A. J. Agopian

Background: The preterm birth rate among infants with trisomy 21 is more than twice the rate among the general population. Maternal hypertension and diabetes are established risk factors for preterm birth in the general population; however, their impact on pregnancies of infants with trisomy 21 is unknown. This study aimed to evaluate the association between maternal hypertensive disorders/diabetes and preterm birth among infants with trisomy 21. Methods: We utilized data from the Texas Birth Defects Registry for deliveries between 1999 and 2018 ( n = 9355). We conducted Poisson regression to estimate crude and adjusted risk ratios for preterm birth associated with any maternal hypertension and any diabetes, and their subtypes (pregestational, gestational). We also evaluated the risk associated with exposure to both (co‐occurring) conditions compared to neither. Stratified analyses were conducted by racial/ethnic subgroups, preterm subtypes (< 32 weeks and 32–36 weeks), and presence/absence of congenital heart defects as part of secondary analyses. Results: We found that maternal hypertension and diabetes were associated with 50% and 21% higher risk for preterm birth, respectively, while the presence of both conditions versus neither was associated with a 71% higher risk. The association with hypertension was much stronger for delivery at < 32 weeks aRR 2.60 (95% CI 1.83, 3.70) than for delivery at 32–36 weeks aRR 1.46 (95% CI 1.28, 1.66). Conclusions: Our findings shed light on the role of maternal hypertension and diabetes in preterm birth risk among infants with trisomy 21, particularly when both conditions co‐occur and for extremely to very preterm birth.

Introduction: Children with birth defects often require complex medical care, contributing to increased healthcare costs. Understanding the economic burden of birth defects is important for resource planning, but recent Texas‐specific data are lacking. Methods: A retrospective data analysis was conducted using the Texas Hospital Inpatient Discharge Public Use Data File (PUDF) for all pediatric discharges (ages 0–17 years) documented between 2021 and 2023. We identified hospitalizations with birth defects based on the presence of an ICD‐10 code (Q00‐Q99) in any of the 26 diagnosis code fields. Median inflation‐adjusted hospitalization charges were calculated for hospitalizations with and without birth defects and were then stratified by characteristics of interest. Median charges were compared using the Wilcoxon‐rank sum test. Among hospitalizations of children with a birth defect in the principal diagnosis code field, charges were examined by birth defect phenotype. A sub‐analysis assessed charges for hospitalizations that occurred primarily in the Intensive Care Unit (ICU). Results: In Texas, 12.5% of all pediatric hospitalizations were for children with a birth defect. Aggregate total charges for these hospitalizations exceeded $26 billion and comprised 34.9% of all pediatric hospitalization charges. Hospitalizations for children with a birth defect had significantly higher median charges ($12,876 vs. $7,813) compared to hospitalizations for children without birth defects ( p < 0.001). Higher charges were observed for hospitalizations among several subgroups (e.g., ICU hospitalizations). Conclusion: Inpatient hospitalization charges for children with birth defects had a disproportionately high impact on hospitalization charges in Texas.

Objective: To evaluate the associations between maternal cigarette smoking and preterm birth (PTB) among infants with orofacial clefts (OFCs). Design: Population-based retrospective cohort study. Setting: Using data from the National Birth Defects Prevention Study (NBDPS, 1997-2011 deliveries) and the Birth Defects Study To Evaluate Pregnancy exposureS (2014-2021 deliveries), we evaluated the association between maternal smoking and PTB (<37 weeks) among liveborn infants with cleft lip with/without cleft palate (CL±P), cleft palate only (CP), or any OFC. Participants: In total, 5618 liveborn infants with OFCs (3699 CL±P and 1919 CP). Main Outcome Measure(s): Adjusted relative risks (aRRs) and 95% confidence intervals (CIs) were calculated using Poisson regression, adjusted for covariates. For each OFC group, smoking (any vs none) was evaluated during 5 pregnancy timepoints (eg, first trimester). Analyses were repeated for smoking intensity (none, 1-14, ≥15 cigarettes/day) (NBDPS only). Any smoking and smoking intensity were also evaluated for extremely-to-very (<32 weeks) and moderate-to-late preterm (32 to <37 weeks). Results: Among infants with OFCs, 14.5% were born preterm. Heavy smoking (≥15 cigarettes/day vs none) in the second trimester was associated with PTB among infants with CP (aRR: 1.89, 95% CI: 1.03-3.45) and extremely-to-very PTB among infants with any OFC (aRR: 3.37, 95% CI: 1.47-7.73). Associations were generally stronger for CP than for CL±P, though imprecise. Conclusions: Heavy smoking during the second trimester may increase the risk of extremely-to-very PTB in infants with OFCs and PTB among infants with CP, further supporting the importance of promoting maternal smoking cessation or reduction.

