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Background: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens., Methods: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA., Results: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol., Conclusions: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers., (© 2019 Wiley Periodicals, Inc.)

Background: Congenital limb deficiencies (CLDs) are a relatively common group of birth defects whose etiology is mostly unknown. Recent studies suggest maternal air pollution exposure as a potential risk factor., Aim: To investigate the relationship between ambient air pollution exposure during early pregnancy and offspring CLDs., Methods: The study population was identified from the National Birth Defects Prevention Study, a population-based multi-center case-control study, and consisted of 615 CLD cases and 5,701 controls with due dates during 1997 through 2006. Daily averages and/or maxima of six criteria air pollutants (particulate matter <2.5 μm [PM 2.5 ], particulate matter <10 μm [PM 10 ], nitrogen dioxide [NO 2 ], sulfur dioxide [SO 2 ], carbon monoxide [CO], and ozone [O 3 ]) were averaged over gestational weeks 2-8, as well as for individual weeks during this period, using data from EPA air monitors nearest to the maternal address. Logistic regression was used to estimate odds ratios (aORs) and 95% confidence intervals (CIs) adjusted for maternal age, race/ethnicity, education, and study center. We estimated aORs for any CLD and CLD subtypes (i.e., transverse, longitudinal, and preaxial). Potential confounding by co-pollutant was assessed by adjusting for one additional air pollutant. Using the single pollutant model, we further investigated effect measure modification by body mass index, cigarette smoking, and folic acid use. Sensitivity analyses were conducted restricting to those with a residence closer to an air monitor., Results: We observed near-null aORs for CLDs per interquartile range (IQR) increase in PM 10 , PM 2.5 , and O 3 . However, weekly averages of the daily average NO 2 and SO 2 , and daily max NO 2 , SO 2 , and CO concentrations were associated with increased odds of CLDs. The crude ORs ranged from 1.03 to 1.12 per IQR increase in these air pollution concentrations, and consistently elevated aORs were observed for CO. Stronger associations were observed for SO 2 and O 3 in subtype analysis (preaxial). In co-pollutant adjusted models, associations with CO remained elevated (aORs: 1.02-1.30); but aORs for SO 2 and NO 2 became near-null. The aORs for CO remained elevated among mothers who lived within 20 km of an air monitor. The aORs varied by maternal BMI, smoking status, and folic acid use., Conclusion: We observed modest associations between CLDs and air pollution exposures during pregnancy, including CO, SO 2 , and NO 2 , though replication through further epidemiologic research is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

To explore a potential association between preeclampsia and selected birth defects, we examined the prevalence of certain birth defects among women with hypertensive disorders including preeclampsia. We analyzed data from 2,499,536 singleton live births in California from 2007 to 2011, including maternal and infant demographics from birth certificates as well as clinical details from delivery hospitalization records. We examined defect groups that were recognizable at birth (e.g., spina bifida and cleft lip). Hypertensive disorders included preexisting hypertension, gestational hypertension, mild preeclampsia, severe preeclampsia/eclampsia, and preeclampsia superimposed on preexisting hypertension. Relative risk values with 95% confidence intervals for each birth defect were calculated by hypertensive group, as well as independent and joint associations of hypertensive and diabetic disorders. Risks of each type of birth defect were higher among offspring of women with hypertensive disorders compared with those without. The risks of birth defects among offspring of women with only a hypertensive disorder were significantly higher than that among women with neither hypertensive nor diabetic disorders (relative risks ranged from 1.37 to 2.77). Risks of birth defects were highest among those born to women with both hypertensive and diabetic disorders compared with those with neither (relative risks ranged from 1.80 to 6.22). These findings support the existence of an association between preeclampsia and certain birth defects and suggest that diabetes may be a contributing factor.

Background: The terrorist attacks of 11 September 2001 (hereafter referred to as 9/11) preceded an increase in male fetal deaths and reduced male live births among exposed gestational cohorts across several geographic locations in the United States, including California. We analyze whether the extreme stressor of 9/11 may have selected against frail males in utero by testing if the prevalence of male births with selected defects in California fell among cohorts exposed to the stressor during gestation., Methods: We used data from the California Birth Defects Monitoring Program from July 1985 to January 2004 (223 conception cohorts). We included six birth defects that as a group of phenotypes disproportionately affect males. We applied time-series methods and defined as "exposed to 9/11" the cohorts conceived in February, March, April, May, June, July, and August 2001., Results: Three of the seven monthly conception cohorts exposed to 9/11 in utero show lower than expected odds of live born males with the studied defects: February 2001 (odds ratio [OR] = 0.39; 95% confidence interval [CI], 0.21-0.71), May 2001 (OR = 0.36; 95% CI, 0.16-0.81), and August 2001 (OR = 0.51; 95% CI, 0.28-0.93)., Conclusion: The population-wide stressor of 9/11 precedes a reduction in the risk of live born males with selected birth defects. Our analysis contributes to the understanding of adaptation to stress among pregnant women exposed to large and unexpected ambient stressors. Results further support the notion that the prevalence of live born defects may reflect temporal variation in cohort selection in utero against frail males. Birth Defects Research 109:1277-1283, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Evidence suggests that exposure to elevated concentrations of air pollution during pregnancy is associated with increased risks of birth defects and other adverse birth outcomes. While current regulations put limits on total PM2.5 concentrations, there are many speciated pollutants within this size class that likely have distinct effects on perinatal health. However, due to correlations between these speciated pollutants, it can be difficult to decipher their effects in a model for birth outcomes. To combat this difficulty, we develop a multivariate spatio-temporal Bayesian model for speciated particulate matter using dynamic spatial factors. These spatial factors can then be interpolated to the pregnant women's homes to be used to model birth defects. The birth defect model allows the impact of pollutants to vary across different weeks of the pregnancy in order to identify susceptible periods. The proposed methodology is illustrated using pollutant monitoring data from the Environmental Protection Agency and birth records from the National Birth Defect Prevention Study., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results

