In the era of whole transcriptome sequencing: Reflections on the Molecular Genetic Effect of Prenatal Sildenafil for Fetal Growth Restriction

In this reflection article, we evaluate a sub study of the STRIDER trial by Terstappen et al., which investigated the molecular effects of prenatal sildenafil administration in pregnancies complicated by fetal growth restriction (FGR). Unfortunately, this trial revealed no clinical benefit and even an increased risk of persistent pulmonary hypertension in neonates. After an early trial cessation, this sub study tried to elucidate tissue-specific sildenafil effects by performing RNA sequencing on placental tissues and human umbilical vein endothelial cells. While no significant differences were found on gene level, modest pathway-level alterations (specifically in nitric oxide and immune signaling pathways) were observed. We here reflect on the methodological strengths of combining clinical and molecular data, but also point out limitations of this study such as the restricted gene set choice and the absence of an analysis stratified by neonatal outcome. For future drug repurposing studies, we highlight the importance of a broad molecular characterization of target tissues to fully explain effects that are observed in clinical trials.