but few causative genes have been identified to date, despite much information from mouse models. Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity. Primary prevention by periconceptional supplementation with folic acid has been demonstrated in clinical trials, leading to food fortification programmes in many countries. Prenatal diagnosis is achieved by ultrasonography, enabling women to seek termination of pregnancy. Individuals who survive to birth have their lesions closed surgically, with subsequent management of associated defects, including the Chiari II brain malformation, hydrocephalus, and urological and orthopaedic sequelae. Fetal surgical repair of myelomeningocele has been associated with improved early neurological outcome compared with postnatal operation. Myelomeningocele affects quality of life during childhood, adolescence and adulthood, posing a challenge for individuals, families and society as a whole. For an illustrated summary of this Primer, visit: http://go.nature.com/fK9XNa.

  View details for PubMedID 27189655

  View details for PubMedCentralID PMC4898641

• 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

• Risk of selected structural abnormalities in infants after increased nuchal translucency measurement AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Baer, R. J., Norton, M. E., Shaw, G. M., Flessel, M. C., Goldman, S., Currier, R. J., Jelliffe-Pawlowski, L. L. 2014; 211 (6)

  Abstract

  We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants.Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by ≥3.5 mm compared to those with measurements <90th percentile for CRL).When considered by CRL adjusted percentile and by measurement ≥3.5 mm, infants with a NT ≥95th percentile were at risk of having ≥1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3-3.4). Infants with a NT measurement ≥95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4).Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements ≥95th percentile. The ≥3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies.

  View details for DOI 10.1016/j.ajog.2014.06.025

  View details for Web of Science ID 000346585300030

  View details for PubMedID 24949541

• Maternal Periconceptional Occupational Pesticide Exposure and Neural Tube Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Makelarski, J. A., Romitti, P. A., Rocheleau, C. M., Burns, T. L., Stewart, P. A., Waters, M. A., Lawson, C. C., Bell, E. M., Lin, S., Shaw, G. M., Olney, R. S. 2014; 100 (11): 877-886

  Abstract

  Adverse associations between maternal pesticide exposure and neural tube defects (NTDs) have been suggested but not consistently observed. This study used data from the multisite National Birth Defects Prevention Study to examine associations between maternal periconceptional (1 month preconception through 2 months postconception) occupational pesticide exposure and NTDs.Mothers of 502 NTD cases and 2950 unaffected live-born control infants with estimated delivery dates from 1997 through 2002 were included. Duration, categorical intensity scores, and categorical frequency scores for pesticide classes (e.g., insecticides) were assigned using a modified, literature-based job-exposure matrix and maternal-reported occupational histories. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated based on fitted multivariable logistic regression models that described associations between maternal periconceptional occupational pesticide exposure and NTDs. The aORs were estimated for pesticide exposure (any [yes/no] and cumulative exposure [intensity × frequency × duration] to any pesticide class, each pesticide class, or combination of pesticide classes) and all NTD cases combined and NTD subtypes.Positive, but marginally significant or nonsignificant, aORs were observed for exposure to insecticides + herbicides for all NTD cases combined and for spina bifida alone. Similarly, positive aORs were observed for any exposure and cumulative exposure to insecticides + herbicides + fungicides and anencephaly alone and encephalocele alone. All other aORs were near unity.Pesticide exposure associations varied by NTD subtype and pesticide class. Several aORs were increased, but not significantly. Future work should continue to examine associations between pesticide classes and NTD subtypes using a detailed occupational pesticide exposure assessment and examine pesticide exposures outside the workplace.

  View details for DOI 10.1002/bdra.23293

  View details for Web of Science ID 000345690600009

  View details for PubMedID 25124525

• Exposure to airborne polycyclic aromatic hydrocarbons during pregnancy and risk of preterm birth ENVIRONMENTAL RESEARCH Padula, A. M., Noth, E. M., Hammond, S. K., Lurmann, F. W., Yang, W., Tager, I. B., Shaw, G. M. 2014; 135: 221-226

  Abstract

  Preterm birth is an important marker of health and has a prevalence of 12-13% in the U.S. Polycyclic aromatic hydrocarbons (PAHs) are a group of organic contaminants that form during the incomplete combustion of hydrocarbons, such as coal, diesel and gasoline. Studies suggest that exposure to PAHs during pregnancy is related to adverse birth outcomes. The aim of this study is to evaluate the association between exposure to PAHs during the pregnancy and preterm birth.The study population included births from years 2001 to 2006 of women whose maternal residence was within 20km of the primary monitoring site in Fresno, California. Data in the Fresno area were used to form a spatio-temporal model to assign daily exposure to PAHs with 4, 5, or 6 rings at the maternal residence throughout pregnancy of all of the births in the study area. Gestational age at birth and relevant covariates were extracted from the birth certificate.We found an association between PAHs during the last 6 weeks of pregnancy and birth at 20-27 weeks (OR=2.74; 95% CI: 2.24-3.34) comparing the highest quartile to the lower three. The association was consistent when each quartile was compared to the lowest (OR2nd=1.49, 95% CI: 1.08-2.06; OR3rd=2.63, 95% CI:1.93-3.59; OR4th=3.94, 95% CI:3.03-5.12). Inverse associations were also observed for exposure to PAHs during the entire pregnancy and the first trimester and birth at 28-31 weeks and 20-27 weeks.An association between PAH exposure during the 6 weeks before delivery and early preterm birth was observed. However, the inverse association with early preterm birth offers an unclear, and potentially complex, inference of these associations.

  View details for DOI 10.1016/j.envres.2014.09.014

  View details for Web of Science ID 000346622800031

  View details for PubMedID 25282280

• Residential agricultural pesticide exposures and risk of selected congenital heart defects among offspring in the San Joaquin Valley of California. Environmental research Carmichael, S. L., Yang, W., Roberts, E., Kegley, S. E., Padula, A. M., English, P. B., Lammer, E. J., Shaw, G. M. 2014; 135: 133-138

  Abstract

  Pesticide exposures are ubiquitous and of substantial public concern. We examined the potential association of congenital heart defects with residential proximity to commercial agricultural pesticide applications in the San Joaquin Valley, California.Study subjects included 569 heart defect cases and 785 non-malformed controls born from 1997 to 2006 whose mothers participated in a population-based case-control study. Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for relevant covariates, for 8 heart defect phenotypes that included ≥50 cases and pesticide exposures with ≥5 exposed cases and controls, which resulted in 235 comparisons.38% of cases and controls were classified as exposed to pesticides within a 500m radius of mother׳s address during a 3-month periconceptional window. Adjusted odds ratios (AORs) with 95% CIs excluding 1.0 were observed for 18 comparisons; all were >1 and ranged from 1.9 to 7.1. They included tetralogy of Fallot (n=101 cases) and neonicotinoids; hypoplastic left heart syndrome (n=59) and strobins; coarctation of the aorta (n=74) and pyridazinones; pulmonary valve stenosis (n=53) and bipyridyliums and organophosphates; ventricular septal defects (n=93) and avermectins and pyrethroids; and atrial septal defects (n=132) and dichlorphenoxy acid or esters, organophosphates, organotins, and pyrethroids. No AORs met both of these criteria for d-transposition of the great arteries (n=58) or heterotaxia (n=53).Most pesticides were not associated with increased risk of specific heart defect phenotypes. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

  View details for DOI 10.1016/j.envres.2014.08.030

  View details for PubMedID 25262086

• Better Diet Quality before Pregnancy Is Associated with Reduced Risk of Gastroschisis in Hispanic Women JOURNAL OF NUTRITION Feldkamp, M. L., Krikov, S., Botto, L. D., Shaw, G. M., Carmichael, S. L. 2014; 144 (11): 1781-1786

  Abstract

  Gastroschisis is unique because of its substantial risk in pregnancies of adolescent women. Adolescents may have poor diet quality, which places them at higher risk of gastroschisis.We investigated whether better maternal diet quality, measured by 2 different indices, reduced the risk of gastroschisis.We used case-control data from the National Birth Defects Prevention Study to investigate maternal diet quality among 1125 gastroschisis cases and 9483 controls (estimated delivery dates between 1997 and 2009). Cases were ascertained from 10 U.S. birth defect surveillance systems. Control subjects were randomly selected from birth certificates or hospital records. Using a 58-item food-frequency questionnaire, interviewers queried mothers about their average food and cereal intake during the year before conception. Diet quality scores [Diet Quality Index (DQI) and Mediterranean diet score (MDS)] were calculated using specific components. Women were excluded if they consumed <500 or >5000 kcal/d, reported pregestational diabetes, or had >1 missing food item. Quartile-specific adjusted ORs (aORs) were calculated, using as reference the lowest quartile.Overall, we observed a statistically significant decrease with increasing diet quality for both the DQI and MDS. When stratified by maternal race/ethnicity, this finding was confined to Hispanic women. Among Hispanic women, the risk of gastroschisis decreased significantly with increasing DQI quartiles: quartile 2, aOR = 0.58 (95% CI: 0.40, 0.86); quartile 3, aOR = 0.52 (95% CI: 0.36, 0.79); and quartile 4, aOR = 0.48 (95% CI: 0.32, 0.76). Increasing diet quality, as measured by the MDS, showed reduced risk of gastroschisis among women, mostly Hispanic, who were born outside the United States: quartile 2, aOR = 0.62 (95% CI: 0.33, 1.16); quartile 3, aOR = 0.51 (95% CI: 0.28, 0.94); and quartile 4, aOR = 0.50 (95% CI: 0.28, 0.90).Increasing diet quality was associated with a reduced risk of gastroschisis only among Hispanic and foreign-born women, but these findings require replication.

  View details for DOI 10.3945/jn.114.201376

  View details for Web of Science ID 000343681400016

  View details for PubMedID 25332477

• Sociodemographic and Hispanic Acculturation Factors and Isolated Anotia/Microtia BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Hoyt, A. T., Canfield, M. A., Shaw, G. M., Waller, D. K., Polen, K. N., Ramadhani, T., Anderka, M. T., Scheuerle, A. E. 2014; 100 (11): 852-862

  Abstract

  It has been observed in several studies that infants with anotia/microtia are more common among Hispanics compared with other racial/ethnic groups. We examined the association between selected Hispanic ethnicity and acculturation factors and anotia/microtia in the National Birth Defects Prevention Study.We examined data from mothers of 351 infants with isolated anotia/microtia and 8435 unaffected infants from the National Birth Defects Prevention Study with an expected delivery date from 1997 to 2007. Sociodemographic, maternal, and acculturation factors (e.g., age, maternal education, household income, body mass index, gestational diabetes, folic acid, smoking, alcohol intake, study center, parental birthplace, and years lived in the United States, maternal language) were assessed as overall risk factors and also as risk factors among subgroups of Hispanics (United States- and foreign-born) versus non-Hispanic whites.Compared with non-Hispanic whites, both United States- and foreign-born Hispanic mothers demonstrated substantially higher odds of delivering infants with anotia/microtia across nearly all strata of sociodemographic and other maternal factors (adjusted odds ratios range: 2.1-11.9). The odds of anotia/microtia was particularly elevated among Hispanic mothers who emigrated from Mexico after age five (adjusted odds ratios = 4.88; 95% confidence interval = 2.93-8.11) or who conducted the interview in Spanish (adjusted odds ratios = 4.97; 95% confidence interval = 3.00-8.24).We observed that certain sociodemographic and acculturation factors are associated with higher risks of anotia/microtia among offspring of Hispanic mothers.

  View details for DOI 10.1002/bdra.23282

  View details for Web of Science ID 000345690600007

  View details for PubMedID 25074828

• Corticosteroid Use and Risk for Orofacial Clefts EDITORIAL COMMENT OBSTETRICAL & GYNECOLOGICAL SURVEY Skuladottir, H., Wilcox, A. J., Ma, C., Lammer, E. J., Rasmussen, S. A., Werler, M. M., Shaw, G. M., Carmichael, S. L. 2014; 69 (10): 573-575

  View details for DOI 10.1097/01.ogx.0000456345.09228.f3

  View details for Web of Science ID 000344453200003

• 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

• Early Pregnancy Agricultural Pesticide Exposures and Risk of Gastroschisis among Offspring in the San Joaquin Valley of California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Yang, W., Roberts, E., Kegley, S. E., Padula, A., English, P. B., Carmichael, S. L. 2014; 100 (9): 686-694

  Abstract

  Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis.We used population-based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California (). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects.Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1-5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking.Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women. Birth Defects Research (Part A), 100:686-694, 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23263

  View details for Web of Science ID 000342625200006

• Early pregnancy agricultural pesticide exposures and risk of gastroschisis among offspring in the San Joaquin Valley of California. Birth defects research. Part A, Clinical and molecular teratology Shaw, G. M., Yang, W., Roberts, E., Kegley, S. E., Padula, A., English, P. B., Carmichael, S. L. 2014; 100 (9): 686-694

  Abstract

  Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis.We used population-based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California (). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects.Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1-5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking.Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women. Birth Defects Research (Part A), 100:686-694, 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23263

  View details for PubMedID 24910073

• 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

• Irf6 regulates Tfap2a and is required for neurulation Kousa, Y. A., Zhu, H., Busch, T. D., Kinoshita, A., Fakhouri, W. D., Roushangar, R. R., Smith, A. L., Dunnwald, M., Williams, T. J., Chai, Y., Amendt, B. A., Murray, J. C., Shaw, G. M., Bassuk, A. G., Finnell, R. H., Schutte, B. C. WILEY-BLACKWELL. 2014: 1883-1884

  View details for Web of Science ID 000340667900030

• Association between maternal characteristics, abnormal serum aneuploidy analytes, and placental abruption. American journal of obstetrics and gynecology Blumenfeld, Y. J., Baer, R. J., Druzin, M. L., El-Sayed, Y. Y., Lyell, D. J., Faucett, A. M., Shaw, G. M., Currier, R. J., Jelliffe-Pawlowski, L. L. 2014; 211 (2): 144 e1-9

  View details for DOI 10.1016/j.ajog.2014.03.027

  View details for PubMedID 24631707

• 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

• Maternal occupational exposure to polycyclic aromatic hydrocarbons and small for gestational age offspring. Occupational and environmental medicine Langlois, P. H., Hoyt, A. T., Desrosiers, T. A., Lupo, P. J., Lawson, C. C., Waters, M. A., Rocheleau, C. M., Shaw, G. M., Romitti, P. A., Gilboa, S. M., Malik, S. 2014; 71 (8): 529-535

  Abstract

  While some of the highest maternal exposures to polycyclic aromatic hydrocarbons (PAHs) occur in the workplace, there is only one previous study of occupational PAH exposure and adverse pregnancy outcomes. We sought to extend this literature using interview data combined with detailed exposure assessment.Data for 1997-2002 were analysed from mothers of infants without major birth defects in the National Birth Defects Prevention Study, a large population-based case-control study in the USA. Maternal telephone interviews yielded information on jobs held in the month before conception through delivery. From 6252 eligible control mothers, 2803 completed the interview, had a job, met other selection criteria, and were included in the analysis. Two industrial hygienists independently assessed occupational exposure to PAHs from the interview and reviewed results with a third to reach consensus. Small for gestational age (SGA) was the only adverse pregnancy outcome with enough exposed cases to yield meaningful results. Logistic regression estimated crude and adjusted ORs.Of the 2803 mothers, 221 (7.9%) had infants who were SGA. Occupational PAH exposure was found for 17 (7.7%) of the mothers with SGA offspring and 102 (4.0%) of the remaining mothers. Almost half the jobs with exposure were related to food preparation and serving. After adjustment for maternal age, there was a significant association of occupational exposure with SGA (OR=2.2, 95% CI 1.3 to 3.8).Maternal occupational exposure to PAHs was found to be associated with increased risk of SGA offspring.

  View details for DOI 10.1136/oemed-2013-101833

  View details for PubMedID 24893704

• Maternal Exposure to Criteria Air Pollutants and Congenital Heart Defects in Offspring: Results from the National Birth Defects Prevention Study ENVIRONMENTAL HEALTH PERSPECTIVES Stingone, J. A., Luben, T. J., Daniels, J. L., Fuentes, M., Richardson, D. B., Aylsworth, A. S., Herring, A. H., Anderka, M., Botto, L., Correa, A., Gilboa, S. M., Langlois, P. H., Mosley, B., Shaw, G. M., Siffel, C., Olshan, A. F. 2014; 122 (8): 863-872

  Abstract

  Epidemiologic literature suggests that exposure to air pollutants is associated with fetal development.We investigated maternal exposures to air pollutants during weeks 2-8 of pregnancy and their associations with congenital heart defects.Mothers from the National Birth Defects Prevention Study, a nine-state case-control study, were assigned 1-week and 7-week averages of daily maximum concentrations of carbon monoxide, nitrogen dioxide, ozone, and sulfur dioxide and 24-hr measurements of fine and coarse particulate matter using the closest air monitor within 50 km to their residence during early pregnancy. Depending on the pollutant, a maximum of 4,632 live-birth controls and 3,328 live-birth, fetal-death, or electively terminated cases had exposure data. Hierarchical regression models, adjusted for maternal demographics and tobacco and alcohol use, were constructed. Principal component analysis was used to assess these relationships in a multipollutant context.Positive associations were observed between exposure to nitrogen dioxide and coarctation of the aorta and pulmonary valve stenosis. Exposure to fine particulate matter was positively associated with hypoplastic left heart syndrome but inversely associated with atrial septal defects. Examining individual exposure-weeks suggested associations between pollutants and defects that were not observed using the 7-week average. Associations between left ventricular outflow tract obstructions and nitrogen dioxide and between hypoplastic left heart syndrome and particulate matter were supported by findings from the multipollutant analyses, although estimates were attenuated at the highest exposure levels.Using daily maximum pollutant levels and exploring individual exposure-weeks revealed some positive associations between certain pollutants and defects and suggested potential windows of susceptibility during pregnancy.

  View details for DOI 10.1289/ehp.1307289

  View details for Web of Science ID 000341713800024

  View details for PubMedID 24727555

  View details for PubMedCentralID PMC4123026

• Association between maternal characteristics, abnormal serum aneuploidy analytes, and placental abruption. American journal of obstetrics and gynecology Blumenfeld, Y. J., Baer, R. J., Druzin, M. L., El-Sayed, Y. Y., Lyell, D. J., Faucett, A. M., Shaw, G. M., Currier, R. J., Jelliffe-Pawlowski, L. L. 2014; 211 (2): 144 e1-9

  Abstract

  The objective of the study was to examine the association between placental abruption, maternal characteristics, and routine first- and second-trimester aneuploidy screening analytes.The study consisted of an analysis of 1017 women with and 136,898 women without placental abruption who had first- and second-trimester prenatal screening results, linked birth certificate, and hospital discharge records for a live-born singleton. Maternal characteristics and first- and second-trimester aneuploidy screening analytes were analyzed using logistic binomial regression.Placental abruption was more frequent among women of Asian race, age older than 34 years, women with chronic and pregnancy-associated hypertension, preeclampsia, preexisting diabetes, previous preterm birth, and interpregnancy interval less than 6 months. First-trimester pregnancy-associated plasma protein-A of the fifth percentile or less, second-trimester alpha fetoprotein of the 95th percentile or greater, unconjugated estriol of the fifth percentile or less, and dimeric inhibin-A of the 95th percentile or greater were associated with placental abruption as well. When logistic models were stratified by the presence or absence of hypertensive disease, only maternal age older than 34 years (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.0-2.0), pregnancy-associated plasma protein-A of the 95th percentile or less (OR, 1.9; 95% CI, 1.2-3.1), and alpha fetoprotein of the 95th percentile or greater (OR, 2.3; 95% CI, 1.4-3.8) remained statistically significantly associated for abruption.In this large, population-based cohort study, abnormal maternal aneuploidy serum analyte levels were associated with placental abruption, regardless of the presence of hypertensive disease.

  View details for DOI 10.1016/j.ajog.2014.03.027

  View details for PubMedID 24631707

• 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

• Haploinsufficiency of insulin gene enhancer protein 1 (ISL1) is associated with d-transposition of the great arteries. Molecular genetics & genomic medicine Osoegawa, K., Schultz, K., Yun, K., Mohammed, N., Shaw, G. M., Lammer, E. J. 2014; 2 (4): 341-351

  Abstract

  Congenital heart defects are the most common malformation, and are the foremost causes of mortality in the first year of life. Among congenital heart defects, conotruncal defects represent about 20% and are severe malformations with significant morbidity. Insulin gene enhancer protein 1 (ISL1) has been considered a candidate gene for conotruncal heart defects based on its embryonic expression pattern and heart defects induced in Isl1 knockout mice. Nevertheless no mutation of ISL1 has been reported from any human subject with a heart defect. From a population base of 974,579 births during 1999-2004, we used multiplex ligation-dependent probe amplification to screen for microdeletions/duplications of ISL1 among 389 infants with tetralogy of Fallot or d-transposition of the great arteries (d-TGA). We also sequenced all exons of ISL1. We identified a novel 20-kb microdeletion encompassing the entire coding region of ISL1, but not including either flanking gene, from an infant with d-TGA. We confirmed that the deletion was caused by nonhomologous end joining mechanism. Sequencing of exons of ISL1 did not reveal any subject with a novel nonsynonymous mutation. This is the first report of an ISL1 mutation of a child with a congenital heart defect.

  View details for DOI 10.1002/mgg3.75

  View details for PubMedID 25077177

  View details for PubMedCentralID PMC4113275

• Maternal stressors and social support as risks for delivering babies with structural birth defects. Paediatric and perinatal epidemiology Carmichael, S. L., Ma, C., Tinker, S., Rasmussen, S. A., Shaw, G. M. 2014; 28 (4): 338-344

  Abstract

  We examined the association of maternal stressful life events and social support with risks of birth defects using National Birth Defects Prevention Study data, a population-based case-control study.We examined seven stressful life events and three social support questions applicable to the periconceptional period, among mothers of 552 cases with neural tube defects (NTDs), 413 cleft palate (CP), 797 cleft lip ± cleft palate (CLP), 189 d-transposition of the great arteries (dTGA), 311 tetralogy of Fallot (TOF), and 2974 non-malformed controls. A stressful life events index equalled the sum of 'yes' responses to the seven questions. Social support questions were also summed to form an index. Data were analyzed using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for maternal race-ethnicity, age, education, body mass index, smoking, drinking, and intake of vitamin supplements.Associations with the stress index tended to be higher with higher scores, but few 95% CIs excluded one. A four-point increase in the index was moderately associated with NTDs (OR 1.5, [95% CI 1.1, 2.0]) and CLP (OR 1.3, [95% CI 1.0, 1.7]). The social support index tended to be associated with reduced risk but most 95% CIs included one, with the exception of dTGA (OR for a score of 3 vs 0 was 0.5 [95% CI 0.3, 0.8]).Maternal periconceptional stressful life events, social support, and the two factors in combination were at most modestly, if at all, associated with risks of the studied birth defects.

  View details for DOI 10.1111/ppe.12123

  View details for PubMedID 24697924

  View details for PubMedCentralID PMC4057295

• 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

• Corticosteroid Use and Risk of Orofacial Clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Skuladottir, H., Wilcox, A. J., Ma, C., Lammer, E. J., Rasmussen, S. A., Werler, M. M., Shaw, G. M., Carmichael, S. L. 2014; 100 (6): 499-506

  Abstract

  Maternal use of corticosteroids during early pregnancy has been inconsistently associated with orofacial clefts in the offspring. A previous report from the National Birth Defect Prevention Study (NBDPS), using data from 1997 to 2002, found an association with cleft lip and palate (odds ratio, 1.7; 95% confidence interval [CI], 1.1-2.6), but not cleft palate only (odds ratio, 0.5, 95%CI, 0.2-1.3). From 2003 to 2009, the study population more than doubled in size, and our objective was to assess this association in the more recent data.The NBDPS is an ongoing multi-state population-based case-control study of birth defects, with ascertainment of cases and controls born since 1997. We assessed the association of corticosteroids and orofacial clefts using data from 2372 cleft cases and 5922 controls born from 2003 to 2009. Maternal corticosteroid exposure was based on telephone interviews.The overall association of corticosteroids and cleft lip and palate in the new data was 1.0 (95% CI, 0.7-1.4). There was little evidence of associations between specific corticosteroid components or timing and clefts.In contrast to the 1997 to 2002 data from the NBDPS, the 2003 to 2009 data show no association between maternal corticosteroid use and cleft lip and palate in the offspring.

  View details for DOI 10.1002/bdra.23248

  View details for Web of Science ID 000338036300006

  View details for PubMedCentralID PMC4283705

• 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

• Congenital heart defects after maternal fever AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Botto, L. D., Panichello, J. D., Browne, M. L., Krikov, S., Feldkamp, M. L., Lammer, E., Shaw, G. M. 2014; 210 (4)

  Abstract

  The purpose of this study was to evaluate whether maternal febrile illnesses in early pregnancy are associated with increased risk for congenital heart defects in the offspring and whether such risk is mitigated by multivitamin supplement use.From a multistate population-based case-control study (National Birth Defects Prevention Study), we compared maternal reports of first-trimester febrile illness from 7020 subjects with heart defects and 6746 unaffected control subjects who were born from 1997 through 2005. Relative risks were computed with no fever or infection during the first trimester as reference group and were adjusted for potential confounders.First-trimester febrile illness was reported by 7.4% of control mothers (1 in 13). Febrile genitourinary infections were associated with selected heart defects, particularly right-sided obstructive defects (odds ratios, >3) and possibly others, whereas common respiratory illnesses were associated with low-to-negligible risks for most heart defects. When risk estimates were elevated, they tended to be mitigated when multivitamin supplements had been taken in the periconceptional period.The source of fever and the use of supplements appear to influence the risk for heart defects. This information can be helpful in counseling and research, in particular with regard to primary prevention.

  View details for DOI 10.1016/j.ajog.2013.10.880

  View details for Web of Science ID 000333401900023

  View details for PubMedID 24184180

• Genetic Epidemiology and Nonsyndromic Structural Birth Defects From Candidate Genes to Epigenetics JAMA PEDIATRICS Hobbs, C. A., Chowdhury, S., Cleves, M. A., Erickson, S., MacLeod, S. L., Shaw, G. M., Shete, S., Witte, J. S., Tycko, B. 2014; 168 (4): 371-377

  Abstract

  Birth defects are a leading cause of infant morbidity and mortality worldwide. The vast majority of birth defects are nonsyndromic, and although their etiologies remain mostly unknown, evidence supports the hypothesis that they result from the complex interaction of genetic, epigenetic, environmental, and lifestyle factors. Since our last review published in 2002 describing the basic tools of genetic epidemiology used to study nonsyndromic structural birth defects, many new approaches have become available and have been used with varying success. Through rapid advances in genomic technologies, investigators are now able to investigate large portions of the genome at a fraction of previous costs. With next-generation sequencing, research has progressed from assessing a small percentage of single-nucleotide polymorphisms to assessing the entire human protein-coding repertoire (exome)-an approach that is starting to uncover rare but informative mutations associated with nonsyndromic birth defects. Herein, we report on the current state of the genetic epidemiology of birth defects and comment on future challenges and opportunities. We consider issues of study design, and we discuss common variant approaches, including candidate gene studies and genome-wide association studies. We also discuss the complexities embedded in exploring interactions between genes and the environment. We complete our review by describing new and promising next-generation sequencing technologies and examining how the study of epigenetic mechanisms could become the key to unraveling the complex etiologies of nonsyndromic structural birth defects.

  View details for DOI 10.1001/jamapediatrics.2013.4858

  View details for Web of Science ID 000336839200014

  View details for PubMedID 24515445

  View details for PubMedCentralID PMC3981910

• Late Detection of Critical Congenital Heart Disease Among US Infants: Estimation of the Potential Impact of Proposed Universal Screening Using Pulse Oximetry. JAMA pediatrics Peterson, C., Ailes, E., Riehle-Colarusso, T., Oster, M. E., Olney, R. S., Cassell, C. H., Fixler, D. E., Carmichael, S. L., Shaw, G. M., Gilboa, S. M. 2014; 168 (4): 361-370

  Abstract

  IMPORTANCE Critical congenital heart disease (CCHD) was added to the Recommended Uniform Screening Panel for Newborns in the United States in 2011. Many states have recently adopted or are considering requirements for universal CCHD screening through pulse oximetry in birth hospitals. Limited previous research is directly applicable to the question of how many US infants with CCHD might be identified through screening. OBJECTIVES To estimate the proportion of US infants with late detection of CCHD (>3 days after birth) based on existing clinical practice and to investigate factors associated with late detection. DESIGN, SETTING, AND PARTICIPANTS Descriptive and multivariable analysis. Data were obtained from a multisite population-based study of birth defects in the United States, the National Birth Defects Prevention Study (NBDPS). We included all live-born infants with estimated dates of delivery from January 1, 1998, through December 31, 2007, and nonsyndromic, clinically verified CCHD conditions potentially detectable through screening via pulse oximetry. MAIN OUTCOMES AND MEASURES The main outcome measure was the proportion of infants with late detection of CCHD through echocardiography or at autopsy under the assumption that universal screening at birth hospitals might reduce the number of such late diagnoses. Secondary outcome measures included prevalence ratios for associations between selected demographic and clinical factors and late detection of CCHD. RESULTS Of 3746 live-born infants with nonsyndromic CCHD, late detection occurred in 1106 (29.5% [95% CI, 28.1%-31.0%]), including 6 (0.2%) (0.1%-0.4%) first receiving a diagnosis at autopsy more than 3 days after birth. Late detection varied by CCHD type from 9 of 120 infants (7.5% [95% CI, 3.5%-13.8%]) with pulmonary atresia to 497 of 801 (62.0% [58.7%-65.4%]) with coarctation of the aorta. In multivariable analysis, late detection varied significantly by CCHD type and study site, and infants with extracardiac defects were significantly less likely to have late detection of CCHD (adjusted prevalence ratio, 0.58 [95% CI, 0.49-0.69]). CONCLUSIONS AND RELEVANCE We estimate that 29.5% of live-born infants with nonsyndromic CCHD in the NBDPS received a diagnosis more than 3 days after birth and therefore might have benefited from routine CCHD screening at birth hospitals. The number of infants in whom CCHD was detected through screening likely varies by several factors, including CCHD type. Additional population-based studies of screening in practice are needed.

  View details for DOI 10.1001/jamapediatrics.2013.4779

  View details for PubMedID 24493342

• Residential Agricultural Pesticide Exposures and Risk of Neural Tube Defects and Orofacial Clefts Among Offspring in the San Joaquin Valley of California AMERICAN JOURNAL OF EPIDEMIOLOGY Yang, W., Carmichael, S. L., Roberts, E. M., Kegley, S. E., Padula, A. M., English, P. B., Shaw, G. M. 2014; 179 (6): 740-748

  Abstract

  We examined whether early gestational exposures to pesticides were associated with an increased risk of anencephaly, spina bifida, cleft lip with or without cleft palate (CLP), or cleft palate only. We used population-based data along with detailed information from maternal interviews. Exposure estimates were based on residential proximity to agricultural pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley, California (1997-2006). Analyses included 73 cases with anencephaly, 123 with spina bifida, 277 with CLP, and 117 with cleft palate only in addition to 785 controls. A total of 38% of the subjects were exposed to 52 chemical groups and 257 specific chemicals. There were relatively few elevated odds ratios with 95% confidence intervals that excluded 1 after adjustment for relevant covariates. Those chemical groups included petroleum derivatives for anencephaly, hydroxybenzonitrile herbicides for spina bifida, and 2,6-dinitroaniline herbicides and dithiocarbamates-methyl isothiocyanate for CLP. The specific chemicals included 2,4-D dimethylamine salt, methomyl, imidacloprid, and α-(para-nonylphenyl)-ω-hydroxypoly(oxyethylene) phosphate ester for anencephaly; the herbicide bromoxynil octanoate for spina bifida; and trifluralin and maneb for CLP. Adjusted odds ratios ranged from 1.6 to 5.1. Given that such odds ratios might have arisen by chance because of the number of comparisons, our study showed a general lack of association between a range of agricultural pesticide exposures and risks of selected birth defects.

  View details for DOI 10.1093/aje/kwt324

  View details for Web of Science ID 000333246800011

  View details for PubMedID 24553680

• Identification of Novel CELSR1 Mutations in Spina Bifida PLOS ONE Lei, Y., Zhu, H., Yang, W., Ross, M. E., Shaw, G. M., Finnell, R. H. 2014; 9 (3)

  Abstract

  Spina bifida is one of the most common neural tube defects (NTDs) with a complex etiology. Variants in planar cell polarity (PCP) genes have been associated with NTDs including spina bifida in both animal models and human cohorts. In this study, we sequenced all exons of CELSR1 in 192 spina bifida patients from a California population to determine the contribution of CELSR1 mutations in the studied population. Novel and rare variants identified in these patients were subsequently genotyped in 190 ethnically matched control individuals. Six missense mutations not found in controls were predicted to be deleterious by both SIFT and PolyPhen. Two TG dinucleotide repeat variants were individually detected in 2 spina bifida patients but not detected in controls. In vitro functional analysis showed that the two TG dinucleotide repeat variants not only changed subcellular localization of the CELSR1 protein, but also impaired the physical association between CELSR1 and VANGL2, and thus diminished the ability to recruit VANGL2 for cell-cell contact. In total, 3% of our spina bifida patients carry deleterious or predicted to be deleterious CELSR1 mutations. Our findings suggest that CELSR1 mutations contribute to the risk of spina bifida in a cohort of spina bifida patients from California.

  View details for DOI 10.1371/journal.pone.0092207

  View details for Web of Science ID 000332858400150

  View details for PubMedID 24632739

  View details for PubMedCentralID PMC3954890

• 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

• Association between Eclampsia, Maternal Characteristics, and Abnormal Levels of First and Second Trimester Serum Biomarkers. Jelliffe-Pawlowski, L., Baer, R., Currier, R., Blumenfeld, Y., El-Sayed, Y., Lyell, D., Shaw, G., Druzin, M. SAGE PUBLICATIONS INC. 2014: 297A

  View details for Web of Science ID 000333813002340

• 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

• Identification of Novel Candidate Gene Loci and Increased Sex Chromosome Aneuploidy Among Infants With Conotruncal Heart Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Osoegawa, K., Iovannisci, D. M., Lin, B., Parodi, C., Schultz, K., Shaw, G. M., Lammer, E. J. 2014; 164 (2): 397-406

  Abstract

  Congenital heart defects (CHDs) are common malformations, affecting four to eight per 1,000 total births. Conotruncal defects are an important pathogenetic subset of CHDs, comprising nearly 20% of the total. Although both environmental and genetic factors are known to contribute to the occurrence of conotruncal defects, the causes remain unknown for most. To identify novel candidate genes/loci, we used array comparative genomic hybridization to detect chromosomal microdeletions/duplications. From a population base of 974,579 total births born during 1999-2004, we screened 389 California infants born with tetralogy of Fallot or d-transposition of the great arteries. We found that 1.7% (5/288) of males with a conotruncal defect had sex chromosome aneuploidy, a sevenfold increased frequency (relative risk = 7.0; 95% confidence interval 2.9-16.9). We identified eight chromosomal microdeletions/duplications for conotruncal defects. From these duplications and deletions, we found five high priority candidate genes (GATA4, CRKL, BMPR1A, SNAI2, and ZFHX4). This is the initial report that sex chromosome aneuploidy is associated with conotruncal defects among boys. These chromosomal microduplications/deletions provide evidence that GATA4, SNAI2, and CRKL are highly dosage sensitive genes involved in outflow tract development. Genome wide screening for copy number variation can be productive for identifying novel genes/loci contributing to non-syndromic common malformations.

  View details for DOI 10.1002/ajmg.a.36291

  View details for Web of Science ID 000331067100017

  View details for PubMedCentralID PMC3946915

• Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects. American journal of medical genetics. Part A Osoegawa, K., Iovannisci, D. M., Lin, B., Parodi, C., Schultz, K., Shaw, G. M., Lammer, E. J. 2014; 164A (2): 397-406

  Abstract

  Congenital heart defects (CHDs) are common malformations, affecting four to eight per 1,000 total births. Conotruncal defects are an important pathogenetic subset of CHDs, comprising nearly 20% of the total. Although both environmental and genetic factors are known to contribute to the occurrence of conotruncal defects, the causes remain unknown for most. To identify novel candidate genes/loci, we used array comparative genomic hybridization to detect chromosomal microdeletions/duplications. From a population base of 974,579 total births born during 1999-2004, we screened 389 California infants born with tetralogy of Fallot or d-transposition of the great arteries. We found that 1.7% (5/288) of males with a conotruncal defect had sex chromosome aneuploidy, a sevenfold increased frequency (relative risk = 7.0; 95% confidence interval 2.9-16.9). We identified eight chromosomal microdeletions/duplications for conotruncal defects. From these duplications and deletions, we found five high priority candidate genes (GATA4, CRKL, BMPR1A, SNAI2, and ZFHX4). This is the initial report that sex chromosome aneuploidy is associated with conotruncal defects among boys. These chromosomal microduplications/deletions provide evidence that GATA4, SNAI2, and CRKL are highly dosage sensitive genes involved in outflow tract development. Genome wide screening for copy number variation can be productive for identifying novel genes/loci contributing to non-syndromic common malformations.

  View details for DOI 10.1002/ajmg.a.36291

  View details for PubMedID 24127225

• One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects. Birth defects research. Part A, Clinical and molecular teratology Shaw, G. M., Yang, W., Carmichael, S. L., Vollset, S. E., Hobbs, C. A., Lammer, E. J., Ueland, P. M. 2014; 100 (2): 107-115

  Abstract

  Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with conotruncal heart defects. A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and conotruncal heart defects by measuring analytes in mid-pregnancy sera.This study included data from a repository of women's mid-pregnancy serum specimens based on screened pregnancies in California from 2002-2007. Each woman's specimen was linked with delivery information to determine whether her fetus had a conotruncal heart defect or another structural malformation, or was nonmalformed. We identified 140 conotruncal cases and randomly selected 280 specimens as nonmalformed controls. Specimens were tested for a variety of analytes, including homocysteine, methylmalonic acid, folate, vitamin B12 , pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, total choline, betaine, methionine, cysteine, cystathionine, arginine, asymmetric and symmetric dimethylarginine.We did not observe statistical evidence for substantial differences between cases and controls for any of the measured analytes. Analyses specifically targeting B-vitamins also did not reveal differences between cases and controls. Birth Defects Research (Part A) 100:107-115, 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23224

  View details for PubMedID 24532477

• Maternal-fetal metabolic gene-gene interactions and risk of neural tube defects MOLECULAR GENETICS AND METABOLISM Lupo, P. J., Mitchell, L. E., Canfield, M. A., Shaw, G. M., Olshan, A. F., Finnell, R. H., Zhu, H. 2014; 111 (1): 46-51

  Abstract

  Single-gene analyses indicate that maternal genes associated with metabolic conditions (e.g., obesity) may influence the risk of neural tube defects (NTDs). However, to our knowledge, there have been no assessments of maternal-fetal metabolic gene-gene interactions and NTDs. We investigated 23 single nucleotide polymorphisms among 7 maternal metabolic genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, and TCF7L2) and 2 fetal metabolic genes (SLC2A2 and UCP2). Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study for birth years 1999-2007. We used a 2-step approach to evaluate maternal-fetal gene-gene interactions. First, a case-only approach was applied to screen all potential maternal and fetal interactions (n = 76), as this design provides greater power in the assessment of gene-gene interactions compared to other approaches. Specifically, ordinal logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each maternal-fetal gene-gene interaction, assuming a log-additive model of inheritance. Due to the number of comparisons, we calculated a corrected p-value (q-value) using the false discovery rate. Second, we confirmed all statistically significant interactions (q < 0.05) using a log-linear approach among case-parent triads. In step 1, there were 5 maternal-fetal gene-gene interactions with q < 0.05. The "top hit" was an interaction between maternal ENPP1 rs1044498 and fetal SLC2A2 rs6785233 (interaction OR = 3.65, 95% CI: 2.32-5.74, p = 2.09×10(-8), q=0.001), which was confirmed in step 2 (p = 0.00004). Our findings suggest that maternal metabolic genes associated with hyperglycemia and insulin resistance and fetal metabolic genes involved in glucose homeostasis may interact to increase the risk of NTDs.

  View details for DOI 10.1016/j.ymgme.2013.11.004

  View details for Web of Science ID 000330158100007

  View details for PubMedID 24332798

• Placental accreta and first and second trimester maternal serum markers and characteristics Lyell, D., Faucett, A., Baer, R., Blumenfeld, Y., Druzin, M., El-Sayed, Y., Shaw, G., Currier, R., Jelliffee-Pawlowski, L. MOSBY-ELSEVIER. 2014: S62

  View details for DOI 10.1016/j.ajog.2013.10.129

  View details for Web of Science ID 000330322600099

• Association between severe early onset preeclampsia (PE) and serum measures of first trimester pregnancy associated plasma protein A (PAPP-A) and human chorionic gonadotrophin (hCG) Jelliffe, L., Druzin, M., Baer, R., Lyell, D., El-Sayed, Y., Blumenfeld, Y., Faucett, A., Shaw, G., Currier, R. MOSBY-ELSEVIER. 2014: S143

  View details for DOI 10.1016/j.ajog.2013.10.302

  View details for Web of Science ID 000330322600270

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

  View details for DOI 10.1016/j.ajog.2013.10.798

  View details for Web of Science ID 000330322600765

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

  Abstract

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

  View details for DOI 10.1371/journal.pone.0094153

  View details for PubMedID 24740117

• 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

• Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism ANDROLOGY Carmichael, S. L., Witte, J. S., Ma, C., Lammer, E. J., Shaw, G. M. 2014; 2 (1): 130-137

  Abstract

  We examined whether variants in genes related to sex hormone biosynthesis and metabolism were associated with hypospadias in humans. We examined 332 relatively common tag single-nucleotide polymorphisms (tagSNPs) in 20 genes. Analyses included 633 cases (84 mild, 322 moderate, 212 severe and 15 undetermined severity) and 855 population-based non-malformed male controls born in California from 1990 to 2003. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each SNP. Several of the 332 studied SNPs had p < 0.01: one in CYP3A4, four in HSD17B3, one in HSD3B1, two in STARD3, 10 in SRD5A2 and seven in STS. In addition, haplotype analyses gave several associations with p < 0.01. For HSD17B3, 14-SNP and 5-SNP blocks had ORs of 1.5 (95% CI 1.1, 2.0, p < 0.001) and 2.8 (95% CI 1.6, 4.8, p < 0.001) respectively. For SRD5A2, 9-SNP, 3-SNP and 8-SNP blocks had ORs of 1.7 (95% CI 1.3, 2.2, p < 0.001), 1.4 (95% CI 1.1, 1.8, p = 0.008) and 1.5 (95% CI 1.2, 1.9, p = 0.002) respectively. Our study indicates that several genes that contribute to sex hormone biosynthesis and metabolism are associated with hypospadias risk.

  View details for DOI 10.1111/j.2047-2927.2013.00165.x

  View details for Web of Science ID 000328729900019

  View details for PubMedID 24281767

• Could genetic polymorphisms related to oxidative stress modulate effects of heavy metals for risk of human preterm birth? Reproductive toxicology Shachar, B. Z., Carmichael, S. L., Stevenson, D. K., Shaw, G. M. 2013; 42: 24-26

  Abstract

  Human preterm birth (PTB) is a complex medical outcome influenced by a combination of genetic and environmental factors. Research on the causative factors of PTB has mostly focused on demographic, socio-behavioral and environmental risk factors. Recent studies turn the spotlight on the effects of heavy metals exposure on adverse pregnancy outcomes. Here we present and evaluate the hypothesis that heavy metals may cause PTB through oxidative stress, and that this effect may be modified by polymorphisms in genes related to oxidative stress. Indeed, accumulating data suggest that the risk of PTB is correlated with polymorphisms in genes involved in detoxification, oxidative stress and lipid metabolism. These and other polymorphisms have independently been associated with susceptibility to the adverse effects of heavy metals.

  View details for DOI 10.1016/j.reprotox.2013.06.072

  View details for PubMedID 23811355

• Hypospadias and Genes Related to Genital Tubercle and Early Urethral Development JOURNAL OF UROLOGY Carmichael, S. L., Ma, C., Choudhry, S., Lammer, E. J., Witte, J. S., Shaw, G. M. 2013; 190 (5): 1884-1892

  Abstract

  PURPOSE: We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans. MATERIALS AND METHODS: We examined 293 relatively common tagSNPs in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2, and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population-based non-malformed male controls born in California from 1990-2003. RESULTS: There were 28 SNPs for which any of the comparisons (i.e., overall or for a specific severity) had a p-value <0.01. The homozygous variant genotypes for four SNPs in BMP7were associated with at least 2-fold increased risk of hypospadias, regardless of severity. Five SNPs for FGF10were associated with 3- to 4-fold increased risks, regardless of severity; for four of them, results were restricted to whites. For GLI1, GLI2and GLI3, there were 12 associated SNPs but results were inconsistent by severity and race-ethnicity. For SHH, one SNP was associated with 2.4-fold increased risk of moderate hypospadias. For WT1, six SNPs were associated with approximately 2-fold increased risks, primarily for severe hypospadias. CONCLUSIONS: This study provides evidence that SNPs in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk.

  View details for DOI 10.1016/j.juro.2013.05.061

  View details for Web of Science ID 000325471400089

  View details for PubMedID 23727413

• Hypospadias and residential proximity to pesticide applications. Pediatrics Carmichael, S. L., Yang, W., Roberts, E. M., Kegley, S. E., Wolff, C., Guo, L., Lammer, E. J., English, P., Shaw, G. M. 2013; 132 (5): e1216-26

  Abstract

  Experimental evidence suggests pesticides may be associated with hypospadias.Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications.The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year.Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9.Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

  View details for DOI 10.1542/peds.2013-1429

  View details for PubMedID 24167181

  View details for PubMedCentralID PMC3813401

• Hypospadias and residential proximity to pesticide applications. Pediatrics Carmichael, S. L., Yang, W., Roberts, E. M., Kegley, S. E., Wolff, C., Guo, L., Lammer, E. J., English, P., Shaw, G. M. 2013; 132 (5): e1216-26

  Abstract

  Experimental evidence suggests pesticides may be associated with hypospadias.Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications.The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). We determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Associations with exposures to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for maternal race or ethnicity and age and infant birth year.Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9.Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

  View details for DOI 10.1542/peds.2013-1429

  View details for PubMedID 24167181

  View details for PubMedCentralID PMC3813401

• Traffic-related air pollution and selected birth defects in the San Joaquin Valley of California. Birth defects research. Part A, Clinical and molecular teratology Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W., Lurmann, F. W., Shaw, G. M. 2013; 97 (11): 730-735

  Abstract

  Birth defects are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some structural anomalies, although evidence is limited and several anomalies have not been investigated previously.We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 26 congenital birth defect phenotypes with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997 to 2006 (874 cases and 849 controls). We calculated odds ratios (adjusted for maternal race/ethnicity, education, and vitamin use; aOR) for 11 phenotypes that had at least 40 cases.Few odds ratios had confidence intervals that did not include 1.0. Odds of esophageal atresia were increased for the highest versus lowest of traffic density (aOR = 2.8, 95% confidence interval [CI], 1.1-7.4) and PM10 exposure (aOR 4.9; 95% CI, 1.4-17.2). PM10 was associated with a decreased risk of hydrocephaly (aOR= 0.3; 95% CI, 0.1-0.9) and CO with decreased risk of anotia/microtia (aOR = 0.4; 95% CI, 0.2-0.8) and transverse limb deficiency (aOR = 0.4; 95% CI, 0.2-0.9), again reflecting highest versus lowest quartile comparisons.Most analyses showed no substantive association between air pollution and the selected birth defects with few exceptions of mixed results. Birth Defects Research (Part A) 97:730-735, 2013. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23175

  View details for PubMedID 24108522

• Periconceptional nutrient intakes and risks of orofacial clefts in California. Pediatric research Wallenstein, M. B., Shaw, G. M., Yang, W., Carmichael, S. L. 2013; 74 (4): 457-465

  Abstract

  Background:Evidence indicates that maternal nutrient intake may play a role in the development of birth defects. We investigated the association of maternal periconceptional intake of vitamin supplements and dietary nutrients with risk of developing cleft palate (CP) and cleft lip with or without cleft palate (CLP).Methods:Data were from a population-based, case-control study of fetuses and liveborn infants delivered in California,1999-2003. Analyses included 170 cases with CP, 425 with CLP, and 534 nonmalformed controls. Dietary intake was estimated from a food frequency questionnaire.Results:Vitamin supplement intake was associated with a modestly decreased risk of clefts, but the confidence intervals include one. Among women who did not use vitamin supplements, dietary intake of several micronutrients was associated with risk of clefts. We found at least a two-fold elevated risk of CP with low intake of riboflavin, magnesium, calcium, vitamin B12, and zinc; all CIs excluded 1.0. For CLP, we found at least a two-fold elevated risk with low intake of niacin, riboflavin, vitamin B12, and calcium, and a decreased risk with high intake of folate and cryptoxanthin; all CIs excluded 1.0.Conclusion:Results suggest that periconceptional nutrient intake may be associated with risk of CP and CLP.Pediatric Research (2013); doi:10.1038/pr.2013.115.

  View details for DOI 10.1038/pr.2013.115

  View details for PubMedID 23823175

• Maternal Dietary Nutrient Intake and Risk of Preterm Delivery AMERICAN JOURNAL OF PERINATOLOGY Carmichael, S. L., Yang, W., Shaw, G. M. 2013; 30 (7): 579-588

  Abstract

  Objective To examine maternal dietary intake and preterm delivery.Study Design Data included 5738 deliveries from the National Birth Defects Prevention Study. Odds ratios (ORs) reflected risks of delivery at <32, 32-34, or 35-36 versus ≥37 weeks for maternal intake in the lowest or highest quartile of nutrient intake compared with the middle two.Results Among deliveries < 32 weeks, many ORs were ≥1.5 or ≤0.7, but few confidence intervals excluded one. ORs were ≥1.5 for lowest quartiles of protein, thiamin, riboflavin, choline, vitamin A, α-carotene, β-carotene, vitamin E, iron, copper, and zinc and for highest quartiles of carbohydrate, glycemic index, and Mediterranean Diet Score. ORs were ≤0.7 for lowest quartiles of glycemic index and betaine and for highest quartiles of protein, alanine, methionine, vitamin B6, betaine, and calcium. Few ORs met these criteria for later preterm deliveries.Conclusions Results suggested an association of nutrient intake with earlier preterm deliveries.

  View details for DOI 10.1055/s-0032-1329686

  View details for Web of Science ID 000322021900009

  View details for PubMedID 23208764

• Hypospadias and Maternal Intake of Phytoestrogens AMERICAN JOURNAL OF EPIDEMIOLOGY Carmichael, S. L., Cogswell, M. E., Ma, C., Gonzalez-Feliciano, A., Olney, R. S., Correa, A., Shaw, G. M. 2013; 178 (3): 434-440

  Abstract

  Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ≥90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.

  View details for DOI 10.1093/aje/kws591

  View details for Web of Science ID 000322734500012

  View details for PubMedID 23752918

  View details for PubMedCentralID PMC3727340

• A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia. Pediatrics Wang, H., St Julien, K. R., Stevenson, D. K., Hoffmann, T. J., Witte, J. S., Lazzeroni, L. C., Krasnow, M. A., Quaintance, C. C., Oehlert, J. W., Jelliffe-Pawlowski, L. L., Gould, J. B., Shaw, G. M., O'Brodovich, H. M. 2013; 132 (2): 290-297

  Abstract

  Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD.The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip.Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative.We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

  View details for DOI 10.1542/peds.2013-0533

  View details for PubMedID 23897914

• Mutations in Planar Cell Polarity Gene SCRIB Are Associated with Spina Bifida PLOS ONE Lei, Y., Zhu, H., Duhon, C., Yang, W., Ross, M. E., Shaw, G. M., Finnell, R. H. 2013; 8 (7)

  Abstract

  Neural tube defects (NTDs) (OMIM #182940) including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5-1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP) genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc) mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R) significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida.

  View details for DOI 10.1371/journal.pone.0069262

  View details for Web of Science ID 000322838900029

  View details for PubMedID 23922697

  View details for PubMedCentralID PMC3724847

• Ambient air pollution and traffic exposures and congenital heart defects in the san joaquin valley of california. Paediatric and perinatal epidemiology Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Yang, W., Lurmann, F., Shaw, G. M. 2013; 27 (4): 329-339

  Abstract

  Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited.We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997-2006 (n = 822 cases and n = 849 controls).Particulate matter < 10 microns (PM10 ) was associated with pulmonary valve stenosis [adjusted odds ratio (aOR)Fourth Quartile  = 2.6] [95% confidence intervals (CI) 1.2, 5.7] and perimembranous ventricular septal defects (aORThird Quartile  = 2.1) [95% CI 1.1, 3.9] after adjusting for maternal race/ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aORThird Quartile  = 2.6) [95% CI 1.1, 6.5] and inversely associated with perimembranous ventricular septal defects (aORFourth Quartile  = 0.5) [95% CI 0.2, 0.9]. Secundum atrial septal defects were inversely associated with carbon monoxide (aORFourth Quartile  = 0.4) [95% CI 0.2, 0.8] and PM2.5 (aORFourth Quartile  = 0.5) [95% CI 0.3, 0.8]. Traffic density was associated with muscular ventricular septal defects (aORFourth Quartile  = 3.0) [95% CI 1.2, 7.8] and perimembranous ventricular septal defects (aORThird Quartile  = 2.4) [95% CI 1.3, 4.6], and inversely associated with transposition of the great arteries (aORFourth Quartile  = 0.3) [95% CI 0.1, 0.8].PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies.