Background: The literature theorizes, but does not test, that variation over time in selective loss in utero affects the observed count of live-born birth defects cases. We test the hypothesis that the risk of birth defects among live-born males varies inversely with the strength of selection against males in utero., Methods: We identified a subset of six birth defect phenotypes among males from the California Birth Defects Monitoring Program, an active surveillance system for over 490,000 male singletons born in eight California counties from 1986 to 2004. We assigned each birth defect case infant to a monthly conception cohort at risk of selection in utero. We used the monthly sex ratio at birth (M:F), derived from each conception cohort, as the indicator of selection against males. We analyzed the odds ratio of birth defects with both individual-level logistic regression and aggregate time-series methods., Results: Consistent with selection in utero, male infants from conception cohorts with low outlying sex ratios (i.e., stronger selectivity) exhibit fewer than expected birth defects (adjusted odds ratio [OR] = 0.86; 95% confidence interval [CI] = 0.76, 0.98). Aggregate time-series tests also yield similar findings (OR = 0.81; 95% CI = 0.71, 0.90)., Conclusions: Our findings among males indicate that variation in the strength of selectivity in utero accounts for a portion of observed cohort differences in morbidity due to birth defects. These findings suggest that "revealed prevalence" of morbidity across birth cohorts varies, at least in part, from selective loss in utero. See video abstract at, http://links.lww.com/EDE/B209.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: We examined whether risks of 32 birth defects were higher than expected in the presence of overweight or obese body mass index (BMI) and low diet quality, based on estimating individual and joint effects of these factors and calculating relative excess risk due to interaction., Methods: Analyses included mothers of 20,250 cases with birth defects and 8617 population-based controls without birth defects born from 1997 to 2009 and interviewed for the National Birth Defects Prevention Study. We used logistic regression to generate adjusted odds ratios (AORs) reflecting the combined effects of BMI and diet quality. We focused analyses on 16 birth defects (n = 11,868 cases, 8617 controls) for which initial results suggested an association with BMI or diet quality., Results: Relative to the reference group (normal weight women with not low diet quality, i.e., >lowest quartile), AORs for low diet quality among normal weight women tended to be >1, and AORs for overweight and obese women tended to be stronger among women who had low diet quality than not low diet quality. For 9/16 birth defects, AORs for obese women who had low diet quality-the group we hypothesized to have highest risk-were higher than other stratum-specific AORs. Most relative excess risk due to interactions were positive but small (<0.5), with confidence intervals that included zero., Conclusion: These findings provide evidence for the hypothesis of highest birth defect risks among offspring to women who are obese and have low diet quality but insufficient evidence for an interaction of these factors in their contribution to risk., (© 2015 Wiley Periodicals, Inc.)

Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic birth defects is not well-understood. Although there is still much work to be done, we have many of the tools needed to accomplish the task. Advances in next-generation sequencing have introduced a sea of possibilities, from disease-gene discovery to clinical screening and diagnosis. These advances have been fruitful in identifying a host of candidate disease genes, spanning the spectrum of birth defects. With the advent of CRISPR-Cas9 gene editing, researchers now have a precise tool for characterizing this genetic variation in model systems. Work in model organisms has also illustrated the importance of epigenetics in human development and birth defects etiology. Here we review past and current knowledge in birth defects genetics. We describe genotyping and sequencing methods for the detection and analysis of rare and common variants. We remark on the utility of model organisms and explore epigenetics in the context of structural malformation. We conclude by highlighting approaches that may provide insight into the complex genetics of birth defects., (© 2015 Wiley Periodicals, Inc.)

Background: The National Birth Defects Prevention Study (NBDPS) contains a wealth of information on affected and unaffected family triads, and thus provides numerous opportunities to study gene-environment interactions (G×E) in the etiology of birth defect outcomes. Depending on the research objective, several analytic options exist to estimate G×E effects that use varying combinations of individuals drawn from available triads., Methods: In this study, we discuss important considerations in the collection of genetic data and environmental exposures., Results: We will also present several population- and family-based approaches that can be applied to data from the NBDPS including case-control, case-only, family-based trio, and maternal versus fetal effects. For each, we describe the data requirements, applicable statistical methods, advantages, and disadvantages., Conclusion: A range of approaches can be used to evaluate potentially important G×E effects in the NBDPS. Investigators should be aware of the limitations inherent to each approach when choosing a study design and interpreting results., (© 2015 Wiley Periodicals, Inc.)

Background: The National Birth Defects Prevention Study (NBDPS) is a large population-based multicenter case-control study of major birth defects in the United States., Methods: Data collection took place from 1998 through 2013 on pregnancies ending between October 1997 and December 2011. Cases could be live born, stillborn, or induced terminations, and were identified from birth defects surveillance programs in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Controls were live born infants without major birth defects identified from the same geographical regions and time periods as cases by means of either vital records or birth hospitals. Computer-assisted telephone interviews were completed with women between 6 weeks and 24 months after the estimated date of delivery. After completion of interviews, families received buccal cell collection kits for the mother, father, and infant (if living)., Results: There were 47,832 eligible cases and 18,272 eligible controls. Among these, 32,187 (67%) and 11,814 (65%), respectively, provided interview information about their pregnancies. Buccal cell collection kits with a cytobrush for at least one family member were returned by 19,065 case and 6,211 control families (65% and 59% of those who were sent a kit). More than 500 projects have been proposed by the collaborators and over 200 manuscripts published using data from the NBDPS through December 2014., Conclusion: The NBDPS has made substantial contributions to the field of birth defects epidemiology through its rigorous design, including case classification, detailed questionnaire and specimen collection, large study population, and collaborative activities across Centers., (© 2015 Wiley Periodicals, Inc.)

