Maternal Blood as a Window to the Fetal Heart: Novel Biomarkers for Early Detection of Septal Defects

Congenital heart defects (CHDs) represent the most common category of congenital malformations and constitute a significant cause of infant morbidity and mortality. Despite advances in prenatal imaging, such as fetal echocardiography, early detection remains challenging, particularly in pregnancies without identified risk factors. Recent studies suggest that maternal circulating non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), may serve as promising non-invasive biomarkers for the prenatal diagnosis of CHDs. Following a review of the most relevant clinical and preclinical studies, it was found that maternal circulating RNA, particularly microRNAs and lncRNAs, shows potential as non-invasive biomarkers for detecting fetal congenital heart defects. Among microRNAs, miR-146a-5p demonstrated the highest diagnostic accuracy for ventricular septal defects (VSDs), while panels of lncRNAs, such as LINC00598, LINC01551, and GATA3-AS1, exhibited high performance for atrial septal defects (ASDs). In addition, miR-19b, miR-29c, and miR-375 were associated with both VSDs and ASDs, suggesting a shared role in septal development. However, the studies displayed variability in biomarker selection and analytical methodologies. The findings indicate that maternal circulating microRNAs and lncRNAs hold significant potential as non-invasive biomarkers for the early detection of CHDs. Nonetheless, methodological heterogeneity and small sample sizes highlight the need for standardized protocols and larger multicenter studies prior to clinical implementation. These observations support the future integration of RNA biomarkers with fetal echocardiography to enhance early CHD screening and to inform prenatal counseling.