Cynthia A. Moore

Background: We calculated prevalences of birth defects among infants of participants in the Centers for Disease Control and Prevention's (CDC) COVID‐19 Vaccine Pregnancy Registry (C19VPR).Methods: C19VPR enrolled women receiving COVID‐19 vaccines ≤ 30 days before the last menstrual period or during pregnancy from December 2020 through June 2021. We included 19,931 participants with singleton pregnancies ending ≥ 20 weeks' gestation who did not report COVID‐19 illness during pregnancy. Clinicians identified birth defects from participant‐reported infant health information up to 4 months after birth. We compared C19VPR birth defect prevalences to published pre‐pandemic estimates. For seven defects originating during embryogenesis (cleft lip with/without cleft palate, atrial septal defect, coarctation of the aorta, ventricular septal defect, esophageal atresia or stenosis, hypospadias, kidney agenesis/hypoplasia/dysplasia), we estimated prevalence ratios comparing those vaccinated < 14 weeks' to those vaccinated ≥ 14 weeks' gestation.Results: Participants reported receiving Pfizer‐BioNTech vaccines (59.0%), Moderna (38.2%), and Janssen (2.8%) vaccines. Most (65.2%) participants received their first COVID‐19 vaccine after the first trimester. The prevalence of major birth defects was 3.8%. Among defects with comparator estimates available (n = 50), 35 were below or within expected ranges. C19VPR prevalences were higher than the comparator confidence interval for 15 defects; however, C19VPR confidence intervals included comparator estimates. Prevalences did not differ by the timing of vaccination for seven defects examined.Conclusions: Birth defects prevalence estimates among infants born to women receiving COVID‐19 vaccines during or just prior to pregnancy were generally similar to pre‐pandemic estimates. While there was no strong evidence of associations between vaccination and specific defects, statistical power was low.

Background: Split‐hand/foot malformation (SHFM) is a rare, genetically heterogeneous, congenital limb defect. Some but not all associated genes are known; therefore, the aim was to identify genes underlying SHFM.Methods: Buccal cell‐derived DNA from 26 children with SHFM and their parents who participated in the National Birth Defects Prevention Study was exome sequenced. Family‐based trio analyzes prioritized rare coding variants by inheritance patterns, predicted pathogenicity, and location within putative limb development genes. Copy‐number variants in SHFM candidate genomic regions were also examined. Case–control analyzes compared coding variants between case children and 1191 controls (parents of children with non‐limb birth defects). Variant validation was by Sanger sequencing or droplet digital polymerase chain reaction.Results: In family‐based analyzes, the prioritized and validated variants (each in a single family) included likely damaging variants that were heterozygous and de novo in speckle type BTB/POZ protein (SPOP) and ubiquitin‐like modifier activating enzyme 2 (UBA2), X‐linked recessive in fibroblast growth factor 13 (FGF13) and RNA binding motif protein 10 (RBM10), and compound heterozygous in interleukin enhancer binding factor 3 (ILF3). Validation assays did not confirm predicted de novo copy‐number gains at chromosomes 10q24 and 19p13.11. Case–control analyzes did not identify statistically significant associations.Conclusion: Exome analysis nominated new susceptibility genes (FGF13, ILF3, RBM10, SPOP) and detected a variant in a known candidate gene (UBA2). Follow‐up investigation is needed to ascertain damaging variants in these genes in additional cases with SHFM and evaluate the impact of the variants on gene expression, protein function, and limb development.

