News Author: Laurie Barclay, MD

April 3, 2006 — Vitamin C and vitamin E supplementation are not helpful for woman with preeclampsia and may be harmful to the fetus, according to the results of a randomized trial published the March 30 Early Online Publication issue of The Lancet.

"Oxidative stress could play a part in pre-eclampsia, and there is some evidence to suggest that vitamin C and vitamin E supplements could reduce the risk of the disorder," write L. Poston, MD, from St. Thomas' Hospital in London, United Kingdom, and colleagues from the Vitamins in Pre-eclampsia (VIP) Trial Consortium. "Our aim was to investigate the potential benefit of these antioxidants in a cohort of women with a range of clinical risk factors."

At 25 hospitals, 2410 women at increased risk for preeclampsia were randomized to receive 1000 mg of vitamin C and 400 IU vitamin E (RRR alpha-tocopherol; n = 1199) or matched placebo (n = 1205) daily from the second trimester of pregnancy until delivery. The main outcome was preeclampsia, and secondary outcomes were low birth weight (<2.5 kg) and small size for gestational age (less than fifth customized birth weight percentile). Analyses were by intent-to-treat.

Data were analyzed for 2395 (99.6%) of 2404 patients treated. The incidence of preeclampsia was 15% (n = 181) in the treatment group and 16% (n = 187) in the placebo group (relative risk [RR], 0.97; 95% confidence interval [CI], 0.80 - 1.17). More low birth weight babies were born to women in the treatment group than in the placebo group (28% [n = 387] vs 24% [n = 335]; RR, 1.15; 95% CI, 1.02 - 1.30]). Small size for gestational age was similar in both groups (21% [n = 294] vs 19% [n = 259]; RR, 1.12; 95% CI, 0.96 - 1.31]).

"Concomitant supplementation with vitamin C and vitamin E does not prevent pre-eclampsia in women at risk, but does increase the rate of babies born with a low birth weight," the authors write. "As such, use of these high-dose antioxidants is not justified in pregnancy."

The authors note that the daily doses of vitamin C and vitamin E given were below the maximum recommended intake in pregnant women (2000 mg/day and 1000 mg [1600 IU] daily, respectively).

"The absence of benefit and evidence of unfavorable outcomes in this study cannot be extrapolated to other antioxidants, including the same vitamins at lower doses," the authors conclude. "Additionally, our findings should not detract from the potential importance of oxidative stress in pre-eclampsia."

Some of the authors have disclosed being principal investigators on the World Health Organization trial of vitamin C and vitamin E supplementation for the prevention of preeclampsia; patents regarding diagnosis of preeclampsia; and/or holding shares in CORRA Life Sciences, a biotech company that develops biomarker tests to predict abnormal pregnancy outcomes.

This trial was funded by the Wellcome Trust, with additional support from Tommy's the baby charity.

In an accompanying editorial, Marshall D. Lindheimer, MD, and Baha M. Sibai, MD, from the University of Chicago in Illinois, note that vitamin C levels were obtained in less than half of the participants and longitudinally in only about 10%. Other potential limitations are possible confounding variables, and a heterogeneous population of high-risk patients limiting generalizability.

"Our limited resources should focus more on basic research, with human studies stressing prediction markers combined with ancillary studies to help define mechanisms (and, of course, the safety and efficacy of therapy)," Drs Lindheimer and Sibai write. "It appears surprising that administration of vitamins in amounts that did not exceed maximum daily tolerable allowances should be associated with adverse effects, but the VIP data are not the first time that vitamin or nutrient supplements administered to populations already consuming considerable amounts of the supplement's content in their diets have had adverse effects.... It would not be surprising if two ongoing trials involving antioxidant supplementation in areas of developing nations where nutrient deficiencies are rampant produced results differing from those here."