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

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

Specific birth defects in pregnancies of women with diabetes: National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Diabetes is associated with an increased risk for many birth defects and is likely to have an increasing impact on birth defect prevalence because of the rise in diabetes in the United States in recent decades. One of the first analyses in which specific birth defects were assessed for their relationship with both pregestational and gestational diabetes used data from the initial 6 years of the National Birth Defects Prevention Study. That analysis reported strong associations for pregestational diabetes with several birth defects, but few exposures among some of the less common birth defects led to unstable estimates with wide confidence intervals. Since that analysis, the study continued to collect data for another 8 years, including information on approximately 19,000 additional cases and 6900 additional controls. OBJECTIVE: Our objective was to use data from the National Birth Defects Prevention Study, the largest population-based birth defects case-control study in the United States, to provide updated and more precise estimates of the association between diabetes and birth defects, including some defects not previously assessed. STUDY DESIGN: We analyzed data on deliveries from October 1997 through December 2011. Mothers of case and control infants were interviewed about their health conditions and exposures during pregnancy, including diagnosis of pregestational (type 1 or type 2) diabetes before the index pregnancy or gestational diabetes during the index pregnancy. Using logistic regression, we separately assessed the association between pregestational and gestational diabetes with specific categories of structural birth defects for which there were at least 3 exposed case infants. For birth defect categories for which there were at least 5 exposed case infants, we calculated odds ratios adjusted for maternal body mass index, age, education, race/ethnicity, and study site; for defect categories with 3 or 4 exposed cases, we calculated crude odds ratios. RESULTS: Pregestational diabetes was reported by 0.6% of mothers of control infants (71 of 11,447) and 2.5% of mothers of case infants (775 of 31,007). Gestational diabetes during the index pregnancy was reported by 4.7% of mothers of control infants (536 of 11,447) and 5.3% of mothers of case infants (1,653 of 31,007). Pregestational diabetes was associated with strong, statistically significant odds ratios (range, 2.5-80.2) for 46 of 50 birth defects considered. The largest odds ratio was observed for sacral agenesis (adjusted odds ratio, 80.2; 95% confidence interval, 46.1-139.3). A greater than 10-fold increased risk was also observed for holoprosencephaly (adjusted odds ratio, 13.1; 95% confidence interval, 7.0-24.5), longitudinal limb deficiency (adjusted odds ratio, 10.1; 95% confidence interval, 6.2-16.5), heterotaxy (adjusted odds ratio, 12.3; 95% confidence interval, 7.3-20.5), truncus arteriosus (adjusted odds ratio, 14.9; 95% confidence interval, 7.6-29.3), atrioventricular septal defect (adjusted odds ratio, 10.5; 95% confidence interval, 6.2-17.9), and single ventricle complex (adjusted odds ratio, 14.7; 95% confidence interval, 8.9-24.3). For gestational diabetes, statistically significant odds ratios were fewer (12 of 56) and of smaller magnitude (range, 1.3- 2.1; 0.5 for gastroschisis). CONCLUSION: Pregestational diabetes is associated with a markedly increased risk for many specific births defects. Because glycemic control before pregnancy is associated with a reduced risk for birth defects, ongoing quality care for persons with diabetes is an important opportunity for prevention.

Maternal genetic markers for risk of celiac disease and their potential association with neural tube defects in offspring.

BACKGROUND: We examined the association between the maternal genotype for celiac disease-associated variants and risk of neural tube defects (NTDs). METHODS: We conducted a case-control study, using data from the National Birth Defects Prevention Study. We evaluated 667 cases (women with an offspring with NTD) and 743 controls (women with an offspring without a birth defect). We classified women as having low, intermediate, or high risk of celiac disease based on human leukocyte antigen (HLA) variants. We used logistic regression to assess the relationship between HLA celiac risk group (low, intermediate, high) and risk of NTDs. Fifteen non-HLA variants (identified from genome-wide association studies of celiac disease) were individually evaluated and modeled additively. RESULTS: There was no association between HLA celiac risk group and NTDs (intermediate vs. low risk: aOR, 1.0; 95% CI, 0.8-1.3; high vs. low risk: aOR, 0.8; 95% CI, 0.5-1.3). Of the fifteen non-HLA variants, we observed five significant associations after accounting for multiple comparisons. Three negative associations were observed with rs10903122, rs13314993, rs13151961 (aOR range: 0.69-0.81), and two positive associations were observed with rs13003464 and rs11221332 (aOR range: 1.27-1.73). CONCLUSION: If confirmed, our results suggest that the maternal variants related to celiac disease may be involved in the risk of NTDs.

