Associations between maternal periconceptional alcohol consumption and risk of omphalocele among offspring, National Birth Defects Prevention Study, 1997-2011.

OBJECTIVE: 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. METHODS: 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. 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. CONCLUSIONS: 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.

Antifungal medication use during early pregnancy and the risk of congenital heart defects in the National Birth Defects Prevention Study, 1997-2011.

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.

Maternal exposure to zolpidem and risk of specific birth defects.

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.

Antifungal medication use during pregnancy and the risk of selected major birth defects in the National Birth Defects Prevention Study, 1997-2011.

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.

Maternal dietary caffeine consumption and risk of birth defects in the National Birth Defects Prevention Study, 1997-2011.

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.

Maternal cyclobenzaprine exposure and risk of birth defects in the National Birth Defects Prevention Study (1997-2011) and Birth Defects Study to Evaluate Pregnancy exposureS (2014-2018).

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.

Agreement between maternal report and medical records on use of medications during early pregnancy in New York.

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.

Risk of birth defects by pregestational type 1 or type 2 diabetes: National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Previous studies found consistent associations between pregestational diabetes and birth defects. Given the different biological mechanisms for type 1 (PGD1) and type 2 (PGD2) diabetes, we used National Birth Defects Prevention Study (NBDPS) data to estimate associations by diabetes type. METHODS: The NBDPS was a study of major birth defects that included pregnancies with estimated delivery dates from October 1997 to December 2011. We compared self-reported PGD1 and PGD2 for 29,024 birth defect cases and 10,898 live-born controls. For case groups with ≥5 exposed cases, we estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the association between specific defects and each diabetes type. We calculated crude ORs (cORs) and 95% CIs with Firth's penalized likelihood for case groups with 3-4 exposed cases. RESULTS: Overall, 252 (0.9%) cases and 24 (0.2%) control mothers reported PGD1, and 357 (1.2%) cases and 34 (0.3%) control mothers reported PGD2. PGD1 was associated with 22/26 defects examined and PGD2 was associated with 29/39 defects examined. Adjusted ORs ranged from 1.6 to 70.4 for PGD1 and from 1.6 to 59.9 for PGD2. We observed the strongest aORs for sacral agenesis (PGD1: 70.4, 32.3-147; PGD2: 59.9, 25.4-135). For both PGD1 and PGD2, we observed elevated aORs in every body system we evaluated, including central nervous system, orofacial, eye, genitourinary, gastrointestinal, musculoskeletal, and cardiac defects. CONCLUSIONS: We observed positive associations between both PGD1 and PGD2 and birth defects across multiple body systems. Future studies should focus on the role of glycemic control in birth defect risk to inform prevention efforts.

Maternal exposure to heparin products and risk of birth defects in the National Birth Defects Prevention Study.

BACKGROUND: Heparin and low-molecular-weight heparin are the preferred anticoagulants during pregnancy as they do not cross the placenta. Although research on the safety of heparin products has been reassuring, previous studies have considered birth defects as a single outcome or by larger organ system and have not examined associations with specific birth defects. METHODS: We analyzed data from the National Birth Defects Prevention Study, a multisite, population-based case-control study from 1997 to 2011. We used unconditional logistic regression with Firth's penalized likelihood to calculate adjusted odds ratios (ORs) and profile likelihood 95% confidence intervals (CIs) for defects with at least five exposed cases. For defects with 3-4 exposed cases, we estimated crude ORs and exact 95% CIs. RESULTS: Of the 42,743 women in our analysis, 117 (0.4%) case and 44 (0.4%) control mothers reported using a heparin product in early pregnancy. The adjusted ORs ranged from 0.9 to 3.9 and were elevated for anorectal atresia (OR = 2.0, 95% CI = 0.8-4.3), longitudinal limb deficiency (3.5, 1.3-7.8), transverse limb deficiency (1.8, 0.6-4.3), atrioventricular septal defect (3.9, 1.4-9.0), and secundum atrial septal defect (2.2, 1.2-3.8). CONCLUSIONS: We observed elevated associations for some birth defects, although heparin is a rare exposure, which limited our ability to evaluate many associations. Future studies that can explore specific birth defects and adequately control for confounding by indication are needed. Given that women with an indication for heparin products during pregnancy often need to take medication, one must remain mindful of the underlying risk of a birth defect that exists regardless of medication use.

The risks of birth defects and childhood cancer with conception by assisted reproductive technology.

