Sildenafil during Pregnancy: A Preclinical Meta-Analysis on Fetal Growth and Maternal Blood Pressure

Abstract

Sildenafil is a new approach to treat fetal growth restriction (FGR) and preeclampsia. We performed a systematic meta-analysis to evaluate effects of sildenafil. Our search identified 22 animal studies (mouse, rat, rabbit, sheep, and guinea pigs) and 2 human randomized controlled trials. Data were pooled using ratio of means and mean differences with 95% confidence intervals for fetal growth and maternal blood pressure, respectively. Meta-regression analyses were performed for study-related factors that might affect efficacy of sildenafil, including the model used (healthy pregnancy versus FGR/preeclampsia) and route of administration. Dose-response curves with dose per metabolic weight (mg/kg0.75 per 24 hours) were fitted using splines. Our analyses show that sildenafil increases fetal growth during FGR/preeclampsia pregnancy compared with healthy pregnancy (1.10 [1.06-1.13] versus 1.03 [0.99-1.06]; P=0.006). There was no significant effect on fetal growth in the absence of FGR/preeclampsia. Effects were similar among different species and largest after oral and continuous administration. There was a positive relation between dose and fetal growth up to a human equivalent dose of ≈450 mg/d. A significant blood pressure-lowering effect of sildenafil is present during FGR/preeclampsia pregnancy only (-19 [-25 to -13] mm Hg; P<0.01), with the effect size being highly dependent on baseline blood pressure and without effect in the absence of hypertension. This meta-analysis supports that sildenafil improves fetal growth and maternal blood pressure regulation during FGR and preeclampsia pregnancy. The greatest beneficial effects on fetal growth are with dosages greater than those currently used in human studies.