Antioxidant Therapy to Prevent Preeclampsia A Randomized Controlled Trial Joseph A. Spinnato II, MD, Salvio Freire, MD, Joao Luiz Pinto e Silva, MD, Marilza Vieira Cunha Rudge, MD, Se ´rgio Martins-Costa, MD, Matthew A. Koch, MD, Norman Goco, Cleide de Barros Santos, MD, Jose Guilherme Cecatti, MD, Roberto Costa, MD, Jose ´ Geraldo Ramos, MD, Nancy Moss, PhD, and Baha M. Sibai, MD OBJECTIVE: To study whether antioxidant supplementa- tion 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 .05. The  level for the final analysis, adjusted for interim looks, was 0.0458. RESULTS: Outcome data for 707 of 739 randomly as- signed 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, pre- term delivery, and small for gestational age or low birth weight infants. Among patients without chronic hyper- tension, there was a slightly higher rate of severe pre- eclampsia 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. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.ClinicalTrials.gov, NCT00097110 (Obstet Gynecol 2007;110:1311–8) LEVEL OF EVIDENCE: I I n response to evidence for the role of oxidative stress in the pathophysiology of the endothelial damage seen in preeclampsia, 1 several clinical studies have been reported that attempt to improve the antioxidant capability of women at risk for pre- eclampsia. In 1999 Chappell et al 2 reported the results of their randomized study of 283 women who were identified as being at an increased risk by abnormal two-stage uterine artery Doppler analysis or a previ- ous history of preeclampsia. Preeclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the group receiving daily vitamin C (1,000 mg) and vitamin E (400 International Units) From the University of Cincinnati College of Medicine, Cincinnati, Ohio; Universidade Federal de Pernambuco, Hospital das Clı ´nicas, Recife, Brazil; Universidade Estadual de Campinas, Campinas, Brazil; Universidade Estadual Paulista, Botucatu, Brazil; Universidade Federal Do Rio Grande Do Sul, Hospital de Clı ´nicas, Porto Alegre, Brazil; RTI International, Research Triangle Park, North Carolina; and National 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, Jose ´ Remı ´gio Neto, Eduardo Costa Ramos; Botucatu: Jose ´ Carlos Perac ¸oli, 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: spinnaja@ucmail.uc.edu. Financial Disclosure The authors have no potential conflicts of interest to disclose. © 2007 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/07 VOL. 110, NO. 6, DECEMBER 2007 OBSTETRICS & GYNECOLOGY 1311