Introduction: We assessed the risk of adverse pregnancy and birth outcomes and birth defects among women living with HIV (WLHIV) on antiretroviral therapy (ART) and HIV-negative women. Methods: We analyzed data on live births, stillbirths, and spontaneous abortions during 2015–2021 from a hospital-based birth defects surveillance system in Kampala, Uganda. ART regimens were recorded from hospital records and maternal self-reports. Using a log-binomial regression model, we compared the prevalence of 16 major external birth defects and other adverse birth outcomes among WLHIV on ART and HIV-negative women. Results: A total of 203,092 births were included from 196,373 women of whom 15,020 (7.6%) were WLHIV on ART. During pregnancy, 15,566 infants were primarily exposed to non-nucleoside reverse transcriptase inhibitor-based ART (n = 13,614; 87.5%). After adjusting for maternal age, parity, and number of antenatal care visits, WLHIV on non-nucleoside reverse transcriptase inhibitor were more likely than HIV-negative women to deliver preterm (adjusted prevalence ratio [aPR] = 1.27, 95% confidence interval: 1.21 to 1.32), post-term (aPR = 1.23, 95% CI: 1.16 to 1.32), or small for gestational age infants (aPR = 1.35, 95% CI: 1.30 to 1.40). Spina bifida was more prevalent among infants born to WLHIV on ART periconceptionally compared with HIV-negative women (aPR = 2.45, 95% CI: 1.27 to 4.33). The prevalence of the other selected birth defects was similar between infants from WLHIV on ART and HIV-negative women. Conclusions: In Uganda, WLHIV on ART were more likely than HIV-negative women to experience selected adverse birth outcomes. Further surveillance of maternal ART exposure, including by drug class and ART regimen, is needed to monitor and prevent adverse birth outcomes in WLHIV.

Background: Although many factors are associated with gastroschisis risk, studies have not systematically explored whether they account for its increasing frequency over the past decades or its inverse association with maternal age. We examined whether previously reported risk factors for gastroschisis from the National Birth Defects Prevention Study (NBDPS) explain the association with increasing temporal prevalence or young maternal age.Methods: Using data from the NBDPS (1997–2011), crude odds ratios (ORs) were calculated for birth years 2005–2011 versus 1997–2004 and maternal age < 25 versus 25+ years. We then adjusted for 16 factors separately with logistic regression (paternal age, interpregnancy interval, parity, alcohol, cigarettes, illicit drugs, oral contraceptives, cold/flu with fever, genitourinary infection, polycyclic aromatic hydrocarbons, diet quality, prepregnancy body mass index, parental race and ethnicity, language spoken at home, years lived in the United States, and household income).Results: The birth year OR (1.28; 95% CI: 1.14, 1.44) was attenuated by 16% after adjustment for polycyclic aromatic hydrocarbon exposure (OR 1.08; 95 CI: 0.92, 1.26). The young maternal age OR (7.76; 95% CI: 6.71, 8.97) was attenuated by 30% after adjustment for paternal age (OR 5.43; 95% CI: 4.55, 6.48) and separately for interpregnancy interval (OR 5.45; 95% CI: 4.43, 6.69).Conclusion: Some evidence suggests that risk factors for gastroschisis account for small amounts of the time trend and maternal age associations. However, it remains unclear what factors underlie the complete calendar time or maternal age associations.

Background: Associations between maternal periconceptional exposure to disinfection by‐products (DBPs) in drinking water and neural tube defects (NTDs) in offspring are inconclusive, limited in part by exposure misclassification.Methods: Maternal interview reports of drinking water sources and consumption from the National Birth Defects Prevention Study were linked with DBP concentrations in public water system monitoring data for case children with an NTD and control children delivered during 2000–2005. DBPs analyzed were total trihalomethanes, the five most common haloacetic acids combined, and individual species. Associations were estimated for all NTDs combined and selected subtypes (spina bifida, anencephaly) with maternal periconceptional exposure to DBPs in public water systems and with average daily periconceptional ingestion of DBPs accounting for individual‐level consumption and filtration information. Mixed effects logistic regression models with maternal race/ethnicity and educational attainment at delivery as fixed effects and study site as a random intercept were applied.Results: Overall, 111 case and 649 control children were eligible for analyses. Adjusted odds ratios for maternal exposure to DBPs in public water systems ranged from 0.8–1.5 for all NTDs combined, 0.6–2.0 for spina bifida, and 0.7–1.9 for anencephaly; respective ranges for average daily maternal ingestion of DBPs were 0.7–1.1, 0.5–1.5, and 0.6–1.8. Several positive estimates (≥1.2) were observed, but all confidence intervals included the null.Conclusions: Using community‐ and individual‐level data from a large, US, population‐based, case–control study, we observed statistically nonsignificant associations between maternal periconceptional exposure to total and individual DBP species in drinking water and NTDs and subtypes.