  View details for DOI 10.1111/ppe.12055

  View details for PubMedID 23772934

  View details for PubMedCentralID PMC3694598

• A Pilot Study Using Residual Newborn Dried Blood Spots to Assess the Potential Role of Cytomegalovirus and Toxoplasma gondii in the Etiology of Congenital Hydrocephalus BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Simeone, R. M., Rasmussen, S. A., Mei, J. V., Dollard, S. C., Frias, J. L., Shaw, G. M., Canfield, M. A., Meyer, R. E., Jones, J. L., Lorey, F., Honein, M. A. 2013; 97 (7): 431-436

  Abstract

  Congenital hydrocephalus is a condition characterized by accumulation of cerebrospinal fluid in the ventricles of the brain. Prenatal infections are risk factors for some birth defects. This pilot study investigated whether residual dried blood spots (DBS) could be used to assess infections as risk factors for birth defects by examining the associations between prenatal infection with Toxoplasma gondii (T. gondii) or cytomegalovirus (CMV) with congenital hydrocephalus.Case-infants with hydrocephalus (N=410) were identified among live-born infants using birth defects surveillance systems in California, North Carolina, and Texas. Control-infants without birth defects were randomly selected from the same geographic areas and time periods as case-infants (N=448). We tested residual DBS from case- and control-infants for T. gondii immunoglobulin M and CMV DNA. When possible, we calculated crude odds ratios (cORs) and confidence intervals (CIs).Evidence for prenatal T. gondii infection was more common among case-infants (1.2%) than control-infants (0%; p=0.11), and evidence for prenatal CMV infection was higher among case-infants (1.5%) than control-infants (0.7%; cOR: 2.3; 95% CI: 0.48, 13.99).Prenatal infections with T. gondii and CMV occurred more often among infants with congenital hydrocephalus than control-infants, although differences were not statistically significant. This pilot study highlighted some challenges in using DBS to examine associations between certain infections and birth defects, particularly related to reduced sensitivity and specimen storage conditions. Further study with increased numbers of specimens and higher quality specimens should be considered to understand better the contribution of these infections to the occurrence of congenital hydrocephalus.

  View details for DOI 10.1002/bdra.23138

  View details for Web of Science ID 000326397800001

  View details for PubMedID 23716471

• Association of early-preterm birth with abnormal levels of routinely collected first- and second-trimester biomarkers AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Jelliffe-Pawlowski, L. L., Shaw, G. M., Currier, R. J., Stevenson, D. K., Baer, R. J., O'Brodovich, H. M., Gould, J. B. 2013; 208 (6)

  Abstract

  The purpose of this study was to examine the relationship between typically measured prenatal screening biomarkers and early-preterm birth in euploid pregnancies.The study included 345 early-preterm cases (<30 weeks of gestation) and 1725 control subjects who were drawn from a population-based sample of California pregnancies who had both first- and second-trimester screening results. Logistic regression analyses were used to compare patterns of biomarkers in cases and control subjects and to develop predictive models. Replicability of the biomarker early-preterm relationships that was revealed by the models was evaluated by examination of the frequency and associated adjusted relative risks (RRs) for early-preterm birth and for preterm birth in general (<37 weeks of gestation) in pregnancies with identified abnormal markers compared with pregnancies without these markers in a subsequent independent California cohort of screened pregnancies (n = 76,588).The final model for early-preterm birth included first-trimester pregnancy-associated plasma protein A in the ≤5th percentile, second-trimester alpha-fetoprotein in the ≥95th percentile, and second-trimester inhibin in the ≥95th percentile (odds ratios, 2.3-3.6). In general, pregnancies in the subsequent cohort with a biomarker pattern that were found to be associated with early-preterm delivery in the first sample were at an increased risk for early-preterm birth and preterm birth in general (<37 weeks of gestation; adjusted RR, 1.6-27.4). Pregnancies with ≥2 biomarker abnormalities were at particularly increased risk (adjusted RR, 3.6-27.4).When considered across cohorts and in combination, abnormalities in routinely collected biomarkers reveal predictable risks for early-preterm birth.

  View details for DOI 10.1016/j.ajog.2013.02.012

  View details for Web of Science ID 000320596600029

  View details for PubMedID 23395922

  View details for PubMedCentralID PMC3672244

• The Association of Ambient Air Pollution and Traffic Exposures With Selected Congenital Anomalies in the San Joaquin Valley of California AMERICAN JOURNAL OF EPIDEMIOLOGY Padula, A. M., Tager, I. B., Carmichael, S. L., Hammond, S. K., Lurmann, F., Shaw, G. M. 2013; 177 (10): 1074-1085

  Abstract

  Congenital anomalies are a leading cause of infant mortality and are important contributors to subsequent morbidity. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. We aimed to investigate whether ambient air pollutant and traffic exposures in early gestation contribute to the risk of selected congenital anomalies in the San Joaquin Valley of California, 1997-2006. Seven exposures and 5 outcomes were included for a total of 35 investigated associations. We observed increased odds of neural tube defects when comparing the highest with the lowest quartile of exposure for several pollutants after adjusting for maternal race/ethnicity, education, and multivitamin use. The adjusted odds ratio for neural tube defects among those with the highest carbon monoxide exposure was 1.9 (95% confidence interval: 1.1, 3.2) compared with those with the lowest exposure, and there was a monotonic exposure-response across quartiles. The highest quartile of nitrogen oxide exposure was associated with neural tube defects (adjusted odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). The adjusted odds ratio for the highest quartile of nitrogen dioxide exposure was 1.7 (95% confidence interval: 1.1, 2.7). Ozone was associated with decreased odds of neural tube defects. Our results extend the limited body of evidence regarding air pollution exposure and adverse birth outcomes.

  View details for DOI 10.1093/aje/kws367

  View details for Web of Science ID 000318801200006

  View details for PubMedID 23538941

  View details for PubMedCentralID PMC3697063

• Maternal occupational exposure to polycyclic aromatic hydrocarbons and risk of oral cleft-affected pregnancies. Cleft palate-craniofacial journal Langlois, P. H., Hoyt, A. T., Lupo, P. J., Lawson, C. C., Waters, M. A., Desrosiers, T. A., Shaw, G. M., Romitti, P. A., Lammer, E. J. 2013; 50 (3): 337-346

  Abstract

  Objective :  To evaluate whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons and oral clefts in offspring. This is the first human study of polycyclic aromatic hydrocarbons and clefts of which the authors are aware. Design :  Case-control study. Setting, Participants :  Data for 1997 to 2002 from the National Birth Defects Prevention Study, a large population-based case-control study in the United States, were analyzed. Maternal telephone interviews yielded information on jobs held in the month before through 3 months after conception. Two industrial hygienists independently assessed occupational exposure to polycyclic aromatic hydrocarbons; all jobs rated as exposed or with rating difficulty were reviewed with a third industrial hygienist to reach consensus on all exposure parameters. Logistic regression estimated crude and adjusted odds ratios with 95% confidence intervals for cleft lip with or without cleft palate and cleft palate alone. Results :  There were 2989 controls (3.5% exposed), 805 cases of cleft lip with or without cleft palate (5.8% exposed), and 439 cases of cleft palate alone (4.6% exposed). The odds of maternal occupational exposure to polycyclic aromatic hydrocarbons (any versus none) during pregnancy was increased for cleft lip with or without cleft palate cases as compared with controls (odds ratio, 1.69; 95% confidence interval, 1.18 to 2.40); the odds ratio was 1.47 (95% confidence interval 1.02 to 2.12) when adjusted for maternal education. There was a statistically significant adjusted exposure-response relationship for cleft lip with or without cleft palate (Ptrend = .02). Odd ratios for cleft palate alone were not statistically significant. Conclusions :  Maternal occupational exposure to polycyclic aromatic hydrocarbons was associated with increased risk of cleft lip with or without cleft palate in offspring.

  View details for DOI 10.1597/12-104

  View details for PubMedID 23136939

• 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

• Considering the vascular hypothesis for the pathogenesis of small intestinal atresia: A case control study of genetic factors AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gupta, T., Yang, W., Iovannisci, D. M., Carmichael, S. L., Stevenson, D. K., Shaw, G. M., Lammer, E. J. 2013; 161A (4): 702-710

  Abstract

  Small intestinal atresia (SIA) is a rare congenital occlusion of the small intestine. SIA development, particularly in the jejunum and ileum, has been associated with in utero disruption of vascular supply. However, the number of studies of the vascular hypothesis is limited. This study considers the vascular hypothesis by exploring risks associated with 32 SNPs of genes involved in vascular processes of homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. A total of 206 SIA cases were ascertained by the California Birth Defects Monitoring Program, and 573 infants with no major congenital anomalies by their first birthday were selected as controls. Genomic DNA was genotyped for 32 SNPs involving the following genes: MTHFR, F2, F5, F7, SERPINE1, FGB, ITGA2, ITGB3, SELE, ICAM1, MMP3, TNF, LTA, NOS3, AGTR1, AGT, NPPA, ADD1, SCNN1A, GNB3, and ADRB2. Risks were estimated as odds ratios, adjusted for maternal age and race, with 95% confidence intervals. Cases were considered collectively and by subgroups based on atresia location (duodenal/jejunum/ileum). Three SNPs had reduced risk: SERPINE1 11053 T/G, MMP3 (-1171) A6/A5, and ADRB2 gln27glu. Two had increased risk: ITGA2 873 G/A and NPPA 2238 T/C. No intestinal subphenotypes showed a unique pattern of SNP associations. The association of two SNPs with increased risk lends some, albeit limited, support to vascular impairment as a possible mechanism leading to SIA. These results also identify genes meriting further exploration in SIA studies. Hence, this study makes an important contribution by exploring the long-held but not well-investigated vascular hypothesis.

  View details for DOI 10.1002/ajmg.a.35775

  View details for Web of Science ID 000316631300012

• Progress in understanding the genetics of bronchopulmonary dysplasia SEMINARS IN PERINATOLOGY Shaw, G. M., O'Brodovich, H. M. 2013; 37 (2): 85-93

  Abstract

  Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in infants. Its treatment imposes considerable healthcare burden and costs in the perinatal and early childhood period and patients are usually left with lifelong deficits in lung function. Evidence exists for different pathophysiologic pathways that can promote the structural changes that characterize BPD, including the impairment in alveolarization; however, there is increasing interest regarding heritable factors that may predispose very low birth weight infants to BPD. Our review focuses on recent publications that have investigated genetic factors that may potentially contribute to such reported heritability. These publications point us toward some possible genomic candidates for further study, but certainly do not identify any particular gene or gene pathway that would be inferred to be contributing substantially to the underlying etiology of BPD.

  View details for DOI 10.1053/j.semperi.2013.01.004

  View details for Web of Science ID 000317870800005

  View details for PubMedID 23582962

  View details for PubMedCentralID PMC3628629

• The Continuing Challenge of Understanding, Preventing, and Treating Neural Tube Defects SCIENCE Wallingford, J. B., Niswander, L. A., Shaw, G. M., Finnell, R. H. 2013; 339 (6123)

  Abstract

  Human birth defects are a major public health burden: The Center for Disease Control estimates that 1 of every 33 United States newborns presents with a birth defect, and worldwide the estimate approaches 6% of all births. Among the most common and debilitating of human birth defects are those affecting the formation of the neural tube, the precursor to the central nervous system. Neural tube defects (NTDs) arise from a complex combination of genetic and environmental interactions. Although substantial advances have been made in the prevention and treatment of these malformations, NTDs remain a substantial public health problem, and we are only now beginning to understand their etiology. Here, we review the process of neural tube development and how defects in this process lead to NTDs, both in humans and in the animal models that serve to inform our understanding of these processes. The insights we are gaining will help generate new intervention strategies to tackle the clinical challenges and to alleviate the personal and societal burdens that accompany these defects.

  View details for DOI 10.1126/science.1222002

  View details for Web of Science ID 000315452000032

  View details for PubMedID 23449594

  View details for PubMedCentralID PMC3677196

• An Innovative Approach to Recruitment and Biospecimen Collection: A Study of Spina Bifida Genetics Lazaruk, K., Sitts, K., Beyer, C., Lammer, E., Shaw, G., Gilbert, D. SAGE PUBLICATIONS INC. 2013: 207A

  View details for Web of Science ID 000329543100491

• Thymidylate synthase polymorphisms and risks of human orofacial clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Yang, W., Perloff, S., Shaw, N. M., Carmichael, S. L., Zhu, H., Lammer, E. J. 2013; 97 (2): 95-100

  Abstract

  Underlying mechanisms are unknown by which folic acid use in early pregnancy may reduce risks of orofacial clefts. Thymidylate synthase (TYMS) is a folate-dependent enzyme that catalyzes reductive methylation of deoxyuridylate to thymidylate, thereby playing a central role in DNA synthesis and repair. We investigated two TYMS functional variants (a 28-bp tandem repeat in the promoter enhancer region of the 5'-UTR; and TYMS 1494del6 (rs16430): a 6-bp deletion in the 3'-UTR) for their risk of cleft palate (CP) and of cleft lip with/without CP (CLP). We investigated effect measure modification between these variants and maternal folate intake for cleft risk.This case-control study included deliveries from July 1999 to June 2003 from select areas of California. Case groups included CLP or CP alone. Nonmalformed, liveborn controls were randomly selected. Maternal interviews provided information on vitamin use and dietary folate intake. DNA was derived from newborn bloodspots.Data were available for 304 CLP cases, 123 CP cases, and 581 controls. 1496del6 variants did not appear to influence risk of CP or CLP. Homozygosity for the 28-bp VNTR variant influenced CP risk (odds ratios, OR = 1.8, 95% confidence interval, 1.1-3.1), particularly among Hispanic infants, OR 2.1 (1.0-4.6). Effect measure modification was observed between the 28-bp VNTR and combined folate intake for CP with an OR of 10.0 (1.6-60.9).Although these findings are consistent with biological mechanisms, they were based on relatively small sample sizes and may represent false-positive discoveries. Replication is warranted in other populations.

  View details for DOI 10.1002/bdra.23114

  View details for Web of Science ID 000314982400004

  View details for PubMedID 23404871

• Diacylglycerol Kinase K Variants Impact Hypospadias in a California Study Population JOURNAL OF UROLOGY Carmichael, S. L., Mohammed, N., Ma, C., Iovannisci, D., Choudhry, S., Baskin, L. S., Witte, J. S., Shaw, G. M., Lammer, E. J. 2013; 189 (1): 305-311

  Abstract

  A recent genome wide association study demonstrated the novel finding that variants in DGKK are associated with hypospadias. Our objectives were to determine whether this finding could be replicated in a more racially/ethnically diverse study population of California births and to provide a more comprehensive investigation of variants.We examined the association of 27 DGKK single nucleotide polymorphisms with hypospadias relative to population based nonmalformed controls born in selected California counties from 1990 to 2003. Analyses included a maximum of 928 controls and 665 cases (mild in 91, moderate in 336, severe in 221 and undetermined in 17). Results for mild and moderate cases were similar, so they were grouped together.For mild and moderate cases OR for 15 of the 27 single nucleotide polymorphisms had p values less than 0.05, with 2 less than 1 and the others ranging from 1.3 to 1.8. Among severe cases ORs tended to be closer to 1, and none of the p values were less than 0.05. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and 2 blocks were generated. These analyses identified a set of 8 variants associated with a threefold to fourfold increased risk relative to the most common haplotype, regardless of severity of the phenotype (OR 4.1, p <10(-4) for mild to moderate cases and 3.3, p = 0.001 for severe cases).This study confirms that DGKK variants are associated with hypospadias. Additional studies are needed to allow a more thorough investigation of DGKK variability and to delineate the mechanism by which DGKK contributes to urethral development.

  View details for DOI 10.1016/j.juro.2012.09.002

  View details for Web of Science ID 000312604800107

  View details for PubMedID 23177175

• Thoughts on the Future of Reproductive and Perinatal Epidemiology PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Ness, R. B., Bodnar, L., Holzman, C., Platt, R. W., Savitz, D. A., Shaw, G. M., Klebanoff, M. 2013; 27 (1): 11-19

  View details for DOI 10.1111/ppe.12017

  View details for Web of Science ID 000312142900004

  View details for PubMedID 23215705

• High Quality Genome-Wide Genotyping from Archived Dried Blood Spots without DNA Amplification. PloS one St Julien, K. R., Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., O'Brodovich, H. M., Krasnow, M. A. 2013; 8 (5): e64710

  Abstract

  Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.

  View details for DOI 10.1371/journal.pone.0064710

  View details for PubMedID 23737996

  View details for PubMedCentralID PMC3667813

• High quality genome-wide genotyping from archived dried blood spots without DNA amplification. PloS one St Julien, K. R., Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., O'Brodovich, H. M., Krasnow, M. A. 2013; 8 (5)

  Abstract

  Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA.

  View details for DOI 10.1371/journal.pone.0064710

  View details for PubMedID 23737996

• Diabetes and Obesity-Related Genes and the Risk of Neural Tube Defects in the National Birth Defects Prevention Study AMERICAN JOURNAL OF EPIDEMIOLOGY Lupo, P. J., Canfield, M. A., Chapa, C., Lu, W., Agopian, A. J., Mitchell, L. E., Shaw, G. M., Waller, D. K., Olshan, A. F., Finnell, R. H., Zhu, H. 2012; 176 (12): 1101-1109

  Abstract

  Few studies have evaluated genetic susceptibility related to diabetes and obesity as a risk factor for neural tube defects (NTDs). The authors investigated 23 single nucleotide polymorphisms among 9 genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, SLC2A2, TCF7L2, and UCP2) associated with type 2 diabetes or obesity. Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study during 1999-2007. Log-linear models were used to evaluate maternal and offspring genetic effects. After application of the false discovery rate, there were 5 significant maternal genetic effects. The less common alleles at the 4 FTO single nucleotide polymorphisms showed a reduction of NTD risk (for rs1421085, relative risk (RR) = 0.73 (95% confidence interval (CI): 0.62, 0.87); for rs8050136, RR = 0.79 (95% CI: 0.67, 0.93); for rs9939609, RR = 0.79 (95% CI: 0.67, 0.94); and for rs17187449, RR = 0.80 (95% CI: 0.68, 0.95)). Additionally, maternal LEP rs2071045 (RR = 1.31, 95% CI: 1.08, 1.60) and offspring UCP2 rs660339 (RR = 1.32, 95% CI: 1.06, 1.64) were associated with NTD risk. Furthermore, the maternal genotype for TCF7L2 rs3814573 suggested an increased NTD risk among obese women. These findings indicate that maternal genetic variants associated with glucose homeostasis may modify the risk of having an NTD-affected pregnancy.

  View details for DOI 10.1093/aje/kws190

  View details for Web of Science ID 000312634900006

  View details for PubMedID 23132673

  View details for PubMedCentralID PMC3571234

• Dietary Glycemic Index and the Risk of Birth Defects AMERICAN JOURNAL OF EPIDEMIOLOGY Parker, S. E., Werler, M. M., Shaw, G. M., Anderka, M., Yazdy, M. M. 2012; 176 (12): 1110-1120

  Abstract

  Prepregnancy diabetes and obesity have been identified as independent risk factors for several birth defects, providing support for a mechanism that involves hyperglycemia and hyperinsulinemia in the development of malformations. Data from the National Birth Defects Prevention Study from 1997 to 2007 were used to investigate the association between the maternal dietary glycemic index (DGI) and the risk of birth defects among nondiabetic women. DGI was categorized by using spline regression models and quartile distributions. Adjusted odds ratios and 95% confidence intervals were calculated. The joint effect of DGI and obesity was also examined. Among the 53 birth defects analyzed, high DGI, categorized by spline regression, was significantly associated with encephalocele (adjusted odds ratio (aOR) = 2.68), diaphragmatic hernia (aOR = 2.58), small intestinal atresia/stenosis (aOR = 2.97) including duodenal atresia/stenosis (aOR = 2.48), and atrial septal defect (aOR = 1.37). Using quartiles to categorize DGI, the authors identified associations with cleft lip with cleft palate (aOR = 1.23) and anorectal atresia/stenosis (aOR = 1.40). The joint effect of high DGI and obesity provided evidence of a synergistic effect on the risk of selected birth defects. High DGI is associated with an increased risk of a number of birth defects under study. Obesity coupled with high DGI appears to increase the risk further for some birth defects.

  View details for DOI 10.1093/aje/kws201

  View details for Web of Science ID 000312634900007

  View details for PubMedID 23171874

  View details for PubMedCentralID PMC3571231

• Improved Survival Among Children with Spina Bifida in the United States JOURNAL OF PEDIATRICS Shin, M., Kucik, J. E., Siffel, C., Lu, C., Shaw, G. M., Canfield, M. A., Correa, A. 2012; 161 (6): 1132-U205

  Abstract

  To evaluate trends in survival among children with spina bifida by race/ethnicity and possible prognostic factors in 10 regions of the United States.A retrospective cohort study was conducted of 5165 infants with spina bifida born during 1979-2003, identified by 10 birth defects registries in the United States. Survival probabilities and adjusted hazard ratios were estimated for race/ethnicity and other characteristics using the Cox proportional hazard model.During the study period, the 1-year survival probability among infants with spina bifida showed improvements for whites (from 88% to 96%), blacks (from 79% to 88%), and Hispanics (from 88% to 93%). The impact of race/ethnicity on survival varied by birth weight, which was the strongest predictor of survival through age 8. There was little racial/ethnic variation in survival among children born of very low birth weight. Among children born of low birth weight, the increased risk of mortality to Hispanics was approximately 4-6 times that of whites. The black-white disparity was greatest among children born of normal birth weight. Congenital heart defects did not affect the risk of mortality among very low birth weight children but increased the risk of mortality 4-fold among children born of normal birth weight.The survival of infants born with spina bifida has improved; however, improvements in survival varied by race/ethnicity, and blacks and Hispanics continued to have poorer survival than whites in the most recent birth cohort from 1998-2002. Further studies are warranted to elucidate possible reasons for the observed differences in survival.

  View details for DOI 10.1016/j.jpeds.2012.05.040

  View details for Web of Science ID 000311348400032

  View details for PubMedID 22727874

• Expected Body Weight in Adolescents: Comparison Between Weight-for-Stature and BMI Methods PEDIATRICS Golden, N. H., Yang, W., Jacobson, M. S., Robinson, T. N., Shaw, G. M. 2012; 130 (6): E1607-E1613

  Abstract

  To test the hypothesis that the weight-for-stature (WFS) and BMI methods are not equivalent in determining expected body weight (EBW) in adolescents with eating disorders and to determine the sensitivity, specificity, and positive predictive value of each method to detect those <75% EBW. We hypothesized that differences in EBW would be greatest at the extremes of height.EBW was determined for 12 047 individual adolescents aged 12 to 19 years by the WFS and BMI methods by utilizing the same National Center for Health Statistics data sets. Absolute difference between the 2 methods for each individual was calculated and plotted against height by using a generalized additive model. The number of individuals whose weights were <75% EBW was determined by each method.For girls, EBW was 3.52 ± 3.13% higher when using the WFS method compared with the BMI method. For boys, EBW(WFS) was 3.45 ± 2.72% higher than EBW(BMI). Among adolescent girls, 65% had EBW(WFS) higher than EBW(BMI). By using the EBW(WFS) method as the gold standard, specificity of the EBW(BMI) method to detect those <75% EBW was 0.999, but sensitivity was only 0.329. Absolute differences in EBW were most pronounced at the extremes of height.The WFS and BMI methods are not equivalent in determining EBW in adolescents and are not interchangeable. EBW(WFS) was ~3.5% higher than EBW(BMI). In adolescents with eating disorders, use of the BMI method will underestimate the degree of malnutrition compared with the WFS method. Which method better predicts meaningful clinical outcomes remains to be determined.

  View details for DOI 10.1542/peds.2012-0897

  View details for PubMedID 23147977

• Association of microtia with maternal nutrition BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Ma, C., Shaw, G. M., Scheuerle, A. E., Canfield, M. A., Carmichael, S. L. 2012; 94 (12): 1026-1032

  Abstract

  Few studies have investigated the potential association of maternal dietary intake and risk of microtia among offspring.The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic cases of microtia were compared to nonmalformed, population-based, live-born control infants by estimating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race or ethnicity, education, folic acid-containing supplement intake, fertility treatment, study site, and total energy intake.Comparing intake in the lowest 10th percentile versus the 10th to 90th percentiles, lower maternal intakes of carbohydrate (OR, 1.59; 95% CI, 1.07-2.38) and dietary folate (OR, 1.57; 95% CI, 1.09-2.25) were associated with elevated risk of microtia. In addition, results suggested that higher diet quality (as measured by the Diet Quality Index, and comparing the highest with the lowest quartile) was protective, but the CI did not exclude one (OR, 0.73; 95% CI, 0.50-1.07). Results were similar among obese and nonobese women.These data contribute to the limited body of evidence regarding the potential contribution of maternal nutrition to the etiology of microtia.

  View details for DOI 10.1002/bdra.23053

  View details for Web of Science ID 000312527100010

  View details for PubMedID 22821770

• Association between weight gain during pregnancy and neural tube defects and gastroschisis in offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, W., Carmichael, S. L., Tinker, S. C., Shaw, G. M. 2012; 94 (12): 1019-1025

  Abstract

  Limited information is available about the association of maternal weight gain during pregnancy and birth defects. The objective of this study was to investigate the association of maternal weight gain with neural tube defects (NTDs) and gastroschisis among offspring.We used data from the National Birth Defects Prevention Study, an ongoing multicenter, population-based, case-control study. Mothers of cases and controls were interviewed by telephone. Analyses included 255 anencephaly, 577 spina bifida, 648 gastroschisis cases, and 5587 controls with deliveries from 1999 to 2005. After subtracting birth weight, the associations of total and average weekly weight gain (kg) with each phenotype were estimated, stratified by gestational age (<37 vs. ≥37 weeks) and adjusted for relevant covariates.Among deliveries <37 weeks gestation, mothers of infants with anencephaly and spina bifida had lower weight gains compared to control mothers; no association between weight gains and gastroschisis was observed. Among deliveries ≥37 weeks, mothers of infants with anencephaly had lower weight gains during pregnancy; a similar association was not observed for spina bifida; mothers of infants with gastroschisis were twice as likely to have weight gains in the highest quartile. Stratification by maternal age (gastroschisis) or body mass index (BMI) or race/ethnicity (all phenotypes) did not alter odds ratio estimates.Altered weight gain during pregnancy may be a consequence of carrying an NTD/gastroschisis affected fetus or a marker for underlying factors common to the etiology of these birth defects. It is possible that whatever mechanisms influence weight gain may also influence the development of NTDs and gastroschisis, but in opposite directions.

  View details for DOI 10.1002/bdra.23057

  View details for Web of Science ID 000312527100009

  View details for PubMedID 22847944

  View details for PubMedCentralID PMC3522774

• Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Chandler, A. L., Hobbs, C. A., Mosley, B. S., Berry, R. J., Canfield, M. A., Qi, Y. P., Siega-Riz, A. M., Shaw, G. M. 2012; 94 (11): 864-874

  Abstract

  Maternal nutritional status has been evaluated to clarify its role in development of neural tube defects (NTDs). Maternal folate intake during pregnancy has been closely evaluated for its association with NTDs. The study objective was to examine associations between NTDs and other dietary periconceptional micronutrient intake, particularly nutrients involved in one-carbon metabolism or antioxidant activity.Using data from the National Birth Defects Prevention Study, 1997-2005, logistic regression models were used to estimate the relative risk of NTDs based on maternal micronutrient intake.Results were stratified according to folic acid supplement use, race/ethnicity, and maternal body mass index. Analyses included 954 cases (300 with anencephaly, 654 with spina bifida) and 6268 controls. Higher intakes of folate, thiamin, betaine, iron, and vitamin A were associated with decreased risk of anencephaly among some ethnic and clinical groups. In some groups, higher intakes of thiamin, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, and retinol were associated with decreased risk of spina bifida.In addition to folic acid, other micronutrients, including thiamin, betaine, riboflavin, vitamin B(6) , vitamin C, vitamin E, niacin, iron, retinol, and vitamin A, may decrease the risk of NTD occurrence. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.

  View details for DOI 10.1002/bdra.23068

  View details for Web of Science ID 000311234400002

  View details for PubMedID 22933447

  View details for PubMedCentralID PMC3518275

• A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study MOLECULAR GENETICS AND METABOLISM Lupo, P. J., Chapa, C., Nousome, D., Duhon, C., Canfield, M. A., Shaw, G. M., Finnell, R. H., Zhu, H. 2012; 107 (3): 592-595

  Abstract

  Tetrahydrobiopterin (BH(4)) is an essential cofactor and an important cellular antioxidant. BH(4) deficiency has been associated with diseases whose etiologies stem from excessive oxidative stress. GTP cyclohydrolase I (GCH1) catalyzes the first and rate-limiting step of de novo BH(4) synthesis. A 3-SNP haplotype in GCH1 (rs8007267, rs3783641, and rs10483639) is known to modulate GCH1 gene expression levels and has been suggested as a major determinant of plasma BH(4) bioavailability. As plasma BH(4) bioavailability has been suggested as a mechanism of neural tube defect (NTD) teratogenesis, we evaluated the association between this GCH1 haplotype and the risk of NTDs. Samples were obtained from 760 NTD case-parent triads included in the National Birth Defects Prevention Study (NBDPS). The three SNPs were genotyped using TaqMan® SNP assays. An extension of the log-linear model was used to assess the association between NTDs and both offspring and maternal haplotypes. Offspring carrying two copies of haplotype C-T-C had a significantly increased NTD risk (risk ratio [RR]=3.40, 95% confidence interval [CI]: 1.02-11.50), after adjusting for the effect of the maternal haplotype. Additionally, mothers carrying two copies of haplotype C-T-C had a significantly increased risk of having an NTD-affected offspring (RR=3.46, 95% CI: 1.05-11.00), after adjusting for the effect of the offspring haplotype. These results suggest offspring and maternal variation in the GCH1 gene and altered BH(4) biosynthesis may contribute to NTD risk.

  View details for DOI 10.1016/j.ymgme.2012.09.020

  View details for Web of Science ID 000310720200050

  View details for PubMedID 23059057

• Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lupo, P. J., Symanski, E., Langlois, P. H., Lawson, C. C., Malik, S., Gilboa, S. M., Lee, L. J., Agopian, A. J., Desrosiers, T. A., Waters, M. A., Romitti, P. A., Correa, A., Shaw, G. M., Mitchell, L. E. 2012; 94 (11): 875-881

  Abstract

  There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring.Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring.The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58-1.67), septal defects (AOR, 1.28; 95% CI, 0.86-1.90), or with any isolated CHD subtype.Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012.

  View details for DOI 10.1002/bdra.23071

  View details for Web of Science ID 000311234400003

  View details for PubMedID 22945317

• Analysis of Selected Maternal Exposures and Non-Syndromic Atrioventricular Septal Defects in the National Birth Defects Prevention Study, 1997-2005 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Patel, S. S., Burns, T. L., Botto, L. D., Riehle-Colarusso, T. J., Lin, A. E., Shaw, G. M., The, P. A. 2012; 158A (10): 2447-2455

  Abstract

  Although the descriptive epidemiology of atrioventricular septal defects (AVSDs), a group of serious congenital heart defects (CHDs), has been recently reported, non-genetic risk factors have not been consistently identified. Using data (1997-2005) from the National Birth Defects Prevention Study, an ongoing multisite population-based case-control study, the association between selected non-genetic factors and non-syndromic AVSDs was examined. Data on periconceptional exposures to such factors were collected by telephone interview from 187 mothers of AVSD case infants and 6,703 mothers of unaffected infants. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated from logistic regression models. Mothers who reported cigarette smoking during the periconceptional period were more likely to have infants with AVSDs compared with non-smokers, independent of maternal age, periconceptional alcohol consumption, infant gestational age, family history of CHDs, and study site (aOR 1.5, 95% CI 1.1-2.4). The association was strongest in mothers who smoked more than 25 cigarettes/day. In addition, mothers with periconceptional passive smoke exposure were more likely to have infants with AVSDs than unexposed mothers, independent of maternal age, active periconceptional smoking, infant gestational age, and family history of CHDs (aOR 1.4, 95% CI 1.0-2.0). No associations were observed between AVSDs and maternal history of a urinary tract infection or pelvic inflammatory disease, maternal use of a wide variety of medications, maternal occupational exposure, parental drug use, or maternal alcohol consumption. If the results of this preliminary study can be replicated, minimizing maternal active and passive smoke exposure may decrease the incidence of AVSDs.

  View details for DOI 10.1002/ajmg.a.35555

  View details for Web of Science ID 000310070700012

• Transcriptional analyses of two mouse models of spina bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Cabrera, R. M., Finnell, R. H., Zhu, H., Shaw, G. M., Wlodarczyk, B. J. 2012; 94 (10): 782-789

  Abstract

  Spina bifida is one of the most common of all human structural birth defects. Despite considerable effort over several decades, the causes and mechanisms underlying this malformation remain poorly characterized.To better understand the pathogenesis of this abnormality, we conducted a microarray study using Mouse Whole Genome Bioarrays which have ~36,000 gene targets, to compare gene expression profiles between two mouse models; CXL-Splotch and FKBP8(Gt(neo)) which express a similar spina bifida phenotype. We anticipated that there would be a collection of overlapping genes or shared genetic pathways at the molecular level indicative of a common mechanism underlying the pathogenesis of spina bifida during embryonic development.A total of 54 genes were determined to be differentially expressed (25 downregulated, 29 upregulated) in the FKBP8Gt((neo)) mouse embryos; whereas 73 genes were differentially expressed (56 downregulated, 17 upregulated) in the CXL-Splotch mouse relative to their wild-type controls. Remarkably, the only two genes that showed decreased expression in both mutants were v-ski sarcoma viral oncogene homolog (Ski), and Zic1, a transcription factor member of the zinc finger family. Confirmation analysis using quantitative real-time (qRT)-PCR indicated that only Zic1 was significantly decreased in both mutants. Gene ontology analysis revealed striking enrichment of genes associated with mesoderm and central nervous system development in the CXL-Splotch mutant embryos, whereas in the FKBP8(Gt(neo)) mutants, the genes involved in dorsal/ventral pattern formation, cell fate specification, and positive regulation of cell differentiation were most likely to be enriched. These results indicate that there are multiple pathways and gene networks perturbed in mouse embryos with shared phenotypes.

  View details for DOI 10.1002/bdra.23081

  View details for Web of Science ID 000310068400006

  View details for PubMedID 23024056

  View details for PubMedCentralID PMC3505988

• Maternal and Infant Gene-Folate Interactions and the Risk of Neural Tube Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Etheredge, A. J., Finnell, R. H., Carmichael, S. L., Lammer, E. J., Zhu, H., Mitchell, L. E., Shaw, G. M. 2012; 158A (10): 2439-2446

  Abstract

  Neural tube defects (NTDs) are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. The authors evaluated maternal or offspring folate-related gene variants and interactions between the gene variants and maternal intake of folates on the risk of NTDs in their offspring. A case-control study was conducted on mothers and/or their fetuses and infants who were born in California from 1999 to 2003 with an NTD (cases n = 222, including 24 mother-infant pairs) or without a major malformation (controls n = 454, including 186 mother-infant pairs). Maternal intake of folates was assessed by food frequency questionnaire and genotyping was performed on samples from mothers and infants. For mothers in the lowest folate-intake group, risk of NTDs in offspring was significantly decreased for maternal MTHFR SNPs rs1476413, rs1801131, and rs1801133 (odds ratio [OR] = 0.55, 80% confidence interval [CI]: 0.20, 1.48; OR = 0.58, 80% CI: 0.24, 1.43; OR = 0.69, 80% CI: 0.41, 1.17, respectively), and TYMS SNPs rs502396 and rs699517 (OR = 0.91, 80% CI: 0.53, 1.56; OR = 0.70, 80% CI: 0.38, 1.29). A gene-only effect was observed for maternal SHMT1 SNP rs669340 (OR = 0.69, 95% CI: 0.49, 0.96). When there was low maternal folate intake, risk of NTDs was significantly increased for infant MTHFD1 SNPs rs2236224, rs2236225, and rs11627387 (OR = 1.58, 80% CI: 0.99, 2.51; OR = 1.53, 80% CI: 0.95, 2.47; OR = 4.25, 80% CI: 2.33, 7.75, respectively) and SHMT1 SNP rs12939757 (OR = 2.01, 80% CI: 1.20, 3.37), but decreased for TYMS SNP rs2847153 (OR = 0.73, 80% CI: 0.37, 1.45). Although power to detect interaction effects was low for this birth defects association study, the gene-folate interactions observed in this study represent preliminary findings that will be useful for informing future studies on the complex etiology of NTDs.

  View details for DOI 10.1002/ajmg.a.35552

  View details for Web of Science ID 000310070700011

  View details for PubMedID 22903727

  View details for PubMedCentralID PMC3448841

• Maternal occupational exposure to polycyclic aromatic hydrocarbons and risk of neural tube defect-affected pregnancies BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Langlois, P. H., Hoyt, A. T., Lupo, P. J., Lawson, C. C., Waters, M. A., Desrosiers, T. A., Shaw, G. M., Romitti, P. A., Lammer, E. J. 2012; 94 (9): 693-700

  Abstract

  This study evaluated whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons (PAHs) and neural tube defects (NTDs) in offspring. This is the first such study of which the authors are aware.Data were analyzed from 1997 to 2002 deliveries in the National Birth Defects Prevention Study, a large population-based case-control study in the United States. Maternal interviews yielded information on jobs held in the month before through 3 months after conception. Three industrial hygienists blinded to case or control status assessed occupational exposure to PAHs. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression.Of the 520 mothers of children with NTDs, 5.0% were classified as exposed to occupational PAHs, as were 3.5% of the 2989 mothers of controls. The crude OR for PAH exposure was 1.43 (95% CI, 0.92-2.22) for any NTD and 1.71 (95% CI, 1.03-2.83) for spina bifida. Adjusted ORs were smaller in magnitude and not significant. Among women who were normal weight or underweight, the crude OR for spina bifida was 3.13 (95% CI, 1.63-6.03) and adjusted OR was 2.59 (95% CI, 1.32-5.07). Based on estimated cumulative exposure, a statistically significant dose-response trend was observed for spina bifida; however, it was attenuated and no longer significant after adjustment.Maternal occupational exposure to PAHs may be associated with increased risk of spina bifida in offspring among women who are normal weight or underweight. Other comparisons between PAHs and NTDs were consistent with no association.

  View details for DOI 10.1002/bdra.23045

  View details for Web of Science ID 000308473800003

  View details for PubMedID 22807044

• Thymidylate Synthase Polymorphisms and Risk of Conotruncal Heart Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H., Yang, W., Shaw, N., Perloff, S., Carmichael, S. L., Finnell, R. H., Shaw, G. M., Lammer, E. J. 2012; 158A (9): 2194-2203

  Abstract

  In this study, we investigated whether the two TYMS functional variants (28 bp VNTR and 1494del6) (275 cases and 653 controls) and six selected SNPs (265 case infants, 535 control infants; 169 case mothers and 276 control mothers) were associated with risks of conotruncal heart defects. Further, we evaluated interaction effects between these gene variants and maternal folate intake for risk of CTD. Cases with diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. DNA samples were collected using buccal brushes or drawn from the repository of newborn screening blood specimens when available. Genetic variants were treated as categorical variables (homozygous referent, heterozygote, homozygous variant). Odds ratios and 95% confidence intervals (CI) were computed to estimate risks among all subjects, Hispanic and non-Hispanic whites, respectively, using logistic regression. Gene-folate interactions were assessed for these variants by adding an interaction term to the logistic model. A dichotomized composite variable, "combined folate intake," was created by combining maternal peri-conceptional use of folic acid-containing vitamin supplements with daily dietary intake of folate. In general, the results do not show strong gene-only effects on risk of CTD. We did, however, observe a 3.6-fold increase in CTD risk (95% CI: 1.1-11.9) among infants who were homozygotes for the 6 bp deletion in the 3'-untranslated region (UTR) (1694del6) and whose mothers had low folate intake during the peri-conceptional period.

  View details for DOI 10.1002/ajmg.a.35310

  View details for Web of Science ID 000310068700015

  View details for PubMedID 22887475

  View details for PubMedCentralID PMC3429723

• Environmental and genetic contributors to hypospadias: A review of the epidemiologic evidence BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Lammer, E. J. 2012; 94 (7): 499-510

  Abstract

  This review evaluates current knowledge related to trends in the prevalence of hypospadias, the association of hypospadias with endocrine-disrupting exposures, and the potential contribution of genetic susceptibility to its etiology. The review focuses on epidemiologic evidence. Increasing prevalence of hypospadias has been observed, but such increases tend to be localized to specific regions or time periods. Thus, generalized statements that hypospadias is increasing are unsupported. Owing to the limitations of study designs and inconsistent results, firm conclusions cannot be made regarding the association of endocrine-disrupting exposures with hypospadias. Studies with more rigorous study designs (e.g., larger and more detailed phenotypes) and exposure assessment that encompasses more breadth and depth (e.g., specific endocrine-related chemicals) will be critical to make better inferences about these important environmental exposures. Many candidate genes for hypospadias have been identified, but few of them have been examined to an extent that enables solid conclusions. Further study is needed that includes larger sample sizes, comparison groups that are more representative of the populations from which the cases were derived, phenotype-specific analyses, and more extensive exploration of variants. In conclusion, examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited.

  View details for DOI 10.1002/bdra.23021

  View details for Web of Science ID 000306186100001

  View details for PubMedID 22678668

  View details for PubMedCentralID PMC3393839

• Nutritional Factors and Hypospadias Risks PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Ma, C., Feldkamp, M. L., Munger, R. G., Olney, R. S., Botto, L. D., Shaw, G. M., Correa, A. 2012; 26 (4): 353-360

  Abstract

  We examined whether hypospadias was associated with several aspects of the diet, including intake of animal products, intake of several nutrients and food groups related to a vegetarian diet and oestrogen metabolism, and diet quality.The study included deliveries from 1997 to 2005 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews, and two diet quality indices were developed based on existing indices. Analyses included 1250 cases with second- or third-degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 3118 male, liveborn, non-malformed controls. All odds ratios (OR) and 95% confidence intervals [CI] were estimated from logistic regression models that included several potential confounders, including energy intake.Intake of animal products was not associated with hypospadias; for example, the adjusted OR for any vs. no intake of meat was 1.0 [95% CI 0.6, 1.6]. Frequency of intake of meat or other animal products was also not associated with hypospadias, nor was intake of iron or several nutrients that are potentially related to oestrogen metabolism. Diet quality was also not associated with hypospadias; the OR for diet quality in the highest vs. lowest quartile for the two diet quality indices were 1.0 [95% CI 0.6, 1.6] and 0.9 [95% CI 0.7, 1.1].This large study does not support an association of a vegetarian diet or worse diet quality with hypospadias.

  View details for DOI 10.1111/j.1365-3016.2012.01272.x

  View details for Web of Science ID 000305121500013

  View details for PubMedID 22686387

  View details for PubMedCentralID PMC3376012

• Cancer in Children with Nonchromosomal Birth Defects JOURNAL OF PEDIATRICS Fisher, P. G., Reynolds, P., Von Behren, J., Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 2012; 160 (6): 978-983

  Abstract

  To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies.We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% CIs based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies.Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% CI, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% CI, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer (HR, 1.58; 95% CI, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors.Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer.

  View details for DOI 10.1016/j.jpeds.2011.12.006

  View details for Web of Science ID 000304377300019

  View details for PubMedID 22244463

• Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons: Effects on Gastroschisis among Offspring in the National Birth Defects Prevention Study ENVIRONMENTAL HEALTH PERSPECTIVES Lupo, P. J., Langlois, P. H., Reefhuis, J., Lawson, C. C., Symanski, E., Desrosiers, T. A., Khodr, Z. G., Agopian, A. J., Waters, M. A., Duwe, K. N., Finnell, R. H., Mitchell, L. E., Moore, C. A., Romitti, P. A., Shaw, G. M. 2012; 120 (6): 910-915

  Abstract

  Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted.Our goal was to conduct a case-control study assessing the association between estimated maternal occupational exposure to PAHs and gastroschisis in offspring.Data from gastroschisis cases and control infants were obtained from the population-based National Birth Defects Prevention Study for the period 1997-2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to determine the association between estimated occupational PAH exposure and gastroschisis among children whose mothers were employed for at least 1 month during the month before conception through the third month of pregnancy.The prevalence of estimated occupational PAH exposure was 9.0% in case mothers (27 of 299) and 3.6% in control mothers (107 of 2,993). Logistic regression analyses indicated a significant association between occupational PAHs and gastroschisis among mothers ≥ 20 years of age [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.27, 5.04] after adjusting for maternal body mass index, education, gestational diabetes, and smoking. This association was not seen in mothers < 20 years (OR = 1.14; 95% CI: 0.55, 2.33), which is notable because although young maternal age is the strongest known risk factor for gastroschisis, most cases are born to mothers ≥ 20 years.Our findings indicate an association between occupational exposure to PAHs among mothers who are ≥ 20 years and gastroschisis. These results contribute to a body of evidence that PAHs may be teratogenic.

  View details for DOI 10.1289/ehp.1104305

  View details for Web of Science ID 000304765700034

  View details for PubMedID 22330681

  View details for PubMedCentralID PMC3385431

• Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H., Yang, W., Lu, W., Etheredge, A. J., Lammer, E. J., Finnell, R. H., Carmichael, S. L., Shaw, G. M. 2012; 158A (5): 1124-1134

  Abstract

  We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.

  View details for DOI 10.1002/ajmg.a.35313

  View details for Web of Science ID 000303000200022

  View details for PubMedID 22495907

  View details for PubMedCentralID PMC3331895

• Risk of bronchopulmonary dysplasia by second-trimester maternal serum levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol PEDIATRIC RESEARCH Jelliffe-Pawlowski, L. L., Shaw, G. M., Stevenson, D. K., Oehlert, J. W., Quaintance, C., Santos, A. J., Baer, R. J., Currier, R. J., O'Brodovich, H. M., Gould, J. B. 2012; 71 (4): 399-406

  Abstract

  Although maternal serum α-fetoprotein (AFP), human chorionic gonandotropin (hCG), and estriol play important roles in immunomodulation and immunoregulation during pregnancy, their relationship with the development of bronchopulmonary dysplasia (BPD) in young infants is unknown despite BPD being associated with pre- and postnatal inflammatory factors.We found that these serum biomarkers were associated with an increased risk of BPD. Risks were especially high when AFP and/or hCG levels were above the 95th percentile and/or when unconjugated estriol (uE3) levels were below the 5th percentile (relative risks (RRs) 3.1-6.7). Risks increased substantially when two or more biomarker risks were present (RRs 9.9-75.9).Data suggested that pregnancies that had a biomarker risk and yielded an offspring with BPD were more likely to have other factors present that suggested early intrauterine fetal adaptation to stress, including maternal hypertension and asymmetric growth restriction.The objective of this population-based study was to examine whether second-trimester levels of AFP, hCG, and uE3 were associated with an increased risk of BPD.

  View details for DOI 10.1038/pr.2011.73

  View details for Web of Science ID 000301884500013

  View details for PubMedID 22391642

  View details for PubMedCentralID PMC3616500

• Paternal Age and Congenital Malformations in Offspring in California, 1989-2002 MATERNAL AND CHILD HEALTH JOURNAL Grewal, J., Carmichael, S. L., Yang, W., Shaw, G. M. 2012; 16 (2): 385-392

  Abstract

  This study examined the association between paternal age and a wide range of structural birth defects. Data were drawn from The California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with defects born between 1989 and 2002. The analysis included 46,114 cases with defects, plus a random sample of 36,838 non-malformed births. After adjustment for maternal age, risks of anomalies of the nervous system for 38 and 42 year-old fathers, as compared to 29 year-old fathers, were 1.05-fold [1.00, 1.11] and 1.10-fold [1.02, 1.18] higher, respectively. Similar results were observed for anomalies of the limbs, where 38 and 42 year-old fathers had a 1.06-fold [1.02, 1.11] and 1.11-fold [1.05, 1.18] higher risk, respectively. Risks of anomalies of the integument were 1.05-fold [1.00, 1.09] and 1.10-fold [1.03, 1.16] higher for 38 and 42 year olds, respectively. Young paternal age, i.e., less than 29 years, was associated with an increased risk of amniotic bands (OR: 0.87 [0.78, 0.97]), pyloric stenosis (OR: 0.93 [0.90, 0.96]) and anomalies of the great veins (OR: 0.93 [0.87, 1.00]). In sum, both advanced and young paternal age was associated with select birth defects in California between 1989 and 2002.

  View details for DOI 10.1007/s10995-011-0759-z

  View details for Web of Science ID 000299370400013

  View details for PubMedID 21344170

• VAX1 Mutation Associated with Microphthalmia, Corpus Callosum Agenesis, and Orofacial Clefting: The First Description of a VAX1 Phenotype in Humans HUMAN MUTATION Slavotinek, A. M., Chao, R., Vacik, T., Yahyavi, M., Abouzeid, H., Bardakjian, T., Schneider, A., Shaw, G., Sherr, E. H., Lemke, G., Youssef, M., Schorderet, D. F. 2012; 33 (2): 364-368

  Abstract

  Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for A/M.

  View details for DOI 10.1002/humu.21658

  View details for Web of Science ID 000300705600012

  View details for PubMedID 22095910

  View details for PubMedCentralID PMC3401628

• Reduced Risks of Neural Tube Defects and Orofacial Clefts With Higher Diet Quality ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Carmichael, S. L., Yang, W., Feldkamp, M. L., Munger, R. G., Siega-Riz, A. M., Botto, L. D., Shaw, G. 2012; 166 (2): 121-126

  Abstract

  To examine whether better maternal diet quality was associated with reduced risk for selected birth defects.A multicenter, population-based case-control study, the National Birth Defects Prevention Study.Ten participating centers in the United States.Eligible subjects' estimated due dates were from October 1997 through December 2005. Telephone interviews were conducted with 72% of case and 67% of control mothers. Analyses included 936 cases with neural tube defects (NTDs), 2475 with orofacial clefts, and 6147 nonmalformed controls.Food-frequency data were used to calculate the Mediterranean Diet Score (MDS) and Diet Quality Index (DQI), modeled after existing indices.Adjusted odds ratios (ORs).After covariate adjustment, increasing diet quality based on either index was associated with reduced risks for the birth defects studied. The strongest association was between anencephaly and DQI; the OR for highest vs lowest quartile was 0.49 (95% CI, 0.31-0.75). The ORs for cleft lip with or without cleft palate and cleft palate and DQI were also notable (0.66 [95% CI, 0.54-0.81] and 0.74 [95%CI, 0.56-0.96], respectively).Healthier maternal dietary patterns, as measured by diet quality scores, were associated with reduced risks of NTDs and clefts. These results suggest that dietary approaches could lead to further reduction in risks of major birth defects and complement existing efforts to fortify foods and encourage periconceptional multivitamin use.

  View details for DOI 10.1001/archpediatrics.2011.185

  View details for Web of Science ID 000301211000002

  View details for PubMedID 21969361

• Spina Bifida Subtypes and Sub-Phenotypes by Maternal Race/Ethnicity in the National Birth Defects Prevention Study AMERICAN JOURNAL OF MEDICAL GENETICS PART A Agopian, A. J., Canfield, M. A., Olney, R. S., Lupo, P. J., Ramadhani, T., Mitchell, L. E., Shaw, G. M., Moore, C. A. 2012; 158A (1): 109-115

  Abstract

  Spina bifida refers to a collection of neural tube defects, including myelomeningocele, meningocele, and myelocele (SB(M) ), as well as lipomyelomeningocele and lipomeningocele (SB(L) ). Maternal race/ethnicity has been associated with an increased risk for spina bifida among offspring. To better understand this relationship, we evaluated different spina bifida subtypes (SB(M) vs. SB(L) ) and sub-phenotypes (anatomic level or presence of additional malformations) by maternal race/ethnicity using data from the National Birth Defects Prevention Study. This study is a large, multisite, population-based study of nonsyndromic birth defects. Prevalence estimates were obtained using data from spina bifida cases (live births, fetal deaths, and elective terminations) and total live births in the study regions. From October 1997 through December 2005, 1,046 infants/fetuses with spina bifida were delivered, yielding a prevalence of 3.06 per 10,000 live births. Differences in the prevalences of SB(M) vs. SB(L) , isolated versus non-isolated SB(M) , and lesion level in isolated SB(M) among case offspring were observed by maternal race/ethnicity. Compared to non-Hispanic (NH) White mothers, offspring of Hispanic mothers had higher prevalences of each subtype and most sub-phenotypes, while offspring of NH Black mothers generally had lower prevalences. Furthermore, differences in race/ethnicity among those with isolated SB(M) were more pronounced by sex. For instance, among male offspring, the prevalence of isolated SB(M) was significantly higher for those with Hispanic mothers compared to NH White mothers [prevalence ratio (PR): 1.55, 95% confidence interval: 1.23-1.95]. These findings provide evidence that certain spina bifida subtypes and sub-phenotypes may be etiologically distinct.

  View details for DOI 10.1002/ajmg.a.34383

  View details for Web of Science ID 000299381800016

  View details for PubMedID 22140002

• A Genetic Signature of Spina Bifida Risk from Pathway-Informed Comprehensive Gene-Variant Analysis PLOS ONE Marini, N. J., Hoffmann, T. J., Lammer, E. J., Hardin, J., Lazaruk, K., Stein, J. B., Gilbert, D. A., Wright, C., Lipzen, A., Pennacchio, L. A., Carmichael, S. L., Witte, J. S., Shaw, G. M., Rine, J. 2011; 6 (11)

  Abstract

  Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.

