Placental Malperfusion Is Associated With Adverse Outcomes in Congenital Heart Disease and With Genetic Variants in Placental Developmental Pathways

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BACKGROUND: Placental malperfusion (PMP), a vascular disorder of impaired maternal or fetal placental perfusion, is common in fetuses with congenital heart disease (CHD), yet its impact on outcomes and underlying mechanisms are unclear. Perturbation of shared developmental pathways between the fetal heart and placenta may play a role in PMP development. OBJECTIVE: This study sought to determine whether CHD fetuses with PMP have adverse outcomes and genomic variation in vascular or placental developmental pathways. METHODS: This was a retrospective case-control study of 299 CHD fetuses with and without PMP. Maternal, genomic, placental, and outcomes data were reviewed. Placentas with PMP met pathologic criteria for maternal or fetal vascular malperfusion (Amsterdam criteria), or placental weight <10%. Rare, predicted deleterious exonic/putative splicing single nucleotide variants, small insertion/deletions, and de novo variants from trios were identified from genome sequencing data, followed by burden analysis and pathway enrichment. Mann-Whitney and Student's-t test or chi-square and Fisher exact tests were performed. RESULTS: PMP was present in 51% of fetuses. Nonsyndromic fetuses with PMP (n = 122) vs without PMP (n = 124) had decreased birth weight (2,986 g vs 3,330 g, P < 0.001), length (48 cm vs 48.9 cm, P < 0.001), and head circumference (33 cm vs 34 cm, P < 0.001); 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). No significant differences were found in syndromic subjects. PMP was associated with increased mortality in univariable analysis (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). The proportion of fetuses with and without PMP with ≥1 angiogenesis pathway or de novo variant was similar and not associated with outcomes. All fetuses with PMP demonstrated distinct enrichment in de novo variants in Notch signaling (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. CONCLUSION: PMP is associated with impaired fetal growth, longer hospitalization, and possibly increased mortality in CHD. CHD fetuses with PMP harbor deleterious de novo variants in several key placental and cardiac developmental pathways, which may represent important mechanisms underlying PMP in CHD.

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