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

BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

Neighborhood Deprivation and Neural Tube Defects.

BACKGROUND: Individual measures of socioeconomic status (SES) have been associated with an increased risk of neural tube defects (NTDs); however, the association between neighborhood SES and NTD risk is unknown. Using data from the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we investigated the association between measures of census tract SES and NTD risk. METHODS: The study population included 10,028 controls and 1829 NTD cases. We linked maternal addresses to census tract SES measures and used these measures to calculate the neighborhood deprivation index. We used generalized estimating equations to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) estimating the impact of quartiles of census tract deprivation on NTDs adjusting for maternal race-ethnicity, maternal education, and maternal age at delivery. RESULTS: Quartiles of higher neighborhood deprivation were associated with NTDs when compared with the least deprived quartile (Q2: aOR = 1.2; 95% CI = 1.0, 1.4; Q3: aOR = 1.3, 95% CI = 1.1, 1.5; Q4 (highest): aOR = 1.2; 95% CI = 1.0, 1.4). Results for spina bifida were similar; however, estimates for anencephaly and encephalocele were attenuated. Associations differed by maternal race-ethnicity. CONCLUSIONS: Our findings suggest that residing in a census tract with more socioeconomic deprivation is associated with an increased risk for NTDs, specifically spina bifida.

Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population-based case-control study of women meeting the folic acid recommendations.

BACKGROUND: Neural tube defects (NTDs) still occur among some women who consume 400 µg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs. OBJECTIVES: To investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations. METHODS: Data were from the National Birth Defects Prevention Study (United States population-based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 µg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center. RESULTS: NTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake. CONCLUSIONS: Our findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

Oxidative balance scores and neural crest cell-related congenital anomalies.

Oxidative stress and redox imbalance adversely affect embryonic development. We developed two oxidative balance scores (OBS) that include dietary and nondietary exposures. We hypothesized that higher scores (i.e., lower oxidative stress) would be associated with lower risk of neural tube defects, orofacial clefts, conotruncal heart defects, and limb deficiencies. We used data from the National Birth Defects Prevention Study to create a dietary OBS based on intake of 13 nutrients and an overall OBS that included the 13 nutrients and eight additional nondietary factors related to oxidative balance (e.g., smoking). We used logistic regression to examine odds ratios associated with having low or high scores (i.e., <10th or >90th percentiles). Continuous models indicated reduced odds associated with high versus low scores (i.e., comparing odds at the 90th versus 10th percentile values of the distribution) on the overall OBS for cleft lip with or without cleft palate [adjusted odds ratio (aOR) 0.72, 95% confidence interval (CI) 0.63-0.82], longitudinal limb deficiency (aOR 0.73, CI 0.54-0.99), and transverse limb deficiency (aOR 0.74, CI 0.58-0.95); increased odds for anencephaly (aOR 1.40, CI 1.07-1.84); and primarily nonsignificant associations with conotruncal heart defects. Results for the dietary OBS were similar. This study provides some evidence that oxidative stress contributes to congenital anomalies related to neural crest cell development.

Linked birth cohort files for perinatal health research: California as a model for methodology and implementation.

PURPOSE: Rigorous perinatal epidemiologic research depends on population-based parental and neonatal sociodemographic and clinical data. Here we describe the creation of linked birth cohort files, an enriched data source that combines information from vital records with maternal delivery and infant hospital encounter records. METHODS: Probabilistic linkage techniques were used to link vital records (i.e., birth and fetal death certificates) from the California Department of Public Health with hospital inpatient, ambulatory surgery and emergency department encounter data for mothers and infants from the California Department of Health Care Access and Information. RESULTS: From 2012 to 2018, 95% of live birth records were successfully linked to maternal and newborn hospital records while 85% of fetal death records were linked to a maternal delivery record. Overall, 93% of postnatal hospital encounters of infants (i.e., <1 year old) were matched to a linked record. CONCLUSIONS: The linked birth cohort files is a rich resource opening many possibilities for understanding perinatal health outcomes and opportunities for linkage to longitudinal, social determinant, and environmental data. To optimally use this file for research, analysts should evaluate possible shortcomings or biases of the data sources being linked.

