Supplementary Material for: Fetal tadalafil exposure increases pulmonary blood flow and reduces right to left heart shunting through the foramen ovale

Introduction: Fetal growth restriction (FGR) increases the risk of poor in utero, neonatal and long-term health outcomes. Tadalafil is the 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 tadalafil has on fetal haemodynamics.

Methods: At 116-117 days gestational age (dGA), pregnant ewes carrying normally grown fetuses (n=9) underwent fetal catheterisation surgery before undergoing MRI scans at 119-123dGA to measure blood flow and oxygenation within the major fetal vessels using phase contrast MRI and T2 oximetry. Baseline measures were performed after a fetal vehicle infusion and then repeated after a fetal tadalafil infusion. Fetal tadalafil concentrations were measured by LC-MS/MS.

Results: Tadalafil 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.

Conclusion: Fetal tadalafil exposure alters pulmonary haemodynamics 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 tadalafil exposed fetuses studied herein exhibited similar haemodynamic profiles as those exposed to sildenafil, further studies investigating neonatal outcomes of fetuses exposed to tadalafil are warranted.