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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: Fungal infections are common among pregnant people. Recent studies suggest positive associations between oral antifungals used to treat fungal infections and congenital heart defects (CHDs). Methods: We estimated associations between first trimester antifungal use and 20 major, specific CHDs using data from the National Birth Defects Prevention Study (NBDPS), a multi‐site, case–control study that included pregnancies with estimated delivery dates from October 1997 through December 2011. Infants with CHDs ("cases") were ascertained from 10 birth defect surveillance programs. Live born infants without major birth defects ("controls") were randomly selected from birth records or hospital discharge lists. First trimester antifungal use was self‐reported via maternal interview. We estimated adjusted odds ratios (AORs) and 95% confidence intervals (CIs) using logistic regression with Firth's penalized likelihood. Results: First trimester antifungal use was reported by 148/11,653 (1.3%) case and 123/11,427 (1.1%) control participants. We estimated AORs for 12 CHDs; six had AORs >1.5 (tetralogy of Fallot, double outlet right ventricle with transposition of the great arteries [DORV‐TGA], atrioventricular septal defect, hypoplastic left heart syndrome, pulmonary atresia, muscular ventricular septal defect), and one (pulmonary valve stenosis) had an AOR <0.7. All CIs included the null, except for DORV‐TGA. Conclusions: First trimester antifungal use was rare. We observed some positive associations for several specific CHDs in our analysis, although the CIs largely included the null. Results do not support a large increase in risk, but smaller increases in risk for certain CHD cannot be ruled out. [ABSTRACT FROM AUTHOR]

Purpose: Recent studies suggest increased birth defect risk associated with maternal use of specific oral antifungals. We estimated associations between first‐trimester antifungal use and selected non‐cardiac birth defects using National Birth Defects Prevention Study (NBDPS) data. Methods: Participants with a pregnancy affected by a study‐eligible birth defect ("cases") were ascertained from 10 birth defect surveillance programs; participants who delivered livebirths without a major birth defect ("controls") were randomly selected from birth records or hospital discharge lists. First‐trimester antifungal use was self‐reported via maternal interview. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for birth defects with ≥5 exposed cases using logistic regression. We estimated crude ORs and exact 95% CIs for birth defects with 3–4 exposed cases. Additionally, we conducted a probabilistic bias analysis of exposure misclassification. Results: Our analysis included 19 624 cases and 11 427 controls; 257 (1.3%) cases and 123 (1.1%) controls reported first‐trimester antifungal use. Of those who reported antifungals, 62.6% of cases and 64.2% of controls reported topical antifungals; 10.1% of cases and 4.9% of controls reported oral antifungals. We observed the strongest associations for encephalocele and Dandy‐Walker malformation and modestly elevated estimates for several other defects. Bias‐adjusted estimates were similar to the main analysis. Conclusion: First‐trimester antifungal use was positively associated with several birth defects in our analysis, although CIs were imprecise. Further study is warranted to investigate associations between antifungal use and birth defects, including potential bias due to confounding by indication. [ABSTRACT FROM AUTHOR]

Purpose: Cyclobenzaprine is a muscle relaxant indicated for acute pain. Little is known about cyclobenzaprine's safety during pregnancy. We explored the association between maternal cyclobenzaprine exposure and risk of birth defects among offspring. Methods: We combined data from two large, multi‐site, population‐based case–control studies in the United States. Cases were identified from birth defects registries across 10 states; controls were liveborn infants without birth defects randomly selected from the same catchment areas. Participants reported cyclobenzaprine use during the month before conception through the third month of pregnancy ("periconception") via computer‐assisted telephone interview. We used logistic regression to assess associations between periconceptional cyclobenzaprine exposure and selected structural birth defects. We calculated crude odds ratios (OR) with corresponding 95% confidence intervals (CI). Results: Our study included 33 615 cases and 13 110 controls. Overall, 51 case (0.15%) and 9 control (0.07%) participants reported periconceptional cyclobenzaprine use. We observed increased risk for all seven defects with ≥3 exposed cases: cleft palate (OR = 4.79, 95% CI 1.71–13.44), cleft lip (OR = 2.50, 95% CI 0.89–7.02), anorectal atresia/stenosis (OR = 6.91, 95% CI 1.67, 28.65), d‐transposition of the great arteries (OR = 6.97, 95% CI 2.17–22.36), coarctation of the aorta (OR = 5.58, 95% CI 1.88–16.58), pulmonary valve stenosis (OR = 4.55, 95% CI 1.10–18.87), and secundum atrial septal defect (OR = 3.08, 95% CI 0.83–11.45). Conclusions: Even in our large sample, cyclobenzaprine use was rare. Our estimates are unadjusted and imprecise so should be interpreted cautiously. These hypothesis‐generating results warrant confirmation and further research to explore possible mechanisms. [ABSTRACT FROM AUTHOR]