Differential newborn DNA methylation among individuals with complex congenital heart defects and childhood lymphoma.

BACKGROUND: There is emerging evidence that children with complex congenital heart defects (CHDs) are at increased risk for childhood lymphoma, but the mechanisms underlying this association are unclear. Thus, we sought to evaluate the role of DNA methylation patterns on "CHD-lymphoma" associations. METHODS: From >3 million live births (1988-2004) in California registry linkages, we obtained newborn dried bloodspots from eight children with CHD-lymphoma through the California BioBank. We performed case-control epigenome-wide association analyses (EWAS) using two comparison groups with reciprocal discovery and validation to identify differential methylation associated with CHD-lymphoma. RESULTS: After correction for multiple testing at the discovery and validation stages, individuals with CHD-lymphoma had differential newborn methylation at six sites relative to two comparison groups. Our top finding was significant in both EWAS and indicates PPFIA1 cg25574765 was hypomethylated among individuals with CHD-lymphoma (mean beta = 0.04) relative to both unaffected individuals (mean beta = 0.93, p = 1.5 × 10-12 ) and individuals with complex CHD (mean beta = 0.95, p = 3.8 × 10-8 ). PPFIA1 encodes a ubiquitously expressed liprin protein in one of the most commonly amplified regions in many cancers (11q13). Further, cg25574765 is a proposed marker of pre-eclampsia, a maternal CHD risk factor that has not been fully evaluated for lymphoma risk in offspring, and the tumor microenvironment that may drive immune cell malignancies. CONCLUSIONS: We identified associations between molecular changes present in the genome at birth and risk of childhood lymphoma among those with CHD. Our findings also highlight novel perinatal exposures that may underlie methylation changes in CHD predisposing to lymphoma.

Factors Associated with Early Neonatal and First-Year Mortality in Infants with Myelomeningocele in California from 2006 to 2011.

OBJECTIVE: The aim of this study is to examine factors associated with early neonatal (death within first 7 days of birth) and infant (death during the first year of life) mortality among infants born with myelomeningocele. STUDY DESIGN: We examined linked data from the California Perinatal Quality Care Collaborative, vital records, and hospital discharge records for infants born with myelomeningocele from 2006 to 2011. Survival probability was calculated using Kaplan-Meier Product Limit method and 95% confidence intervals (CI) using Greenwood's method; Cox proportional hazard models were used to estimate unadjusted and adjusted hazard ratios (HR) and 95% CI. RESULTS: Early neonatal and first-year survival probabilities among infants born with myelomeningocele were 96.0% (95% CI: 94.1-97.3%) and 94.5% (95% CI: 92.4-96.1%), respectively. Low birthweight and having multiple co-occurring birth defects were associated with increased HRs ranging between 5 and 20, while having congenital hydrocephalus and receiving hospital transfer from the birth hospital to another hospital for myelomeningocele surgery were associated with HRs indicating a protective association with early neonatal and infant mortality. CONCLUSION: Maternal race/ethnicity and social disadvantage did not predict early neonatal and infant mortality among infants with myelomeningocele; presence of congenital hydrocephalus and the role of hospital transfer for myelomeningocele repair should be further examined. KEY POINTS: · Mortality in myelomeningocele is a concern. · Social disadvantage was not associated with death. · Hospital-based factors should be further examined.

Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index.