  View details for DOI 10.1371/journal.pone.0028408

  View details for Web of Science ID 000298168100069

  View details for PubMedID 22140583

  View details for PubMedCentralID PMC3227667

• Periconceptional Intake of Folic Acid and Food Folate and Risks of Preterm Delivery AMERICAN JOURNAL OF PERINATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Siega-Riz, A. M. 2011; 28 (10): 747-751

  Abstract

  We investigated multiple sources of folate and folic acid to determine whether their periconceptional intakes were associated with preterm delivery. Studied were controls from the National Birth Defects Prevention Study delivered September 1998 to December 2005. Telephone interviews were conducted with 5952 (68% of eligible) mothers. Women were queried about intake of vitamin supplements in the 12 weeks before conception through delivery. A version of the Nurse's Health Study food frequency questionnaire was used to assess food sources. Eight percent of infants ( N = 487) were preterm (<37 weeks). Compared with women who began intake of supplements with folic acid before pregnancy, those who began any time during pregnancy had an ~20% lowered risk of preterm delivery. Lower dietary intakes showed a modest increased risk of preterm delivery: odds ratios were 1.44 (1.01 to 2.04) for lowest quartile intake of folate and 1.27 (0.95 to 1.69) for lowest quartile intake of folic acid compared with the highest. Findings suggest some evidence that folates influenced risks; however, an interpretation of results was also consistent with no association between intake of folates and preterm delivery.

  View details for DOI 10.1055/s-0031-1280855

  View details for Web of Science ID 000298200500002

  View details for PubMedID 21681695

• Estimated dietary phytoestrogen intake and major food sources among women during the year before pregnancy NUTRITION JOURNAL Carmichael, S. L., Gonzalez-Feliciano, A. G., Ma, C., Shaw, G. M., Cogswell, M. E. 2011; 10

  Abstract

  Phytoestrogens may be associated with a variety of different health outcomes, including outcomes related to reproductive health. Recently published data on phytoestrogen content of a wide range of foods provide an opportunity to improve estimation of dietary phytoestrogen intake.Using the recently published data, we estimated intake among a representative sample of 6,584 women of reproductive age from a multi-site, population-based case-control study, the National Birth Defects Prevention Study (NBDPS). The NBDPS uses a shortened version of the Willett food frequency questionnaire to estimate dietary intake during the year before pregnancy. We estimated intake among NBDPS control mothers.Lignans contributed 65% of total phytoestrogen intake; isoflavones, 29%; and coumestrol, 5%. Top contributors to total phytoestrogen intake were vegetables (31%) and fruit (29%); for isoflavones, dairy (33%) and fruit (21%); for lignans, vegetables (40%) and fruit (29%); and for coumestans, fruit (55%) and dairy (18%). Hispanic women had higher phytoestrogen intake than non-Hispanic white or black women. Associations with maternal age and folic acid-containing supplements were more modest but indicated that older mothers and mothers taking supplements had higher intake.The advantage of the approach used for the current analysis lies in its utilization of phytoestrogen values derived from a single laboratory that used state-of-the-art measurement techniques. The database we developed can be applied directly to other studies using food frequency questionnaires, especially the Willett questionnaire. The database, combined with consistent dietary intake assessment, provides an opportunity to improve our ability to understand potential associations of phytoestrogen intake with health outcomes.

  View details for DOI 10.1186/1475-2891-10-105

  View details for Web of Science ID 000295960300001

  View details for PubMedID 21978267

  View details for PubMedCentralID PMC3196693

• Discovery of Genetic Susceptibility Factors for Human Birth Defects: An Opportunity for a National Agenda AMERICAN JOURNAL OF MEDICAL GENETICS PART A Olshan, A. F., Hobbs, C. A., Shaw, G. M. 2011; 155A (8): 1794-1797

  Abstract

  A recent workshop highlighted the current challenges and new opportunities for studying the role of genetic factors in the etiology of human birth defects. The workshop provided a series of recommendations pertaining to the use of animal models, key elements of population-based designs, the need for national collaborative projects, biorepositories, and consortia, investigation of new types of structural genetic variants, examination of gene-exposure interactions, and a strategy for gene variant discovery. A key reason to hold the recent workshop and contribute this concise communication to the literature is to draw attention to and initiate action toward advancing discoveries about the genetic etiologies of birth defects.

  View details for DOI 10.1002/ajmg.a.34103

  View details for Web of Science ID 000294088100005

  View details for PubMedID 21739590

• Defective Sumoylation Pathway Directs Congenital Heart Disease BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Wang, J., Chen, L., Wen, S., Zhu, H., Yu, W., Moskowitz, I. P., Shaw, G. M., Finnell, R. H., Schwartz, R. J. 2011; 91 (6): 468-476

  Abstract

  Congenital heart defects (CHDs) are the most common of all birth defects, yet molecular mechanism(s) underlying highly prevalent atrial septal defects (ASDs) and ventricular septal defects (VSDs) have remained elusive. We demonstrate the indispensability of "balanced" posttranslational small ubiquitin-like modifier (SUMO) conjugation-deconjugation pathway for normal cardiac development. Both hetero- and homozygous SUMO-1 knockout mice exhibited ASDs and VSDs with high mortality rates, which were rescued by cardiac reexpression of the SUMO-1 transgene. Because SUMO-1 was also involved in cleft lip/palate in human patients, the previous findings provided a powerful rationale to question whether SUMO-1 was mutated in infants born with cleft palates and ASDs. Sequence analysis of DNA from newborn screening blood spots revealed a single 16 bp substitution in the SUMO-1 regulatory promoter of a patient displaying both oral-facial clefts and ASDs. Diminished sumoylation activity whether by genetics, environmental toxins, and/or pharmaceuticals may significantly contribute to susceptibility to the induction of congenital heart disease worldwide. Birth Defects Research (Part A) 2011. © 2011 Wiley-Liss, Inc.

  View details for DOI 10.1002/bdra.20816

  View details for Web of Science ID 000291545100007

  View details for PubMedID 21563299

• Maternal nutrition and gastroschisis: findings from the National Birth Defects Prevention Study AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Feldkamp, M. L., Carmichael, S. L., Shaw, G. M., Panichello, J. D., Moore, C. A., Botto, L. D. 2011; 204 (5)

  Abstract

  Gastroschisis is increasing in many countries, especially among young women. Because young women may have inadequate nutrition, we assessed the relationship between individual nutrients and the risk for gastroschisis.We analyzed data from the National Birth Defects Prevention Study, a population-based case-control study. Cases were ascertained from 10 birth defect surveillance systems. Controls were randomly selected from birth certificates or hospital records. Nutrient intake was estimated for the year prior to conception from maternal interviews based on a 58-item food frequency questionnaire and cereal consumption reported. A total of 694 cases and 6157 controls were available for analysis.Reported intake of individual nutrients did not substantially affect the risk for gastroschisis. Stratification by maternal age, preconception body mass index, folic acid-containing supplements, or energy intake (kilocalories) did not alter risk estimates.This study does not support an increased risk for gastroschisis with decreasing tertiles of individual nutrients.

  View details for DOI 10.1016/j.ajog.2010.12.053

  View details for Web of Science ID 000290206200025

  View details for PubMedID 21396620

• Effect of specimen storage conditions on newborn dried blood spots used to assess Toxoplasma gondii immunoglobulin M (IgM) CLINICA CHIMICA ACTA Mei, J. V., Li, L., Rasmussen, S. A., Collier, S., Frias, J. L., Honein, M. A., Shaw, G. M., Lorey, F., Meyer, R., Chaing, S., Canfield, M. A., Jones, J., Hannon, W. H. 2011; 412 (5-6): 455-459

  Abstract

  Newborn screening programs store-under varying conditions-residual dried blood spots (DBS). Residual DBS were used to investigate the contribution of congenital infection with Toxoplasma gondii to the etiology of hydrocephalus and as a key step, we assessed the effect of storage conditions on the stability of newborn screening biomarkers.Infants with hydrocephalus (410 cases) were identified using population-based birth defects surveillance systems in California, North Carolina, and Texas. Infants without birth defects (448 controls) were randomly selected from the same geographic areas and time periods. California stores DBS with controlled temperature, while North Carolina and Texas store DBS under ambient conditions. After removal of personal identifiers, DBS were tested for Toxo-specific immunoglobulin-M (Toxo-IgM). Because of poor elution of DBS stored in ambient conditions, additional biomarkers were tested on a specimen subset.Among 858 DBS tested, Toxo-IgM was found in 3 cases and no controls from California (N=515) and in no specimens from North Carolina or Texas (N=343). Among the 98 specimens tested for selected biomarkers, statistically significant differences were found for California vs. combined North Carolina and Texas DBS (thyroid stimulating hormone, phenylalanine, methionine, leucine and citrulline p<0.0001; tyrosine and valine p<0.001).Storage conditions for residual DBS had an effect on the ability to extract, recover, and accurately measure Toxo-IgM and other biomarkers from the filter paper matrix.

  View details for DOI 10.1016/j.cca.2010.11.028

  View details for Web of Science ID 000286713800009

  View details for PubMedID 21114968

• Craniosynostosis and Nutrient Intake during Pregnancy BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Rasmussen, S. A., Lammer, E. J., Ma, C., Shaw, G. M. 2010; 88 (12): 1032-1039

  Abstract

  To examine the association of craniosynostosis with maternal intake of folic acid-containing supplements and dietary nutrients.The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic infants with craniosynostosis (n = 815) were compared to nonmalformed, population-based liveborn control infants (n = 6789), by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included mother's age, parity, race-ethnicity, education, body mass index, smoking, alcohol, fertility treatments, plurality, and study center. We compared quartiles of intake and specified nutrients as continuous.Intake of folic acid-containing supplements was not associated with craniosynostosis (AORs were close to 1). Analyses of dietary nutrients were restricted to mothers who took supplements during the first trimester (i.e., most women). Based on continuous specifications of nutrients, sagittal synostosis risk was significantly lower among women with higher intake of riboflavin and vitamins B₆, E, and C; metopic synostosis risk was significantly higher among women with higher intakes of choline and vitamin B₁₂; and coronal synostosis risk was significantly lower among women with higher intake of methionine and vitamin C. As examples, AORs for sagittal synostosis among women with intakes of vitamin B₆ and riboflavin in the highest versus lowest quartiles were 0.4 (95% CI, 0.2-0.6) and 0.5 (95% CI, 0.3-0.7), respectively.This analysis suggests that dietary intake of certain nutrients may be associated with craniosynostosis, and results may vary by suture type.

  View details for DOI 10.1002/bdra.20717

  View details for Web of Science ID 000285396200006

  View details for PubMedID 20842649

  View details for PubMedCentralID PMC3136510

• Association of Microtia With Maternal Obesity and Periconceptional Folic Acid Use AMERICAN JOURNAL OF MEDICAL GENETICS PART A Ma, C., Carmichael, S. L., Scheuerle, A. E., Canfield, M. A., Shaw, G. M. 2010; 152A (11): 2756-2761

  Abstract

  The study objective was to examine the association of microtia with maternal intake of folic-acid-containing supplements and obesity. The study data included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Non-syndromic cases of microtia were compared to non-malformed, population-based liveborn control infants, by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race/ethnicity, education, and study site. Maternal obesity was only weakly associated with microtia. Maternal periconceptional intake of folic-acid-containing vitamin supplements reduced the risk for microtia, but only among non-obese women (OR: 0.63; 95% CI: 0.44-0.91). The reduced risk was stronger when analyses were restricted to isolated cases (OR: 0.51; 95% CI: 0.34-0.77), and it was independent of the level of maternal dietary folate intake. Adjusting for maternal race/ethnicity did not reveal alternative interpretations of this association. This analysis suggests that maternal periconceptional intake of folic-acid-containing supplements may provide protection from microtia for non-obese women.

  View details for DOI 10.1002/ajmg.a.33694

  View details for Web of Science ID 000284005700013

  View details for PubMedID 20949601

• Candidate Gene Sequencing of LHX2, HESX1, and SOX2 in a Large Schizencephaly Cohort AMERICAN JOURNAL OF MEDICAL GENETICS PART A Mellado, C., Poduri, A., Gleason, D., Elhosary, P. C., Barry, B. J., Partlow, J. N., Chang, B. S., Shaw, G. M., Barkovich, A. J., Walsh, C. A. 2010; 152A (11): 2736-2742

  Abstract

  Schizencephaly is a malformation of cortical development characterized by gray matter-lined clefts in the cerebral cortex and a range of neurological presentations. In some cases, there are features of septo-optic dysplasia concurrently with schizencephaly. The etiologies of both schizencephaly and septo-optic dysplasia are thought to be heterogeneous, but there is evidence that at least some cases have genetic origin. We hypothesized that these disorders may be caused by mutations in three candidate genes: LHX2, a gene with an important cortical patterning role, and HESX1 and SOX2, genes that have been associated with septo-optic dysplasia. We sequenced a large cohort of patients with schizencephaly, some with features of septo-optic dysplasia, for mutations in these genes. No pathogenic mutations were observed, suggesting that other genes or non-genetic factors influencing genes critical to brain development must be responsible for schizencephaly.

  View details for DOI 10.1002/ajmg.a.33684

  View details for Web of Science ID 000284005700010

  View details for PubMedID 20949537

  View details for PubMedCentralID PMC2965295

• Folic acid in early pregnancy: a public health success story FASEB JOURNAL Obican, S. G., Finnell, R. H., Mills, J. L., Shaw, G. M., Scialli, A. R. 2010; 24 (11): 4167-4174

  Abstract

  Folate is a water-soluble B vitamin that must be obtained in the diet or through supplementation. For >50 yr, it has been known that folate plays an integral role in embryonic development. In mice, inactivation of genes in the folate pathway results in malformations of the neural tube, heart, and craniofacial structures. It has been shown that diets and blood levels of women who had a fetus with a neural tube defect are low for several micronutrients, particularly folate. Periconceptional use of folic acid containing supplements decreased recurrent neural tube defects in the offspring of women with a previously affected child and the occurrence of a neural tube defect and possibly other birth defects in the offspring of women with no prior history. Based on these findings, the U.S. Public Health Service recommended that all women at risk take folic acid supplements, but many did not. Mandatory food fortification programs were introduced in numerous countries, including the United States, to improve folate nutritional status and have resulted in a major decrease in neural tube defect prevalence. The success story of folate represents the cooperation of embryologists, experimentalists, epidemiologists, public health scientists, and policymakers.

  View details for DOI 10.1096/fj.10-165084

  View details for Web of Science ID 000283861100004

  View details for PubMedID 20631328

  View details for PubMedCentralID PMC2974421

• Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study BMC MEDICAL GENETICS Lu, W., Guzman, A. R., Yang, W., Chapa, C. J., Shaw, G. M., Greene, R. M., Pisano, M. M., Lammer, E. J., Finnell, R. H., Zhu, H. 2010; 11

  Abstract

  Spina bifida is a malformation of the neural tube and is the most common of neural tube defects (NTDs). The etiology of spina bifida is largely unknown, although it is thought to be multi-factorial, involving multiple interacting genes and environmental factors. Mutations in transcriptional co-activator genes-Cited2, p300, Cbp, Tfap2α, Carm1 and Cart1 result in NTDs in murine models, thus prompt us to investigate whether homologues of these genes are associated with NTDs in humans.Data and biological samples from 297 spina bifida cases and 300 controls were derived from a population-based case-control study conducted in California. 37 SNPs within CITED2, EP300, CREBBP, TFAP2A, CARM1 and ALX1 were genotyped using an ABI SNPlex assay. Odds ratios and 95% confidence intervals were calculated for alleles, genotypes and haplotypes to evaluate the risk for spina bifida.Several SNPs showed increased or decreased risk, including CITED2 rs1131431 (OR = 5.32, 1.04~27.30), EP300 rs4820428 (OR = 1.30, 1.01~1.67), EP300 rs4820429 (OR = 0.50, 0.26~0.50, in whites, OR = 0.7, 0.49~0.99 in all subjects), EP300 rs17002284 (OR = 0.43, 0.22~0.84), TFAP2A rs3798691 (OR = 1.78, 1.13~2.87 in Hispanics), CREBBP rs129986 (OR = 0.27, 0.11~0.69), CARM1 rs17616105 (OR = 0.41, 0.22~0.72 in whites). In addition, one haplotype block in EP300 and one in TFAP2A appeared to be associated with increased risk.Modest associations were observed in CITED2, EP300, CREBBP, TFAP2A and CARM1 but not ALX1. However, these modest associations were not statistically significant after correction for multiple comparisons. Searching for potential functional variants and rare causal mutations is warranted in these genes.

  View details for DOI 10.1186/1471-2350-11-141

  View details for Web of Science ID 000283360200001

  View details for PubMedID 20932315

  View details for PubMedCentralID PMC2964532

• Prepregnancy Obesity: A Complex Risk Factor for Selected Birth Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 2010; 88 (10): 804-810

  Abstract

  Obesity is associated with increased risk of many adverse health conditions. During pregnancy, obesity presents particularly important challenges for both mother and baby. Over the last 20 years, studies have emerged indicating an association between prepregnancy weight and risks of birth defects. However, few studies have examined the mechanisms through which this association occurs. Understanding the underlying mechanisms may provide clues to public health strategies for the prevention of birth defects associated with maternal obesity. This article briefly reviews existing literature on the association between maternal obesity and birth defects, discusses potential underlying mechanisms, and suggests research needed to improve our understanding of this important association.

  View details for DOI 10.1002/bdra.20679

  View details for Web of Science ID 000283638500006

  View details for PubMedID 20973050

• Prevalence of Spina Bifida Among Children and Adolescents in 10 Regions in the United States 48th Annual Meeting of the Teratology-Society Shin, M., Besser, L. M., Siffel, C., Kucik, J. E., Shaw, G. M., Lu, C., Correa, A. AMER ACAD PEDIATRICS. 2010: 274–79

  Abstract

  The goal was to estimate the number of children and adolescents, 0 to 19 years of age, living with spina bifida (SB) in the United States.A retrospective study was conducted by using population-based, birth defect surveillance data from 10 US regions, with vital status ascertainment. Birth defect surveillance data were obtained from Arkansas, Georgia (5 central counties of metropolitan Atlanta), California (11 counties), Colorado, Iowa, New York (New York City excluded), North Carolina, Oklahoma, Texas, and Utah. We estimated the numbers of children 0 to 19 years of age who were living with SB in the 10 US regions in 2002, according to age group, race/ethnicity, and gender, and examined a long-term trend in the prevalence of SB among children 0 to 11 years of age in 1991-2002.The overall prevalence of SB among children and adolescents 0 to 19 years of age in the study regions was 3.1 cases per 10,000 in 2002. The prevalence of SB among children was lower among male and non-Hispanic black children.The prevalence estimates of SB among children and adolescents varied according to region, race/ethnicity, and gender, which suggests possible variations in prevalence at birth and/or inequities in survival rates. Additional studies are warranted to elucidate the reasons for these variations and to derive prevalence estimates of SB among adults.

  View details for DOI 10.1542/peds.2009-2084

  View details for Web of Science ID 000280565700013

  View details for PubMedID 20624803

• Periconceptional Nutrient Intakes and Risks of Neural Tube Defects in California 6th International Conference on Neural Tube Defects Carmichael, S. L., Yang, W., Shaw, G. M. WILEY-LISS. 2010: 670–78

  Abstract

  This study investigated the association of neural tube defects (NTDs) with maternal periconceptional intake of folic acid-containing supplements and dietary nutrients, including folate, among deliveries that occurred after folic acid fortification in selected California counties.The population-based case-control study included fetuses and live born infants with spina bifida (189) or anencephaly (141) and 625 nonmalformed, live born controls delivered from 1999 to 2003. Mothers reported supplement use during telephone interviews, which included a 107-item food frequency questionnaire. For dietary nutrients, intakes <25th, 25th to <75th (reference), and > or =75th percentile were compared, based on control distributions.After adjustment for potential confounders, any versus no supplement intake resulted in ORs of 0.8 (95% CI, 0.5-1.3) for anencephaly and 0.8 (95% CI, 0.6-1.2) for spina bifida. After stratification by maternal intake of vitamin supplements, most factors in the glycemic pathway were not associated with either NTD, with the exception of low levels of fructose and glucose that were significantly associated with anencephaly. Some nutrients that contribute to one-carbon metabolism showed lowered risks (folate, riboflavin, vitamins B(6) and B(12)); others did not (choline, methionine, zinc). Antioxidant nutrients tended to be associated with lowered risks (vitamins C, E, A, beta-carotene, lutein).Mothers' intake of vitamin supplements was modestly if at all associated with a lowered risk of NTDs. Dietary intake of several nutrients contributing to one-carbon metabolism and oxidative stress were associated with reduced NTD risk.

  View details for DOI 10.1002/bdra.20675

  View details for Web of Science ID 000281529700009

  View details for PubMedID 20740594

  View details for PubMedCentralID PMC2929981

• Hypospadias and halogenated organic pollutant levels in maternal mid-pregnancy serum samples CHEMOSPHERE Carmichael, S. L., Herring, A. H., Sjoedin, A., Jones, R., Needham, L., Ma, C., Ding, K., Shaw, G. M. 2010; 80 (6): 641-646

  Abstract

  Environmental contaminants that disrupt endocrine function may contribute to hypospadias etiology.To compare levels of selected halogenated organic pollutants in women delivering infants with and without hypospadias.This study examined levels of nine polybrominated flame retardants (PBDEs), 30 polychlorinated biphenyls (PCBs) and nine persistent pesticides in mid-pregnancy serum samples from 20 women who delivered infants with hypospadias and 28 women who delivered unaffected infants, in California. Analytes were measured using isotope dilution high-resolution mass spectrometry. Values below individual limits of detection (LOD) for each analyte were imputed based on a truncated multivariate normal distribution. Levels of 17 analytes for which at least 50% of cases and controls had values above the LOD were compared using t-tests and by generating odds ratios from logistic regression analyses.Means were greater for cases than controls for 11 of the 17 reported analytes (4 of 5 PBDEs, 7 of 9 PCBs, and 0 of 3 other persistent pesticides), but none of the differences were statistically significant. Eleven of the 17 odds ratios exceeded one (the same analytes that had greater means), but none of the confidence intervals excluded one. After adjustment for sample processing time and foreign-born Hispanic race-ethnicity, only four of the odds ratios exceeded one.Levels of the PBDEs and PCBs were not statistically significantly different, but the sample size was small. The current study adds to a relatively limited knowledge base regarding the potential association of specific contaminants with hypospadias or other birth defects.

  View details for DOI 10.1016/j.chemosphere.2010.04.055

  View details for Web of Science ID 000280749500005

  View details for PubMedID 20494400

  View details for PubMedCentralID PMC2944405

• Maternal Nutrition and Risk for Gastroschisis: Findings from the National Birth Defects Prevention Study Feldkamp, M. L., Stone, M., Carmichael, S. L., Shaw, G. M., Moore, C. A., Botto, L. D. WILEY-BLACKWELL. 2010: 505

  View details for Web of Science ID 000279716900012

• Does global hypomethylation contribute to susceptibility to neural tube defects? AMERICAN JOURNAL OF CLINICAL NUTRITION Finnell, R. H., Blom, H. J., Shaw, G. M. 2010; 91 (5): 1153-1154

  View details for DOI 10.3945/ajcn.2010.29534

  View details for Web of Science ID 000276845100002

  View details for PubMedID 20375188

  View details for PubMedCentralID PMC2854894

• A Maternally Inherited Chromosome 18q22.1 Deletion in a Male With Late-Presenting Diaphragmatic Hernia and Microphthalmia-Evaluation of DSEL as a Candidate Gene for the Diaphragmatic Defect AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zayed, H., Chao, R., Moshrefi, A., LopezJimenez, N., Delaney, A., Chen, J., Shaw, G. M., Slavotinek, A. M. 2010; 152A (4): 916-923

  Abstract

  Using an Affymetrix GeneChip(R) Human Mapping 100K Set to study a patient with a late-presenting, right-sided diaphragmatic hernia and microphthalmia, we found a maternally inherited deletion that was 2.7 Mb in size at chromosome 18q22.1. Mapping of this deletion using fluorescence in situ hybridization revealed three deleted genes-CDH19, DSEL, and TXNDC10, and one gene that contained the deletion breakpoint, CCDC102B. We selected DSEL for further study in 125 patients with diaphragmatic hernias, as it is involved in the synthesis of decorin, a protein that is required for normal collagen formation and that is upregulated during myogenesis. We found p.Met14Ile in an unrelated patient with a late-presenting, anterior diaphragmatic hernia. In the murine diaphragm, Dsel was only weakly expressed at the time of diaphragm closure and its expression in C2C12 myoblast cells did not change significantly during myoblast differentiation, thus reducing the likelihood that the gene is involved in myogenesis of the diaphragm. Although it is possible that the 18q22.1 deletion and haploinsufficiency for DSEL contributed to the diaphragmatic defect in the patient, a definite role for DSEL and decorin in the formation of the collagen-containing, central tendon of the diaphragm has not yet been established.

  View details for DOI 10.1002/ajmg.a.33341

  View details for Web of Science ID 000276754000017

  View details for PubMedID 20358601

  View details for PubMedCentralID PMC2922899

• Patterns of tobacco exposure before and during pregnancy ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA Anderka, M., Romitti, P. A., Sun, L., Druschel, C., Carmichael, S., Shaw, G. 2010; 89 (4): 505-514

  Abstract

  To describe maternal exposure to tobacco in the three months before conception and throughout pregnancy, examine risk factors associated with tobacco exposure in pregnancy and smoking cessation, assess use of pharmacotherapy for smoking cessation and evaluate birth outcomes by smoking status.A cohort of women from a multi-site United States study were asked retrospectively about their exposure to tobacco.The study population was comprised of 4,667 mothers of non-malformed control infants who participated in the National Birth Defects Prevention Study from 1997 to 2003.Using computer-assisted telephone interview responses from this population-based sample, we assessed patterns of maternal smoking and exposure to environmental tobacco smoke (ETS) as well as use of pharmacotherapy for quitting smoking during pregnancy.Overall, 961 (20.6%) mothers reported any smoking and 1,401 (30.0%) reported any exposure to ETS at home or work during the three months before conception through pregnancy. Of the 961 smokers, 512 (53.3%) reportedly quit smoking before or during pregnancy, including 379 (74% of quitters) in the first trimester, and 420 (43.7%) continued to smoke throughout the pregnancy. Only 2.1% of smokers reportedly used pharmacotherapy to quit smoking anytime from three months before conception through pregnancy. Low birthweight and preterm delivery rates were lowest among offspring of non-smokers and highest in offspring of those who continued to smoke throughout pregnancy.About one-half of mothers who reported preconceptional smoking quit before or during pregnancy. Use of pharmacotherapy to quit smoking during pregnancy was not common.

  View details for DOI 10.3109/00016341003692261

  View details for Web of Science ID 000277094700011

  View details for PubMedID 20367429

• Examination of FGFRL1 as a candidate gene for diaphragmatic defects at chromosome 4p16.3 shows that Fgfrl1 null mice have reduced expression of Tpm3, sarcomere genes and Lrtm1 in the diaphragm HUMAN GENETICS LopezJimenez, N., Gerber, S., Popovici, V., Mirza, S., Copren, K., Ta, L., Shaw, G. M., Trueb, B., Slavotinek, A. M. 2010; 127 (3): 325-336

  Abstract

  Fgfrl1 (also known as Fgfr5; OMIM 605830) homozygous null mice have thin, amuscular diaphragms and die at birth because of diaphragm hypoplasia. FGFRL1 is located at 4p16.3, and this chromosome region can be deleted in patients with congenital diaphragmatic hernia (CDH). We examined FGFRL1 as a candidate gene for the diaphragmatic defects associated with 4p16.3 deletions and re-sequenced this gene in 54 patients with CDH. We confirmed six known coding single nucleotide polymorphisms (SNPs): c.209G > A (p.Pro20Pro), c.977G > A (p.Pro276Pro), c.1040T > C (p.Asp297Asp), c.1234C > A (p.Pro362Gln), c.1420G > T (p.Arg424Leu), and c.1540C > T (p.Pro464Leu), but we did not identify any gene mutations. We genotyped additional CDH patients for four of these six SNPs, including the three non-synonymous SNPs, to make a total of 200 chromosomes, and found that the allele frequency for the four SNPs, did not differ significantly between patients and normal controls (p > or = 0.05). We then used Affymetrix Genechip Mouse Gene 1.0 ST arrays and found eight genes with significantly reduced expression levels in the diaphragms of Fgfrl1 homozygous null mice when compared with wildtype mice-Tpm3, Fgfrl1 (p = 0.004), Myl2, Lrtm1, Myh4, Myl3, Myh7 and Hephl1. Lrtm1 is closely related to Slit3, a protein associated with herniation of the central tendon of the diaphragm in mice. The Slit proteins are known to regulate axon branching and cell migration, and inhibition of Slit3 reduces cell motility and decreases the expression of Rac and Cdc42, two genes that are essential for myoblast fusion. Further studies to determine if Lrtm1 has a similar function to Slit3 and if reduced Fgfrl1 expression can cause diaphragm hypoplasia through a mechanism involving decreased myoblast motility and/or myoblast fusion, seem indicated.

  View details for DOI 10.1007/s00439-009-0777-8

  View details for Web of Science ID 000274456500006

  View details for PubMedID 20024584

  View details for PubMedCentralID PMC2893560

• Periconceptional Nutrient Intakes and Risks of Conotruncal Heart Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Lammer, E. J. 2010; 88 (3): 144-151

  Abstract

  Few inquiries into periconceptional nutrition, other than folate, and risk of heart defects exist. We investigated the observed association between conotruncal heart defects and periconceptional vitamin use, as well as potential associations with other dietary nutrients.Data derived from a population-based, case-control study of fetuses and liveborn infants among California births between July 1999 and June 2004; 76% of eligible case mothers and 77% of eligible control mothers were interviewed. Cases included 140 with d-transposition of great arteries (dTGA), and 163 with tetralogy of Fallot (TOF). Total number of controls was 698. Use of vitamins was elicited by questionnaire for the periconceptional period. Dietary nutrient intake was elicited by a well-known food frequency questionnaire.The odds ratio for dTGA associated with supplemental vitamin use was 1.0 (95% confidence interval [CI], 0.7-1.5) and for TOF was 0.9 (95% CI, 0.6-1.3). We observed increased risks associated with lower dietary intakes of linoleic acid, total carbohydrate, and fructose for dTGA, whereas decreased risks were observed for lower intakes of total protein and methionine for TOF. Lower dietary intake of several micronutrients-namely folate, niacin, riboflavin, and vitamins B(12), A, and E, even after simultaneous adjustment for other studied nutrients-was associated with increased risk of dTGA but not TOF. These associations were observed among women who did not use vitamin supplements periconceptionally. Analytic consideration of several potential confounders did not reveal alternative interpretations of the results.Evidence continues to accumulate to show that nutrients, particularly folate, influence risks of structural birth defects. Our results extend observations that other nutrients may also be important in heart development.

  View details for DOI 10.1002/bdra.20648

  View details for Web of Science ID 000276125800002

  View details for PubMedID 20063270

  View details for PubMedCentralID PMC2849796

• Planar Cell Polarity Pathway Genes and Risk for Spina Bifida AMERICAN JOURNAL OF MEDICAL GENETICS PART A Wen, S., Zhu, H., Lu, W., Mitchell, L. E., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2010; 152A (2): 299-304

  Abstract

  Spina bifida, a neural tube closure defect (NTD) involving the posterior portion of what will ultimately give rise to the spinal cord, is one of the most common and serious birth defects. The etiology of spina bifida is thought to be multi-factorial and involve multiple interacting genes and environmental factors. The causes of this congenital malformation remain largely unknown. However, several candidate genes for spina bifida have been identified in lower vertebrates, including the planar cell polarity (PCP) genes. We used data from a case-control study conducted in California to evaluate the association between variation within several key PCP genes and the risk of spina bifida. The PCP genes included in this study were the human homologs of the Xenopus genes Flamingo, Strabismus, Prickle, Dishevelled, and Scrib, two of the homologs of Xenopus Wnt genes, WNT5A and WNT11, and two of the homologs of Xenopus Frizzled, FZD3 and FZD6. None of the 172 SNPs that were evaluated were significantly associated with spina bifida in any racial/ethnic group after correction for multiple testing. However, several SNPs in the PRICKLE2 gene had unadjusted P-value <0.01. In conclusion, our results, though largely negative, suggest that the PRICKLE2 gene may potentially modify the risk of spina bifida and deserves further investigation.

  View details for DOI 10.1002/ajmg.a.33230

  View details for Web of Science ID 000274508300005

  View details for PubMedID 20101694

  View details for PubMedCentralID PMC2815123

• Fetal Constraint as a Potential Risk Factor for Craniosynostosis AMERICAN JOURNAL OF MEDICAL GENETICS PART A Sanchez-Lara, P. A., Carmichael, S. L., Graham, J. M., Lammer, E. J., Shaw, G. M., Ma, C., Rasmussen, S. A. 2010; 152A (2): 394-400

  Abstract

  Non-syndromic craniosynostosis is multifactorial, and fetal head constraint has been hypothesized as one factor thought to play a role. Data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, were used to evaluate associations between four selected factors related to fetal constraint and craniosynostosis: plurality (twins or higher), macrosomia (birth weight >4,000 g), post-term gestational age (> or =42 weeks), and nulliparity (no previous live births). Case infants (n = 675) had craniosynostosis documented either by radiographic evidence or by surgical intervention. Infants with a recognized or strongly suspected single-gene conditions or chromosomal abnormalities were excluded. Control infants (n = 5,958) had no major birth defects and were randomly selected from the same population as case infants. Logistic regression was used to estimate odds ratios for the association between these four factors and craniosynostosis, while adjusting for several covariates. We found that plurality and nulliparity were associated with a twofold increased risk for metopic craniosynostosis, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were also associated with craniosynostosis. In conclusion, these four constraint-related factors were not found to be associated with craniosynostosis when all suture types were combined, though some types of craniosynostosis were associated with individual constraint-related factors.

  View details for DOI 10.1002/ajmg.a.33246

  View details for Web of Science ID 000274508300019

  View details for PubMedID 20101684

  View details for PubMedCentralID PMC2815148

• Association of Congenital Cardiovascular Malformations with 33 Single Nucleotide Polymorphisms of Selected Cardiovascular Disease-Related Genes BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Kuehl, K., Loffredo, C., Lammer, E. J., Iovannisci, D. M., Shaw, G. M. 2010; 88 (2): 101-110

  Abstract

  Clark (1996) proposed that abnormal blood flow is related to some congenital cardiovascular malformations (CCVMs), particularly CCVM with obstruction to blood flow. Our hypothesis is that CCVMs may relate to genes that affect blood coagulation or flow. We studied whether polymorphisms of such genes are related to CCVMs; previous association of these SNPs to conotruncal CCVMs is described.We assessed risk of pulmonary stenosis (PS, N = 120), atrial septal defect (ASD, N = 108), aortic stenosis (AS, N = 36), and coarctation of the aorta (CoAo, N = 64), associated with 33 candidate genes, selected for their relationship to blood flow affected by homocysteine metabolism, coagulation, cell-cell interaction, inflammation, or blood pressure regulation.Effects were specific to cardiac phenotype and race. CoAo was associated with MTHFR (-667) C>T (odds ratio [OR] for TT 3.5, 95% confidence limits [CI] 1.4-8.6). AS was associated with a polymorphism of SERPINE1, G5>G4, OR = 5.6 for the homozygote with 95% CI 1.4-22.9. Unique polymorphisms were associated with increased risk of ASD and PS: NPPA 664G>A with ASD (OR of 2.4, 95%CI 1.3-4.4) and NOS3 (-690) C>T with PS (OR 6.1; 95% CI 1.6-22.6 in the African American population only). For ASD, the NPPA (-664) G>A SNP there was increased risk from the variant genotype only in maternal smokers (OR 2.6; 95% CI 1.0-7.2).Genes affecting vascular function and coagulation appear to be promising candidates for the etiology of cardiac malformations and warrant further study.

  View details for DOI 10.1002/bdra.20630

  View details for Web of Science ID 000275389800005

  View details for PubMedID 19764075

• Second-Trimester Serum Cytokines in Women Who Develop Spontaneous Preterm Labor at Less than 28 Weeks' Gestation versus Term Labor AMERICAN JOURNAL OF PERINATOLOGY Yang, Q., El Sayed, Y., Shaw, G. M., Fu, J., Schilling, J., Madan, A. 2010; 27 (1): 31-36

  Abstract

  We sought to determine if there is a relationship between serum concentrations of cytokines and the development of preterm labor. A panel of 28 cytokines was measured using the multiplex assay in serum samples collected between 15 and 18 weeks' gestation from women who developed spontaneous preterm labor and delivered between 24 and 28 weeks' gestation (N = 25) and from women who delivered at term (>or=37 weeks; N = 25). Sixteen of the 28 cytokines measured were detected. Except for vascular endothelial growth factor, which showed a trend toward a significant increase in patients who developed preterm labor, there was no difference in cytokine levels between groups in preterm labor and in term labor. Serum cytokine changes in women who develop spontaneous preterm labor possibly occur in the period between 18 weeks' gestation and the onset of labor.

  View details for DOI 10.1055/s-0029-1234037

  View details for Web of Science ID 000273825200006

  View details for PubMedID 19644787

• Nested Case-Control Study of One-Carbon Metabolites in Mid-Pregnancy and Risks of Cleft Lip With and Without Cleft Palate PEDIATRIC RESEARCH Shaw, G. M., Vollset, S. E., Carmichael, S. L., Yang, W., Finnell, R. H., Blom, H., Ueland, P. M. 2009; 66 (5): 501-506

  Abstract

  Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with cleft lip with/without cleft palate (CLP). A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and CLP by measuring nutrient analytes in mid-pregnancy sera. This study included data from a repository of women's mid-pregnancy serum specimens collected in California from 2003-04. Each woman's specimen was linked with delivery information to determine whether her fetus had CLP or another structural malformation, or was nonmalformed. We identified 89 CLP cases. We randomly selected 409 specimens as controls. Specimens were tested for homocysteine, methylmalonic acid, folate, vitamin B12, pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, choline, betaine, methionine, methionine sulfoxide, cysteine, cystathionine, arginine, and asymmetric and symmetric dimethylarginine. We observed three analytes with odds ratios unlikely to be explained by random variation, i.e., elevated CLP risks were observed for low levels and for high levels of pyridoxal phosphate (vitamin B6), higher levels of choline, and low levels of symmetric dimethylarginine. These data did not show meaningful differences between cases and controls for any other analytes.

  View details for Web of Science ID 000271039100003

  View details for PubMedID 19668105

• Control Selection and Participation in an Ongoing, Population-based, Case-Control Study of Birth Defects AMERICAN JOURNAL OF EPIDEMIOLOGY Cogswell, M. E., Bitsko, R. H., Anderka, M., Caton, A. R., Feldkamp, M. L., Sherlock, S. M., Meyer, R. E., Ramadhani, T., Robbins, J. M., Shaw, G. M., Mathews, T. J., Royle, M., Reefhuis, J. 2009; 170 (8): 975-985

  Abstract

  To evaluate the representativeness of controls in an ongoing, population-based, case-control study of birth defects in 10 centers across the United States, researchers compared 1997-2003 birth certificate data linked to selected controls (n = 6,681) and control participants (n = 4,395) with those from their base populations (n = 2,468,697). Researchers analyzed differences in population characteristics (e.g., percentage of births at > or =2,500 g) for each group. Compared with their base populations, control participants did not differ in distributions of maternal or paternal age, previous livebirths, maternal smoking, or diabetes, but they did differ in other maternal (i.e., race/ethnicity, education, entry into prenatal care) and infant (i.e., birth weight, gestational age, and plurality) characteristics. Differences in distributions of maternal, but not infant, characteristics were associated with participation by selected controls. Absolute differences in infant characteristics for the base population versus control participants were < or =1.3 percentage points. Differences in infant characteristics were greater at centers that selected controls from hospitals compared with centers that selected controls from electronic birth certificates. These findings suggest that control participants in the National Birth Defects Prevention Study generally are representative of their base populations. Hospital-based control selection may slightly underascertain infants affected by certain adverse birth outcomes.

  View details for DOI 10.1093/aje/kwp226

  View details for Web of Science ID 000270445300007

  View details for PubMedID 19736223

• Socioeconomic Measures, Orofacial Clefts, and Conotruncal Heart Defects in California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Ma, C., Shaw, G. M. 2009; 85 (10): 850-857

  Abstract

  To examine the association of multiple measures of socioeconomic status (SES) with risks of orofacial clefts and conotruncal heart defects.Data were from a recent population-based case-control study conducted in California that included 608 patients with orofacial clefts, 277 patients with conotruncal heart defects, and 617 nonmalformed controls.The odds ratio for the worst versus best score on a household-level SES index was strongest for cleft lip with or without palate, at 1.7 (95% confidence interval, 0.9-3.4); the odds ratios for this comparison were closer to 1 and less precise for the other defect groups. An index based on neighborhood-level SES was also not associated with increased risk of the studied defects.This detailed analysis of SES and selected birth defects did not suggest worse SES was associated with increased risk of the studied defects, with the possible exception of cleft lip with or without cleft palate.

  View details for DOI 10.1002/bdra.20614

  View details for Web of Science ID 000271348700006

  View details for PubMedID 19645048

  View details for PubMedCentralID PMC2865188

• Choline and Risk of Neural Tube Defects in a Folate-fortified Population EPIDEMIOLOGY Shaw, G. M., Finnell, R. H., Blom, H. J., Carmichael, S. L., Vollset, S. E., Yang, W., Ueland, P. M. 2009; 20 (5): 714-719

  Abstract

  Folic acid is known to reduce risk of neural tube defects (NTDs). Even so, NTDs continue to occur despite individual supplementation or population fortification with folic acid. We investigated other nutrients related to one-carbon metabolism that may affect NTD risk.This prospective study included data from more than 180,000 pregnant women in California from 2003 through 2005. Midpregnancy serum specimens were linked with delivery information regarding the presence of a NTD, another structural malformation, or no malformation in the fetus. We identified 80 NTD-affected pregnancies (cases) and we randomly selected 409 pregnancy controls. Serum specimens were tested for methylmalonic acid, homocysteine, cysteine, methionine, total choline, betaine, cystathionine, vitamin B6, folate, vitamin B12, riboflavin, and creatinine.We observed elevated NTD risks associated with lower levels of total choline, and reduced risks with higher levels of choline. Specifically, we observed an odds ratio of 2.4 (95% confidence interval = 1.3-4.7) associated with the lowest decile and an odds ratio of 0.14 (0.02-1.0) associated with the highest decile, both relative to the 25th-74th percentiles of the control distribution. These data did not show meaningful differences between cases and controls for any other analytes.This is the first study to investigate total choline in NTD-affected pregnancies. Our findings for choline, for which low levels were a risk factor and higher levels were a protective factor for NTDs, may offer a useful clue toward understanding the complex etiologies of NTDs in an era of folic acid fortification of the food supply.

  View details for DOI 10.1097/EDE.0b013e3181ac9fe7

  View details for Web of Science ID 000269103500017

  View details for PubMedID 19593156

• Maternal Nutrient Intake and Risks for Transverse and Longitudinal Limb Deficiencies: Data from the National Birth Defects Prevention Study, 1997-2003 48th Annual Meeting of the Teratology-Society Robitaille, J., Carmichael, S. L., Shaw, G. M., Olney, R. S. WILEY-BLACKWELL. 2009: 773–79

  Abstract

  The association between periconceptional intake of supplements containing folic acid with specific subtypes of limb deficiencies has been inconsistent. The objective was to investigate whether intake of nutrients involved in one-carbon metabolism (folate, vitamin B(6), vitamin B(12), riboflavin, choline, betaine, zinc, and methionine) through diet alone or in combination with a supplement containing folic acid influenced the risk for transverse limb deficiency (TLD) and longitudinal limb deficiency (LLD).We analyzed 1997-2003 data from the National Birth Defects Prevention Study and included 324 case infants with TLD, 158 case infants with LLD, and 4982 nonmalformed control infants. A food frequency questionnaire was used to estimate nutrient intakes. Use of supplements containing folic acid 1 month before through 2 months after conception was recorded.Use of a supplement containing folic acid was not associated with LLD or TLD. For nonsupplement users, within (1) the lowest quartile of dietary folate intake or vitamin B(6) intake, adjusted odds ratios (aORs) for LLD were, respectively, 3.86 (95% confidence interval [CI]: 1.08-13.78) and 4.36 (95% CI: 0.93-20.48); and (2) the lowest quartile for riboflavin intake, the aOR for TLD was 2.94 (95% CI: 1.04-8.32). For supplement users within the lowest quartile of folate intake or riboflavin intake, the aORs for TLD were, respectively, 1.52 (95% CI: 0.91-2.54) and 1.54 (95% CI: 1.00-2.37).TLD and LLD were not associated with supplement use, but TLD was associated with low intakes of riboflavin from diet.

  View details for DOI 10.1002/bdra.20587

  View details for Web of Science ID 000270586400004

  View details for PubMedID 19350655

• Whole genome microarray analysis, from neonatal blood cards BMC GENETICS Hardin, J., Finnell, R. H., Wong, D., Hogan, M. E., Horovitz, J., Shu, J., Shaw, G. M. 2009; 10

  Abstract

  Neonatal blood, obtained from a heel stick and stored dry on paper cards, has been the standard for birth defects screening for 50 years. Such dried blood samples are used, primarily, for analysis of small-molecule analytes. More recently, the DNA complement of such dried blood cards has been used for targeted genetic testing, such as for single nucleotide polymorphism in cystic fibrosis. Expansion of such testing to include polygenic traits, and perhaps whole genome scanning, has been discussed as a formal possibility. However, until now the amount of DNA that might be obtained from such dried blood cards has been limiting, due to inefficient DNA recovery technology.A new technology is employed for efficient DNA release from a standard neonatal blood card. Using standard Guthrie cards, stored an average of ten years post-collection, about 1/40th of the air-dried neonatal blood specimen (two 3 mm punches) was processed to obtain DNA that was sufficient in mass and quality for direct use in microarray-based whole genome scanning. Using that same DNA release technology, it is also shown that approximately 1/250th of the original purified DNA (about 1 ng) could be subjected to whole genome amplification, thus yielding an additional microgram of amplified DNA product. That amplified DNA product was then used in microarray analysis and yielded statistical concordance of 99% or greater to the primary, unamplified DNA sample.Together, these data suggest that DNA obtained from less than 10% of a standard neonatal blood specimen, stored dry for several years on a Guthrie card, can support a program of genome-wide neonatal genetic testing.

  View details for DOI 10.1186/1471-2156-10-38

  View details for Web of Science ID 000269503400001

  View details for PubMedID 19624846

• Maternal Corticosteroid Use and Hypospadias JOURNAL OF PEDIATRICS Carmichael, S. L., Ma, C., Werler, M. M., Olney, R. S., Shaw, G. M. 2009; 155 (1): 39-44

  Abstract

  To explore whether women who reported corticosteroid use during pregnancy were more likely to deliver an infant with hypospadias than women who did not.The analysis encompassed data on deliveries with an estimated due date between 1997 and 2004 from the National Birth Defects Prevention Study, a large population-based, case-control study conducted in the United States. Included were 1165 cases of moderate to severe hypospadias and 3000 nonmalformed male controls.The mothers of 39 cases (3.3%) and 62 controls (2.1%) reported using a corticosteroid medication during the period extending from 4 weeks before conception to 14 weeks after conception. The odds ratio (OR) for any corticosteroid exposure versus no corticosteroid exposure was 1.6 (95% confidence interval [CI] = 1.1 to 2.5); after adjustment for maternal race/ethnicity, education, age, and study site, it was 1.3 (95% CI = 0.8 to 2.0). Analyses by route of administration and specific component suggest that elevated ORs occurred only for nasal spray/inhaled corticosteroids (OR = 1.5; 95% CI = 0.9 to 2.6).Maternal use of corticosteroid medications was weakly associated with risk of hypospadias, but the association was negligible after adjustment for potential confounders.

  View details for DOI 10.1016/j.jpeds.2009.01.039

  View details for Web of Science ID 000267672600013

  View details for PubMedID 19394038

• Anencephaly and Spina Bifida among Hispanics: Maternal, Sociodemographic, and Acculturation Factors in the National Birth Defects Prevention Study 21st Annual Meeting of the Society-for-Pediatric-Epidemiology-Research Canfield, M. A., Ramadhani, T. A., Shaw, G. M., Carmichael, S. L., Waller, D. K., Mosley, B. S., Royle, M. H., Olney, R. S. WILEY-BLACKWELL. 2009: 637–46

  Abstract

  We used data from the multisite National Birth Defects Prevention Study for expected delivery dates from October 1997 through 2003, to determine whether the increased risk in anencephaly and spina bifida (neural tube defects (NTDs)) in Hispanics was explained by selected sociodemographic, acculturation, and other maternal characteristics.For each type of defect, we examined the association with selected maternal characteristics stratified by race/ethnicity and the association with Hispanic parents' acculturation level, relative to non-Hispanic whites. We used logistic regression and calculated crude odds ratios (ORs) and their 95% confidence intervals (CIs).Hispanic mothers who reported the highest level of income were 80% less likely to deliver babies with spina bifida. In addition, highly educated Hispanic and white mothers had 76 and 35% lower risk, respectively. Other factors showing differing effects for spina bifida in Hispanics included maternal age, parity, and gestational diabetes. For spina bifida there was no significant elevated risk for U.S.-born Hispanics, relative to whites, but for anencephaly, corresponding ORs ranged from 1.9 to 2.3. The highest risk for spina bifida was observed for recent Hispanic immigrant parents from Mexico or Central America residing in the United States <5 years (OR = 3.28, 95% CI = 1.46-7.37).Less acculturated Hispanic parents seemed to be at highest risk of NTDs. For anencephaly, U.S.-born and English-speaking Hispanic parents were also at increased risk. Finally, from an etiologic standpoint, spina bifida and anencephaly appeared to be etiologically heterogeneous from these analyses.

  View details for DOI 10.1002/bdra.20582

  View details for Web of Science ID 000268426000007

  View details for PubMedID 19334286

• 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects BMC MEDICAL GENETICS Shaw, G. M., Lu, W., Zhu, H., Yang, W., Briggs, F. B., Carmichael, S. L., Barcellos, L. F., Lammer, E. J., Finnell, R. H. 2009; 10

  Abstract

  Folic acid taken in early pregnancy reduces risks for delivering offspring with several congenital anomalies. The mechanism by which folic acid reduces risk is unknown. Investigations into genetic variation that influences transport and metabolism of folate will help fill this data gap. We focused on 118 SNPs involved in folate transport and metabolism.Using data from a California population-based registry, we investigated whether risks of spina bifida or conotruncal heart defects were influenced by 118 single nucleotide polymorphisms (SNPs) associated with the complex folate pathway. This case-control study included 259 infants with spina bifida and a random sample of 359 nonmalformed control infants born during 1983-86 or 1994-95. It also included 214 infants with conotruncal heart defects born during 1983-86. Infant genotyping was performed blinded to case or control status using a designed SNPlex assay. We examined single SNP effects for each of the 118 SNPs, as well as haplotypes, for each of the two outcomes.Few odds ratios (ORs) revealed sizable departures from 1.0. With respect to spina bifida, we observed ORs with 95% confidence intervals that did not include 1.0 for the following SNPs (heterozygous or homozygous) relative to the reference genotype: BHMT (rs3733890) OR = 1.8 (1.1-3.1), CBS (rs2851391) OR = 2.0 (1.2-3.1); CBS (rs234713) OR = 2.9 (1.3-6.7); MTHFD1 (rs2236224) OR = 1.7 (1.1-2.7); MTHFD1 (hcv11462908) OR = 0.2 (0-0.9); MTHFD2 (rs702465) OR = 0.6 (0.4-0.9); MTHFD2 (rs7571842) OR = 0.6 (0.4-0.9); MTHFR (rs1801133) OR = 2.0 (1.2-3.1); MTRR (rs162036) OR = 3.0 (1.5-5.9); MTRR (rs10380) OR = 3.4 (1.6-7.1); MTRR (rs1801394) OR = 0.7 (0.5-0.9); MTRR (rs9332) OR = 2.7 (1.3-5.3); TYMS (rs2847149) OR = 2.2 (1.4-3.5); TYMS (rs1001761) OR = 2.4 (1.5-3.8); and TYMS (rs502396) OR = 2.1 (1.3-3.3). However, multiple SNPs observed for a given gene showed evidence of linkage disequilibrium indicating that the observed SNPs were not individually contributing to risk. We did not observe any ORs with confidence intervals that did not include 1.0 for any of the studied SNPs with conotruncal heart defects. Haplotype reconstruction showed statistical evidence of nonrandom associations with TYMS, MTHFR, BHMT and MTR for spina bifida.Our observations do not implicate a particular folate transport or metabolism gene to be strongly associated with risks for spina bifida or conotruncal defects.

  View details for DOI 10.1186/1471-2350-10-49

  View details for PubMedID 19493349

• Orofacial Clefts in the National Birth Defects Prevention Study, 1997-2004 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Genisca, A. E., Frias, J. L., Broussard, C. S., Honein, M. A., Lammer, E. J., Moore, C. A., Shaw, G. M., Murray, J. C., Yang, W., Rasmussen, S. A. 2009; 149A (6): 1149-1158

  Abstract

  Orofacial clefts are among the most common types of birth defects, but their clinical presentation has not been well described in a geographically diverse US population. To describe the birth prevalence and phenotype of nonsyndromic clefts, we used data from the National Birth Defects Prevention Study (NBDPS), a multi-site, population-based, case-control study aimed at identifying genetic and environmental risk factors for birth defects. Included in the study were infants born during 1997-2004 with a cleft lip (CL), cleft lip with cleft palate (CLP), or cleft palate (CP). Infants with clefts associated with recognized single-gene disorders, chromosome abnormalities, holoprosencephaly, or amniotic band sequence were excluded. A total of 3,344 infants with nonsyndromic orofacial clefts were identified, including 751 with CL, 1,399 with CLP, and 1,194 with CP, giving birth prevalence estimates of 0.3, 0.5, and 0.4/1,000 live births, respectively. Among infants with CLP where cleft laterality was specified, about twice as many had unilateral vs. bilateral involvement, while for CL there were over 10 times as many with unilateral versus bilateral involvement. Involvement was most often left-sided. About one-quarter of infants with CP had Pierre Robin sequence. Over 80% of infants had an isolated orofacial cleft. Among infants with CL or CLP, heart, limb, and other musculoskeletal defects were most commonly observed, while heart, limb, and central nervous system defects were most common among infants with CP. Better understanding of the birth prevalence and phenotype may help guide clinical care as well as contribute to an improved understanding of pathogenesis.

