Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.

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.

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.

Neighborhood Deprivation and Neural Tube Defects.

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.

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.

Testing and Validating Semi-automated Approaches to the Occupational Exposure Assessment of Polycyclic Aromatic Hydrocarbons.

INTRODUCTION: When it is not possible to capture direct measures of occupational exposure or conduct biomonitoring, retrospective exposure assessment methods are often used. Among the common retrospective assessment methods, assigning exposure estimates by multiple expert rater review of detailed job descriptions is typically the most valid, but also the most time-consuming and expensive. Development of screening protocols to prioritize a subset of jobs for expert rater review can reduce the exposure assessment cost and time requirement, but there is often little data with which to evaluate different screening approaches. We used existing job-by-job exposure assessment data (assigned by consensus between multiple expert raters) from a large, population-based study of women to create and test screening algorithms for polycyclic aromatic hydrocarbons (PAHs) that would be suitable for use in other population-based studies. METHODS: We evaluated three approaches to creating a screening algorithm: a machine-learning algorithm, a set of a priori decision rules created by experts based on features (such as keywords) found in the job description, and a hybrid algorithm incorporating both sets of criteria. All coded jobs held by mothers of infants participating in National Birth Defects Prevention Study (NBDPS) (n = 35,424) were used in developing or testing the screening algorithms. The job narrative fields considered for all approaches included job title, type of product made by the company, main activities or duties, and chemicals or substances handled. Each screening approach was evaluated against the consensus rating of two or more expert raters. RESULTS: The machine-learning algorithm considered over 30,000 keywords and industry/occupation codes (separate and in combination). Overall, the hybrid method had a similar sensitivity (87.1%) as the expert decision rules (85.5%) but was higher than the machine-learning algorithm (67.7%). Specificity was best in the machine-learning algorithm (98.1%), compared to the expert decision rules (89.2%) and hybrid approach (89.1%). Using different probability cutoffs in the hybrid approach resulted in improvements in sensitivity (24-30%), without the loss of much specificity (7-18%). CONCLUSION: Both expert decision rules and the machine-learning algorithm performed reasonably well in identifying the majority of jobs with potential exposure to PAHs. The hybrid screening approach demonstrated that by reviewing approximately 20% of the total jobs, it could identify 87% of all jobs exposed to PAHs; sensitivity could be further increased, albeit with a decrease in specificity, by adjusting the algorithm. The resulting screening algorithm could be applied to other population-based studies of women. The process of developing the algorithm also provides a useful illustration of the strengths and potential pitfalls of these approaches to developing exposure assessment algorithms.

Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects.

Importance: Antidepressants are commonly used during pregnancy, but limited information is available about individual antidepressants and specific birth defect risks. Objective: To examine associations between individual antidepressants and specific birth defects with and without attempts to partially account for potential confounding by underlying conditions. Design, Setting, and Participants: The population-based, multicenter case-control National Birth Defects Prevention Study (October 1997-December 2011) included cases with selected birth defects who were identified from surveillance systems; controls were randomly sampled live-born infants without major birth defects. Mothers of cases and controls participated in an interview after the expected delivery date. The data were analyzed after the completion of the National Birth Defects Prevent Study's data collection. Exposures: Self-reported antidepressant exposure was coded to indicate monotherapy exposure to antidepressants. Main Outcomes and Measures: We used multivariable logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals for associations between maternal antidepressant use and birth defects. We compared early pregnancy antidepressant-exposed women with those without antidepressant exposure and, to partially account for confounding by underlying maternal conditions, those exposed to antidepressants outside of the birth defect development critical period. Results: This study included 30 630 case mothers of infants with birth defects and 11 478 control mothers (aged 12-53 years). Early pregnancy antidepressant use was reported by 1562 case mothers (5.1%) and 467 control mothers (4.1%), for whom elevated aORs were observed for individual selective serotonin reuptake inhibitors (SSRIs) and selected congenital heart defects (CHD) (eg, fluoxetine and anomalous pulmonary venous return: aOR, 2.56; 95% CI, 1.10-5.93; this association was attenuated after partially accounting for underlying conditions: aOR, 1.89; 95% CI, 0.56-6.42). This pattern was observed for many SSRI-CHD combinations. Associations between SSRIs and non-CHD birth defects often persisted or strengthened after partially accounting for underlying conditions (eg, citalopram and diaphragmatic hernia: aOR, 5.11; 95% CI, 1.29-20.24). Venlafaxine had elevated associations with multiple defects that persisted after partially accounting for underlying conditions (eg, anencephaly and craniorachischisis: aOR, 9.14; 95% CI, 1.91-43.83). Conclusions and Relevance: We found some associations between maternal antidepressant use and specific birth defects. Venlafaxine was associated with the highest number of defects, which needs confirmation given the limited literature on venlafaxine use during pregnancy and risk for birth defects. Our results suggest confounding by underlying conditions should be considered when assessing risk. Fully informed treatment decision-making requires balancing the risks and benefits of proposed interventions against those of untreated depression or anxiety.