Spontaneous preterm birth (sPTB) is a major cause of infant morbidity and mortality. While metabolic changes leading to preterm birth are unknown, several factors including dyslipidemia and inflammation have been implicated and paradoxically both low (<18.5 kg/m2) and high (>30 kg/m2) body mass indices (BMIs) are risk factors for this condition. The objective of the study was to identify BMI-associated metabolic perturbations and potential mid-gestation serum biomarkers of preterm birth in a cohort of underweight, normal weight and obese women experiencing either sPTB or full-term deliveries (n = 102; n = 17/group). For this purpose, we combined untargeted metabolomics and lipidomics with targeted metabolic profiling of major regulators of inflammation and metabolism, including oxylipins, endocannabinoids, bile acids and ceramides. Women who were obese and had sPTB showed elevated oxidative stress and dyslipidemia characterized by elevated serum free fatty acids. Women who were underweight-associated sPTB also showed evidence of dyslipidemia characterized by elevated phospholipids, unsaturated triglycerides, sphingomyelins, cholesteryl esters and long-chain acylcarnitines. In normal weight women experiencing sPTB, the relative abundance of 14(15)-epoxyeicosatrienoic acid and 14,15-dihydroxyeicosatrienoic acids to other regioisomers were altered at mid-pregnancy. This phenomenon is not yet associated with any biological process, but may be linked to estrogen metabolism. These changes were differentially modulated across BMI groups. In conclusion, using metabolomics we observed distinct BMI-dependent metabolic manifestations among women who had sPTB. These observations suggest the potential to predict sPTB mid-gestation using a new set of metabolomic markers and BMI stratification. This study opens the door to further investigate the role of cytochrome P450/epoxide hydrolase metabolism in sPTB.

Asthma Medication Use and Risk of Birth Defects: National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Evidence regarding associations between maternal asthma medication use and birth defects is mixed. OBJECTIVE: Estimate associations between asthma medciation use and 52 birth defects using National Birth Defects Prevention Study data from 1997 to 2011. METHODS: We compared self-reported maternal asthma medication use for 28,481 birth defect cases and 10,894 nonmalformed controls. We calculated adjusted odds ratios (95% CIs) to estimate the risk of birth defects associated with early pregnancy asthma medication use (the month before through the third month of pregnancy), controlling for maternal age, race/ethnicity, body mass index, smoking, folic acid-containing supplement use, and parity. We calculated risks by medication groupings: bronchodilators, anti-inflammatories, and both. RESULTS: Overall, 1304 (5%) case and 449 (4%) control women reported early pregnancy asthma medication use. We observed an association between asthma medication use and longitudinal limb deficiency (1.81; 95% CI, 1.27-2.58). Early pregnancy bronchodilator-only use was associated with cleft palate (1.50; 95% CI, 1.11-2.02), cleft lip (1.58; 95% CI, 1.12-2.23), longitudinal limb deficiency (2.35; 95% CI, 1.55-3.54), and truncus arteriosus (2.48; 95% CI, 1.13-5.42). Although early pregnancy anti-inflammatory-only use was not associated with the birth defects studied, use of both medications was associated with biliary atresia (3.60; 95% CI, 1.55-8.35) and pulmonary atresia (2.50; 95% CI, 1.09-5.78). CONCLUSIONS: Consistent with previous National Birth Defects Prevention Study analyses, asthma medication use was not associated with most birth defects examined, but we observed modest risks for bronchodilator use and several birth defects. Our findings support maintaining adequate asthma treatment during pregnancy, because early pregnancy asthma exacerbations have been associated with adverse birth outcomes, including birth defects.

Treating Center Volume and Congenital Diaphragmatic Hernia Outcomes in California.

OBJECTIVE: To examined outcomes for infants born with congenital diaphragmatic hernias (CDH), according to specific treatment center volume indicators. STUDY DESIGN: A population-based retrospective cohort study was conducted involving neonatal intensive care units in California. Multivariable analysis was used to examine the outcomes of infants with CDH including mortality, total days on ventilation, and respiratory support at discharge. Significant covariables of interest included treatment center surgical and overall neonatal intensive care unit volumes. RESULTS: There were 728 infants in the overall CDH cohort, and 541 infants (74%) in the lower risk subcohort according to a severity-weighted congenital malformation score and never requiring extracorporeal membrane oxygenation. The overall cohort mortality was 28.3% (n = 206), and 19.8% (n = 107) for the subcohort. For the lower risk subcohort, the adjusted odds of mortality were significantly lower at treatment centers with higher CDH repair volume (OR, 0.41; 95% CI, 0.23-0.75; P = .003), ventilator days were significantly lower at centers with higher thoracic surgery volume (OR, 0.56; 9 5% CI, 0.33-0.95; P = .03), and respiratory support at discharge trended lower at centers with higher neonatal intensive care unit admission volumes (OR, 0.51; 9 5% CI, 0.26-1.02; P = .06). CONCLUSIONS: Overall and surgery-specific institutional experience significantly contribute to optimized outcomes for infants with CDH. These data and follow-on studies may help inform the ongoing debate over the optimal care setting and relevant quality indicators for newborn infants with major surgical anomalies.