Background: Approximately 6.3 million live births and fetal deaths occurred during the ascertainment period in the California Birth Defects Monitoring Program registry. American-Indian and non-Hispanic white women delivered 40,268 and 2,044,118 births, respectively. While much information has been published about non-Hispanic white infants, little is known regarding the risks of birth defects among infants born to American-Indian women., Methods: This study used data from the California Birth Defects Monitoring Program to explore risks of selected birth defects in offspring of American-Indian relative to non-Hispanic white women in California. The study population included all live births and fetal deaths 20 weeks or greater from 1983 to 2010. Prevalence ratios and corresponding 95% confidence intervals (CI) were computed using Poisson regression for 51 groupings of birth defects., Results: Prevalence ratios were estimated for 51 groupings of birth defects. Of the 51, nine had statistically precise results ranging from 0.78 to 1.85. The eight groups with elevated risks for American-Indian births were reduction deformities of brain, anomalies of anterior segments, specified anomalies of ear, ostium secundum type atrial septal defect, specified anomalies of heart, anomalies of the aorta, anomalies of great veins, and cleft lip with cleft palate., Conclusion: Our results suggest that American-Indian women having babies in California may be at higher risk for eight birth defect phenotypes compared with non-Hispanic whites. Further research is needed to determine whether these risks are observed among other populations of American-Indian women or when adjusted for potential covariates., (© 2015 Wiley Periodicals, Inc.)

Objective: We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants., Study Design: Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by ≥3.5 mm compared to those with measurements <90th percentile for CRL)., Results: When considered by CRL adjusted percentile and by measurement ≥3.5 mm, infants with a NT ≥95th percentile were at risk of having ≥1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3-3.4). Infants with a NT measurement ≥95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4)., Conclusion: Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements ≥95th percentile. The ≥3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: We examined the association of maternal stressful life events and social support with risks of birth defects using National Birth Defects Prevention Study data, a population-based case-control study., Methods: We examined seven stressful life events and three social support questions applicable to the periconceptional period, among mothers of 552 cases with neural tube defects (NTDs), 413 cleft palate (CP), 797 cleft lip ± cleft palate (CLP), 189 d-transposition of the great arteries (dTGA), 311 tetralogy of Fallot (TOF), and 2974 non-malformed controls. A stressful life events index equalled the sum of 'yes' responses to the seven questions. Social support questions were also summed to form an index. Data were analyzed using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for maternal race-ethnicity, age, education, body mass index, smoking, drinking, and intake of vitamin supplements., Results: Associations with the stress index tended to be higher with higher scores, but few 95% CIs excluded one. A four-point increase in the index was moderately associated with NTDs (OR 1.5, [95% CI 1.1, 2.0]) and CLP (OR 1.3, [95% CI 1.0, 1.7]). The social support index tended to be associated with reduced risk but most 95% CIs included one, with the exception of dTGA (OR for a score of 3 vs 0 was 0.5 [95% CI 0.3, 0.8])., Conclusions: Maternal periconceptional stressful life events, social support, and the two factors in combination were at most modestly, if at all, associated with risks of the studied birth defects., (© 2014 John Wiley & Sons Ltd.)

Birth defects are a leading cause of infant morbidity and mortality worldwide. The vast majority of birth defects are nonsyndromic, and although their etiologies remain mostly unknown, evidence supports the hypothesis that they result from the complex interaction of genetic, epigenetic, environmental, and lifestyle factors. Since our last review published in 2002 describing the basic tools of genetic epidemiology used to study nonsyndromic structural birth defects, many new approaches have become available and have been used with varying success. Through rapid advances in genomic technologies, investigators are now able to investigate large portions of the genome at a fraction of previous costs. With next-generation sequencing, research has progressed from assessing a small percentage of single-nucleotide polymorphisms to assessing the entire human protein-coding repertoire (exome)-an approach that is starting to uncover rare but informative mutations associated with nonsyndromic birth defects. Herein, we report on the current state of the genetic epidemiology of birth defects and comment on future challenges and opportunities. We consider issues of study design, and we discuss common variant approaches, including candidate gene studies and genome-wide association studies. We also discuss the complexities embedded in exploring interactions between genes and the environment. We complete our review by describing new and promising next-generation sequencing technologies and examining how the study of epigenetic mechanisms could become the key to unraveling the complex etiologies of nonsyndromic structural birth defects.

Background: Birth defects are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some structural anomalies, although evidence is limited and several anomalies have not been investigated previously., Methods: We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 26 congenital birth defect phenotypes with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997 to 2006 (874 cases and 849 controls). We calculated odds ratios (adjusted for maternal race/ethnicity, education, and vitamin use; aOR) for 11 phenotypes that had at least 40 cases., Results: Few odds ratios had confidence intervals that did not include 1.0. Odds of esophageal atresia were increased for the highest versus lowest of traffic density (aOR = 2.8, 95% confidence interval [CI], 1.1-7.4) and PM10 exposure (aOR 4.9; 95% CI, 1.4-17.2). PM₁₀ was associated with a decreased risk of hydrocephaly (aOR= 0.3; 95% CI, 0.1-0.9) and CO with decreased risk of anotia/microtia (aOR = 0.4; 95% CI, 0.2-0.8) and transverse limb deficiency (aOR = 0.4; 95% CI, 0.2-0.9), again reflecting highest versus lowest quartile comparisons., Conclusion: Most analyses showed no substantive association between air pollution and the selected birth defects with few exceptions of mixed results., (Copyright © 2013 Wiley Periodicals, Inc.)

Prepregnancy diabetes and obesity have been identified as independent risk factors for several birth defects, providing support for a mechanism that involves hyperglycemia and hyperinsulinemia in the development of malformations. Data from the National Birth Defects Prevention Study from 1997 to 2007 were used to investigate the association between the maternal dietary glycemic index (DGI) and the risk of birth defects among nondiabetic women. DGI was categorized by using spline regression models and quartile distributions. Adjusted odds ratios and 95% confidence intervals were calculated. The joint effect of DGI and obesity was also examined. Among the 53 birth defects analyzed, high DGI, categorized by spline regression, was significantly associated with encephalocele (adjusted odds ratio (aOR) = 2.68), diaphragmatic hernia (aOR = 2.58), small intestinal atresia/stenosis (aOR = 2.97) including duodenal atresia/stenosis (aOR = 2.48), and atrial septal defect (aOR = 1.37). Using quartiles to categorize DGI, the authors identified associations with cleft lip with cleft palate (aOR = 1.23) and anorectal atresia/stenosis (aOR = 1.40). The joint effect of high DGI and obesity provided evidence of a synergistic effect on the risk of selected birth defects. High DGI is associated with an increased risk of a number of birth defects under study. Obesity coupled with high DGI appears to increase the risk further for some birth defects.

