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Meta-Analysis
. 2025 May;132(6):698-708.
doi: 10.1111/1471-0528.18070. Epub 2025 Jan 12.

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

Maureen Makama  1   2 , Annie R A McDougall  1   3 , Jenny Cao  1 , Kate Mills  1 , Phi-Yen Nguyen  1 , Roxanne Hastie  4 , Anne Ammerdorffer  5 , A Metin Gülmezoglu  5 , Joshua P Vogel  1   3
Affiliations
Meta-Analysis

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

Maureen Makama et al. BJOG. 2025 May.

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.

Keywords: L‐arginine; L‐citrulline; hypertensive disorders of pregnancy; pregnant women; pre‐eclampsia.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
PRISMA flow chart of included studies. *Research integrity assessment tool was designed to assess randomised trials only. Non‐randomised trials did not undergo the research integrity assessment.
FIGURE 2
FIGURE 2
Forest plots of primary outcomes: (A) pre‐eclampsia prevention and (B) severe pre‐eclampsia prevention.
FIGURE 3
FIGURE 3
Forest plots of secondary maternal outcomes: (A) caesarean section, (B) nitric oxide serum level, (C) mean systolic blood pressure and (D) mean diastolic blood pressure.
FIGURE 4
FIGURE 4
Forest plots of secondary fetal/neonatal outcomes: (A) preterm birth, (B) fetal growth restriction, (C) neonatal mortality and (D) stillbirth.
See this image and copyright information in PMC

References

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