Background: Persistent pulmonary hypertension (PPH) is one of the main causes of mortality and
morbidity in infants affected by congenital diaphragmatic hernia (CDH). Since the structural changes that lead to
PPH take place already in utero, a treatment starting in the prenatal phase may prevent the occurrence of this
Objective: To summarize the development process of antenatal sildenafil for CDH.
Methods: The pharmacokinetics and efficacy of sildenafil have been assessed in the rat and the rabbit model. The
transfer of the drug through the human placenta has been measured with the ex-vivo placenta perfusion model.
Results from this experiment are being incorporated in a pregnancy-physiologically based pharmacokinetic (p-
PBPK) model. A phase I-IIb placental transfer and safety study is ongoing.
Results: Sildenafil administration to pregnant rats and rabbits led to therapeutic foetal drug levels without maternal
and foetal toxicity, although it was associated with impaired vascular development in foetuses with nonhypoplastic
lungs. Peak concentrations and 24-hour exposure were higher in pregnant rabbits compared to nonpregnant
ones. In rat and rabbit foetuses with CDH, sildenafil rescued the lung vascular anomalies and partially
improved parenchymal development. Sildenafil crossed the human placenta at a high rate ex-vivo, independently
from the initial maternal concentration.
Conclusion: There is preclinical evidence that maternally administered sildenafil prevents the vascular changes
that lead to PPH in CDH newborns. The phase I/IIb clinical study together with the p-PBPK model will define the
maternal dose needed for a therapeutic effect in the foetus. Foetal safety will be investigated both in the clinical
study and in the sheep. The final step will be a multicentre, randomized, placebo-controlled trial.