A.J. Agopian

Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons: Effects on Gastroschisis among Offspring in the National Birth Defects Prevention Study

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted. Objective: Our goal was to conduct a case–control study assessing the association between estimated maternal occupational exposure to PAHs and gastroschisis in offspring. Methods: Data from gastroschisis cases and control infants were obtained from the population-based National Birth Defects Prevention Study for the period 1997–2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to determine the association between estimated occupational PAH exposure and gastroschisis among children whose mothers were employed for at least 1 month during the month before conception through the third month of pregnancy. Results: The prevalence of estimated occupational PAH exposure was 9.0% in case mothers (27 of 299) and 3.6% in control mothers (107 of 2,993). Logistic regression analyses indicated a significant association between occupational PAHs and gastroschisis among mothers ≥ 20 years of age [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.27, 5.04] after adjusting for maternal body mass index, education, gestational diabetes, and smoking. This association was not seen in mothers < 20 years (OR = 1.14; 95% CI: 0.55, 2.33), which is notable because although young maternal age is the strongest known risk factor for gastroschisis, most cases are born to mothers ≥ 20 years. Conclusion: Our findings indicate an association between occupational exposure to PAHs among mothers who are ≥ 20 years and gastroschisis. These results contribute to a body of evidence that PAHs may be teratogenic.

Diabetes and Obesity-Related Genes and the Risk of Neural Tube Defects in the National Birth Defects Prevention Study

Few studies have evaluated genetic susceptibility related to diabetes and obesity as a risk factor for neural tube defects (NTDs). The authors investigated 23 single nucleotide polymorphisms among 9 genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, SLC2A2, TCF7L2, and UCP2) associated with type 2 diabetes or obesity. Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study during 1999-2007. Log-linear models were used to evaluate maternal and offspring genetic effects. After application of the false discovery rate, there were 5 significant maternal genetic effects. The less common alleles at the 4 FTO single nucleotide polymorphisms showed a reduction of NTD risk (for rs1421085, relative risk (RR) = 0.73 (95% confidence interval (CI): 0.62, 0.87); for rs8050136, RR = 0.79 (95% CI: 0.67, 0.93); for rs9939609, RR = 0.79 (95% CI: 0.67, 0.94); and for rs17187449, RR = 0.80 (95% CI: 0.68, 0.95)). Additionally, maternal LEP rs2071045 (RR = 1.31, 95% CI: 1.08, 1.60) and offspring UCP2 rs660339 (RR = 1.32, 95% CI: 1.06, 1.64) were associated with NTD risk. Furthermore, the maternal genotype for TCF7L2 rs3814573 suggested an increased NTD risk among obese women. These findings indicate that maternal genetic variants associated with glucose homeostasis may modify the risk of having an NTD-affected pregnancy.

Case–Control Study of Maternal Residential Atrazine Exposure and Male Genital Malformations

Exposure to endocrine disrupting chemicals has been associated with risk for male genital malformations. However, residential prenatal exposure to atrazine, an endocrine disrupting pesticide, has not been evaluated. We obtained data from the Texas Birth Defects Registry for 16,433 cases with isolated male genital malformations and randomly selected, population‐based controls delivered during 1999–2008. County‐level estimates of atrazine exposure from the United States Geological Survey were linked to all subjects. We evaluated the relationship between estimated maternal residential atrazine exposure and risk for male genital malformations in offspring. Separate unconditional logistic regression analyses were conducted for hypospadias, cryptorchidism, and small penis. We observed modest, but consistent, associations between medium‐low and/or medium levels of estimated periconceptional maternal residential atrazine exposure and every male genital malformation category evaluated (e.g., adjusted odds ratio for medium compared to low atrazine levels and all male genital malformations: 1.2, 95% confidence interval: 1.1–1.3). Previous literature from animal and epidemiological studies supports our findings. Our results provide further evidence of a suspected teratogenic role of atrazine.

