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There is relatively little epidemiologic information about Ebstein anomaly (EA) ─ a rare congenital heart defect. Thus, we analyzed characteristics of EA in a geographically and ethnically diverse population. Data from the National Birth Defects Prevention Study were used to study infants born from 1997-2007 with EA. Birth prevalence and prevalence ratio (PR) estimates were derived from the number of affected infants per 10,000 live births in the catchment area. Case characteristics were examined, stratified by the presence of other cardiac and extracardiac defects. Predictive modeling using logistic regression was conducted to understand infant mortality risk factors. There were 249 cases with EA, for a birth prevalence of 0.55/10,000 live births. Other cardiac defects were present in 41.0% and extracardiac defects in 10% of cases. Prevalence was higher among multiple births compared to singletons (PR 2.41, 95% confidence interval (CI) 1.46-3.92) and preterm compared to term infants (PR 1.84, 95% CI 1.27-2.64). Compared to EA cases without other defects, those with additional defects were more likely to die (crude Odds Ratio (cOR) 4.07, 95% CI 1.71-9.93) or undergo cardiac surgery (cOR 6.06, 95% CI 2.78-13.49). Risk for death during infancy was increased by being small for gestational age (adjusted (a) OR 2.97, 95% CI 1.13-7.76) and having extracardiac defects (aOR 6.31, 95% CI 2.28-17.52). Some findings are consistent with previous work, but further studies of EA could clarify risk factors for occurrence and mortality. Knowing population characteristics could guide development of prevention strategies and may improve clinical care.

In the studies described in this dissertation, we investigated the roles of p53 in normal development, teratogen-induced apoptosis, and birth defects. In the first study, the activation of p53 and its target genes, p21, NOXA, and PUMA, were examined during neural tube closure in mouse embryos exposed to hyperthermia (HS) or 4- peroxycyclophosphamide (4CP), teratogens known to induce neural tube defects (NTDs). In the second study, using p53-deficient mice, we examined the expression of mRNAs and microRNAs (miRNAs) during neural tube closure. In the third study, the incidence of NTDs was investigated in p53- and p21-deficient mouse embryos exposed to HS. Finally, we examined the induction of apoptosis in p53-deficient mouse embryos exposed to HS. HS and 4CP induced the activation of p53 by phosphorylation and accumulation of the protein, leading to an increase in p21 proteins and mRNAs. Although HS and 4CP also induced the expression of Noxa and Puma mRNAs, no significant increases in NOXA and PUMA proteins were observed, suggesting a possible role of transcriptionindependent apoptosis. In the second study, we showed that the expression of 388 genes and 5 miRNAs were significantly altered in p53 -/- compared to p53 +/+ embryos. Finally, we showed that 10% of p53 -/- pups exhibit exencephaly, spina bifida, and/or preaxial polydactyly, whereas no malformations were observed among p21 -/- offspring in the absence of HS. HS resulted in an increased incidence of exencephaly in both p53 and p21 null mice indicating that these two proteins act as teratogen suppressors. Our preliminary data additionally showed that a decreased level of apoptosis was observed in HS-treated embryos lacking a p53 allele, suggesting that too little apoptosis may be causally linked to NTDs observed in embryos exposed to HS. Taken together, these studies suggest that precise control of apoptosis and cell cycle arrest pathways are critical for neural tube development and the prevention of teratogen-induced NTDs.

Background: Primary prevention efforts for both gastroschisis and omphalocele are limited by the lack of known risk factors. Our objective was to investigate associations between potential maternal risk factors and gastroschisis and omphalocele within a large population-based sample of participants enrolled in the National Birth Defects Prevention Study (NBDPS). Methods: Demographic, health-related, and environmental exposure data from the NBDPS were collected from women with expected delivery dates between October 1997 and December 2003. Data were collected on 485 cases of gastroschisis, 168 cases of omphalocele, and 4967 controls. Results: Women who had offspring with gastroschisis were younger (adjusted odds ratio [AOR], 0.84; 95% confidence interval [CI], 0.81-0.86) and less likely to be black (AOR, 0.54; 95% CI, 0.34-0.85) than controls. They also were more likely to have smoked (AOR, 1.51; 95% CI, 1.12-2.03), taken ibuprofen (AOR, 1.61; 95% CI, 1.23-2.10), and consumed alcohol (AOR, 1.38; 95% CI, 1.06-1.79) than controls. Women who had offspring with omphaloceles were more likely to have consumed alcohol (AOR, 1.53; 95% CI, 1.04-2.25) and be heavy smokers (AOR, 4.26; 95% CI, 1.58-11.52) than controls. Conclusions: Our results suggest a moderately increased risk of gastroschisis among women who used tobacco, alcohol, and ibuprofen during early pregnancy. A modestly elevated risk was observed for omphaloceles among women who used alcohol during the first trimester and among women who were heavy smokers.