Prenatal and postnatal inflammation-related risk factors for retinopathy of prematurity.

OBJECTIVE: To evaluate the relationship between prenatal and postnatal inflammation-related risk factors and severe retinopathy of prematurity (ROP). STUDY DESIGN: The study included infants born <30 weeks in California from 2007 to 2011. Multivariable log-binomial regression was used to assess the association between prenatal and postnatal inflammation-related exposures and severe ROP, defined as stage 3-5 or surgery for ROP. RESULTS: Of 14,816 infants, 10.8% developed severe ROP. Though prenatal inflammation-related risk factors were initially associated with severe ROP, after accounting for the effect of these risk factors on gestational age at birth through mediation analysis, the association was non-significant (P = 0.6). Postnatal factors associated with severe ROP included prolonged oxygen exposure, sepsis, intraventricular hemorrhage, and necrotizing enterocolitis. CONCLUSION: Postnatal inflammation-related factors were associated with severe ROP more strongly than prenatal factors. The association between prenatal inflammation-related factors and ROP was explained by earlier gestational age in infants exposed to prenatal inflammation.

Stillbirth and Live Birth at Periviable Gestational Age: A Comparison of Prevalence and Risk Factors.

OBJECTIVE: We compared the prevalence of and risk factors for stillbirth and live birth at periviable gestational age (20-25 weeks). STUDY DESIGN: This is a cohort study of 2.5 million singleton births in California from 2007 to 2011. We estimated racial-ethnic prevalence ratios and used multivariable logistic regression for risk factor comparisons. RESULTS: In this study, 42% of deliveries at 20 to 25 weeks' gestation were stillbirths, and 22% were live births who died within 24 hours. The prevalence of delivery at periviable gestation was 3.4 per 1,000 deliveries among whites, 10.9 for blacks, 3.5 for Asians, and 4.4 for Hispanics. Nonwhite race-ethnicity, lower education, uninsured status, being U.S. born, older age, obesity, smoking, pre-pregnancy hypertension, nulliparity, interpregnancy interval, and prior preterm birth or stillbirth were all associated with increased risk of both stillbirth and live birth at 20 to 25 weeks' gestation, compared with delivery of a live birth at 37 to 41 weeks. CONCLUSION: Inclusion of stillbirths and live births in studies of deliveries at periviable gestations is important.

Congenital heart disease complexity and childhood cancer risk.

BACKGROUND: Childhood cancer is increased in those with birth defects, including those with congenital heart disease (CHD). Lymphoma risk is increased in children with CHD. This study analyzes the effect of CHD and CHD severity on childhood cancer risk. METHODS: We analyzed cancer risk in a population-based cohort of children with and without CHD born between 1988 and 2004 by linking data from the California Birth Defects Monitoring Program with data from the California Cancer Registry. We compared cancer risk in children with and without CHD, excluding children with chromosomal anomalies. RESULTS: Of >3 million children in the birth cohort, 65,585 had birth defects (2%), 25,981 with CHD. Cancer occurred in 4,781 (0.15%) children, 43 (0.17%) with CHD. Cancer risk in CHD was increased (hazard ratio [HR]) 2.63, 95% CI: 1.95, 3.55). Leukemia was the most common cancer in those without CHD (1,722/4,738, 36%), central nervous system tumors were second (1,073/4,738, 23%), and lymphoma third (410/4,738, 9%). Among children with CHD, lymphoma and leukemia occurred with the same frequency (12/43, 28% for each). HR for lymphoma was 8.37 (CI: 4.71, 14.86) with CHD versus without. HR for leukemia was 2.05 (CI: 1.16, 3.61) with CHD versus without. CHD complexity was higher in lymphoma (3, interquartile range [IQR]: 2-3) than those with leukemia (1, IQR, 1-2; p < .02). CONCLUSION: Cancer risk is increased in children with CHD. Lymphoma risk is increased in CHD and is correlated with more complex CHD. These results suggest a shared developmental origin for CHD and lymphoma may be present.