Background: Few studies have investigated the potential association of maternal dietary intake and risk of microtia among offspring., Methods: The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic cases of microtia were compared to nonmalformed, population-based, live-born control infants by estimating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race or ethnicity, education, folic acid-containing supplement intake, fertility treatment, study site, and total energy intake., Results: Comparing intake in the lowest 10th percentile versus the 10th to 90th percentiles, lower maternal intakes of carbohydrate (OR, 1.59; 95% CI, 1.07-2.38) and dietary folate (OR, 1.57; 95% CI, 1.09-2.25) were associated with elevated risk of microtia. In addition, results suggested that higher diet quality (as measured by the Diet Quality Index, and comparing the highest with the lowest quartile) was protective, but the CI did not exclude one (OR, 0.73; 95% CI, 0.50-1.07). Results were similar among obese and nonobese women., Conclusions: These data contribute to the limited body of evidence regarding the potential contribution of maternal nutrition to the etiology of microtia., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies., Study Design: We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% CIs based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies., Results: Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% CI, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% CI, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer (HR, 1.58; 95% CI, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors., Conclusion: Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer., (Copyright © 2012 Mosby, Inc. All rights reserved.)

This study examined the association between paternal age and a wide range of structural birth defects. Data were drawn from The California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with defects born between 1989 and 2002. The analysis included 46,114 cases with defects, plus a random sample of 36,838 non-malformed births. After adjustment for maternal age, risks of anomalies of the nervous system for 38 and 42 year-old fathers, as compared to 29 year-old fathers, were 1.05-fold [1.00, 1.11] and 1.10-fold [1.02, 1.18] higher, respectively. Similar results were observed for anomalies of the limbs, where 38 and 42 year-old fathers had a 1.06-fold [1.02, 1.11] and 1.11-fold [1.05, 1.18] higher risk, respectively. Risks of anomalies of the integument were 1.05-fold [1.00, 1.09] and 1.10-fold [1.03, 1.16] higher for 38 and 42 year olds, respectively. Young paternal age, i.e., less than 29 years, was associated with an increased risk of amniotic bands (OR: 0.87 [0.78, 0.97]), pyloric stenosis (OR: 0.93 [0.90, 0.96]) and anomalies of the great veins (OR: 0.93 [0.87, 1.00]). In sum, both advanced and young paternal age was associated with select birth defects in California between 1989 and 2002.

Obesity is associated with increased risk of many adverse health conditions. During pregnancy, obesity presents particularly important challenges for both mother and baby. Over the last 20 years, studies have emerged indicating an association between prepregnancy weight and risks of birth defects. However, few studies have examined the mechanisms through which this association occurs. Understanding the underlying mechanisms may provide clues to public health strategies for the prevention of birth defects associated with maternal obesity. This article briefly reviews existing literature on the association between maternal obesity and birth defects, discusses potential underlying mechanisms, and suggests research needed to improve our understanding of this important association., (© 2010 Wiley-Liss, Inc.)

To evaluate the representativeness of controls in an ongoing, population-based, case-control study of birth defects in 10 centers across the United States, researchers compared 1997-2003 birth certificate data linked to selected controls (n = 6,681) and control participants (n = 4,395) with those from their base populations (n = 2,468,697). Researchers analyzed differences in population characteristics (e.g., percentage of births at > or =2,500 g) for each group. Compared with their base populations, control participants did not differ in distributions of maternal or paternal age, previous livebirths, maternal smoking, or diabetes, but they did differ in other maternal (i.e., race/ethnicity, education, entry into prenatal care) and infant (i.e., birth weight, gestational age, and plurality) characteristics. Differences in distributions of maternal, but not infant, characteristics were associated with participation by selected controls. Absolute differences in infant characteristics for the base population versus control participants were < or =1.3 percentage points. Differences in infant characteristics were greater at centers that selected controls from hospitals compared with centers that selected controls from electronic birth certificates. These findings suggest that control participants in the National Birth Defects Prevention Study generally are representative of their base populations. Hospital-based control selection may slightly underascertain infants affected by certain adverse birth outcomes.

Orofacial clefts are among the most common types of birth defects, but their clinical presentation has not been well described in a geographically diverse US population. To describe the birth prevalence and phenotype of nonsyndromic clefts, we used data from the National Birth Defects Prevention Study (NBDPS), a multi-site, population-based, case-control study aimed at identifying genetic and environmental risk factors for birth defects. Included in the study were infants born during 1997-2004 with a cleft lip (CL), cleft lip with cleft palate (CLP), or cleft palate (CP). Infants with clefts associated with recognized single-gene disorders, chromosome abnormalities, holoprosencephaly, or amniotic band sequence were excluded. A total of 3,344 infants with nonsyndromic orofacial clefts were identified, including 751 with CL, 1,399 with CLP, and 1,194 with CP, giving birth prevalence estimates of 0.3, 0.5, and 0.4/1,000 live births, respectively. Among infants with CLP where cleft laterality was specified, about twice as many had unilateral vs. bilateral involvement, while for CL there were over 10 times as many with unilateral versus bilateral involvement. Involvement was most often left-sided. About one-quarter of infants with CP had Pierre Robin sequence. Over 80% of infants had an isolated orofacial cleft. Among infants with CL or CLP, heart, limb, and other musculoskeletal defects were most commonly observed, while heart, limb, and central nervous system defects were most common among infants with CP. Better understanding of the birth prevalence and phenotype may help guide clinical care as well as contribute to an improved understanding of pathogenesis.

