Obstetric complications in pregnant people with Fontan circulation: Identifying candidate pathologic pathways in the placenta

Abstract Background/Purpose Pregnant people with Fontan circulation have high rates of fetal growth restriction (FGR) and preterm birth (PTB). The mechanisms underlying these complications are poorly understood. Methods Pregnancies occurring in individuals with Fontan circulation cared for in a single Cardio‐Obstetrics program were identified. Demographic and clinical data were abstracted from the electronic medical record. A subset of FGR and PTB placental samples was processed for histopathology evaluation. Regions with dense representation of pathology were selected for sequencing by a placental pathologist. Sequencing was performed on the Visium CytAssist platform, with analysis in Loupe Browser and R Studio. Gene Ontologies were generated using the DAVID analytic suite. Results A total of 21 placentas from pregnancies complicated by maternal Fontan circulation were identified and six were selected to undergo spatial transcriptomic analysis. FGR and PTB prior to 34 weeks gestation were represented in half of the placentas (3/6, respectively); the remaining three placentas represented gestational age‐appropriate fetal growth. The most common histopathologic findings were subchorionic hematomas (13/21) and accelerated maturation (12/21). Decidual arteriopathy and features of fetal vascular malperfusion were rarely observed (1/21 and 4/21). Comparing the spatially aligned RNA expression spots from the placentas with and without FGR, 1473 genes were differentially expressed ( p < 0.05). Functional clustering of the top 100 differentially expressed genes revealed alterations in stress‐related hormones/transcription factors and pregnancy‐modulating hormone pathways. These markers of endocrinologic stress and shallow placentation were overexpressed by synciotrophoblasts. PAPPA and the PSG family of transcripts were upregulated in FGR and spontaneous PTB cases; these transcripts have been previously associated with placental hypoxia. Conclusion Comparative spatial transcriptomic analysis of placentas from individuals with Fontan circulation who did and did not experience major obstetric complications identified upregulation of markers associated with poor placentation and endocrinologic stress.