Background: Gastroschisis has increased worldwide over several decades; however, there are significant gaps in understanding risk factors for development of the defect, particularly those that might be modifiable. Despite advances in survival, little is known about longer‐term outcomes for affected individuals.Methods: On April 27– and 28, 2023, the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention (CDC) and March of Dimes sponsored a meeting entitled “Public Health Priorities for Gastroschisis”. The meeting goals were to review current knowledge on gastroschisis, discuss research gaps, and identify future priorities for public health surveillance, research, and action related to gastroschisis. Meeting participants encompassed a broad range of expertise and experience, including public health, clinical care of individuals with gastroschisis, affected individuals and families, and representatives from professional organizations and federal agencies.Results: Several goals were identified for future public health surveillance and research, including focused theory‐driven research on risk factors and increased study of longer‐term effects of gastroschisis through improved surveillance. Certain public health actions were identified, that which could improve the care of affected individuals, including increased education of providers and enhanced resources for patients and families.Conclusions: These efforts may lead to an improved understanding of pathogenesis, risk factors, and outcomes and to improved care throughout the lifespan.

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.

Zika virus (ZIKV) was identified as a teratogen in 2016 when an increase in severe microcephaly and other brain defects was observed in fetuses and newborns following outbreaks in French Polynesia (2013–2014) and Brazil (2015–2016) and among travelers to other countries experiencing outbreaks. Some have questioned why ZIKV was not recognized as a teratogen before these outbreaks: whether novel genetic changes in ZIKV had increased its teratogenicity or whether its association with birth defects had previously been undetected. Here we examine the evidence for these two possibilities. We describe evidence for specific mutations that arose before the French Polynesia outbreak that might have increased ZIKV teratogenicity. We also present information on children born with findings consistent with congenital Zika syndrome (CZS) as early as 2009 and epidemiological evidence that suggests increases in CZS‐type birth defects before 2013. We also explore reasons why a link between ZIKV and birth defects might have been missed, including issues with surveillance of ZIKV infections and of birth defects, challenges to ZIKV diagnostic testing, and the susceptibility of different populations to ZIKV infection at the time of pregnancy. Although it is not possible to prove definitively that ZIKV had teratogenic properties before 2013, several pieces of evidence support the hypothesis that its teratogenicity had been missed in the past. These findings emphasize the need for further investments in global surveillance for emerging infections and for birth defects so that infectious teratogens can be identified more expeditiously in the future.

During the Centers for Disease Control and Prevention's Zika Virus Response, birth defects surveillance programs adapted to monitor birth defects potentially related to Zika virus (ZIKV) infection during pregnancy. Pregnancy outcomes occurring during January 2016 to June 2017 in 22 U.S. states and territories were used to estimate the prevalence of those brain and eye defects potentially related to ZIKV. Jurisdictions were divided into three groups: areas with widespread ZIKV transmission, areas with limited local ZIKV transmission, and areas without local ZIKV transmission. Prevalence estimates for selected brain and eye defects and microcephaly per 10,000 live births were estimated. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated using Poisson regression for areas with widespread and limited ZIKV transmission compared with areas without local ZIKV transmission. Defects with significantly higher prevalence in areas of widespread transmission were pooled, and PRs were calculated by quarter, comparing subsequent quarters to the first quarter (January-March 2016). Nine defects had significantly higher prevalence in areas of widespread transmission. The highest PRs were seen in intracranial calcifications (PR = 12.6, 95% CI [7.4, 21.3]), chorioretinal abnormalities (12.5 [7.1, 22.3]), brainstem abnormalities (9.3 [4.7, 18.4]), and cerebral/cortical atrophy (6.7 [4.2, 10.8]). The PR of the nine pooled defects was significantly higher in three quarters in areas with widespread transmission. The largest difference in prevalence was observed for defects consistently reported in infants with congenital ZIKV infection. Birth defects surveillance programs could consider monitoring a subset of birth defects potentially related to ZIKV in pregnancy.