The objective of this study was to characterize the prevalence, demographic risk factors, and malformations associated with agenesis and hypoplasia of the corpus callosum diagnosed in infancy. Using a large population-based registry of birth defects, we ascertained 630 cases of agenesis (ACC) and hypoplasia (HCC) of the corpus callosum diagnosed in the first year of life among 3.4 million live births from 1983 to 2003. Infants with destructive lesions or specific complex central nervous system (CNS) malformations (neural tube defects, lissencephaly, and holoprosencephaly) were excluded. Multivariable Poisson regression analysis was used to examine demographic risk factors. The combined prevalence of ACC and HCC was 1.8 per 10,000 live births. Fifty-two percent of cases were male. Infants with ACC had an almost fourfold higher prevalence among infants born prematurely when compared with children born > or =37 weeks gestation (RR 3.7, 95% CI 2.5-5.3). After adjusting for paternal age, advanced maternal age >/=40 years was associated with ACC in infants with a chromosomal disorder (ACC RR 5.9; 95% CI 1.8-19.3, HCC RR 3.5; 95% CI 0.9-14.1). Paternal age was not significantly associated with ACC after adjusting for maternal age. Callosal anomalies were often seen in the context of a chromosomal abnormality (17.3%) and with accompanying somatic (musculoskeletal 33.5% and cardiac 27.6%) and CNS malformations (49.5%). Callosal anomalies form a clinically significant and relatively frequent group of malformations of the CNS that are associated with increased risk of premature birth, are more common with advanced maternal age and are frequently part of a complex, multisystem disorder., (Copyright 2008 Wiley-Liss, Inc.)

Background: Prepregnant obesity has been shown to be related to several birth defects, most notably neural tube defects. We investigated the previously observed association between obesity and spina bifida and also possible associations between obesity and other birth defects., Results: We conducted a case-control study of fetuses and liveborn infants among California births, July 1999 and June 2004. Of those eligible, 80% of case mothers (n = 659) and 77% of control mothers (n = 700) were interviewed. Cases were 147 infants with anencephaly, 191 with spina bifida, 142 with d-transposition of great arteries, and 181 with tetralogy of Fallot. Maternal body mass index (BMI) was based on prepregnant weight and height., Results: The odds ratios of birth defects with obesity (BMI > or =30 relative to normal BMI) were 1.6 for anencephaly (95% confidence intervals = 1.0-2.6); 1.4 for spina bifida (0.8-2.2); 0.7 for d-transposition of great arteries (0.4-1.4); and 0.8 for tetralogy of Fallot (0.4-1.4). Modestly elevated odds ratios were observed with obesity among women who reported weight gain in their waist before pregnancy-for anencephaly, 2.4 (1.2-5.1) and for spina bifida, 1.8 (0.9-3.6)., Conclusion: These data do not fully support earlier findings with respect to the relationships of obesity with anencephaly and spina bifida.

Investigations for co-occurring malformations can serve as a first step to discover new risk factors and provide insights into malformation etiologies. Our objective was to explore the risks of occurrence of structural congenital malformation phenotypes in 5,481 infants with hypospadias, using data from a population-based active surveillance system. Ascertainment was performed among 1,816,258 liveborn and 12,203 stillborn male offspring of women who were residents of registry counties during 1983-1997. Malformations other than hypospadias were grouped according to the 3- and 4-digit BPA malformation codes. Prevalences of each malformation grouping were calculated among all births with hypospadias and their three subgroups and all births without hypospadias but with another structural malformation. Relative risks were estimated based on the ratio of two prevalences, and the corresponding 95% confidence intervals were computed using Poisson regression models. Observed relative risks indicated that all malformation groupings were less likely to co-occur with hypospadias and their three subgroups than with other types of malformations, with relative risks ranging from 0.04 to 0.93. For most malformations, risks were relatively similar among all births with hypospadias and the three subgroups of hypospadias. The observed relative risks were not substantially changed in analyses that adjusted for maternal age, race/ethnicity, and parity. Computations were extended to 4-digit level BPA codes. Almost all observed relative risks for malformations co-occurring with hypospadias overall and three subgroups were less than 1., ((c) 2007 Wiley-Liss, Inc.)

Food insecurity represents a lack of access to enough food to meet basic needs. We hypothesized that food insecurity may increase birth defect risks, because it is an indicator of increased stress or compromised nutrition, which are both implicated in birth defect etiologies. This study used population-based case-control data. Included in the analysis were 1,189 case mothers and 695 control mothers who were interviewed by telephone. We calculated a food insecurity score as the number of affirmative responses to 5 questions from a shortened instrument designed to measure food insecurity. OR for the food insecurity score specified as a linear term indicated that a higher score was associated with increased risk of cleft palate, d-transposition of the great arteries, tetralogy of Fallot, spina bifida, and anencephaly, but not with cleft lip with or without cleft palate, after adjustment for maternal race-ethnicity, education, BMI, intake of folic acid-containing supplements, dietary intake of folate and energy, neighborhood crime, and stressful life events. In addition, several models suggested effect modification by certain factors. For example, for anencephaly, among women with the worst score for neighborhood crime (i.e. 6), the OR associated with a 1-unit change in the food insecurity score was 1.57 (95% CI 1.06, 2.33), whereas among women with a low crime score (i.e. 2), the corresponding OR was 1.16 (95% CI 0.96, 1.38). This study suggests that increased risks of certain birth defects may be included among the negative consequences of food insecurity.

Objective: To describe the relation between maternal obesity, overweight and underweight status, and 16 categories of structural birth defects., Design: An ongoing multisite, case-control study. Clinical geneticists reviewed all of the cases, excluding those that had or were strongly suspected to have a single-gene disorder or chromosomal abnormality. Mothers with preexisting diabetes were also excluded. Body mass index was based on maternal report of height and weight prior to pregnancy., Setting: Eight participating states in the United States., Participants: Mothers enrolled in the National Birth Defects Prevention Study who had index pregnancies between October 1, 1997, and December 31, 2002., Main Exposure: Maternal obesity., Main Outcome Measures: Crude and adjusted odds ratios., Results: Mothers of offspring with spina bifida, heart defects, anorectal atresia, hypospadias, limb reduction defects, diaphragmatic hernia, and omphalocele were significantly more likely to be obese than mothers of controls, with odds ratios ranging between 1.33 and 2.10. Mothers of offspring with gastroschisis were significantly less likely to be obese than mothers of controls., Conclusions: To our knowledge, this is the first population-based study of its scale to examine prepregnancy obesity and a range of structural birth defects. These results suggest a weak to moderate positive association of maternal obesity with 7 of 16 categories of birth defects and a strong inverse association with gastroschisis. The mechanisms underlying these associations are not yet understood but may be related to undiagnosed diabetes.

