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