An application of data mining to identify potential risk factors for anophthalmia and microphthalmia.

BACKGROUND: We examined a large number of variables to generate new hypotheses regarding a wider range of risk factors for anophthalmia/microphthalmia using data mining. METHODS: Data were from the National Birth Defects Prevention Study, a multicentre, case-control study from 10 centres in the United States. There were 134 cases of "isolated" and 87 "nonisolated" (with other major birth defects) of anophthalmia/microphthalmia and 11 052 nonmalformed controls with delivery dates October 1997-December 2011. Using random forest, a data mining procedure, we compared the two case types with controls for 201 variables. Variables considered important ranked by random forest were included in a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals. RESULTS: Predictors for isolated cases included paternal race/ethnicity, maternal intake of certain nutrients and foods, and childhood health problems in relatives. Using regression, inverse associations were observed with greater maternal education and with increasing intake of folate and potatoes. Odds were slightly higher with greater paternal education, for increased intake of carbohydrates and beans, and if relatives had a childhood health problem. For nonisolated cases, predictors included paternal race/ethnicity, maternal intake of certain nutrients, and smoking in the home the month before conception. Odds were higher for Hispanic fathers and smoking in the home and NSAID use the month before conception. CONCLUSIONS: Results appear to support previously hypothesised risk factors, socio-economic status, NSAID use, and inadequate folate intake, and potentially provide new areas such as passive smoking pre-pregnancy, and paternal education and ethnicity, to explore for further understanding of anophthalmia/microphthalmia.

Antioxidant Consumption is Associated with Decreased Odds of Congenital Limb Deficiencies.

BACKGROUND: Approximately 1 in 2000 infants is born with a limb deficiency in the US. Research has shown that women's periconceptional diet and use of vitamin supplements can affect risk of birth defects. We investigated whether maternal consumption of nutritional antioxidants was associated with occurrence of transverse limb deficiency (TLD) and longitudinal limb deficiencies (LLD). METHODS: We analysed case-control data from mothers and their singleton infants with TLD (n = 566), LLD (n = 339), or no malformation (controls; n = 9384) in the National Birth Defects Prevention Study (1997-2009). Using a modified food frequency, we estimated usual pre-pregnancy antioxidant consumption by total fruit and vegetable consumption (in grams) grouped into tertiles, and cumulative antioxidant score (ranging from 1 to 10) based on consumption of three antioxidants: beta-carotene, lycopene, and lutein. We estimated odds ratios (OR) adjusted for maternal age, race/ethnicity, education, smoking, alcohol use, body mass index, and total energy. RESULTS: Compared to women in the lowest tertile of fruit and vegetable consumption, women in the highest tertile were less likely to have infants with TLD (OR 0.74, 95% CI 0.57, 0.96) or LLD (OR 0.82, 95% CI 0.59, 1.13). Compared to the lowest antioxidant consumption score of 1, those with the highest score of 10 had ORs of 0.68 (95% CI 0.48, 0.95) for TLD and 0.77 (95% CI 0.50, 1.17) for LLD. CONCLUSIONS: Dietary intake of antioxidants was associated with reduced odds of limb deficiencies. These findings add further evidence for women's periconceptional diet reducing occurrence of some birth defects.

Maternal Smoking, Alcohol, and Caffeine Exposures and Risk of Hypospadias.

BACKGROUND: We examined the association of hypospadias risk with maternal smoking and consumption of alcohol and caffeine. METHODS: We analyzed data from mothers of 2437 moderate/severe cases and 5472 nonmalformed controls born from 1997 to 2011 who participated in the National Birth Defects Prevention Study (NBDPS). Exposures were assessed by maternal telephone interviews. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for mother's age, parity, race-ethnicity, education, vitamin/mineral supplement intake, obesity, and study center. RESULTS: Active smoking during the first month of pregnancy was associated with reduced risk, with smaller ORs for increasing quantity smoked; the OR for smoking >1/2 pack/day was 0.7 (95% CI, 0.5-0.9). Among nonsmokers, the OR for any secondhand smoke exposure was 0.8 (95% CI, 0.7-0.9). ORs for alcohol and caffeine consumption were near one and CIs included 1.0. In an analysis of joint exposures to smoking and alcohol and caffeine consumption, the only OR for which the 95% CI excluded 1.0 was for women who smoked, drank, and had low caffeine consumption (OR, 0.6; 95% CI, 0.4-0.8). CONCLUSION: Maternal exposure to cigarette smoke was associated with reduced risk, and women who smoked, drank, and had low caffeine intake were at lowest risk. We do not interpret these results to suggest that these exposures have overall benefit to a pregnant woman or developing fetus. They may, however, offer clues to help us understand mechanisms that lead to hypospadias. Birth Defects Research 109:1127-1133, 2017. © 2017 Wiley Periodicals, Inc.

