Share this article on:

Antioxidant Therapy to Prevent Preeclampsia: A Randomized Controlled Trial

Spinnato, Joseph A. II MD; Freire, Salvio MD; Pinto e Silva, Joao Luiz MD; Cunha Rudge, Marilza Vieira MD; Martins-Costa, Sérgio MD; Koch, Matthew A. MD; Goco, Norman; Santos, Cleide de Barros MD; Cecatti, Jose Guilherme MD; Costa, Roberto MD; Ramos, José Geraldo MD; Moss, Nancy PhD; Sibai, Baha M. MD

doi: 10.1097/01.AOG.0000289576.43441.1f
Original Research

OBJECTIVE: To study whether antioxidant supplementation will reduce the incidence of preeclampsia among patients at increased risk.

METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted at four Brazilian sites. Women between 12 0/7 weeks and 19 6/7 weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomly assigned to daily treatment with both vitamin C (1,000 mg) and vitamin E (400 International Units) or placebo. Analyses were adjusted for clinical site and risk group (prior preeclampsia, chronic hypertension, or both). A sample size of 734 would provide 80% power to detect a 40% reduction in the risk of preeclampsia, assuming a placebo group rate of 21% and α=.05. The α level for the final analysis, adjusted for interim looks, was 0.0458.

RESULTS: Outcome data for 707 of 739 randomly assigned patients revealed no significant reduction in the rate of preeclampsia (study drug, 13.8% [49 of 355] compared with placebo, 15.6% [55 of 352], adjusted risk ratio 0.87 [95.42% confidence interval 0.61–1.25]). There were no differences in mean gestational age at delivery or rates of perinatal mortality, abruptio placentae, preterm delivery, and small for gestational age or low birth weight infants. Among patients without chronic hypertension, there was a slightly higher rate of severe preeclampsia in the study group (study drug, 6.5% [11 of 170] compared with placebo, 2.4% [4 of 168], exact P=.11, odds ratio 2.78, 95% confidence interval 0.79–12.62).

CONCLUSION: This trial failed to demonstrate a benefit of antioxidant supplementation in reducing the rate of preeclampsia among patients with chronic hypertension and/or prior preeclampsia.



In this randomized, placebo-controlled, double-blind clinical trial among 739 patients at risk for preeclampsia, there was no benefit from vitamins C plus E supplementation.

From the 1University of Cincinnati College of Medicine, Cincinnati, Ohio; 2Universidade Federal de Pernambuco, Hospital das Clínicas, Recife, Brazil; 3Universidade Estadual de Campinas, Campinas, Brazil; 4Universidade Estadual Paulista, Botucatu, Brazil; 5Universidade Federal Do Rio Grande Do Sul, Hospital de Clínicas, Porto Alegre, Brazil; 6RTI International, Research Triangle Park, North Carolina; and 7National Institute of Child Health and Human Development, Bethesda, Maryland.

Supported by Grant Number 1 U01 HD40565 cosponsored by the National Institute of Child Health and Human Development and the Bill and Melinda Gates Foundation.

The authors thank Jutta Thornberry, Janet Bartz, Steve Litavecz, and Ty Hartwell, RTI International; Susie Meikle, our initial National Institute of Child Health and Human Development Project officer; and members of our site research teams: Cincinnati: Les Myatt; Recife: Elias Ferreira de Melo, Antonio Carlos Barbosa Lima, Angelo Manoel Barreto, José Remígio Neto, Eduardo Costa Ramos; Botucatu: José Carlos Peraçoli, Joelcio Francisco Abbade, Anice Vieira de Camargo Martins, Grasiela Bossolan, Kleber Campos, Tania Prevedel; Porto Alegre: Melissa Prade Hemesath, Cristiano Dhil Zaffari; Campinas: Fernanda G Surita, Eliana Amaral, Mary A. Parpinelli, Fabiana Krupa. Additionally, we thank Soubhi Kahhale and his research team at the University of Sao Paulo, Brasil, for their important initial contributions to this research.

Corresponding author: Joseph A. Spinnato II, MD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, PO Box 2670526, Cincinnati, OH 40267-0526; e-mail:

Financial Disclosure The authors have no potential conflicts of interest to disclose.

© 2007 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.