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

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/kg 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]; =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;