Using Supervised Learning Methods to Develop a List of Prescription Medications of Greatest Concern during Pregnancy.

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.

Neural Tube Defects in Pregnancies Among Women With Diagnosed HIV Infection - 15 Jurisdictions, 2013-2017.

In May 2018, a study of birth defects in infants born to women with diagnosed human immunodeficiency virus (HIV) infection in Botswana reported an eightfold increased risk for neural tube defects (NTDs) among births with periconceptional exposure to antiretroviral therapy (ART) that included the integrase inhibitor dolutegravir (DTG) compared with other ART regimens (1). The World Health Organization* (WHO) and the U.S. Department of Health and Human Services† (HHS) promptly issued interim guidance limiting the initiation of DTG during early pregnancy and in women of childbearing age with HIV who desire pregnancy or are sexually active and not using effective contraception. On the basis of additional data, WHO now recommends DTG as a preferred treatment option for all populations, including women of childbearing age and pregnant women. Similarly, the U.S. recommendations currently state that DTG is a preferred antiretroviral drug throughout pregnancy (with provider-patient counseling) and as an alternative antiretroviral drug in women who are trying to conceive.§ Since 1981 and 1994, CDC has supported separate surveillance programs for HIV/acquired immunodeficiency syndrome (AIDS) (2) and birth defects (3) in state health departments. These two surveillance programs can inform public health programs and policy, linkage to care, and research activities. Because birth defects surveillance programs do not collect HIV status, and HIV surveillance programs do not routinely collect data on occurrence of birth defects, the related data have not been used by CDC to characterize birth defects in births to women with HIV. Data from these two programs were linked to estimate overall prevalence of NTDs and prevalence of NTDs in HIV-exposed pregnancies during 2013-2017 for 15 participating jurisdictions. Prevalence of NTDs in pregnancies among women with diagnosed HIV infection was 7.0 per 10,000 live births, similar to that among the general population in these 15 jurisdictions, and the U.S. estimate based on data from 24 states. Successful linking of data from birth defects and HIV/AIDS surveillance programs for pregnancies among women with diagnosed HIV infection suggests that similar data linkages might be used to characterize possible associations between maternal diseases or maternal use of medications, such as integrase strand transfer inhibitors used to manage HIV, and pregnancy outcomes. Although no difference in NTD prevalence in HIV-exposed pregnancies was found, data on the use of integrase strand transfer inhibitors in pregnancy are needed to understand the safety and risks of these drugs during pregnancy.

Maternal occupational exposure to solvents and gastroschisis in offspring - National Birth Defects Prevention Study 1997-2011.

