Abstract 4373702: Fetal left ventricular outflow tract obstruction and placental syncytiotrophoblast differentiation

Abstract

Introduction: Placental dysfunction is an emerging contributor to neonatal morbidity and mortality in pregnancies complicated by fetal congenital heart disease (CHD). Previous work in mouse models of CHD and examination of human placental pathology indicates that the maternal-fetal interface, specifically the syncytiotrophoblast layer, can be dysmorphic in fetal CHD-affected pregnancies. We hypothesized that gene expression in a subset of placentas affected by fetal CHD would show differences in genes required for syncytiotrophoblast differentiation and function. Methods: Placentas from pregnancies affected by fetal CHD were sampled and stored as formalin-fixed paraffin embedded blocks per pathology core standard protocol. A subset of fetal CHD cases affected by left ventricular outflow tract obstruction (LVOTO) without genetic diagnoses or major extracardiac anomalies were selected for transcriptomic analysis. Results: Placentas affected by fetal LVOTO (n=20) demonstrated markedly reduced expression of genes associated with terminally differentiated syncytiotrophoblasts compared to controls (n=10). Specifically, aromatase (p<0.0001), placental growth hormone (p<0.0001), and multiple chorionic gonadotropin subunits and pregnancy specific glycoproteins were downregulated. Transcription factor GCM1, a master regulator of trophoblast differentiation, was also downregulated (p<0.0001). Syncytin-1, a product of syncytiotrophoblasts that facilitates their formation from cytotrophoblasts, was downregulated (p<0.0001) and syncytin-1 receptor expressed on cytotrophoblasts was upregulated (p<0.0001) in the LVOTO affected placentas. Abundance of cytotrophoblasts did not differ between groups, which showed similar expression of cytotrophoblast markers including E-cadherin and cytokeratins. Conclusions: Dysregulation of the heart-placenta axis in fetal CHD may be a result of altered syncytiotrophoblast differentiation, resulting in decreased functional surface area at the maternal-fetal interface.