May 23, 2011 — Dietary supplementation during pregnancy with L-arginine and antioxidant vitamins helps prevent preeclampsia in a high-risk population, according to the results of a blinded, randomized controlled trial reported online May 19 in the BMJ.

"In the past, the role of nutrition in the development of pre-eclampsia has been a subject of considerable discussion," write Felipe Vadillo-Ortega, from the Department of Experimental Medicine, School of Medicine, Universidad Nacional, Autonoma de Mexico, Ciudad Universitaria, Mexico, and colleagues. "Although little evidence exists to show that dietary manipulations can prevent pre-eclampsia, the notion that they might moderate the secondary features of the syndrome remains in favour. Substantial experimental data in animals and humans indicate that L-arginine could have a beneficial effect on haemodynamics."

The goal of the study was to test the hypothesis that a relative deficiency in L-arginine, which is the substrate needed to synthesize the vasodilator nitric oxide, may lead to development of preeclampsia in a high-risk population.

At a tertiary public hospital in Mexico City, high-risk pregnant women with a history of preeclampsia in a previous pregnancy or preeclampsia in a first-degree relative were studied from weeks 14 to 32 of gestation and monitored until delivery for development of preeclampsia or eclampsia. During pregnancy, participants were randomly assigned to receive supplementation with food bars containing L-arginine plus antioxidant vitamins (n = 228), antioxidant vitamins alone (n = 222), or placebo (n = 222). While receiving the bars, participants had 4 to 8 prenatal visits.

Preeclampsia developed in 30.2% of the placebo group, 22.5% of the vitamin-only group, and 12.7% in the L-arginine plus vitamin group.

Compared with women receiving placebo, those receiving L-arginine plus antioxidant vitamins had a lower incidence of preeclampsia (χ² = 19.41; P < .001; absolute risk reduction [RR], 0.17; 95% confidence interval [CI], 0.12 - 0.21). The group receiving L-arginine plus antioxidant vitamins also had a lower incidence of preeclampsia vs the group receiving antioxidant vitamins alone (χ² = 8.16; P = .004; absolute RR, 0.09; 95% CI, 0.05 - 0.14).

There was also a nonstatistically significant benefit for antioxidant vitamins alone vs placebo (χ² = 3.76; P = .052; absolute RR, 0.07; 95% CI, 0.005 - 0.15).

"Supplementation during pregnancy with a medical food containing L-arginine and antioxidant vitamins reduced the incidence of pre-eclampsia in a population at high risk of the condition," the study authors write. "Antioxidant vitamins alone did not have a protective effect for prevention of pre-eclampsia. Supplementation with L-arginine plus antioxidant vitamins needs to be evaluated in a low risk population to determine the generalisability of the protective effect, and the relative contributions of L-arginine and antioxidant vitamins to the observed effects of the combined treatment need to be determined."

Limitations of this study include lack of generalizability to pregnant women at low risk for preeclampsia, lack of data on the effects of L-arginine alone, insufficient power to detect a less than 50% reduction in preeclampsia, and failure to rigorously test time of supplementation and outcome.

In an accompanying editorial, Liam Smeeth, from the London School of Hygiene and Tropical Medicine, and David Williams, from the Institute for Women's Health, University College London Hospital, both in London, United Kingdom, further discuss study strengths and limitations.

"What is the mechanism of action of L-arginine and vitamins together; what are the effects (including potential adverse effects) of L-arginine given alone; what are the effects in other settings and populations?" Drs. Smeeth and Williams write. "This is not the conventional 'more research is needed' call. Indeed, a crucial first step before more trials are started would be a rigorous systematic review of the numerous inconsistent strands of evidence relating to L-arginine and its possible effects on pre-eclampsia."

The Bill and Melinda Gates Foundation, National Institutes of Health, and Fondo de Salud, CONACyT (MO-303) supported this study. The study authors have disclosed no relevant financial relationships. Dr. Smeeth has undertaken consultancy for GSK and Dr. Williams for Roche, neither of which was related to the content of the editorial. Dr. Smeeth is supported by a senior clinical fellowship from the Wellcome Trust.

BMJ. 2011;342:d2777, d2901. Abstract Extract

Clinical Context

Clinical Implications

• L-arginine supplementation with antioxidants is associated with a reduced risk for preeclampsia and preterm births among women at high risk for preeclampsia.
• In women at high risk for preeclampsia, antioxidant supplementation is not associated with a reduced risk for preeclampsia or improved neonatal outcomes.

CME Test