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

Factors associated with employment status before and during pregnancy: Implications for studies of pregnancy outcomes

Background: Potential confounding or effect modification by employment status is frequently overlooked in pregnancy outcome studies. Methods: To characterize how employed and non-employed women differ, we compared demographics, behaviors, and reproductive histories by maternal employment status for 8,343 mothers of control (non-malformed) infants in the National Birth Defects Prevention Study (1997–2007) and developed a multivariable model for employment status anytime during pregnancy and the 3 months before conception. Results: Sixteen factors were independently associated with employment before or during pregnancy, including: maternal age, pre-pregnancy body mass index, pregnancy intention, periconceptional/first trimester smoking and alcohol consumption, and household income. Conclusions: Employment status was significantly associated with many common risk factors for adverse pregnancy outcomes. Pregnancy outcome studies should consider adjustment or stratification by employment status. In studies of occupational exposures, these differences may cause uncontrollable confounding if non-employed women are treated as unexposed instead of excluded from analysis. Am. J. Ind. Med. 60:329–341, 2017. © 2017 Wiley Periodicals, Inc

Association between maternal periconceptional alcohol consumption and neural tube defects: Findings from the National Birth Defects Prevention Study, 1997–2011

Background: Neural tube defects (NTD)s are common birth defects with a multifactorial etiology. Findings from human studies examining environmental (non-inherited) exposures tend to be inconclusive. In particular, although animal studies of alcohol exposure and NTDs support its teratogenic potential, human studies are equivocal. Using data from the National Birth Defects Prevention Study (NBDPS), associations between maternal periconceptional (1 month before through 1 month after conception) alcohol consumption and NTDs in offspring were examined. Methods: NTD cases and unaffected live born singleton controls with expected dates of delivery from October 1997–December 2011 were enrolled in the NBDPS. Interview reports of alcohol consumption (quantity, frequency, variability, type) from 1,922 case and 11,251 control mothers were analyzed. Crude and adjusted odds ratios (aOR)s and 95% confidence intervals (CI)s for alcohol consumption and all NTDs combined and selected subtypes (spina bifida, anencephaly, encephalocele) were estimated using unconditional logistic regression analysis. Results: Among mothers in the NBDPS, 28% of NTD case and 35% of control mothers reported any periconceptional alcohol consumption. For each measure of alcohol consumption, inverse associations were observed for all NTDs combined (aORs = 0.6–1.0). Results for NTD subtypes tended to be similar, but CIs for spina bifida and encephalocele were more likely to include the null. Conclusions: These findings suggest a lack of positive associations between maternal periconceptional alcohol consumption and NTDs. Future studies should continue to evaluate the association between maternal alcohol consumption and NTDs in offspring accounting for methodological limitations such as potential misclassification from self-reported alcohol consumption

Quantification of selection bias in studies of risk factors for birth defects among livebirths

Background: Risk factors for birth defects are frequently investigated using data limited to liveborn infants. By conditioning on survival, results of such studies may be distorted by selection bias, also described as “livebirth bias.” However, the implications of livebirth bias on risk estimation remain poorly understood. Objectives: We sought to quantify livebirth bias and to investigate the conditions under which it arose. Methods: We used data on 3994 birth defects cases and 11 829 controls enrolled in the National Birth Defects Prevention Study to compare odds ratio (OR) estimates of the relationship between three established risk factors (antiepileptic drug use, smoking, and multifetal pregnancy) and four birth defects (anencephaly, spina bifida, omphalocele, and cleft palate) when restricted to livebirths as compared to among livebirths, stillbirths, and elective terminations. Exposures and birth defects represented varying strengths of association with livebirth; all controls were liveborn. We performed a quantitative bias analysis to evaluate the sensitivity of our results to excluding terminated and stillborn controls. Results: Cases ranged from 33% liveborn (anencephaly) to 99% (cleft palate). Smoking and multifetal pregnancy were associated with livebirth among anencephaly (crude OR [cOR] 0.61 and cOR 3.15, respectively) and omphalocele cases (cOR 2.22 and cOR 5.22, respectively). For analyses of the association between exposures and birth defects, restricting to livebirths produced negligible differences in estimates except for anencephaly and multifetal pregnancy, which was twofold higher among livebirths (adjusted OR [aOR] 4.93) as among all pregnancy outcomes (aOR 2.44). Within tested scenarios, bias analyses suggested that results were not sensitive to the restriction to liveborn controls. Conclusions: Selection bias was generally limited except for high mortality defects in the context of exposures strongly associated with livebirth. Findings indicate that substantial livebirth bias is unlikely to affect studies of risk factors for most birth defects

Maternal exposure to disinfection by-products and risk of hypospadias in the national birth defects prevention study (2000–2005)

The purpose of this study was to estimate the association between 2nd and 3rd degree hypospadias and maternal exposure to disinfection by-products (DBPs) using data from a large case-control study in the United States. Concentration estimates for total trihalomethanes (TTHMs), the sum of the five most prevalent haloacetic acids (HAA5), and individual species of each were integrated with data on maternal behaviors related to water use from the National Birth Defects Prevention Study (NBDPS) to create three different exposure metrics: (1) household DBP concentrations; (2) estimates of DBP ingestion; (3) predicted uptake (i.e., internal dose) of trihalomethanes (THMs) via ingestion, showering, and bathing. The distribution of DBP exposure was categorized as follows: (Q1/referent) < 50%; (Q2) ≥ 50% to < 75%; and (Q3) ≥ 75%. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Generally, null associations were observed with increasing TTHM or HAA5 exposure. An increased risk was observed among women with household bromodichloromethane levels in the second quantile (aOR: 1.8; 95% CI: 1.2, 2.7); however, this association did not persist after the inclusion of individual-level water-use data. Findings from the present study do not support the hypothesis that maternal DBP exposures are related to the occurrence of hypospadias