  View details for DOI 10.1002/ajmg.a.32854

  View details for Web of Science ID 000266684200006

  View details for PubMedID 19441124

• Increased Prevalence of Cardiovascular Defects Among 56,709 California Twin Pairs AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hardin, J., Carmichael, S. L., Selvin, S., Lammer, E. J., Shaw, G. M. 2009; 149A (5): 877-886

  Abstract

  This study compared the prevalence of cardiovascular defects in twin and singleton births and explored the influences of zygosity (monozygotic and dizygotic) and maternal age (<35 and >or=35 years of age) on concordance. Data on twin and singleton infants with (n = 628 twin pairs and n = 14,078 singletons) and without (n = 53,974 twin pairs and n = 4,858,255 singletons) cardiovascular defects were obtained from the California Birth Defects Monitoring Program and the California vital statistics birth and fetal death records during the period 1983-2003. Prevalence ratios (PR) (prevalence of twin/singleton) and approximate 95% confidence intervals were calculated for 16 congenital cardiovascular categories. Poisson regression techniques using log-linear models were employed to assess whether the probability of concordance of defects within each cardiovascular category varied by zygosity or maternal age. An increased prevalence was observed in twins compared to singletons in all 16 cardiovascular categories. Seven of the cardiovascular categories had at least double the prevalence in twins compared to singletons. Like-sex twins, as a proxy of monozygosity, had an increased prevalence of cardiovascular defects compared to unlike sex twins. Probabilities of concordance for flow lesions were higher among monozygotic than dizygotic twins. Our study provides evidence that twinning is associated with more cardiovascular defects than singletons. Increased concordance for flow lesions in monozygotic twins was observed, an observation that is in agreement with findings from familial recurrence studies of cardiovascular defects.

  View details for DOI 10.1002/ajmg.a.32745

  View details for Web of Science ID 000265805900010

  View details for PubMedID 19353581

• Sequence variants in the HLX gene at chromosome 1q41-1q42 in patients with diaphragmatic hernia CLINICAL GENETICS Slavotinek, A. M., Moshrefi, A., Lopez Jiminez, N., Chao, R., Mendell, A., Shaw, G. M., Pennacchio, L. A., Bates, M. D. 2009; 75 (5): 429-439

  Abstract

  Congenital diaphragmatic hernia (CDH) is a common birth defect for which few causative genes have been identified. Several candidate regions containing genes necessary for normal diaphragm development have been identified, including a 4-5 Mb deleted region at chromosome 1q41-1q42 from which the causative gene(s) has/have not been cloned. We selected the HLX gene from this interval as a candidate gene for CDH, as the Hlx homozygous null mouse has been reported to have diaphragmatic defects and the gene was described as being expressed in the murine diaphragm. We re-sequenced HLX in 119 CDH patients and identified four novel single nucleotide substitutions that predict amino acid changes: p.S12F, p.S18L, p.D173Y and p.A235V. These sequence alterations were all present in patients with isolated CDH, although patients with both isolated CHD and CDH with additional anomalies were studied. The single-nucleotide substitutions were absent in more than 186 control chromosomes. In-situ hybridization studies confirmed expression of Hlx in the developing murine diaphragm at the site of the junction of the diaphragm and the liver. Although functional studies to determine if these novel sequence variants altered the inductive activity of Hlx on the alpha-smooth muscle actin and SM22alpha promoters showed no significant differences between the variants and wild-type Hlx, sequence variants in HLX may still be relevant in the pathogenesis of CDH in combination with additional genetic and environmental factors.

  View details for DOI 10.1111/j.1399-0004.2009.01182.x

  View details for Web of Science ID 000265708200005

  View details for PubMedID 19459883

• Neural tube defects: an analysis of neighbourhood- and individual-level socio-economic characteristics PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Grewal, J., Carmichael, S. L., Song, J., Shaw, G. M. 2009; 23 (2): 116-124

  Abstract

  Several studies have reported that neural tube defects (NTD) occur more frequently among children born to women of lower socio-economic status (SES). This study investigated the relationship between individual- and neighbourhood-level SES and the risk of an NTD-affected pregnancy. Data were drawn from a population-based case-control study of fetuses and infants among a cohort of California births between July 1999 and June 2003. Information on individual SES was obtained via telephone interviews with mothers of 337 (76% of eligible) cases and 626 (79% of eligible) non-malformed liveborn controls. Respondents' addresses were linked to the 2000 US Census to characterise six measures of neighbourhood SES (education, poverty, unemployment, occupation, crowding and rental occupancy). The analyses indicated that relative to women with a high school education, those with less than a high school education had a 1.7-fold increased risk of delivering infants with NTDs [95% CI 1.2, 2.6]. Twofold elevated risks for NTDs were observed for women with less than a high school education who lived in neighbourhoods where a majority of residents had not graduated from high school [95% CI 1.3, 3.1]. No consistent risk gradients were observed between NTD-affected pregnancies and indicators of lower neighbourhood SES. Results for phenotype subgroups were similar to those for all cases. Low maternal education was associated with an elevated risk of NTD in offspring. This risk varied by the education profile of the neighbourhood: women who did not graduate from high school and lived in less educated neighbourhoods exhibited a higher risk.

  View details for DOI 10.1111/j.1365-3016.2008.00992.x

  View details for Web of Science ID 000262645600003

  View details for PubMedID 19159398

• Trends in the Probability of Twins and Males in California, 1983-2003 TWIN RESEARCH AND HUMAN GENETICS Hardin, J., Carmichael, S. L., Selvin, S., Shaw, G. M. 2009; 12 (1): 93-102

  Abstract

  This study examines the probability of twins by birth year, maternal race-ethnicity, age, and parity and the influences of these demographic factors on the probability of male in twins and singletons in a large, racially diverse population. Recent publications note steep increases in twin births while the probability of male births has been reported to vary by parental race-ethnicity and age and birth order. Probability of male stratified by plurality has not been investigated in California prior to this study. Cubic spline estimates and Poisson regression techniques were employed to describe trends in twins and males using California vital statistics birth and fetal death records over the period from 1983-2003. This study includes 127,787 twin pair and 11,025,106 singleton births. The probability of twins varied by birth year, maternal race-ethnicity, age, and parity. The probability of twins increased by 10.1% from 1983-1992 and increased by 20.1% from 1993-2003, nearly doubling the previous increase. All maternal race-ethnicity groups showed increases in probability of twins with increasing maternal age. Parous women compared to nulliparous women had larger increases in the probability of twins. The probability of males in twins decreased from 1983-1992 and increased from 1993-2003; while in singletons the probability appeared unchanged. These findings show increases in the probability of twins in California from 1983-2003 and identify maternal age, race-ethnicity, and parity groups most likely to conceive twins. The cause of the increase in twins is unknown but coincides with trends towards delayed childbearing and increased use of subfertility treatments.

  View details for Web of Science ID 000263635000011

  View details for PubMedID 19210184

• The Estimated Probability of Dizygotic Twins: A Comparison of Two Methods TWIN RESEARCH AND HUMAN GENETICS Hardin, J., Selvin, S., Carmichael, S. L., Shaw, G. M. 2009; 12 (1): 79-85

  Abstract

  This study presents a general model of two binary variables and applies it to twin sex pairing data from 21 twin data sources to estimate the frequency of dizygotic twins. The purpose of this study is to clarify the relationship between maximum likelihood and Weinberg's differential rule zygosity estimation methods. We explore the accuracy of these zygosity estimation measures in relation to twin ascertainment methods and the probability of a male. Twin sex pairing data from 21 twin data sources representing 15 countries was collected for use in this study. Maximum likelihood estimation of the probability of dizygotic twins is applied to describe the variation in the frequency of dizygotic twin births. The differences between maximum likelihood and Weinberg's differential rule zygosity estimation methods are presented as a function of twin data ascertainment method and the probability of a male. Maximum likelihood estimation of the probability of dizygotic twins ranges from 0.083 (95% approximate CI: 0.082, 0.085) to 0.750 (95% approximate CI: 0.749, 0.752) for voluntary ascertainment data sources and from 0.374 (95% approximate CI: 0.373, 0.375) to 0.987 (95% approximate CI: 0.959, 1.016) for active ascertainment data sources. In 17 of the 21 twin data sources differences of 0.01 or less occur between maximum likelihood and Weinberg zygosity estimation methods. The Weinberg and maximum likelihood estimates are negligibly different in most applications. Using the above general maximum likelihood estimate, the probability of a dizygotic twin is subject to substantial variation that is largely a function of twin data ascertainment method.

  View details for Web of Science ID 000263635000009

  View details for PubMedID 19210182

• Genetic Polymorphisms in the Thioredoxin 2 (TXN2) Gene and Risk for Spina Bifida AMERICAN JOURNAL OF MEDICAL GENETICS PART A Wen, S., Lu, W., Zhu, H., Yang, W., Shaw, G. M., Lammer, E. J., Islam, A., Finnell, R. H. 2009; 149A (2): 155-160

  Abstract

  TXN2 encodes human thioredoxin 2, a small redox protein important in cellular antioxidant defenses, as well as in the regulation of apoptosis. Txn2 knockout mice fail to complete neural tube closure by E10.5 and die in utero. We hypothesized that genetic variation in human TXN2 gene may alter the function of the encoded protein in a manner associated with an increased risk for neural tube defects (NTDs). A DNA re-sequencing effort of the human TXN2 gene was taken. After a variation in the promoter was identified, the transcriptional activity of different alleles was investigated. The possible association between these variations and the risk of spina bifida was further evaluated in a subset of samples obtained from a large population-based case-control study in California in two different ethnicity groups, non-Hispanic white and Hispanic white. We identified a novel promoter insertion polymorphism located 9 base pairs upstream of the transcription start site of exon 1(-9 insertion). The GA, G and GGGA insertions were associated with a marked decrease of transcriptional activity when overexpressed in both U2-OS (an osteosarcoma cell line) and 293 cells (derived from human embryonic kidney). Further analysis revealed that the GA insertion was associated with increased spina bifida risk for Hispanic whites. Our study revealed a novel Ins/Del polymorphism in the human TXN2 gene proximal promoter region that altered the transcriptional activity and is associated with spina bifida risk. This polymorphism may be a genetic modifier of spina bifida risk in this California population.

  View details for DOI 10.1002/ajmg.a.32589

  View details for Web of Science ID 000263433400005

  View details for PubMedID 19165900

• Neural Tube Defects and Maternal Folate Intake Among Pregnancies Conceived After Folic Acid Fortification in the United States AMERICAN JOURNAL OF EPIDEMIOLOGY Mosley, B. S., Cleves, M. A., Siega-Riz, A. M., Shaw, G. M., Canfield, M. A., Waller, D. K., Werler, M. M., Hobbs, C. A. 2009; 169 (1): 9-17

  Abstract

  Rates of neural tube defects have decreased since folic acid fortification of the food supply in the United States. The authors' objective was to evaluate the associations between neural tube defects and maternal folic acid intake among pregnancies conceived after fortification. This is a multicenter, case-control study that uses data from the National Birth Defects Prevention Study, 1998-2003. Logistic regression was used to compute crude and adjusted odds ratios between cases and controls assessing maternal periconceptional use of folic acid and intake of dietary folic acid. Among 180 anencephalic cases, 385 spina bifida cases, and 3, 963 controls, 21.1%, 25.2%, and 26.1%, respectively, reported periconceptional use of folic acid supplements. Periconceptional supplement use did not reduce the risk of having a pregnancy affected by a neural tube defect. Maternal intake of dietary folate was not significantly associated with neural tube defects. In this study conducted among pregnancies conceived after mandatory folic acid fortification, the authors found little evidence of an association between neural tube defects and maternal folic acid intake. A possible explanation is that folic acid fortification reduced the occurrence of folic acid-sensitive neural tube defects. Further investigation is warranted to possibly identify women who remain at increased risk of preventable neural tube defects.

  View details for DOI 10.1093/aje/kwn331

  View details for Web of Science ID 000262152200002

  View details for PubMedID 18953063

• Chromosomal Abnormalities among Children Born with Conotruncal Cardiac Defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lammer, E. J., Chak, J. S., Iovannisci, D. M., Schultz, K., Osoegawa, K., Yang, W., Carmichael, S. L., Shaw, G. M. 2009; 85 (1): 30-35

  Abstract

  Conotruncal heart defects compose 25% to 30% of nonsyndromic congenital heart defects. This study describes the frequency of chromosome abnormalities and microdeletion of 22q11 associated among infants and fetuses delivered with conotruncal heart malformations.From a population base of 974,579 infants/fetuses delivered, 622 California infants/fetuses were ascertained with a defect of aortopulmonary septation. Infants whose primary cardiac defect was tetralogy of Fallot (n = 296) or d-transposition of the great arteries (n = 189) were screened for microdeletion of 22q11.Of the infants who had routine karyotypes, 5% had chromosomal abnormalities, including four with extra sex chromosomes. Thirty infants had chromosome 22q11 microdeletions, providing a cause for 10% of infants whose primary defect was tetralogy of Fallot. Right aortic arch, abnormal branching patterns of the major arteries arising from the thoracic aorta, and pulmonary artery abnormalities were observed more frequently among infants with tetralogy of Fallot caused by 22q11 microdeletion.We found an unusual number of infants with an extra sex chromosome and a conotruncal defect. Infants with tetralogy of Fallot owing to 22q11 microdeletion showed more associated vascular anomalies than infants with tetralogy without a 22q11 microdeletion. Although these associated vascular anomalies provide clues as to which infants with tetralogy of Fallot are more likely to carry the microdeletion, the overall risk of 10% among infants with tetralogy of Fallot warrants chromosome analysis and fluorescent in situ hybridization (FISH) testing routinely, which may be supplanted by genome-wide copy number testing as it becomes more widely utilized.

  View details for DOI 10.1002/bdra.20541

  View details for Web of Science ID 000262904800005

  View details for PubMedID 19067405

• Hypospadias and Intake of Nutrients Related to One-Carbon Metabolism JOURNAL OF UROLOGY Carmichael, S. L., Yang, W., Correa, A., Olney, R. S., Shaw, G. M. 2009; 181 (1): 315-321

  Abstract

  We examined whether hypospadias is associated with maternal intake of folic acid containing vitamin/mineral supplements or dietary intake of nutrients related to one-carbon metabolism (folate, choline, vitamins B12 and B6, thiamine, riboflavin, methionine and zinc).The study included births from October 1997 to December 2003 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews. Analyses included 915 cases with second or third degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 2,266 male, liveborn, nonmalformed controls. All ORs and 95% CIs were estimated from logistic regression models that included several potential confounders. Nutrient based analyses also included energy intake.Hypospadias risk was not associated with supplement use (adjusted ORs were 1.2, 95% CI 0.9-1.6 for intake beginning in the month before or the first month of pregnancy and 1.1, 95% CI 0.8-1.4 for intake beginning in the second or third month, relative to no intake). Among women who took supplements reduced hypospadias risk was associated with higher dietary intakes of choline, methionine and vitamin B12. The respective ORs (CIs) for the highest vs lowest quartiles were 0.7 (0.5-1.1), 0.6 (0.4-0.9) and 0.7 (0.5-1.0). Among women who did not take supplements increased risk of hypospadias was associated with higher vitamin B12 intake. The OR (CI) for the highest vs lowest quartile was 3.1 (1.1-9.0).This study suggests an association of hypospadias with intake of certain nutrients related to one-carbon metabolism.

  View details for DOI 10.1016/j.juro.2008.09.041

  View details for Web of Science ID 000261705900175

  View details for PubMedID 19013591

• Nutrient Pathways and Neural Tube Defects A Semi-Bayesian Hierarchical Analysis EPIDEMIOLOGY Carmichael, S. L., Witte, J. S., Shaw, G. M. 2009; 20 (1): 67-73

  Abstract

  We used conventional and hierarchical logistic regression to examine the association of neural tube defects (NTDs) with intake of 26 nutrients that contribute to the mechanistic pathways of methylation, glycemic control, and oxidative stress, all of which have been implicated in NTD etiology. The hierarchical approach produces more plausible, more stable estimates than the conventional approach, while adjusting for potential confounding by other nutrients.Analyses included 386 cases and 408 nonmalformed controls with complete data on nutrients and potential confounders (race/ethnicity, education, obesity, and intake of vitamin supplements) from a population-based case-control study of deliveries in California from 1989 to 1991. Nutrients were specified as continuous, and their units were standardized to have a mean of zero and standard deviation (SD) of 1 for comparability of units across pathways. ORs reflect a 1-SD increase in the corresponding nutrient.Among women who took vitamin supplements, semi-Bayesian hierarchical modeling results suggested no associations between nutrient intake and NTDs. Among women who did not take supplements, both conventional and hierarchical models (HM) suggested an inverse association between lutein intake and NTD risk (HM odds ratio [OR] = 0.6; 95% confidence interval = 0.5-0.9) and a positive association with sucrose (HM OR 1.4; 1.1-1.8) and glycemic index (HM OR 1.3; 1.0-1.6).Our findings for lutein, glycemic index, and sucrose suggest that further study of NTDs and the glycemic control and oxidative stress pathways is warranted.

  View details for DOI 10.1097/EDE.0b013e31818f6375

  View details for Web of Science ID 000261930800013

  View details for PubMedID 19234400

• Mid-Pregnancy Cotinine and Risks of Orofacial Clefts and Neural Tube Defects JOURNAL OF PEDIATRICS Shaw, G. M., Carmichael, S. L., Vollset, S. E., Yang, W., Finnell, R. H., Blom, H., Midttun, O., Ueland, P. M. 2009; 154 (1): 17-19

  Abstract

  Past studies of cigarette smoking as a contributor to orofacial clefts and neural tube defects (NTDs) used self-reports of smoke exposures. We have correlated measurements of cotinine (a nicotine metabolite) in mid-pregnancy sera with clefts and NTDs.From a repository of >180 000 mid-pregnancy serum specimens collected in California from 2003 to 2005 and linked to delivery outcome information, we identified 89 orofacial cleft-associated pregnancies, 80 NTD-affected pregnancies, and randomly selected 409 pregnancy specimens that corresponded to infants without malformations as control subjects. Cotinine was measured by liquid chromatography-mass spectrometry. No smoke exposure was defined as cotinine values <2 ng/mL, and any exposure was defined as >or=2 ng/mL.We observed odds ratios of 2.1 (95% CI, 1.0-4.4) for clefts and 0.4 (95% CI, 0.1-1.7) for NTDs associated with exposure. After adjusting for race/ethnicity, age, and serum folate levels, odds ratios were 2.4 (95% CI, 1.1-5.3) and 0.6 (95% CI, 0.1-2.5). We explored 2 cotinine levels, 2 to 10 ng/mL and >10 ng/mL for clefts (data were too sparse for NTDs). Odds ratios for these levels were 3.3 (95% CI, 0.9-11.9) and 1.7 (95% CI, 0.7-4.2), respectively.Smoking exposures, as measured with cotinine levels during mid-pregnancy, were associated with increased risks of clefts and possibly reduced risks of NTDs.

  View details for DOI 10.1016/j.jpeds.2008.08.006

  View details for Web of Science ID 000262272500006

  View details for PubMedID 18990410

• Bayesian Methods for Correcting Misclassification An Example from Birth Defects Epidemiology EPIDEMIOLOGY MacLehose, R. F., Olshan, A. F., Herring, A. H., Honein, M. A., Shaw, G. M., Romitti, P. A. 2009; 20 (1): 27-35

  Abstract

  Cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are common congenital malformations. Numerous epidemiologic studies have shown an increased risk for orofacial clefts among children whose mothers smoked during early pregnancy; however, there is concern that the results of these studies may have been biased because of exposure misclassification. The purpose of this study is to use previous research on the reliability of self-reported cigarette smoking to produce corrected point estimates (and associated credible intervals) of the effect of maternal smoking on children's risk of clefts.We accounted for misclassification using 4 Bayesian models that made different assumptions about the sensitivity and specificity of self-reported maternal smoking data. We used results from previous studies to specify the prior distributions for sensitivity and specificity of reporting and used Markov chain Monte Carlo algorithms to calculate the posterior distribution of the effect of maternal smoking on children's risk for CL/P and CPO.After correcting for potential sources of misclassification in data from the National Birth Defects Prevention Study, we found an increased risk of CL/P among children born to mothers who smoked during early pregnancy (posterior odds ratio [OR] = 1.6, 95% credible interval = 1.1-2.2). The posterior effect of smoking on CPO provided less evidence of effect (posterior OR = 1.1, 95% credible interval = 0.7-1.7).Our results lend some credibility to the hypothesis that periconceptional maternal smoking increases the risk of a child being born with CL/P. The results concerning CPO provide no overall evidence of effect, although the estimates were relatively imprecise. We suggest that future research should emphasize validity studies, especially those of differential reporting, rather than replicating existing analyses of the relationship between maternal smoking and clefts. We discuss how our approach is also applicable to evaluating misclassification in a wide range of exposure-outcome scenarios.

  View details for DOI 10.1097/EDE.0b013e31818ab3b0

  View details for Web of Science ID 000261930800007

  View details for PubMedID 19234399

• Periconceptional glycaemic load and intake of sugars and their association with neural tube defects in offspring PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Siega-Riz, A. M. 2008; 22 (6): 514-519

  Abstract

  In a California population, we previously observed increased neural tube defect (NTD) risks associated with maternal intakes of periconceptional diets predicting higher glycaemic responses and higher sucrose. Our objective here was to replicate these results in a larger study of multiple regions within the United States. This population-based case-control study included deliveries from 1997 to 2003 from the National Birth Defects Prevention Study. NTD cases were infants or fetuses born with spina bifida or anencephaly. Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. There were 720 NTD case and 4699 control mothers with completed interviews included in analyses. Diet was assessed using a 58-item food frequency questionnaire focusing on the year before conception, whereas cereals, beverages and supplement use was assessed periconceptionally. We found no increased risks of NTD-affected pregnancies with increased intakes (adjusted for kcal/day) of sucrose, glucose, fructose or with maternal diets with a higher glycaemic load. The reasons for current findings to be inconsistent with previous findings are unknown.

  View details for DOI 10.1111/j.1365-3016.2008.00964.x

  View details for Web of Science ID 000259818200003

  View details for PubMedID 19000288

• Markers of Acculturation and Risk of NTDs among Hispanic Women in California BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Song, J., Abrams, B. 2008; 82 (11): 755-762

  Abstract

  Prevalences of NTDs are typically 50-100% greater among Hispanic women compared to non-Hispanic Whites. This article examines whether markers of acculturation such as "language preference" allow the identification of high-risk groups within the Hispanic population. It also examines whether known NTD risk factors explain observed differences in risk among Hispanic women who are more and less acculturated.This population-based case-control study of deliveries in selected California counties from 1999-2003 included 337 NTD cases and 626 nonmalformed, liveborn controls.Relative to less acculturated US-born Hispanic women (i.e., women who preferred reading and speaking Spanish), other subgroups (i.e., US-born Hispanic women who preferred English, foreign-born Hispanic women regardless of "language preference", and non-Hispanic White women) had approximately twofold increased risks of spina bifida. Only the less acculturated foreign-born women (i.e., women with a preference for Spanish) had substantially increased risk of anencephaly (OR 1.7; 95% CI 0.9, 3.4). Adjustment for several NTD risk factors (maternal intake of folic acid-containing supplements, dietary folate intake, body mass index, food insecurity, stressful life events, smoking, alcohol intake, education, income, and neighborhood education and poverty) resulted in modest or no reductions in most of the ORs.The explanation for variability in NTD risks among Hispanic and non-Hispanic White women therefore likely extends beyond most known NTD risk factors.

  View details for DOI 10.1002/bdra.20517

  View details for Web of Science ID 000261567200004

  View details for PubMedID 18985703

• Autoantibodies to folate receptor during pregnancy and neural tube defect risk JOURNAL OF REPRODUCTIVE IMMUNOLOGY Cabrera, R. M., Shaw, G. M., Ballard, J. L., Carmichael, S. L., Yang, W., Lammer, E. J., Finnell, R. H. 2008; 79 (1): 85-92

  Abstract

  Periconceptional folic acid can reduce the occurrence of neural tube defects (NTDs) by up to 70%, and autoantibodies for folate receptors (FRs) have been observed in serum from women with a pregnancy complicated by an NTD. This population-based cohort study has examined serum from pregnant mothers for autoantibodies to FRs, antibodies to bovine folate binding protein (FBP), and inhibition of folic acid binding to FR and FBP in association with NTD risk. The mid-gestational maternal serum specimens used for this study were collected during the 15-18th week of pregnancy. Samples were obtained from the California Birth Defects Monitoring Program; 29 mothers had a pregnancy complicated by spina bifida and 76 mothers had unaffected children. The presence of IgG and IgM antibodies to human FR, bovine FBP, and inhibition of folic acid binding to FR and FBP was determined. Higher activity of IgM to FBP in cases verses controls was observed (P=0.04). Higher activity of IgM and IgG autoantibodies to FR was observed (P<0.001 and P=0.04, respectively). Risk estimates at two standard deviations above average control antibody concentrations were OR=2.07 (CI=1.02, 4.06) for anti-FBP IgM, OR=2.15 (CI=1.02, 4.69) for anti-FR IgG and OR=3.19 (CI=1.47, 6.92) for anti-FR IgM. These data support the hypothesis that high titers of antibodies and blocking of folic acid binding to FRs by maternal serum should be regarded as risk factors for NTDs.

  View details for DOI 10.1016/j.jri.2008.08.002

  View details for Web of Science ID 000260989000012

  View details for PubMedID 18804286

• Agenesis of the Corpus Callosum in California 1983-2003: A Population-Based Study AMERICAN JOURNAL OF MEDICAL GENETICS PART A Glass, H. C., Shaw, G. M., Ma, C., Sherr, E. H. 2008; 146A (19): 2495-2500

  Abstract

  The objective of this study was to characterize the prevalence, demographic risk factors, and malformations associated with agenesis and hypoplasia of the corpus callosum diagnosed in infancy. Using a large population-based registry of birth defects, we ascertained 630 cases of agenesis (ACC) and hypoplasia (HCC) of the corpus callosum diagnosed in the first year of life among 3.4 million live births from 1983 to 2003. Infants with destructive lesions or specific complex central nervous system (CNS) malformations (neural tube defects, lissencephaly, and holoprosencephaly) were excluded. Multivariable Poisson regression analysis was used to examine demographic risk factors. The combined prevalence of ACC and HCC was 1.8 per 10,000 live births. Fifty-two percent of cases were male. Infants with ACC had an almost fourfold higher prevalence among infants born prematurely when compared with children born > or =37 weeks gestation (RR 3.7, 95% CI 2.5-5.3). After adjusting for paternal age, advanced maternal age >/=40 years was associated with ACC in infants with a chromosomal disorder (ACC RR 5.9; 95% CI 1.8-19.3, HCC RR 3.5; 95% CI 0.9-14.1). Paternal age was not significantly associated with ACC after adjusting for maternal age. Callosal anomalies were often seen in the context of a chromosomal abnormality (17.3%) and with accompanying somatic (musculoskeletal 33.5% and cardiac 27.6%) and CNS malformations (49.5%). Callosal anomalies form a clinically significant and relatively frequent group of malformations of the CNS that are associated with increased risk of premature birth, are more common with advanced maternal age and are frequently part of a complex, multisystem disorder.

  View details for DOI 10.1002/ajmg.a.32418

  View details for Web of Science ID 000260202700007

  View details for PubMedID 18642362

• Nicotinamide N-Methyl Transferase (NNMT) Gene Polymorphisms and Risk for Spina Bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lu, W., Zhu, H., Wen, S., Yang, W., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2008; 82 (10): 670-675

  Abstract

  Moderate hyperhomocysteinemia is a known risk factor for NTDs in a variety of experimental model systems and is believed to be important in humans as well. The enzyme nicotinamide N-methyl transferase (NNMT) was identified in a genome-wide linkage scan as being an important regulator of homocysteine homeostasis in a Spanish population, making it an interesting candidate gene for NTDs.We evaluated 11 SNPs (single nucleotide polymorphism) of the NNMT gene in our study population. In this study, 252 cases (infants with spina bifida) and 335 controls (nonmalformed infants), born during the period 1983-1986 in selected counties in California, were genotyped for variants of the NNMT gene. Allelic, genotype, and haplotype associations with spina bifida risk were evaluated and analyzed.None of the SNPs studied alone showed allelic or genotypic associations with spina bifida. However, the TCAG haplotype for block 3 (rs2852447, ra2852425, rs4646337, and rs11569688) showed a decreased risk for spina bifida among non-Hispanic Whites (OR 0.4; 95%CI: 0.1-1.0).No association was found between infant NNMT gene variants and risk for spina bifida in our study population. However, small sample sizes for most variant groups and for phase-unknown haplotype data limited the power of the study.

  View details for DOI 10.1002/bdra.20474

  View details for Web of Science ID 000260523300006

  View details for PubMedID 18553462

• The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US AMERICAN JOURNAL OF MEDICAL GENETICS PART A Waller, D. K., Correa, A., Vo, T. M., Wang, Y., Hobbs, C., Langlois, P. H., Pearson, K., Romitti, P. A., Shaw, G. M., Hecht, J. T. 2008; 146A (18): 2385-2389

  Abstract

  There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population-based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780-1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330-1/47,620 livebirths). In Texas, fathers that were 25-29, 30-34, 35-39, and > or =40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population-based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records.

  View details for DOI 10.1002/ajmg.a.32485

  View details for Web of Science ID 000259480200011

  View details for PubMedID 18698630

• Gastroschisis: A gene-environment model involving the VEGF-NOS3 pathway AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS Lammer, E. J., Iovannisci, D. M., Tom, L., Schultz, K., Shaw, G. M. 2008; 148C (3): 213-218

  Abstract

  Gastroschisis is a severe major malformation in which an infant is delivered with a portion of intestines and possible other abdominal organs extruding through a defect in the abdominal wall, usually to the right of the umbilical cord. Etiologies of gastroschisis are largely unknown, and even its pathogenesis is poorly understood. Several recent epidemiological studies have identified interactions between maternal smoking during pregnancy, genetic variants of endothelial nitric oxide synthase, and risk for gastroschisis. We present a brief review of the endothelial nitric oxide synthase pathway and its relationship to vasculogenesis, suggesting that disruption of this pathway by environmental exposures or by genetic variation may represent one pathogenetic model for gastroschisis.

  View details for DOI 10.1002/ajmg.c.30182

  View details for Web of Science ID 000258293400007

  View details for PubMedID 18655103

• NTD prevalences in central California before and after folic acid fortification International Neural Tube Defect Meeting Chen, B. H., Carmichael, S. L., Selvin, S., Abrams, B., Shaw, G. M. WILEY-BLACKWELL. 2008: 547–52

  Abstract

  In many regions, NTD prevalences were already declining prior to folic acid fortification. This study examined whether the declining prefortification (1989-1996) NTD prevalences continued into the postfortification period (1998-2003) in selected California counties.This population-based study used vital statistics data and birth defects registry data that were actively ascertained from medical records. The study population included all live births and stillbirths delivered in central California counties from 1989 to 2003. Cases included deliveries with NTDs during the same time period.For all NTDs combined, the slopes indicated that NTD prevalence was decreasing by 7.5 (slope: -7.5; 95% CI: -12.4, -2.5) cases per 100,000 deliveries per year before fortification, whereas NTD prevalence was no longer decreasing after fortification. Comparison of the difference in the two slopes indicated that the postfortification slope exceeded the prefortification slope by 12.6 (95% CI: 2.6, 22.6) cases per 100,000 deliveries per year.Annual NTD prevalences in central California did not continue to decrease after implementation of folic acid fortification.

  View details for DOI 10.1002/bdra.20466

  View details for Web of Science ID 000258763500001

  View details for PubMedID 18496833

• Prepregnant obesity and risks of selected birth defects in offspring EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L. 2008; 19 (4): 616-620

  Abstract

  Prepregnant obesity has been shown to be related to several birth defects, most notably neural tube defects. We investigated the previously observed association between obesity and spina bifida and also possible associations between obesity and other birth defects.We conducted a case-control study of fetuses and liveborn infants among California births, July 1999 and June 2004. Of those eligible, 80% of case mothers (n = 659) and 77% of control mothers (n = 700) were interviewed. Cases were 147 infants with anencephaly, 191 with spina bifida, 142 with d-transposition of great arteries, and 181 with tetralogy of Fallot. Maternal body mass index (BMI) was based on prepregnant weight and height.The odds ratios of birth defects with obesity (BMI > or =30 relative to normal BMI) were 1.6 for anencephaly (95% confidence intervals = 1.0-2.6); 1.4 for spina bifida (0.8-2.2); 0.7 for d-transposition of great arteries (0.4-1.4); and 0.8 for tetralogy of Fallot (0.4-1.4). Modestly elevated odds ratios were observed with obesity among women who reported weight gain in their waist before pregnancy-for anencephaly, 2.4 (1.2-5.1) and for spina bifida, 1.8 (0.9-3.6).These data do not fully support earlier findings with respect to the relationships of obesity with anencephaly and spina bifida.

  View details for DOI 10.1097/EDE.0b013e3181761fa3

  View details for Web of Science ID 000256865100018

  View details for PubMedID 18552593

• Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies 20th Annual Meeting of the Society-for-Pediatric-and-Perinatal-Epidemiologic-Research Grewal, J., Carmichael, S. L., Ma, C., Lammer, E. J., Shaw, G. M. WILEY-BLACKWELL. 2008: 519–26

  Abstract

  This study examined the association between maternal smoking and alcohol use (including binge drinking) during the periconceptional period (i.e., 2 months before through 2 months after conception) and the risk of orofacial clefts, NTDs, and conotruncal heart defects in offspring.Data were drawn from a population-based case-control study of fetuses and live-born infants among a cohort of California births between July 1999 and June 2003. The 1,355 cases comprised of 701 orofacial clefts, 337 NTDs, and 323 conotruncal heart defects. Information on smoking and alcohol consumption was obtained via telephone interviews with mothers of 1,355 (80% of eligibles) cases and 700 (77% of eligibles) nonmalformed, live-born controls.Maternal smoking of five cigarettes or less per day was associated with reduced risks of NTDs (OR 0.7; 95% CI: 0.3, 1.4), whereas the risk associated with higher cigarette consumption was lower for conotruncal heart defects (OR 0.5; 95% CI: 0.2, 1.2). Maternal intake of alcohol less than 1 day per week was associated with a 1.6- to 2.1-fold higher risk of NTDs (95% CI: 0.9, 2.6), d-transposition of the great arteries (95% CI: 1.1, 3.2), and multiple cleft lip with or without cleft palate (CLP) (95% CI: 0.8, 4.5). Risks associated with more frequent alcohol intake were 2.1 for NTDs (95% CI: 1.1, 4.0) and 2.6 for multiple CLP (95% CI: 1.1, 6.1).This study observed that maternal alcohol intake increased the risk for d-transposition of the great arteries, NTDs, and multiple CLP in infants. By contrast, smoking was associated with a lower risk of NTDs and conotruncal heart defects.

  View details for DOI 10.1002/bdra.20461

  View details for Web of Science ID 000257906800004

  View details for PubMedID 18481814

• Gene-nutrient interactions: Importance of folic acid and vitamin B-12 during early embryogenesis FOOD AND NUTRITION BULLETIN Finnell, R. H., Shaw, G. M., Lammer, E. J., Rosenquist, T. H. 2008; 29 (2): S86-S98

  Abstract

  The role that nutritional factors play in mammalian development has received renewed attention over the past two decades as the scientific literature has exploded with reports that folic acid supplementation in the periconceptional period can protect embryos from a number of highly significant malformations. As is often the case, the relationship between B vitamin supplementation and improved pregnancy outcomes is more complicated than initially perceived, as the interaction between nutritional factors and selected genes must be considered. In this review, we attempt to summarize the complex clinical and experimental literature on nutritional factors, their biological transport mechanisms, and interactions with genetic polymorphisms that impact early embryogenesis. While not exhaustive, our goal was to provide an overview of important gene-nutrient interactions, focusing on folic acid and vitamin B12, to serve as a framework for understanding the multiple roles they play in early embryogenesis.

  View details for Web of Science ID 000257425800011

  View details for PubMedID 18709884

• Increasing prevalence of gastroschisis: Population-based study in California JOURNAL OF PEDIATRICS Vu, L. T., Nobuhara, K. K., Laurent, C., Shaw, G. M. 2008; 152 (6): 807-811

  Abstract

  To evaluate time trend of gastroschisis and examine the epidemiological risk factors for gastroschisis.This population-based study analyzed the active surveillance data from the California Birth Defects Monitoring Program from 1987 to 2003.The overall birth prevalence of gastroschisis was 2.6 cases per 10,000 births (908 cases in >3.5 million births). In the adjusted analysis, by using the age of 25 to 29 years as the reference, mothers aged 12 to 15 years had a 4.2-times greater birth prevalence (95% CI, 2.5-7.0), and fathers aged 16 to 19 years and 20 to 24 years had 1.6- and 1.5-times greater birth prevalence (95% CI, 1.1-2.1 and 1.2-1.8), respectively. Compared with non-Hispanic whites and US-born Hispanic, both foreign-born Hispanics and blacks had adjusted prevalence ratio of 0.6 (95% CI, 0.5-0.7 and 0.4-0.9, respectively). In addition, nulliparity was also associated with gastroschisis. Independent of maternal age, paternal age, and maternal ethnicity, the birth prevalence increased 3.2-fold (95% CI, 2.3-4.3) during the 17-year study period.The birth prevalence of gastroschisis continues to increase in California, and young, nulliparous women are at the greatest risk of having a child with gastroschisis.

  View details for DOI 10.1016/j.jpeds.2007.11.037

  View details for Web of Science ID 000256373800018

  View details for PubMedID 18492521

• Nutrient intakes in women and congenital diaphragmatic hernia in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, W., Shaw, G. M., Carmichael, S. L., Rasmussen, S. A., Waller, D. K., Pober, B. R., Anderka, M. 2008; 82 (3): 131-138

  Abstract

  Congenital diaphragmatic hernia (CDH) is a severe birth defect where there is an opening in the diaphragm through which a portion of the abdominal contents protrudes into the thoracic cavity. The etiologies of CDH remain unknown, although experimental animal data suggest dietary factors might play a role. This study examined whether maternal nutrient intakes were associated with delivering infants with CDH.We analyzed infants with isolated CDH who were born from 1997 to 2003 and recruited into the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study. Exposure data were obtained from telephone interviews, which were completed within 24 months after delivery, and were available for 377 case mothers and 5,008 control mothers. A food frequency questionnaire was used to derive nutrient intakes during the year before pregnancy.A crude OR of 0.6 (95% CI: 0.3-1.0) was observed for higher intake of choline. Elevated ORs (1.4 to 1.7) were found for lower intakes of choline, cysteine, methionine, and protein. Among women who took vitamin supplements, higher intakes of B vitamins (i.e., folate, vitamin B1, B2, B6, and B12), minerals (i.e., calcium, iron, magnesium, and zinc), and vitamin E were inversely associated with CDH (ORs from 0.7-0.3). Moreover, among women who did not take vitamin supplements, lower intakes of calcium, retinol, selenium, vitamin B12, and vitamin E had positive associations with CDH (ORs from 1.4 to 2.1).Our observations contribute to a limited body of evidence suggesting a woman's periconceptional diet might be associated with CDH in her offspring.

  View details for DOI 10.1002/bdra.20436

  View details for Web of Science ID 000254601400002

  View details for PubMedID 18181217

• Craniosynostosis and maternal smoking 47th Annual Meeting of the Teratology-Society Carmichael, S. L., Ma, C., Rasmussen, S. A., Honein, M. A., Lammer, E. J., Shaw, G. M. WILEY-BLACKWELL. 2008: 78–85

  Abstract

  Several previous studies suggested increased risk of craniosynostosis among infants born to women who smoked.This study used data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study of infants delivered from 1997-2003. Nonmalformed, liveborn controls were selected randomly from birth certificates or birth hospitals. Data from maternal telephone interviews were available for 531 cases and 5008 controls.Smoking during the first month of pregnancy was not associated with craniosynostosis. Smoking later in pregnancy was associated with increased risk, but only among mothers who smoked at least one pack/day. For example, during the second trimester, the odds ratio for smoking <5 cigarettes/day was 1.0 (95% confidence interval [CI] 0.6, 1.8), but the odds ratio (OR) for smoking 15 or more cigarettes/day was 1.6 (95% CI 0.9, 2.8), after adjustment for maternal age, education, race-ethnicity, sub-fertility, parity, folic acid supplement intake, body mass index, and study center. Among women who did not smoke, adjusted odds ratios suggested that secondhand smoke exposure at home, but not at work/school, was associated with modestly increased risk; the OR for home exposure was 1.3 (95% CI 0.9, 1.9). Results followed a similar pattern for some, but not all, specific suture types, but numbers for some groupings were small.The results suggest moderately increased risk of craniosynostosis among mothers who were the heaviest smokers and who continued to smoke after the first trimester. Results are somewhat equivocal, given that most confidence intervals included one.

  View details for DOI 10.1002/bdra.20426

  View details for Web of Science ID 000253624800002

  View details for PubMedID 18050313

• Socioeconomic status in relation to selected birth defects in a large multicentered US case-control study AMERICAN JOURNAL OF EPIDEMIOLOGY Yang, J., Carmichael, S. L., Canfield, M., Song, J., Shaw, G. M. 2008; 167 (2): 145-154

  Abstract

  This study examined individual and household socioeconomic status (SES) in relation to phenotypes of neural tube defects, orafacial clefts, and conotruncal heart defects using data from the National Birth Defects Prevention Study with 2,551 nonmalformed liveborn controls and 1,841 cases delivered in 1997-2000. The individual SES was measured by maternal and paternal education, occupation, and household income. All individual SES measures were combined to create a household SES index. Elevated risks were found for maternal low education in association with anencephaly and dextrotransposition of the great arteries (dTGA) (adjusted odds ratios (AORs) > or = 1.4); paternal low education in association with anencephaly, cleft palate, tetralogy of Fallot (TOF), and dTGA (AORs > or = 1.4); low household income in association with TOF (AOR = 1.4, 95% confidence interval (CI): 0.8, 2.5); maternal operator/laborer occupation in association with cleft palate, TOF, and dTGA (AORs > or = 1.4); paternal operator/laborer occupation in association with spina bifida (AOR = 1.4, 95% CI: 1.0, 2.0); and either parent's unemployment in association with dTGA (AOR > or = 1.4). Subjects with the lowest household SES index had the greatest risks of all selected birth defects except TOF. This study reveals consistently increased risks of selected birth defects in association with household SES index but not individual SES measures.

  View details for DOI 10.1093/aje/kwm283

  View details for Web of Science ID 000252498200003

  View details for PubMedID 17947220

• Population-based analysis of left- and right-sided diaphragmatic hernias demonstrates different frequencies of selected additional anomalies Festschrift Symposium 2007 held in Honor of M Michael Cohen Slavotinek, A. M., Warmerdam, B., Lin, A. E., Shaw, G. M. WILEY-BLACKWELL. 2007: 3127–36

  Abstract

  Congenital diaphragmatic hernia (CDH) is a common birth defect that can be subdivided into several different types depending on the anatomical structures affected. Several studies have demonstrated that right-sided CDH (R-CDH) and left-sided CDH (L-CDH) in humans are associated with different clinical presentations and outcomes. We hypothesized that R-CDH and L-CDH are phenotypically and pathogenically distinct, and that the frequency of associated anomalies would differ among patients with R-CDH compared to patients with L-CDH. Using population-based data from ongoing studies in the California Birth Defects Monitoring Program (CBDMP), we compared 146 CDH cases, 38 with R-CDH (26%) and 108 with L-CDH (74%). The frequencies of atrial septal defect (1/38 R-CDH and 20/108 L-CDH cases; P = 0.015), bilateral pulmonary hypoplasia (22/108 L-CDH cases and 15/38 R-CDH cases; P = 0.029), abnormal skull or facial shape (17/108 L-CDH patients and 1/38 R-CDH cases; P = 0.043), assorted digital anomalies excluding syndactyly, polydactyly or absence of a digit (13/108 L-CDH patients and 0/38 R-CDH patients; P = 0.021) and assorted limb anomalies excluding limb reduction defects (18/108 L-CDH patients and 0.38 R-CDH patients; P = 0.004) all showed a statistically significant difference in frequency between R- and L-CDH patients. This descriptive epidemiological study using newborn surveillance data represents the largest comparison of right and left-sided CDH patients so far performed. Several anomalies as listed above were noted to be different in frequency between R- and L-CDH patients, although the interpretation of the significant variability in the frequency of these anomalies is not yet established and the findings require replication. Birth defects monitoring programs can provide the interface for epidemiology and clinical genetics, which in this case, may generate hypotheses to establish the pathogenesis of CDH laterality. (c) 2007 Wiley-Liss, Inc.

  View details for DOI 10.1002/ajmg.a.32100

  View details for Web of Science ID 000251405100033

  View details for PubMedID 18008313

• Maternal corticosteroid use and orofacial clefts AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Carmichael, S. L., Shaw, G. M., Ma, C., Werler, M. M., Rasmussen, S. A., Lammer, E. J. 2007; 197 (6)

  Abstract

  The purpose of this study was to examine whether maternal corticosteroid use during pregnancy is associated with delivering an infant with an orofacial cleft.This study included data on deliveries from the National Birth Defects Prevention Study, which is a population-based case-control study. Exposures were assessed by telephone interviews for mothers of 1141 cases with cleft lip +/- cleft palate (CLP), 628 with cleft palate (CP), and 4143 controls.Mothers of 33 infants with CLP (2.9%), mothers of 6 infants with CP (1.0%), and 72 control subjects (1.7%) reported corticosteroid use from 4 weeks before through 12 weeks after conception. The crude odds ratio for "any" vs "no" use was 1.7 (95% CI, 1.1-2.6) for CLP and 0.5 (0.2-1.3) for CP. When analyzed by route of administration and medication components, odds ratios for CLP tended to be elevated, and odds ratios for CP tended to be close to 1.Our results suggest a moderately increased risk of CLP among women who use corticosteroids during early pregnancy.

  View details for DOI 10.1016/j.ajog.2007.05.046

  View details for Web of Science ID 000251675700008

  View details for PubMedID 18060943

• Congenital malformations co-occurring with hypospadias in California, 1983-1997 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Yang, W., Cartnichael, S. L., Shaw, G. M. 2007; 143A (22): 2627-2634

  Abstract

  Investigations for co-occurring malformations can serve as a first step to discover new risk factors and provide insights into malformation etiologies. Our objective was to explore the risks of occurrence of structural congenital malformation phenotypes in 5,481 infants with hypospadias, using data from a population-based active surveillance system. Ascertainment was performed among 1,816,258 liveborn and 12,203 stillborn male offspring of women who were residents of registry counties during 1983-1997. Malformations other than hypospadias were grouped according to the 3- and 4-digit BPA malformation codes. Prevalences of each malformation grouping were calculated among all births with hypospadias and their three subgroups and all births without hypospadias but with another structural malformation. Relative risks were estimated based on the ratio of two prevalences, and the corresponding 95% confidence intervals were computed using Poisson regression models. Observed relative risks indicated that all malformation groupings were less likely to co-occur with hypospadias and their three subgroups than with other types of malformations, with relative risks ranging from 0.04 to 0.93. For most malformations, risks were relatively similar among all births with hypospadias and the three subgroups of hypospadias. The observed relative risks were not substantially changed in analyses that adjusted for maternal age, race/ethnicity, and parity. Computations were extended to 4-digit level BPA codes. Almost all observed relative risks for malformations co-occurring with hypospadias overall and three subgroups were less than 1.

  View details for DOI 10.1002/ajmg.a.32001

  View details for Web of Science ID 000250708900001

  View details for PubMedID 17937439

• Nutrient intakes in women and risks of anophthalmia and microphthalmia in their offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Louik, C., Finnell, R. H., Lammer, E. J. 2007; 79 (10): 708-713

  Abstract

  There is a paucity of information about risk factors for the human eye anomalies anophthalmia and microphthalmia. In this population-based case-control study we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, vitamin A, and several other nutrients were associated with these eye defects.This study included data on deliveries that had estimated due dates from 1997-2002 and were part of the National Birth Defects Prevention Study (the National Birth Defects Prevention Study is a population-based case-control study of a wide spectrum of birth defects, incorporating data from 10 birth defects surveillance systems in the United States [Arkansas, California, Georgia/Centers for Disease Control and Prevention, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah]). Cases were those infants or fetuses born with either anophthalmia or microphthalmia. Liveborn infants without major malformations were eligible as controls. Maternal interviews were conducted, primarily by telephone, in English or Spanish. Participation in the interview was 71% among case mothers and 68% among control mothers. Interviews were completed with 89 case mothers and 4,143 control mothers. A shortened version of the food frequency questionnaire from the Nurse's Health Study was used to assess frequency of intake of 58 food items during the year before pregnancy.Our results did not indicate reduced risks for these eye malformations associated with maternal intake of vitamin supplements containing folic acid. The data did not show an association between malformation risk and higher or lower intakes of vitamin A. We also did not observe strong evidence that an abundance or a lack of dietary intake of any other nutrient was associated with increased risk of the studied eye malformations.Our observations contribute to a limited body of findings on these rare eye defects.

  View details for DOI 10.1002/bdra.20398

  View details for Web of Science ID 000250222400007

  View details for PubMedID 17847120

• Association between 49 infant gene polymorphisms and preterm delivery AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chen, B. H., Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Lammer, E. J. 2007; 143A (17): 1990-1996

  Abstract

  The occurrence of preterm delivery has been increasing in the U.S. Previous studies have identified risk factors for preterm delivery that may have genetic influences. We conducted a case-control study comparing the frequencies of 49 genetic polymorphisms among 62 preterm infants and 553 term infants. The polymorphisms that we examined were involved in xenobiotic-metabolism, blood pressure, coagulation, the inflammatory response, cell-cell interaction, or folate-homocysteine metabolism. Univariate analyses on the individual polymorphisms revealed a statistically significant effect for the variant genotypes compared to the wildtype genotypes in SERPINE1 11053G > T (OR = 0.4, 95% CI = 0.2-0.8). This finding suggests the coagulation/thrombophilic pathway may influence the development of preterm delivery.

  View details for DOI 10.1002/ajmg.a31868

  View details for Web of Science ID 000249173900007

  View details for PubMedID 17676631

• Maternal food insecurity is associated with increased risk of certain birth defects JOURNAL OF NUTRITION Carmichael, S. L., Yang, W., Herring, A., Abrams, B., Shaw, G. M. 2007; 137 (9): 2087-2092

  Abstract

  Food insecurity represents a lack of access to enough food to meet basic needs. We hypothesized that food insecurity may increase birth defect risks, because it is an indicator of increased stress or compromised nutrition, which are both implicated in birth defect etiologies. This study used population-based case-control data. Included in the analysis were 1,189 case mothers and 695 control mothers who were interviewed by telephone. We calculated a food insecurity score as the number of affirmative responses to 5 questions from a shortened instrument designed to measure food insecurity. OR for the food insecurity score specified as a linear term indicated that a higher score was associated with increased risk of cleft palate, d-transposition of the great arteries, tetralogy of Fallot, spina bifida, and anencephaly, but not with cleft lip with or without cleft palate, after adjustment for maternal race-ethnicity, education, BMI, intake of folic acid-containing supplements, dietary intake of folate and energy, neighborhood crime, and stressful life events. In addition, several models suggested effect modification by certain factors. For example, for anencephaly, among women with the worst score for neighborhood crime (i.e. 6), the OR associated with a 1-unit change in the food insecurity score was 1.57 (95% CI 1.06, 2.33), whereas among women with a low crime score (i.e. 2), the corresponding OR was 1.16 (95% CI 0.96, 1.38). This study suggests that increased risks of certain birth defects may be included among the negative consequences of food insecurity.

  View details for Web of Science ID 000249110600016

  View details for PubMedID 17709447

• Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFR alpha reveals rare variants in diaphragmatic hernia patients EUROPEAN JOURNAL OF HUMAN GENETICS Bleyl, S. B., Moshrefi, A., Shaw, G. M., Saijoh, Y., Schoenwolf, G. C., Pennacchio, L. A., Slavotinek, A. M. 2007; 15 (9): 950-958

  Abstract

  Congenital diaphragmatic hernia (CDH) is a common, life threatening birth defect. Although there is strong evidence implicating genetic factors in its pathogenesis, few causative genes have been identified, and in isolated CDH, only one de novo, nonsense mutation has been reported in FOG2 in a female with posterior diaphragmatic eventration. We report here that the homozygous null mouse for the Pdgfralpha gene has posterolateral diaphragmatic defects and thus is a model for human CDH. We hypothesized that mutations in this gene could cause human CDH. We sequenced PDGFRalpha and FOG2 in 96 patients with CDH, of which 53 had isolated CDH (55.2%), 36 had CDH and additional anomalies (37.5%), and 7 had CDH and known chromosome aberrations (7.3%). For FOG2, we identified novel sequence alterations predicting p.M703L and p.T843A in two patients with isolated CDH that were absent in 526 and 564 control chromosomes respectively. These altered amino acids were highly conserved. However, due to the lack of available parental DNA samples we were not able to determine if the sequence alterations were de novo. For PDGFRalpha, we found a single variant predicting p.L967V in a patient with CDH and multiple anomalies that was absent in 768 control chromosomes. This patient also had one cell with trisomy 15 on skin fibroblast culture, a finding of uncertain significance. Although our study identified sequence variants in FOG2 and PDGFRalpha, we have not definitively established the variants as mutations and we found no evidence that CDH commonly results from mutations in these genes.