Background: Several previous studies suggest that maternal stress may be associated with increased risk of certain birth defects. This study examined the association of maternal stressful life events with risks of several birth defects., Methods: The data are from a recent, population-based case-control study. Telephone interviews were conducted with 1355 eligible case mothers and 700 control mothers. Maternal stress was measured by responses to 18 yes/no questions about life events that occurred from 2 months before through 2 months after conception., Results: An increase in the stressful life events index (ie, number of "yes" responses to the 18 life-events questions) was associated with increased risk of cleft palate, cleft lip with or without cleft palate, d-transposition of the great arteries, and tetralogy of Fallot, after adjustment for maternal race-ethnicity, education, obesity, age, smoking, drinking, intake of folic acid-containing supplements, neighborhood crime, and food insecurity. For example, the odds ratio for a 3-unit change in the stress index was 1.45 (95% confidence interval = 1.03-2.06) for cleft palate. Increased stress was associated with an increased risk of spina bifida and anencephaly particularly among women who did not take folic acid supplements. A 3-unit change in stress was associated with a 2.35-fold increased risk of anencephaly among women who did not take supplements (CI =1.47-3.77) and a 1.42-fold increased risk among women who did (CI = 0.89-2.25)., Conclusion: The adverse health effects of stress may include increased risks of certain birth defects.

Background: Maternal obesity and diabetes are both associated with increased risk of congenital central nervous system (CNS) malformations in the offspring and may share a common underlying mechanism. Our objective was to evaluate whether gestational diabetes influenced the association of prepregnancy maternal obesity and risks for CNS birth defects., Methods: This Texas population-based case-control study evaluated births occurring January 1997 through June 2001. Data came from structured telephone interviews. Cases (n=477) were mothers of offspring with anencephaly (n=120), spina bifida (n=184), holoprosencephaly (n=49), or isolated hydrocephaly (n=124). Controls (n=497) were mothers of live infants without abnormalities randomly selected from the same hospitals as cases. Response rates were approximately 60% for both cases and controls. We evaluated maternal obesity (body mass index > or =30.0 kg/m) and risks for CNS birth defects, as well as whether gestational diabetes influenced the risks., Results: After adjusting for maternal ethnicity, age, education, smoking, alcohol use, and periconceptional vitamin use, obese women had substantially increased risks of delivering offspring with anencephaly (odds ratio=2.3; 95% confidence interval=1.2-4.3), spina bifida (2.8; 1.7-4.5), or isolated hydrocephaly (2.7; 1.5-5.0), but not holoprosencephaly (1.4; 0.5-3.8). Odds ratios were higher for the joint effects of maternal obesity and gestational diabetes, with evidence for interaction on a multiplicative scale., Conclusions: Maternal obesity and gestational diabetes may increase the risk of CNS birth defects through shared causal mechanisms.

Background: Little is known about the occurrence of specific congenital malformations among offspring of mixed race-ethnicity., Methods: Using data from a population-based registry, we explored the occurrence of selected malformation phenotypes in offspring to parents who were of different race-ethnicity. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.6 million live births and stillbirths occurred during 1989-2000. Information on parental race-ethnicity (non-Hispanic white, Hispanic, black, and Asian) was obtained from birth certificates and fetal death files. Malformation phenotypes studied were spina bifida, anencephaly, cleft lip, cleft palate, tetralogy of Fallot, d-transposition of great arteries, hypospadias, small intestinal atresia, preaxial polydactyly, microtia, and hypertrophic pyloric stenosis., Results: A total of 11.2% of births were to parents of mixed race-ethnicity. Compared to births of parents who were both white, moderately increased risks (risk ratio >/= 1.7) of anencephaly, polydactyly, and microtia, and decreased risks (risk ratio

Background: Little is known about risks of most specific birth defects among infants born to U.S.-born and foreign-born Hispanic or African-American women., Methods: Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of U.S.-born and foreign-born Hispanic and African-American women, relative to non-Hispanic white women, in California. Approximately 2.2 million live births and stillbirths occurred during the ascertainment period, 1989-1997. Information on maternal racial-ethnic background and other covariates was obtained from birth certificate and fetal death files., Results: Adjusted relative risks (ARRs) for the 20 groupings of malformations designated by three-digit British Pediatric Association (BPA) codes ranged from 0.6 (genital organ malformations, among infants born to foreign-born Hispanics) to 1.7 (anencephaly, also among infants born to foreign-born Hispanics). Grouping by four-digit BPA codes revealed that among infants born to U.S.-born Hispanics, 46 of the ARRs were < or = 0.8 and 12 were > or = 1.3; among infants born to foreign-born Hispanics, 75 of the ARRs were < or = 0.8 and 15 were > or = 1.3; and among infants born to African-American women, 45 ARRs were < or = 0.8 and 25 were > or = 1.3. For each racial-ethnic group of women, the observed variability in risks covered most organ systems., Conclusions: Although the results suggested that (in comparison with non-Hispanic whites) each racial-ethnic group was more likely to have reduced risk for specific defects (rather than elevated risk), in general, the range of the relative risks was comparatively narrow., (Copyright 2004 Wiley-Liss, Inc.)