Paternal and joint parental occupational pesticide exposure and spina bifida in the National Birth Defects Prevention Study, 1997 to 2002

Background: Because of persistent concerns over the association between pesticides and spina bifida, we examined the role of paternal and combined parental occupational pesticide exposures in spina bifida in offspring using data from a large population-based study of birth defects. Methods: Occupational information from fathers of 291 spina bifida cases and 2745 unaffected live born control infants with estimated dates of delivery from 1997 to 2002 were collected by means of maternal report. Two expert industrial hygienists estimated exposure intensity and frequency to insecticides, herbicides, and fungicides. Multivariable logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for exposure to any pesticide and to any class of pesticide (yes/no; and by median), and exposure to combinations of pesticides (yes/no) and risk of spina bifida. Adjusted odds ratios were also estimated by parent exposed to pesticides (neither, mother only, father only, both parents). RESULTS: Joint parental occupational pesticide exposure was positively associated with spina bifida (aOR, 1.5; 95% CI, 0.9–2.4) when compared with infants with neither maternal nor paternal exposures; a similar association was not observed when only one parent was exposed. There was a suggested positive association between combined paternal insecticide and fungicide exposures and spina bifida (aOR, 1.5; 95% CI, 0.8–2.8), however, nearly all other aORs were close to unity. Conclusion: Overall, there was little evidence paternal occupational pesticide exposure was associated with spina bifida. However, the small numbers make it difficult to precisely evaluate the role of pesticide classes, individually and in combination. Birth Defects Research (Part A) 106:963–971, 2016

Maternal exposure to outdoor air pollution and congenital limb deficiencies in the National Birth Defects Prevention Study

Background: Congenital limb deficiencies (CLDs) are a relatively common group of birth defects whose etiology is mostly unknown. Recent studies suggest maternal air pollution exposure as a potential risk factor. Aim: To investigate the relationship between ambient air pollution exposure during early pregnancy and offspring CLDs. Methods: The study population was identified from the National Birth Defects Prevention Study, a population-based multi-center case-control study, and consisted of 615 CLD cases and 5,701 controls with due dates during 1997 through 2006. Daily averages and/or maxima of six criteria air pollutants (particulate matter &lt;2.5 μm [PM2.5], particulate matter &lt;10 μm [PM10], nitrogen dioxide [NO2], sulfur dioxide [SO2], carbon monoxide [CO], and ozone [O3]) were averaged over gestational weeks 2–8, as well as for individual weeks during this period, using data from EPA air monitors nearest to the maternal address. Logistic regression was used to estimate odds ratios (aORs) and 95% confidence intervals (CIs) adjusted for maternal age, race/ethnicity, education, and study center. We estimated aORs for any CLD and CLD subtypes (i.e., transverse, longitudinal, and preaxial). Potential confounding by co-pollutant was assessed by adjusting for one additional air pollutant. Using the single pollutant model, we further investigated effect measure modification by body mass index, cigarette smoking, and folic acid use. Sensitivity analyses were conducted restricting to those with a residence closer to an air monitor. Results: We observed near-null aORs for CLDs per interquartile range (IQR) increase in PM10, PM2.5, and O3. However, weekly averages of the daily average NO2 and SO2, and daily max NO2, SO2, and CO concentrations were associated with increased odds of CLDs. The crude ORs ranged from 1.03 to 1.12 per IQR increase in these air pollution concentrations, and consistently elevated aORs were observed for CO. Stronger associations were observed for SO2 and O3 in subtype analysis (preaxial). In co-pollutant adjusted models, associations with CO remained elevated (aORs: 1.02–1.30); but aORs for SO2 and NO2 became near-null. The aORs for CO remained elevated among mothers who lived within 20 km of an air monitor. The aORs varied by maternal BMI, smoking status, and folic acid use. Conclusion: We observed modest associations between CLDs and air pollution exposures during pregnancy, including CO, SO2, and NO2, though replication through further epidemiologic research is warranted

Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways

A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery = 3978; Nreplication = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT = 440; Nreplication_TDT = 275) and case–control analyses separately in infants (Ndiscovery_CCI = 1635; Nreplication_CCI = 990) and mothers (case status defined by infant; Ndiscovery_CCM = 1703; Nreplication_CCM = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery = 4.08 × 10−9; preplication = 2.44 × 10−4). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery = 1.61 × 10−7; preplication = 0.0016). Two other SNPs were suggestively associated (p &lt; 1 × 10−6) with OHD in only the discovery sample. In the case–control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds (× discovery &lt; 1 × 10−5 and preplication &lt; 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery = 1.42 × 10−6; preplication = 0.04). Additional SNPs with pdiscovery &lt; 1 × 10−5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings

Exome sequencing of child–parent trios with bladder exstrophy: Findings in 26 children

Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect