L‐Arginine and L‐Citrulline for Prevention and Treatment of Pre‐Eclampsia: A Systematic Review and Meta‐Analysis

ABSTRACT Background Evidence suggests L‐arginine may be effective at reducing pre‐eclampsia and related outcomes. However, whether L‐arginine can prevent or only treat pre‐eclampsia, and thus the target population and timing of initiation, remains unknown. Objectives To evaluate the effects of L‐arginine and L‐citrulline (precursor of L‐arginine) on the prevention and treatment of pre‐eclampsia. Search Strategy MEDLINE, Embase, CINAHL, Global Index Medicus and the Cochrane Library were searched through 7 February 2024. Selection Criteria Trials administering L‐arginine or L‐citrulline to pregnant women, with the comparison group receiving placebo or standard care, were included. Data Collection and Analysis Meta‐analyses were conducted separately for prevention or treatment trials, using random‐effects models. Main Results Twenty randomised controlled trials (RCTs) (2028 women) and three non‐randomised trials (189 women) were included. The risk of bias was ‘high’ in eight RCTs and showed ‘some concerns’ in 12. In prevention trials, L‐arginine was associated with a reduced risk of pre‐eclampsia (relative risk [RR] 0.52; 95% confidence interval [CI], 0.35, 0.78; low‐certainty evidence, four trials) and severe pre‐eclampsia (RR 0.23; 95% CI, 0.09, 0.55; low‐certainty evidence, three trials). In treatment trials, L‐arginine may reduce mean systolic blood pressure (MD −5.64 mmHg; 95% CI, −10.66, −0.62; very low‐certainty evidence, three trials) and fetal growth restriction (RR 0.46; 95% CI, 0.26, 0.81; low‐certainty evidence, two trials). Only one study (36 women) examined L‐citrulline and reported no effect on pre‐eclampsia or blood pressure. Conclusions L‐arginine may be promising for pre‐eclampsia prevention and treatment, but findings should be interpreted cautiously. More trials are needed to determine the optimal dose and time to commence supplementation and support clinical decision‐making.