Evidence comparing the yield of chromosomal microarray analysis to noninvasive prenatal screening in pregnancies with congenital heart anomalies is currently limited.

This study aimed to examine the residual risk of clinically significant chromosomal microarray analysis results in fetuses with congenital heart defects by its various subtypes following a normal noninvasive prenatal screening.

Using a population-based, countrywide computerized database, we retrieved the reports of all pregnancies undergoing chromosomal microarray analysis because of congenital heart defects through the years 2013–2019. We examined the risk of clinically significant (pathogenic and likely pathogenic) chromosomal microarray analysis results and compared it with the results of a local cohort of low-risk pregnancies. Of 5541 fetuses, 78 (1.4%) showed abnormal results. The residual risk of abnormal chromosomal microarray analysis results was calculated using several options—trisomies 21, 18, and 13; sex chromosome aneuploidies; 22q11.2 deletion, and deletions and duplications of at least 10 MB in size (genome-wide noninvasive prenatal screening)—following the exclusion of theoretically detectable noninvasive prenatal screening anomalies.

Of the 1728 fetuses with congenital heart defects, 93 (5.4%) showed clinically significant chromosomal microarray analysis results (relative risk, 2.7; 95% confidence interval, 2.3–3.1). The result of pregnancies with fetuses with congenital heart defects was compared with the results of the control population. Unique variants were found in 15 pregnancies (16.1%). The detection rate of noninvasive prenatal screening in isolated congenital heart defects varied from 1.0% (aimed at 3 common trisomies) to 2.2% (aimed at 5 common aneuploidies and 22q11.2 deletion) using noninvasive prenatal screening. In nonisolated congenital heart defects, the noninvasive prenatal screening detection rates ranged from 7.8% (aimed at common autosomal trisomies) to 9.2% using genome-wide noninvasive prenatal screening. The residual risk of clinically significant chromosomal microarray analysis results following normal noninvasive prenatal screening ranged from 2.0% to 2.8% in isolated congenital heart defects and 4.5% to 5.9% in nonisolated cases and was significantly higher than those of the control cohort in all noninvasive prenatal screening options. In addition, the residual risk following noninvasive prenatal screening aimed at chromosomes 13, 18, 21, X, and Y was significantly higher than those of the control cohort for most specific congenital heart defect subtypes, except for ventricular septal defects and aberrant right subclavian artery.

The residual risk of clinically significant chromosomal microarray analysis results in pregnancies with fetuses with congenital heart defects following normal noninvasive prenatal screening was higher than those in pregnancies with normal ultrasound in most isolated and nonisolated congenital heart defect subtypes. This information should be taken into account by obstetricians and genetic counselors when considering the option of diagnostic testing.