OBJECTIVES: The aim of this study was to assess the association between maternal occupational exposure to solvents and gastroschisis in offspring. METHODS: We used data from the National Birth Defects Prevention Study, a large population-based case-control study of major birth defects conducted in 10 US states from 1997 to 2011. Infants with gastroschisis were ascertained by active birth defects surveillance systems. Control infants without major birth defects were selected from vital records or birth hospital records. Self-reported maternal occupational histories were collected by telephone interview. Industrial hygienists reviewed this information to estimate exposure to aromatic, chlorinated and petroleum-based solvents from 1 month before conception through the first trimester of pregnancy. Cumulative exposure to solvents was estimated for the same period accounting for estimated exposure intensity and frequency, job duration and hours worked per week. ORs and 95% CIs were estimated to assess the association between exposure to any solvents or solvent classes, and gastroschisis risk. RESULTS: Among 879 cases and 7817 controls, the overall prevalence of periconceptional solvent exposure was 7.3% and 7.4%, respectively. Exposure to any solvent versus no exposure to solvents was not associated with gastroschisis after adjusting for maternal age (OR 1.00, 95% CI 0.75 to 1.32), nor was an association noted for solvent classes. There was no exposure-response relationship between estimated cumulative solvent exposure and gastroschisis after adjusting for maternal age. CONCLUSION: Our study found no association between maternal occupational solvent exposure and gastroschisis in offspring. Further research is needed to understand risk factors for gastroschisis.

Association between maternal occupational exposure to polycyclic aromatic hydrocarbons and rare birth defects of the face and central nervous system.

BACKGROUND: Previous studies suggested associations between maternal smoking, a source of exposure to polycyclic aromatic hydrocarbons (PAHs) and other chemicals, and central nervous system and face birth defects; however, no previous studies have evaluated maternal occupational PAH exposure itself. METHODS: Jobs held in the periconceptional period were retrospectively assigned for occupational PAH exposures. Associations between maternal occupational PAH exposure and selected rare defects of the face (cataracts, microphthalmia, glaucoma, microtia, and choanal atresia) and central nervous system (holoprosencephaly, hydrocephaly, cerebellar hypoplasia, and Dandy-Walker malformation) were evaluated using data from the National Birth Defects Prevention Study, a population-based case-control study in the United States. Crude and adjusted odds ratios (ORs) with 95% confidence intervals were calculated to estimate associations between each evaluated defect and PAH exposure using multivariable logistic regression. RESULTS: Food and beverage serving, as well as cooks and food preparation occupations, were among the most frequent jobs held by exposed mothers. Cataracts, microtia, microphthalmia, and holoprosencephaly were significantly associated with PAH exposure with evidence of dose-response (P-values for trend ≤.05). Hydrocephaly was associated with any PAH exposure, but not significant for trend. Sensitivity analyses that reduced possible sources of exposure misclassification tended to strengthen associations. CONCLUSIONS: This is the first population-based case-control study to evaluate associations between maternal occupational PAH exposures and these rare birth defects of the central nervous system and face.

Maternal surgery and anesthesia during pregnancy and risk of birth defects in the National Birth Defects Prevention Study, 1997-2011.

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.

Atypical antipsychotic use during pregnancy and birth defect risk: National Birth Defects Prevention Study, 1997-2011.

PURPOSE: To examine the prevalence of, and factors associated with, atypical antipsychotic use among U.S. pregnant women, and potential associations between early pregnancy atypical antipsychotic use and risk for 14 birth defects. METHODS: We analyzed data from the National Birth Defects Prevention Study (1997-2011), a U.S. population-based case-control study examining risk factors for major structural birth defects. RESULTS: Atypical antipsychotic use during pregnancy was more common among women with pre-pregnancy obesity, and women who reported illicit drug use before and during pregnancy, smoking during pregnancy, alcohol use during pregnancy, or use of other psychiatric medications during pregnancy. We observed elevated associations (defined as a crude odds ratio [cOR] ≥2.0) between early pregnancy atypical antipsychotic use and conotruncal heart defects (6 exposed cases; cOR: 2.3, 95% confidence interval [CI]: 0.9-6.1), and more specifically Tetralogy of Fallot (3 exposed cases; cOR: 2.5, 95% CI: 0.7-8.8), cleft palate (4 exposed cases, cOR: 2.5, 95% CI: 0.8-7.6), anorectal atresia/stenosis (3 exposed cases, cOR: 2.8, 95% CI: 0.8-9.9), and gastroschisis (3 exposed cases, cOR: 2.1, 95% CI: 0.6-7.3). CONCLUSIONS: Our findings support the close clinical monitoring of pregnant women using atypical antipsychotics. Women treated with atypical antipsychotics generally access healthcare services before pregnancy; efforts to reduce correlates of atypical antipsychotic use might improve maternal and infant health in this population.