Spina bifida subtypes and sub‐phenotypes by maternal race/ethnicity in the National Birth Defects Prevention Study

Spina bifida refers to a collection of neural tube defects, including myelomeningocele, meningocele, and myelocele (SBM), as well as lipomyelomeningocele and lipomeningocele (SBL). Maternal race/ethnicity has been associated with an increased risk for spina bifida among offspring. To better understand this relationship, we evaluated different spina bifida subtypes (SBM vs. SBL) and sub‐phenotypes (anatomic level or presence of additional malformations) by maternal race/ethnicity using data from the National Birth Defects Prevention Study. This study is a large, multisite, population‐based study of nonsyndromic birth defects. Prevalence estimates were obtained using data from spina bifida cases (live births, fetal deaths, and elective terminations) and total live births in the study regions. From October 1997 through December 2005, 1,046 infants/fetuses with spina bifida were delivered, yielding a prevalence of 3.06 per 10,000 live births. Differences in the prevalences of SBM vs. SBL, isolated versus non‐isolated SBM, and lesion level in isolated SBM among case offspring were observed by maternal race/ethnicity. Compared to non‐Hispanic (NH) White mothers, offspring of Hispanic mothers had higher prevalences of each subtype and most sub‐phenotypes, while offspring of NH Black mothers generally had lower prevalences. Furthermore, differences in race/ethnicity among those with isolated SBM were more pronounced by sex. For instance, among male offspring, the prevalence of isolated SBM was significantly higher for those with Hispanic mothers compared to NH White mothers [prevalence ratio (PR): 1.55, 95% confidence interval: 1.23–1.95]. These findings provide evidence that certain spina bifida subtypes and sub‐phenotypes may be etiologically distinct.

Preconceptional folic acid‐containing supplement use in the national birth defects prevention study

BACKGROUND Despite public health campaigns encouraging women to take a daily folic acid supplement, the proportion of reproductive age women, in the United States, who comply with this recommendation is less than optimal. The objective of this analysis was to identify predictors of preconceptional folic acid-containing supplement use to define subgroups of women who may benefit from targeted folic acid campaigns. METHODS This study included 6570 mothers of live born infants from the control population of National Birth Defects Prevention Study (1997-2005). Logistic regression analyses were used to identify predictors of preconceptional folic acid supplementation. A classification and regression tree (CART) analysis was used to define subgroups of women with different patterns of preconceptional folic acid supplementation. RESULTS Race/ethnicity, education, age at delivery, nativity, employment, income, number of dependents, smoking, and birth control use were significantly associated with preconceptional folic acid-containing supplement use. Based on a CART analysis, education, race/ethnicity, and age were the most distinguishing factors between women with different preconceptional supplementation patterns. Non-white women with <4 years of a college education were the least likely to use folic acid-containing supplements (11%). However, even in the most compliant subgroup (women with ≥4 years of college), only 60% of women supplemented with folic acid. CONCLUSION These results demonstrate the need for continued efforts to increase folic acid supplementation among all reproductive aged women. However, the success of such efforts may be improved if maternal characteristics such as education, race/ethnicity, and age, are considered in the development of future interventions.

Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Congenital Heart Defects among Offspring in the National Birth Defects Prevention Study

BACKGROUND There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring. METHODS Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring. RESULTS The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58-1.67), septal defects (AOR, 1.28; 95% CI, 0.86-1.90), or with any isolated CHD subtype. CONCLUSIONS Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012.

Descriptive epidemiology of nonsyndromic omphalocele in Texas, 1999-2004.

Omphalocele is a congenital malformation that involves protrusion of abdominal contents into the umbilicus. Though omphalocele may present as a manifestation of several chromosomal and Mendelian syndromes, the etiology for nonsyndromic omphalocele is unknown. The present study sought to estimate the birth prevalence of nonsyndromic omphalocele in offspring of women residing in Texas from 1999 to 2004, and to describe prevalence as a function of parental and infant demographic characteristics. Data on 325 cases with nonsyndromic omphalocele and 2,208,758 live births delivered during 1999–2004 were obtained from the Texas Birth Defects Registry. These data were used to estimate omphalocele birth prevalence and obtain both crude and adjusted prevalence ratios for the association of nonsyndromic omphalocele with parental and infant demographic characteristics. Nonsyndromic omphaloceles were significantly more common among the offspring of women without previous live births (adjusted prevalence ratio: 1.80, 95% CI: 1.41–2.30), compared to the offspring of women with previous live births. The prevalence of nonsyndromic omphalocele was also increased among women aged 25–29 (adjusted prevalence ratio: 1.68, 95% CI: 1.12–2.50) and women aged 40 and older (adjusted prevalence ratio: 4.83, 95% CI: 2.63–8.86) compared to the offspring of women age <20, and in infants of multiple gestation pregnancies compared to singleton infants (adjusted prevalence ratio: 2.03, 95% CI: 1.22–3.37). In addition, among Hispanic women, the prevalence of nonsyndromic omphalocele was higher in the offspring of those born in the U.S. as compared to those born elsewhere (adjusted prevalence ratio: 1.50, 95% CI: 1.12–2.00). These findings augment the existing omphalocele literature.

