L-arginine promising for pre-eclampsia prevention and treatment, suggests research

In 2022, the Accelerating Innovations for Mothers (AIM) project identified L-arginine as one of five high-potential medicines under investigation for pre-eclampsia prevention. L-arginine is a precursor for the endogenous synthesis of nitric oxide, a potent vasodilator that mediates vascular smooth muscle relaxation and inhibits platelet aggregation. Abnormal placentation, dysregulation of angiogenesis, oxidative stress, and endothelial dysfunction are important aspects of the pathogenesis of pre-eclampsia. Thus, the availability of L-arginine opposes the vasoconstriction that occurs in pre-eclampsia.

L-arginine is a semi-essential amino acid obtained through dietary intake (fish, meats, soy, nuts and seeds), protein turnover and endogenous synthesis from L-citrulline. In pregnancy, bioavailable L-arginine levels may diminish due to increased metabolic demand resulting from fetal growth. Also, when dietary L-arginine and/or L-citrulline intake is low, the de novo endogenous synthesis of L-arginine from L-citrulline cannot increase to compensate. Maternal infections such as malaria may further deplete endogenous L-arginine, making pregnant women in malaria-endemic regions particularly vulnerable to arginine deficiency. Therefore, L-arginine may be necessary to provide the substrate for nitric oxide synthesis during pregnancy. L-arginine or L-citrulline could be affordable and scalable interventions to improve birth outcomes, particularly in resource-limited settings.

Recent reviews on L-arginine in pregnancy have not explored the effects of L-arginine for prevention differently from the treatment of pre-eclampsia. This has significant clinical implications for the optimal timing of supplementation initiation and understanding which women would benefit from L-arginine. Furthermore, no review has considered the effects of L-citrulline during pregnancy on pre-eclampsia. This review examines the effects of L-arginine and L-citrulline on prevention separately from the treatment of pre-eclampsia and related maternal, fetal and neonatal outcomes.

To evaluate the effects of L-arginine and L-citrulline (precursor of L-arginine) on the prevention and treatment of pre-eclampsia. MEDLINE, Embase, CINAHL, Global Index Medicus and the Cochrane Library were searched through 7 February 2024. Trials administering L-arginine or L-citrulline to pregnant women, with the comparison group receiving placebo or standard care, were included. Meta-analyses were conducted separately for prevention or treatment trials, using random effects models.

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 −5.64mmHg; 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.

This is the first systematic review to evaluate the evidence on Larginine and L-citrulline for the prevention or treatment of preeclampsia, separately. This distinction is critical for informing clinical practice and policy, as different stages of the aetiology are targeted by prevention or treatment trials. Authors found low certainty evidence that L-arginine in pregnancy decreases the risk of pre-eclampsia and severe pre-eclampsia among women at risk of pre-eclampsia. The evidence is very uncertain about the effect of L-arginine on mean systolic BP, and L-arginine may decrease the risk of FGR in treatment trials. L-arginine may also decrease the risk of preterm birth and SGA and increase nitric oxide serum levels in prevention trials. Authors are uncertain of the effects of L-arginine on other secondary outcomes.

Consistent with previous reviews, they found that L-arginine may be promising for preventing pre-eclampsia. However, this data should be interpreted with caution, as the certainty of the evidence is low, requiring further research. This review defined trials including women without a diagnosis of pre-eclampsia as prevention trials; however, only four trials specifically examined the efficacy of L-arginine to prevent pre-eclampsia in women at increased risk. These trials included women who were nulliparous, had a previous history of pre-eclampsia, had pre-eclampsia in a first-degree relative, had chronic hypertension, had gestational hypertension without proteinuria or had a body mass index ≥30.

L-arginine is promising for pre-eclampsia prevention, and authors are uncertain of its effect as a treatment for women with established pre-eclampsia. L-arginine could constitute an important addition to the management protocol of women at risk of preeclampsia, but further research is needed to establish the population that would benefit, the optimal dose, time of initiation and duration of supplementation. An individual participant data meta-analysis may provide definitive answers to these questions. Future L-arginine trials should use standardised pre-eclampsia screening tools, define the type of pre-eclampsia experienced and investigate co-administration with aspirin or calcium.

Source: Maureen Makama, Annie R. A. McDougall, Jenny Cao; BJOG: An International Journal of Obstetrics & Gynaecology, 2025; 0:1–11 https://doi.org/10.1111/1471-0528.18070