Advanced paternal age at birth and risk of cyanotic congenital heart defects in the United States

INTRODUCTION: Limited inconsistent evidence suggests a potential association between advanced paternal age (APA) and simple congenital heart defects, which often resolve without surgical interventions, in offspring. There is no reported potential relationship between APA with major cardiac defects like cyanotic congenital heart defects (CCHD). This study evaluated the association between APA (age at birth ≥40 years) and the occurrence of CCHD among livebirths in the USA, accounting for maternal and other potential confounding factors. METHODS: Data were from the National Vital Statistics System, comprising 9.9 million singleton first-time livebirths among mothers and fathers aged ≥15 years from 2016 to 2023. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: From 2016 to 2023, the proportion of births to fathers with APA increased from 7.5% to 7.9%. A greater proportion of fathers with APA had offspring with CCHD (62.0 vs. 53.1 per 100,000), used infertility treatment (9.5% vs. 2.3%), and their partners were also older (34.6 vs. 27.0 years). In models adjusted for paternal factors (age, race and ethnicity, and education), APA was associated with a modest elevated odds for CCHD (OR = 1.22, 95% CI 1.11-1.34) which remained significant after further control for maternal pre-pregnancy sociodemographic and health factors (OR = 1.12, 95% CI 1.01-1.25). However, additional adjustments for infertility treatment attenuated the observed association (OR = 1.08, 95% CI 0.98-1.20). CONCLUSIONS: The findings of this large population-based study suggest no association between APA and CCHD after accounting for important confounders, including maternal factors and infertility treatment.