Prenatal genetic findings and pregnancy outcomes in fetuses with congenital heart disease: a decade-long retrospective analysis at a tertiary hospital

Abstract

This study aimed to investigate the relationship between fetal congenital heart disease (CHD) phenotypes and genetic abnormalities and to evaluate the use of stepwise genetic testing [karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES)] for prenatal diagnosis and outcome prediction. This retrospective study included 1,354 CHD fetuses undergoing karyotyping and CMA; cases with negative results underwent WES. CHD was classified by type, complexity, and extracardiac anomalies. Phenotype-outcome associations were analyzed. Among 1,354 fetuses, karyotyping and CMA detected pathogenic abnormalities in 11.5% (156/1.354); WES identified 16 pathogenic/likely pathogenic (P/LP) (12.2%) and 2 variant of uncertain significance (VOUS) (1.5%) variants among the 131 cases negative on karyotyping and CMA. The highest detection rates occurred in conotruncal anomalies (25.0%) and atrioventricular septal defects (45.5%). Rates were higher in non-isolated versus isolated CHD (p < 0.001) and complex versus simple CHD (p < 0.05). Pathogenic abnormalities were associated with lower live birth rates (p < 0.001), largely attributed to pregnancy termination. Fetal CHD is strongly associated with genetic abnormalities, which can be effectively detected via stepwise testing (karyotyping, CMA, and WES) and are linked to adverse outcomes. Ultrasound findings suggest that genetic risk varies by CHD type, complexity, and extracardiac anomalies. Integrating detailed phenotypes may inform more precise prenatal genetic risk stratification, though prospective validation is needed to establish clinical utility.