Background: Studies evaluating associations between medication use in pregnancy and birth outcomes rely on various sources of exposure information. We sought to assess agreement between self‐reported use of medications during early pregnancy and medication information in prenatal medical records to understand the reliability of each of these information sources. Methods: We compared self‐reported prescription medication use in early pregnancy to medical records from 184 New York women with deliveries in 2018 who participated in the Birth Defects Study To Evaluate Pregnancy exposureS. We assessed medications used chronically and episodically, and medications within 12 therapeutic groups. We calculated agreement using kappa (κ) coefficients, sensitivity, and specificity. We assessed differences by case/control status, maternal age, education, time to interview, and interview language. Results: Medications used chronically showed substantial agreement between self‐report and medical records (κ = 0.75, 0.61–0.88), with agreement for therapeutic groups used chronically ranging from κ = 0.61 for antidiabetics to κ = 1.00 for antihypertensives. Prescription medications used episodically showed worse agreement (κ = 0.40, 0.25–0.54), with the lowest agreement for opioid analgesics (κ = 0.20) and anti‐infectives (κ = 0.33). Agreement did not differ by the characteristics examined, although we observed potential differences by interview language. Conclusions: Among our sample, we observed good agreement between self‐report and medical records for medications used chronically and substantially less agreement for medications used episodically. Differences by source may be due to poor recall in self‐reports, non‐adherence with prescribed medications and lack of complete prescription information within medical records. Limitations should be considered when assessing prescription medication exposures during early pregnancy in epidemiologic studies. [ABSTRACT FROM AUTHOR]

Background: Gastroschisis is particularly prevalent among offspring of young women and has increased over recent decades. Although previous studies suggest that maternal alcohol consumption is associated with increased gastroschisis risk, none have explored whether maternal age modifies that association. Objective: The objective of the study was to evaluate associations between self‐reported maternal periconceptional alcohol consumption (1 month prior through the third month after conception) and risk of gastroschisis among offspring, by maternal age. Methods: We used data from the National Birth Defects Prevention Study (NBDPS), a multi‐site population‐based case‐control study. The analysis included 1450 gastroschisis cases and 11,829 unaffected liveborn controls delivered during 1997–2011 in ten US states. We estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the individual and joint effects of alcohol consumption and young maternal age at delivery (<25 years vs ≥25 years) on gastroschisis risk. We estimated the relative excess risk due to interaction (RERI) to quantify additive interaction. Results: Periconceptional alcohol consumption was common regardless of maternal age (women <25 years: cases 38.8%, controls 29.3%; women ≥25: cases 43.5%, controls 39.5%). Compared with women ≥25 years who did not consume alcohol, we observed increased risk of gastroschisis among women <25 years, with higher estimates among those who consumed alcohol (women <25 years who did not consume alcohol. aOR 5.90, 95% CI 4.89, 7.11; women <25 years who did consume alcohol: aOR 8.21, 95% CI 6.69, 10.07). Alcohol consumption among women ≥25 years was not associated with gastroschisis (aOR 1.12, 95% CI 0.88, 1.42). This suggests super‐additive interaction between alcohol consumption and maternal age (RERI −2.19, 95% CI 1.02, 3.36). Conclusions: Periconceptional alcohol consumption may disproportionately increase risk of gastroschisis among young mothers. Our findings support public health recommendations to abstain from alcohol consumption during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Congenital diaphragmatic hernia (CDH) occurs when abnormal diaphragm development allows herniation of abdominal organs into the thoracic cavity. Its etiopathogenesis is not well understood, but cigarette smoking and alcohol exposure may impact diaphragm development. Using data from a large, population‐based case–control study, we examined associations between maternal cigarette smoking and alcohol consumption and CDH in offspring. Methods: We analyzed maternal interview reports of cigarette smoking and alcohol consumption during early pregnancy for 831 children with CDH and 11,416 children without birth defects with estimated dates of delivery during 1997–2011. Generalized linear mixed effects models with a random intercept for study site were used to estimate associations between measures of exposure to smoking (any, type, frequency, duration) and alcohol (any, quantity, frequency, variability, type) for all CDH combined and selected subtypes (Bochdalek and Morgagni). Results: Mothers of 280 (34.0%) case and 3,451 (30.3%) control children reported early pregnancy exposure to cigarette smoking. Adjusted odds ratios for all CDH were increased for any (1.3; 95% confidence interval 1.1–1.5), active (1.3, 1.0–1.7), and passive (1.4, 1.1–1.7) smoking. Early pregnancy alcohol consumption was reported by mothers of 286 (34.9%) case and 4,200 (37.0%) control children; odds were near the null for any consumption (0.9, 0.8–1.1) and consumption with (0.9, 0.7, 1.1) or without (0.9, 0.8, 1.1) binging. Estimates for smoking and alcohol tended to be higher for Bochdalek CDH and Morgagni CDH than those for all CDH. Conclusions: Findings suggest that maternal early pregnancy exposure to cigarette smoking, but less so to alcohol consumption, contributes to CDH. These findings need to be replicated in additional large studies that use systematic case ascertainment and classification, detailed exposure assessment, and examine subtype‐specific associations. [ABSTRACT FROM AUTHOR]

