Fetal Tadalafil Exposure Increases Pulmonary Blood Flow and Reduces Right to Left Heart Shunting through the Foramen Ovale.

Fetal growth restriction (FGR) increases the risk of poor in utero, neonatal, and long-term health outcomes. Tadalafil (TAD) is the current focus of a phase II exploratory trial (TADAFER IIb) to determine its efficacy as an intervention for FGR. Herein, we aimed to determine the impact that TAD has on fetal hemodynamics. At 116-117 days of gestational age (dGA), pregnant ewes carrying normally grown fetuses (n = 9) underwent fetal catheterization surgery before undergoing MRI scans at 119-123 dGA to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase contrast MRI and T2 oximetry. Baseline measures were performed after a fetal vehicle infusion and then repeated after a fetal TAD infusion. Fetal TAD concentrations were measured by LC-MS/MS. TAD did not impact right or left ventricular (LV) output but was associated with an increase in pulmonary blood flow with reduced blood flow through both the ductus arteriosus and foramen ovale (FO). The difference in blood oxygenation between the ascending aorta and main pulmonary artery was significantly reduced, but cerebral oxygen delivery was maintained by increased carotid artery blood flow. Fetal TAD exposure alters pulmonary hemodynamics and reduces the proportion of the LV preload blood pool that is made up of oxygen-rich blood from the FO. Given fetal exposure to sildenafil increases the rate of persistent pulmonary hypertension after birth and that the TAD exposed fetuses studied herein exhibited similar hemodynamic profiles as those exposed to sildenafil, further studies investigating neonatal outcomes of fetuses exposed to TAD are warranted.