A BREAKTHROUGH study has shown that congenital heart disease is frequently accompanied by placental malperfusion, a vascular disorder that disrupts blood flow and is linked to poorer birth outcomes, longer hospital stays, and genetic variants affecting placental and cardiac development.
Shared Developmental Pathways in Congenital Heart Disease
The placenta and heart share key developmental pathways, and disturbances in one can influence the other. In cases of congenital heart disease (CHD), placental malperfusion (PMP) is increasingly recognised as a critical factor influencing fetal growth and survival. Researchers from the Children’s Hospital of Philadelphia examined how PMP impacts outcomes in CHD and whether genetic variants affecting placental formation could explain the high rate of complications.
Genomic Findings and Clinical Outcomes
In this retrospective study of 299 fetuses with congenital heart disease, PMP was identified in 51% of cases. Nonsyndromic fetuses with PMP (n = 122) had lower birth weight (2,986 g vs 3,330 g, P < 0.001), shorter length (48 cm vs 48.9 cm, P < 0.001), and smaller head circumference (33 cm vs 34 cm, P < 0.001) than those without PMP. They also required longer hospitalisation (21 days vs 15 days, P = 0.04) and showed a trend toward higher mortality (12.3% vs 5.6%, P = 0.07). Genetic analysis revealed enrichment of de novo variants in pathways involved in Notch signalling (NOTCH1, NOTCH3, DLL4, SMAD6) and extracellular matrix regulation (COL4A4, MMP2, FN1), all essential for placental vascular development. These findings indicate that PMP and CHD may share molecular mechanisms originating early in gestation.
Implications for Prenatal and Clinical Management
The results of the study emphasise that placental abnormalities are not mere bystanders but active contributors to adverse outcomes in congenital heart disease. For clinicians, early identification of PMP could improve prenatal risk assessment and guide targeted monitoring. Integrating placental evaluation into routine CHD care may help detect complications sooner and inform therapeutic interventions. Future studies should focus on multiomic approaches to pinpoint biomarkers of placental dysfunction, paving the way for interventions that enhance placental perfusion and improve survival in affected infants.
Reference
Josowitz R et al. Placental malperfusion is associated with adverse outcomes in congenital heart disease and with genetic variants in placental developmental pathways. JACC. 2025;86 (19):1704-20.
