Contradicting claims of disease prevention, an analysis of previous studies indicates that the antioxidant supplements beta carotene, vitamin A, and vitamin E may increase the risk of death, according to a meta-analysis and review article JAMA

Many people take antioxidant supplements, believing they improve their health and prevent diseases. Whether these supplements are beneficial or harmful is uncertain, according to background information in the article.

Goran Bjelakovic, M.D., Dr.Med.Sci., of the Center for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark, and colleagues conducted an analysis of previous studies to examine the effects of antioxidant supplements (beta carotene, vitamins A and E, vitamin C [ascorbic acid], and selenium) on all-cause death of adults included in primary and secondary prevention trials. Using electronic databases and bibliographies, the researchers identified and included 68 randomized trials with 232,606 participants in the review and meta-analysis. The authors also classified the trials according to the risk of bias based on the quality of the methods used in the study, and stratified trials as "low-bias risk" (high quality) or "high-bias risk" (low quality).

In an analysis that pooled all low-bias risk and high bias risk trials, there was no significant association between antioxidant use and mortality. In 47 low-bias trials involving 180,938 participants, the antioxidant supplements were associated with a 5 percent increased risk of mortality. Among low-bias trials, use of beta carotene, vitamin A, and vitamin E was associated with 7 percent, 16 percent and 4 percent, respectively, increased risk of mortality, whereas there was no increased mortality risk associated with vitamin C or selenium use.

"Our systematic review contains a number of findings. Beta carotene, vitamin A, and vitamin E given singly or combined with other antioxidant supplements significantly increase mortality. There is no evidence that vitamin C may increase longevity. We lack evidence to refute a potential negative effect of vitamin C on survival. Selenium tended to reduce mortality, but we need more research on this question," the authors write.

"Our findings contradict the findings of observational studies, claiming that antioxidants improve health. Considering that 10 percent to 20 percent of the adult population (80-160 million people) in North America and Europe may consume the assessed supplements, the public health consequences may be substantial. We are exposed to intense marketing with a contrary statement, which is also reflected by the high number of publications per included randomized trial found in the present review."

"There are several possible explanations for the negative effect of antioxidant supplements on mortality. Although oxidative stress has a hypothesized role in the pathogenesis of many chronic diseases, it may be the consequence of pathological conditions. By eliminating free radicals from our organism, we interfere with some essential defensive mechanisms . Antioxidant supplements are synthetic and not subjected to the same rigorous toxicity studies as other pharmaceutical agents. Better understanding of mechanisms and actions of antioxidants in relation to a potential disease is needed," the researchers conclude.

(JAMA. 2007;297:842-857 Available pre-embargo to the media at http://www.jamamedia.org/)

Editor's Note: Supported by The Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.