  View details for DOI 10.1038/sj.ejhg.5201872

  View details for Web of Science ID 000249144200008

  View details for PubMedID 17568391

• Prepregnancy obesity as a risk factor for structural birth defects ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Waller, D. K., Shaw, G. M., Rasmussen, S. A., Hobbs, C. A., Canfield, M. A., Siega-Riz, A., Gallaway, M. S., Correa, A. 2007; 161 (8): 745-750

  Abstract

  To describe the relation between maternal obesity, overweight and underweight status, and 16 categories of structural birth defects.An ongoing multisite, case-control study. Clinical geneticists reviewed all of the cases, excluding those that had or were strongly suspected to have a single-gene disorder or chromosomal abnormality. Mothers with preexisting diabetes were also excluded. Body mass index was based on maternal report of height and weight prior to pregnancy.Eight participating states in the United States.Mothers enrolled in the National Birth Defects Prevention Study who had index pregnancies between October 1, 1997, and December 31, 2002.Maternal obesity.Crude and adjusted odds ratios.Mothers of offspring with spina bifida, heart defects, anorectal atresia, hypospadias, limb reduction defects, diaphragmatic hernia, and omphalocele were significantly more likely to be obese than mothers of controls, with odds ratios ranging between 1.33 and 2.10. Mothers of offspring with gastroschisis were significantly less likely to be obese than mothers of controls.To our knowledge, this is the first population-based study of its scale to examine prepregnancy obesity and a range of structural birth defects. These results suggest a weak to moderate positive association of maternal obesity with 7 of 16 categories of birth defects and a strong inverse association with gastroschisis. The mechanisms underlying these associations are not yet understood but may be related to undiagnosed diabetes.

  View details for Web of Science ID 000248583000003

  View details for PubMedID 17679655

• Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts CLEFT PALATE-CRANIOFACIAL JOURNAL Ramirez, D., Lammer, E. J., Iovannisci, D. M., Laurent, C., Finnell, R. H., Shaw, G. M. 2007; 44 (4): 366-373

  Abstract

  To examine the interactions between four fetal xenobiotic metabolizing gene polymorphisms, maternal cigarette smoking, and risk for oral cleft defects.California population-based case-control study of 431 infants born with isolated orofacial clefts and 299 nonmalformed controls.Infants were genotyped for functional polymorphisms of the detoxification enzymes microsomal epoxide hydrolase-1 (EPHX1 T-->C [Tyr113His], and A-->G [His139Arg]), and glutathione-S transferase Pi-1 (GSTP1 A-->G [Ile105Val] and C-->T [Ala114Val]), and risks for cleft outcomes were measured for gene only and gene-maternal smoking effects.Although smoking was associated with an increased risk for isolated cleft lip+/-palate, we found no independent associations of genotypes of EPHX1-codon 113 or GSTP1-codon 105 polymorphisms for either isolated cleft lip+/-palate or isolated cleft palate. The heterozygote genotype for the EPHX1-codon 139 polymorphism was associated with an increased risk of isolated cleft palate (odds ratio=1.6 [95% confidence interval, 1.0 to 2.6]). Infant EPHX1 and GTSP1 polymorphic variants did not appreciably alter the risks for clefts associated with maternal smoking, nor were any EPHX1 combined genotype-specific risks found. Infant genotypes of the GSTP1-codon 105 polymorphism, combined with glutathione-S-transferase-mu-1 null genotypes, did not appreciably alter the risk of orofacial clefts.Our results suggest that genetic variation of the detoxification enzymes EPHX1 and GSTP1 did not increase the risks of orofacial clefting, nor do they influence the risks associated with maternal smoking.

  View details for DOI 10.1597/06-011.1

  View details for Web of Science ID 000248295300003

  View details for PubMedID 17608547

• Comprehensive EMX2 genotyping of a large schizencephaly case series AMERICAN JOURNAL OF MEDICAL GENETICS PART A Tietjen, I., Bodell, A., Apse, K., Mendonza, A. M., Chang, B. S., Shaw, G. M., Barkovich, A. J., Lammer, E. J., Walsh, C. A. 2007; 143A (12): 1313-1316

  Abstract

  Schizencephaly is a brain malformation disorder characterized by one or more full-thickness clefts through the cerebral cortex. While initial reports suggested that EMX2 mutations are a common cause of schizencephaly, more recent evidence suggests that EMX2 mutations are not a common cause of this malformation. To determine the frequency of EMX2 mutations in patients with schizencephaly, we sequenced EMX2 in a cohort of 84 affected probands. No pathologic mutations were identified in this cohort, suggesting that EMX2 mutations are an uncommon cause of schizencephaly.

  View details for DOI 10.1002/ajmg.a.31767

  View details for Web of Science ID 000246955500027

  View details for PubMedID 17506092

• Maternal reproductive and demographic characteristics as risk factors for hypospadias PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Laurent, C., Olney, R. S., Lammer, E. J. 2007; 21 (3): 210-218

  Abstract

  This study examined the association of hypospadias risk with several maternal reproductive and demographic characteristics: age, parity, body mass index (BMI), nausea and vomiting of pregnancy (NVP), multiple pregnancy, fertility treatments and procedures, education and race-ethnicity. The study included data on deliveries with estimated due dates from October 1997 to December 2000 that were part of the National Birth Defects Prevention Study, a multi-state case-control study of many birth defects. The analysis included 502 cases with second or third degree hypospadias (i.e. the urethra opened at the penile shaft, scrotum or perineum) and 1286 male, liveborn, non-malformed controls. Risks were estimated from a multivariable logistic regression model that included all exposures of interest. Results indicated particularly elevated risks among births to women who were primiparae, aged >or=35 years and had a BMI of >26, compared with women who were multiparae, aged <30 years and had a BMI of

  View details for Web of Science ID 000245676100003

  View details for PubMedID 17439529

• Maternal stressful life events and risks of birth defects EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Abrams, B., Lammer, E. J. 2007; 18 (3): 356-361

  Abstract

  Several previous studies suggest that maternal stress may be associated with increased risk of certain birth defects. This study examined the association of maternal stressful life events with risks of several birth defects.The data are from a recent, population-based case-control study. Telephone interviews were conducted with 1355 eligible case mothers and 700 control mothers. Maternal stress was measured by responses to 18 yes/no questions about life events that occurred from 2 months before through 2 months after conception.An increase in the stressful life events index (ie, number of "yes" responses to the 18 life-events questions) was associated with increased risk of cleft palate, cleft lip with or without cleft palate, d-transposition of the great arteries, and tetralogy of Fallot, after adjustment for maternal race-ethnicity, education, obesity, age, smoking, drinking, intake of folic acid-containing supplements, neighborhood crime, and food insecurity. For example, the odds ratio for a 3-unit change in the stress index was 1.45 (95% confidence interval = 1.03-2.06) for cleft palate. Increased stress was associated with an increased risk of spina bifida and anencephaly particularly among women who did not take folic acid supplements. A 3-unit change in stress was associated with a 2.35-fold increased risk of anencephaly among women who did not take supplements (CI =1.47-3.77) and a 1.42-fold increased risk among women who did (CI = 0.89-2.25).The adverse health effects of stress may include increased risks of certain birth defects.

  View details for DOI 10.1097/01.ede.0000259986.85239.87

  View details for Web of Science ID 000245993300010

  View details for PubMedID 17435445

• Association between CFLI gene polymorphisms and spina bifida risk in a California population BMC MEDICAL GENETICS Zhu, H., Enaw, J. O., Ma, C., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2007; 8

  Abstract

  CFL1 encodes human non-muscle cofilin (n-cofilin), which is an actin-depolymerizing factor and is essential in cytokinesis, endocytosis, and in the development of all embryonic tissues. Cfl1 knockout mice exhibit failure of neural tube closure at E10.5 and die in utero. We hypothesized that genetic variation within the human CFL1 gene may alter the protein's function and result in defective actin depolymerizing and cellular activity during neural tube closure. Such alterations may be associated with an increased risk for neural tube defects (NTDs).Having re-sequenced the human CFL1 gene and identified five common single nucleotide polymorphisms (SNPs) in our target population, we investigated whether there existed a possible association between the genetic variations of the CFL1 gene and risk of spina bifida. Samples were obtained from a large population-based case-control study in California. Allele association, genotype association and haplotype association were evaluated in two different ethnicity groups, non-Hispanic white and Hispanic white.Homozygosity for the minor alleles of the SNPs studied (rs652021, rs665306, rs667555, rs4621 and rs11227332) appeared to produce an increased risk for spina bifida. Subjects with the haplotype composed of all minor alleles (CCGGT) appeared to have increased spina bifida risk (OR = 1.6, 95% CI: 0.9~2.9), however, this finding is not statistically significant likely due to limited sample size.The sequence variation of human CFL1 gene is a genetic modifier for spina bifida risk in this California population.

  View details for DOI 10.1186/1471-2350-8-12

  View details for Web of Science ID 000245452200001

  View details for PubMedID 17352815

• Screening for novel PAX3 polymorphisms and risks of spina bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lu, W., Zhu, H., Wen, S., Laurent, C., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2007; 79 (1): 45-49

  Abstract

  PAX3 plays an important role in mammalian embryonic development. Known mutations in PAX3 are etiologically associated with Waardenburg syndrome and syndromic neural tube defects (NTDs). Mutations in the murine homologue, pax3, are responsible for the phenotype of splotch mice, in which nullizygotes are 100% penetrant for NTDs.The study sample included 74 infants with spina bifida (cases) and 87 nonmalformed infant controls. The conserved paired-box domain as well as the upstream genomic region of PAX3 were subjected to resequencing and those identified SNPs were evaluated as haplotypes. The associations of haplotypes for selected gene regions and the risks of spina bifida were further studied.Nineteen SNPs were observed; 15 observed in controls had been submitted to the National Center for Biotechnology Information (NCBI) database with allele frequencies. The PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC of nine SNPs, were found to be associated with an increased risk of spina bifida, with an OR of 3.5 (95% CI: 1.2-10.0) among Hispanic Whites.Our analyses indicated that PAX3 SNPs were not strong risk factors for human spina bifida. However, additional follow-up of the PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC, may be important in other populations.

  View details for DOI 10.1002/bdra.20322

  View details for Web of Science ID 000243314500007

  View details for PubMedID 17149730

• Infant C677T MTHFR polymorphism and severe mental retardation BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Jelliffe-Pawlowski, L., Nelson, V., Zhu, H., Harris, J. A., Finnell, R. H. 2007; 79 (1): 24-26

  Abstract

  We investigated whether infants with homozygous genotype TT of the MTHFR gene were at increased risk of severe mental retardation.One hundred children with severe mental retardation (cases) were investigated from a large geographic-based study of infants born in California in 1992-1993. Cases were compared to 743 randomly selected nonmalformed control infants born in California during 1987-1991. DNA was extracted from newborn screening filter papers. Cases and controls were genotyped TT if homozygous for the MTHFR C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild type) allele.Overall, case and control infants had similar percentages of TT and CT genotypes. Percentages between cases and controls differed somewhat across race/ethnic groups. Elevated ORs of 1.9 (95% CI: 0.7-5.0) and 2.6 (95% CI: 1.1-5.8) were observed for the TT and CT genotypes, respectively, among Hispanic children. Observed results were not substantially altered for analyses that removed 41 case children who also had structural birth defects.Folate-related mechanisms are important to investigate for etiologies of birth defects, and such lines of inquiry may be revealing for mental retardation given the relationships between mental retardation and birth defects and potential relationships between folate, DNA methylation, and mental retardation.

  View details for DOI 10.1002/bdra.20321

  View details for Web of Science ID 000243314500004

  View details for PubMedID 17149733

• CHKA and PCYT1A gene polymorphisms, choline intake and spina bifida risk in a California population BMC MEDICINE Enaw, J. O., Zhu, H., Yang, W., Lu, W., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2006; 4

  Abstract

  Neural tube defects (NTDs) are among the most common of all human congenital defects. Over the last two decades, accumulating evidence has made it clear that periconceptional intake of folic acid can significantly reduce the risk of NTD affected pregnancies. This beneficial effect may be related to the ability of folates to donate methyl groups for critical physiological reactions. Choline is an essential nutrient and it is also a methyl donor critical for the maintenance of cell membrane integrity and methyl metabolism. Perturbations in choline metabolism in vitro have been shown to induce NTDs in mouse embryos.This study investigated whether single nucleotide polymorphisms (SNPs) in human choline kinase A (CHKA) gene and CTP:phosphocholine cytidylytransferase (PCYT1A) gene were risk factors for spina bifida. Fluorescence-based allelic discrimination analysis was performed for the two CHKA intronic SNPs hCV1562388 (rs7928739) and hCV1562393, and PCYT1A SNP rs939883 and rs3772109. The study population consisted of 103 infants with spina bifida and 338 non-malformed control infants who were born in selected California counties in the period 1989-1991.The CHKA SNP hCV1562388 genotypes with at least one C allele were associated with a reduced risk of spina bifida (odds ratio = 0.60, 95%CI = 0.38-0.94). The PCYT1A SNP rs939883 genotype AA was associated with a twofold increased risk of spina bifida (odds ratio = 1.89, 95% CI = 0.97-3.67). These gene-only effects were not substantially modified by analytic consideration to maternal periconceptional choline intake.Our analyses showed genotype effects of CHKA and PCYT1A genes on spina bifida risk, but did not show evidence of gene-nutrient interactions. The underlying mechanisms are yet to be resolved.

  View details for DOI 10.1186/1741-7015-4-36

  View details for Web of Science ID 000244873200001

  View details for PubMedID 17184542

• Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Cheng, S., Lammer, E. J. 2006; 140A (22): 2433-2440

  View details for DOI 10.1002/ajmg.a.31505

  View details for Web of Science ID 000241746200006

• Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. American journal of medical genetics. Part A Carmichael, S. L., Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Cheng, S., Lammer, E. J. 2006; 140 (22): 2433-2440

  Abstract

  This study explored risks of limb deficiency anomalies associated with 29 single nucleotide polymorphisms (SNPs) of genes involved in homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. The authors genotyped 96 cases and 437 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Increased risk of limb anomaly was observed for three SNPs: heterozygosity for F5 Arg506Gln, with an odds ratio (OR) of 2.5 (95% confidence interval (CI), 1.0, 6.5); heterozygosity for TNF (-376)G > A, OR 2.1 (0.7, 6.2); and homozygosity for NPPA 2238T > C, OR 4.0 (1.1, 15.4). We hypothesized that effects of variant genotypes in the presence of maternal smoking, and/or in the absence of supplement intake, may exceed effects of any of these factors alone. In particular, findings for polymorphisms in SERPINE1, ITGA2, SELE, TNF, LTA, NPPA, GNB3, and ADRB2 supported the hypotheses, both for smoking and for supplement intake. These results suggest involvement of genetic variation of biologically relevant candidate genes, and gene-environment interaction, for some limb anomalies whose pathogenesis may be related to altered vascular tone or integrity.

  View details for PubMedID 17036337

• Candidate gene polymorphisms do not differ between newborns with stroke and normal controls STROKE Miller, S. P., Wu, Y. W., Lee, J., Lammer, E. J., Iovannisci, D. M., Glidden, D. V., Bonifacio, S. L., Collins, A., Shaw, G. M., Barkovich, A. J., Ferriero, D. M. 2006; 37 (11): 2678-2683

  Abstract

  Neonatal stroke is increasingly recognized with an estimated incidence of one in 4000 live births per year. Pathways involved in the pathophysiology of neonatal stroke are diverse and may include thrombosis and thrombolysis, vascular reactivity, and inflammation.We compared frequencies of polymorphisms in genes regulating thrombosis and thrombolysis, nitric oxide, cytokines, vascular tone, and cell adhesion in a hospital-based cohort of 59 newborns with stroke relative to a random sample of 437 California newborns.Of the 31 polymorphisms evaluated, no variant allele was significantly more common than the reference allele in newborns with stroke than in the general population.Using a series of polymorphisms in pathways implicated in the etiology of stroke, newborns with stroke were not distinguished from a normal control group. Further studies are needed to determine the interaction of genetic polymorphisms with environmental risk factors in the pathogenesis of neonatal stroke.

  View details for DOI 10.1161/01.STR.0000244810.91105.c9

  View details for Web of Science ID 000241798800016

  View details for PubMedID 17008620

• Selected gene polymorphisms and their interaction with maternal smoking, as risk factors for gastroschisis 45th Annual Meeting of the Teratology-Society Torfs, C. P., Christianson, R. E., Iovannisci, D. M., Shaw, G. M., Lammer, E. J. WILEY-LISS. 2006: 723–30

  Abstract

  Gastroschisis is a severe birth defect in which the infant is born with a portion of the intestines extruding through a small tear in the abdominal wall, usually to the right of the umbilical cord. Its etiology is unknown, but the prevailing hypothesis is that it results from a vascular accident at the time of involution of the right umbilical vein or of the development of the superior mesenteric artery.In a case-control study of 57 cases of gastroschisis and 506 controls, we tested DNA for polymorphisms of 32 genes representing enzymes involved in angiogenesis, blood vessel integrity, inflammation, wound repair, and dermal or epidermal strength.In logistic regression, controlling for maternal ethnicity, and using the homozygote wild-type as referent, the following gene polymorphisms were associated with an increased risk for a gastroschisis for heterozygotes: ICAM1 gly241arg (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1 -3.4); NOS3 glu298asp (OR, 1.9; 95% CI, 1.1-3.4); NPPA 2238T > C (OR, 1.9; 95% CI, 1.0-3.4); and ADD1 gly460trp (OR, 1.5; 95% CI, 0.8-2.8). Additionally, for the NPPA and ADD1 single-nucleotide polymorphisms (SNPs), the homozygote variants had a significantly higher risk than the heterozygotes (OR, 7.5; 95% CI, 1.7-33.5 and OR, 4.9; 95% CI, 1.9-12.9, respectively). Three SNPs showed a strong interaction with maternal smoking. The risk for smokers with 1 or 2 variant alleles compared to nonsmokers with the wild-type allele were: NOS3 (OR, 5.2; 95% CI, 2.4-11.4); ICAM1 (OR, 5.2; 95% CI, 2.1-12.7); and NPPA (OR, 6.4; 95% CI, 2.8-14.6).These results support the hypothesis of a vascular compromise as part of a multifactorial etiology of gastroschisis involving both genes and environmental factors.

  View details for DOI 10.1002/bdra.20310

  View details for Web of Science ID 000241591400005

  View details for PubMedID 17051589

• Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Yang, W., Iovannisci, D. M., Lammer, E. 2006; 140A (18): 1915-1922

  View details for DOI 10.1002/ajmg.a.31402

  View details for Web of Science ID 000240391800005

• Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake. American journal of medical genetics. Part A Carmichael, S. L., Shaw, G. M., Yang, W., Iovannisci, D. M., Lammer, E. 2006; 140 (18): 1915-1922

  Abstract

  Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.

  View details for PubMedID 16906563

• Neural tube defects and folate: case far from closed NATURE REVIEWS NEUROSCIENCE Blom, H. J., Shaw, G. M., den Heijer, M., Finnell, R. H. 2006; 7 (9): 724-731

  Abstract

  Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents approximately 50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.

  View details for DOI 10.1038/nrn1986

  View details for Web of Science ID 000240512500014

  View details for PubMedID 16924261

• Array comparative genomic hybridization in patients with congenital diaphragmatic hernia: mapping of four CDH-critical regions and sequencing of candidate genes at 15q26.1-15q26.2 EUROPEAN JOURNAL OF HUMAN GENETICS Slavotinek, A. M., Moshrefi, A., Davis, R., Leeth, E., Schaeffer, G. B., Burchard, G. E., Shaw, G. M., James, B., Ptacek, L., Pennacchio, L. A. 2006; 14 (9): 999-1008

  Abstract

  Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. There have been few studies that have assessed copy number changes in CDH. We present array comparative genomic hybridization data for 29 CDH patients to identify and map chromosome aberrations in this disease. Three patients with 15q26.1-15q26.2 deletions had heterogeneous breakpoints that overlapped with the critical 4 Mb region previously delineated for CDH, confirming 15q26.1-15q26.2 as a critical region for CDH. The three other most compelling CDH-critical regions for genomic deletions based on these data and a literature review are located at chromosomes 8p23.1, 4p16.3-4pter, and 1q41-1q42.1. Based on these recurrent deletions at 15q26.1-15q26.2, we hypothesized that loss-of-function mutations in a gene or genes from this region could cause CDH and sequenced six candidate genes from this region in more than 100 patients with CDH. For three of these genes (CHD2, ARRDC4, and RGMA), we identified missense changes and that were not identified in normal controls; however, none of these alterations appeared unambiguously causal with CDH. These data suggest that CDH caused by chromosome deletions at 15q26.2 may arise because of a contiguous gene deletion syndrome or may have a multifactorial etiology. In addition, there is evidence for substantial genetic heterogeneity in CDH and diaphragmatic hernias can be non-penetrant in patients who have deletions involving CDH-critical regions.

  View details for DOI 10.1038/sj.ejhg.5201652

  View details for Web of Science ID 000239996600006

  View details for PubMedID 16736036

• Maternal nutrient intakes and risk of orofacial clefts EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Laurent, C., Rasmussen, S. A. 2006; 17 (3): 285-291

  Abstract

  Information about nutritional factors as potential risks of orofacial clefts is limited.In this population-based case-control study, we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, and several other nutrients were associated with orofacial clefts. We included data on deliveries from 1997 through 2000 in the National Birth Defects Prevention Study. Orofacial cleft cases were infants or fetuses born with cleft palate (CP) or with cleft lip with or without cleft palate (CLP). Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. Interviews were completed for 704 CLP cases, 404 CP cases, and 2594 controls.The odds ratio (OR) for CLP associated with use of vitamin supplements containing folic acid was 0.88 (95% confidence interval = 0.73-1.07) and for CP was 1.09 (0.84-1.40). Adjusting for maternal race/ethnicity, age, and education produced an OR of 1.01 (0.82-1.24) for CLP and 1.02 (0.77-1.34) for CP. We found some evidence for decreased CLP risks (>or=30% reduction in risk) with increasing intakes of total protein, choline, and methionine. Decreased CP risk was associated with increased intake of cysteine. Intakes of only 2 micronutrients, iron and riboflavin, were found to reduce CLP risk when adjusted for other nutrients.Our observations contribute to the limited body of evidence suggesting a woman's periconceptional diet may influence clefting risks in her offspring. Our finding of no reduction in clefting risk with periconceptional use of supplements containing folic acid is inconsistent with many previous observations but not all.

  View details for DOI 10.1097/01.ede.0000208348.30012..35

  View details for Web of Science ID 000236926500014

  View details for PubMedID 16570024

• Understanding the increased risk of neural tube defect-affected pregnancies among Mexico-born women in California: immigration and anthropometric factors PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Velie, E. M., Shaw, G. M., Malcoe, L. H., Schaffer, D. M., Samuels, S. J., Todoroff, K., Block, G. 2006; 20 (3): 219-230

  Abstract

  Mexico-born women in the United States have an unexplained twofold increased risk of neural tube defect (NTD)-affected pregnancies. We examined whether immigration characteristics were associated with the NTD risk and whether anthropometric factors contributed to the increased risk among Mexico-born women. Data were derived from a large population-based case-control study in California. In-person interviews were conducted with mothers of 538 (88% of eligible) NTD-affected fetuses/infants and mothers of 539 (88%) randomly selected non-malformed control infants. The crude odds ratio (OR) for NTDs among all Mexico-born women, women residing <2 years in the US, and women >16 years old at immigration compared with non-Hispanic white women was 2.4 [95% confidence interval (CI) = 1.8, 3.3], 7.2 [95% CI = 3.7, 14.0] and 3.0 [95% CI = 2.0, 4.4], respectively. Risk for second- or third-generation Mexican-Americans was similar to that of white women. The crude OR for all Mexico-born women was reduced from 2.4 to 2.0 [95% CI = 1.3, 3.0] and for those residing <2 years in the US from 8.4 to 7.1 [95% CI = 3.2, 15.3] after adjustment for maternal body mass index (BMI), height, compromised diet, diabetes, and other known risk factors. In term pregnancies, additional adjustment for pregnancy weight gain reduced the OR in all Mexico-born women and recent immigrants by 16% and 25%, respectively. Low pregnancy weight gain (<10 vs. 10-14 kg) was particularly associated with increased NTD risk among Mexico-born women (OR(ADJ) = 5.8; 95% CI = 2.1, 15.8). Findings indicate that recent Mexican immigrants have a sevenfold increased risk for NTDs. Maternal BMI and height contributed very little, and inadequate weight gain contributed modestly to the NTD risk disparity for Mexican immigrants.

  View details for Web of Science ID 000236672800005

  View details for PubMedID 16629696

• Recovery of genomic DNA from residual frozen archival blood clots suitable for amplification and use in genotyping assays GENETIC TESTING Iovannisci, D. M., Ha, T. T., Shaw, G. M. 2006; 10 (1): 44-49

  Abstract

  A greatly neglected source of DNA potentially useful for genetic or forensic studies is the clot remaining from blood samples collected for serum chemistry measurements. We have investigated the utility of residual clots remaining from venipunctures collected for California's Expanded Maternal Serum Alpha-Fetoprotein Screening Program. We report a protocol based on the salting out method for the extraction of DNA from samples which have been archived and frozen for up to 2.5 years. As much as 57 microg of high-quality DNA can be obtained from a 2-ml clot as determined by PicoGreen (Molecular Probes, Inc., Eugene, OR) fluorescence measurements. Quality of the purified DNA was evaluated by its ability to serve as template in polymerase chain reaction (PCR) amplifications, using primers that flank the polymorphic regions of six genes of pharmacogenetic interest distributed throughout the human genome. Sizes of the gene regions successfully amplified range from 215 bp to 2064 bp, using as little as 10 ng of template DNA. Because many genotyping protocols routinely recommend the design of amplicons in the 100-200 bp range, and 10-50 ng of template, we conclude that the clot remaining after serum has been removed from blood collected for serum chemistry measurements can serve as a reliable source of DNA for genotyping studies.

  View details for Web of Science ID 000236347300008

  View details for PubMedID 16545003

• Epidemiologic characteristics of congenital diaphragmatic hernia among 2.5 million California births, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, W., Carmichael, S. L., Harris, J. A., Shaw, G. M. 2006; 76 (3): 170-174

  Abstract

  Congenital diaphragmatic hernia (CDH) is a severe birth defect of unknown etiology. The aims of the current report were to extend the literature on the descriptive epidemiology of CDH and to determine whether its mortality rate decreased in California during the study period.Using data from a large population-based registry, we ascertained 631 CDH cases from 1989 to 1997. We also classified cases as isolated or nonisolated based on the presence and type of major accompanying malformations. Approximately 2.5 million live and stillbirths occurred during the ascertainment period. Multivariate Poisson regression analysis was applied to examine the time trend and risk factors.The overall prevalence of CDH was 2.49 per 10,000 live and stillbirths and did not vary over the study period. Isolated cases, which accounted for 58% of cases, revealed a prevalence of 1.45 per 10,000. Heart malformations were the most frequent major anomalies accompanying CDH. We observed a lower risk of isolated CDH among blacks. Advanced maternal age groups had a higher risk for nonisolated CDH. Multiparous women tended to have a lower risk for nonisolated CDH. Male infants and multiple births had an increased risk for isolated and nonisolated CDH. Infant mortality was slightly decreased over the study period. CDH cases with additional anomalies had higher mortality rates than isolated cases.Our observations add to the relatively few population-based descriptive epidemiologic studies of the prevalence and mortality, and maternal and infant characteristics of CDH.

  View details for DOI 10.1002/bdra.20230

  View details for Web of Science ID 000236494400003

  View details for PubMedID 16511883

• Correlates of intake of folic acid-containing supplements among pregnant women AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Laurent, C., Herring, A., Royle, M. H., Canfield, M. 2006; 194 (1): 203-210

  Abstract

  This study describes the timing and correlates of folic acid supplement intake among pregnant women.Data from 2518 women with estimated delivery dates from 1997 to 2000, collected for the National Birth Defects Prevention Study, a population-based case-control study, were analyzed. Multinomial logistic regression was used to identify correlates of supplement intake.Fifty-three percent of women began taking folic acid supplement during the periconceptional period, 35% during early pregnancy, and 8% during late pregnancy (ie, 3 months before through 1 month after conception, 2-3 months after conception, or more than 3 months after conception, respectively). Women who did not take folic acid supplement periconceptionally tended to be nonwhite, speak Spanish, have low education, be younger than 25 years old, be nulliparous, smoke, have no previous miscarriage and no fertility treatments, begin prenatal care and become aware of their pregnancy after the first trimester, have nonplanned pregnancies, and eat less breakfast cereal.This study identifies correlates of folic acid supplement intake, which may contribute to the design of interventions to improve intake during early pregnancy.

  View details for DOI 10.1016/j.ajog.2005.06.018

  View details for Web of Science ID 000234386200031

  View details for PubMedID 16389033

• A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida MOLECULAR GENETICS AND METABOLISM Zhu, H. P., Yang, W., Lu, W., Zhang, J., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2006; 87 (1): 66-70

  Abstract

  Folate binding protein 1 (Folr1) knockout mice with low maternal folate concentrations have been shown to be excellent animal models for human folate-responsive neural tube defects (NTDs). Previous studies using the Folr1 knockout mice revealed that maternal folate supplementation up-regulates the expression of the PCMT1 gene in Folr1 nullizygous neural tube tissue during neural tube closure. PCMT1 encodes the protein repair enzyme l-isoaspartate (d-aspartate) O-methyltransferase (PIMT) that converts abnormal d-aspartyl and l-isoaspartyl residues to the normal l-aspartyl form. PIMT is known to protect certain neural cells from Bax-induced apoptosis. Pcmt1-deficient mice present with abnormal AdoMet/AdoHcy homeostasis. We hypothesized that a known functional polymorphism (Ile120Val) in the human PCMT1 gene is associated with an increased risk of folate-responsive human NTDs. A case-control study was conducted to investigate a possible association between this polymorphism and risk of spina bifida. Compared to the Ile/Ile and Ile/Val genotypes, the homozygous Val/Val genotype showed decreased risk for spina bifida (adjusted odds ratio=0.6, 95% confidence interval: 0.4-0.9). Our results showed that the Ile120Val polymorphism of PCMT1 gene is a genetic modifier for the risk of spina bifida. Val/Val genotype was associated with a reduction in risk for spina bifida.

  View details for DOI 10.1016/j.ymgme.2005.09.008

  View details for Web of Science ID 000234689300009

  View details for PubMedID 16256389

• Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 162 (12): 1207-1214

  Abstract

  Orofacial clefts have been associated with maternal cigarette smoking and lack of folic acid supplementation (which results in higher plasma homocysteine concentrations). Because endothelial nitric oxide synthase (NOS3) activity influences homocysteine concentration and because smoking compromises NOS3 activity, genetic variation in NOS3 might interact with smoking and folic acid use in clefting risk. The authors genotyped 244 infants with isolated cleft lip with or without cleft palate (CL/P), 99 with isolated cleft palate, and 588 controls from a California population-based case-control study (1987-1989 birth cohort) for two NOS3 polymorphisms: A(-922)G and G894T. Analyses of gene-only effects for each polymorphism revealed a 60% increased risk of CL/P among NOS3 A(-922)G homozygotes (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.6). There was some evidence for higher risk of CL/P with maternal periconceptional smoking in infants with an NOS3 -922G allele (for homozygotes, OR = 2.5, 95% CI: 1.2, 5.6) but not in those with an 894T allele. For CL/P risk, odds ratios were over 4 among mothers who smoked, who did not use vitamins, and whose infants had at least one variant allele for each NOS3 polymorphism (for A(-922)G, OR = 4.6, 95% CI: 2.1, 10.2; for 894T, OR = 4.4, 95% CI: 1.8, 10.7). No similar patterns were observed for risk of cleft palate.

  View details for DOI 10.1093/aje/kwi336

  View details for Web of Science ID 000233850400009

  View details for PubMedID 16269583

• Hypospadias and maternal exposures to cigarette smoke PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Laurent, C., Lammer, E. J., Olney, R. S. 2005; 19 (6): 406-412

  Abstract

  The few previous studies of hypospadias and smoking have suggested either no association or a reduced risk. This study, which uses data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study, includes data on males born with severe hypospadias (i.e. the urethra opens at the penile shaft, scrotum or perineum) from 1997 to 2000. Non-malformed, liveborn male controls were selected randomly from birth certificates or from birth hospitals. Maternal interviews were completed by telephone with 453 case mothers and 1267 control mothers. Maternal smoking was not associated with hypospadias risk. For example, during the third month of pregnancy, smoking < 0.5 pack/day had an odds ratio (OR) of 1.1 [95% CI 0.6, 1.9]; 0.5 pack/day, 0.6 [0.4, 1.1]; and > or = 1 pack/day, 0.8 [0.4, 1.6]. Exposure to any secondhand smoke at home during the third month of pregnancy showed an OR of 0.6 [95% CI 0.4, 1.0], and exposure at work or school, an OR of 0.7 [0.5, 1.1]. Similar risks were observed for other months during the periconceptional period, and adjustment for several potential confounders did not substantially alter results. This analysis does not confirm a recent report suggesting that maternal smoking is associated with a reduced risk of having offspring with hypospadias.

  View details for Web of Science ID 000233020700002

  View details for PubMedID 16269066

• Gene-environment interactions in rare diseases that include common birth defects 45th Annual Meeting of the Teratology-Society Graham, J. M., Shaw, G. M. WILEY-BLACKWELL. 2005: 865–67

  Abstract

  Rare syndromes often feature specific types of birth defects that frequently are major diagnostic clues to the presence of a given disorder. Despite this specificity, not everyone with the same syndrome is equally or comparably affected, and not everyone with a specific birth defect manifests the same syndrome or is affected with all the features of a particular syndrome. A symposium sponsored by the National Institutes of Health Office of Rare Diseases, and the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction attempted to explore how much of this variability is due to genetic factors and how much is due to environmental factors. The specific types of birth defects examined included cardiovascular defects, holoprosencephaly, clefts of the lip and/or palate, neural tube defects, and diaphragmatic hernias.

  View details for DOI 10.1002/bdra.20193

  View details for Web of Science ID 000233709800002

  View details for PubMedID 16265646

• Genetic variation in the proto-oncogene SKI and risk for orofacial clefting MOLECULAR GENETICS AND METABOLISM Lu, W., Volcik, K., Zhu, H. P., Wen, S., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2005; 86 (3): 412-416

  Abstract

  SKI is a proto-oncogene that is required for development of the central nervous system and skeletal muscle, and is involved in specifying selected cranial neural-crest-derived craniofacial structures. To identify genetic variants within the SKI gene and investigate the potential association between SKI polymorphisms and risk for orofacial defects, we initially re-sequenced the gene.DNA re-sequencing of all seven exons of the SKI gene was performed on 100 control samples. Subsequently, we genotyped 394 samples (148 CLP cases, 99 CP cases, and 147 control infants) for a novel SNP identified in the DNA re-sequencing effort using restriction fragment length polymorphism (RFLP) analysis.We identified one polymorphism in exon 1 of the SKI gene (257C>G) from controls. This SNP resulted in an amino acid change from alanine to glycine (A62G, GenBank Accession No. NM_003036). Among all samples genotyped by the RFLP method, variants (CG, GG) were found in 10.5% of the cases, compared to a prevalence of 17.7% in the controls. The odds ratio was calculated to be 0.6, with a 95% confidence interval (CI) of 0.3-1.0.In a population of California infants with craniofacial defects, a novel polymorphism of the SKI gene was found to be associated with a decreased risk for orofacial defects. The function of this polymorphism and how it might confer protection to the embryo against craniofacial malformations is currently under investigation in our laboratory.

  View details for DOI 10.1016/j.ymgme.2005.06.003

  View details for Web of Science ID 000233327600011

  View details for PubMedID 16054854

• Maternal progestin intake and risk of hypospadias ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Carmichael, S. L., Shaw, G. M., Laurent, C., Croughan, M. S., Olney, R. S., Lammer, E. J. 2005; 159 (10): 957-962

  Abstract

  Previous studies have suggested that maternal intake of progestins during early pregnancy may be associated with an increased risk of hypospadias. Progesterone and its derivatives are commonly prescribed during early pregnancy, for example, in cases of luteal phase dysfunction and in conjunction with ovulation stimulation drugs.To examine whether risk of hypospadias was associated with periconceptional progestin intake.The National Birth Defects Prevention Study, a population-based, multistate, case-control study including deliveries that had estimated due dates from October, 1997 to December, 2000.Participation in the study was 71% among case mothers and 68% among control mothers. This analysis included 502 subjects diagnosed with second- or third-degree hypospadias (ie, the urethra opened at the penile shaft, scrotum, or perineum) and 1286 male, live-born, nonmalformed control subjects.Forty-two case mothers (8.4%) and 31 control mothers (2.4%) reported any pregnancy-related progestin intake from 4 weeks before through 14 weeks after conception, resulting in an odds ratio of 3.7 (95% confidence interval [CI], 2.3-6.0). Analyses stratified by several potential covariates also suggested elevated risks. For example, among the 10 cases and 13 controls who did not report any fertility-related procedures or treatments other than progestins, the odds ratio was 2.2 (95% CI, 1.0-5.0). Progestin intake for the purpose of contraception was not associated with increased risk.This study found that pregnancy-related intake of progestins was associated with increased hypospadias risk.

  View details for Web of Science ID 000232322000008

  View details for PubMedID 16203941

• Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 138A (1): 21-26

  View details for DOI 10.1002/ajmg.a.30924

  View details for Web of Science ID 000231635400005

• Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes. American journal of medical genetics. Part A Shaw, G. M., Iovannisci, D. M., Yang, W., Finnell, R. H., Carmichael, S. L., Cheng, S., Lammer, E. J. 2005; 138 (1): 21-26

  Abstract

  Investigating possible genetic polymorphisms and gene-environment interactions in the etiology of human conotruncal defects is a prudent research approach. In this study we explore gene-only and gene-environment effects of 32 single nucleotide polymorphisms (SNPs) on conotruncal defect risks. The genes bearing these SNPs participate in one of five pathogenetic processes, homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. We used DNA samples and data from a California population-based case-control interview study (1987-1988 birth cohort). We employed a multilocus allele-specific hybridization assay. Allelic variants were determined by genotyping 155 infants with conotruncal defects (cases) and 437 infants without malformations (controls). Among the 32 SNPs, four were associated with odds ratios of 2 or more, and two with odds ratios of 0.5 or less. The four SNPs were F2 G20210A (prothrombin) with an odds ratio of 2.5 (95% confidence interval; 0.9-7.0), F7 promoter (-323) 10-bp del/ins with an odds ratio of 2.3 (0.8-6.8), ITGB3 leu33pro (platelet glycoprotein IIIa) with an odds ratio of 2.2 (0.9-5.7), and NPPA T2238C (atrial natriuretic precursor peptide) with an odds ratio of 2.9 (0.8-10.1). Two SNPs were associated with decreased risks: TNF (tumor necrosis factor, G (-376A)) and ADD1 gly460trp (alpha adducin) with odds ratios of 0.5 (0.1-2.3) and 0.5 (0.2-1.9), respectively. Analyses that investigated a potential gene-nutrient interaction between maternal periconceptional vitamin use and MTHFR genotypes did not indicate that the CT or TT genotype contributed to conotruncal defect risk in infants even in the absence of maternal use of multivitamin supplements with folic acid. Analyses that investigated a potential interaction on risk between NOS3 genes and maternal cigarette smoking, revealed some evidence for higher risk of conotruncal defects in infants whose mothers smoked cigarettes periconceptionally and who had one of the variant alleles for NOS3 A(-922G) or NOS3 glu298asp compared to those infants whose mothers did not smoke and whose genotypes were wild-type. Our results provide some support for involvement of genetic variation of biologically relevant candidate genes for some birth defects whose pathogenesis may be related to altered vascular tone or integrity. In particular, NPPA appears to be a good candidate gene for conotruncal defects and warrants further investigation.

  View details for PubMedID 16100725

• Maternal smoking, genetic variation of glutathione S-transferases, and risk for orofacial clefts EPIDEMIOLOGY Lammer, E. J., Shaw, G. M., Iovannisci, D. M., Finnell, R. H. 2005; 16 (5): 698-701

  Abstract

  Maternal smoking is a known risk factor for orofacial clefts. We investigated whether risk is greater among offspring who lack the genetic capacity to produce glutathione S-transferase enzymes relevant to detoxification of chemicals in cigarette smoke.Using a population-based case-control design, we genotyped 423 California infants with an isolated cleft and 294 nonmalformed controls for null variants of the glutathione S-transferases GSTT1 and GSTM1.If a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, the risk of isolated cleft lip with or without cleft palate was tripled (odds ratio = 2.9; 95% confidence interval = 1.2-7.2). For fetuses who were homozygous null for GSTM1 and whose mothers smoked >/=20 cigarettes per day, we found nearly a 7-fold increased risk (6.8; 0.82-57). Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers was associated with a nearly 6-fold increased risk for cleft lip (6.3; 1.3-42). A similar increased risk for cleft palate was associated with absence of GSTM1, but not for absence of GSTT1.Maternal smoking during pregnancy increases risks for clefts among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals.

  View details for DOI 10.1097/01.ede.0000172136.26733.4b

  View details for Web of Science ID 000231783200017

  View details for PubMedID 16135950

• Genes encoding catalytic subunits of protein kinase A and risk of spina bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Zhu, H. P., Lu, W., Laurent, C., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2005; 73 (9): 591-596

  Abstract

  PRKACA and PRKACB are genes encoding the cAMP-dependent protein kinase A (PKA) catalytic subunits alpha and beta, respectively. PKA is known to be involved in embryonic development, as it down-regulates the Hedgehog (Hh) signaling pathway, which is critical to normal pattern formation and morphogenesis. The PKA-deficient mouse model, which has only a single catalytic subunit, provided intriguing evidence demonstrating a relationship between decreased PKA activity and risk for posterior neural tube defects (NTDs) in the thoracic to sacral regions of gene-knockout mice. Unlike most other mutant mouse models of NTDs, the PKA-deficient mice develop spina bifida with 100% penetrance. We hypothesized that sequence variations in human genes encoding the catalytic subunits may alter the PKA activity and similarly increase the risk of spina bifida.We sequenced the coding regions and the exon/intron boundaries of PRKACA and PRKACB. We also examined 3 common single-nucleotide polymorphisms (SNPs) of these 2 genes by allele discrimination.Five sequence variants in coding region and 2 intronic sequence variants proximal to exons were detected. None of the 3 SNPs examined in the association study appeared to be associated with substantially increased risk for spina bifida.Our results did not reveal a strong association between these PKA SNPs and spina bifida risk. Nonetheless, it is important to examine the possible gene-gene interactions between PRKACA and PRKACB when evaluating the risk for NTDs, as well as genes encoding regulatory subunits of PKA. In addition, interactions with other genes such as Sonic Hedgehog (SHH) should also be considered for future investigations.

  View details for DOI 10.1002/bdra.20175

  View details for Web of Science ID 000232323300002

  View details for PubMedID 16080189

• Schizencephaly: Heterogeneous etiologies in a population of 4 million California births AMERICAN JOURNAL OF MEDICAL GENETICS PART A Curry, C. J., Lammer, E. J., Nelson, V., Shaw, G. M. 2005; 137A (2): 181-189

  View details for DOI 10.1002/ajmg.a.30862

  View details for Web of Science ID 000231634600011

• Schizencephaly: heterogeneous etiologies in a population of 4 million California births. American journal of medical genetics. Part A Curry, C. J., Lammer, E. J., Nelson, V., Shaw, G. M. 2005; 137 (2): 181-189

  Abstract

  Schizencephaly is a rare congenital brain defect characterized by gray matter lined clefts of the cerebral mantle, frequently accompanied by other defects of the CNS such as absence of the corpus callosum. This study in a California population of >4 million births from 1985-2001 found a population prevalence of 1.54/100,000. Among 63 cases, there was an association with young parental age in isolated schizencephaly (RR 3.9 mothers; 5.8 fathers), which was also seen in mothers but not fathers of non-isolated cases (RR 3.2). Monozygotic twins may also be at increased risk for schizencephaly (RR 2.1). One third of cases had a non-CNS abnormality, over half of which could be classified as secondary to vascular disruption, including gastroschisis, bowel atresias, and amniotic band disruption sequence. Other apparent rare causes included chromosomal aneuploidy, non-random associations, and unusual syndromes. Our observations suggest that schizencephaly has heterogeneous etiologies many of which are vascular disruptive in origin.

  View details for PubMedID 16059942

• Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989-1997 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Finnell, R. H., Lammer, E. J. 2005; 137A (1): 36-40

  View details for DOI 10.1002/ajmg.a.30840

  View details for Web of Science ID 000231009900006

• Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989-1997. American journal of medical genetics. Part A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Finnell, R. H., Lammer, E. J. 2005; 137 (1): 36-40

  Abstract

  There is a paucity of epidemiologic information about the eye malformations anophthalmia and microphthalmia. Using data from a large population-based registry, we explored prevalences and maternal/infant characteristics associated with anophthalmia and bilateral microphthalmia. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.5 million births (liveborn and stillborn) occurred during the ascertainment period, 1989-1997. Information on maternal and infant/fetal characteristics was obtained from California birth certificate and fetal death files. The prevalence per 10,000 livebirths and stillbirths for anophthalmia was 0.18 and for bilateral microphthalmia was 0.22. These estimates reflect prevalences among births without chromosomal anomalies. Relative risks of anophthalmia were modestly higher among women aged 40 or more (relative risk = 2.0, 95% confidence interval 0.5-8.6). Risks were substantially lower for those mothers with >12 years of education, even after adjusting for other study factors, relative risk = 0.6 (0.2-1.7). The risk of anophthalmia was approximately twofold among multiple births compared to singletons. Similar to results for anophthalmia, decreased risks for bilateral microphthalmia were observed for maternal education of 12 years or more and increased risks observed for multiple births. These data show descriptive epidemiologic features of anophthalmia and bilateral microphthalmia.

  View details for PubMedID 16007635

• Risks for severe mental retardation occurring in isolation and with other developmental disabilities AMERICAN JOURNAL OF MEDICAL GENETICS PART A Jelliffe-Pawlowski, L. L., Shaw, G. M., Nelson, V., Harris, J. A. 2005; 136A (2): 152-157

  View details for DOI 10.1002/ajmg.a.30801

  View details for Web of Science ID 000230229100007

• Risks for severe mental retardation occurring in isolation and with other developmental disabilities. American journal of medical genetics. Part A Jelliffe-Pawlowski, L. L., Shaw, G. M., Nelson, V., Harris, J. A. 2005; 136 (2): 152-157

  Abstract

  Individual and maternal characteristics as potential risk factors for having severe mental retardation (SMR) occurring with and without cerebral palsy (CP), epilepsy, or a pervasive developmental disorder (PDD) were explored among a cohort of 119,404 children without Down syndrome born in the California Central Valley in 1992 and 1993. Unadjusted and adjusted relative risks (RRs) and their 95% confidence intervals (CIs) based on the Poisson distribution were used to estimate the risks associated with each individual and maternal factor studied for each SMR diagnostic category. The most notable increased risks for SMR occurring in isolation or with CP or epilepsy was for children born low-birth-weight or preterm who were at a substantially increased risk (RRs 2.6-9.9). In contrast, the risk of SMR occurring with a PDD was the greatest among males compared to females (RR = 3.4, 95% CI 1.5, 7.9), Blacks compared to Whites (RR = 5.1, 95% CI 1.7, 15.5), and Asians compared to Whites (RR = 3.9, 95% CI 1.3, 12.0). Etiologic heterogeneity when SMR occurs with a PDD was suggested.

  View details for PubMedID 15940698

• Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts. American journal of medical genetics. Part A Olshan, A. F., Shaw, G. M., Millikan, R. C., Laurent, C., Finnell, R. H. 2005; 135 (3): 268-273

  Abstract

  Repairing DNA damage is critical during embryogenesis because development involves sensitive periods of cell proliferation, and abnormal cell growth or death can result in malformations. Knockout mouse experiments have demonstrated that disruption of DNA repair genes results in embryolethality and structural defects. Studies using mid-organogenesis rat embryos showed that DNA repair genes were variably expressed. It is hypothesized that polymorphisms that alter the functionality of DNA repair enzymes may modify the risk of malformations. We conducted a case-control analysis to investigate the relationship between DNA repair gene polymorphisms and the risk of spina bifida and oral clefts. Newborn screening blood spot DNA was obtained for 250 cases (125 spina bifida, 125 oral clefts) identified by the California Birth Defects Monitoring Program, and 350 non-malformation controls identified from birth records. Six single nucleotide polymorphisms of five DNA repair genes representing three distinct repair pathways were interrogated including: XRCC1 (Arg399Gln), APE1 (Asp148Glu), XRCC3 (Thr241Met), hOGG1(Ser326Cys), XPD (Asp312Asn, Lys751Gln). Elevated or decreased odds ratios (OR, adjusted for race/ethnicity) for spina bifida were found for genotypes containing at least one copy of the variant allele for XPD [751Gln, OR = 1.62; 95% confidence interval (CI) = 1.05-2.50] and APE 148 (OR = 0.58; CI = 0.37-0.90). A decreased risk of oral clefts was found for XRCC3 (OR = 0.62; CI = 0.39-0.99) and hOGG1 (326 Cys/Cys, OR = 0.22; CI = 0.06-0.78). This study suggested that polymorphisms of DNA repair genes, representing different major repair pathways, may affect risk of two major birth defects. Future, larger studies, examining additional repair genes, birth defects, and interaction with exposures are recommended.

  View details for PubMedID 15887293

• Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts? American journal of medical genetics. Part A Zhu, H., Curry, S., Wen, S., Wicker, N. J., Shaw, G. M., Lammer, E. J., Yang, W., Jafarov, T., Finnell, R. H. 2005; 135 (3): 274-277

  Abstract

  Abnormalities in folate and/or homocysteine metabolism may adversely influence embryonic development, leading to the birth of infants with a variety of congenital malformations, including neural tube defects (NTDs) and craniofacial abnormalities. Based upon suggestive evidence that periconceptional folic acid supplementation is effective in preventing a significant proportion of the aforementioned birth defects, genetic variation in the folate biosynthetic pathways may influence the infant's susceptibility to these birth defects. The goal of our study was to investigate sequence variations in the betaine-homocysteine methyltransferase (BHMT) and betaine-homocysteine methyltransferase (BHMT2) genes as modifiers of risk of spina bifida, cleft palate, and cleft lip and palate. The results of this study indicated that individuals homozygous for the single nucleotide polymorphism R239Q in BHMT did not have elevated risks for spina bifida. Genotype frequencies for the BHMT2 rs626105 polymorphism also did not reveal any elevated risks for spina bifida, and only a modest, imprecise elevation of risk for orofacial clefts. The results of these experiments suggest that variants of the BHMT/BHMT2 genes in infants do not substantially contribute to the risk of spina bifida or orofacial clefts in our study population.

  View details for PubMedID 15887275

• Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts? AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zhu, H. P., Curry, S., Wen, S., Wicker, N. J., Shaw, G. M., Lammer, E. J., Yang, W., Jafarov, T., Finnell, R. H. 2005; 135A (3): 274-277

  View details for DOI 10.1002/ajmg.a.30739

  View details for Web of Science ID 000229415200005

• Polymorphisms in DNA repair genes as risk factors for spina bifida and Orofacial clefts AMERICAN JOURNAL OF MEDICAL GENETICS PART A Olshan, A. F., Shaw, G. M., Millikan, R. C., Laurent, C., Finnell, R. H. 2005; 135A (3): 268-273

  View details for DOI 10.1002/ajmg.a.30713

  View details for Web of Science ID 000229415200004

• Periconceptional dietary intake of myo-inositol and neural tube defects in offspring BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Schaffer, D. M. 2005; 73 (3): 184-187

  Abstract

  Periconceptional intake of nutrients in addition to folic acid may contribute to neural tube defect (NTD) etiologies; a likely candidate is myo-inositol. We investigated whether maternal periconceptional dietary intake of myo-inositol influenced NTD risk.Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 454 NTD cases and with mothers of 462 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake.We observed small increases in risk, with increases slightly more evident for anencephaly, associated with intakes of myo-inositol less than the highest intake quartile, e.g., risk of anencephaly was 1.3 (0.7-2.4) among fetuses whose mothers consumed lowest versus highest intakes of myo-inositol. These small increases, however, were imprecise, and also did not indicate increasing risk with decreasing level of myo-inositol intake. Adjusted risk estimates did not differ considerably from their unadjusted counterparts.Our results do not indicate that myo-inositol intake, as measured in this study, is strongly associated with risk of human NTDs.