Few population-based epidemiologic data are available on malformation phenotypes that co-occur with orofacial clefts. We explored the occurrence of structural congenital malformations in offspring with cleft palate (CP) and in offspring with cleft lip with or without CP (CLP), using data from a population-based active surveillance system. Ascertainment was performed among 3548991 liveborn and 23239 stillborn offspring of California women who delivered in nonmilitary hospitals during the period, 1983-1997. Structural congenital malformations were found in 91888 births. Among them, 2343 had CP and 4072 had CLP. Malformations were grouped according to 3- and 4-digit codes of the British Pediatric Association (BPA). Prevalences of each malformation grouping, defined by these codes, were calculated among: (1). all births with CP; (2). all births with CLP; (3). all births without CP or CLP but with another structural malformation; and (4). all births in the population at risk. These various prevalence measures were the basis of estimating relative risks. Observed relative risks indicated that some phenotypes were more likely and some were less likely to co-occur with either CP or CLP, with relative risks ranging from 0.5 to 2.4. For both CP and CLP, estimated relative risks were highest for malformations involving the respiratory system and lowest for spina bifida. The exclusion of all births (n = 10702) with chromosomal anomalies from comparisons did not materially alter observed relative risk estimates. Computations extended to 4-digit level BPA codes revealed elevated risks for a number of more specific diagnoses seen within the larger (3-digit level) groupings defined as eye, ear, respiratory, upper alimentary tract, and other musculoskeletal anomalies. In this large population-based cohort of infants and fetuses with CLP or CP, we observed several noncleft malformation groupings to be more common and others to be less common in their co-occurrence with orofacial clefts relative to their co-occurrence with any other malformation. These observed patterns tended to be similar for CP and for CLP., (Copyright 2003 Wiley-Liss, Inc.)

Background: Although many studies have observed variations in the prevalence of specific malformations by sex, there is a lack of population-based data on potential malformation prevalence differences by sex at birth., Methods: Our objective was to explore differences in the prevalence of structural congenital malformation phenotypes between sexes in a California population of 2.5 million live- and stillbirths, using data from a population-based active surveillance system. Ascertainment was performed among offspring of California women who delivered in nonmilitary hospitals during the period of 1989-1997. Malformations were grouped according to the four-digit malformation codes of the British Pediatric Association., Results: Overall, 32,619 males and 21,835 females were considered to have structural congenital malformations, with prevalences of 2.52% and 1.76%, respectively. Thus, males demonstrated a malformation prevalence that was 22% higher than that in females. Using a criterion of a 40% increase or decrease in the relative risk for males, increased risks for 15 and decreased risks for 17 specific malformation categories were observed. Increased risks were associated with most organ systems, with the notable exception of the nervous system (increased risks for nervous system malformations were observed among female births). Risks were not substantially influenced by adjusting for maternal age, race/ethnicity, parity, or education., Conclusions: Our observations extend the relatively few studies that have investigated differential prevalences of a large number of specific structural malformations between male and female births., (Copyright 2003 Wiley-Liss, Inc.)

Background: A paucity of epidemiologic research exists concerning the co-occurrence of birth defects and mental retardation (MR). Study of this co-occurrence may yield important clues about the causes of both., Objective: To examine the co-occurrence of birth defects and MR, taking into consideration the type of birth defect, level of MR, co-occurrence of MR with other developmental disabilities, and individual and maternal factors., Design: A retrospective cohort study of infants born in the California Central Valley with and without a structural birth defect by 1 year of age, and with or without MR by 7 to 9 years of age., Setting and Participants: One-year survivors (N = 119 556) born in nonmilitary hospitals in 8 California counties between January 1, 1992, and December 31, 1993, for whom information about birth defects was recorded within the first year of life., Main Outcome Measure: Diagnosis of MR by age 7 years considered as being mild or severe and as occurring without other developmental disabilities (isolated MR) or as occurring with other developmental disabilities, including cerebral palsy, epilepsy, or a pervasive developmental disorder., Results: Children with birth defects were nearly 27 times more likely to have MR by 7 years of age compared with children without a diagnosed birth defect regardless of type of defect (prevalence ratio, 26.8; 95% confidence interval, 22.7-31.7). Among those with birth defects, children with Down syndrome (prevalence ratio, 211.7; 95% confidence interval, 171.3-261.5) and children with sex chromosomal defects (prevalence ratio, 57.4; 95% confidence interval, 23.7-138.6) were at the highest risk for MR. Children with nonchromosomal defects, including central nervous system defects and all types of organ and system defects, were at substantially increased risk for all levels of MR. Risks of MR among children with Down syndrome and nonchromosomal defects were not substantially altered when adjusted for individual and maternal factors., Conclusions: Children with chromosomal and other structural birth defects are at a substantially increased risk for having MR by 7 years of age compared with children born without a birth defect. Children with birth defects are at an especially increased risk for having severe MR and MR occurring independently of other developmental disabilities.

Background: Concerns about potential health effects of trihalomethanes (THMs) have prompted investigations on whether infants whose mothers were periconceptionally exposed to drinking water containing THMs are at greater risk of congenital malformations., Methods: We used two large case-control maternal interview studies that were conducted among California deliveries from 1987 through 1991. One study comprised 538 infants/fetuses with neural tube defects (NTDs) and 539 nonmalformed control infants. The second study included an additional 265 infants with NTDs, 207 infants with conotruncal heart defects, 409 infants with orofacial clefts, and 481 control infants. Expert personnel from municipal water companies estimated THM levels for a particular residence and specific periconceptional time period using quarterly monitoring measurements. Estimates were also made for four individual THM levels and for the total THM level., Results: NTD risk in the first study was inversely associated with total THM exposure. Although the second study did not show the same inverse relationship for NTDs, there were no positive associations of NTDs or the other malformations with total THM as estimated from continuous models. Elevated risks were observed for the lowest category of exposure (1-24 ppb), but risks were either not substantially elevated or were imprecise for higher exposure levels. Thus no evidence was observed for an exposure-response relation., Conclusions: Our results do not provide a clear pattern of association between THM exposure and risks of specific congenital malformations. Imprecise exposure measures coupled with a lack of information about other possible sources of THM exposure may have caused associations to be underestimated.