Background: There is little recent research on the teratogenicity of maternal anesthesia exposure. We used National Birth Defects Prevention Study data to describe surgical procedures conducted during pregnancy and to estimate the risk of birth defects associated with periconceptional anesthesia exposure. Methods: We used logistic regression to assess associations between general and local anesthesia for surgery during the periconceptional period and specific birth defects. We calculated odds ratios and 95% confidence intervals for 25 birth defects with at least five exposed cases (11,501 controls, 24,337 cases), adjusted for maternal race/ethnicity, age, body mass index, periconceptional exposure to X‐ray, CT, or radionuclide scans, and study site. Results: The most commonly reported procedures were dental, dermatologic, and cervical cerclage procedures, regardless of gestational timing. Overall, 226 case and 73 control women reported periconceptional general anesthesia; 230 case and 89 control women reported periconceptional local anesthesia. Women who reported general or local anesthesia were disproportionately non‐Hispanic white and were more likely to report periconceptional opioid use and at least one periconceptional X‐ray/CT/radionuclide scan. Women who reported general anesthesia were also more likely to report periconceptional injury. We did not observe any significant associations between either type of anesthesia exposure and the birth defects studied. Odds ratios were generally close to null and imprecise. Conclusions: Our study population reported a wide range of surgical procedures during pregnancy, requiring both general and local anesthesia. Our findings suggest that periconceptional anesthesia is not strongly associated with the birth defects assessed in this study. [ABSTRACT FROM AUTHOR]

Previous studies of alcohol consumption during pregnancy and omphalocele have produced mixed results. We updated an earlier analysis of National Birth Defects Prevention Study (NBDPS) data, adding six years of participants, to examine associations between maternal alcohol consumption and omphalocele. NBDPS was a multi-site, population-based case-control study in the United States. Cases were identified from birth defect surveillance programs in 10 states; controls were liveborn infants without a birth defect randomly selected from the same catchment areas. Mothers self-reported alcohol consumption during the periconceptional period (one month before through the third gestational month) via telephone interview. Our study included mothers of 410 omphalocele cases and 11,219 controls with estimated dates of delivery (EDDs) during 1997–2011. We used logistic regression to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for periconceptional alcohol consumption and omphalocele. We performed a probabilistic bias analysis to evaluate the impact of alcohol exposure misclassification on our results. Overall, 44% of case and 38% of control mothers reported periconceptional alcohol consumption; 22% and 17%, respectively, reported binge drinking. Any maternal periconceptional alcohol consumption was associated with modestly increased odds of omphalocele (AOR 1.35, 95% CI 1.09, 1.68), as was binge drinking (AOR 1.47, 95% CI 1.08, 2.01). Our bias analysis yielded estimates further from the null. We observed modest associations between maternal periconceptional alcohol consumption and omphalocele. Based on our bias analysis, studies of alcohol and birth defects not accounting for exposure misclassification may underestimate associations. • Omphalocele is a rare abdominal wall defect with few known modifiable risk factors. • We analyzed 410 omphalocele cases and 11,219 controls from the United States. • Periconceptional alcohol consumption was associated with higher omphalocele risk. • Self-reported alcohol data likely biases risk estimates towards the null. [ABSTRACT FROM AUTHOR]

