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High-dose vitamin C, E may increase preeclampsia risk: new study reverses antioxidant findings.

TORONTO -- High-dose antioxidant supplementation may be harmful in pregnant women at risk for preeclampsia, according to a study presented at the annual meeting of the Society for Gynecologic Investigation.

The study, comparing placebo with high daily doses of vitamins C (1,000 mg) and E (400 IU) in high-risk women, suggested that high doses of these vitamins conveyed no protective effect against preeclampsia. In fact, these large doses of the two antioxidants were associated with a greater risk of low birth weight, gestational hypertension, and an arterial cord pH less than 7, reported Lucilla Poston, Ph.D., lead author and professor of fetal health at Guy's, King's, and St. Thomas's School of Medicine in London.

The study, fast-tracked to the Lancet (published online March 30, doi:10.1016/S01406736[06]684 33-X), should not be interpreted as evidence against regular prenatal vitamins, which include much lower doses of antioxidants, Dr. Poston said in an interview: "There's no suggestion that women taking pregnancy vitamins had any adverse effects."

This is the first study to suggest a risk of high-dose antioxidants in pregnancy, and contrasts with previous work by the same group of investigators that suggested a protective effect of supplementation (Lancet 1999; 354:810-6).

"It's quite possible that our previous findings were an error as a result of our small numbers," Dr. Poston said, explaining that the previous study included only 160 women, with an 8% rate of preeclampsia.

She said although it has long been accepted that preeclampsia is associated with oxidative stress, her results suggest that rather than being the cause, oxidative stress may simply be a consequence of the condition. "I'm afraid to say that oxidative stress is probably an innocent bystander in preeclampsia as a result of the disease process," she noted.

This concept is consistent with mainstream cardiology research, she said. "There is overwhelming evidence that atherosclerosis and other cardiovascular complications are associated with oxidative stress, but when people have been supplemented with antioxidants there has been no effect on mortality or morbidity."

The study analyzed 2,395 pregnant women who were at risk for preeclampsia and randomized them at 14-22 weeks' gestation to either high-dose antioxidant therapy or placebo. Subjects who were already taking prenatal vitamins at randomization were allowed to continue taking them.

High-dose antioxidant therapy failed to protect against preeclampsia, which occurred in 15% of the high-dose antioxidant group and 16% of the placebo group.

Additionally, there was an association between high-dose antioxidant therapy and low birth weight, defined as less than 2.5 kg. Low-birth-weight babies comprised 28% of the babies in the high-dose antioxidant group, compared with 24% of the placebo group (risk ratio 1.15).

Regarding secondary outcomes, high-dose antioxidant therapy again compared unfavorably with placebo, resulting in higher risks of arterial cord pH less than 7 (RR 2.2), intravenous antihypertensive therapy (RR 1.9), magnesium sulfate therapy for preeclampsia (RR 1.8), gestational hypertension (RR 1.5), and antenatal steroid use (RR 1.4). An additional exploratory analysis of the data revealed that high-dose antioxidants were associated with a greater risk of stillbirth (RR 2.7), but a lower risk of death due to immaturity (RR 0.2), although these results could be due to chance, since they were generated from a post hoc analysis, she said.

The harmful potential of large doses of antioxidants is particularly troubling, but consistent with some controversial evidence that high-dose vitamin E has an adverse effect on mortality and morbidity in people with cardiovascular disease, Dr. Poston noted. "It could be that a little bit of oxidative stress is actually a good thing," she suggested. "Oxidative stress is involved in a lot of biological processes and it could be there is some fundamental biological process that depends on a little bit of oxidative stress."

The study raises ethical concerns about ongoing antioxidant research in populations that are at risk for preeclampsia, said Dr. Poston. However, she said she has contacted investigators on similar U.S. (National Institutes of Health) and Canadian (Medical Research Council) studies who have decided, after performing interim analyses, to continue their studies despite her findings.

Another smaller study presented in a poster at the meeting also found no protective effect of high-dose antioxidant therapy against preeclampsia. However, the study was done in a normal, nulliparous population, rather than a high-risk group. In fact, there was a trend toward higher preeclampsia rates among women taking high doses of antioxidants (16.7%) compared with those taking placebo (9.7%), said Dr. Heather Mertz, an ob.gyn. at Wake Forest University, Winston-Salem, N.C.

The study of 177 women did show a significant benefit of high-dose antioxidant therapy on neonatal outcome, Dr. Mertz said, but overall, her study did not provide enough evidence to counsel patients either for or against high-dose antioxidant therapy during pregnancy.


Montreal Bureau
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Title Annotation:Obstetrics
Author:Johnson, Kate
Publication:OB GYN News
Date:Apr 15, 2006
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