(972) Preterm birth in patients with Fontan circulation: looking to the placenta for answers

Objective: Pregnant patients with Fontan circulation have relative hypoxemia with limited ability to augment cardiac output. Preterm birth (PTB) and fetal growth restriction (FGR) are common complications. We integrate clinical, histopathologic, and spatial transcriptomic data to characterize PTB with and without FGR in this population.

Study Design: 17 live births in 15 patients with Fontan circulation were identified and Cardio-obstetric variables were abstracted from the medical record. Placentas were analyzed by a pathologist. RNA was extracted from 6 preterm (3 normally grown, 3 FGR), formalin fixed, paraffin embedded samples with representative findings for spatial transcriptomics. Samples were sequenced with Visium CytAssist and analyzed in Loupe Browser/R.

Results: Mean pre-pregnancy SpO2 was 93.3±3.5%, where SpO2 at delivery decreased with increasing gestational age (GA, R=-0.48, P=0.046). Over 1/3 (41.2%, N=7/17) had FGR and most (82.4%, N=14/17) had PTBs (mean GA  233.1±24.9 days [33 weeks]). Of PTBs, 64.2% (N=9/14) labored spontaneously. 64.7% of the placentas (N=11/17) showed accelerated maturation for GA (Fig 1). Spatial capture spots clustered based on clinical and histopathologic features, contrasting samples from FGR vs normally grown placentas and regions of frank vs minimal pathology (Fig 2). Spots with frank pathology showed upregulation of hypoxia pathways with peri-lesion upregulation of pro-fibrotic transcripts; structural integrity transcripts (PLEC, SPTAN1, SRGN) were downregulated. Regions without frank pathology in FGR placentas also overexpressed pro-fibrotic markers and markers of placental dysfunction (PSG11, ALPP). Adverse pregnancy outcome markers (PAEP, PAPPA2) were upregulated in early PTB (< 34 weeks) compared to late PTB; PLEC, SPTAN1, SRGN were downregulated.

Conclusion: We identify a transcriptomic profile of consistently downregulated structural genes that unify placentas from early PTB with histopathologic placental findings in patients with Fontan circulation. These markers should be explored as potential mediators of PTB in cases of significant maternal cardiac disease.