Background: There are limited data on the relationship between antihypertensive medication use in early pregnancy and risk of birth defects. Methods: Using data from the National Birth Defects Prevention Study, we examined associations between specific antihypertensive medication classes and 28 noncardiac birth defects. We analyzed self‐reported data on 17,038 case and 11,477 control pregnancies with estimated delivery dates during 1997–2011. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals, adjusted for maternal age, race/ethnicity, body mass index, parity, pregestational diabetes, and study site, for associations between individual birth defects and antihypertensive medication use during the first trimester of pregnancy. We compared risk among women reporting early pregnancy antihypertensive medication use to normotensive women. Results: Hypertensive women who reported early pregnancy antihypertensive medication use were more likely to be at least 35 years old, non‐Hispanic Black, obese, multiparous, and to report pregestational diabetes than normotensive women. Compared to normotensive women, early pregnancy antihypertensive medication use was associated with increased risk of small intestinal atresia (adjusted OR 2.4, 95% CI 1.2–4.7) and anencephaly (adjusted OR 1.9, 95% CI 1.0–3.5). Risk of these defects was not specific to any particular medication class. Conclusions: Maternal antihypertensive medication use was not associated with the majority of birth defects we analyzed, but was associated with an increased risk for some birth defects. Because we cannot entirely rule out confounding by the underlying hypertension and most ORs were based on small numbers, the increased risks observed should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Previous NBDPS (National Birth Defects Prevention Study) findings from 1997 to 2003 suggested that maternal antihypertensive use was associated with congenital heart defects (CHDs). We re-examined associations between specific antihypertensive medication classes and specific CHDs with additional NBDPS data from 2004 to 2011. After excluding mothers missing hypertension information or who reported pregestational diabetes mellitus, a multiple birth, or antihypertensive use but no hypertension, we compared self-reported maternal exposure data on 10 625 CHD cases and 11 137 nonmalformed controls. We calculated adjusted odds ratios [95% confidence intervals] to estimate the risk of specific CHDs associated with antihypertensive use during the month before conception through the third month of pregnancy, controlling for maternal age, race/ethnicity, body mass index, first trimester cigarette smoking, and NBDPS site. Overall, 164 (1.5%) case mothers and 102 (0.9%) control mothers reported early pregnancy antihypertensive use for their hypertension. We observed increased risk of 4 CHD phenotypes, regardless of antihypertensive medication class reported: coarctation of the aorta (2.50 [1.52-4.11]), pulmonary valve stenosis (2.19 [1.44-3.34]), perimembranous ventricular septal defect (1.90 [1.09-3.31]), and secundum atrial septal defect (1.94 [1.36-2.79]). The associations for these phenotypes were statistically significant for mothers who reported β-blocker use or renin-angiotensin system blocker use; estimates for other antihypertensive medication classes were generally based on fewer exposed cases and were less stable but remained elevated. Our results support and expand on earlier NBDPS findings that antihypertensive medication use may be associated with increased risk of specific CHDs, although we cannot completely rule out confounding by underlying disease characteristics. [ABSTRACT FROM AUTHOR]

First trimester entry into prenatal care is recommended for all women, and especially women with pre-pregnancy conditions. Our objective was to determine whether women with pre-pregnancy conditions were at lower risk of entry after the first trimester (delayed entry) into prenatal care than women without a pre-pregnancy health condition. We used data from 10,890 participants in the National Birth Defects Prevention Study who delivered liveborn infants without birth defects. Women reported pre-pregnancy conditions and timing of entry into prenatal care during a computer-assisted telephone interview. Multivariable logistic regression analyses were conducted to evaluate whether having a pre-pregnancy condition was associated with delayed entry into prenatal care compared to women without pre-pregnancy conditions. Approximately 13% of women reported delayed entry into prenatal care, and 18% of women reported a pre-pregnancy condition. Delayed entry into prenatal care was not associated with pre-pregnancy cardiometabolic or neurologic conditions. Women with thyroid conditions were less likely to report delayed entry into prenatal care (prevalence odds ratio (OR), 95% confidence interval (CI): 0.55 [0.32, 0.94]), but women with hematologic and respiratory conditions were more likely to report delayed entry into prenatal care (OR: 1.95 [1.00, 3.82] and 1.27 [0.95, 1.72], respectively), compared to those without any chronic conditions. Future research investigating the success of early prenatal care among women with thyroid conditions could identify ways to reduce delayed prenatal care among women with other pre-pregnancy conditions. [ABSTRACT FROM AUTHOR]