Birth defects that co-occur with non-syndromic gastroschisis and omphalocele.

Gastroschisis and omphalocele are the two most common abdominal wall birth defects, and epidemiologic characteristics and frequency of occurrence as part of a syndromic condition suggest distinct etiologies between the two defects. We assessed complex patterns of defect co-occurrence with these defects separately using the Texas Birth Defects Registry. We used co-occurring defect analysis (CODA) to compute adjusted observed-to-expected (O/E) ratios for all observed birth defect patterns. There were 2,998 non-syndromic (i.e., no documented syndrome diagnosis identified) cases with gastroschisis and 789 (26%) of these had additional co-occurring defects. There were 720 non-syndromic cases with omphalocele, and 404 (56%) had additional co-occurring defects. Among the top 30 adjusted O/E ratios for gastroschisis, most of the co-occurring defects were related to the gastrointestinal system, though cardiovascular and kidney anomalies were also present. Several of the top 30 combinations co-occurring with omphalocele appeared suggestive of OEIS (omphalocele, exstrophy of cloaca, imperforate anus, spinal defects) complex. After the exclusion of additional cases with features suggestive of OEIS in a post-hoc sensitivity analysis, the top combinations involving defects associated with OEIS (e.g., spina bifida) were no longer present. The remaining top combinations involving omphalocele included cardiovascular, gastrointestinal, and urogenital defects. In summary, we identified complex patterns of defects that co-occurred more frequently than expected with gastroschisis and omphalocele using a novel software platform. Better understanding differences in the patterns between gastroschisis and omphalocele could lead to additional etiologic insights.

Assessing the Role of Asthma on the Relationship between Neurodevelopmental Disabilities and Adverse Birth Outcomes.

BACKGROUND: Investigating asthma as an effect modifier between adverse birth outcomes and neurodevelopmental disabilities (NDDs) across different races is crucial for tailored interventions and understanding variable susceptibility among diverse populations. METHODS: Data were collected through the National Survey of Children's Health. This cross-sectional study included 131,774 children aged 0 to 17 years. Study exposures comprised adverse birth outcomes including preterm birth and low birth weight. Weighted prevalence estimates and odds ratios with 95% confidence intervals (CIs) among children with and without adverse birth outcomes were calculated for NDDs including attention-deficit/hyperactivity disorder, autism spectrum disorder, cerebral palsy, seizure, and several others including behavior problems. Adjusted odds ratios were stratified by asthma status and separate interactions were assessed for each outcome. RESULTS: Of 131,774 participants, 10,227 were born low birth weight (9.12%; 95% CI: 8.77% to 9.49%), 14,058 were born preterm (11.35%; 95% CI: 10.94% to 11.76%), and 16,166 participants had asthma (11.97%; 95% CI: 11.58% to 12.37%). There were 68,100 males (51.11%), 63,674 females (48.89%), 102,061 non-Hispanic Whites (NHW) (66.92%), 8,672 non-Hispanic Blacks (NHB) (13.97%), and 21,041 participants (19.11%) categorized as other. NHB children with adverse birth outcomes had higher prevalence of several NDDs compared to NHW children. CONCLUSIONS: Asthma was not shown to be an effect modifier of the association between adverse birth outcomes and NDDs. Nevertheless, these results suggest that NDDs are more prevalent within US children with adverse birth outcomes, with higher rates among NHB compared to NHW children. These findings support screening for NDDs in pediatric health care settings among patients with adverse birth outcomes, particularly among those from ethnic minority backgrounds.

Demographic differences and potential bias from automated occupation coding among mothers of babies born with or without cleft lip and/or cleft palate in the Texas Birth Defects Registry.

OBJECTIVE: To compare maternal demographics based on occupation coding status and evaluate potential bias by excluding manually coded occupations. METHODS: This case-control study assessed cases with clefts obtained from the Texas Birth Defects Registry. The NIOSH Industry and Occupation Computerized Coding System automatically coded occupations, with manual coding for unclassified cases. Maternal demographics were tabulated by occupation coding status (manual vs. automatic). Logistic regression examined associations between major occupation groups and clefts. RESULTS: Automatic coding covered over 90% of all mothers. Building, grounds cleaning, and maintenance occupations, and office and administrative support occupations were significantly associated with cleft lip with or without cleft palate, even after excluding manually coded occupations. CONCLUSION: We found consistent associations before and after excluding manually coded data for most comparisons, suggesting that machine learning can facilitate occupation-related birth defects research.

Maternal effect genes as risk factors for congenital heart defects.

Maternal effect genes (MEGs) encode factors (e.g., RNA) in the oocyte that control embryonic development prior to activation of the embryonic genome. Over 80 mammalian MEGs have been identified, including several that have been associated with phenotypes in humans. Maternal variation in MEGs is associated with a range of adverse outcomes, which, in humans, include hydatidiform moles, zygotic cleavage failure, and offspring with multi-locus imprinting disorders. In addition, data from both animal models and humans suggest that the MEGs may be associated with structural birth defects such as congenital heart defects (CHDs). To further investigate the association between MEGs and CHDs, we conducted gene-level and gene-set analyses of known mammalian MEGs (n = 82) and two common groups of CHDs: conotruncal heart defects and left ventricular outflow tract defects. We identified 14 candidate CHD-related MEGs. These 14 MEGs include three (CDC20, KHDC3L, and TRIP13) of the 11 known human MEGs, as well as one (DNMT3A) of the eight MEGs that have been associated with structural birth defects in animal models. Our analyses add to the growing evidence that MEGs are associated with structural birth defects, in particular CHDs. Given the large proportion of individuals with structural birth defects for whom etiology of their condition is unknown, further investigations of MEGs as potential risk factors for structural birth defects are strongly warranted.

Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States.

Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS (N = 1472 total cases) and three without 22q11.2DS (N = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work.

Patterns of co-occurring birth defects among infants with hypospadias.

INTRODUCTION: Hypospadias, one of the most common male genital birth defects, occurs in 1 out of every 200 male births in the United States and is increasing in prevalence globally. OBJECTIVE: This study aimed to characterize the combinations of birth defects that co-occur with hypospadias more often than expected by chance, while accounting for the complex clustering patterns of congenital defects. STUDY DESIGN: We analyzed cases with hypospadias and at least one additional co-occurring defect from the Texas Birth Defect Registry born between 1999 and 2014. For each combination, we calculated adjusted observed-to-expected (O/E) ratios, using Co-Occurring Defect Analysis (CODA). RESULTS: Among 16,442 cases with hypospadias and without known syndromes, 2,084 (12.7%) had at least one additional defect. Many of the birth defect combinations within the highest adjusted O/E ratios included cardiac, musculoskeletal, and additional urogenital defects. For example, a top combination with an adjusted O/E of 139.0 included renal agenesis and dysgenesis, reduction defects of the upper limb, and other anomalies of upper limb (including shoulder girdle). High adjusted O/E ratios were also observed in combinations that included defects outside of the urogenital developmental field. For instance, the combination with the highest O/E ratio included buphthalmos, and congenital cataract and lens anomalies (adjusted O/E ratio: 192.9). Similar results were obtained when we restricted our analyses to cases with second- or third-degree hypospadias. DISCUSSION: Many combinations in the top results were expected (e.g., multiple urogenital defects); however, some combinations with seemingly unrelated patterns of defects may suggest the presence of some etiologic mechanisms yet to be identified. CONCLUSION: In summary, this study described patterns of co-occurring defect combinations with hypospadias that can inform further study and may provide insights for screening and diagnostic practices.