Air pollution, neighborhood acculturation factors, and neural tube defects among Hispanic women in California.

BACKGROUND: Neural tube defects (NTDs) are one of the most common types of birth defects. Environmental pollutants and acculturation have been associated with NTDs independently. The potential effect modification of acculturation in the relationship between ambient air pollution and risks of NTDs is not well understood. METHODS: We investigated whether associations between traffic-related air pollutant exposure in early gestation and NTDs, and more specifically spina bifida, were modified by individual and neighborhood acculturation factors among 139 cases and 466 controls born in the San Joaquin Valley of California, 1997 to 2006. Five criteria pollutant exposures in tertiles, two outcomes, and seven neighborhood acculturation factors from the U.S. Census at the block group level were included for a total of 280 investigated associations. Estimates were adjusted for maternal education and multivitamin use in the first 2 months of pregnancy. Additional analyses were stratified by nativity. RESULTS: Increased odds of NTDs were observed for individuals who had high exposures to carbon monoxide, nitrogen oxide, or nitrogen dioxide and lived in neighborhoods that were more acculturated. Conversely, there were increased odds of NTDs for those who had high prenatal exposure to PM10 and lived in neighborhoods that were less acculturated. The results of spina bifida alone were generally stronger in magnitude. When stratified by individual nativity (U.S.- vs. foreign-born), carbon monoxide, nitrogen oxide, and nitrogen dioxide were more strongly associated with NTDs among U.S.-born Hispanic mothers. CONCLUSION: Neighborhood acculturation factors were modifiers of the relationship between air pollution and NTDs in California, though not in a consistent direction for all pollutants. Birth Defects Research 109:403-422, 2017. © 2017 Wiley Periodicals, Inc.

Maternal prepregnancy body mass index and risk of bronchopulmonary dysplasia.

BackgroundWe examined the relationship between women's prepregnancy BMI and development of bronchopulmonary dysplasia (BPD) in their preterm offspring, hypothesizing that obesity-associated inflammation may increase risk.MethodsWe studied infants born in California between 2007 and 2011, using linked data from California Perinatal Quality Care Collaborative neonatal intensive care units, hospital discharge, and vital statistics. We included infants with birthweight <1,500 g or gestational age at birth of 22-29 weeks. BPD was defined as continuous supplemental oxygen use at 36 weeks' postmenstrual age.ResultsAmong 12,621 infants, 4,078 (32%) had BPD. After adjustment for maternal race/ethnicity, age, education, payer source, and infant sex, BMI status underweight I (BMI <16.9, odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3-2.1) and obesity III (BMI ⩾40.0, OR 1.3, 95% CI 1.0-1.6) were associated with an increased risk of BPD. When considering maternal BMI as a continuous variable, a nonlinear association with BPD was observed for male infants and infants delivered at 25-29 weeks of gestational age, but not for other subgroups.ConclusionBoth high and low maternal BMI were associated with increased BPD risk. These findings support the notion that BPD is a multi-factorial disease that may sometimes have its origins in utero and be influenced by maternal inflammation.

An Investigation of Connections between Birth Defects and Cancers Arising in Adolescence and Very Young Adulthood.

This study investigated the relationship between birth defects and cancer in adolescents and very young adults using California's population-based registries. Although overall cancer risk was elevated among individuals with chromosomal birth defects, this was not observed in those with nonchromosomal birth defects, as was demonstrated previously in younger children.