STUDY QUESTION: Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? SUMMARY ANSWER: The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. WHAT IS KNOWN ALREADY: The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83 946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Delayed entry into prenatal care among women with pre-pregnancy health conditions, National Birth Defects Prevention Study, 1997-2011.

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.

Interaction of maternal medication use with ambient heat exposure on congenital heart defects in the National Birth Defects Prevention Study.

BACKGROUND: Maternal exposure to weather-related extreme heat events (EHEs) has been associated with congenital heart defects (CHDs) in offspring. Certain medications may affect an individual's physiologic responses to EHEs. We evaluated whether thermoregulation-related medications modified associations between maternal EHE exposure and CHDs. METHODS: We linked geocoded residence data from the U.S. National Birth Defects Prevention Study, a population-based case-control study, to summertime EHE exposures. An EHE was defined using the 90th percentile of daily maximum temperature (EHE90) for each of six climate regions during postconceptional weeks 3-8. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between EHE90 and the risk of CHDs were estimated by strata of maternal thermoregulation-related medication use and climate region. Interaction effects were evaluated on multiplicative and additive scales. RESULTS: Over 45% of participants reported thermoregulation-related medication use during the critical period of cardiogenesis. Overall, these medications did not significantly modify the association between EHEs and CHDs. Still, medications that alter central thermoregulation increased aORs (95% CI) of EHE90 from 0.73 (0.41, 1.30) among non-users to 5.09 (1.20, 21.67) among users in the Southwest region, U.S. This effect modification was statistically significant on the multiplicative (P = 0.03) and additive scales, with an interaction contrast ratio (95% CI) of 1.64 (0.26, 3.02). CONCLUSION: No significant interaction was found for the maternal use of thermoregulation-related medications with EHEs on CHDs in general, while medications altering central thermoregulation significantly modified the association between EHEs and CHDs in Southwest U.S. This finding deserves further research.

Maternal cigarette smoking and alcohol consumption and congenital diaphragmatic hernia.

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.

Maternal periconceptional alcohol consumption and gastroschisis in the National Birth Defects Prevention Study, 1997-2011.

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.

Maternal hereditary hemolytic anemia and birth defects in the National Birth Defects Prevention Study.

OBJECTIVES: Hereditary hemolytic anemia (HHA) results from genetic mutations that cause red blood cell abnormalities. Little research exists on the relationship between HHA and birth defects. Using data from the National Birth Defects Prevention Study (NBDPS), we described characteristics of HHA-exposed women and estimated associations between HHA during pregnancy and specific birth defects. METHODS: The NBDPS was a population-based, case-control study of major birth defects and included pregnancies with estimated delivery dates from October 1997 through December 2011. Participants were ascertained from hospital discharge lists or birth defect registries at 10 sites. Trained interviewers collected information about pregnancy exposures via telephone questionnaire. We described characteristics among HHA-exposed women and calculated crude odds ratios and exact 95% confidence intervals for defects with ≥3 exposed cases. RESULTS: Among 31 HHA-exposed women (28 cases/3 controls), 13 (42%) reported sickle cell anemia, 17 (55%) reported thalassemia, and one (3%) reported hereditary spherocytosis. The average age at delivery for HHA-exposed case women was 27.3 years (range: 17-38). The majority (82%) of HHA-exposed case women reported additional conditions during pregnancy, including hypertension, genitourinary infections, and respiratory illnesses. Additionally, 93% of case women reported using medication during pregnancy. Among the 28 cases, 18 (64%) had isolated birth defects. The defects with ≥3 exposed cases were anencephaly, atrial septal defect, gastroschisis, and cleft palate. Except for anencephaly, the 95% confidence intervals for all estimates were close to or included the null. CONCLUSION: This hypothesis-generating study adds to the sparse literature on the association between HHA and birth defects.

Factors associated with maternal consent for use of residual newborn bloodspots in the National Birth Defects Prevention Study.