Descriptive Epidemiology of Non-syndromic Complete Atrioventricular Canal Defects

BACKGROUND Complete atrioventricular canal defects (CAVC) are a common heart defect, but few epidemiologic studies have evaluated non-syndromic CAVC. Risk factors for non-syndromic CAVC have not been well established. METHODS To assess the relationship between risk for non-syndromic CAVC in offspring and several sociodemographic and reproductive parental factors, including maternal diabetes and obesity, we conducted Poisson regression analyses, using data ascertained through the Texas Birth Defects Registry, a large, population-based birth defects registry. Data were evaluated for 563 non-syndromic cases with CAVC. RESULTS Significant associations were observed between non-syndromic CAVC in offspring and maternal pregestational diabetes (adjusted prevalence ratio (aPR) 6.74; 95% confidence interval (CI) 3.67, 12.37), gestational diabetes (aPR 1.69; 95% CI 1.03, 2.79) and obesity (aPR 1.69; 95% CI 1.24, 2.30). CONCLUSIONS  Our findings add non-syndromic CAVC to the growing list of birth defects that appear to be associated with maternal diabetes and obesity.

Evaluating the effects of maternal exposure to benzene, toluene, ethyl benzene, and xylene on oral clefts among offspring in Texas: 1999–2008

BACKGROUND There is evidence from previous studies that maternal occupational exposure to hazardous air pollutants (HAPs) is positively associated with oral clefts; however, studies evaluating the association between residential exposure to these toxicants and oral clefts are lacking. Therefore, our goal was to conduct a case-control study examining the association between estimated maternal residential exposure to benzene, toluene, ethyl benzene, and xylene (BTEX) and the risk of oral clefts among offspring. METHODS Data on 6045 nonsyndromic isolated oral cleft cases (3915 cleft lip with or without cleft palate [CL ± P] and 2130 nonsyndromic isolated cleft palate [CP] cases) delivered between 1999 and 2008 were obtained from the Texas Birth Defects Registry. The control group was a sample of unaffected live births, frequency matched to cases on year of birth. Census tract-level estimates of annual average exposures were obtained from the U.S. Environmental Protection Agency 2005 Hazardous Air Pollutant Exposure Model (HAPEM5) for each pollutant and assigned to each subject based on maternal residence during pregnancy. Logistic regression was used to assess the relationship between estimated maternal exposure to each pollutant (BTEX) separately and the risk of oral clefts in offspring. RESULTS High estimated maternal exposure to benzene was not associated with oral clefts, compared with low estimated exposure (CL ± P adjusted OR = 0.95; 95% CI = 0.81 - 1.12; CP adjusted OR = 0.85; 95% CI = 0.67 - 1.09). Similar results were seen for the other pollutants. CONCLUSION In our study, there was no evidence that maternal exposure to environmental levels of BTEX was associated with oral clefts.

Association between thyroxine levels at birth and choanal atresia or stenosis among infants in Texas, 2004–2007

BACKGROUND The causes of choanal atresia or stenosis (CA) are largely unknown. Infant thyroxine (T(4) ) levels collected during newborn screening may be proxy measures for a risk factor present during the critical period of development. Therefore, we conducted a case-control study to examine the association between newborn T(4) levels and CA. METHODS Data for cases with CA and controls were obtained from the Texas Birth Defects Registry for the period of 2004 to 2007. Information on infant T(4) levels at birth was obtained from the Texas Newborn Screening Program. Controls (n = 3570) were drawn from unaffected births in Texas for the same period and frequency matched to cases (n = 69) on year of birth, then linked to the newborn screening database. Logistic regression was used to evaluate the association between continuous and categorical infant T(4) levels and nonsyndromic CA. RESULTS After adjustment for gestational age and year of birth, infant T(4) levels were inversely associated with CA (adjusted odds ratio [AOR], 0.85; 95% confidence interval [CI], 0.80-0.90). We observed a linear trend (p < 0.001) across quartiles of T(4) ; compared to infants with low levels, AORs for CA were 0.50 (95% CI, 0.28-0.91), 0.39 (95% CI, 0.20-0.75), and 0.15 (95% CI, 0.06-0.40) for infants with medium-to-low, medium, and high levels, respectively. CONCLUSIONS Our findings suggest a role of low thyroid hormone levels in the development of CA, or that low newborn T(4) levels are potential proxy measures of a risk factor present during the critical period. Birth Defects Research (Part A), 2012.