Background: Prenatal stress and social support are associated with adverse birth outcomes, including stillbirth, in the general population. Their relationship to stillbirth among fetuses with birth defects is unclear. Using data from the National Birth Defects Prevention Study and the Birth Defects Study To Evaluate Pregnancy exposureS, we examined associations between maternal stress and social support and the risk of stillbirth among fetuses with birth defects and whether these associations differed by maternal race/ethnicity. Methods: Participants self‐reported exposure to stressors and social supports experienced 3 months before conception through the first trimester. Using log‐binomial models, we estimated relative risks (RR) and 95% confidence intervals (CI) of stillbirth associated with high stress and low social support, adjusting for maternal age and race/ethnicity. We assessed additive and multiplicative effect measure modification by maternal race/ethnicity. Results: Neither stress nor social support was associated with stillbirth among fetuses with birth defects. Although we did not observe interaction, we observed increased risk of stillbirth among non‐Hispanic Black women with low stress (RR = 2.1, 95% CI = 1.3–3.6), Hispanic women with low stress (1.4, 1.0–2.1), and non‐Hispanic Black women with high stress (2.8, 1.4–5.2) compared to non‐Hispanic White women with low stress. We observed a similar pattern of results for low social support. Conclusions: Stress and social support were not associated with stillbirth in fetuses with birth defects. We observed elevated risk of stillbirth among non‐Hispanic Black women regardless of stress and social support levels.

Background: Residing in socioeconomically vulnerable areas is known to be associated with increased preterm birth (PTB) risk in the general population. However, the relationship between social vulnerability and PTB remains unexplored among infants with trisomy 21, who experience more than twice the PTB rate of the general population. Objectives: The primary objective was to examine the association between maternal socioeconomic vulnerability, as measured by the SVI, and PTB among infants with trisomy 21. Methods: We conducted a retrospective cohort study among infants with trisomy 21 born in Texas (1999–2018). We examined the association between neighbourhood vulnerability, measured by Social Vulnerability Index (SVI) quartiles, and PTB utilising data from the Texas Birth Defects Registry. Using Poisson regression, we estimated crude and adjusted risk ratios (RRs) and 95% confidence intervals (CIs), accounting for maternal demographic characteristics and health factors. Results: Of the 8823 eligible infants included in the analysis, 2269 (25.7%) were born preterm. Maternal residence in the highest vulnerability quartile was associated with an increased risk of PTB (RR 1.17, 95% CI 1.04, 1.32) and moderate to late PTB (RR 1.19, 95% CI 1.05, 1.35), compared to the least vulnerable quartile. In secondary analyses stratified by race/ethnicity, the association with high vulnerability was particularly strong among non‐Hispanic Black women (RR 1.44, 95% CI 1.00, 2.07). Conclusions: These findings underscore the importance of neighbourhood social vulnerability in influencing perinatal health risks, particularly PTB among infants with trisomy 21.

BACKGROUND: Atrial septal defects (ASDs) are a prevalent type of congenital heart disease. Previous GWAS (Genome-Wide Association Studies) have identified common variants associated with ASDs, though their mechanisms remain unknown. We aimed to expand insights into the architecture of common variants associated with ASD risk and elucidate functional mechanisms. METHODS: We conducted a GWAS using isolated ASD cases and healthy controls and replicated findings in an independent cohort. We examined epigenetic marks within this ASD locus in human induced pluripotent stem cell-derived cardiomyocytes and fetal human hearts. We characterized the consequences of deletions introduced by CRISPR-Cas9 mutagenesis of human induced pluripotent stem cells to assess the effect on downstream gene expression. In addition, we investigated the 3-dimensional genome architecture of the locus using chromosome conformation capture sequencing. RESULTS: We identified a novel ASD locus on chromosome 3p12.3 encompassing the ROBO2 gene, which encodes the Roundabout guidance receptor 2 for Slit ligands. This locus includes 15 common single nucleotide polymorphisms, an enhancer, and a CCCTC-binding factor (CTCF)-binding site. Deletions of varying lengths within the ASD-associated locus in human induced pluripotent stem cell-derived cardiomyocytes reduced ROBO2 expression and dysregulated the expression of extracellular matrix genes. Chromosome conformation capture sequencing indicated that this region physically interacts with the ROBO2 promoter and demonstrates that the CTCF-binding site is essential for this contact. CONCLUSIONS: Novel common single nucleotide polymorphisms in regulatory elements controlling ROBO2 transcription contribute to risk for ASDs. These data infer key roles for the Roundabout guidance receptor 2 and Slit ligands in embryogenic development and maturation of the atrial septa.

Objectives: To estimate sibling recurrence risk for non‐chromosomal birth defects using statewide, population‐based data. Methods: We analyzed data from the Florida Birth Defects Registry to identify singleton siblings born 2000–2019 with any of 43 non‐chromosomal birth defects. Multivariable logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between birth defect occurrence in the older sibling (exposure) and in the younger sibling (outcome). Two analytic scenarios were considered: (1) any birth defect in the younger sibling, and (2) concordant recurrence, defined as a defect within the same body region. Models adjusted for maternal sociodemographic and perinatal characteristics from linked birth certificate and hospital discharge data. Results: The study population included 1,372,831 sibling pairs, of which 29,611 (2.2%) had an older sibling with a birth defect. Among sibling pairs in which the older sibling was affected, 4.8% of younger siblings also had a birth defect. Younger siblings had over twice the odds of having any birth defect if their older sibling was affected compared to those with an unaffected older sibling (adjusted ROR: 2.1, 95% CI: 2.0–2.2). Recurrence risk varied by body system, with the highest adjusted odds of concordant recurrence observed for orofacial defects (adjusted ROR: 18.7, 95% CI: 13.9–25.1). Conclusions: Our findings provide contemporary, system‐specific estimates of sibling recurrence that may inform family counseling, preconception care, and clinical decision‐making.

Background: We sought to assess the extent to which folic acid supplementation and dietary folate intake are associated with preterm delivery among infants with spina bifida. Methods: We conducted a retrospective population‐based study using the National Birth Defects Prevention Study (NBDPS; 1999–2011) and the Birth Defects Study To Evaluate Pregnancy exposureS (BD‐STEPS; 2014–2019). We utilized robust Poisson regression to calculate the risk ratio (RR) and 95% confidence interval (CI) for the associations between preterm birth (< 37 weeks) and maternal use of folic acid‐containing supplements, dietary folate intake quartile, and a combined variable accounting for supplementation and dietary folate status. Results: Among 1199 infants with spina bifida (1011 in NBDPS, 188 in BD‐STEPS), 217 (18.1%) were born preterm. There were no statistically significant associations between preterm birth and lack of supplementation (RR 1.24, 95% CI: 0.92–1.69) or maternal dietary folate intake quartile (RRs 1.12–1.39). The combination of lack of supplementation and low dietary folate intake had the strongest association with preterm birth (RR 1.73, 95% CI: 1.01–2.96), compared to women who took supplements and had higher dietary folate intake. Conclusions: Our findings suggest a modestly elevated risk of preterm birth among infants with spina bifida born to women with the combination of no supplementation and low dietary folate intake. Future work confirming these findings and further investigating the timing of supplementation could help elucidate whether low folate intake is a risk factor for preterm birth in spina bifida–affected pregnancies.