PURPOSE: We investigated factors associated with maternal consent to use residual newborn dried bloodspots (DBS) in a national case-control study of birth defects. METHODS: A subset of sites in the National Birth Defects Prevention Study (NBDPS; 1997-2011) asked participants to provide consent for investigators to retrieve DBS from local newborn screening programs to use for research on risk factors for birth defects. We assessed whether consent differed by factors including maternal age, education, parity, body mass index, language of interview, country of birth, and case-control status. RESULTS: Of 5,850 mothers of cases and 2,534 mothers of controls, 57% provided consent for the DBS component. Mothers of cases were more likely to participate than mothers of controls (61% vs. 52%), as were mothers who self-reported white race, >12 years of education, and born in the United States. CONCLUSIONS: Retrieval of DBS can be integrated into retrospective studies of neonatal outcomes including birth defects. In NBDPS, participation in the DBS component was moderate and varied by some sociodemographic factors. Further research is needed to better understand families' perspectives on using residual DBS for secondary research. Representative participation is important to reduce the potential for selection bias in future studies using DBS for children's health research.

Maternal exposure to hydroxychloroquine and birth defects.

BACKGROUND: Hydroxychloroquine is a treatment for rheumatic disease and considered safe during pregnancy. Interest in hydroxychloroquine has increased as it is being examined as a potential treatment and prophylaxis for coronavirus disease 2019. Data on the risks of specific birth defects associated with hydroxychloroquine use are sparse. METHODS: Using data from two case-control studies (National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study), we described women who reported hydroxychloroquine use in pregnancy and the presence of specific major birth defects in their offspring. Cases had at least one major birth defect and controls were live-born healthy infants. Women self-reported medication use information in the few months before pregnancy through delivery. RESULTS: In total, 0.06% (19/31,468) of case and 0.04% (5/11,614) of control mothers in National Birth Defects Prevention Study, and 0.04% (11/29,838) of case and 0.05% (7/12,868) of control mothers in Birth Defects Study reported hydroxychloroquine use. Hydroxychloroquine users had complicated medical histories and frequent medication use for a variety of conditions. The observed birth defects among women taking hydroxychloroquine were varied and included nine oral cleft cases; the elevated observed:expected ratios for specific oral cleft phenotypes and for oral clefts overall had 95% confidence intervals that included 1.0. CONCLUSION: While teratogens typically produce a specific pattern of birth defects, the observed birth defects among the hydroxychloroquine-exposed women did not present a clear pattern, suggesting no meaningful evidence for the risk of specific birth defects. The number of exposed cases is small; results should be interpreted cautiously.

Modification of the association between diabetes and birth defects by obesity, National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Maternal pregestational diabetes and obesity are risk factors for birth defects. Diabetes and obesity often occur together; it is unclear whether their co-occurrence compounds birth defect risk. METHODS: We analyzed 1997-2011 data on 29,671 cases and 10,963 controls from the National Birth Defects Prevention Study, a multisite case-control study. Mothers self-reported height, pregestational weight, and diabetes (pregestational and gestational; analyzed separately). We created four exposure groups: no obesity or diabetes (referent), obesity only, diabetes only, and both obesity and diabetes. We estimated odds ratios (ORs) using logistic regression and the relative excess risk due to interaction (RERI). RESULTS: Among mothers with pregestational obesity without diabetes, modest associations (OR range: 1.1-1.5) were observed for neural tube defects, small intestinal atresia, anorectal atresia, renal agenesis/hypoplasia, omphalocele, and several congenital heart defects. Pregestational diabetes, regardless of obesity, was strongly associated with most birth defects (OR range: 2.0-75.9). Gestational diabetes and obesity had a stronger association than for obesity alone and the RERI (in parentheses) suggested additive interaction for hydrocephaly (1.2; 95% confidence interval [CI]: -0.1, 2.5), tetralogy of Fallot (0.9; 95% CI: -0.01, 1.8), atrioventricular septal defect (1.1; 95% CI: -0.1, 2.3), hypoplastic left heart syndrome (1.1; 95% CI: -0.2, 2.4), and atrial septal defect secundum or not otherwise specified (1.0; 95% CI: 0.3, 1.6; only statistically significant RERI). CONCLUSIONS: Our results do not support a synergistic relationship between obesity and diabetes for most birth defects examined. However, there are opportunities for prevention by reducing obesity and improving glycemic control among women with pregestational diabetes before conception.

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth.

PURPOSE: Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects. METHODS: Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins). RESULTS: In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins. CONCLUSION: Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.

The risk of birth defects with conception by ART.

STUDY QUESTION: What is the association between ART conception and treatment parameters and the risk of birth defects? SUMMARY ANSWER: Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively. WHAT IS KNOWN ALREADY: Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother's information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. E.W. is a contract vendor for SART; all other authors report no conflicts. TRIAL REGISTRATION NUMBER: N/A.