Microcephaly inpatient hospitalization and potential Zika outbreak in Texas: A cost and predicted economic burden analysis.

OBJECTIVE: Estimate inpatient hospitalization costs for patients with microcephaly, and predict cost increases due to a potential Zika virus outbreak. METHODS: We identified Texas-wide inpatient hospitalization discharge records (2008-2015), for newborns and non-newborns with microcephaly. We estimated the cost of each hospitalization by applying cost-to-charge ratios on the actual hospitalization charge. For comparison, newborn visits for patients without microcephaly were also identified, and hospital costs were compared between patients with and without microcephaly. We estimated costs for microcephaly during the first year of life following a Zika outbreak (possible 1-50% increase in birth prevalence) in Texas. RESULTS: There were 8005 microcephaly hospitalizations ($203,899,042; total cost). The median admission cost for newborns with microcephaly (N = 1393) was higher compared to those without microcephaly ($6751 vs $725, p < 0.001). Microcephaly hospitalizations of newborns had a lower median cost compared to non-newborns ($6751 vs $9754, p < 0.001). Based on these observed hospitalization costs, we estimated that a potential Zika virus outbreak in Texas could result in an additional $1-6 million per year for hospitalizations. CONCLUSION: Hospitalizations of patients with microcephaly are associated with high costs. An increase in microcephaly prevalence due to a Zika outbreak in Texas could have a considerable impact on health care costs.

Maternal Lactase Polymorphism (rs4988235) Is Associated with Neural Tube Defects in Offspring in the National Birth Defects Prevention Study.

BACKGROUND: The risk of neural tube defect (NTD)-affected pregnancies is reduced with adequate folic acid intake during early pregnancy. However, NTDs have been observed among offspring of women with adequate folic acid intake. Some of these women are possibly not absorbing enough folic acid. Because lactase deficiency can lead to poor nutrient absorption, we hypothesized that lactase-deficient women will be at increased risk of having offspring with NTDs. OBJECTIVE: We examined the association between maternal rs4988235 (a lactase deficiency genetic marker) and NTDs in offspring. METHODS: We conducted a case-control study using data from the National Birth Defects Prevention Study, United States, 1997-2009, restricting to non-Hispanic white (NHW) and Hispanic women. Cases were women with an offspring with an NTD (n = 378 NHW, 207 Hispanic), and controls were women with an offspring without a birth defect (n = 461 NHW, 165 Hispanic). Analyses were conducted separately by race/ethnicity, using logistic regression. Women with the CC genotype were categorized as being lactase deficient. To assess potential effect modification, analyses were stratified by lactose intake, folic acid supplementation, dietary folate, and diet quality. RESULTS: Among NHW women, the odds of being lactase deficient were greater among cases compared with controls (OR: 1.37; 95% CI: 1.02, 1.82). Among Hispanic women, the odds of being lactase deficient were significantly lower among cases compared with controls (OR: 0.50, 95% CI: 0.33, 0.77). The association differed when stratified by lactose intake in NHW women (higher odds among women who consumed ≥12 g lactose/1000 kcal) and by dietary folate in Hispanic women (opposite direction of associations). The association did not differ when stratified by folic acid supplementation or diet quality. CONCLUSIONS: Our findings suggest that maternal lactase deficiency is associated with NTDs in offspring. However, we observed opposite directions of effect by race/ethnicity that could not be definitively explained.

Fish consumption prior to pregnancy and pregnancy outcomes in the National Birth Defects Prevention Study, 1997-2011.