Birth defects are the leading cause of infant death in the United States. Research has linked poor maternal micronutrient intake to birth defects including neural tube defects, heart defects, and oral clefts. After investigating spatial patterns of these birth defects in the City of Dallas and the neighborhood characteristics within clusters, geospatial access to supermarkets and convenience stores measured by proximity and concentrations are examined as environmental risk factors for nutrition-related birth defects. Spatial clusters of all three nutrition-related birth defects exist in the City of Dallas. Cluster for NTD occurs in vulnerable places with lower income and high minority population specifically Hispanics with no supermarkets. Cluster for heart defects mostly occurs in high income and predominantly white neighborhoods with many supermarkets. Clusters of oral clefts mostly occurs in middle-class income with relatively high minority populations with many convenience stores. For the entire study area, geographical access to supermarkets that include healthy foods are shown to be spatially reachable from most of mothers of infants with nutrition-related birth defects as well as convenience stores that typically include the majority of unhealthy processed foods with very few nutrients. Thus, not only easy geographical access to healthy food vendors but to convenience stores with low quality produces is observed at the same time.

Orofacial clefts (OFCs) are facial malformations that happen during early pregnancy and have a complex and heterogeneous etiology, involving both genetic and environmental risk factors. This project examined the association between maternal nutrition, folaterelated biomarkers, candidate genes involved in one-carbon metabolism (OCM), and OFCs in order to achieve more comprehensive knowledge of how nutrition and genetics influence OFC risk. First, the association between maternal periconceptional multivitamin (PCMV) use, maternal dietary patterns during the periconceptional period, and OFC risk was examined. This study showed that neither PCMV use nor healthy dietary pattern score alone was individually associated with OFC risk. However, the combination of PCMV use and a higher score reflecting the ideal Dietary Approach to Stop Hypertension diet was associated with 55% reduction in the risk of isolated OFCs, evidence that the prevention of OFCs may require attention to both PCMV use and improving maternal diets. Second, the association between maternal multivitamin use, folic acid supplemental intake, and measured blood folate levels in case mothers of OFC children and control mothers was examined. Mothers who had an OFC-affected pregnancy compared with control mothers had lower mean levels of plasma folate in both multivitamin users and non-users. At levels of folic acid intake >400µg/day, the difference in plasma folate between case mothers and control mothers narrowed, evidence that higher folate intake levels may be required for mothers with a history of OFC-affected pregnancy. The ability to utilize supplement folic acid might be modified by MTHFR C677T genotype. In mothers with 677CC genotype, both case and control mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake, although case mothers’ plasma folate concentrations were always significantly lower than control mothers’ until folate supplemental intake reached 400µg. In mothers with 677CT genotype, control but not case mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake. In mothers with 677TT genotype, case but not control mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake. Lastly, variations in folate-related OCM genes were examined in association with risk of OFCs using GWAS data and the case-parent trio approach. Several genes in the OCM pathway were associated with isolated, non-syndromic OFCs with some through genetic effects alone but most through gene-environment interaction effects with maternal multivitamin supplementation during periconceptional period and maternal biomarker concentrations for OCM-related nutrients. These results emphasize the need to consider gene-environment interactions when searching for genes influencing isolated OFCs. Reduction in the prevalence of OFCs could have tremendous importance. The results of this dissertation may help identify factors important to OFCs etiology and in turn, provide valuable targets for preventive intervention. Children born with an OFC require medical care from birth until adulthood and encounter a higher mortality rate. The costs incurred from caring for children born with OFCs not only include the clinical care of many disciplines but also involve the emotional disturbance and social and employment exclusion for affected individuals. Reducing the risk of OFCs would lessen considerable financial and emotional burdens to families and societies.

