Background The efficacy and safety of phosphodiesterase-5(PDE-5) inhibitors in the management of fetal growth restriction (FGR) remains inconclusive and new evidence continues to emerge. This study aimed to evaluate the most recent evidence about the clinical outcomes and safety profiles of PDE-5 inhibitors used to manage FGR. Methods Eight databases were searched for articles published in English and Chinese from the database inception to 30th September 2022. Randomized controlled trials (RCTs) reporting the use of PDE-5 inhibitors in FGR were included. Odds ratio (OR) and mean difference (MD) (95% confidence intervals) were pooled for analysis. Results From 229 citations identified, 16 studies involving 1492 pregnant women met the inclusion criteria. Only sildenafil (15 RCTs) and tadalafil (1 RCT) were investigated for their use in FGR. Sildenafil use was associated with an increase in birth weight (MD:164.07, 95%CI:61.55-266.59), pregnancy prolongation (MD:6.09,95%CI:2.15–10.03) and umbilical artery pulsatility indices (MD: -0.24, 95%CI: -0.32 - -0.15). However, sildenafil also had an increased risk of pulmonary hypertension in newborns (OR:4.37, 95%CI:1.49–12.80), as well as headache (OR:5.57, 95%CI:2.89–10.72) and flushing/rash in mothers (OR:5.11, 95%CI:2.08–12.53). No clinical differences in gestation age, perinatal mortality or major neonatal morbidity, stillbirth, neonate death, infants admitted to neonatal intensive care unit, intraventricular hemorrhage and necrotizing enterocolitis in infants were reported with the use of sildenafil. There was no evidence of any increase in the risk of pregnancy hypertension and gastrointestinal side effects in mothers. Subgroup analyses by age showed similar significant effects of sildenafil on birth weight for mothers younger than 30 years old (MD:198.6, 95%CI:19.95-377.25) and those aged 30 years or older (MD:82.73, 95%CI:7.14-158.32). However, no significant effect was observed for pregnancy prolongation. Conclusions The evidence from this review indicates that PDE-5 inhibitors improve birth weight and duration of pregnancy without causing severe maternal side effects. However, it has been shown that sildenafil can also increase the risk of neonatal pulmonary hypertension. It remains uncertain whether the benefits of PDE-5 inhibitors in FGR outweighs the risks and further investigation with larger studies is warranted.

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