OBJECTIVE: To evaluate the relationships between maternal fish consumption and pregnancy outcomes in a large, population-based sample of women in the USA. DESIGN: We collected average fish consumption prior to pregnancy using a modified version of the semi-quantitative Willett FFQ. We estimated adjusted OR (aOR) and 95 % CI for associations between different levels of fish consumption and preterm birth (<37 weeks), early preterm birth (<32 and <35 weeks) and small-for-gestational-age infants (SGA; <10th percentile). SETTING: The National Birth Defects Prevention Study (NBDPS). SUBJECTS: Control mother-infant pairs with estimated delivery dates between 1997 and 2011 (n 10 919). RESULTS: No significant associations were observed between fish consumption and preterm birth or early preterm birth (aOR = 0·7-1·0 and 0·7-0·9, respectively). The odds of having an SGA infant were elevated (aOR = 2·1; 95 % CI 1·2, 3·4) among women with daily fish consumption compared with women consuming fish less than once per month. No associations were observed between other levels of fish consumption and SGA (aOR = 0·8-1·0). CONCLUSIONS: High intake of fish was associated with twofold higher odds of having an SGA infant, while moderate fish consumption prior to pregnancy was not associated with preterm or SGA. Our study, like many other studies in this area, lacked information regarding preparation methods and the specific types of fish consumed. Future studies should incorporate information on nutrient and contaminant contents, preparation methods and biomarkers to assess these relationships.

Multiple bias analysis using logistic regression: an example from the National Birth Defects Prevention Study.

PURPOSE: Exposure misclassification, selection bias, and confounding are important biases in epidemiologic studies, yet only confounding is routinely addressed quantitatively. We describe how to combine two previously described methods and adjust for multiple biases using logistic regression. METHODS: Weights were created from selection probabilities and predictive values for exposure classification and applied to multivariable logistic regression models in a case-control study of prepregnancy obesity (body mass index ≥30 vs. <30 kg/m2) and cleft lip with or without cleft palate (CL/P) using data from the National Birth Defects Prevention Study (2523 cases, 10,605 controls). RESULTS: Adjusting for confounding by race/ethnicity, prepregnancy obesity, and CL/P were weakly associated (odds ratio [OR]: 1.10; 95% confidence interval: 0.98, 1.23). After weighting the data to account for exposure misclassification, missing exposure data, selection bias, and confounding, multiple bias-adjusted ORs ranged from 0.94 to 1.03 in nonprobabilistic bias analyses and median multiple bias-adjusted ORs ranged from 0.93 to 1.02 in probabilistic analyses. CONCLUSIONS: This approach, adjusting for multiple biases using a logistic regression model, suggested that the observed association between obesity and CL/P could be due to the presence of bias.

Depression Prevalence and Exposure to Organophosphate Esters in Aircraft Maintenance Workers.

INTRODUCTION: Previous studies found that aircraft maintenance workers may be exposed to organophosphates in hydraulic fluid and engine oil. Studies have also illustrated a link between long-term low-level organophosphate pesticide exposure and depression. METHODS: A questionnaire containing the Patient Health Questionnaire 8 depression screener was e-mailed to 52,080 aircraft maintenance workers (with N = 4801 complete responses) in a cross-sectional study to determine prevalence and severity of depression and descriptions of their occupational exposures. RESULTS: There was no significant difference between reported depression prevalence and severity in similar exposure groups in which aircraft maintenance workers were exposed or may have been exposed to organophosphate esters compared to similar exposure groups in which they were not exposed. However, a dichotomous measure of the prevalence of depression was significantly associated with self-reported exposure levels from low (OR: 1.21) to moderate (OR: 1.68) to high exposure (OR: 2.70) and with each exposure route including contact (OR: 1.68), inhalation (OR: 2.52), and ingestion (OR: 2.55). A self-reported four-level measure of depression severity was also associated with a self-reported four-level measure of exposure. DISCUSSION: Based on self-reported exposures and outcomes, an association is observed between organophosphate exposure and depression; however, we cannot assume that the associations we observed are causal because some workers may have been more likely to report exposure to organophosphate esters and also more likely to report depression. Future studies should consider using a larger sample size, better methods for characterizing crew chief exposures, and bioassays to measure dose rather than exposure. Hardos JE, Whitehead LW, Han I, Ott DK, Waller DK. Depression prevalence and exposure to organophosphate esters in aircraft maintenance workers. Aerosp Med Hum Perform. 2016; 87(8):712-717.