Dextromethorphan and guaifenesin are the main active components in over-the-counter cough medications. Prenatal exposure to dextromethorphan has been shown to be teratogenic in animal models. Data from human studies for either dextromethorphan or guaifenesin are limited and inconclusive. We used data from the population-based National Birth Defects Prevention Study (NBDPS) to examine associations between maternal periconceptional (one month before through three months after conception) use of cough medications containing dextromethorphan, with or without guaifenesin, and isolated neural tube defects (NTDs). We also used NBDPS data to explore associations between such exposures and other isolated major birth defects, as well as associations between maternal periconceptional use of cough medications containing guaifenesin alone and isolated major birth defects. Enrolled cases comprised 19,538 live births, still births, and elective terminations with isolated major birth defects, and enrolled controls comprised 10,200 live births without defects delivered from October 1997 through December 2009. Telephone interview reports of pregnancy exposures, including periconceptional use of cough medications, were obtained from mothers of case and control infants. Two approaches were used to build multivariable models: backward model selection and comparing the change in odds ratios (ORs) by adding each covariable individually into the main effect models. Adjusted ORs (aORs) and 95% confidence intervals (CIs) for maternal periconceptional exposure of cough medications containing dextromethorphan, with or without guaifenesin, or guaifenesin alone, respectively, and 22 types of birth defects were estimated using multivariable logistic regression analysis. Applying our first multivariable model building approach, we observed that maternal periconceptional use of dextromethorphan, with or without guaifenesin, was marginally significantly associated with an increased risk of all NTDs combined (aOR=1.7, 95%CI=1.0-2.9), or spina bifida alone (aOR=1.9, 95%CI=1.0-3.5). Applying our second model-building approach confirmed the associations with all NTDs combined and spina bifida alone (aOR==1.9, 95% CI=1.2-3.0 and aOR=2.1, 95% CI=1.2-3.8; respectively). For other isolated birth defects, a positive, marginally significant association was observed for maternal periconceptional use of dextromethorphan, with or without guaifenesin, and cleft lip with or without cleft palate (aOR=1.3, 95%CI=1.0-1.7) applying our first model building approach. Our second model-building approach produced significant associations between such exposure and gastroschisis (aOR=1.8, 95%CI=1.2-2.8). With regard to maternal periconceptional use of cough medications containing guaifenesin alone, we observed marginally significant associations with all NTDs combined (aOR=1.9, 95%CI=1.1-3.5), spina bifida alone (aOR=2.3, 95%CI=1.1-4.4), or anorectal atresia (aOR=1.9, 95%CI=1.0-3.6) applying our first model-building approach. Applying our second model-building approach did not suggest significant associations between such exposure and birth defects. Our findings suggest that maternal periconceptional use of cough medications containing dextromethorphan or guaifenesin may produce selected major structural birth defects in offspring. These findings provide important evidence to better understand the safety of these cough medications and informs about the potential of this modifiable exposure to cause isolated birth defects. Additional population-based research is necessary to validate these positive associations between cough medications and selected isolated birth defects identified in our study.

Purpose To investigate associations between maternal use of selected medications during early pregnancy and the risk of hypospadias in male infants. Methods We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1,537 case infants with second or third degree isolated hypospadias and 4,314 male control infants born from 1997-2007. Exposure was based on reported use of any prescription or over-the-counter medication or herbal product, for which there were at least 5 exposed cases, from 1 month before to 4 months after conception, excluding topicals, vitamins, minerals, and products for which the components were unknown. Adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using multivariable logistic regression, adjusting for several confounders. Results Of the 195 medication components with at least 5 exposed cases, 89 components met the inclusion criteria and were assessed-28 herbal and 61 non-herbal components. Hypospadias was associated with reported use of cephalexin (aOR 3.06; 95% CI 1.02, 9.18), phenylpropanolamine HCl (aOR 2.68; 95% CI 1.06, 6.80), and ibuprofen (aOR 1.16; 95% CI 1.00, 1.34), in primary analyses. Conclusions We replicated a previously observed association between maternal exposure to phenylpropanolamine HCl and hypospadias. The associations with cephalexin and ibuprofen have not previously been reported. Given the exploratory nature of the analyses, these results should be considered hypothesis-generating. Better understanding of the potential fetal effects will allow clinicians and women of childbearing age to make more informed decisions regarding the use of medications during pregnancy.

This study investigated the effect of chronic alcohol exposure on the responses of the maternal hypothalamus-pituitary adrenal axis (HPA-axis) and thyroid hormones throughout gestation using an ovine model. Maternal plasma concentrations of ACTH, cortisol and the thyroid hormones T3, free T4 and total T4 were determined in response to infusion of 0.75, 1.25 and 1.75 g/kg alcohol. Maternal endocrine responses to alcohol administration have been investigated before in rodent models. However, this is the first study using a large animal model (sheep), in which all three human trimester equivalents occur in utero. Different concentrations of alcohol were administered intermittently from gestational day 4 to 132 in a pattern that modeled human binge drinking during pregnancy. Maternal blood samples were collected on specific days (GD 6, 40, 90, 132) and at multiple time-points (0, 0.5, 1, 1.5, 2, 6, 24 hours) and were analyzed to determine blood alcohol concentrations (BACs) and ACTH, cortisol, free T4, total T4 and T3 plasma concentrations. Alcohol readily permeates the placenta and can directly affect fetal cells and tissues. Alcohol also causes endocrine imbalances in the mother and interferes with maternal-fetal hormonal interactions and the mother’s ability to maintain a healthy pregnancy, thus also indirectly affecting fetal development. Sheep receiving either 0.75, 1.25 or 1.75 g/kg alcohol achieved peak BAC values of 93 + 5, 126 + 5 and 183 + 5 respectively. Alcohol exposure resulted in increased plasma ACTH and cortisol concentrations peaking at 2 hours after beginning of the infusion and returning to baseline values at 6 hours after beginning of the infusion. There was no effect of alcohol on any of the plasma thyroid hormone concentrations. Thyroid hormone concentrations changed as a result of progressing pregnancy. Plasma concentrations of total T4 and free T4 were higher on gestational days 6 and 40 compared to GDs 90 and 132, and plasma T3 concentrations were highest on GD 6. The results of this study show that alcohol stimulates the HPA-axis in a dose dependent fashion in pregnant sheep. The response of the HPA-axis to repeated alcohol exposure throughout gestation remained unchanged. Alcohol exposure did not affect the release of thyroid hormones. Thyroid hormone concentrations changed during pregnancy in sheep in a manner similar to changes observed in pregnant women.

