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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.

Many examples of the use of real-world data in the area of pharmacoepidemiology include "big data," such as insurance claims, medical records, or hospital discharge databases. However, "big" is not always better, particularly when studying outcomes with narrow windows of etiologic relevance. Birth defects are such an outcome, for which specificity of exposure timing is critical. Studies with primary data collection can be designed to query details about the timing of medication use, as well as type, dose, frequency, duration, and indication, that can better characterize the "real world." Because birth defects are rare, etiologic studies are typically case‑control in design, like the National Birth Defects Prevention Study, Birth Defects Study to Evaluate Pregnancy Exposures, and Slone Birth Defects Study. Recall bias can be a concern, but the ability to collect detailed information about both prescription and over-the-counter medication use and other exposures such as diet, family history, and sociodemographic factors is a distinct advantage over claims and medical record data sources. Case‑control studies with primary data collection are essential to advancing the pharmacoepidemiology of birth defects. This article is part of a Special Collection on Pharmacoepidemiology. [ABSTRACT FROM AUTHOR]

Background: The use of chlorine to treat drinking water produces disinfection by‐products (DBPs), which have been associated with congenital heart defects (CHDs) in some studies. Methods: Using National Birth Defects Prevention Study data, we linked geocoded residential addresses to public water supply measurement data for DBPs. Self‐reported water consumption and filtration methods were used to estimate maternal ingestion of DBPs. We estimated adjusted odds ratios and 95% confidence intervals using logistic regression controlling for maternal age, education, body mass index (BMI), race/ethnicity, and study site to examine associations between CHDs and both household DBP level and estimated ingestion of DBPs. Results: Household DBP exposure was assessed for 2717 participants (1495 cases and 1222 controls). We observed a broad range of positive, null, and negative estimates across eight specific CHDs and two summary exposures (trihalomethanes and haloacetic acids) plus nine individual DBP species. Examining ingestion exposure among 2488 participants (1347 cases, 1141 controls) produced similarly inconsistent results. Conclusions: Assessing both household DBP level and estimated ingestion of DBPs, we did not find strong evidence of an association between CHDs and DBPs. Despite a large study population, DBP measurements were available for less than half of participant addresses, limiting study power. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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). Conclusion: Variation in the genes identified in this population‐based study may help to further explain the genetics of PCG. [ABSTRACT FROM AUTHOR]

Introduction Women and healthcare providers lack adequate information on medication safety during pregnancy. While resources describing fetal risk are available, information is provided in multiple locations, often with subjective assessments of available data. We developed a list of medications of greatest concern during pregnancy to help healthcare providers counsel reproductive-aged and pregnant women. Methods Prescription drug labels submitted to the U.S. Food and Drug Administration with information in the Teratogen Information System (TERIS) and/or Drugs in Pregnancy and Lactation by Briggs & Freeman were included (N = 1,186 medications; 766 from three data sources, 420 from two). We used two supervised learning methods ('support vector machine' and 'sentiment analysis') to create prediction models based on narrative descriptions of fetal risk. Two models were created per data source. Our final list included medications categorized as 'high' risk in at least four of six models (if three data sources) or three of four models (if two data sources). Results We classified 80 prescription medications as being of greatest concern during pregnancy; over half were antineoplastic agents (n = 24), angiotensin converting enzyme inhibitors (n = 10), angiotensin II receptor antagonists (n = 8), and anticonvulsants (n = 7). Discussion This evidence-based list could be a useful tool for healthcare providers counseling reproductive-aged and pregnant women about medication use during pregnancy. However, providers and patients may find it helpful to weigh the risks and benefits of any pharmacologic treatment for both pregnant women and the fetus when managing medical conditions before and during pregnancy., Author(s): Elizabeth C. Ailes [sup.1] , John Zimmerman [sup.2] , Jennifer N. Lind [sup.1] , Fanghui Fan [sup.2] , Kun Shi [sup.2] , Jennita Reefhuis [sup.1] , Cheryl S. Broussard [...]

Maternal smoking during pregnancy is one proposed risk factor for gastroschisis, but reported associations have been modest, suggesting that differences in genetic susceptibility might play a role. We included 108 non-Hispanic white and 62 Hispanic families who had infants with gastroschisis, and 1,147 non-Hispanic white and 337 Hispanic families who had liveborn infants with no major structural birth defects (controls) in these analyses. DNA was extracted from buccal cells collected from infants and mothers, and information on periconceptional smoking history was obtained from maternal interviews, as part of the National Birth Defects Prevention Study. We analyzed five polymorphisms in three genes that code for enzymes involved in metabolism of some cigarette smoke constituents (CYP1A1, CYP1A2, and NAT2). Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) independently for maternal smoking and maternal and infant gene variants, and to assess joint associations of maternal smoking and maternal or infant gene variants with gastroschisis. In analyses adjusted for maternal age at delivery and stratified by maternal race-ethnicity, we identified three suggestive associations among 30 potential associations with sufficient numbers to calculate ORs: CYP1A1*2A for non-Hispanic white mothers who smoked periconceptionally (aOR = 0.38, 95% CI 0.15-0.98), and NAT2*6 for Hispanic non-smoking mothers (aOR = 2.17, 95% CI 1.12-4.19) and their infants (aOR = 2.11, 95% CI 1.00-4.48). This analysis does not support the occurrence of effect modification between periconceptional maternal smoking and most of the xenobiotic metabolizing enzyme gene variants assessed.