Impact of Missing Data for Body Mass Index in an Epidemiologic Study.

Objective To assess the potential impact of missing data on body mass index (BMI) on the association between prepregnancy obesity and specific birth defects. Methods Data from the National Birth Defects Prevention Study (NBDPS) were analyzed. We assessed the factors associated with missing BMI data among mothers of infants without birth defects. Four analytic methods were then used to assess the impact of missing BMI data on the association between maternal prepregnancy obesity and three birth defects; spina bifida, gastroschisis, and cleft lip with/without cleft palate. The analytic methods were: (1) complete case analysis; (2) assignment of missing values to either obese or normal BMI; (3) multiple imputation; and (4) probabilistic sensitivity analysis. Logistic regression was used to estimate crude and adjusted odds ratios (aOR) and 95 % confidence intervals (CI). Results Of NBDPS control mothers 4.6 % were missing BMI data, and most of the missing values were attributable to missing height (~90 %). Missing BMI data was associated with birth outside of the US (aOR 8.6; 95 % CI 5.5, 13.4), interview in Spanish (aOR 2.4; 95 % CI 1.8, 3.2), Hispanic ethnicity (aOR 2.0; 95 % CI 1.2, 3.4), and <12 years education (aOR 2.3; 95 % CI 1.7, 3.1). Overall the results of the multiple imputation and probabilistic sensitivity analysis were similar to the complete case analysis. Conclusions Although in some scenarios missing BMI data can bias the magnitude of association, it does not appear likely to have impacted conclusions from a traditional complete case analysis of these data.

Association Between Ambient Levels of Polycyclic Aromatic Hydrocarbons and Small for Gestational Age Hispanic Infants Born Along the United States-Mexico Border.

Few studies have examined associations between polycyclic aromatic hydrocarbons (PAHs) and birth outcomes, and no studies have been conducted in El Paso County Texas, along the United States-Mexico border. Infants born from 2005-2007 to Hispanic mothers with a birth weight less than the 10th percentile for gestational age and sex were classified as small for gestational age (SGA). PAH exposures were estimated for the entire period of gestation and for each trimester of pregnancy using ambient air monitoring data from 2004-2007. Logistic regression was used to estimate odds ratios for the association between PAH levels and SGA infants. There was marked seasonal variation in the carcinogenic PAHs. Established risk factors for SGA were observed to be associated with SGA births in this population. No associations were detected between PAH levels and SGA births. These findings provide no evidence of an association between PAHs and SGA infants.

Risk Factors for Community-associated Clostridium difficile-associated Diarrhea in Children.

BACKGROUND: Clostridium difficile-associated diarrhea (CDAD) is increasingly diagnosed in children in community settings. This study aims to assess recent antibiotic use and other risk factors in children with community-associated (CA-) CDAD compared with children with other diarrheal illnesses in a tertiary care setting. METHODS: Children with CA-CDAD evaluated at Texas Children's Hospital (Houston, TX) from January 1, 2012 to June 30, 2013 were identified. Two control subjects with community-associated diarrhea who tested negative for C. difficile were matched to case subjects. Data on demographics, medication exposure and outpatient healthcare encounters were collected from medical records. Multivariate logistic regression was performed to identify predictors of pediatric CA-CDAD. RESULTS: Of 69 CA-CDAD cases, most (62.3%) had an underlying chronic medical condition and 40.6% had antibiotic exposure within 30 days of illness. However, no traditional risk factor for CDAD was identified in 23.2% and 15.9% of CA-CDAD cases within 30 and 90 days of illness onset, respectively. Outpatient healthcare encounters within 30 days were more common among CA-CDAD cases than control subjects (66.7% vs. 48.6%; P = 0.01). In the final multivariate model, CA-CDAD was associated with cephalosporin use within 30 days [odds ratio: 3.32; 95% confidence interval: 1.10-10.01] and the presence of a gastrointestinal feeding device (odds ratio: 2.59; 95% confidence interval: 1.07-6.30). CONCLUSIONS: Recent use of cephalosporins and the presence of gastrointestinal feeding devices are important risk factors for community- associated CDAD in children. Reduction in the use of outpatient antibiotics may decrease the burden of CA-CDAD in children.