Our research investigated the correlations of five key contaminants in drinking water in the State of Illinois with the incidence rates of three different categories of negative reproductive outcomes: birth defects, adverse pregnancy outcomes and preterm births. The five water contaminants included three agrichemical-based contaminants (atrazine, nitrate and nitrite) and two disinfectant byproducts (total trihalomethanes and haloacetic acids). We obtained nearly 38,000 measurements of the individual concentrations of these five contaminants from the Illinois Environmental Protection Agency (IEPA). These data, spanning over a five-year period (1998-2002), were collected from nearly 1,800 community water supplies (CWS) located in all 102 Illinois counties. The county-specific incidence rate data for the same time period for preterm births, seven groups of birth defects and seven groups of adverse pregnancy outcomes were collected from the Illinois Department of Public Health (IDPH). The traditional approach of establishing correlation of one explanatory variable at a time indicated that nitrate concentration in drinking water was statistically correlated to the incidence rate of only one category of negative reproductive outcome, i.e., birth defects. However, multiple regression analysis, which took into consideration all water contaminant data simultaneously, established statistical significance of the correlation between nitrate and all three categories of negative reproductive outcomes. Total trihalomethanes (TTHM) and haloacetic acids (HAA5) were also found to be the statistically significant explanatory variables for all three types of negative reproductive outcomes. Nitrite was found to be associated with adverse pregnancy outcomes and preterm births only; its correlation with birth defect rates could not be established at 80% confidence level. Atrazine was found to be among the significant explanatory variables for all three negative reproductive outcomes. However, its correlations with birth defect model developed using censored data and preterm birth model developed based on observed data were not statistically significant. Nearly 21.5%, 35.8% and 16.6% of the variabilities in incidence rates of different types of birth defects, adverse pregnancy outcomes and preterm births, respectively, were correlated to average concentrations of above mentioned five contaminants in community drinking water supplies. The monthly average concentrations of two of three agrichemical-based contaminants, i.e., atrazine and nitrate were significantly higher in SW(surface water)-based than GW(ground water)-based community water supplies. On the other hand, concentrations of both disinfectant byproducts and the other agrichemical-based contaminant, i.e., nitrite were significantly higher in GW-based water supplies. Further correlation analysis based on the actual observed concentration (excluding all 0 detections) was conducted utilizing SW-based atrazine and nitrate data and GW-based nitrite, TTHM and HAA5 data. All categories of negative reproductive outcomes were found significantly correlated with at least one type of water contaminants. The overall negative reproductive outcomes were correlated with nitrate, nitrite and atrazine. Birth defects specifically correlated with nitrate and TTHM, whereas adverse pregnancy outcomes were correlated with nitrate, nitrite and HAA5; preterm birth was correlated with the concentrations of nitrite, atrazine and TTHM. Further investigation indicated significant correlations among the explanatory variables (drinking water contaminants data), which is referred as multicollinearity. In such case, multiple linear regression based analysis may not provide reliable results. Partial least squares (PLS) approach of regression analysis was introduced into our study to overcome the multicollinearity problem. As much as 65.5% of the variability in the county-wide average concentrations of five contaminants in public drinking water supplies was explained by the 4 component PLS regression model, whereas only 7.7% of the incidence rates of different types of birth defects, adverse pregnancy outcomes and preterm births in various Illinois counties, were explained by PLS regression. Although, individual negative reproductive outcome model could be generated, the low R2 values indicated the poor reliability of these models. We attempted to corroborate our statistical analysis findings with the physiological effects of various water contaminants reported in the literature. It is well known that excessive exposure to any of the five key water contaminants may cause malfunction of organism or the immune system, reproduction, nervous and endocrine system and others, which may further result in potential risk of developing adverse effects. Nitrate and nitrite in drinking water associate to a certain extent with congenital malformations, such as central nervous system abnormalities, in human offsprings. Excessive exposure to atrazine is known to increase the risk of potential cardiovascular or reproductive system problems. A certain type of TTHM, i.e., BDCM are known to be associated with an increased risk of spontaneous miscarriage in pregnant women. It also may result in an increased risk of reproductive problem, such as fetal growth restriction.