Background: Although previous studies provide some evidence that timing of prenatal care initiation is associated with risks of congenital malformation, the issue has not previously been examined in depth. This study uses data from a large population-based registry to explore the association of timing of prenatal care initiation with risks of selected congenital malformation phenotypes., Methods: Data on cases were grouped according to four-digit malformation codes of the International Classification of Diseases, Ninth Revision (ICD-9). A randomly selected group of 10,000 nonmalformed deliveries served as the comparison group. Information on month of initiation of prenatal care (categorized as during months 1-3 of gestation, months 4-7, or after month 7) and other maternal characteristics were derived from vital statistics data., Results: Among the 176 four-digit ICD groupings, 67 had an adjusted odds ratio for at least one of the two prenatal care categories that was either < or = 0.67 or > or = 1.50. Later prenatal care initiation was associated with risk > or = 1.50 for most groups. Later care was associated with risk < or = 0.67 for only two groups, and the effects were imprecise. Statistical interaction between parity and prenatal care was indicated for 13 groups (P < 0.10). Risks among women with no previous pregnancy tended to increase with later prenatal care initiation; risks among parous women tended to be somewhat weaker. In general, associations applied to a wide range of malformation groups., Conclusions: This is the first large-scale study of the association of timing of prenatal care initiation and congenital malformation risks. Further defining the phenomena that surround prenatal care as a marker may help clarify the etiologies of a variety of malformations., (Copyright 2002 Wiley-Liss, Inc.)

Background: Advances in quantitative analysis and molecular genotyping have provided unprecedented opportunities to add biological sampling and genetic information to epidemiologic studies. The purpose of this article is to describe the incorporation of DNA sample collection into the National Birth Defects Prevention Study (NBDPS), an ongoing case-control study in an eight-state consortium with a primary goal to identify risk factors for birth defects., Methods: Babies with birth defects are identified through birth defects surveillance systems in the eight participating centers. Cases are infants with one or more of over 30 major birth defects. Controls are infants without defects from the same geographic area. Epidemiologic information is collected through an hour-long interview with mothers of both cases and controls. We added the collection of buccal cytobrush DNA samples for case-infants, control-infants, and their parents to this study., Results: We describe here the methods by which the samples have been collected and processed, establishment of a centralized resource for DNA banking, and quality control, database management, access, informed consent, and confidentiality issues., Conclusions: Biological sampling and genetic analyses are important components to epidemiologic studies of birth defects aimed at identifying risk factors. The DNA specimens collected in this study can be used for detection of mutations, study of polymorphic variants that confer differential susceptibility to teratogens, and examination of interactions among genetic risk factors. Information on the methods used and issues faced by the NBDPS may be of value to others considering the addition of DNA sampling to epidemiologic studies.

Background: Little is known about reproductive outcome risks for Vietnamese women delivering infants and fetuses in the U.S., Methods: Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of Vietnamese women in California. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 3.4 million births (liveborn and stillborn) occurred during the ascertainment period, 1985-97. Information on maternal race/ethnic background was obtained from California birth certificate and fetal death files. Vietnamese women delivered 45,453 births and 1,257,853 births were delivered to non-Hispanic white women., Results: The overall prevalence of structural congenital malformations was 1.92 among Vietnamese and 2.63 among non-Hispanic whites per 100 births and fetal deaths. Grouping by 20 3-digit malformation codes of the International Classification of Diseases-Ninth Revision revealed relative risks of 0.8 or less for spina bifida, eye, upper alimentary, genital, urinary, musculoskeletal, "other" limb, and "other" musculoskeletal anomalies, and relative risks of 1.3 or more for anencephaly and chromosomal anomalies. Grouping by the more specific 4-digit malformation codes revealed 50, among 178, malformation groupings with associated relative risks of >or=1.3 or

The authors evaluated the effect of air pollution on the occurrence of birth defects ascertained by the California Birth Defects Monitoring Program in neonates and fetuses delivered in southern California in 1987-1993. By using measurements from ambient monitoring stations of carbon monoxide (CO), nitrogen dioxide, ozone, and particulate matter <10 microm in aerodynamic diameter, they calculated average monthly exposure estimates for each pregnancy. Conventional, polytomous, and hierarchical logistic regression was used to estimate odds ratios for subgroups of cardiac and orofacial defects. Odds ratios for cardiac ventricular septal defects increased in a dose-response fashion with increasing second-month CO exposure (odds ratio (OR)(2nd quartile) CO = 1.62, 95% confidence interval (CI): 1.05, 2.48; OR(3rd quartile) CO = 2.09, 95% CI: 1.19, 3.67; OR(4th quartile) CO = 2.95, 95% CI: 1.44, 6.05). Similarly, risks for aortic artery and valve defects, pulmonary artery and valve anomalies, and conotruncal defects increased with second-month ozone exposure. The study was inconclusive for other air pollutants. The authors' results are supported by the specificity of the timing of the effect and some evidence from animal data; however, this is the first known study to link ambient air pollution during a vulnerable window of development to human malformations. Confirmation by further studies is needed.

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

BackgroundGastroschisis is a birth defect where loops of bowel are protruding from the abdominal wall at birth. Previous research has suggested that gastroschisis cases can occur in clusters. The objective of this study was to identify if there were areas of elevated gastroschisis risk using data from the National Birth Defects Prevention Study (NBDPS), 1997 through 2007.MethodsWe obtained data on cases (n = 371) through population-based birth defects surveillance systems in Arkansas, California, and Utah; controls (n = 2359) were selected from the same geographic areas as cases. Mothers were interviewed on demographic information and exposures during pregnancy, including residential history. We used first trimester maternal addresses and generalized additive models to create a continuous map surface of odds ratios (OR) by smoothing over latitude and longitude. Permutation tests were used to assess whether location of maternal residence was important and identify locations with statistically significant ORs.ResultsIn Arkansas, adjusted ORs in the southwest corner were 2.0 and the global deviance was not statistically significant (p-value: 0.57). Adjusted ORs for California indicated areas of increased risk with ORs 1.3 (p-value: 0.34). In Utah, the adjusted ORs were elevated (OR: 2.4) in the south-eastern corner of the study area (p-value: 0.34).ConclusionThe results of this study, while not statistically significant, suggest there were spatial variations in gastroschisis births. We cannot rule out that these variations were due to edge effects or residual confounding.

Background: Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking. Objectives: To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS. Methods: We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case‐control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid‐spina bifida and ondansetron‐cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over‐ (or under‐) representation to produce the crude OR (cOR) in NBDPS. For the smoking‐hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR. Results: Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid‐exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron‐exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking‐exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking‐hypospadias OR = 2.02). Conclusions: Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research. [ABSTRACT FROM AUTHOR]