Maternal reporting of prenatal ultrasounds among women in the National Birth Defects Prevention Study.

BACKGROUND: Increased availability and usage of ultrasound screening have led to improved identification of fetal structural abnormalities prenatally. Few population-based studies have been published on prenatal detection for structural birth defects in the United States. The aim of this study is to determine the frequency of maternal reporting of abnormal prenatal ultrasounds for selected birth defects and to investigate associated maternal characteristics. METHODS: Participants included 4013 mothers enrolled in the National Birth Defects Prevention Study who carried a fetus with at least one of 14 structural birth defects between 1997 and 2004. Frequencies of abnormal prenatal ultrasounds were based on maternal report and computed for isolated and multiple defects. Associations between maternal characteristics and abnormal prenatal ultrasounds were assessed using logistic regression. RESULTS: Overall, 46% of participants reported an abnormal ultrasound. Infants with omphalocele, anencephaly, gastroschisis, and renal agenesis were more likely to have abnormal prenatal ultrasounds than those with cleft and limb abnormalities. Hispanic women were less likely to report abnormal prenatal ultrasounds of birth defects than Caucasians, as were women who had a body mass index ≥ 30 kg/m(2) compared with those with a normal body mass index. CONCLUSION: Of the 14 selected birth defects in this study, less than half were reported by mothers of affected infants to have had an abnormal ultrasound during pregnancy. The frequency of reporting abnormal prenatal ultrasounds varies by type of defect, maternal race/ethnicity, and maternal body mass index status.

A case-control study of maternal bathing habits and risk for birth defects in offspring.

BACKGROUND: Nearly all women shower or take baths during early pregnancy; however, bathing habits (i.e., shower and bath length and frequency) may be related to the risk of maternal hyperthermia and exposure to water disinfection byproducts, both of which are suspected to increase risk for multiple types of birth defects. Thus, we assessed the relationships between bathing habits during pregnancy and the risk for several nonsyndromic birth defects in offspring. METHODS: Data for cases with one of 13 types of birth defects and controls from the National Birth Defects Prevention Study delivered during 2000-2007 were evaluated. Logistic regression analyses were conducted separately for each type of birth defect. RESULTS: There were few associations between shower frequency or bath frequency or length and risk for birth defects in offspring. The risk for gastroschisis in offspring was increased among women who reported showers lasting ≥15 compared to <15 minutes (adjusted odds ratio: 1.43, 95% confidence interval: 1.18-1.72). In addition, we observed modest increases in the risk for spina bifida, cleft lip with or without cleft palate, and limb reduction defects in offspring of women who showered ≥15 compared to <15 minutes. The results of comparisons among more specific categories of shower length (i.e., <15 minutes versus 15-19, 20-29, and ≥ 30 minutes) were similar. CONCLUSIONS: Our findings suggest that shower length may be associated with gastroschisis, but the modest associations with other birth defects were not supported by analyses of bath length or bath or shower frequency. Given that showering for ≥15 minutes during pregnancy is very common, further evaluation of the relationship between maternal showering habits and birth defects in offspring is worthwhile.

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.

Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects.

OBJECTIVE: The purpose of this study was to examine the risk of birth defects in relation to diabetes mellitus and the lack of use of periconceptional vitamins or supplements that contain folic acid. STUDY DESIGN: The National Birth Defects Prevention Study (1997-2004) is a multicenter, population-based case-control study of birth defects (14,721 cases and 5437 control infants). Cases were categorized into 18 types of heart defects and 26 noncardiac birth defects. We estimated odds ratios for independent and joint effects of preexisting diabetes mellitus and a lack of periconceptional use of vitamins or supplements that contain folic acid. RESULTS: The pattern of odds ratios suggested an increased risk of defects that are associated with diabetes mellitus in the absence vs the presence of the periconceptional use of vitamins or supplements that contain folic acid. CONCLUSION: The lack of periconceptional use of vitamins or supplements that contain folic acid may be associated with an excess risk for birth defects due to diabetes mellitus.