  View details for DOI 10.1002/bdra.20112

  View details for Web of Science ID 000228049200010

  View details for PubMedID 15744734

• Maternal obesity, gestational diabetes, and central nervous system birth defects EPIDEMIOLOGY Anderson, J. L., Waller, D. K., Canfield, M. A., Shaw, G. M., Watkins, M. L., Werler, M. M. 2005; 16 (1): 87-92

  Abstract

  Maternal obesity and diabetes are both associated with increased risk of congenital central nervous system (CNS) malformations in the offspring and may share a common underlying mechanism. Our objective was to evaluate whether gestational diabetes influenced the association of prepregnancy maternal obesity and risks for CNS birth defects.This Texas population-based case-control study evaluated births occurring January 1997 through June 2001. Data came from structured telephone interviews. Cases (n=477) were mothers of offspring with anencephaly (n=120), spina bifida (n=184), holoprosencephaly (n=49), or isolated hydrocephaly (n=124). Controls (n=497) were mothers of live infants without abnormalities randomly selected from the same hospitals as cases. Response rates were approximately 60% for both cases and controls. We evaluated maternal obesity (body mass index > or =30.0 kg/m) and risks for CNS birth defects, as well as whether gestational diabetes influenced the risks.After adjusting for maternal ethnicity, age, education, smoking, alcohol use, and periconceptional vitamin use, obese women had substantially increased risks of delivering offspring with anencephaly (odds ratio=2.3; 95% confidence interval=1.2-4.3), spina bifida (2.8; 1.7-4.5), or isolated hydrocephaly (2.7; 1.5-5.0), but not holoprosencephaly (1.4; 0.5-3.8). Odds ratios were higher for the joint effects of maternal obesity and gestational diabetes, with evidence for interaction on a multiplicative scale.Maternal obesity and gestational diabetes may increase the risk of CNS birth defects through shared causal mechanisms.

  View details for DOI 10.1097/01.ede.0000147122.97061.bb

  View details for Web of Science ID 000226079600013

  View details for PubMedID 15613950

• Nutrient effects upon embryogenesis: Folate, vitamin A and iodine 55th Nestle Pediatric Nutrition Workshop Rosenquist, T. H., van Waes, J. G., Shaw, G. M., Finnell, R. D. KARGER. 2005: 29–48

  View details for Web of Science ID 000227493800003

  View details for PubMedID 16632927

• Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl-N-transferase 1 (NAT1), and risk for Orofacial clefts BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Lammer, E. J., Shaw, G. M., Iovannisci, D. M., Finnell, R. H. 2004; 70 (11): 846-852

  Abstract

  Periconceptional supplementation of multivitamins that include folic acid have been shown to prevent several birth defects, including neural tube defects and orofacial clefts. We investigated whether polymorphic variants of fetal acetyl-N-transferase 1 (NAT1), an enzyme involved in the catabolism of folates, differentially interacted with maternal multivitamin use during early pregnancy to alter the risk of delivering an infant with an orofacial cleft malformation.Using a large population-based case-control study, we genotyped 421 California infants born with an isolated cleft and 299 controls for two NAT1 polymorphisms.Compared to the homozygous wild-type genotypes, odds ratios for isolated cleft lip with/without cleft palate were slightly increased among infants who were homozygous for the variant alleles of NAT1 1088 and 1095. For isolated cleft palate, no similar associations with these two NAT1 variants were observed. For NAT1 1088 genotypes, we did not observe any differential risks for clefts related to maternal multivitamin intake. For NAT1 1095 genotypes, however, we found a two-fold higher risk for isolated cleft lip with/without cleft palate among infants who were homozygous for the variant allele and whose mothers did not take multivitamins during early pregnancy.We found evidence suggestive of an interaction between the NAT1 1095 polymorphism and lack of maternal multivitamin use that increased risks of isolated cleft lip with/without cleft palate.

  View details for DOI 10.1002/bdra.20081

  View details for Web of Science ID 000225522500005

  View details for PubMedID 15523664

• Risks of selected congenital malformations among offspring of mixed race-ethnicity BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Yang, J., Carmichael, S. L., Kaidarova, Z., Shaw, G. M. 2004; 70 (10): 820-824

  Abstract

  Little is known about the occurrence of specific congenital malformations among offspring of mixed race-ethnicity.Using data from a population-based registry, we explored the occurrence of selected malformation phenotypes in offspring to parents who were of different race-ethnicity. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.6 million live births and stillbirths occurred during 1989-2000. Information on parental race-ethnicity (non-Hispanic white, Hispanic, black, and Asian) was obtained from birth certificates and fetal death files. Malformation phenotypes studied were spina bifida, anencephaly, cleft lip, cleft palate, tetralogy of Fallot, d-transposition of great arteries, hypospadias, small intestinal atresia, preaxial polydactyly, microtia, and hypertrophic pyloric stenosis.A total of 11.2% of births were to parents of mixed race-ethnicity. Compared to births of parents who were both white, moderately increased risks (risk ratio >/= 1.7) of anencephaly, polydactyly, and microtia, and decreased risks (risk ratio

  View details for DOI 10.1002/bdra.20025

  View details for Web of Science ID 000224970800005

  View details for PubMedID 15390318

• State birth defects surveillance program directory BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Wertelecki, W., Hilliard, P., Schoellhorn, J., Mumaw, S., Flood, T. J., Varga, A. K., Mosley, B. S., Hobbs, C. A., Campodonica, M. J., Shaw, G. M., Schonbeck, M., Miller, L. A., Okafor, M., Liu, C. F., Baker, J., Voss, B., Long-White, D., Brooks, J., Correia, J. A., Grimm, E., O'Leary, L. A., Cragan, J. D., Hersh, D. L., Joshi, H., Merz, R. D., Duke, R. A., Egler, T., Shen, T. F., Meade, N. B., Romitti, P. A., McDowell, B. D., Stueve, J. H., Nelson, C. S., Robl, J. M., Fawbush, S. G., Pippins, L. B., Mulcahy, E., Day, P. Y., Panny, S. R., Baumgardner, R. A., Casey, L., Higgins, C., Copeland, G., Simmons, L., Falken, M., Symonik, D., McClure, J., Terry, P., Bakewell, J. M., Clack, S., Becker, C. M., Wright, J., Deyhle, G. M., Moeschler, J. B., Flanagan, V. A., Beres, L. M., Knapp, M. M., Nalder, S., Murphy, T., Cross, P. K., Druschel, C., Meyer, R. E., Williams, J., Bohn, T., Schor, D. P., Starr, A. E., Pearson, K. A., Rosenberg, K. D., Horner, S. B., Staver, R. F., Correa, E. M., Valencia, D., Viner-Brown, S., Quaedvlieg, M., Stevenson, R. E., Dean, J. H., Stein, Q., Law, D. J., Canfield, M. A., Langlois, P., Feldkamp, M. L., MacLeod, L. M., Brozicevic, P., Burley, J., Williams, S. K., Ford, N. C., Peters, R., Cummons, K. G., Baker, M. A., Oftedahl, E., Helm-Quest, P., Ailes, D., Ryan, M., Aran, R. 2004; 70 (9): 609-676

  View details for DOI 10.1002/bdra.20071

  View details for Web of Science ID 000223947300011

• Gene-nutrient interactions: importance of folates and retinoids during early embryogenesis TOXICOLOGY AND APPLIED PHARMACOLOGY Finnell, R. H., Shaw, G. M., Lammer, E. J., Brandl, K. L., Carmichael, S. L., Rosenquist, T. H. 2004; 198 (2): 75-85

  Abstract

  The role that nutritional factors play in mammalian development has received renewed attention over the past two decades, as the scientific literature exploded with reports of retinoid compounds disrupting craniofacial development, and with other reports that folic acid supplementation in the periconceptional period can protect embryos from highly significant malformations. As was often the case, the situation became far more complicated, as the interaction between nutritional factors with selected genes was recognized. In this review, we attempt to summarize a complex clinical and experimental literature of nutritional factors, their biological transport mechanisms, and the impact that they have during early embryogenesis. Although not exhaustive, our goal was to provide an overview of important gene-nutrient interactions and a framework for their investigation.

  View details for DOI 10.1016/j.taap.2003.09.031

  View details for Web of Science ID 000222713900001

  View details for PubMedID 15236946

• Periconceptional dietary intake of choline and betaine and neural tube defects in offspring AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Carmichael, S. L., Yang, W., Selvin, S., Schaffer, D. M. 2004; 160 (2): 102-109

  Abstract

  Periconceptional intake of folic acid prevents some neural tube defects (NTDs). Other nutrients may also contribute to NTD etiologies; a likely candidate is choline. Similar to folic acid, choline is involved in one-carbon metabolism for methylation of homocysteine to methionine. The authors investigated whether maternal periconceptional dietary intakes of choline and its metabolite betaine influence NTD risk. Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. In-person interviews were conducted with mothers of 424 NTD cases and with mothers of 440 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake. Dietary intakes of choline were associated with reduced NTD risks. Controlling for intake of supplemental folic acid, dietary folate, dietary methionine, and other covariates did not substantially influence risk estimates for choline. NTD risk estimates were lowest for women whose diets were rich in choline, betaine, and methionine. That is, for women whose intake was above the 75th percentile compared with below the 25th percentile for all three nutrients, the odds ratio was 0.17 (95% confidence interval: 0.04, 0.76). Study findings for dietary components other than folic acid offer additional clues about the complex etiologies of NTDs.

  View details for DOI 10.1093/aje/kwh187

  View details for Web of Science ID 000222556600002

  View details for PubMedID 15234930

• Epidemiologic characteristics of anotia and microtia in California, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Kaidarova, Z., Harris, J. A. 2004; 70 (7): 472-475

  Abstract

  There is a paucity of epidemiologic information about the external ear malformations anotia and microtia.Using data from a large population-based registry, we explored prevalences and maternal/infant characteristics associated with anotia and microtia. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.5 million births (live-born and stillborn) occurred during the ascertainment period, 1989-1997. Information on maternal and infant/fetal characteristics was obtained from California birth certificate and fetal death files.The prevalence of anotia/microtia was 2.50 per 10,000 live births and stillbirths. Isolated cases, i.e., those live births and stillbirths with no other accompanying anomaly diagnoses, revealed a prevalence of 0.63 per 10,000, whereas among nonisolated cases, the prevalence was 1.53 per 10,000 live births and stillbirths. Prevalences of isolated anotia/microtia were substantially higher among U.S.-born Hispanics, foreign-born Hispanics, and Asians compared to non-Hispanic whites, with relative risks ranging from three- to seven-fold. Similar prevalences for maternal race/ethnicity (except for Asians) were observed for live births and stillbirths with nonisolated cases of anotia/microtia, but the magnitude of risks were lower than those observed for isolated cases. Prevalence of nonisolated anotia/microtia was substantially lower among women whose education was 12 years or more.These data reveal descriptive epidemiologic features of anotia/microtia most notably substantial risks associated with race/ethnic groups and lower maternal education. Additional study for factors associated with these characteristics could reveal clues for the etiology of these ear anomalies.

  View details for DOI 10.1002/bdra.20042

  View details for Web of Science ID 000222987400006

  View details for PubMedID 15259037

• Congenital malformations in offspring of Hispanic and African-American women in California, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Kaidarova, Z. 2004; 70 (6): 382-388

  Abstract

  Little is known about risks of most specific birth defects among infants born to U.S.-born and foreign-born Hispanic or African-American women.Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of U.S.-born and foreign-born Hispanic and African-American women, relative to non-Hispanic white women, in California. Approximately 2.2 million live births and stillbirths occurred during the ascertainment period, 1989-1997. Information on maternal racial-ethnic background and other covariates was obtained from birth certificate and fetal death files.Adjusted relative risks (ARRs) for the 20 groupings of malformations designated by three-digit British Pediatric Association (BPA) codes ranged from 0.6 (genital organ malformations, among infants born to foreign-born Hispanics) to 1.7 (anencephaly, also among infants born to foreign-born Hispanics). Grouping by four-digit BPA codes revealed that among infants born to U.S.-born Hispanics, 46 of the ARRs were < or = 0.8 and 12 were > or = 1.3; among infants born to foreign-born Hispanics, 75 of the ARRs were < or = 0.8 and 15 were > or = 1.3; and among infants born to African-American women, 45 ARRs were < or = 0.8 and 25 were > or = 1.3. For each racial-ethnic group of women, the observed variability in risks covered most organ systems.Although the results suggested that (in comparison with non-Hispanic whites) each racial-ethnic group was more likely to have reduced risk for specific defects (rather than elevated risk), in general, the range of the relative risks was comparatively narrow.

  View details for DOI 10.1002/bdra.20012

  View details for Web of Science ID 000222419100002

  View details for PubMedID 15211706

• Limb deficiency defects, MSX1, and exposure to tobacco smoke AMERICAN JOURNAL OF MEDICAL GENETICS PART A Carmichael, S. L., Shaw, G. M., Yang, W., Lammer, E. J., Zhu, H. P., Finnell, R. H. 2004; 125A (3): 285-289

  Abstract

  There is increasing evidence from epidemiologic studies that genetic susceptibilities may modify the teratogenic effects of smoking. A previous study suggested that maternal smoking in the presence of a dinucleotide repeat polymorphism for MSX1 produced an almost fivefold increased risk for limb anomalies, providing evidence for a gene-environment interaction. The current study examined this potential interaction, using case-control data with several methodologic improvements, including a larger sample size and more detailed information on cigarette smoke exposures. Cases (n = 92) were ascertained from pregnancies ending in 1987-1989, and controls (n = 180) were randomly selected from eligible liveborn infants. In telephone interviews, women reported smoking behaviors during the month before pregnancy through the end of the first trimester. Odds ratios (OR) for maternal and paternal smoking ranged from 1.0 to 1.4, risk estimates were imprecise; for example, the OR for maternal smoking >or=20 cigarettes per day, versus none, was 1.3 (95% confidence interval (CI) 0.5-3.4). Relative to the homozygous wildtype, the OR was 1.5 (95% CI 0.7-3.5) for the homozygous variant genotype and 0.8 (95% CI 0.5-1.4) for the heterozygous variant genotype. There was no evidence that maternal smoking or both parents smoking, in combination with a susceptible MSX1 genotype, conferred an additional increase in risk of limb defects. This study did not find a gene-environment interaction between maternal smoking, infant MSX1 CA repeat polymorphism, and risk of limb deficiency defects. This finding contrasts with results of a previous study, which provided initial evidence for such an interaction. Several important methodological differences may have contributed to the differences in findings between the two studies.

  View details for DOI 10.1002/ajmg.a.20517

  View details for Web of Science ID 000189316800011

  View details for PubMedID 14994238

• Congenital malformations in births with orofacial clefts among 3.6 million California births, 1983-1997 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Carmichael, S. L., Yang, W., Harris, J. A., Lammer, E. J. 2004; 125A (3): 250-256

  Abstract

  Few population-based epidemiologic data are available on malformation phenotypes that co-occur with orofacial clefts. We explored the occurrence of structural congenital malformations in offspring with cleft palate (CP) and in offspring with cleft lip with or without CP (CLP), using data from a population-based active surveillance system. Ascertainment was performed among 3548991 liveborn and 23239 stillborn offspring of California women who delivered in nonmilitary hospitals during the period, 1983-1997. Structural congenital malformations were found in 91888 births. Among them, 2343 had CP and 4072 had CLP. Malformations were grouped according to 3- and 4-digit codes of the British Pediatric Association (BPA). Prevalences of each malformation grouping, defined by these codes, were calculated among: (1). all births with CP; (2). all births with CLP; (3). all births without CP or CLP but with another structural malformation; and (4). all births in the population at risk. These various prevalence measures were the basis of estimating relative risks. Observed relative risks indicated that some phenotypes were more likely and some were less likely to co-occur with either CP or CLP, with relative risks ranging from 0.5 to 2.4. For both CP and CLP, estimated relative risks were highest for malformations involving the respiratory system and lowest for spina bifida. The exclusion of all births (n = 10702) with chromosomal anomalies from comparisons did not materially alter observed relative risk estimates. Computations extended to 4-digit level BPA codes revealed elevated risks for a number of more specific diagnoses seen within the larger (3-digit level) groupings defined as eye, ear, respiratory, upper alimentary tract, and other musculoskeletal anomalies. In this large population-based cohort of infants and fetuses with CLP or CP, we observed several noncleft malformation groupings to be more common and others to be less common in their co-occurrence with orofacial clefts relative to their co-occurrence with any other malformation. These observed patterns tended to be similar for CP and for CLP.

  View details for DOI 10.1002/ajmg.a.20508

  View details for Web of Science ID 000189316800005

  View details for PubMedID 14994232

• Maternal smoking and the risk of orofacial clefts - Susceptibility with NAT1 and NAT2 polymorphisms EPIDEMIOLOGY Lammer, E. J., Shaw, G. M., Iovannisci, D. M., Van Waes, J., Finnell, R. H. 2004; 15 (2): 150-156

  Abstract

  Orofacial clefts are etiologically heterogeneous malformations. One probable cause is maternal smoking during pregnancy. The effect of maternal smoking may be modified by genes involved in biotransformation of toxic compounds derived from tobacco. We investigated whether polymorphic variants of fetal acetyl-N-transferases 1 (NAT1) and 2 (NAT2) interact with maternal cigarette smoking during early pregnancy to increase the risk of delivering an infant with an orofacial cleft.In a California population-based case-control study, we genotyped 421 infants born with an isolated cleft and 299 nonmal-formed controls for 2 NAT1 and 3 NAT2 single nucleotide polymorphismsAlthough smoking was independently associated with increased risks for both isolated cleft lip +/- cleft palate and isolated cleft palate, no independent associations were found for NAT1 1088 or 1095 genotypes or for NAT2 acetylator status. However, the infant NAT1 1088 and 1095 polymorphisms were strongly associated with the risk of clefts among smoking mothers; infants with NAT1 1088 genotype AA versus TT (odds ratio [OR] = 3.9; 95% confidence interval = 1.1-17.2) and with NAT1 1095 genotype AA versus CC (OR = 4.2; 1.2-18.0). Infant NAT2 acetylator status did not appreciably affect susceptibility of the fetus to the teratogenic effects of maternal smoking.Our results suggest that maternal smoking during pregnancy may increase risk for orofacial clefts particularly among smokers whose fetuses have polymorphic variants of NAT1, an enzyme involved in phase II detoxification of tobacco smoke constituents.

  View details for DOI 10.1097/01.ede.0000112214.33432.cc

  View details for Web of Science ID 000189286900006

  View details for PubMedID 15127906

• Occurrence of low birthweight and preterm delivery among California infants before and after compulsory food fortification with folic acid PUBLIC HEALTH REPORTS Shaw, G. M., Carmichael, S. L., Nelson, V., Selvin, S., Schaffer, D. M. 2004; 119 (2): 170-173

  Abstract

  Studies suggest that folic acid intake influences the occurrence of low birthweight and preterm delivery. Since 1998, there has been compulsory fortification of flour and other grains with folic acid in the U.S. The objective of this study was to investigate the frequencies of low birthweight and preterm delivery after mandatory folic acid fortification among approximately six million California births.The authors investigated prevalences of low birthweight and preterm delivery before and after compulsory fortification among 5,916,630 singleton California live births that occurred from January 1990 through December 2000.The unadjusted prevalences of very low birthweight, low birthweight, and preterm delivery did not substantially vary across birth years. That is, substantial decreased prevalences during the fortification period relative to the period preceding it were not observed. However, analyses that simultaneously adjusted for maternal age, parity, race/ethnicity, education, year of birth, and fortification period revealed the following relative risk ratios (RR) and 95% confidence intervals (CI): RR = 0.91, CI 0.88, 0.94 for very low birthweight, RR = 0.94; 95% CI 0.93, 0.96 for low birthweight, and RR = 0.96; 95% CI 0.94, 0.97 for preterm delivery.Findings indicate small reductions in prevalences of these outcomes associated with the timing of fortification of the U.S. food supply.

  View details for Web of Science ID 000226363500011

  View details for PubMedID 15192904

• Promoter haplotype combinations for the human PDGFRA gene are associated with risk of neural tube defects MOLECULAR GENETICS AND METABOLISM Zhu, F. P., Wicker, N. J., Volcik, K., Zhang, J., Shaw, G. M., Lammer, E. J., Suarez, L., Canfield, M., Finnell, R. H. 2004; 81 (2): 127-132

  Abstract

  Recent animal studies suggested that deregulated expression of the platelet-derived growth factor receptor alpha (PDGFRalpha) may contribute to the failure of normal neural tube closure (NTC). There is also suggestive evidence that the promoter haplotype of the PDGFRA is associated with genetic susceptibility in human neural tube defects (NTDs). The purpose of our study was to investigate the association between promoter haplotype combinations of the human PDGFRA gene and risk for NTDs in a Hispanic population from the Texas-Mexico border region. This population has a considerably higher prevalence of NTDs (16/10,000 live births) than that generally reported in the United States (8-10/10,000 live births). In the present study, NTDs were defined as spina bifida or anencephaly. The haplotype of PDGFRA gene promoter was determined by direct DNA sequence analysis. Two novel haplotypes, H2epsilon and H1beta, were found. We observed significant differences among variable haplotype groups from in vitro transient transfection studies in U2-OS osteosarcoma cell and two other cell lines (HeLa cell and MCF7 cell). Result from our case-control study demonstrated that the frequencies of haplotypes with low transcription activity were significantly higher in NTD mothers than that observed in control mothers (odds ratio=2.2, 95% CI=1.0-4.6). Infants with at least one low activity allele showed slightly higher risk (odds ratio=1.5, 95%=0.8-3.1). Our study suggests that the reduced transcriptional activity of PDGFRA gene could increase the risk of having an NTD-affected pregnancy.

  View details for DOI 10.1016/j.ymgme.2003.11.003

  View details for Web of Science ID 000188718400008

  View details for PubMedID 14741194

• Dieting behaviors and risk of neural tube defects AMERICAN JOURNAL OF EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Schaffer, D. M., Laurent, C., Selvin, S. 2003; 158 (12): 1127-1131

  Abstract

  The authors examined whether maternal dieting behaviors were associated with increased neural tube defect (NTD) risk among offspring, using population-based, case-control data. The analysis included 538 cases and 539 nonmalformed controls delivered from 1989 to 1991 in selected California counties, and exposures were assessed by in-person maternal interview. Among four reported dieting behaviors involving restricted food intake, diets to lose weight (odds ratio=2.1, 95% confidence interval: 1.1, 4.1), fasting diets (odds ratio=5.8, 95% confidence interval: 1.7, 20.0), and eating disorders (odds ratio=1.7, 95% confidence interval: 0.8, 3.6) were associated with increased NTD risk during the first trimester of pregnancy. Risk estimates for these behaviors during the 3 months before conception tended to be closer to 1. The fourth behavior, "other special diets," was not associated with increased NTD risk during either period. Women also reported whether they took diet pills, laxatives, or diuretics, engaged in binge eating, induced vomiting, or exercised excessively from the first 3 months before conception through the end of pregnancy. Only the intake of diuretics was associated with substantially increased NTD risk (odds ratio=2.7, 95% confidence interval: 0.7, 10.2). This study suggests that maternal dieting behaviors involving restricted food intake during the first trimester may be associated with increased NTD risk.

  View details for Web of Science ID 000187216600001

  View details for PubMedID 14652296

• Differential risks to males and females for congenital malformations among 2.5 million California births, 1989-1997 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Shaw, G. M., Carmichael, S. L., Kaidarova, Z., Harris, J. A. 2003; 67 (12): 953-958

  Abstract

  Although many studies have observed variations in the prevalence of specific malformations by sex, there is a lack of population-based data on potential malformation prevalence differences by sex at birth.Our objective was to explore differences in the prevalence of structural congenital malformation phenotypes between sexes in a California population of 2.5 million live- and stillbirths, using data from a population-based active surveillance system. Ascertainment was performed among offspring of California women who delivered in nonmilitary hospitals during the period of 1989-1997. Malformations were grouped according to the four-digit malformation codes of the British Pediatric Association.Overall, 32,619 males and 21,835 females were considered to have structural congenital malformations, with prevalences of 2.52% and 1.76%, respectively. Thus, males demonstrated a malformation prevalence that was 22% higher than that in females. Using a criterion of a 40% increase or decrease in the relative risk for males, increased risks for 15 and decreased risks for 17 specific malformation categories were observed. Increased risks were associated with most organ systems, with the notable exception of the nervous system (increased risks for nervous system malformations were observed among female births). Risks were not substantially influenced by adjusting for maternal age, race/ethnicity, parity, or education.Our observations extend the relatively few studies that have investigated differential prevalences of a large number of specific structural malformations between male and female births.

  View details for DOI 10.1002/bdra.10129

  View details for Web of Science ID 000187445400001

  View details for PubMedID 14745913

• Associations between polymorphisms within the thymidylate synthase gene and spina bifida BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Volcik, K. A., Shaw, G. M., Zhu, H. P., Lammer, E. J., Laurent, C., Finnell, R. H. 2003; 67 (11): 924-928

  Abstract

  Polymorphisms within the thymidylate synthase (TS) gene that influence enzyme activity may affect plasma folate levels and, indirectly, plasma homocysteine concentrations. We investigated whether TS polymorphisms contribute to spina bifida (SB) risk, given that a reduction in the risk of SB has been linked to folate metabolism.Genomic DNA was extracted from newborn-screening blood spots obtained from case infants with SB, and randomly selected, nonmalformed control infants. Genotype frequencies of two polymorphisms in the TS gene-a 28-bp tandem repeat in the promoter enhancer region (TSER) and a 6-bp deletion in the 3'UTR-were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Additionally, all seven exons of the TS gene were sequenced to identify variations within the coding region of the gene.We found that the TSER 2/2 homozygous genotype was associated with a slightly increased risk for SB infants (odds ratio [OR] = 1.4 [0.8-2.4], p = 0.1). When the cohort was divided into separate ethnic groups, this risk increased by 4-fold with the TSER 2/2 homozygous genotype (OR = 4.0 [1.8-8.8], p = 0.001), and by 3-fold with the 3'UTR +/+ homozygous genotype (OR = 3.6 [1.3-10.1], p = 0.02) in non-Hispanic white cases. The combined TSER,3'UTR (2/2,+/+) genotype showed a more than 4-fold increased risk for SB within this specific ethnic group (OR = 4.7 [1.1-19.8], p = 0.04).This study is the first to evaluate how TS polymorphisms contribute to the risk of SB. The current findings indicate that polymorphisms in the untranslated regions of the TS gene are associated with 4-fold or more increased risks of SB in non-Hispanic whites, but not in Hispanic whites, African-Americans, or Asian-Americans.

  View details for DOI 10.1002/bdra.10029

  View details for Web of Science ID 000186851600007

  View details for PubMedID 14745930

• Hypospadias in California - Trends and descriptive epidemiology EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Nelson, V., Selvin, S., Torfs, C. P., Curry, C. J. 2003; 14 (6): 701-706

  Abstract

  The occurrence of hypospadias has been reported to be increasing. The objectives of this study were to extend the literature on the descriptive epidemiology of hypospadias and to determine whether its birth prevalence increased in California in recent years. We used actively ascertained, population-based data for which detailed clinical descriptions permitted careful phenotypic classifications.We examined registry data on 5838 male live births and stillbirths that occurred in California from 1984 through 1997. To reduce pathogenic heterogeneity, cases were classified as mild, severe, or not otherwise specified based on the anatomic position of the urethral opening. We also classified cases as isolated or nonisolated based on the presence and type of accompanying malformations. We used multivariable Poisson regression analysis to examine time trends and risk factors.There was no evidence for an increase in prevalence of any of the case groups between 1989 and 1997. The adjusted relative risk (RR) for change in prevalence per year of isolated severe cases was 0.99 (95% confidence interval = 0.96-1.03). Adjusted RRs indicated increased risks for specific types of hypospadias with maternal non-Hispanic white race-ethnicity, higher education, older age, and nulliparity. Delivery before 37 weeks and multiple births tended either not to be associated with risk or to be associated with reduced risk. Lower birthweight was associated with increased risk for all case groups.This study suggests that hypospadias prevalence has not been increasing in California in recent years. Differences by phenotype suggest that examining certain phenotypes separately could help to understand hypospadias etiology.

  View details for DOI 10.1097/01.ede.0000091603.43531.d0

  View details for Web of Science ID 000186160300011

  View details for PubMedID 14569186

• Neural tube defects associated with maternal periconceptional dietary intake of simple sugars and glycemic index AMERICAN JOURNAL OF CLINICAL NUTRITION Shaw, G. M., Quach, T., Nelson, V., Carmichael, S. L., Schaffer, D. M., Selvin, S., Yang, W. 2003; 78 (5): 972-978

  Abstract

  Maternal diabetes, prepregnancy obesity, hyperinsulinemia, and intakes of sweets have been associated with increased risks of neural tube defects (NTDs). The interdependence of these factors suggests a common pathogenesis via altered glycemic control and insulin demand.We investigated whether maternal periconceptional dietary intakes of sucrose, glucose, fructose, and foods with higher glycemic index values influence the risk of having NTD-affected pregnancies.In a population-based case-control study, all hospitals in 55 of the 58 counties in California participated. In-person interviews were conducted with the mothers of 454 NTD cases (including fetuses and infants who were electively terminated, stillborn, or born alive) and with the mothers of 462 nonmalformed controls within an average of 5 mo from the term delivery date. The risk of having an NTD-affected pregnancy was the main outcome measure.Risks of having an NTD-affected pregnancy were not substantially elevated in relation to periconceptional intakes of glucose or fructose. Elevated risks of approximately 2-fold were observed for higher intakes of sucrose and foods with higher glycemic index values. Elevated risks were observed for high sucrose intake irrespective of whether adjustment was made for other covariates such as maternal folic acid intake. For higher glycemic index values, adjusted elevated risks of > or = 4-fold were observed in women whose body mass index (in kg/m(2)) was > 29.Our observed associations support observations that potential problems in glucose control are associated with NTD risk even among nondiabetic women.

  View details for Web of Science ID 000186146500013

  View details for PubMedID 14594784

• Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Zhu, H. P., Lammer, E. J., Yang, W., Finnell, R. H. 2003; 158 (8): 747-752

  Abstract

  How folate reduces the risks of congenital anomalies is unknown. The authors focused on a gene involved in folate transport-reduced folate carrier-1 gene (RFC1). Using data from a California case-control study (1987-1989 births), the authors investigated whether the risks of orofacial clefts or conotruncal heart defects were influenced by a polymorphism of infant RFC1 or by an interaction between the RFC1 gene and maternal periconceptional use of vitamins containing folic acid. A total of 305 liveborn infants with cleft lip with or without cleft palate, 123 with cleft palate, 163 with conotruncal heart defects, and 364 nonmalformed controls were genotyped. Odds ratios of 1.6 (95% confidence interval: 0.9, 2.8) for the G80/G80 genotype and of 2.3 (95% confidence interval: 1.3, 3.9) for the G80/A80 genotype were observed relative to the A80/A80 genotype for conotruncal defects. Among mothers who did not use vitamins, the risk of conotruncal defects was 2.1 (95% confidence interval: 0.7, 5.9) for infants with genotype G80/G80 compared with those with the A80/A80 genotype. Among mothers who did use vitamins, the risk was 1.3 (95% confidence interval: 0.7, 2.7). Substantially elevated risks for either cleft group were not observed irrespective of genotype and use/nonuse of vitamins. Thus, this study found modest evidence for a gene-nutrient interaction between infant RFC1 genotype and periconceptional intake of vitamins on the risk of conotruncal defects.

  View details for DOI 10.1098/aje/kwg189

  View details for Web of Science ID 000185897700005

  View details for PubMedID 14561664

• Maternal periconceptional alcohol consumption and risk for conotruncal heart defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Carmichael, S. L., Shaw, G. M., Yang, W., Lammer, E. J. 2003; 67 (10): 875-878

  Abstract

  In this study we investigated whether the risk of delivering infants with conotruncal heart defects was increased among mothers who consumed alcohol during the periconceptional period (i.e., 1 month before conception to 3 months after conception).Data were obtained from a population-based case-control study of California births from 1987-1988. Information concerning alcohol consumption was obtained via telephone interviews with mothers of 207 (87% of eligibles) case infants and 481 (76%) nonmalformed control infants.Bivariate results indicated that relative to nonconsumers, women who consumed alcohol less than once a week had a 1.3-fold increased risk of delivering infants with a conotruncal heart defect (95% confidence interval (CI) 1.0, 1.9), and women who consumed alcohol once a week or more had a 1.9-fold increased risk (95% CI 1.0, 3.4). The risks associated with consuming five or more drinks per drinking occasion were 1.6 (95% CI 0.8, 3.2) for less than once a week, and 2.4 for once a week or more (95% CI 0.6, 9.7). The results for the phenotypic subgroups were similar to those for all cases. Adjustment for potential covariates resulted in somewhat weaker, but still elevated, risks.This study found that the risk of conotruncal heart defects in offspring was moderately elevated among women who consumed alcoholic beverages during the periconceptional period, and that risk was higher with increased frequency of drinking or increased number of drinks consumed per occasion. Most of the risk estimates were imprecise, and chance could not be ruled out as an explanation for the observed findings.

  View details for DOI 10.1002/bdra.10087

  View details for Web of Science ID 000186148500007

  View details for PubMedID 14745941

• Risk of mental retardation among children born with birth defects ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Jelliffe-Pawlowski, L. L., Shaw, G. M., Nelson, V., Harris, J. A. 2003; 157 (6): 545-550

  Abstract

  A paucity of epidemiologic research exists concerning the co-occurrence of birth defects and mental retardation (MR). Study of this co-occurrence may yield important clues about the causes of both.To examine the co-occurrence of birth defects and MR, taking into consideration the type of birth defect, level of MR, co-occurrence of MR with other developmental disabilities, and individual and maternal factors.A retrospective cohort study of infants born in the California Central Valley with and without a structural birth defect by 1 year of age, and with or without MR by 7 to 9 years of age. Setting andOne-year survivors (N = 119 556) born in nonmilitary hospitals in 8 California counties between January 1, 1992, and December 31, 1993, for whom information about birth defects was recorded within the first year of life.Diagnosis of MR by age 7 years considered as being mild or severe and as occurring without other developmental disabilities (isolated MR) or as occurring with other developmental disabilities, including cerebral palsy, epilepsy, or a pervasive developmental disorder.Children with birth defects were nearly 27 times more likely to have MR by 7 years of age compared with children without a diagnosed birth defect regardless of type of defect (prevalence ratio, 26.8; 95% confidence interval, 22.7-31.7). Among those with birth defects, children with Down syndrome (prevalence ratio, 211.7; 95% confidence interval, 171.3-261.5) and children with sex chromosomal defects (prevalence ratio, 57.4; 95% confidence interval, 23.7-138.6) were at the highest risk for MR. Children with nonchromosomal defects, including central nervous system defects and all types of organ and system defects, were at substantially increased risk for all levels of MR. Risks of MR among children with Down syndrome and nonchromosomal defects were not substantially altered when adjusted for individual and maternal factors.Children with chromosomal and other structural birth defects are at a substantially increased risk for having MR by 7 years of age compared with children born without a birth defect. Children with birth defects are at an especially increased risk for having severe MR and MR occurring independently of other developmental disabilities.

  View details for Web of Science ID 000183408900007

  View details for PubMedID 12796234

• Food fortification with folic acid and twinning among California infants AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shaw, G. M., Carmichael, S. L., Nelson, V., Selvin, S., Schaffer, D. M. 2003; 119A (2): 137-140

  Abstract

  This study sought to determine whether a change in twinning prevalence was associated with mandatory folic acid fortification. As of January 1998, it became mandatory in the United States that grain products be fortified with folic acid. The effectiveness of this fortification for neural tube defects has been explored, but other possible implications of fortification has not. We computed the prevalence of twinning among more than 2.5 million California births occurring from 1990 to 1999. The prevalence of twin births in California increased over the last decade with increases observed among most maternal race/ethnic, age, and parity groupings. Unadjusted prevalence measures did not reveal substantial increases in twinning prevalence among these groupings after the fortification period relative to the period immediately preceding it. Analyses that simultaneously adjusted for age, parity, race/ethnicity, sexes of twin pair (as a measure of zygosity), year of birth, and fortification period also did not reveal an association between fortification and twinning. Our results do not suggest a change in twinning prevalence associated with folic acid fortification of the US food supply among women delivering in California.

  View details for DOI 10.1002/ajmg.a.20145

  View details for Web of Science ID 000182930600006

  View details for PubMedID 12749051

• Fertility treatments and craniosynostosis: California, Georgia, and Iowa, 1993-1997 PEDIATRICS Reefhuis, J., Honein, M. A., Shaw, G. M., Romitti, P. A. 2003; 111 (5): 1163-1166

  Abstract

  Craniosynostosis, a malformation caused by premature closure of 1 or more cranial sutures, is a rare birth defect usually of unknown cause; however, it is often associated with advanced maternal age. Because fertility treatments are also associated with increased maternal age, this study investigated the possible association between fertility treatments and craniosynostosis.Data from the Birth Defect Risk Factor Surveillance study were used, which included infants who were delivered from 1993 through 1997 in California, Georgia, and Iowa. Cases were defined as infants who had nonfamilial, nonsyndromic craniosynostosis and were ascertained through existing birth defect surveillance systems. Controls, infants without birth defects, were selected from the same regions and time period.Mothers of 99 case infants and 777 control infants from the 3 study locations participated in this study by completing a telephone interview. Unadjusted analyses showed associations with craniosynostosis for mothers who had used clomiphene citrate (odds ratio[OR]: 3.8; 95% confidence interval [CI]: 1.1-12.3), artificial insemination (OR: 4.2; 95% CI: 0.8-9.4), or assisted reproductive techniques (OR: 4.2; 95% CI: 0.5-27.3).This is the first study that has found associations between fertility treatments and craniosynostosis. However, the numbers are small; therefore, the results should be viewed with caution.

  View details for Web of Science ID 000182579700008

  View details for PubMedID 12728131

• Maternal occupational chemical exposures and biotransformation genotypes as risk factors for selected congenital anomalies AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Nelson, V., Iovannisci, D. M., Finnell, R. H., Lammer, E. J. 2003; 157 (6): 475-484

  Abstract

  In a case-control study using an assessment of occupational tasks by an industrial hygienist, the authors investigated whether women's occupational exposures increased risks of delivering infants with cleft palate (CP), cleft lip with or without cleft palate (CLP), conotruncal defects, or limb deficiencies. For CP and CLP, exposures were further considered in the presence/absence of infant genetic variants for glutathione-S-transferase M1, glutathione-S-transferase T1, and N-acetyltransferases 1 and 2. The study included 1987-1989 California stillbirths and livebirths. Telephone interviews were conducted with mothers of 662 CLP and CP cases, 207 conotruncal defect cases, 165 limb deficiency cases, and 734 nonmalformed controls. Occupational tasks were assigned to a priori-defined exposure categories: 74 chemical groups and nine "end-use" chemical groups. Odds ratios of 1.5 or greater were observed for a small number of exposure-defect comparisons. Risks associated with end-use groups revealed odds ratios of 1.5 or greater for exposures to dyes and pigments (conotruncal and CP), propellants (CP), and insecticides (conotruncal and CP). Numerous odds ratios of 2.5 or greater were observed for combined effects of exposures and homozygous mutant genotypes, particularly for CP. Although potential associations were observed, most results suggested that maternal occupational chemical exposures did not contribute substantially to the occurrence of these anomalies in this California population.

  View details for Web of Science ID 000181611600001

  View details for PubMedID 12631536

• Evaluation of infant methylenetetrahydrofolate reductase genotype, maternal vitamin use, and risk of high versus low level spina bifida defects BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Volcik, K. A., Shaw, G. M., Lammer, E. J., Zhu, H. P., Finnell, R. H. 2003; 67 (3): 154-157

  Abstract

  Several studies have suggested that homozygosity for the C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) variant is a potential risk factor for neural tube defects (NTDs), as individuals homozygous for the C677T allele have slightly elevated homocysteine concentrations under conditions of low folic acid intake. It has been hypothesized that maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme.Genomic DNA was extracted from newborn screening blood spots obtained from 145 infants with spina bifida (SB) and 260 nonmalformed control infants. The MTHFR C677T genotype was determined by restriction enzyme digestion of PCR amplification products with Hinf1. We investigated whether infant MTHFR genotype influenced the risk for the anatomic level of the SB lesion (high vs. low); we also explored whether maternal vitamin use influenced this risk.Compared to controls, the frequency of SB infants with the homozygous 677 TT genotype was greatest in those infants with high level SB defects (26%; odds ratio [OR] = 2.9; 95% confidence interval [CI] = 0.9-10.1) than for those with low level SB defects (22%; OR = 1.8; 95% CI = 0.9-3.2). Furthermore, homozygous 677TT infants whose mothers did not use vitamins containing folic acid had a modestly increased risk of SB (OR = 1.8; 95% CI = 0.8-3.9), with this risk increasing more than three-fold (OR = 5.5; 95% CI = 0.8-28.1) for those infants with high level SB defects whose mothers did not use vitamins.Based upon our observations, it is suggested that the association between the infant MTHFR homozygous variant genotype and spina bifida risk may be conditional upon both lesion level and maternal vitamin use.

  View details for DOI 10.1002/bdra.10008

  View details for Web of Science ID 000185286600002

  View details for PubMedID 12797455

• Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects MOLECULAR GENETICS AND METABOLISM Zhu, H. P., Wicker, N. J., Shaw, G. M., Lammer, E. J., Hendricks, K., Suarez, L., Canfield, M., Finnell, R. H. 2003; 78 (3): 216-221

  Abstract

  Folic acid supplementation can effectively reduce the risk of neural tube defects (NTDs); however, the mechanism underlying this beneficial effect remains unclear. Recent evidence suggests that certain folate pathway genes, as well as those related to homocysteine metabolism might be contributing to this effect. The purpose of this study is to investigate whether gene polymorphisms of methionine synthase (MTR) and methionine synthase reductase (MTRR) are involved in the risk for NTDs, specifically spina bifida. We detected MTR A2756G and MTRR A66G polymorphisms using PCR-RFLP analysis in a group of NTD infants, their mothers and normal controls. We found that infants with the MTRR mutant genotype had a 2.6-fold higher risk of NTDs when compared to the AA genotype (OR = 2.6, 95%CI = 1.3-5.3). Mothers with the MTRR mutant genotype also had a 1.9-fold higher risk of having an NTD baby compared to AA genotype (OR = 1.9, 95%CI = 1.1-3.1). Infants who carry mutant alleles for both MTRR and MTR had exceptionally elevated NTD risks, with odds ratios of 5.1 compared to infants with the wild type genotype at both loci (AA + AA) (OR = 5.1, 95%CI = 1.7-15.4). A comparable result was observed in the mothers of NTD cases (OR = 2.1, 95%CI = 1.0-4.7). Our results indicate that MTRR and MTR genes may interact to increase the infants' NTD risks. These results did not appear to be influenced by maternal periconceptional folic acid intake. However,the sample size of this study was limited, and a larger population study is needed to pursue these initial observations.

  View details for DOI 10.1016/S1096-7192(03)00008-8

  View details for Web of Science ID 000181975800007

  View details for PubMedID 12649067

• Diet quality and risk of neural tube defects MEDICAL HYPOTHESES Carmichael, S. L., Shaw, G. M., Selvin, S., Schaffer, D. M. 2003; 60 (3): 351-355

  Abstract

  Many studies have examined the impact of single nutrients on neural tube defect (NTD) risk, particularly folate. The impact of dietary patterns or nutrients in combination has received much less attention. This study examines the association of diet quality with NTD risk, using food frequency data from a population-based case-control study of NTDs (n=454 cases and 462 controls). The diet quality score was based on low (<10th percentile among controls) versus high (>90th percentile) values for intakes of iron, vitamins B(6) and A, calcium, folate, and percentage of kilocalories from fat and from sweets (range=0-14). Women with a low score (i.e., <4, or <10th percentile) had an elevated risk of an NTD-affected pregnancy (odds ratio 1.6, 95% CI 1.0-2.6). Stratified analyses suggested that the effect may be restricted to certain groups of women who may be at greater nutritional risk (i.e., women who did not take vitamin supplements or regularly consume breakfast cereals before pregnancy).

  View details for DOI 10.1016/S0306-9877(02)00402-4

  View details for Web of Science ID 000181152100012

  View details for PubMedID 12581611

• Trihalomethane exposures from municipal water supplies and selected congenital malformations EPIDEMIOLOGY Shaw, G. M., Ranatunga, D., Quach, T., Neri, E., Correa, A., Neutra, R. R. 2003; 14 (2): 191-199

  Abstract

  Concerns about potential health effects of trihalomethanes (THMs) have prompted investigations on whether infants whose mothers were periconceptionally exposed to drinking water containing THMs are at greater risk of congenital malformations.We used two large case-control maternal interview studies that were conducted among California deliveries from 1987 through 1991. One study comprised 538 infants/fetuses with neural tube defects (NTDs) and 539 nonmalformed control infants. The second study included an additional 265 infants with NTDs, 207 infants with conotruncal heart defects, 409 infants with orofacial clefts, and 481 control infants. Expert personnel from municipal water companies estimated THM levels for a particular residence and specific periconceptional time period using quarterly monitoring measurements. Estimates were also made for four individual THM levels and for the total THM level.NTD risk in the first study was inversely associated with total THM exposure. Although the second study did not show the same inverse relationship for NTDs, there were no positive associations of NTDs or the other malformations with total THM as estimated from continuous models. Elevated risks were observed for the lowest category of exposure (1-24 ppb), but risks were either not substantially elevated or were imprecise for higher exposure levels. Thus no evidence was observed for an exposure-response relation.Our results do not provide a clear pattern of association between THM exposure and risks of specific congenital malformations. Imprecise exposure measures coupled with a lack of information about other possible sources of THM exposure may have caused associations to be underestimated.

  View details for Web of Science ID 000181174300012

  View details for PubMedID 12606885

• Social networks and risk of neural tube defects EUROPEAN JOURNAL OF EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M., Neri, E., Schaffer, D. M., Selvin, S. 2003; 18 (2): 129-133

  Abstract

  The contribution of social support and social networks to risk of neural tube defects (NTDs) has not been explored, despite evidence that various aspects of the social environment contribute to their etiology. Using data from a population-based case-control study of deliveries occurring in California from 1989 to 1991, this study investigates whether social networks, as measured by the presence and frequency of various types of social contacts, are associated with NTD risk. In-person interviews were conducted with 538 (88% of eligible) mothers of NTD cases and with mothers of 539 non-malformed controls (88%) on average 5 months from the term delivery date. Unadjusted results indicate that women who reported having close friends, close relatives, or monthly contacts with close friends or relatives had 30-70% lower risks of having NTD-affected pregnancies, relative to women reporting 'none' to any of these measures. Only the presence of close friends was associated with reduced NTD risk after adjustment for other aspects of the social network and several potential covariates. This study is the first to investigate the association between social networks and risk of NTDs. Stronger inferences await replication and extension of these results.

  View details for Web of Science ID 000182005200006

  View details for PubMedID 12733834

• Timing of prenatal care initiation and risk of congenital malformations TERATOLOGY Carmichael, S. L., Shaw, G. M., Nelson, V. 2002; 66 (6): 326-330

  Abstract

  Although previous studies provide some evidence that timing of prenatal care initiation is associated with risks of congenital malformation, the issue has not previously been examined in depth. This study uses data from a large population-based registry to explore the association of timing of prenatal care initiation with risks of selected congenital malformation phenotypes.Data on cases were grouped according to four-digit malformation codes of the International Classification of Diseases, Ninth Revision (ICD-9). A randomly selected group of 10,000 nonmalformed deliveries served as the comparison group. Information on month of initiation of prenatal care (categorized as during months 1-3 of gestation, months 4-7, or after month 7) and other maternal characteristics were derived from vital statistics data.Among the 176 four-digit ICD groupings, 67 had an adjusted odds ratio for at least one of the two prenatal care categories that was either < or = 0.67 or > or = 1.50. Later prenatal care initiation was associated with risk > or = 1.50 for most groups. Later care was associated with risk < or = 0.67 for only two groups, and the effects were imprecise. Statistical interaction between parity and prenatal care was indicated for 13 groups (P < 0.10). Risks among women with no previous pregnancy tended to increase with later prenatal care initiation; risks among parous women tended to be somewhat weaker. In general, associations applied to a wide range of malformation groups.This is the first large-scale study of the association of timing of prenatal care initiation and congenital malformation risks. Further defining the phenomena that surround prenatal care as a marker may help clarify the etiologies of a variety of malformations.

  View details for DOI 10.1002/tera.10117

  View details for Web of Science ID 000180093600010

  View details for PubMedID 12486766

• Maternal periconceptional vitamins: Interactions with selected factors and congenital anomalies? EPIDEMIOLOGY Shaw, G. M., Nelson, V., Carmichael, S. L., Lammer, E. J., Finnell, R. H., Rosenquist, T. H. 2002; 13 (6): 625-630

  Abstract

  The mechanisms by which folic acid may contribute to reductions in risk of several congenital anomalies are unknown. The data gap includes a lack of information on possible effect modification between maternal folic acid use and other maternal exposures. We hypothesized that effects of congenital anomalies associated with maternal fever, cigarette smoking or alcohol use would be modified by intake of vitamins.We explored case-control data that showed risk reductions among infants and fetuses whose mothers consumed vitamins. Data were from California deliveries of infants and fetuses in the period 1987-1989. Maternal telephone interviews were completed for 207 (87%) conotruncal cases, 489 (85%) orofacial cleft cases, 265 (84%) neural tube defect cases, 165 (82%) limb anomaly cases, and 734 controls (nonmalformed infants).Considering women who reported vitamin use and no periconceptional fever as referents, for each anomaly group we observed elevated effects for the combinations of maternal vitamin use/fever, no use/no fever and no use/fever. Effects were most elevated for the combination of no vitamin use and fever. Adjusted for maternal body mass index, education and race/ethnicity, odds ratios were 2.4 (95% confidence inter-val = 1.0-5.9) for conotruncal defects, 2.9 (1.4-5.8) for cleft lip with or without cleft palate, 1.3 (0.4-3.9) for cleft palate, 3.1 (1.4-6.8) for neural tube defects, and 2.6 (1.0-6.4) for limb-deficiency defects. These interactions were further investigated relative to maternal use of fever-reducing medications. Effects tended to be highest among those women who did not use vitamins, had fevers, and did not use fever-reducing medications. Compared with women who used vitamins and did not smoke periconceptionally, anomaly risks tended to be highest among women who did not use vitamins and smoked. No specific pattern emerged involving alcohol intake.These data further suggest that the underlying mechanisms of folic acid associated with congenital anomalies may be complex.

  View details for DOI 10.1097/01.EDE.0000032431.83648.8D

  View details for Web of Science ID 000178637200005

  View details for PubMedID 12410002

• Apolipoprotein E and apolipoprotein B genotypes and risk for spina bifida TERATOLOGY Volcik, K. A., Zhu, H. P., Shaw, G. M., Lammer, E. J., Finnell, R. H. 2002; 66 (5): 257-259

  Abstract

  Altered cholesterol metabolism and defects in cholesterol biosynthesis may influence abnormal central nervous system (CNS) development. During early stages of embryonic development, high levels of cholesterol are needed by rapidly proliferating cells that utilize cholesterol as a key cell membrane component. Alterations in cholesterol levels are influenced by variations in the apolipoprotein E (apoE) and apolipoprotein B (apoB) genes. The purpose of our study was to explore the possible association between infant genetic variations in the apoE and apoB genes and spina bifida (SB) risk.Genomic DNA was extracted from newborn screening blood spots obtained from 26 infants with SB and 73 non-malformed control infants. ApoE and apoB genotypes were determined by restriction enzyme digestion of PCR amplification products.Genotype frequencies for the apoE and apoB polymorphisms were not statistically different between case and control infants. For each apoB polymorphism, however, the frequency of the wild-type allele was higher in SB infants as compared to controls. Additionally, the apoE genotype E2/E3 was observed more frequently in the controls than in SB infants [15% in controls compared to 4% in cases; OR = 0.2 (0-1.6)].Results from this study suggest that genetic variations in the apoE and apoB genes, known to regulate cholesterol metabolism, do not substantially contribute to the risk of SB in infants.

  View details for DOI 10.1002/tera.10097

  View details for Web of Science ID 000178997500011

  View details for PubMedID 12397634

• Paternal occupational group and risk of offspring with neural tube defects PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Shaw, G. M., Nelson, V., Olshan, A. F. 2002; 16 (4): 328-333

  Abstract

  Selected paternal occupations as well as specific occupational exposures to chemicals such as organic solvents have been suggested as possible risk factors for neural tube defects (NTD). We investigated data from a population-based, case-control study of fetuses and liveborn infants with NTDs among 1989-91 California births and fetal deaths. Interviews were conducted with mothers of 538 NTD cases and 539 non- malformed controls. Mothers were asked to report the occupations that the fathers had in the period 3 months before and 3 months after conception. Each job title and industry reported was coded in accordance with the 1990 US Census. Considering those fathers who worked in managerial and professional occupations as the reference group, elevated odds ratios (OR) for NTDs were observed for the categories: technical, sales and administrative, OR = 1.5 [95% confidence interval 1.0, 2.4]; service, OR = 2.0 [1.2, 3.1]; farming, forestry and fishing, OR = 2.1 [1.3, 3.3]; operators, fabricators and labourers, OR = 1.8 [1.2, 2.7]; and military, OR = 1.9 [0.7, 5.0]. Stratification by NTD phenotype revealed that these elevated ORs were primarily observed for spina bifida phenotypes. Analyses adjusted for maternal body mass index, maternal periconceptional use of multivitamins containing folic acid, paternal race/ethnicity, maternal race/ethnicity and maternal education revealed attenuated risk estimates for most of the occupational groups. Analyses of 182 more specific occupational groups defined by aggregating fathers on similar job titles, when compared with fathers who worked in managerial and professional occupations, revealed that four job title groups were associated with fairly precise effect estimates of >or=1.5. These groups were: cooks; janitors and cleaners; farm workers; and groundsmen/gardeners. Using occupational titles as defined in previous investigations, we did not observe an elevated OR associated with paternal occupational solvent exposures, OR = 0.8 [0.5, 1.3]. These analyses generated potential clues regarding paternal occupational exposures as NTD risk factors. Risk variation observed by spina bifida phenotype is interesting and will need to be investigated further.