Maternal Occupational Oil Mist Exposure and Birth Defects, National Birth Defects Prevention Study, 1997⁻2011.

Workers in various industries can be exposed to oil mists when oil-based fluids are aerosolized during work processes. Oil mists can be inhaled or deposited on the skin. Little research exists on the reproductive effects of oil mist exposure in pregnant workers. We aimed to investigate associations between occupational oil mist exposure in early pregnancy and a spectrum of birth defects using data from 22,011 case mothers and 8140 control mothers in the National Birth Defects Prevention Study. In total, 150 mothers were rated as exposed. Manufacturing jobs, particularly apparel manufacturing, comprised the largest groups of exposed mothers. Mothers of infants with septal heart defects (odds ratio (OR): 1.8, 95% confidence interval (CI): 1.0-3.3), and especially perimembranous ventricular septal defects (OR: 2.5, CI: 1.2-5.2), were more likely to be occupationally exposed to oil mists in early pregnancy than control mothers; and their rater-estimated cumulative exposure was more likely to be higher. This was the first U.S. study evaluating associations between oil mist exposure and a broad spectrum of birth defects. Our results are consistent with previous European studies, supporting a potential association between oil-based exposures and congenital heart defects. Further research is needed to evaluate the reproductive effects of occupational oil mist exposure.

Gastroschisis Trends and Ecologic Link to Opioid Prescription Rates - United States, 2006-2015.

Prevalence of gastroschisis, a serious birth defect of the abdominal wall resulting in some of the abdominal contents extending outside the body at birth, has been increasing worldwide (1,2). Gastroschisis requires surgical repair after birth and is associated with digestive and feeding complications during infancy, which can affect development. Recent data from 14 U.S. states indicated an increasing prevalence of gastroschisis from 1995 to 2012 (1). Young maternal age has been strongly associated with gastroschisis, but research suggests that risk factors such as smoking, genitourinary infections, and prescription opioid use also might be associated (3-5). Data from 20 population-based state surveillance programs were pooled and analyzed to assess age-specific gastroschisis prevalence during two 5-year periods, 2006-2010 and 2011-2015, and an ecologic approach was used to compare annual gastroschisis prevalence by annual opioid prescription rate categories. Gastroschisis prevalence increased only slightly (10%) from 2006-2010 to 2011-2015 (prevalence ratio = 1.1, 95% confidence interval [CI] = 1.0-1.1), with the highest prevalence among mothers aged <20 years. During 2006-2015, the prevalence of gastroschisis was 1.6 times higher in counties with high opioid prescription rates (5.1 per 10,000 live births; CI = 4.9-5.3) and 1.4 times higher where opioid prescription rates were medium (4.6 per 10,000 live births; CI = 4.4-4.8) compared with areas with low prescription rates (3.2 per 10,000 live births; CI = 3.1-3.4). Public health research is needed to understand factors contributing to the association between young maternal age and gastroschisis and assess the effect of prescription opioid use during pregnancy on this pregnancy outcome.

Impact of sample collection participation on the validity of estimated measures of association in the National Birth Defects Prevention Study when assessing gene-environment interactions.