Do foreign- and U.S.-born mothers across racial/ethnic groups have a similar risk profile for selected sociodemographic and periconceptional factors?

BACKGROUND: We examined differences in selected pregnancy-related risk factors, including maternal sociodemographic characteristics, health-related conditions, and periconceptional behavioral factors, among foreign-born versus U.S.-born control mothers across race/ethnic groups. METHODS: We used data from the National Birth Defects Prevention Study, and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of the risk factors, for foreign-born Hispanic, non-Hispanic white, non-Hispanic black, and Asian/Pacific Islander (API) mothers, compared to their U.S.-born counterparts. RESULTS: Across all race/ethnic groups, foreign-born mothers were older and had lower odds of obesity compared to their U.S.-born counterparts. With the exception of foreign-born black mothers, foreign-born mothers from other race/ethnic groups had significantly lower odds of binge drinking during the periconceptional period. Compared to U.S.-born, foreign-born Hispanic mothers had twice the odds of gestational diabetes (OR = 2.23; 95% CI = 1.36-3.66). Certain health behaviors were less prevalent in foreign-born black mothers (e.g., folic acid use; OR = 0.54; 95% CI = 0.31-0.96) and foreign-born API mothers (e.g., cigarette smoking; OR = 0.10; 95% CI = 0.02-0.48). CONCLUSIONS: Significant differences in pregnancy related risk factors during the periconceptional period and throughout pregnancy were observed between maternal nativity groups and across race/ethnicity. Prevention efforts for both prepregnancy and after conception should be designed and delivered according to maternal nativity for each racial/ethnic group.

Maternal exposure to ambient levels of benzene and neural tube defects among offspring: Texas, 1999-2004.

BACKGROUND: Previous studies have reported positive associations between maternal exposure to air pollutants and several adverse birth outcomes. However, there have been no studies assessing the association between environmental levels of hazardous air pollutants, such as benzene, and neural tube defects (NTDs), a common and serious group of congenital malformations. OBJECTIVE: Our goal was to conduct a case-control study assessing the association between ambient air levels of benzene, toluene, ethylbenzene, and xylene (BTEX) and the prevalence of NTDs among offspring. METHODS: The Texas Birth Defects Registry provided data on NTD cases (spina bifida and anencephaly) delivered between 1999 and 2004. The control group was a random sample of unaffected live births, frequency matched to cases on year of birth. Census tract-level estimates of annual BTEX levels were obtained from the U.S. Environmental Protection Agency 1999 Assessment System for Population Exposure Nationwide. Restricted cubic splines were used in mixed-effects logistic regression models to determine associations between each pollutant and NTD phenotype. RESULTS: Mothers living in census tracts with the highest benzene levels were more likely to have offspring with spina bifida than were women living in census tracts with the lowest levels (odds ratio = 2.30; 95% confidence interval, 1.22-4.33). No significant associations were observed between anencephaly and benzene or between any of the NTD phenotypes and toluene, ethylbenzene, or xylene. CONCLUSION: In the first study to assess the relationship between environmental levels of BTEX and NTDs, we found an association between benzene and spina bifida. Our results contribute to the growing body of evidence regarding air pollutant exposure and adverse birth outcomes.

Polytomous logistic regression as a tool for exploring heterogeneity across birth defect subtypes: an example using anencephaly and spina bifida.

