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Dietary Supplement May Help Prevent Preeclampsia in High-Risk Populations

  • Authors: News Author: Laurie Barclay, MD
    CME Author: Désirée Lie, MD, MSEd
  • CME Released: 5/23/2011
  • Valid for credit through: 5/23/2012
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Target Audience and Goal Statement

This article is intended for primary care clinicians, obstetricians, and other specialists who care for women at risk for preeclampsia.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Describe the effect of L-arginine with antioxidant supplementation on preeclampsia and other pregnancy outcomes in women at high risk for preeclampsia.
  2. Describe the effect of antioxidant supplementation on preeclampsia and other pregnancy outcomes in high-risk women.


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  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC


    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.


  • Brande Nicole Martin

    CME Clinical Editor, Medscape, LLC


    Disclosure: Brande Nicole Martin has disclosed no relevant financial relationships.

CME Author(s)

  • Désirée Lie, MD, MSEd

    Clinical Professor; Director of Research and Faculty Development, Department of Family Medicine, University of California, Irvine at Orange


    Disclosure: Désirée Lie, MD, MSEd, has disclosed the following relevant financial relationship:
    Served as a nonproduct speaker for: "Topics in Health" for Merck Speaker Services

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  • Sarah Fleischman

    CME Program Manager, Medscape, LLC


    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Dietary Supplement May Help Prevent Preeclampsia in High-Risk Populations

Authors: News Author: Laurie Barclay, MD CME Author: Désirée Lie, MD, MSEdFaculty and Disclosures

CME Released: 5/23/2011

Valid for credit through: 5/23/2012


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

Preeclampsia and eclampsia are among the leading causes of maternal and neonatal morbidity and mortality, and no preventive measures have been shown to be effective. Past studies have suggested a role for antioxidant supplementation, but a recent Cochrane review does not support this. L-arginine is the substrate for nitric oxide, which is a vasodilator that may counteract the vasoconstrictive effect of uterine vasculature remodeling that occurs in preeclampsia. Pregnancy produces an arginine-deficient state; thus, there is a rationale for L-arginine supplementation to prevent preeclampsia.

This is a randomized blinded placebo-controlled trial.

Study Highlights

  • Included were women presenting to a single institution for obstetric care between 2001 and 2005. They were deemed at high risk for preeclampsia, defined as having had preeclampsia in the past, or having a first-degree relative with preeclampsia.
  • Excluded were women with multiple gestation, fetal anomalies, diabetes mellitus or gestational diabetes, renal or other disease, or a strong family history of cancer.
  • A history of preeclampsia was confirmed by medical record review, and family history of preeclampsia was confirmed by patient self-report.
  • Gestational age was assessed by last menstrual period and first-trimester ultrasound test.
  • Participants in the L-arginine group received a daily dose provided by medical food bars containing 6.6 g of L-arginine and antioxidants in 2 bars.
  • Those in the antioxidant and placebo groups received identical-looking bars with the respective components.
  • Women received 5 weeks of treatment at a time and were told to continue supplementation until the day of delivery.
  • A basal blood sample was taken for arginine and a urine sample for protein.
  • Follow-up visits occurred every 3 to 4 weeks, with measurement of arterial blood pressure (BP), venous blood draw for arginine concentration, 24-hour urine for proteinuria, compliance review with diaries, and nutritional counseling.
  • Primary outcome was the rate of preeclampsia, defined as systolic BP of 140 mm Hg or higher; diastolic BP of 90 mm Hg or higher, or both; and proteinuria of more than 300 mg in 24 hours in women after 20 weeks' gestation with previously normal BP.
  • Mild preeclampsia was defined as hypertension and proteinuria without organ damage.
  • Severe preeclampsia was defined as systolic and diastolic BP of 160/110 mm Hg or higher and proteinuria above 2.0 g per 24 hours.
  • Other outcomes were preterm birth, small for gestational age, birth weight, and Apgar scores.
  • Of 672 women randomly assigned, 222 received placebo, 228 received L-arginine with antioxidants, and 222 received antioxidants alone.
  • Mean age was 28 years, gestational age at enrollment was 21 weeks, median parity was 2, and median number of cesarean deliveries was 1.
  • The groups each consumed an average of 1.1 to 1.2 bars daily.
  • Reported adverse effects were more frequent in the L-arginine group and consisted of nausea, dyspepsia, dizziness, palpitations, and headache, but they did not lead to a higher discontinuation rate.
  • 125 women dropped out but were followed up and were included in analysis.
  • The incidence of preeclampsia/eclampsia was significantly lower in the L-arginine with antioxidant group vs placebo (absolute RR, 0.17; 95% CI, 0.12 - 0.21; P < .001), with a number needed to treat of 5.73.
  • The incidence of hypertensive disease was also reduced in the L-arginine with antioxidant group.
  • The antioxidant-alone group did not show a significant reduction in the risk for preeclampsia or eclampsia vs placebo.
  • The L-arginine group had a significant reduction in risk vs the antioxidant-only group (absolute RR, 0.09; 95% CI, 0.05 - 0.14; number needed to treat, 10.20).
  • Treatment before 24 weeks with L-arginine and antioxidants was associated with a RR for preeclampsia (RR, 0.37; 95% CI, 0.23 - 0.58), whereas treatment after 24 weeks was not associated with RR.
  • L-arginine levels at the first visit were lower in women in whom preeclampsia subsequently developed.
  • L-arginine supplementation also reduced the rate of preterm birth, but birth weight, small for gestational age, and obstetric complication rates were similar in the 3 groups.
  • There were no maternal deaths.
  • The authors concluded that L-arginine with antioxidants in early pregnancy reduced the risk for preeclampsia in high-risk women.

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.

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