Article Impact Level: HIGH Data Quality: STRONG Summary of JACC, https://doi.org/10.1016/j.jacc.2025.07.069 Dr. Rebecca Josowitz et al.
Points
- Placental malperfusion affects over half of fetuses with congenital heart disease, impacting their overall health.
- Nonsyndromic fetuses with placental malperfusion show reduced birth weight, length, and head circumference at birth.
- These same fetuses also experience significantly longer hospitalizations and a trend towards higher mortality rates.
- Placental malperfusion is associated with increased mortality in univariable analysis, maintaining borderline significance multivariably.
- Deleterious de novo genetic variants were identified in key placental and cardiac developmental pathways, potentially explaining the link.
Summary
Association of Placental Malperfusion with Adverse Outcomes in Congenital Heart Disease: A Retrospective Case-Control Study
This retrospective case-control study investigated the association between placental malperfusion, a vascular disorder affecting maternal or fetal placental perfusion, and adverse outcomes in a cohort of 299 fetuses with congenital heart disease. The study aimed to elucidate the impact of placental malperfusion on clinical outcomes and to identify underlying genetic mechanisms. Pathologic criteria, including maternal or fetal vascular malperfusion or placental weight below the tenth percentile, defined placental malperfusion.
The findings revealed that placental malperfusion was present in 51% of the studied fetuses. Nonsyndromic fetuses with placental malperfusion (n = 122) exhibited significantly decreased birth weight (2986 grams vs. 3330 grams, P < 0.001), length (48 cm vs. 48.9 cm, P < 0.001), and head circumference (33 cm vs. 34 cm, P < 0.001) compared to those without placental malperfusion (n = 124). Additionally, these fetuses experienced a longer index hospitalization (21 days vs. 15 days, P = 0.04) and a trend toward increased mortality (12.3% vs. 5.6%, P = 0.07).
Univariable analysis indicated placental malperfusion was associated with increased mortality (unadjusted HR: 1.5; 95% CI: 1.03–2.17; P = 0.03), with borderline significance in multivariable analysis (adjusted HR: 1.44; 95% CI: 0.995–2.09; P = 0.054). Genomic sequencing revealed distinct enrichment of de novo variants in Notch signaling pathways (NOTCH1, NOTCH3, DLL4, SMAD6, MMP2, ID2, SOX9, CHD7) and extracellular matrix regulation and epithelial-to-mesenchymal transition (COL4A4, FN1, MMP2, VIM, TIE1, DSP, PUF60, HNRNPK, SPON1) in genes critical for trophoblast and placental vascular development among all fetuses with placental malperfusion. These genetic variants may represent important mechanisms underlying placental malperfusion in congenital heart disease.
Link to the article: https://www.jacc.org/doi/10.1016/j.jacc.2025.07.069
References
Josowitz, R., Woyciechowski, S., Jadhav, T., Jammihal, T., Linn, R. L., Rychik, J., Gaynor, J. W., Rajagopalan, R., & Spinner, N. B. (2025). Placental malperfusion is associated with adverse outcomes in congenital heart disease and with genetic variants in placental developmental pathways. JACC, 86(19), 1704–1720. https://doi.org/10.1016/j.jacc.2025.07.069