BACKGROUND: In birth defect epidemiology, phenotypic subgroups are often combined into a composite phenotype in an effort to increase statistical power. Although the validity of using composite phenotypes has been questioned, formal evaluations of the underlying assumption of effect homogeneity across component phenotypes have not been conducted. METHODS: Polytomous logistic regression was used to assess effect heterogeneity of several generally accepted neural tube defect (NTD) risk factors across the component phenotypes of anencephaly and spina bifida. Data for these analyses were obtained from the National Birth Defects Prevention Study. RESULTS: The use of a composite phenotype has the potential to mask associations specific to a component phenotype and in some cases the effect of a variable may be misattributed to the composite phenotype. For example, an association between infant sex and anencephaly (adjusted odds ratio [AOR], 1.5; 95% CI, 1.1-1.9) was masked when data from all NTDs were analyzed (AOR, 1.1; 95% CI, 0.9-1.3), whereas an association with maternal body mass index that was specific to spina bifida (AOR, 1.9; 95% CI, 1.6-2.4) was attributed to all NTDs (AOR, 1.6; 95% CI, 1.4-2.0). Furthermore, conclusions regarding effect heterogeneity based on ad hoc comparisons, rather than some formal assessment, may be vulnerable to considerable subjectivity, as was the case for the association of maternal Hispanic ethnicity with spina bifida (AOR, 1.4; 95% CI, 1.2-1.8) and anencephaly (AOR, 2.0; 95% CI, 1.5-2.8). CONCLUSIONS: Polytomous logistic regression provides a useful tool for evaluating putative risk factors for which there is no a priori basis for assuming effect homogeneity across component phenotypes.

Differences in exposure assignment between conception and delivery: the impact of maternal mobility.

In studies of reproductive outcomes, maternal residence at delivery is often the only information available to characterise environmental exposures during pregnancy. The goal of this investigation was to describe residential mobility during pregnancy and to assess the extent to which change of residence may result in exposure misclassification when exposure is based on the address at delivery. Maternal residential mobility was compared between neural tube defect cases and unaffected controls from Texas participants in the National Birth Defects Prevention Study (NBDPS). Maternal residential information was obtained from the NBDPS interview. Data from the U.S. EPA National Air Toxics Assessment [Assessment System for Population Exposure Nationwide (ASPEN)], modelled at the census tract level, were used to estimate benzene exposure based on address at conception and address at delivery. Quartiles of exposure were assigned based on these estimates and the quartile assignments based on address at conception and address at delivery were compared using traditional methods (kappa statistics) and a novel application of mixed-effects ordinal logistic regression. Overall, 30% of case mothers and 24% of control mothers moved during pregnancy. Differences in maternal residential mobility were not significant between cases and controls, other than case mothers who moved did so earlier during pregnancy than control mothers (P = 0.01). There was good agreement between quartiles of estimated benzene exposure at both addresses (kappa = 0.78, P < 0.0001). Based on the mixed-effects regression model, address at delivery was not significantly different from using address at conception when assigning quartile of benzene exposure based on estimates from ASPEN (odds ratio 1.03, 95% confidence interval 0.85, 1.25). Our results indicate that, in this Texas population, maternal residential movement is generally within short distances, is typically not different between cases and controls, and does not significantly influence benzene exposure assessment.

Maternal fever during early pregnancy and the risk of oral clefts.

An increased risk of birth defects after hyperthermic exposures has been confirmed in animal studies, but population studies have yielded inconsistent results. Oral clefts are a common birth defect and have been associated with these exposures in some of these studies. In this study, data from the National Birth Defects Prevention Study was used to evaluate the association of maternal report of febrile illness in early pregnancy and the risk of oral clefts. All oral cleft cases born between 1997 and 2004 were compared with nonmalformed controls born in the same geographical region during the same time period. Mothers reporting febrile illness during pregnancy were stratified by fever grade and antipyretic use. Logistic regression models were used to generate crude and adjusted odds ratios for exposure to fever and association with each oral cleft phenotype. The dataset included 5821 controls, 1567 cases of cleft lip with or without cleft palate (CL+/-P) and 835 cases of cleft palate only. A modestly increased risk was observed for isolated CL+/-P (odds ratio, 1.28; 95% confidence interval, 1.01-1.63). Stratification by fever grade (body temperature <101.5 degrees or > or =101.5 degrees F) did not yield significant differences in risk. Risk estimates were higher among women who reported a fever, but did not take antipyretics to control their fever, particularly for nonisolated compared with isolated oral clefts. This finding suggests that adequate control of fever may diminish the deleterious effects of fever in cases of oral cleft.