  View details for Web of Science ID 000179413600007

  View details for PubMedID 12445149

• Integration of DNA sample collection into a multi-site birth defects case-control study TERATOLOGY Rasmussen, S. A., Lammer, E. J., Shaw, G. M., Finnell, R. H., McGehee, R. E., Gallagher, M., Romitti, P. A., Murray, J. C. 2002; 66 (4): 177-184

  Abstract

  Advances in quantitative analysis and molecular genotyping have provided unprecedented opportunities to add biological sampling and genetic information to epidemiologic studies. The purpose of this article is to describe the incorporation of DNA sample collection into the National Birth Defects Prevention Study (NBDPS), an ongoing case-control study in an eight-state consortium with a primary goal to identify risk factors for birth defects.Babies with birth defects are identified through birth defects surveillance systems in the eight participating centers. Cases are infants with one or more of over 30 major birth defects. Controls are infants without defects from the same geographic area. Epidemiologic information is collected through an hour-long interview with mothers of both cases and controls. We added the collection of buccal cytobrush DNA samples for case-infants, control-infants, and their parents to this study.We describe here the methods by which the samples have been collected and processed, establishment of a centralized resource for DNA banking, and quality control, database management, access, informed consent, and confidentiality issues.Biological sampling and genetic analyses are important components to epidemiologic studies of birth defects aimed at identifying risk factors. The DNA specimens collected in this study can be used for detection of mutations, study of polymorphic variants that confer differential susceptibility to teratogens, and examination of interactions among genetic risk factors. Information on the methods used and issues faced by the NBDPS may be of value to others considering the addition of DNA sampling to epidemiologic studies.

  View details for DOI 10.1002/tera.10086

  View details for Web of Science ID 000178375100006

  View details for PubMedID 12353214

• Physical activity and risk of neural tube defects. Maternal and child health journal Carmichael, S. L., Shaw, G. M., Neri, E., Schaffer, D. M., Selvin, S. 2002; 6 (3): 151-157

  Abstract

  Owing to its association with known risk factors for neural tube defects (NTDs) and its impact on physiologic processes relevant to fetal development, physical activity was identified as a potential risk factor for NTD-affected pregnancy.Using data from a population-based case-control study of deliveries occurring in California from 1989 to 1991, we estimated the potential risk of having an NTD-affected pregnancy associated with variation in maternal physical activity. In-person interviews were conducted with 538 (88% of eligible) mothers of NTD cases and with mothers of 539 (88%) nonmalformed controls on average 5 months from the term delivery date. An index reflecting reported frequency and exertion level for six activity groups (e.g., jogging and running) was used to summarize each woman's physical activity level in the periconceptional period.Unadjusted analyses indicated that compared to women considered inactive by this index, physically active women had 30-50% lower risk for NTD-affected pregnancies. After adjustment for several potential confounders and an evaluation of potential effect modification, results suggested that the association was restricted to women who did not take multivitamin/mineral supplements during the periconceptional period. Excluding mothers with reported medical problems did not substantially alter findings.This study suggests that the benefits of physical activity may extend to reduction of NTD risk among certain subgroups of women.

  View details for PubMedID 12236662

• Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States TERATOLOGY Williams, L. J., Mai, C. T., Edmonds, L. D., Shaw, G. M., Kirby, R. S., Hobbs, C. A., Sever, L. E., Miller, L. A., Meaney, F. J., Levitt, M. 2002; 66 (1): 33-39

  Abstract

  In 1992, the United States Public Health Service recommended that all women of childbearing age consume 400 microg of folic acid daily. The Food and Drug Administration authorized the addition of synthetic folic acid to grain products in March 1996 with mandatory compliance by January 1998. The impact of these public health policies on the prevalence of neural tube defects needs to be evaluated. We sought to determine the prevalences of spina bifida and anencephaly during the transition to mandatory folic acid fortification.Twenty-four population-based surveillance systems were used to identify 5,630 cases of spina bifida and anencephaly from 1995-99. Cases were divided into three temporal categories depending on whether neural tube development occurred before folic acid fortification (January 1995 to December 1996), during optional fortification (January 1997 to September 1998), or during mandatory fortification (October 1998 to December 1999). Prevalences for each defect were calculated for each time period. Data were also stratified by programs that did and did not ascertain prenatally diagnosed cases.The prevalence of spina bifida decreased 31% (prevalence ratio [PR] = 0.69, 95% confidence interval [CI] = 0.63-0.74) from the pre- to the mandatory fortification period and the prevalence of anencephaly decreased 16% (PR = 0.84, 95% CI = 0.75-0.95). Stratification by prenatal ascertainment did not alter results for spina bifida but did impact anencephaly trends.The decline in the prevalence of spina bifida was temporally associated with folic acid fortification of US grain supplies. The temporal association between fortification and the prevalence of anencephaly is unclear.

  View details for DOI 10.1002/tera.10060

  View details for Web of Science ID 000176651400007

  View details for PubMedID 12115778

• Does prenatal screening for 5,10-methylenetetrahydrofolate reductase (MTHFR) mutations in high-risk neural tube defect pregnancies make sense? GENETIC TESTING Finnell, R. H., Shaw, G. M., Lammer, E. J., Volcik, K. A. 2002; 6 (1): 47-52

  Abstract

  Despite the fact that neural tube defects (NTDs) are the most common congenital malformations of the central nervous system, investigators have yet to identify responsible gene(s). Research efforts have been productive in the identification of environmental factors, such as periconceptional folic acid supplementation, that modulate risk for the development of NTDs. Studies of the folic acid biosynthetic pathway led to the discovery of an association between elevated levels of homocysteine and NTD risk. Researchers subsequently identified single nucleotide polymorphisms in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Association studies suggested it was a potential risk factor for NTDs, because the thermolabile form of the enzyme led to elevated homocysteine concentrations when folic acid intake is low. Numerous studies analyzing MTHFR variants have resulted in positive associations with increased NTD risk only in certain populations, suggesting that these variants are not large contributors to the etiology of NTDs. With our limited understanding of the genes involved in regulating NTD susceptibility, the paucity of data on how folic acid protects the developing embryo, as well as the observed decrease in birth prevalence of NTDs following folic acid supplementation and food fortification, it makes little sense for prospective parents to be tested for MTHFR variants, or for variants of other known folate pathway genes.

  View details for Web of Science ID 000176105200008

  View details for PubMedID 12180076

• Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida AMERICAN JOURNAL OF MEDICAL GENETICS Shaw, G. M., Lammer, E. J., Zhu, H. P., Baker, M. W., Neri, E., Finnell, R. H. 2002; 108 (1): 1-6

  Abstract

  Women who consume folic acid in early pregnancy reduced their risks for delivering offspring with neural tube defects (NTDs). The underlying process by which folic acid facilitated this risk reduction is unknown. Investigating genetic variation that influences cellular absorption, transport, and metabolism of folate will help fill this data gap. We focused our studies on a candidate gene that is involved in folate transport, the reduced folate carrier 1 (RFC1). Using data from a California population-based case control interview study (1989-1991 birth cohorts), we investigated whether spina bifida risk was influenced by an interaction between a polymorphism of infant RFC1 at nucleotide 80 (A80G) and maternal periconceptional use of vitamins containing folic acid. Allelic variants of RFC1 were determined by genotyping 133 live-born spina bifida case infants and 188 control infants. The percentages of case infants with the A80/A80, G80/G80, and G80/A80 genotypes were 27.2%, 28.0%, and 44.7%, respectively. The percentages of control infants were similar: 26.1%, 29.3%, and 44.7%. Odds ratios of 1.0 (95% confidence interval 0.5-2.0) for the G80/G80 genotype and 1.1 (0.6-2.0) for the G80/A80 genotype were observed relative to the A80/A80 genotype. Among mothers who did not use vitamins, spina bifida risk was 2.4 (0.8-6.9) for infants with genotype G80/G80 compared to those with A80/A80 genotype. Among mothers who did use vitamins, the risk was 0.5 (0.1-3.1) for infants with the G80/G80 genotype. Although this study did not find an increased spina bifida risk for infants who were heterozygous or homozygous for RFC1 A80G, it did reveal modest evidence for a gene-nutrient interaction between infant homozygosity for the RFC1 G80/G80 genotype and maternal periconceptional intake of vitamins containing folic acid on the risk of spina bifida.

  View details for Web of Science ID 000173503500001

  View details for PubMedID 11857541

• Analysis of the EPHX1 113 polymorphism and GSTM1 homozygous null polymorphism and oral clefting associated with maternal smoking AMERICAN JOURNAL OF MEDICAL GENETICS Hartsfield, J. K., Hickman, T. A., Everett, E. T., Shaw, G. M., Lammer, E. J., Finnell, R. A. 2001; 102 (1): 21-24

  Abstract

  Maternal cigarette smoking during the first trimester of pregnancy is associated with an increased risk of having a child with an oral cleft. Compounds present in cigarette smoke undergo bioactivation and/or detoxication. Phase I of this process results in the formation of reactive epoxides, which can form DNA adducts initiating and promoting mutagenesis, carcinogenesis, or teratogenesis. Microsomal epoxide hydrolase (mEH; gene symbol EPHX1) catalyzes hydrolysis of epoxides. Phase II involves attachment of a moiety (e.g., glutathione) to the compound mediated by a variety of enzymes, including glutathione S-transferase, generally resulting in a decreased reactivity. Recent studies suggest an association between the EPHX1 codon 113 polymorphism or homozygous null GSTM1 allele and the risk of carcinogenesis, emphysema, phenytoin-associated oral clefting, and the risk of spontaneous abortion. This study explores the association between EPHX1 codon 113 and homozygous null GSTM1 genotypes and oral clefting among infants whose mothers smoked during pregnancy. Case infants were diagnosed with isolated cleft lip with or without cleft palate (CL/P). EPHX1 codon 113 allelotyping was performed on 195 samples (85 cases, 110 controls) by PCR/RFLP analysis. 130 samples (79 cases, 51 controls) were tested for the GSTM1 homozygous null genotype using PCR. Using the odds ratio as a measure of association, we did not observe elevated risks of CL/P associated with either allelic comparison. This suggests that when mothers smoke periconceptionally, their infants having these alleles at either (or both) loci were not at substantially increased risk for CL/P compared to infants with the wild-type alleles.

  View details for Web of Science ID 000169706400004

  View details for PubMedID 11471167

• Role of structural birth defects in preterm delivery PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Shaw, G. M., Savitz, D. A., Nelson, V., Thorp, J. M. 2001; 15 (2): 106-109

  Abstract

  The proportion of preterm births associated with structural birth defects has not been adequately quantified. We explored the proportion of preterm infants with structural birth defects diagnosed in the first year of life, as well as the specific phenotypes of birth defects occurring among preterm infants. The data used were from the California Birth Defects Monitoring Program, a population-based registry, as well as data from California vital records corresponding to births and fetal deaths in the period 1984-96. The prevalence of structural birth defects exceeded 8% among deliveries with gestational ages < or = 30 weeks, and prevalence decreased to 2% as gestational age increased to > or = 37 weeks gestation. The decreasing prevalence pattern with increasing gestational age was observed for a variety of anatomically defined birth defect groups suggesting that certain birth defects were not the sole contributors to the elevated prevalences among preterm births. Decreasing prevalence with increasing gestational age was also observed across strata of maternal race/ethnicities, ages, infant's sex and each year studied. These data indicate that structural birth defects may contribute significantly to the proportion of infants who are delivered before 37 weeks gestation.

  View details for Web of Science ID 000168980500003

  View details for PubMedID 11383574

• Maternal exposure to nitrate from drinking water and diet and risk for neural tube defects AMERICAN JOURNAL OF EPIDEMIOLOGY Croen, L. A., Todoroff, K., Shaw, G. M. 2001; 153 (4): 325-331

  Abstract

  In this population-based case-control study conducted in California between June 1989 and May 1991, the authors investigated the association between maternal periconceptional exposure to nitrate from drinking water and diet and risk for neural tube defects. The mothers of 538 cases and 539 nonmalformed controls were interviewed regarding residential history, consumption of tap water at home, and dietary intake during the periconceptional period. Dietary nitrate exposure was not associated with increased risk for neural tube defects. Exposure to nitrate in drinking water at concentrations above the 45 mg/liter maximum contaminant level was associated with increased risk for anencephaly (odds ratio (OR) = 4.0, 95% confidence interval (CI): 1.0, 15.4), but not for spina bifida. Increased risks for anencephaly were observed at nitrate levels below the maximum contaminant level among groundwater drinkers only (OR = 2.1, 95% CI: 1.1,4.1 for 5-15 mg/liter; OR = 2.3, 95% CI: 1.1, 4.5 for 16-35 mg/liter; and OR = 6.9, 95% CI: 1.9, 24.9 for 36-67 mg/liter compared with <5 mg/liter). Adjustment for identified risk factors for anencephaly did not substantially alter these associations, nor did control for maternal dietary nitrate, total vitamin C intake, and quantity of tap water consumed. The lack of an observed elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater may indicate that something other than nitrate accounts for these findings.

  View details for Web of Science ID 000166886400004

  View details for PubMedID 11207149

• Lowered weight gain during pregnancy and risk of neural tube defects among offspring INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Todoroff, K., Carmichael, S. L., Schaffer, D. M., Selvin, S. 2001; 30 (1): 60-65

  Abstract

  Maternal nutritional factors have been implicated in the complex aetiology of neural tube defects (NTD). We investigated whether the amount of weight a woman gained during pregnancy was associated with her risk of delivering an infant with an NTD.We conducted a population-based case-control study within the cohort of 708 129 live births and fetal deaths occurring in selected California counties in 1989-1991. Face-to-face interviews were conducted with mothers of 538 (88% of eligible) NTD cases (including those electively terminated, stillborn, or liveborn) and with mothers of 539 (88%) non-malformed liveborn controls within an average of 5 months from the term delivery date. Respondent-reported weight gain during pregnancy (kg) was analysed. Risks of infants having NTD were estimated among women who gained <10 kg compared to those who gained > or =10 kg during > or =38 week gestations.Compared to women who gained > or =10 kg, an increased risk for NTD offspring was observed among women who gained <10 kg (odds ratio [OR] = 3.2, 95% CI : 2.3-4.6). The OR was 5.0 (95% CI : 2.6-9.7) among those women who gained <5 kg during pregnancy. The increased risk was not attributable to maternal non-use of a multivitamin containing folic acid, diabetes, NTD-pregnancy history, age, race/ethnicity, education, gravidity, alcohol use, cigarette use, prepregnant obesity, low socioeconomic status, dieting, nausea, nor to lower dietary intakes of folate, zinc, energy, protein, fat, carbohydrates, and methionine. An increased risk was observed even after simultaneous adjustment for most of these factors (OR = 2.2, 95% CI : 1.2-3.8). The risk associated with gaining <10 kg was greater for anencephaly, but still elevated for spina bifida.We did not have information on weight gain during early pregnancy. Because weight gain during the relevant embryological period for NTD (first month post-conception) is relatively small and often variable, it seems less likely that elevated NTD risks indicate a causal association between lowered weight gain throughout pregnancy and abnormal development of the neural tube. It seems more likely that lowered weight gain is a consequence of carrying an NTD-affected fetus. However, what this consequence is and why risk was substantially larger for anencephaly is unknown.

  View details for Web of Science ID 000167587300019

  View details for PubMedID 11171858

• Periconceptional intake of vitamin supplements and risk of multiple congenital anomalies AMERICAN JOURNAL OF MEDICAL GENETICS Shaw, G. M., Croen, L. A., Todoroff, K., Tolarova, M. M. 2000; 93 (3): 188-193

  Abstract

  Numerous studies have reported reduced risks for a variety of single congenital anomaly phenotypes associated with maternal periconceptional use of vitamin supplements containing folic acid. Here we investigated whether periconceptional use of vitamin supplements containing folic acid by women altered their risk for delivering infants with multiple congenital anomalies (MCAs). Data were derived from a case-control study representing deliveries (fetal deaths and infants) from 2 California counties between January 1993 and July 1996. MCAs were defined as 2 or more congenital anomalies affecting more than one organ system or a major anomaly in combination with 2 minor anomalies. Controls were randomly selected from nonmalformed live-born infants. Telephone interviews were conducted with 112 (73.7% of eligible) case and 195 (78.0% of eligible) control mothers. Compared to women who did not use multivitamin supplements containing folic acid in the period 3 months before through 3 months after conception, women who used in this time period were observed to have an elevated risk to deliver fetuses or infants with MCAs, odds ratio = 2.6 (95% confidence interval 1.1-6.2). This elevated risk was not substantially altered (adjusted odds ratio = 2.9 [0.8-10.3]) by adjusting for maternal race/ethnicity, education, gravidity, body mass index, alcohol consumption, and cigarette smoking. No particular organ system seemed to be uniquely represented among the MCA fetuses and infants whose mothers used vitamin supplements. The observed elevated risk associated with maternal vitamin use is considered to be preliminary and needs to be replicated in other populations.

  View details for Web of Science ID 000087965900005

  View details for PubMedID 10925379

• Maternal height and prepregnancy body mass index as risk factors for selected congenital anomalies PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Shaw, G. M., Todoroff, K., Schaffer, D. M., Selvin, S. 2000; 14 (3): 234-239

  Abstract

  Previous studies have observed an increased risk of approximately twofold or more for neural tube defects (NTD) associated with maternal obesity before pregnancy based on a body mass index (BMI) of > 29 kg/m2. No additional maternal factor appeared substantially to influence this association. Here, we explore further the association between BMI and NTD risk by considering the separate contributions of maternal prepregnant BMI and height. We also explore whether selected congenital anomalies, in addition to NTDs, were associated with maternal height or prepregnant BMI. Data were derived from two California population-based case-control studies. One study comprised 538 NTD cases and 539 non-malformed control infants. The other study included an additional 265 NTD cases, as well as 207 conotruncal cases, 165 limb anomaly cases, 662 orofacial cleft cases and 734 non-malformed controls. Maternal interviews in both studies elicited information on maternal height and prepregnant weight. Anomaly risk was described using additive linear logistic regression models. Results revealed increasing NTD risk with increasing maternal prepregnant BMI, controlling for maternal height. These patterns were observed overall as well as for most race/ethnic groups. Increasing NTD risk for decreasing height controlling for maternal BMI was also observed in one NTD study, but was not as evident in the other. Elevated risks for increasing maternal BMI and decreasing maternal height were not observed consistently for the other studied anomalies. The mechanisms underlying the association between maternal weight, or possibly maternal height, and NTD-affected pregnancy risk are unknown. Exploration of other data sets will be needed to determine whether similar patterns of NTD risk or lack of risk for other anomalies are associated with the two maternal anthropometric variables, height and prepregnant weight.

  View details for Web of Science ID 000088859700007

  View details for PubMedID 10949215

• Spina bifida phenotypes in infants or fetuses of obese mothers TERATOLOGY Shaw, G. M., Todoroff, K., Finnell, R. H., Lammer, E. J. 2000; 61 (5): 376-381

  Abstract

  A twofold or greater risk of neural tube defect (NTD)-affected pregnancy has been associated with prepregnant obesity, where obesity was defined as body mass index (BMI) of >29 kg/m(2). Risks have been more elevated for spina bifida than for anencephaly.We investigated whether finer phenotypic classifications of spina bifida, in combination with other factors, were associated with a BMI of >29 kg/m(2). Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 277 spina bifida cases and 517 nonmalformed controls.Women with a BMI of >29 kg/m(2) compared with those 29 kg/m(2) compared with males whose mothers were

  View details for Web of Science ID 000086815900009

  View details for PubMedID 10777833

• Microsatellites proximal to leptin and leptin receptor as risk factors for spina bifida TERATOLOGY Shaw, G. M., Barber, R., Todoroff, K., Lammer, E. J., Finnell, R. H. 2000; 61 (3): 231-235

  Abstract

  Several recent studies have observed an association between neural tube defect risk and prepregnant obesity. This association was generally stronger for spina bifida and was observed irrespective of additional maternal factors, including periconceptional intake of vitamin supplements. Other studies have identified mutations within the genes that code for leptin (LEP) and its receptor (LEPR), which have been linked to obesity in mice and humans. We investigated the potential association between nucleotide variation at the LEP and LEPR loci, and increased risk of spina bifida. We searched specifically for allelic association at a pair of highly polymorphic microsatellites closely linked to either the LEP or LEPR gene. Data were derived from a population-based case-control study that had previously identified an association between a woman's prepregnant obesity and her risk of delivering an infant with spina bifida. A total of 56 spina bifida case infants and 126 nonmalformed control infants were genotyped for 10 microsatellite alleles closely linked to the LEP gene, and 49 cases and 125 controls were genotyped for 10 microsatellite alleles closely linked to the LEPR gene. In general, alleles were not observed to be exclusively associated with substantially greater spina bifida risk in the body mass index (BMI) category (obese) of >29 kg/m(2) compared with the BMI category (nonobese) of 29 kg/m; (2) having either allele and BMI 29 kg/m(2). The odds ratios (95% confidence interval) for these comparisons were: for allele 257, 4.5 (1.1-19.4), 1.9 (0.5-6.3), and 2.9 (1.3-6.4), respectively, and for allele 271, 6.7 (1.6-30.4), 2.7 (0.7-10.9), and 2.7 (1.2-5.9), respectively. Owing to the exploratory nature of this investigation, the significance of these latter results is unclear.

  View details for Web of Science ID 000085525700011

  View details for PubMedID 10661913

• Risk factors for cytogenetically normal holoprosencephaly in California: A population-based case-control study AMERICAN JOURNAL OF MEDICAL GENETICS Croen, L. A., Shaw, G. M., Lammer, E. J. 2000; 90 (4): 320-325

  Abstract

  Holoprosencephaly is a developmental field defect manifested by a spectrum of abnormalities of the forebrain and midface. Approximately 50% of holoprosencephaly cases are associated with a cytogenetic abnormality or a monogenic syndrome. Suggested risk factors for the remaining 50% of cases have been described in case reports, but have not been confirmed in systematically conducted studies. We report the results of a population-based case-control study of holoprosencephaly. Live births, fetal deaths, and terminations with a diagnosis of cytogenetically normal holoprosencephaly were identified by the California Birth Defects Monitoring Program. Telephone interviews were conducted with the mothers of 58 cases and 107 live born, nonmalformed controls. Women were questioned about their health and reproductive histories, family demographics, and exposures occurring during their pregnancies. Among nonsyndromic cases, increased risks were observed for females (OR=1.8, 95% C.I. 0.9-3.9), foreign-born vs. U.S. or Mexico-born women (OR=3.1, 95% C.I. 1.1-8.6), and women with early menarche (OR=2.3, 95% C.I. 0.9-5.7). Maternal periconceptional exposures associated with increased risks for nonsyndromic holoprosencephaly included alcohol consumption (OR=2.0, 95% C.I. 0.9-4.5), cigarette smoking (OR=4.1, 95% C.I. 1.4-12.0), and combined alcohol and smoking (OR=5.4, 95% C.I. 1.4-20.0), insulin-dependent diabetes (OR=10.2, 95% C.I. 1.9-39.4), medications for respiratory illnesses (OR=2.3, 95% C.I. 0.9-6.0), and salicylate-containing medications (OR=2.5, 95% C.I. 0.8-7.9). These findings are consistent with risk factors identified in some previous reports, and identify several new potential risk factors that require confirmation in future studies.

  View details for Web of Science ID 000085166200011

  View details for PubMedID 10710231

• Maternal life event stress and congenital anomalies EPIDEMIOLOGY Carmichael, S. L., Shaw, G. M. 2000; 11 (1): 30-35

  Abstract

  We used data from a population-based case-control study to explore the relation between certain life events during the periconceptional period and several types of congenital anomalies. We ascertained cases from pregnancies ending in 1987-1989 and randomly selected controls from eligible liveborn infants. In telephone interviews, women reported deaths of anyone close to them. They also reported job losses or separations/divorces, for themselves or anyone close to them. Experiencing at least one stressful event during the periconceptional period was associated with a prevalence odds ratio of 1.4-1.5 for the delivery of infants with conotruncal heart defects, neural tube defects, and isolated cleft lip with or without palate. These associations tended to be restricted to women who were not obese and women with less than or equal to a high school education. This study suggests that women who experience stressful life events around the time of conception or early gestation may be at increased risk of delivering infants with certain congenital anomalies.

  View details for Web of Science ID 000084316000008

  View details for PubMedID 10615840

• Genetic basis of susceptibility to environmentally induced neural tube defects. Annals of the New York Academy of Sciences Finnell, R. H., Gelineau-Van Waes, J., Bennett, G. D., Barber, R. C., Wlodarczyk, B., Shaw, G. M., Lammer, E. J., Piedrahita, J. A., Eberwine, J. H. 2000; 919: 261-277

  Abstract

  Neural tube defects (NTDs) are among the most common of all human congenital defects, with multifactorial etiologies comprising both environmental and genetic components. Several murine model systems have been developed in an effort to elucidate genetic factors regulating expression of NTDs. Strain-dependent differences in susceptibility to teratogenic insults and altered patterns of gene expression observed within the neuroepithelium of affected embryos support the hypothesis that subtle genetic changes can result in NTDs. Since several affected genes are folate-regulated, transgenic knockout mice lacking a functional folate receptor were developed. Nullizygous embryos died in utero with significant morphological defects, supporting the critical role of folic acid in early embryogenesis. While epidemiological studies have not established an association between polymorphisms in the human folate receptor gene and NTDs, it is known that folate supplementation reduces infant NTD risk. Continued efforts are therefore necessary to reveal the mechanism by which folate works and the nature of the gene(s) responsible for human NTDs.

  View details for PubMedID 11083116

• Maternal corticosteroid use and risk of selected congenital anomalies AMERICAN JOURNAL OF MEDICAL GENETICS Carmichael, S. L., Shaw, G. M. 1999; 86 (3): 242-244

  Abstract

  Evidence for the teratogenicity of corticosteroids in humans is limited and has resulted in inconsistent recommendations regarding their use during early pregnancy. We examined the association between women's corticosteroid use during the periconceptional period (1 month before to 3 months after conception) and delivering infants with selected congenital anomalies. Data were derived from a population-based case-control study that included cases of orafacial clefts (n = 662), conotruncal heart defects (n = 207), neural tube defects (n = 265), and limb reduction defects (n = 165). Information on medication use was collected via maternal telephone interviews. Corticosteroid use was associated with an increased risk for isolated cleft lip with or without cleft palate (odds ratio 4.3, 95% confidence interval 1.1-17.2) and isolated cleft palate (odds ratio 5.3, 95% confidence interval 1.1-26.5). Increased risks were not observed for the other anomaly groups studied. These data in conjunction with other epidemiologic data suggest a possible causal association between cleft lip and palate and corticosteroid use.

  View details for Web of Science ID 000082714300009

  View details for PubMedID 10482873

• Maternal supplemental and dietary zinc intake and the occurrence of neural tube defects in California AMERICAN JOURNAL OF EPIDEMIOLOGY Velie, E. M., Block, G., Shaw, G. M., Samuels, S. J., Schaffer, D. M., Kulldorff, M. 1999; 150 (6): 605-616

  Abstract

  The authors investigated the association between maternal preconceptional supplemental and dietary zinc intake and risk of neural tube defects (NTDs) in a population-based case-control study conducted between 1989 and 1991 in California. Cases were 430 NTD-affected fetuses/infants, and controls were 429 randomly selected non-malformed infants. Mothers reported their preconceptional use of vitamin, mineral, and food supplements, and completed a 98-item food frequency questionnaire. Increased total preconceptional zinc intake was associated with a reduced risk for NTDs (quintile 5 vs. quintile 1, odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.43, 0.99). Phytate intake, a constituent of the diet known to impede zinc absorption, appeared to modify the zinc - NTD association. In addition, increased servings of animal products, the most bioavailable food source of zinc, was associated with a reduced risk for NTDs (quintile 5 vs. quintile 1, OR = 0.49, 95% CI 0.32, 0.76). Risk estimates for zinc intake were changed little after controlling for multiple sociodemographic factors and total folate intake, but were attenuated after controlling for nutrients highly correlated with dietary sources of zinc, such as protein. In sum, the analyses indicate that risk of NTDs in infants and fetuses decreased with increasing maternal preconceptional zinc intake. However, it remains unclear whether increased zinc intake, or another nutrient or combination of nutrients highly correlated with zinc intake in the diet, is causally associated with reduced NTD risk.

  View details for Web of Science ID 000082602300009

  View details for PubMedID 10490000

• Maternal periconceptional use of electric bed-heating devices and risk for neural tube defects and orofacial clefts TERATOLOGY Shaw, G. M., Nelson, V., Todoroff, K., Wasserman, C. R., Neutra, R. R. 1999; 60 (3): 124-129

  Abstract

  Electric and magnetic fields are of concern as risk factors for adverse reproductive outcomes, including congenital anomalies. Among residential exposures to electric and magnetic fields, electric bed-heating devices such as electric blankets may be a substantial source of such exposures, and their use is fairly common. Two population-based case-control studies were analyzed to investigate whether the periconceptional use of electric blankets, bed warmers, or electrically heated waterbeds increased the risk of women to deliver infants or fetuses with neural tube defects (NTDs) or orofacial clefts. We obtained information on bed-heating devices from 538 NTD cases and their 539 controls in one study, and 265 NTD cases and 481 controls and 652 orofacial cleft cases and their 734 controls from another study. Our results revealed a few modestly elevated risks of certain anomaly phenotypes with maternal use of certain bed-heating devices, but risks tended to be imprecise. In general, women who reported more frequent use of a bed-heating device, or longer duration of use, did not appear to have a higher risk for delivering offspring with anomalies than were women who reported less frequent or shorter-duration use.

  View details for Web of Science ID 000082421200006

  View details for PubMedID 10471895

• The effect of congenital anomalies on mortality risk in White and Black infants AMERICAN JOURNAL OF PUBLIC HEALTH Malcoe, L. H., Shaw, G. M., Lammer, E. J., Herman, A. A. 1999; 89 (6): 887-892

  Abstract

  This population-based study examined the effect of all major congenital anomalies on the mortality of White and Black infants by infant sex, birthweight, gestational age, and lethality of the anomaly. The study also determined the total contribution of anomalies to infant mortality.California Birth Defects Monitoring Program data were merged with linked birth-death files for 278,646 singleton non-Hispanic White and Black infants born in 1983 through 1986. Malformed infants were compared with nonmalformed infants to determine the effect of anomalies on mortality.The presence of any congenital anomaly increased mortality 9.0-fold (95% CI = 7.3, 11.1) for Black infants and 17.8-fold (95% CI = 16.2, 19.6) for White infants. Even "non-lethal" anomalies increased mortality up to 8.9-fold. Overall, anomalies contributed to 33% of White infant deaths, to 19% of Black infant deaths, and to over 60% of deaths among Black and White neonates weighing over 1499 g.The contribution of congenital anomalies to mortality of both low- (< 2500 g) and normal-birth-weight infants is substantially higher than previously estimated, representing a large public health problem for both Black and White infants.

  View details for Web of Science ID 000080548000015

  View details for PubMedID 10358680

• Maternal periconceptional alcohol consumption and risk for orofacial clefts JOURNAL OF PEDIATRICS Shaw, G. M., Lammer, E. J. 1999; 134 (3): 298-303

  Abstract

  To investigate whether periconceptional maternal alcohol consumption increased the risk of delivering infants with orofacial cleft phenotypes.Data were derived from a large population-based case control study of fetuses and infants among a cohort of California births from 1987 to 1989 (n = 548,844). Information concerning alcohol consumption was obtained by telephone interviews with mothers of 731 infants (84.7% of eligible) with orofacial clefts and of 734 (78.2%) infants in a nonmalformed control group.Thirty-nine percent of mothers in the case group and 42% of mothers in the control group reported that they consumed alcohol during the period 1 month before through 3 months after conception. Relative to nonconsumers, women who reported alcohol consumption (/=5 drinks per drinking occasion compared with those who did not, we observed increased risks for isolated (no other major congenital anomaly) cleft lip with or without cleft palate, odds ratio = 3.4 (95% confidence interval, 1.1 to 9.7); multiple cleft lip with or without cleft palate, odds ratio = 4.6 (1. 2 to 18.8); and "known syndrome" clefts, odds ratio = 6.9 (1.9 to 28. 6). Adjustment for maternal cigarette smoking, race, education, or vitamin use did not substantially change observed risks.We observed a lack of increased risks of clefts for relatively low quantities of maternal alcohol consumption and increased risks of clefts for higher quantities of maternal alcohol consumption.

  View details for Web of Science ID 000078985800011

  View details for PubMedID 10064665

• Maternal occupational and hobby chemical exposures as risk factors for neural tube defects EPIDEMIOLOGY Shaw, G. M., Velie, E. M., Katz, E. A., Morland, K. B., Schaffer, D. M., Nelson, V. 1999; 10 (2): 124-129

  Abstract

  In a case-control study, we investigated whether occupational and nonoccupational (hobbies) chemical exposures to women in the periconceptional period increased their risk for having neural tube defect-affected pregnancies. Women were asked about occupational tasks and hobbies performed during the 3 months before through 3 months after conception. Based on her reported occupational tasks and hobbies, an industrial hygienist assigned a priori defined exposure categories to each task and hobby. The exposure categories included 74 chemical groups, 9 "end-use" chemical groups, and organic solvents. Face-to-face interviews were conducted with mothers of 538 (88% of eligible) infants or fetuses with neural tube defect and mothers of 539 (88%) randomly selected, nonmalformed, live-born infants from a population-based 1989-1991 cohort of California births (N = 703,518). Our results suggested that maternal exposures in the periconceptional period to a variety of chemicals associated with occupational and nonoccupational activities did not contribute substantially to risk of neural tube defects in offspring. We observed no effect estimate greater than 2.0 for maternal exposures to the chemical agent groups studied. We did not observe substantially elevated risks associated with maternal exposures to any of the end-use chemical groups or to organic solvents. Considering occupational exposures only among women who worked did not substantially alter results. Adjustment for maternal vitamin use, race/ethnicity, or education level also did not substantially alter the observed associations.

  View details for Web of Science ID 000078746100007

  View details for PubMedID 10069246

• Maternal pesticide exposure from multiple sources and selected congenital anomalies EPIDEMIOLOGY Shaw, G. M., Wasserman, C. R., O'Malley, C. D., Nelson, V., Jackson, R. J. 1999; 10 (1): 60-66

  Abstract

  We explored the relation between various potential sources of maternal periconceptional pregnancy exposures to pesticides and congenital anomalies in offspring. Data were derived from a case-control study of fetuses and liveborn infants with orofacial clefts, neural tube defects, conotruncal defects, or limb anomalies, among 1987-1989 California births and fetal deaths. We conducted telephone interviews with mothers of 662 (85% of eligible) orofacial cleft cases, 265 (84%) neural tube defect cases, 207 (87%) conotruncal defect cases, 165 (84%) limb cases, and 734 (78%) nonmalformed controls. The odds ratio (OR) estimates did not indicate increased risk for any of the studied anomaly groups among women whose self-reported occupational tasks were considered by an industrial hygienist likely to involve pesticide exposures. Paternal occupational exposure to pesticides, as reported by the mother, revealed elevated ORs for only two of the cleft phenotypes [OR = 1.7 [95% confidence interval (CI) = 0.9-3.4] for multiple cleft lip with/without cleft palate and OR = 1.6 [95% CI = 0.7-3.4] for multiple cleft palate]. Use of pesticide products for household gardening, by mothers or by professional applicators, was associated with ORs > or =1.5 for most of the studied anomalies. Use of pesticide products for the control of pests in or around homes was not associated with elevated risks for most of the studied anomalies, although women who reported that a professional applied pesticides to their homes had increased risks for neural tube defect-affected pregnancies [OR = 1.6 (95% CI = 1.1-2.5)] and limb anomalies [OR = 1.6 (95% CI = 1.0-2.7)]. Having a pet cat or dog and treating its fleas was not associated with increased anomaly risk. Women who reported living within 0.25 miles of an agricultural crop revealed increased risks for offspring with neural tube defects [OR = 1.5 (95%CI = 1.1-2.1)]. For many of the comparisons, data were sparse, resulting in imprecise effect estimation. Despite our investigating multiple sources of potential pesticide exposures, without more specific information on chemical and level of exposure, we could not adequately discriminate whether the observed effects are valid, whether biased exposure reporting contributed to the observed elevated risks, or whether nonspecific measurement of exposure was responsible for many of the observed estimated risks not being elevated.

  View details for Web of Science ID 000077715100011

  View details for PubMedID 9888281

• Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip AMERICAN JOURNAL OF MEDICAL GENETICS Shaw, G. M., Rozen, R., Finnell, R. H., Todoroff, K., Lammer, E. J. 1998; 80 (3): 196-198

  Abstract

  Studies have reported an association between homozygosity for a variant form of the methylenetetrahydrofolate reductase (MTHFR) gene and risk for neural tube defects. Because of MTHFR's involvement with folate metabolism and evidence that maternal use of a multivitamin with folic acid in early pregnancy reduces risk for cleft lip with or without cleft palate (CLP), we hypothesized that infants homozygous for the C677T genotype would be at increased risk for CLP because of lower MTHFR enzymatic activity. Data were derived from a large population-based, case-control study of fetuses and liveborn infants among a cohort of 1987 to 1989 California births. The analyses involved 310 infants with isolated CLP whose mothers completed a telephone interview and whose DNA was available from newborn screening blood specimens and involved 383 control infants without a congenital anomaly whose mothers completed a telephone interview and whose DNA was available. Cases and controls were genotyped TT if homozygous for the C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild-type) allele. Odds ratios for CLP were 0.89 (0.55 to 1.4) and 0.78 (0.56 to 1.1) for infants with TT versus CC and infants with CT versus CC genotypes, respectively. Compared with the CC genotype, the odds ratios for CLP among infants with the TT genotype were 0.74 (0.39 to 1.4) for those infants whose mothers were users and 1.4 (0.54 to 3.6) for those infants whose mothers were not users of multivitamins containing folic acid periconceptionally. The two estimates were not statistically heterogeneous (P = 0.30). Our results did not indicate increased risks for CLP among infants homozygous for the C677T genotype, nor do they indicate an interaction between infant C677T genotype and maternal multivitamin use on the occurrence of CLP.

  View details for Web of Science ID 000077117700002

  View details for PubMedID 9843036

• Socioeconomic status, neighborhood social conditions, and neural tube defects AMERICAN JOURNAL OF PUBLIC HEALTH Wasserman, C. R., Shaw, G. M., Selvin, S., Gould, J. B., Syme, S. L. 1998; 88 (11): 1674-1680

  Abstract

  This study evaluated the contributions of lower socioeconomic status (SES) and neighborhood socioeconomic characteristics to neural tube defect etiology. The influence of additional factors, including periconceptional multivitamin use and race/ethnicity, was also explored.Data derived from a case-control study of California pregnancies from 1989 to 1991. Mothers of 538 (87.8% of eligible) case infants/fetuses with neural tube defects and mothers of 539 (88.2%) nonmalformed infants were interviewed about their SES. Reported addresses were linked to 1990 US census information to characterize neighborhoods.Twofold elevated risks were observed for several SES indicators. Risks were somewhat confounded by vitamin use, race/ethnicity, age, body mass index, and fever but remained elevated after adjustment. A risk gradient was seen with increasing number of lower SES indicators. Women with 1 to 3 and 4 to 6 lower SES indicators had adjusted odds ratios of 1.6 (1.1-2.2) and 3.2 (1.9-5.4), respectively, compared with women with no lower SES indicators.Both lower SES and residence in a SES-lower neighborhood increased the risk of an neural tube defect-affected pregnancy, with risks increasing across a gradient of SES indicators.

  View details for Web of Science ID 000076694100014

  View details for PubMedID 9807535

• Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983-1992 AMERICAN JOURNAL OF MEDICAL GENETICS Croen, L. A., Shaw, G. M., Wasserman, C. R., Tolarova, M. M. 1998; 79 (1): 42-47

  Abstract

  To investigate variations in the prevalence of oral cleft anomalies according to parental race and ethnicity and maternal country of birth, the authors analyzed a cohort of 2,221,755 live births and fetal deaths delivered between 1983 and 1992 to residents of California. A total of 2,329 cleft lip with or without cleft palate (CL +/- P) cases and 1,475 cleft palate alone (CP) cases were identified by the California Birth Defects Monitoring Program, a population-based registry. Compared to Whites, the prevalence of CL +/- P was lower among African Americans (prevalence ratio (PR) = 0.56, 95% confidence interval (CI) = 0.45-0.69), higher among Native Americans (PR = 1.81, CI = 1.20-2.69), and the same among the Japanese (PR = 1.07, CI = 0.62-1.82) and Chinese (PR = 0.96, CI = 0.71-1.29). The risk of CL +/- P was slightly lower among the offspring of foreign-born Chinese women relative to U.S.-born Chinese women (PR = 0.71, CI = 0.33-1.57), and slightly higher among foreign-born Filipinos relative to their U.S.-born counterparts (PR = 1.37, CI = 0.57-3.53), although confidence intervals around these risk estimates were wide owing to sparse data. For CP, lower prevalences were observed among African Americans (PR = 0.72, CI = 0.58-0.91) and Hispanics (PR = 0.77, CI = 0.67-0.87) than among Whites. The risk of CP was higher among foreign-born Filipinos compared to U.S.-born Filipinos (PR = 1.52, CI = 0.58-4.33), although the confidence interval around this estimate included unity. These prevalence variations may reflect differences in both environmental and genetic factors affecting clefting risk.

  View details for Web of Science ID 000075620300011

  View details for PubMedID 9738868

• Energy and nutrient intakes and health practices of Latinas and white non-Latinas in the 3 months before pregnancy JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION Schaffer, D. M., Velie, E. M., Shaw, G. M., Todoroff, K. P. 1998; 98 (8): 876-884

  Abstract

  To describe the health practices and energy and nutrient intakes from diet and supplements of foreign- and US-born Latinas and white non-Latinas in the 3 months before pregnancy.A descriptive study in which data were obtained retrospectively from 2 questionnaires: an interviewer-administered questionnaire on the subject's medical, reproductive, family, occupational, and lifestyle history and a subject-administered (and interviewer-assisted) 100-item food frequency questionnaire.A population-based sample of California women (n = 462) who gave birth between 1989 and 1991 to single, live-born infants. One third of women were Latinas, of whom 58.1% were foreign born.Means, standard deviations, and percentiles were computed for energy and nutrient intakes of the total population and for white non-Latinas; US-born Latinas; and foreign-born Latinas. One-way analysis of variance was used to compare group means.Mean and median energy intake in all ethnic groups exceeded 2,000 kcal/day, although less than half of the population consumed 5 servings of fruit and vegetables per day. For iron, half of the women were below the Recommended Dietary Allowance. In contrast to the dietary intake of white non-Latinas and US-born Latinas, foreign-born Latinas had the lowest contribution of fat to total energy intake and the highest dietary intake of carbohydrate, cholesterol, fiber, grain products, protein foods, folate, vitamin C, iron, and zinc.A woman's ethnicity, as well as whether her place of birth was within or outside of the United States, may be predictors of her dietary and health practices before pregnancy. Vitamin, mineral, and food supplementation and consumption of cold breakfast cereal may be avenues for improving perinatal micronutrient intake.

  View details for Web of Science ID 000075215700018

  View details for PubMedID 9710657

• Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Rozen, R., Finnell, R. H., Wasserman, C. R., Lammer, E. J. 1998; 148 (1): 30-37

  Abstract

  Maternal periconceptional use of vitamin supplements containing folic acid substantially reduces the risk of neural tube defects (NTDs) in the offspring. The mechanism underlying this reduction in risk is unknown. Several recent studies have reported an association between homozygosity for a variant form (the C677T genotype) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and risk for NTDs in individuals. It has been hypothesized that maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme. Using data from two California case-control interview studies (1987-1991 birth cohorts), the authors investigated whether an interaction for spina bifida risk existed between infant MTHFR C677T genotype and maternal use of supplements containing folic acid. The authors genotyped the allelic variants of MTHFR in 214 liveborn case infants with spina bifida and 503 control infants for whom information on maternal periconceptional vitamin use was available. The percentage of all case infants with the C677T MTHFR mutation, for both homozygous (TT) and heterozygous (TC) genotypes, was slightly higher than that of controls. The C677T genotype was substantially more frequent among both case and control Hispanic infants than among non-Hispanic infants. Among all infants whose mothers did not periconceptionally use vitamins containing folic acid, the risk of spina bifida, as measured by the odds ratio, was 1.6 (95% confidence interval (CI) 0.8-3.1) for all infants with the TT genotype and 2.0 (95% CI 0.5-7.4) for non-Hispanic white infants with the TT genotype, as compared with infants with the CC genotype. This result indicates a modestly increased risk associated with the C677T genotype. A lower risk estimate (odds ratio=1.2, 95% CI 0.4-4.0) was observed among infants whose mothers periconceptionally used vitamin supplements containing folic acid. This population-based California study found a modestly increased risk of spina bifida among infants who were homozygous for the C677T genotype, but only minimal evidence of an interaction between the C677T genotype and maternal folic acid intake in the occurrence of spina bifida. If this mutant MTHFR genotype plays a role in the association between maternal vitamin use and NTD risk, it may be a small role, or it may be conditional on maternal genotype.

  View details for Web of Science ID 000074710300006

  View details for PubMedID 9663401

• Infant TGF-alpha genotype, orofacial clefts, and maternal periconceptional multivitamin use CLEFT PALATE-CRANIOFACIAL JOURNAL Shaw, G. M., Wasserman, C. R., Murray, J. C., Lammer, E. J. 1998; 35 (4): 366-370

  Abstract

  We previously demonstrated a strong association between periconceptional maternal cigarette smoking, infant transforming growth factor-alpha (TGFa) genotype, and risk of orofacial clefts. Because serum folate may be decreased by cigarette smoking and because maternal periconceptional use of multivitamins containing folic acid has been associated with a reduced risk of clefting, we explored whether a potential relation existed between infant TGFa genotype, maternal multivitamin use, and risk of orofacial cleft phenotypes.Data were derived from a population-based case-control study of fetuses and live-born infants among a cohort of 1987 to 1989 California births (n = 548,844). Information concerning periconceptional multivitamin use was obtained via telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants, and of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening bloodspots and genotyped for the Taql polymorphism of TGFa. Among infants of interviewed mothers, genotypes were available for 571 (78.1%) case infants and 640 (87.2%) control infants.The study encompassed all hospitals in selected California counties.The main outcome measures were the risks of specific cleft phenotypes among infants with uncommon TGFa genotypes and whose mothers did not use multivitamins periconceptionally.Compared with infants homozygous for the common TGFa genotype and whose mothers used multivitamins, increased clefting risks were observed for infants with the A2 genotype (homozygous or heterozygous) and whose mothers did not use multivitamins. Risk estimates were 3.0 (1.4-6.6 [95% confidence interval]) for isolated cleft lip with or without cleft palate (CLP), 2.4 (0.69-11.6) for multiple CLP, 2.6 (0.97-7.7) for isolated cleft palate (CP), 4.2 (1.3-16.2) for multiple CP, and 8.1 (2.6-27.7) for "known-syndrome" clefts. Clefting risks for infants with the A2 genotype and whose mothers used multivitamins were substantially smaller, as were the risks for infants with the A1 genotype whose mothers did not use multivitamins.These data provide preliminary evidence for a gene-nutrient interaction in risk of clefting.

  View details for Web of Science ID 000075675900013

  View details for PubMedID 9684776

• Neural tube and craniofacial defects with special emphasis on folate pathway genes CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE Finnell, R. H., Greer, K. A., Barber, R. C., Piedrahita, J. A., Shaw, G. M., Lammer, E. J. 1998; 9 (1): 38-53

  Abstract

  Neural tube and orofacial defects are common congenital malformations in humans. While etiologically heterogeneous, they are for the most part multifactorial in their pathogenesis, having both genetic and environmental components in their development. In recent years, there has been a great deal of epidemiologic evidence demonstrating that women who received multivitamins containing folic acid periconceptionally had significantly reduced occurrence and recurrence risks for producing infants with such malformations. This risk reduction is not observed in all populations, further suggestive of a genetic regulation of this phenomenon. Unfortunately, the mechanisms underlying the beneficial effects of folic acid are not well-understood. In this article, we review the relevant epidemiologic data on both neural tube defects and orofacial malformations, the fundamental embryological processes involved in closing the neural tube, and the development of the craniofacies, and propose a working hypothesis for susceptibility to these malformations. This hypothesis is based on the interworkings of cellular folate transport, focusing on the key elements involved in potocytosis. We propose that infants with mutations in the folate receptor alpha gene might be at increased risk for congenital anomalies due to a reduced binding affinity for 5-methyltetrahydrofolate, the physiologic form of folic acid. Various experimental approaches to test the working hypothesis are considered.

  View details for Web of Science ID 000071886700003

  View details for PubMedID 9488247

• Is dietary intake of methionine associated with a reduction in risk for neural tube defect-affected pregnancies? TERATOLOGY Shaw, G. M., Velie, E. M., Schaffer, D. M. 1997; 56 (5): 295-299

  Abstract

  Results from experimental animals and other laboratory data have suggested a role for methionine, an essential amino acid, in normal closure of the neural tube. We hypothesized that women who had higher dietary intakes of methionine would be at lower risk for neural tube defect (NTD)-affected pregnancies. Data were derived from a population-based case-control study of fetuses and liveborn infants with NTDs among a 1989-1991 California birth cohort. Interviews, which included a 100-item food frequency questionnaire, were conducted with mothers of 424 NTD cases and 440 nonmalformed controls. Risk for having an NTD-affected pregnancy was estimated according to quartiles (established from intakes among control mothers) of average daily maternal dietary intake of methionine in the 3 months before conception. We observed an approximately 30-40% reduction in NTD-affected pregnancies among women whose average daily dietary intake of methionine was above the lowest quartile of intake (> 1,341.86 mg/ day). These reductions in NTD risk were observed for both anencephaly and spina bifida; remained after adjustment for maternal race/ethnicity and education; and were observed irrespective of maternal level of folate intake. Although we were unable to establish whether the observed reductions in NTD risk were attributable to maternal periconceptional methionine intake or to another highly correlated nutrient, these data add to the growing body of evidence that maternal diet plays a role in neural tube closure.

  View details for Web of Science ID 000071353300001

  View details for PubMedID 9451752

• Risk for neural tube defect-affected pregnancies among women of Mexican descent and white women in California AMERICAN JOURNAL OF PUBLIC HEALTH Shaw, G. M., Velie, E. M., Wasserman, C. R. 1997; 87 (9): 1467-1471

  Abstract

  This study investigated a previously reported 50% or more increased risk for neural tube defect-affected pregnancies among Latina women compared with White women.Data were derived from a population-based case-control study of fetuses and live-born infants with neural tube defects in a 1989-through-1991 California birth cohort. Interviews were conducted with mothers of 538 (88% of eligible) infants/fetuses with neural tube defects and mothers of 539 (88%) nonmalformed control infants.The risk for a neural tube defect-affected pregnancy was approximately twice as high among women of Mexican descent than among White women (odds ratio = 1.9, 95% confidence interval [CI] = 1.5, 2.8). The odds ratio for Mexico-born Mexican women compared with White women was 2.4 (95% CI = 1.7, 3.2), whereas the risk for US-born women of Mexican and other racial/ethnic descent was not substantially higher than that for Whites. The higher risk among Mexico-born Mexican women was not attributable to differences in numerous studied parental characteristics and exposures.Given that nearly 20% of all California births are to Mexico-born Mexican women, the increased risks observed are relevant to the population burden of neural tube defects.

  View details for Web of Science ID A1997XY23500012

  View details for PubMedID 9314798

• Multivitamin supplementation and multiple births AMERICAN JOURNAL OF MEDICAL GENETICS Werler, M. M., Cragan, J. D., Wasserman, C. R., Shaw, G. M., Erickson, J. D., Mitchell, A. A. 1997; 71 (1): 93-96

  Abstract

  It is well established that maternal multivitamin supplementation reduces the risk of neural tube defects and evidence suggests that it may be associated with other reproductive outcomes. The present study was prompted by a report from a randomized trial in Hungary which showed a 40% increase in multiple births among periconceptional vitamin users. Retrospectively collected data on multivitamin supplementation were obtained on multiple and singleton births from three separate studies: Atlanta Birth Defects Case-Control Study (ABDCCS) malformed and nonmalformed infants born 1968-1980, California Birth Defects Monitoring Program (CBDMP) malformed and nonmalformed infants born 1987-1989, and Boston University Slone Epidemiology Unit Birth Defects Study (SEU-BDS) malformed infants born 1987-1994. Supplementation was divided into three mutually exclusive categories based on timing: "periconceptional" use--before through at least the third month after conception; "early" use--beginning in the first month and continuing through at least the third month after conception; and "later" use--beginning in the second or third month after conception. For periconceptional use, four of five datasets showed a 30 to 60% greater prevalence of supplementation among mothers of multiple births. In contrast, this pattern was not evident for "early" and "later" use. Overall, the study findings are tentative, due to a lack of consistency across all five datasets and they should not alter recent recommendations related to folate supplementation for the prevention of neural tube defects.

  View details for Web of Science ID A1997XG44200017

  View details for PubMedID 9215776

• Maternal residential proximity to hazardous waste sites and risk for selected congenital malformations EPIDEMIOLOGY Croen, L. A., Shaw, G. M., SANBONMATSU, L., Selvin, S., Buffler, P. A. 1997; 8 (4): 347-354

  Abstract

  Using data from two population-based case-control studies, we investigated whether maternal residential proximity to hazardous waste sites increased the risk for neural tube defects, conotruncal heart defects, and oral cleft defects in California. We obtained a residential history by interview for mothers of 507 neural tube defect cases (82.7% of eligible) and their 517 controls (84.6%); and 201 heart cases (84.4%), 439 cleft cases (82.2%), and their 455 controls (72.1%). We identified the locations of 764 inactive hazardous waste sites and systematically collected information on site-related contamination for the subset of 105 National Priority List sites. After controlling for several potential confounders, we found little or no increased risk for maternal residence in a census tract containing a site [odds ratio (OR) = 0.9, 95% confidence interval (CI) = 0.7-1.3 for neural tube defects; OR = 1.3, 95% CI = 0.8-2.1 for heart cases; OR = 1.2, 95% CI = 0.8-1.8 for clefts], but elevated risks for neural tube defects (OR = 2.1, 95% CI = 0.6-7.6) and heart defects (OR = 4.2, 95% CI = 0.7-26.5) for maternal residence within 1/4 mile of a National Priority List site. Furthermore, we observed elevated ORs (> or = 2.0) for neural tube defects and heart defects in association with maternal residence within 1 mile of National Priority List sites containing selected chemical contaminants. Among controls, only 0.6% and 4.4% lived within 1/4 mile and 1 mile of a National Priority List site, respectively, resulting in imprecision in risk estimation.

