Prenatal Sildenafil and Fetal-placental Programming in Human Pregnancies Complicated by Fetal Growth Restriction: A Retrospective Gene Expression Analysis

Objective: Fetal growth restricted (FGR) offspring are more susceptible to develop cardiovascular and renal disease. The potential therapeutic value of sildenafil to improve fetal growth has recently been evaluated in several randomized clinical trials. Here we investigate whether administration of sildenafil during pregnancies complicated by FGR influences fetal-placental programming profiles, especially related to cardiorenal development and disease. Methods: We collected human umbilical vein endothelial cells (HUVECs) and placental tissue within the Dutch STRIDER trial, in which sildenafil versus placebo treatment were randomly assigned to pregnancies complicated by severe early-onset FGR. Differential expression of genes of these samples were studied by whole genome RNA-sequencing. In addition, we performed gene set enrichment analysis focused on cardiovascular and renal gene sets to examine differentially expressed gene sets related to cardiorenal development and health. Results: Our study showed similar gene expression profiles between treatment groups in HUVECs (n=12 sildenafil; n=8 placebo) and placentas (n=13 per group). Prenatal sildenafil exposure did not change cardiovascular or renal programming in pregnancies complicated by FGR. In placental tissue, prenatal sildenafil altered a few gene sets involved with the nitric oxide pathway potentially reflecting the mechanism of action of sildenafil. Prenatal sildenafil also upregulated gene sets related to immune pathways in placental tissue. Conclusions: Overall, our study showed that sildenafil has the potential to alter placental (but not fetal) expression of gene sets related to immune pathways and did not support (in)direct reprogramming of cardiovascular or renal health in human pregnancies complicated by FGR.