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Background The National Birth Defects Prevention Study (NBDPS) is a large population-based multi-center 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 via 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.

Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the Reprints and permissions: sagepub.com/journalsPermissions.nav Corresponding Author: L.M. Moreno Uribe, Orthodontics-Dows Institute, University of Iowa, 401 DSB, Iowa City, IA 52242, USA. lina-moreno@uiowa.edu. * Authors contributing equally as senior authors. Author ContributionsL.M. Moreno Uribe, G.L. Wehby, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; T. Fomina, H.K. Gjessing, M. Gjerdevik, contributed to data analysis, critically revised the manuscript; R.G. Munger, P.A. Romitti, M.M. Jenkins, K. Christensen, contributed to data acquisition, critically revised the manuscript; A.J. Wilcox, J.C. Murray, contributed to data acquisition and interpretation, critically revised the manuscript; R.T. Lie, contributed to conception, design, data acquisition, analysis, and interpretation, critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.A supplemental appendix to this article is available online. HHS Public AccessAuthor manuscript J Dent Res. Author manuscript; available in PMC 2017 October 01. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a motherchild dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent.

Conducting research to identify modifiable risk factors for birth defects is difficult for a variety of reasons. While some challenges are familiar to researchers across many disciplines, the confluence of issues affecting birth defects research may not be well understood by those outside of the field. This article describes several methodological challenges to the study of birth defects and ways these challenges might be addressed: (1) ascertainment, definition and classification of birth defects; (2) exposure assessment on modifiable risk factors; (3) analytical challenges related to small numbers and multiple statistical tests; (4) the role of genetics, including the collection of specimens and analysis of genetic data; and (5) challenges in translating research and demonstrating public health impact. Understanding these issues is important for researchers planning studies, reviewers evaluating the scientific merit of results from these studies, and consumers of the research, including fellow researchers, policy makers, health care providers, and families.

Maternal smoking during pregnancy is one proposed risk factor for gastroschisis, but reported associations have been modest, suggesting that differences in genetic susceptibility might play a role. We included 108 non-Hispanic white and 62 Hispanic families who had infants with gastroschisis, and 1147 non-Hispanic white and 337 Hispanic families who had liveborn infants with no major structural birth defects (controls) in these analyses. DNA was extracted from buccal cells collected from infants and mothers, and information on periconceptional smoking history was obtained from maternal interviews, as part of the National Birth Defects Prevention Study. We analyzed five polymorphisms in three genes that code for enzymes involved in metabolism of some cigarette smoke constituents (CYP1A1, CYP1A2, and NAT2). Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) independently for maternal smoking and maternal and infant gene variants, and to assess joint associations of maternal smoking and maternal or infant gene variants with gastroschisis. In analyses adjusted for maternal age at delivery and stratified by maternal race-ethnicity, we identified three suggestive associations among 30 potential associations with sufficient numbers to calculate ORs: CYP1A1*2A for non-Hispanic white mothers who smoked periconceptionally (aOR=0.38, 95% CI 0.15-0.98), and NAT2*6 for Hispanic non-smoking mothers (aOR=2.17, 95% CI 1.12-4.19) and their infants (aOR=2.11, 95% CI 1.00-4.48). This analysis does not support the occurrence of effect modification between periconceptional maternal smoking and most of the xenobiotic metabolizing enzyme gene variants assessed.

To assess attitudes toward DNA collection in an epidemiological study, focus groups were assembled in September 2007 with mothers who had participated in a case-control study of birth defects. Each recruited mother previously had completed an interview and had received a mailed kit containing cytobrushes to collect buccal cells for DNA from herself, her infant, and her infant's father during the period July 2004 through July 2007. A total of 38 mothers attended six focus groups comprising: (1) non-Hispanic Black mothers of case infants who participated or (2) did not participate in DNA collection, (3) mothers of any race or ethnicity who had case infants of low birth weight who participated or (4) did not participate in DNA collection, and (5) non-Hispanic Black mothers of control infants who participated or (6) did not participate in DNA collection. Moderator-led discussions probed maternal attitudes toward providing specimens, factors that influenced decision making, and collection method preferences. Biologics participants reported that they provided DNA for altruistic reasons. Biologics nonparticipants voiced concerns about government involvement and how their DNA will be used. Information provided (or not provided) on DNA use, storage, and disposal influenced decision making. Biologics participants and nonparticipants reported that paternal skepticism was a barrier to participation. All mothers were asked to rank DNA collection methods in terms of preference (cytobrushes, saliva, mouthwash, newborn blood spots, and blood collection). Preferred methods were convenient and noninvasive. Better understanding attitudes toward DNA collection and preferred collection methods might allow more inclusive participation and benefit future studies.

Background While there is strong evidence that genetic risk factors play an important role in the etiologies of structural birth defects, compared to other diseases, there have been relatively few genome‐wide association studies (GWAS) of these conditions. We reviewed the current landscape of GWAS conducted for birth defects, noting novel insights, and future directions. Methods This article reviews the literature with regard to GWAS of structural birth defects. Key defects included in this review include oral clefts, congenital heart defects (CHDs), biliary atresia, pyloric stenosis, hypospadias, craniosynostosis, and clubfoot. Additionally, other issues related to GWAS are considered, including the assessment of polygenic risk scores and issues related to genetic ancestry, as well as utilizing genome‐wide single nucleotide polymorphism array data to evaluate gene–environment interactions and Mendelian randomization. Results For some birth defects, including oral clefts and CHDs, several novel susceptibility loci have been identified and replicated through GWAS, including 8q24 for oral clefts, DGKK for hypospadias, and 4p16 for CHDs. Relatively common birth defects for which there are currently no published GWAS include neural tube defects, anotia/microtia, anophthalmia/microphthalmia, gastroschisis, and omphalocele. Conclusions Overall, GWAS have been successful in identifying several novel susceptibility genes and genomic regions for structural birth defects. These findings have provided new insights into the etiologies of these phenotypes. However, GWAS have been underutilized for understanding the genetic etiologies of several birth defects.

To understand motivations and barriers to participation in studies that include DNA collection, focus group discussions were held with mothers who had participated in a case-control study of birth defects. Recruited mothers had completed an interview and had received a mailed kit containing cytobrushes to collect buccal cells for DNA from herself, her infant, and her infant's father. Six moderator-led focus groups were attended by a total of 38 women residing in Atlanta, Georgia. Focus groups were segmented by DNA collection status (biologics participants or nonparticipants), infant case-control status, infant birthweight, and maternal race and ethnicity. This report assesses maternal attitudes toward study materials and communication strategies. Across groups, respondents expressed concern about how their contact information was obtained. Study materials were described as clear and professional by most women, although some respondents reported confusion about disclosure of individual genetic results. Respondents generally reported that monetary incentives were not a motivation to participate, but increased perceived study legitimacy. Biologics nonparticipants expressed concerns about kit component sterility; government involvement; and DNA sample use, storage, and disposal. Respondents suggested that investigators provide feedback on whether sample collection was performed correctly and provide materials targeted to fathers to help alleviate paternal skepticism. Participation in DNA collection might be improved by strengthening study materials and communication strategies.