Summary: Zolpidem is a non‐benzodiazepine agent indicated for treatment of insomnia. While zolpidem crosses the placenta, little is known about its safety in pregnancy. We assessed associations between self‐reported zolpidem use 1 month before pregnancy through to the end of the third month ("early pregnancy") and specific birth defects using data from two multi‐site case–control studies: National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study. Analysis included 39,711 birth defect cases and 23,035 controls without a birth defect. For defects with ≥ 5 exposed cases, we used logistic regression with Firth's penalised likelihood to estimate adjusted odds ratios and 95% confidence intervals, considering age at delivery, race/ethnicity, education, body mass index, parity, early‐pregnancy antipsychotic, anxiolytic, antidepressant use, early‐pregnancy opioid use, early‐pregnancy smoking, and study as potential covariates. For defects with three–four exposed cases, we estimated crude odds ratios and 95% confidence intervals. Additionally, we explored differences in odds ratios using propensity score‐adjustment and conducted a probabilistic bias analysis of exposure misclassification. Overall, 84 (0.2%) cases and 46 (0.2%) controls reported early‐pregnancy zolpidem use. Seven defects had sufficient sample size to calculate adjusted odds ratios, which ranged from 0.76 for cleft lip to 2.18 for gastroschisis. Four defects had odds ratios > 1.8. All confidence intervals included the null. Zolpidem use was rare. We could not calculate adjusted odds ratios for most defects and estimates are imprecise. Results do not support a large increase in risk, but smaller increases in risk for certain defects cannot be ruled out. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: Our findings suggest that residing in a census tract with more socioeconomic deprivation is associated with an increased risk for NTDs, specifically spina bifida. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

The objective of this analysis was to describe patterns of prescription medication use during pregnancy, including secular trends, with consideration of indication, and distributions of use within demographic subgroups. We conducted a descriptive secondary analysis using data from 9,755 women whose infants served as controls in two large United States case–control studies from 1997–2011 and 2014–2018. After excluding vitamin, herbal, mineral, vaccine, i.v. fluid, and topical products and over‐the‐counter medications, the proportion of women that reported taking at least one prescription medication in the first trimester increased over the study years, from 37% to 50% of women. The corresponding proportions increased with increasing maternal age and years of education, were highest for non‐Hispanic White women (47%) and lowest for Hispanic women (24%). The most common indication for first trimester use of a medication was infection (12–15%). Increases were observed across the years for medications used for indications related to nausea/vomiting, depression/anxiety, infertility, thyroid disease, diabetes, and epilepsy. The largest relative increase in use among women was observed for medications to treat nausea/vomiting, which increased from 3.8% in the earliest years of the study (1997–2001) to 14.8% in 2014–2018, driven in large part by ondansetron use. Prescription medication use in the first trimester of pregnancy is common and increasing. Many medical conditions require treatments among pregnant women, often involving pharmacotherapy, which necessitates consideration of the risk and safety profiles for both mother and fetus. [ABSTRACT FROM AUTHOR]

In May 2015, the World Health Organization (WHO) reported an outbreak of Zika virus disease in Brazil (1). Zika virus is a single-stranded RNA virus spread primarily by Aedes aegypti [...]

Background: Caffeine consumption is common during pregnancy, but published associations with birth defects are mixed. We updated estimates of associations between prepregnancy caffeine consumption and 48 specific birth defects from the National Birth Defects Prevention Study (NBDPS) for deliveries from 1997 to 2011. Methods: NBDPS was a large population‐based case–control study conducted in 10 U.S. states. We categorized self‐reported total dietary caffeine consumption (mg/day) from coffee, tea, soda, and chocolate as: <10, 10 to <100, 100 to <200, 200 to <300, and ≥ 300. We used logistic regression to estimate adjusted odds ratios (aORs [95% confidence intervals]). Analyses for defects with ≥5 exposed case children were adjusted for maternal race/ethnicity, age at delivery, body mass index, early pregnancy cigarette smoking and alcohol use, and study site. Results: Our analysis included 30,285 case and 11,502 control children, with mothers of 52% and 54%, respectively, reporting consuming <100 mg caffeine, and 11% of mothers of both cases and controls reported consuming ≥300 mg per day. Low (10 to <100 mg/day) levels of prepregnancy caffeine consumption were associated with statistically significant increases in aORs (1.2–1.7) for 10 defects. Associations with high (≥300 mg/day) levels of caffeine were generally weaker, except for craniosynostosis and aortic stenosis (aORs = 1.3 [1.1–1.6], 1.6 [1.1–2.3]). Conclusions: Given the large number of estimates generated, some of the statistically significant results may be due to chance and thus the weakly increased aORs should be interpreted cautiously. This study supports previous observations suggesting lack of evidence for meaningful associations between caffeine consumption and the studied birth defects. [ABSTRACT FROM AUTHOR]