To better understand the impact that nonresponse for specimen collection has on the validity of estimates of association, we examined associations between self-reported maternal periconceptional smoking, folic acid use, or pregestational diabetes mellitus and six birth defects among families who did and did not submit buccal cell samples for DNA following a telephone interview as part of the National Birth Defects Prevention Study (NBDPS). Analyses included control families with live born infants who had no birth defects (N = 9,465), families of infants with anorectal atresia or stenosis (N = 873), limb reduction defects (N = 1,037), gastroschisis (N = 1,090), neural tube defects (N = 1,764), orofacial clefts (N = 3,836), or septal heart defects (N = 4,157). Estimated dates of delivery were between 1997 and 2009. For each exposure and birth defect, odds ratios and 95% confidence intervals were calculated using logistic regression stratified by race-ethnicity and sample collection status. Tests for interaction were applied to identify potential differences between estimated measures of association based on sample collection status. Significant differences in estimated measures of association were observed in only four of 48 analyses with sufficient sample sizes. Despite lower than desired participation rates in buccal cell sample collection, this validation provides some reassurance that the estimates obtained for sample collectors and noncollectors are comparable. These findings support the validity of observed associations in gene-environment interaction studies for the selected exposures and birth defects among NBDPS participants who submitted DNA samples.

Population-based case-control study of the association between weather-related extreme heat events and neural tube defects.

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

Agreement between two methods for retrospective assessment of occupational exposure intensity to six chlorinated solvents: Data from The National Birth Defects Prevention Study.

The wide variety of jobs encountered in population-based studies makes retrospective exposure assessment challenging in occupational epidemiology. In this analysis, two methods for estimating exposure intensity to chlorinated solvents are compared: rated (assigned by an expert rater) and modeled (assigned using statistical models). Estimates of rated and modeled intensities were compared for jobs held by mothers participating in the National Birth Defects Prevention Study with possible exposure to six chlorinated solvents: carbon tetrachloride, chloroform, methylene chloride, perchloroethylene, 1,1,1-trichloroethane, and trichloroethylene. For each possibly exposed job, an industrial hygienist assigned (1) an exposure intensity (rated intensity) and (2) determinants of exposure to be used in a statistical model of exposure intensity (modeled intensity). Of 12,326 reported jobs, between 31 (0.3%) and 746 (6%) jobs were rated as possibly exposed to each of the six solvents. Agreement between rated and modeled intensities was low overall (Spearman correlation coefficient range: -0.09 to 0.28; kappa range: -0.23 to 0.43). Although no air measurements were available to determine if rated or modeled estimates were more accurate, review of participants' job titles showed that modeled estimates were often unexpectedly high given the low-exposure tasks found in these jobs. Differences between the high-exposure jobs used to create the statistical models (obtained from air measurements in the published literature) and the low-exposure jobs in the actual study population is a potential explanation for the disagreement between the two methods. Investigators should be aware that statistical models estimating exposure intensity using existing data from one type of worker population might not be generalizable to all populations of workers.

Association between antibiotic use among pregnant women with urinary tract infections in the first trimester and birth defects, National Birth Defects Prevention Study 1997 to 2011.

BACKGROUND: Previous studies noted associations between birth defects and some antibiotics (e.g., nitrofurantoin, sulfonamides) but not others (e.g., penicillins). It is unclear if previous findings were due to antibiotic use, infections, or chance. To control for potential confounding by indication, we examined associations between antibiotic use and birth defects, among women reporting urinary tract infections (UTIs). METHODS: The National Birth Defects Prevention Study is a multi-site, population-based case-control study. Case infants/fetuses have any of over 30 major birth defects and controls are live-born infants without major birth defects. We analyzed pregnancies from 1997 to 2011 to estimate the association between maternally reported periconceptional (month before conception through the third month of pregnancy) use of nitrofurantoin, trimethoprim-sulfamethoxazole, or cephalosporins and specific birth defects, among women with periconceptional UTIs. Women with periconceptional UTIs who reported penicillin use served as the comparator. RESULTS: Periconceptional UTIs were reported by 7.8% (2029/26,068) of case and 6.7% (686/10,198) of control mothers. Most (68.2% of case, 66.6% of control mothers) also reported antibiotic use. Among 608 case and 231 control mothers reporting at least one periconceptional UTI and certain antibiotic use, compared with penicillin, nitrofurantoin use was associated with oral clefts in the offspring (adjusted odds ratio, 1.97 [95% confidence interval, 1.10-3.53]), trimethoprim-sulfamethoxazole use with esophageal atresia (5.31 [1.39-20.24]) and diaphragmatic hernia (5.09 [1.20-21.69]), and cephalosporin use with anorectal atresia/stenosis (5.01 [1.34-18.76]). CONCLUSION: Periconceptional exposure to some antibiotics might increase the risk for certain birth defects. However, because individual birth defects are rare, absolute risks should drive treatment decisions.Birth Defects Research (Part A) 106:940-949, 2016.© 2016 Wiley Periodicals, Inc.

Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports.

OBJECTIVE: To follow up on previously reported associations between periconceptional use of selective serotonin reuptake inhibitors (SSRIs) and specific birth defects using an expanded dataset from the National Birth Defects Prevention Study. DESIGN: Bayesian analysis combining results from independent published analyses with data from a multicenter population based case-control study of birth defects. SETTING: 10 centers in the United States. PARTICIPANTS: 17,952 mothers of infants with birth defects and 9857 mothers of infants without birth defects, identified through birth certificates or birth hospitals, with estimated dates of delivery between 1997 and 2009. EXPOSURES: Citalopram, escitalopram, fluoxetine, paroxetine, or sertraline use in the month before through the third month of pregnancy. Posterior odds ratio estimates were adjusted to account for maternal race/ethnicity, education, smoking, and prepregnancy obesity. MAIN OUTCOME MEASURE: 14 birth defects categories that had associations with SSRIs reported in the literature. RESULTS: Sertraline was the most commonly reported SSRI, but none of the five previously reported birth defects associations with sertraline was confirmed. For nine previously reported associations between maternal SSRI use and birth defect in infants, findings were consistent with no association. High posterior odds ratios excluding the null value were observed for five birth defects with paroxetine (anencephaly 3.2, 95% credible interval 1.6 to 6.2; atrial septal defects 1.8, 1.1 to 3.0; right ventricular outflow tract obstruction defects 2.4, 1.4 to 3.9; gastroschisis 2.5, 1.2 to 4.8; and omphalocele 3.5, 1.3 to 8.0) and for two defects with fluoxetine (right ventricular outflow tract obstruction defects 2.0, 1.4 to 3.1 and craniosynostosis 1.9, 1.1 to 3.0). CONCLUSIONS: These data provide reassuring evidence for some SSRIs but suggest that some birth defects occur 2-3.5 times more frequently among the infants of women treated with paroxetine or fluoxetine early in pregnancy.

Maternal occupational pesticide exposure and risk of congenital heart defects in the National Birth Defects Prevention Study.

BACKGROUND: Congenital heart defects (CHDs) are common birth defects, affecting approximately 1% of live births. Pesticide exposure has been suggested as an etiologic factor for CHDs, but previous results were inconsistent. METHODS: We examined maternal occupational exposure to fungicides, insecticides, and herbicides for 3328 infants with CHDs and 2988 unaffected control infants of employed mothers using data for 1997 through 2002 births from the National Birth Defects Prevention Study, a population-based multisite case-control study. Potential pesticide exposure from 1 month before conception through the first trimester of pregnancy was assigned by an expert-guided task-exposure matrix and job history details self-reported by mothers. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. RESULTS: Maternal occupational exposure to pesticides was not associated with CHDs overall. In examining specific CHD subtypes compared with controls, some novel associations were observed with higher estimated pesticide exposure: insecticides only and secundum atrial septal defect (OR = 1.8; 95% CI, 1.3-2.7, 40 exposed cases); both insecticides and herbicides and hypoplastic left heart syndrome (OR = 5.1; 95% CI, 1.7-15.3, 4 exposed cases), as well as pulmonary valve stenosis (OR = 3.6; 95% CI, 1.3-10.1, 5 exposed cases); and insecticides, herbicides, and fungicides and tetralogy of Fallot (TOF) (OR = 2.2; 95% CI, 1.2-4.0, 13 exposed cases). CONCLUSION: Broad pesticide exposure categories were not associated with CHDs overall, but examining specific CHD subtypes revealed some increased odds ratios. These results highlight the importance of examining specific CHDs separately. Because of multiple comparisons, additional work is needed to verify these associations.