  View details for Web of Science ID A1997XG00500005

  View details for PubMedID 9209846

• Incorporating molecular genetic variation and environmental exposures into epidemiologic studies of congenital anomalies REPRODUCTIVE TOXICOLOGY Shaw, G. M., Lammer, E. J. 1997; 11 (2-3): 275-280

  Abstract

  Epidemiologic studies of congenital anomalies rarely incorporate measurements of both environmental and genetic factors. Given the suspected etiologic heterogeneity that exists among congenital anomalies, focusing on only environmental or on only genetic factors may substantially decrease the likelihood for identifying either type of factor as a contributor to the risk of congenital anomalies. Incorporating information on genotypic variation into an epidemiologic study of environmental exposures may potentially lead to improvements in case classification with accompanying potential improvements in risk estimation. Such genotypic information may also lead to a clearer understanding of the underlying pathogenesis and etiology of congenital anomalies. Using recent research findings on congenital anomalies, we illustrated the issues of case classification and how a clearer impression of the underlying pathogenesis can be achieved with the addition of genotypic information to epidemiologic studies of congenital anomalies.

  View details for Web of Science ID A1997WQ84000016

  View details for PubMedID 9100302

• Periconceptional intake of vitamin A among women and risk of neural tube defect-affected pregnancies TERATOLOGY Shaw, G. M., Velie, E. M., Schaffer, D., Lammer, E. J. 1997; 55 (2): 132-133

  View details for Web of Science ID A1997WW96500002

  View details for PubMedID 9143093

• Parental recreational drug use and risk for neural tube defects AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Velie, E. M., Morland, K. B. 1996; 144 (12): 1155-1160

  Abstract

  The authors investigated whether maternal or paternal periconceptional use of recreational drugs increased the risk of having neural tube defect (NTD)-affected pregnancies using a population-based case-control study of fetuses and liveborn infants with NTDs among 1989-1991 California births. Face-to-face interviews were conducted with mothers of 538 (88% of eligible) NTD cases and 539 (88%) nonmalformed controls, usually within 5 months of delivery. Periconceptional maternal use of cocaine (odds ratio (OR) = 0.74, 95% confidence interval (CI) 0.40-1.4), amphetamines/speed (OR = 0.68, 95% CI 0.39-1.2), or marijuana (OR = 0.64, 95% CI 0.43-0.95) or preconceptional use of alcohol as < 1 drink/day (OR = 0.80, 95% CI 0.62-1.0) or > or = 1 drink/day (OR = 0.69, 95% CI 0.42-1.2) or of cigarettes as < 1 pack/day (OR = 0.90, 95% CI 0.65-1.2) or > or = 1 pack/day (OR = 0.59, 95% CI 0.36-0.96) did not increase the risk for delivering NTD-affected offspring. Risks were not substantially altered after adjustment for maternal age, race/ethnicity, vitamin use, education, and household income. Increased NTD risk was also not generally associated with paternal drug use. The authors could not discern whether the decreased risks observed for these maternal exposures reflected a true association or were due to reporting bias, a disproportionate number of drug-exposed NTD cases among spontaneous abortuses that could not be ascertained, or some other bias.

  View details for Web of Science ID A1996VX62500009

  View details for PubMedID 8956628

• Impact of prenatal diagnosis and elective termination on prevalence and risk estimates of neural tube defects in California, 1989-1991 AMERICAN JOURNAL OF EPIDEMIOLOGY Velie, E. M., Shaw, G. M. 1996; 144 (5): 473-479

  Abstract

  The authors examined the impact of prenatal diagnosis and elective termination of neural tube defect (NTD)-affected pregnancies on NTD prevalence and risk estimates. Prevalence data were actively ascertained and were derived from a population-based 1989-1991 cohort of California births. Included were 664 singleton infants/fetuses with an NTD. The birth prevalence (livebirths and stillbirths only) was 48.4% of the total prevalence (including elective terminations) for anencephaly and 70.2% for spina bifida. The authors also used in-person interview data from mothers of 538 of the ascertained NTD cases and mothers of 539 randomly selected nonmalformed control infants to examine maternal/infant characteristics. Compared with women who delivered liveborn/stillborn infants with an NTD, women who electively terminated NTD-affected pregnancies were disproportionately white, were more highly educated, had higher incomes, and used vitamins containing folic acid more often. For factors associated with elective terminations, risk estimates appeared biased when only liveborn and stillborn infants were included among cases compared with analyses in which all clinically recognized NTD-affected pregnancies were included.

  View details for Web of Science ID A1996VE90000006

  View details for PubMedID 8781462

• Holoprosencephaly: Epidemiologic and clinical characteristics of a California population AMERICAN JOURNAL OF MEDICAL GENETICS Croen, L. A., Shaw, G. M., Lammer, E. J. 1996; 64 (3): 465-472

  Abstract

  Holoprosencephaly is a brain defect resulting from incomplete cleavage of the embryonic forebrain. It involves forebrain and facial malformations that can range from mild to severe. The epidemiology of holoprosencephaly is largely unknown. Published prevalence estimates have been derived from clinic-based case series, and suggested risk factors for holoprosencephaly have been identified in case reports, without confirmation from systematically conducted population-based studies. Using data from a population-based birth defects registry in California, we describe the epidemiologic and clinical characteristics of cytogenetically and phenotypically distinct types of holoprosencephaly. A total of 121 cases was identified among a cohort of 1,035,386 live births and fetal deaths. The prevalence of holoprosencephaly was 1.2 per 10,000 births (95% confidence interval 1.0-1.4 per 10,000). Of all cases, 41% (50/121) had a chromosomal abnormality, most commonly Trisomy 13. Among the 71 cytogenetically apparently normal cases, 18 had recognizable syndromes and the remaining 53 were of unknown cause. Among the cytogenetically abnormal cases, females had a greater risk than males (odds ratio = 2.3,95% confidence interval [1.2, 4.4]). Among the cytogenetically normal cases, increased risks were observed among Hispanic whites (OR = 1.8 [0.9, 3.6]) and cases whose mother was born in Mexico (OR = 2.2 [1.0, 4.5]). Approximately 46% of all cases had alobar holoprosencephaly, the most severe form of the forebrain malformation. The facial phenotype did not strongly predict the severity of the brain defect; however, severity was inversely correlated with length of survival. This study is the first to present findings based on such a large population-based series of infants/fetuses affected by holoprosencephaly, and demonstrates the importance of investigating the component subgroups of this rare phenotype.

  View details for Web of Science ID A1996VC48400004

  View details for PubMedID 8862623

• Epidemiologic characteristics of conotruncal heart defects in California, 1987-1988 TERATOLOGY OMALLEY, C. D., Shaw, G. M., Wasserman, C. R., Lammer, E. J. 1996; 53 (6): 374-377

  Abstract

  In this population-based case-control study, we explored the association of selected parental and infant characteristics from the birth certificates of children with conotruncal heart defects. We compared 252 cases to a random sample of 5,000 nonmalformed infants from a cohort of 341,839 California live births for 1987-1988. The prevalence of conotruncal defects was 0.732 per 1,000 total births. A decreased risk (OR = 0.55, 95% CI0.33-0.89) for delivering infants with conotruncal defects was found among mothers born in Mexico compared to mothers born in California. An increased risk was observed for Native American mothers compared to non-Hispanic whites (OR = 2.6, 95% CI 1.1-6.0). We also compared risks associated with the individual diagnoses that comprise the group of conotruncal defects. Only minor differences in risk estimates between the anatomic diagnoses were observed, lending support to the methodologic approach of using conotruncal defects as a single category of heart defects in etiologic investigations.

  View details for Web of Science ID A1996VP64400008

  View details for PubMedID 8910983

• Risk of neural tube defect-affected pregnancies among obese women JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Shaw, G. M., Velie, E. M., Schaffer, D. 1996; 275 (14): 1093-1096

  Abstract

  To investigate the risk for neural tube defect (NTD)-affected pregnancies among obese women (ie, women with a body mass index [BMI] > 29kg/m2) compared with women of average prepregnancy weight.Population-based case-control study.All hospitals in 55 of 58 counties in California.In-person interviews were conducted with mothers of 538 (88% of eligible) NTD cases (including fetuses and infants electively terminated, stillborn, or born alive) and with mothers of 539 nonmalformed controls (88%) within an average of 5 months from the term delivery date.The risk of an NTD-affected pregnancy among obese women.Compared with women whose BMI was less than or equal to 29 kg/m2, an increased risk for NTD-affected pregnancy was observed among obese women (odds ratio, 1.9; 95% confidence interval, 1.3 to 2.9). The increased risk was not attributable to maternal nonuse of a vitamin containing folic acid, diabetes, use of diet pills, lower dietary folate intake, or an NTD-pregnancy history. Adjustment for maternal age, education, gravidity, use of vitamins, and use of alcohol did not change the odds ratio. The risk associated with maternal obesity was greater for spina bifida and for other less prevalent NTDs than for anencephaly.Because as many as 10% of women may be obese periconceptionally, the observed twofold increased risk is relevant to the population burden of NTDs.

  View details for Web of Science ID A1996UD02700025

  View details for PubMedID 8601928

• Parental cigarette smoking and risk for congenital anomalies of the heart, neural tube, or limb TERATOLOGY Wasserman, C. R., Shaw, G. M., OMALLEY, C. D., Tolarova, M. M., Lammer, E. J. 1996; 53 (4): 261-267

  Abstract

  Risks for selected congenital anomalies from parental smoking were investigated in a case-control study in California. Mothers of 207 infants with conotruncal heart defects, 264 infants with neural tube defects, 178 infants with limb deficiencies, and 481 live born control infants delivered in 1987-1988 were interviewed by telephone. Modestly elevated risks were observed for conotruncal heart defects and limb deficiencies, associated primarily with both parents smoking. An odds ratio of 1.9 (95 percent confidence interval 1.2-3.1) was observed for conotruncal heart defects and an odds ratio of 1.7 (95% confidence interval 0.96-2.9) for limb deficiencies when both parents smoked compared to neither parent smoking. We did not observe increased risks associated with maternal smoking in the absence of paternal smoking, although an increased risk associated with paternal smoking in the absence of maternal smoking was observed for limb deficiencies in offspring. For conotruncal defects, the risks associated with parental smoking differed among race/ethnic groups. Parental smoking was not associated with increased risks for neural tube defects. Observed risks did not change substantially when adjusted for maternal vitamin use, alcohol use, and gravidity. Some heterogeneity in risk was observed for phenotypic case subgroups, but data were too sparse to draw firm inferences.

  View details for Web of Science ID A1996VA37300010

  View details for PubMedID 8864168

• Chorionic villus sampling and transverse digital deficiencies: Evidence for anatomic and gestational-age specificity of the digital deficiencies in two studies AMERICAN JOURNAL OF MEDICAL GENETICS Botto, L. D., Olney, R. S., Mastroiacovo, P., Khoury, M. J., Moore, C. A., Alo, C. J., Costa, P., Edmonds, L. D., Flood, T. J., Harris, J. A., Howe, H. L., Olsen, C. L., Panny, S. R., Shaw, G. M. 1996; 62 (2): 173-178

  Abstract

  Several but not all studies indicate that chorionic villus sampling (CVS) is associated with an increased risk for transverse limb deficiencies, including digital deficiencies. It has been suggested that variations in results regarding the transverse digital deficiencies (TDDs) may be due to the use of different classification criteria. We present the combined analysis of two case-control studies, the U.S. Multistate CVS (US) study and the Italian Multicentric Birth Defects (IP-IMC) study, using two different definitions of TDDs. We compared the frequency of CVS exposure in control infants with that among those infants with any number of affected digits (any TDD), and those with all five digits of at least one limb affected (extensive TDDs). The estimated relative risk (RR) for any TDD following CVS was 10.6 (IPIMC) and 6.6 (US). For the extensive TDDs, the RR was 30.5 (IPIMC) and 10.7 (US). In both studies, extensive TDDs were less than 25% of all TDDs. Compared to all TDDs, extensive TDDs were more likely to occur after CVS performed earlier in the first trimester (before 10-11 weeks' gestation). These findings suggest a relationship between the timing of CVS and the severity of TDDs; indicate that using a restrictive definition of TDDs (all five digits affected) may limit the ability to evaluate the association between CVS and TDDs in populations in whom CVS is usually performed at or after 10 weeks' gestation; and highlight the necessity to consider gestational age in any evaluation of the relative risk for limb deficiencies associated with CVS.

  View details for Web of Science ID A1996UA04200012

  View details for PubMedID 8882399

• Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants AMERICAN JOURNAL OF HUMAN GENETICS Shaw, G. M., Wasserman, C. R., Lammer, E. J., OMALLEY, C. D., Murray, J. C., Basart, A. M., Tolarova, M. M. 1996; 58 (3): 551-561

  Abstract

  Results of studies to determine whether women who smoke during early pregnancy are at increased risk of delivering infants with orofacial clefts have been mixed, and recently a gene-environment interaction between maternal smoking, transforming growth factor-alpha (TGFa), and clefting has been reported. Using a large population-based case-control study, we investigated whether parental periconceptional cigarette smoking was associated with an increased risk for having offspring with orofacial clefts. We also investigated the influence of genetic variation of the TGFa locus on the relation between smoking and clefting. Parental smoking information was obtained from telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants and with mothers of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening blood spots and genotyped for the allelic variants of TGFa. We found that risks associated with maternal smoking were most elevated for isolated cleft lip with or without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and for isolated cleft palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked > or =20 cigarettes/d. Analyses controlling for the potential influence of other variables did not reveal substantially different results. Clefting risks were even greater for infants with the TGFa allele previously associated with clefting whose mothers smoked > or =20 cigarettes/d. These risks for white infants ranged from 3-fold to 11-fold across phenotypic groups. Paternal smoking was not associated with clefting among the offspring of nonsmoking mothers, and passive smoke exposures were associated with at most slightly increased risks. This study offers evidence that the risk for orofacial clefting in infants may be influenced by maternal smoke exposures alone as well as in combination (gene-environment interaction) with the presence of the uncommon TGFa allele.

  View details for Web of Science ID A1996TV56400014

  View details for PubMedID 8644715

• Does periconceptional multivitamin use reduce the risk of neural tube defects associated with other birth defects? Data from two population-based case-control studies AMERICAN JOURNAL OF MEDICAL GENETICS Khoury, M. J., Shaw, G. M., Moore, C. A., Lammer, E. J., Mulinare, J. 1996; 61 (1): 30-36

  Abstract

  The role of periconceptional folic acid in the prevention of neural tube defects (NTDs) is well established. However, it is not clear whether a protective effect exists for the subset of nonsyndromic NTD with other "unrelated" major structural birth defects (NTD-multiples). This question is important to investigate because of shared pathogenetic mechanisms between NTD and other types of birth defects, and because of the epidemiologic differences that have been shown between NTD-multiples and NTD-singles. We analyzed data from two population-based case-control studies of NTDs, Atlanta 1968-1980, and California 1989-1991, to assess whether periconceptional multivitamin use reduces the risk of NTD-multiples. Maternal vitamin histories were assessed for 47 and 65 NTD-multiples cases and 3,029 and 539 control babies in Atlanta, and California, respectively. There was a substantial risk reduction associated with periconceptional multivitamin use (-3 to +3 months) for NTD-multiples (pooled odds ratio = 0.36, 95% C.I. 0.18-0.72) that persisted after adjustment for maternal race/ethnicity and education. Also, no specific types of NTDs or NTDs with specific defects explained the risk reduction with vitamin use. These data suggest that multivitamins reduce the risk of nonsyndromic NTD cases associated with other major birth defects. The implication of this finding for the role of vitamins in the prevention of non-NTD birth defects should be further explored.

  View details for Web of Science ID A1996TM20600007

  View details for PubMedID 8741914

• MATERNAL PERICONCEPTIONAL USE OF MULTIVITAMINS AND REDUCED RISK FOR CONOTRUNCAL HEART-DEFECTS AND LIMB DEFICIENCIES AMONG OFFSPRING AMERICAN JOURNAL OF MEDICAL GENETICS Shaw, G. M., OMALEY, C. D., Wasserman, C. R., Tolarova, M. M., Lammer, E. J. 1995; 59 (4): 536-545

  Abstract

  We investigated whether a woman's periconceptional use of a multivitamin containing folic acid was associated with a reduced risk for delivering offspring with a conotruncal heart defect or a limb deficiency. Data were derived from a population-based case-control study of fetuses and liveborn infants with conotruncal or limb defects among a 1987-88 cohort of births in California. Telephone interviews were conducted with mothers of 207 (87.0% of eligible) conotruncal cases, 178 (82.0%) limb defect cases, and of 481 (76.2%) randomly selected liveborn nonmalformed control infants. Reduced risks were observed for maternal use of multivitamins containing folic acid from one month before until two months after conception. Odds ratios and 95% confidence intervals for any compared to no multivitamin use were 0.70 (0.46-1.1) for conotruncal defects and 0.64 (0.41-1.0) for limb defects. Controlling for maternal race/ethnicity, age, education, gravidity, alcohol use, and cigarette use resulted in a further reduction to the odds ratio for conotruncal defects, 0.53 (0.34-0.85), but not for limb defects. Among non-vitamin using women, consumption of cereal containing folic acid was also associated with reduced risk for both defects. Women who take multivitamins have 30-35% lower risk of delivering offspring with either conotruncal or limb defects. This association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin components, or some unknown behaviors that highly correlate with regular use of a multivitamin. However, should the association prove causal, it offers an important opportunity for preventing thousands of serious birth defects.

  View details for Web of Science ID A1995TG90800026

  View details for PubMedID 8585581

• Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis--United States, 1985-1994. MMWR. CDC surveillance summaries : Morbidity and mortality weekly report. CDC surveillance summaries / Centers for Disease Control Cragan, J. D., Roberts, H. E., Edmonds, L. D., Khoury, M. J., Kirby, R. S., Shaw, G. M., Velie, E. M., Merz, R. D., Forrester, M. B., Williamson, R. A., Krishnamurti, D. S., Stevenson, R. E., Dean, J. H. 1995; 44 (4): 1-13

  Abstract

  The reported prevalence of anencephaly and spina bifida in the United States has steadily declined since the late 1960s. During this time, the ability to diagnose these defects prenatally has progressed rapidly. Many U.S. birth defects surveillance systems ascertain defects only among live-born infants or among infants and fetuses beyond a certain gestational age, thus excluding defects among pregnancies prenatally diagnosed as being affected by a neural tube defect (NTD) and electively terminated before the gestational age limit. The impact of prenatal diagnosis and subsequent pregnancy termination on the reported prevalence of anencephaly and spina bifida in the United States has not been well established. However, assessment of this impact is crucial to the use of surveillance data to monitor trends in the occurrence of NTDs and the effectiveness of interventions for these defects (e.g., increased consumption of folic acid).This report presents data from birth defects surveillance systems in six states over different time periods: Arkansas, 1985-1989; California, 1989-1991; Georgia, 1990-1991; Hawaii, 1988-1994; Iowa, 1985-1990; and South Carolina, 1992-1993.Population-based data about a) live-born and stillborn infants with anencephaly and spina bifida and b) pregnancies electively terminated after prenatal diagnosis of these defects were analyzed from the Arkansas Reproductive Health Monitoring System; the California Birth Defects Monitoring Program; CDC's Metropolitan Atlanta Congenital Defects Program; the Iowa Birth Defects Registry, the University of Iowa, and the Iowa Department of Public Health; and the Greenwood Genetic Center in South Carolina. Data also were analyzed from the Hawaii Birth Defects Monitoring Program, which includes data for some women who were not residents of the state. The systems differed in the size and racial/ethnic composition of the populations studied, the surveillance methods used, the completeness of ascertainment, and the availability and utilization of prenatal testing and pregnancy termination.Among all pregnancies ascertained in which the infant or fetus had anencephaly or spina bifida, the percentages that were electively terminated ranged from 9% in Arkansas to 42% in Atlanta and Hawaii, with a corresponding increase in the adjusted prevalence of these defects compared with the prevalence at birth. In each system, pregnancies associated with anencephaly were terminated more frequently than were those associated with spina bifida. These data indicate that the impact of prenatal diagnosis and subsequent pregnancy termination on the prevalence at birth of anencephaly and spina bifida differs among geographic areas and populations. Comprehensive surveillance for these defects requires inclusion of pregnancies that are prenatally diagnosed and then terminated.CDC will use these data to promote the inclusion of prenatally diagnosed and terminated pregnancies in estimates of the prevalence of anencephaly and spina bifida generated by birth defects surveillance programs in the United States. Including such pregnancies is crucial to the ability of these programs to monitor trends accurately and to establish the effectiveness of interventions, including the use of folic acid, for these defects.

  View details for PubMedID 7637675

• RISKS OF OROFACIAL CLEFTS IN CHILDREN BORN TO WOMEN USING MULTIVITAMINS CONTAINING FOLIC-ACID PERICONCEPTIONALLY LANCET Shaw, G. M., Lammer, E. J., Wasserman, C. R., OMALLEY, C. D., Tolarova, M. M. 1995; 346 (8972): 393-396

  Abstract

  Women are advised to take folic acid before they conceive as a precaution against neural-tube defects. However, the use of folic acid in preventing orofacial clefts is unknown. We investigated whether a woman's periconceptional use of multivitamins containing folic acid was associated with a reduced risk of orofacial clefts. We derived data from a population-based case-control study of fetuses and liveborn infants with orofacial anomalies among a 1987-89 cohort of births in California. We interviewed 731 (84.7%) of eligible mothers with orofacial cleft case infants and 734 (78.2%) mothers with non-malformed control infants. We found a reduced risk of orofacial clefts if the mother had used multivitamins containing folic acid during the period from one month before through two months after conception. The odds ratios ranged from 0.50-0.73 depending on cleft phenotype. Controlling for the potential influence of other variables did not substantially alter the results. Maternal daily consumption of cereal containing folic acid was also associated with a reduced risk of orofacial clefts. Women who used multivitamins containing folic acid periconceptionally had a 25-50% reduction in risk for offspring with orofacial clefts compared to women who did not use such vitamins. However, this association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin supplement components, or behaviours, that are highly correlated with the use of multivitamins containing folic acid.

  View details for Web of Science ID A1995RN65600007

  View details for PubMedID 7623568

• PERICONCEPTIONAL VITAMIN USE, DIETARY-FOLATE, AND THE OCCURRENCE OF NEURAL-TUBE DEFECTS EPIDEMIOLOGY Shaw, G. M., Schaffer, D., Velie, E. M., Morland, K., Harris, J. A. 1995; 6 (3): 219-226

  Abstract

  With a case-control study, we investigated whether periconceptional intake of supplemental or dietary folate reduced the risk of having a neural tube defect (NTD)-affected pregnancy. Mothers of 549 (88% of eligible) cases and 540 (88%) controls were interviewed in person about vitamin supplements used in either the 3 months before or the 3 months after conception and also about usual diet in the 3 months before conception. Women with any use of a folic acid-containing vitamin in the 3 months before conception had a lower risk of having an NTD-affected pregnancy [odds ratio (OR) = 0.65; 95% confidence interval (CI) = 0.45-0.94]. ORs were similar for 3 levels (< 0.4, 0.4-0.9, and > 0.9 mg per day) of average daily intake of folic acid. Any level of use in the first 3 months after conception resulted in a lowered risk as well (OR = 0.60; 95% CI = 0.46-0.79). Reduced risks were less marked for Hispanics and were not observed among women who graduated from college. Modest reduced risks were noted among non-vitamin users whose estimated daily dietary intake of folate was more than 0.227 mg. We observed decreasing risk with increasing folate intake from combined dietary sources and vitamin supplements. A reduction in NTD risk associated with folate intake is consistent with other studies; however, the reduced risk may be particular to subsets of the population, primarily non-Hispanic women and women whose education does not exceed high school.

  View details for Web of Science ID A1995QU35400005

  View details for PubMedID 7619926

• YOUNG MATERNAL AGE AND CONGENITAL-MALFORMATIONS - A POPULATION-BASED STUDY AMERICAN JOURNAL OF PUBLIC HEALTH Croen, L. A., Shaw, G. M. 1995; 85 (5): 710-713

  Abstract

  This study examined the prevalence of congenital malformations across the maternal age spectrum and identified specific malformation types that contributed to the overall prevalence among mothers under the age of 20 years. Data were derived from the California Birth Defects Monitoring Program for 1983 through 1988 live births. The distribution of prevalences of all nonchromosomal malformations was U-shaped across maternal age. Furthermore, several specific malformation types, representing nearly every organ system, were elevated among the infants of women under 20 years of age in comparison with those of women 25 to 29 years old.

  View details for Web of Science ID A1995QW83900020

  View details for PubMedID 7733434

• INCREASED RISK FOR TRANSVERSE DIGITAL DEFICIENCY AFTER CHORIONIC VILLUS SAMPLING - RESULTS OF THE UNITED-STATES MULTISTATE CASE-CONTROL STUDY, 1988-1992 TERATOLOGY Olney, R. S., Khoury, M. J., Alo, C. J., Costa, P., Edmonds, L. D., Flood, T. J., Harris, J. A., Howe, H. L., Moore, C. A., Olsen, C. L., Panny, S. R., Shaw, G. M. 1995; 51 (1): 20-29

  Abstract

  Although numerous infants have been reported with transverse limb deficiencies after their mothers had undergone chorionic villus sampling (CVS), it has been unclear whether the procedure caused these defects. We report the results of the first multistate case-control study to assess and quantify the risk for specific limb deficiencies associated with CVS. Case subjects were 131 infants with nonsyndromic limb deficiency ascertained from 7 population-based birth defect surveillance programs, and born from 1988-1992 to mothers 34 years of age or older. Control subjects were 131 infants with other birth defects. We ascertained exposure to CVS from medical records and maternal and physician questionnaires. We assessed rates and timing of exposure to CVS, and estimated relative and absolute risks for anatomic subtypes of limb deficiency. The odds ratio for all types of limb deficiency after CVS from 8-12 weeks' gestation was 1.7 (95% confidence interval, 0.4-6.3). For specific anatomic subtypes, the strongest association was for transverse digital deficiency (odds ratio = 6.4; 95% confidence interval, 1.1-38.6). The risk for transverse digital deficiency increased with earlier gestational exposure (P < 0.01 for trend). We estimated that the absolute risk for transverse digital deficiency in infants after CVS was 1 per 2,900 births (0.03%). Exposure to CVS was associated with a sixfold increase in risk for transverse digital deficiency. The causality of this association is supported by its strength, specificity, biologic plausibility, and consistency with the results of previous studies. Although some centers already inform patients about risk for limb deficiency, this study quantifies the magnitude of risk associated with CVS from 8-12 weeks' gestation.

  View details for Web of Science ID A1995QQ24500003

  View details for PubMedID 7597654

• EXPOSURE ASSESSMENT IN EPIDEMIOLOGIC STUDIES OF BIRTH-DEFECTS BY INDUSTRIAL-HYGIENE REVIEW OF MATERNAL INTERVIEWS AMERICAN JOURNAL OF INDUSTRIAL MEDICINE Katz, E. A., Shaw, G. M., Schaffer, D. M. 1994; 26 (1): 1-11

  Abstract

  In epidemiologic studies of birth defects, occupational titles have frequently been used as surrogates for exposure. To avoid the error associated with such proxy exposure measures, we have designed a process in which an industrial hygienist systematically imputes exposures derived from maternal interviews. In response to a structured questionnaire, mothers of cases and controls recalled occupational and nonoccupational tasks performed or products used around the time of conception. Maternal exposures were then assigned to several a priori defined categories by an industrial hygienist. The central exposure category consists of 74 chemical families, e.g., alcohols, lead compounds. Other exposure categories are individual chemical compounds; nonchemical agents, e.g., ionizing radiation, infectious diseases; and product end-use categories, e.g., insecticides, combustion products. A detailed description of this approach and its exposure assessment potential is presented using exposure data from 220 maternal interviews.

  View details for Web of Science ID A1994NQ32700001

  View details for PubMedID 8074117

• HUMAN ADVERSE REPRODUCTIVE OUTCOMES AND ELECTROMAGNETIC-FIELD EXPOSURES - REVIEW OF EPIDEMIOLOGIC STUDIES ENVIRONMENTAL HEALTH PERSPECTIVES Shaw, G. M., Croen, L. A. 1993; 101: 107-119

  Abstract

  Concerns have been raised regarding a relation between residential and occupational electromagnetic (EM) field exposures and adverse reproductive effects. This paper reviews the epidemiologic evidence for this possible relation, including some pertinent methodologic issues, notes relevant findings from the experimental literature, and discusses areas for future research. Evidence is lacking for a strong association between a woman's use of a video display terminal (VDT) during pregnancy and spontaneous abortion. The evidence for a strong association between a women's use of a VDT and other adverse reproductive endpoints is also lacking, with some suggestive findings for congenital malformations and too few data to reach a conclusion about other endpoints. With respect to low-level EM field exposures other than VDTs, the paucity of data prevents one from determining whether there are reproductive health risks associated with such exposures. Therefore, this is an area that needs further investigation. Given that altered growth may be an underlying biologic effect of EM field exposures, endpoints that might be pursued in future studies include congenital malformations not associated with chromosomal anomalies, intrauterine growth retardation, and chromosomally normal spontaneous abortions.

  View details for Web of Science ID A1993MY18000013

  View details for PubMedID 8206019

• Surveillance for and comparison of birth defect prevalences in two geographic areas--United States, 1983-88. MMWR. CDC surveillance summaries : Morbidity and mortality weekly report. CDC surveillance summaries / Centers for Disease Control Schulman, J., Edmonds, L. D., MCCLEARN, A. B., Jensvold, N., Shaw, G. M. 1993; 42 (1): 1-7

  Abstract

  CDC and a number of states have developed surveillance systems to monitor the birth prevalence of major defects.This report covers birth defects surveillance in Metropolitan Atlanta, Georgia and selected jurisdictions in California for the years 1983-1988.The California Birth Defects Monitoring Program and the Metropolitan Atlanta Congenital Defects Program are two population based surveillance systems that employ similar data collection methods. The prevalence estimates for 44 diagnostic categories are based on data from 1983 to 1988 for 639,837 births in California and 152,970 births in metropolitan Atlanta. The prevalences in the two areas are compared adjusting for race, sex and maternal age using Poisson regression.Regional differences in the prevalence of aortic stenosis, fetal alcohol syndrome, hip dislocation/dysplasia, microcephalus, obstruction of the kidney/ureter, and scoliosis/lordosis may be attributable to general diagnostic variability. However, differences in the prevalences of arm/hand limb reduction, encephalocele, spina bifida, or trisomy 21 (Down Syndrome) are probably not attributable to differences in ascertainment because these defects are relatively easy to diagnose.Regional differences in prenatal diagnosis and pregnancy termination may affect prevalences of trisomy 21 and spina bifida. However, the reason for differences in arm/hand limb reduction is unknown, but may be related to variability in environmental exposure, heterogeneity in gene pool, or random variation.Because of the similarities of these data bases, several collaborative studies are being implemented. In particular, the differences in the birth prevalence of spina bifida and Down Syndrome will focus attention on the impact of prenatal diagnosis.

  View details for PubMedID 8474427

• EXPOSURE MISCLASSIFICATION DUE TO RESIDENTIAL-MOBILITY DURING PREGNANCY IN EPIDEMIOLOGIC INVESTIGATIONS OF CONGENITAL-MALFORMATIONS ARCHIVES OF ENVIRONMENTAL HEALTH Schulman, J., Selvin, S., Shaw, G. M., Malcoe, L. H. 1993; 48 (2): 114-119

  Abstract

  This study addressed the question of how maternal migration between conception and birth affects estimates of risk in studies of congenital malformations when movement is related to the exposure. For example, in studying the potential association between proximity to a chemical waste site and the occurrence of birth defects, incorrect inferences might be drawn if maternal residence at birth was used as a surrogate for exposure at conception in the case when a significant amount of media attention influenced some women to move away from the site after becoming pregnant. A simple statistical model is proposed that defines the distance to a fixed exposure point measured at birth as a function of the distance to the point measured at conception, the probability of movement, the direction of movement, and the distance moved. Bias is the difference between the expected results when distance is measured at birth versus conception. The amount of bias can be substantial for movement patterns that may be likely to occur. This simplified model was used in an effort to explore and better understand the relationships between maternal migration and risk.

  View details for Web of Science ID A1993LA30000009

  View details for PubMedID 8476302

• ROLE OF EXPOSURE DATABASES IN EPIDEMIOLOGY ARCHIVES OF ENVIRONMENTAL HEALTH Matanoski, G., Selevan, S. G., Akland, G., Bornschein, R. L., Dockery, D., Edmonds, L., Greife, A., Mehlman, M., Shaw, G. M., Elliott, E. 1992; 47 (6): 439-446

  Abstract

  At present, exposure databases record data primarily for regulatory purposes; they have not focused on serving the needs of epidemiologists or public health. However, the modification of exposure databases could facilitate their use in epidemiology. Characteristics necessary to enhance the use of all databases include easy access by users; documentation of methods, sampling bias, error, and inconsistences; widespread coverage in time and space; and methods and measures for estimating exposure of individuals as well as populations. Also needed are exposure scenarios and models to estimate exposures for geographic areas and time intervals not currently sampled. Multidisciplinary teams are needed to examine current databases, to review strategies for improving data collection, and to suggest and help implement appropriate changes. A long-term goal is to develop and validate data from exposure scenarios and models using data on the relationship of exposure to doses measured in humans.

  View details for Web of Science ID A1992KH56600005

  View details for PubMedID 1485807

• MOTHERS MOTIVATIONS TO PARTICIPATE IN A PREGNANCY HEALTH SURVEY PUBLIC HEALTH REPORTS Schaffer, D., Shaw, G. M. 1992; 107 (6): 731-733

  Abstract

  An important question in interpreting epidemiologic data is why some persons agree to participate in a health survey while others do not. Information about why people agree to interview or answer a questionnaire could help researchers to devise procedures for a health survey and to chose information to be communicated in the interview or questionnaire so as to increase subjects' participation. The authors interviewed 180 mothers who gave birth to a child with a birth defect and 198 mothers whose children were born without a birth defect. The interviews were part of two case-control studies to determine risk factors for selected birth defects. In the course of the interviews, each mother was asked why she agreed to be interviewed, and whether anything about the survey procedures that were followed could be improved. Among both the case mothers and the control mothers the most common reason for agreeing to be interviewed was humanitarian, expressed as "to help others" or "to prevent what happened to my baby from happening to babies in the future." Case mothers, more frequently than control mothers, gave as their reason for participating either to help themselves, their child, their family, or to further scientific understanding. Emphasizing these as benefits of participation to those who are survey subjects at the time of the initial contact could increase the proportion who agree to respond.

  View details for Web of Science ID A1992KB79900021

  View details for PubMedID 1454988

• REPORTING AND SELECTION BIAS IN CASE-CONTROL STUDIES OF CONGENITAL-MALFORMATIONS EPIDEMIOLOGY Swan, S. H., Shaw, G. M., Schulman, J. 1992; 3 (4): 356-363

  Abstract

  Retrospective studies of congenital malformations frequently rely on exposures reported by study subjects. Differential error in exposure reporting by cases and controls, which has alternatively been referred to as "recall bias" and "reporting bias," may result in a biased effect measure. Some authors have attempted to avoid reporting bias by comparing exposures between two malformed groups, rather than between cases and nonmalformed controls. This approach, however, may introduce its own bias, which we call selection bias. Both reporting bias and selection bias are shown to be algebraically equivalent to bias arising from exposure misclassification. The magnitudes of these biases are compared for a range of plausible parametric values. The case-control design is sensitive to both differential reporting and selection bias, and the choice of study design involves balancing these two sources of bias.

  View details for Web of Science ID A1992JE26900011

  View details for PubMedID 1637899

• RESIDENTIAL-MOBILITY DURING PREGNANCY FOR MOTHERS OF INFANTS WITH OR WITHOUT CONGENITAL CARDIAC ANOMALIES - A REPRINT ARCHIVES OF ENVIRONMENTAL HEALTH Shaw, G. M., Malcoe, L. H. 1992; 47 (3): 236-238

  Abstract

  Maternal residence at time of delivery is sometimes used as a proxy for residence during early pregnancy to estimate environmental exposures. Residential addresses during time of conception through the first trimester were obtained from mothers of 152 infants with congenital cardiac anomalies and 175 controls, and they were compared with the addresses at delivery abstracted from birth certificates. An estimated 24.8% (95% CI = 20.3, 29.9) of women moved between the time of conception and delivery, and the percentage of cases and controls who moved was similar. Use of address at time of delivery may reduce the likelihood of finding an association between a congenital malformation and a maternal environmental exposure.

  View details for Web of Science ID A1992JA81000011

  View details for PubMedID 1596108

• POTENTIAL SOURCES OF BIAS AND CONFOUNDING IN ENVIRONMENTAL EPIDEMIOLOGIC STUDIES OF PREGNANCY OUTCOMES EPIDEMIOLOGY Neutra, R. R., Swan, S. H., HERTZPICCIOTTO, I., Windham, G. C., Wrensch, M., Shaw, G. M., Fenster, L., Deane, M. 1992; 3 (2): 134-142

  Abstract

  Biases familiar to all epidemiologists take on new importance when studying spontaneous abortion because of the significance of the timing of exposure during gestation, and because the gestational age at which the pregnancy is recognized may be related to risk factors under study. In this paper, we systematically review the principal biases that might affect epidemiologic studies of pregnancy loss, in the context of a series of studies that found associations between adverse reproductive outcomes and prenatal use of tap or bottled water. These biases relate to availability of subjects for study, exposure opportunity, recall of exposure, recall of disease, and confounding. In one of the studies, the rate of bottled water use changed dramatically over the course of the study period, providing an opportunity to test indirectly for biased recall of exposure. We conclude that a less complete recall of water intake among women with normal pregnancies, as compared with those with spontaneous abortions, may have produced, or increased the magnitude of, the associations seen in these studies.

  View details for Web of Science ID A1992HH93800012

  View details for PubMedID 1576219

• CONGENITAL-MALFORMATIONS AND BIRTH-WEIGHT IN AREAS WITH POTENTIAL ENVIRONMENTAL CONTAMINATION ARCHIVES OF ENVIRONMENTAL HEALTH Shaw, G. M., Schulman, J., FRISCH, J. D., Cummins, S. K., Harris, J. A. 1992; 47 (2): 147-154

  Abstract

  Public concern exists about the potential for reproductive damage that may result from exposures to environmental contaminants. Therefore, the authors sought to determine if there was an association between a child's congenital malformation or a child's lowered weight at birth and his or her mother's residence in a census tract where a site of environmental contamination had been documented. Exposure designations were derived from existing sources of information. Except for an elevated risk (odds ratio = 1.5) for infants with malformations of the heart and circulatory system, this investigation did not reveal increased risks for most malformations or for lowered birthweight among babies born to women who lived in these census tracts. Methodologic issues inherent to investigations that rely on existing data sources are discussed.

  View details for Web of Science ID A1992HR03300010

  View details for PubMedID 1567240

• Birth defects monitoring in California: a resource for epidemiological research. Paediatric and perinatal epidemiology Croen, L. A., Shaw, G. M., Jensvold, N. G., Harris, J. A. 1991; 5 (4): 423-427

  Abstract

  The California Birth Defects Monitoring Program maintains a population-based birth defects registry of structural congenital malformations, monitoring over 600,000 resident births annually. Cases are actively ascertained from hospitals and genetic centres throughout California and from selected facilities in adjacent states. Field staff identify presumptive cases from careful review of medical records. Diagnostic and demographic information is collected from in-patient and genetic centre medical charts for children diagnosed with major structural malformations between conception and 1 year of age. The application of these data to epidemiological investigations of birth defects is described in the context of prevalence studies, aetiological studies and evaluative studies, and the strengths and limitations of the registry data are discussed.

  View details for PubMedID 1754501

• RESIDENTIAL-MOBILITY DURING PREGNANCY FOR MOTHERS OF INFANTS WITH OR WITHOUT CONGENITAL CARDIAC ANOMALIES ARCHIVES OF ENVIRONMENTAL HEALTH Shaw, G. M., Malcoe, L. H. 1991; 46 (5): 310-312

  View details for Web of Science ID A1991GP05800009

• ISOLATED ORAL CLEFT MALFORMATIONS - ASSOCIATIONS WITH MATERNAL AND INFANT CHARACTERISTICS IN A CALIFORNIA POPULATION TERATOLOGY Shaw, G. M., Croen, L. A., Curry, C. J. 1991; 43 (3): 225-228

  Abstract

  Data on isolated oral cleft malformations from a birth defects registry covering a large population base were examined to describe potential associations with maternal and infant characteristics. Infants with cleft palate (CP) were analyzed separately from infants with cleft lip with or without cleft palate (CLP). The prevalence of isolated CLP per 1,000 births was 0.741, approximately twice the prevalence of isolated CP, which was 0.383. Male infants were more likely to be born with CLP (OR = 1.9) but less likely to be born with CP (OR = 0.56) than were females. Women 39 years or more of age were twice as likely as 25-29 year olds to have a child with either type of cleft. Black, nonhispanic infants had a lowered risk for CLP compared to white, nonhispanics (OR = 0.40). These risks were found to be independent of each other based on multivariate analyses. Associations with either type of cleft malformation were not observed for plurality, number of previous live births, and maternal birthplace.

  View details for Web of Science ID A1991EZ23300005

  View details for PubMedID 2014485

• EPIDEMIOLOGIC RESEARCH USING EXISTING DATABASES OF ENVIRONMENTAL MEASURES ARCHIVES OF ENVIRONMENTAL HEALTH FRISCH, J. D., Shaw, G. M., Harris, J. A. 1990; 45 (5): 303-307

  Abstract

  When detailed information on individuals is not available, databases of environmental measures are sometimes used in epidemiologic studies to provide data on human exposure. The use of such databases is based on the assumption that the data are representative of individual human exposure and are applicable to the study. Twenty-six databases that contained data on the environment pertaining to California were summarized and evaluated by categorical criteria of spatial and temporal precision, availability, amount of quantitative information, "machine-readability," and type of environmental measure.

  View details for Web of Science ID A1990EN63700008

  View details for PubMedID 2256714

• AN ASSESSMENT OF ERROR IN PARENTAL OCCUPATION FROM THE BIRTH CERTIFICATE AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Malcoe, L. H., Croen, L. A., Smith, D. F. 1990; 131 (6): 1072-1079

  Abstract

  This study used data obtained through interview with the mother to determine whether parental occupations from the California birth certificate were representative of maternal occupations during the first trimester of pregnancy or paternal occupations 3 months before conception. For 71% of mothers and 80% of fathers, the occupation on the birth certificate was the same as the occupation elicited from the interview. The sensitivity of the birth certificate for determining whether a mother or father was employed or employed in a particular standard occupational category ranged from 50 to 100%. The bias to the odds ratio associated with a sensitivity of 75% and a specificity of 80% is presented. The results suggest that the use of birth certificate information on parental occupation to screen for associations with congenital malformations will miss all but very strong associations.

  View details for Web of Science ID A1990DG76200015

  View details for PubMedID 2188499

• DETECTION OF EXCESS DISEASE NEAR AN EXPOSURE POINT - A CASE-STUDY ARCHIVES OF ENVIRONMENTAL HEALTH Schulman, J., Selvin, S., Shaw, G. M., Merrill, D. 1990; 45 (3): 168-174

  Abstract

  Many studies have evaluated the likelihood of adverse health effects associated with environmental contamination from point source exposures. Two statistical measures used in these studies are the ratio, R, of the observed to the expected number of cases occurring in the area containing the point and the average distance, D, between the cases and the point. This paper estimates the probability of detecting an association between disease and exposure when one actually exists (power) for R and D for several specific and plausible statistical models. Results are presented in the context of rare diseases such as congenital malformations. The practical implications of using these measures for the evaluation of risk of disease in environmental epidemiologic investigations are discussed.

  View details for Web of Science ID A1990DW53200006

  View details for PubMedID 2386422

• Maternal water consumption during pregnancy and congenital cardiac anomalies. Epidemiology Shaw, G. M., Swan, S. H., Harris, J. A., Malcoe, L. H. 1990; 1 (3): 206-211

  Abstract

  This case-control study, conducted in a California county that had a local incident of water contamination in 1981, investigated the relation between a mother's reported consumption of tap water during pregnancy and congenital cardiac anomalies in their offspring born during 1981-1983. Data were obtained from telephone interviews with 145 mothers of children born with a severe cardiac anomaly and 176 mothers of children born without such an anomaly. A positive association between a mother's consumption of home tap water during the first trimester of pregnancy and cardiac anomalies in her infant was unrelated to the incident of water contamination, the mother's race, or her educational level. A negative relation was found between a mother's use of bottled water and cardiac anomalies among the infants. These findings corresponded primarily to births in 1981. These data could not fully distinguish between a potential causal agent in the water and differential reporting of exposure by study subjects.

  View details for PubMedID 2081254

• CONGENITAL CARDIAC ANOMALIES IN RELATION TO WATER CONTAMINATION, SANTA-CLARA COUNTY, CALIFORNIA, 1981-1983 AMERICAN JOURNAL OF EPIDEMIOLOGY Swan, S. H., Shaw, G., Harris, J. A., Neutra, R. R. 1989; 129 (5): 885-893

  Abstract

  In November 1981, a leak of solvents from an underground storage tank was detected at an electronics manufacturing plant in Santa Clara County, California. Solvents (predominantly 1,1,1-trichloroethene, or methyl chloroform) were found in a nearby well which supplied drinking water to the surrounding community. Residents were concerned about a possible relation between adverse reproductive outcomes and consumption of contaminated water. To address this concern, the California Department of Health Services conducted two epidemiologic studies: one of these, reported here, is a county-wide study of cardiac anomalies. This study, which looked at major cardiac anomalies among births throughout Santa Clara County in 1981-1983, found an increased prevalence in the service area of the water company which operated the contaminated well. During the potentially exposed time period (January 1981 through August 1982), 12 babies with major cardiac anomalies were born to residents of this area. This represents an excess of six cases over the number expected based on the prevalence in the remainder of the county (relative risk = 2.2, 95 per cent confidence interval 1.2-4.0). No excess was observed in the unexposed time period (September 1982 through December 1983). However, the temporal distribution of major cardiac cases born during the exposed time period suggests that the solvent leak is an unlikely explanation for this excess.

  View details for Web of Science ID A1989U333700003

  View details for PubMedID 2784935

• ILLNESS AND ABSENTEEISM AMONG CALIFORNIA HIGHWAY PATROL OFFICERS RESPONDING TO HAZARDOUS MATERIAL SPILLS ARCHIVES OF ENVIRONMENTAL HEALTH English, P. B., Shaw, G. M., Windham, G. C., Neutra, R. R. 1989; 44 (2): 117-119

  Abstract

  Highway patrol officers are the primary responders to hazardous material spills in California, yet little is known regarding the health effects resulting from this exposure. A historical cohort study of 993 California highway patrol officers who responded to hazardous material spills in 1984 was conducted. The records of officers who were exposed to acutely toxic chemicals were followed for the subsequent week to determine if they demonstrated more absenteeism or illness compared to officers who were not exposed to toxic chemicals. No significant differences in the frequency of absenteeism or illness was found between the two groups during the week following exposure. No indication was found that exposure to hazardous materials during a highway patrol spill response results in increased absenteeism.

  View details for Web of Science ID A1989U001200008

  View details for PubMedID 2930246

• AN EXAMINATION OF 3 SPATIAL DISEASE CLUSTERING METHODOLOGIES INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Shaw, G. M., Selvin, S., Swan, S. H., Merrill, D., Schulman, J. 1988; 17 (4): 913-919

  Abstract

  Patterns of disease in space are often analysed to determine whether a relationship exists between a disease outcome and environmental exposures. This report examines the performance of three cluster analytical methods when applied to a single data set. These methods, designed to assess the purely spatial variation of events, have been examined to assess their ability to detect clustering in an area where disease rates have previously been shown to be significantly elevated. The ability of these methods to detect spatial clustering was also examined using simulation techniques. All three methods were found to be poor at detecting spatially localized disease rates which were approximately three time the expected rate, as measured by the relative risk.

  View details for Web of Science ID A1988T103100038

  View details for PubMedID 3225103

• ON RATES OF BIRTH-DEFECTS TERATOLOGY Schulman, J., Shaw, G., Selvin, S. 1988; 38 (5): 427-429

  Abstract

  The proportion of children born with a particular defect is not a "birth defect rate" but, rather, a prevalence proportion. The implications of confusing a rate and a proportion are discussed in terms of the interpretation of birth defect data. It is recommended that "prevalence proportion" or "prevalence" be used to report the frequency of various defects rather than the often-used "prevalence rate."

  View details for Web of Science ID A1988Q752300004

  View details for PubMedID 3238600

• SPATIAL-DISTRIBUTION OF DISEASE - 3 CASE-STUDIES JOURNAL OF THE NATIONAL CANCER INSTITUTE Selvin, S., Shaw, G., Schulman, J., Merrill, D. W. 1987; 79 (3): 417-423

  Abstract

  Maps transformed so as to have constant density of residential population were used to analyze the spatial distribution of disease in three specific areas. Each area had received recent attention because of suspected environmental pollution. The area adjacent to the Rocky Flats Facility (CO) was examined to identify any association between possible plutonium releases and increases in lung cancer or leukemia incidence. The industrial area of northern Contra Costa County (CA) was studied to explore a relationship between petrochemical industrial emissions and histologic-specific lung cancers. Finally, a suspected increase in the risk of congenital cardiac defects possibly related to pollution of the Santa Clara County (CA) water supply was investigated. No evidence of elevated risk of disease was found to be associated with either the Rocky Flats Facility or the polluted water of Santa Clara County. An increase in lung cancer, found by other investigators in earlier years, was shown to persist in association with industrial emissions in Contra Costa County.

  View details for Web of Science ID A1987K015900003

  View details for PubMedID 3476785

• ASSESSMENT OF POTENTIAL ACUTE HEALTH-EFFECTS IN AGRICULTURAL-WORKERS EXPOSED DURING THE APPLICATION OF CHLORDIMEFORM JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE KURTZ, P. H., Shaw, G., Kelter, A., Jackson, R. J. 1987; 29 (7): 592-595

  Abstract

  Agricultural workers exposed to chlordimeform (Cdf) used as a pesticide on cotton in Imperial County, California, were monitored during the 1982 application season. Cdf metabolites were found in the urine of 132 workers and were positively correlated with the length of exposure and nature of job activity. Persons mixing and loading and engaged in miscellaneous tasks such as cleaning and maintenance of equipment had the greatest exposure. There was no evidence of urinary tract irritation by microscopic analysis of the urine, nor were significant differences found between preseason and postseason serum chemistry results. Despite the use of protective clothing and closed system transfer devices, Cdf was absorbed by workers as evidenced by urinary metabolite excretion.

  View details for Web of Science ID A1987J236300006

  View details for PubMedID 3612336

• CHARACTERISTICS OF HAZARDOUS MATERIAL SPILLS FROM REPORTING SYSTEMS IN CALIFORNIA AMERICAN JOURNAL OF PUBLIC HEALTH Shaw, G. M., Windham, G. C., Leonard, A., Neutra, R. R. 1986; 76 (5): 540-543

  Abstract

  Data on hazardous material releases that occurred between January 1, 1982 and September 30, 1983 in California were obtained from the California Highway Patrol (CHP) and the US Department of Transportation (DOT). The majority of incidents involved highway transport of hazardous materials, although some information was available on air, rail, and stationary facility releases. Vehicle accidents and failure of or damage to the container were the most frequent causes of releases. Proportionately more hazardous materials incidents occurred in early summer than at other times of the year, during weekdays, and daytime hours. The largest proportions of incidents involved the chemical categories of corrosives and fuels. Reported exposures and injuries to response personnel and other people at the scene were relatively few; no fatalities were reported. Few incidents were reported in both data sources, suggesting that the examination of only one data source would yield a gross underestimate of the total number of hazardous materials incidents in California. The lack of available denominator data limits the interpretation of the findings.

  View details for Web of Science ID A1986C009600012

  View details for PubMedID 3963282

• ASSOCIATION OF CHILDHOOD LEUKEMIA WITH MATERNAL AGE, BIRTH-ORDER, AND PATERNAL OCCUPATION - A CASE-CONTROL STUDY AMERICAN JOURNAL OF EPIDEMIOLOGY Shaw, G., Lavey, R., Jackson, R., Austin, D. 1984; 119 (5): 788-795

  Abstract

  Previous investigations have drawn conflicting conclusions concerning the association between childhood leukemia and maternal age, birth order, socioeconomic status, and paternal occupation. In this study, 255 childhood leukemia cases diagnosed in California between 1975 and 1980 were individually matched with two living controls on the basis of sex, date of birth, and county of birth. Data were derived from subjects' birth certificates. Socioeconomic status and paternal benzene exposure were determined from the paternal occupation stated on the birth certificate. Hispanics and males were overrepresented in the case group. Cases were also less likely to be of birth order one. No difference was found between case and control groups for maternal age or paternal occupation. Analyses with stratification on age, sex, and leukemia cell type are reported.

  View details for Web of Science ID A1984SR57500013

  View details for PubMedID 6720675