Perinatal deaths after sildenafil treatment of fetal growth restriction raise the issue of safety in randomised clinical trials

Abstract

Sildenafil citrate (SC) is a drug developed for male erectile dysfunction (ED), specifically able to block phosphodiesterase (PDE) type 5, a nitric oxide‐cyclic guanosine monophosphate (cGMP) catabolising enzyme found in vascular smooth muscle. SC is under evaluation for several medical uses, such as Raynaud s phenomenon, stroke, achalasia, endothelial dysfunction, and neonatal‐ and adult‐onset pulmonary hypertension (PH). SC has been also experimented in the management of fetal growth restriction (FGR), a major cause of perinatal mortality and morbidity. Some pregnancies with FGR have in fact elevated peripheral maternal vascular resistance in uterine arteries, and SC seems to increase uterine blood flow and to potentiate oestrogen‐ induced vasodilation. A 2017 systematic review evaluating maternal tolerance and obstetric and perinatal outcomes following SC use in human pregnancy concluded, despite limited data, that there does not appear to be any severe adverse maternal side effects, nor increase in stillbirths, neonatal deaths, or congenital anomalies rates attributed to SC. Recently, five multicentre randomised placebo‐controlled trials have been launched (STRIDER trials), and some results have already been published. In contrast with the evidences reported in the above mentioned review, authors concluded that SC did not prolong pregnancy or improve pregnancy outcomes in severe early‐onset FGR, and no relevant safety issue was reported. Unfortunately, the attention on SC trials raised globally when a Dutch trial using SC to correct FGR has been halted after 11 babies died unexpectedly. A review by a committee of the STRIDER trial declared that lung complications were more common in the babies born to women given SC, of whom 17 had lung problems, and 11