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

2025-01-12
BJOG : an international journal of obstetrics and gynaecology 132(6)
- Maureen Makama
- Annie R A McDougall
- Jenny Cao
- Kate Mills
- Phi-Yen Nguyen
- Roxanne Hastie
- Anne Ammerdorffer
- A Metin Gülmezoglu
- Joshua P Vogel

PubMed: 39800868
DOI: 10.1111/1471-0528.18070

Study Design

Type: Meta-Analysis
Sample size: n = 2,028
Population: pregnant women (2028 in RCTs, 189 in non-randomised trials)
Methods: Meta-analysis of 20 RCTs and 3 non-randomised trials; search of MEDLINE, Embase, CINAHL, Global Index Medicus, Cochrane Library through 7 February 2024; random-effects models

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.

Research Insights

L-Arginine→Reduced Pre-eclampsia Risk
Only one study (36 women) examined L-citrulline and reported no effect on pre-eclampsia or blood pressure.
Effect
Neutral
Effect size
Small
Dose
not specified in abstract
L-Arginine→Reduced Risk of Fetal Growth Restriction
and fetal growth restriction (RR 0.46; 95% CI, 0.26, 0.81; low-certainty evidence, two trials)
Effect
Beneficial
Effect size
Large
Dose
not specified in abstract
L-Arginine→Reduced Risk of Severe Pre-eclampsia
and severe pre-eclampsia (RR 0.23; 95% CI, 0.09, 0.55; low-certainty evidence, three trials)
Effect
Beneficial
Effect size
Large
Dose
not specified in abstract
L-Arginine→Reduced Systolic Blood Pressure
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)
Effect
Beneficial
Effect size
Moderate
Dose
not specified in abstract
L-Citrulline→Reduced Blood Pressure
Only one study (36 women) examined L-citrulline and reported no effect on pre-eclampsia or blood pressure.
Effect
Neutral
Effect size
Small
Dose
not specified in abstract
L-Citrulline→Reduced Pre-eclampsia Risk
Only one study (36 women) examined L-citrulline and reported no effect on pre-eclampsia or blood pressure.
Effect
Neutral
Effect size
Small
Dose
not specified in abstract