Multivitamin Use, Folate, and Colon Cancer in Women in the Nurses’ Health Study

Source: Giovannucci E, et al. Ann Intern Med 1998;129:517-524.

This study asks about determinants of colon cancer. The data are the dietary reports from a cohort of the Nurses’ Health Study. This subgroup was composed of 88,756 women followed since 1976. In 1980, Giovannucci and colleagues started tracking dietary habits at two-year intervals using a semiquantitative food-frequency questionnaire. Subjects also provided information about vitamin use, hormone use, smoking, physical activity, aspirin use, colonoscopy or sigmoidoscopy, and parental history of colorectal cancer. After controlling for an array of potentially confounding factors, Giovannucci et al found that those women who used multivitamins for more than 15 years showed a significant reduction in rates of colorectal cancer. Folate from dietary sources alone was related to a modest reduction in risk, whereas the benefits of long-term multivitamin use were seen at all levels of dietary intake.

Comment by Sarah L. Berga, MD

The present study also addresses the hypothesis that diet can modify the incidence of colorectal cancer. The surprising aspect of this study is that it suggests that dietary sources of folate may be less efficacious in reducing the risk of colon cancer because the folate in multivitamins is more bioavailable than that in foods. This finding conflicts with the customary dictum that the best source of most nutrients is a balanced diet. But some nutrients are difficult to extract from food or are not common in our standard diet. Previous evidence reviewed herein has suggested that it is difficult to get enough vitamin E (Berga SL. OB/GYN Clin Alert 1997;14:27-28). Recently, I reviewed a report suggesting that many people also have inadequate vitamin D levels (Berga SL. OB/GYN Clin Alert 1998;15:9-10). Vitamin D is made when the skin is exposed to the appropriate wavelength of sunlight, but dermatologists warn against getting too much sun. It has been suggested that more foods be fortified with vitamin D because, currently, the most common food to which it is added is milk, and most people don’t drink enough milk to meet their vitamin D requirements.

Now we have folate and its sources to consider when advising women about the chemoprevention of aging. Folate might well be nominated as the vitamin of the year. Not only does its intake reduce the risk of neural tube defects in pregnant women, but its use also has been touted as a way to diminish the risk of cardiovascular disease due to elevated homocysteine levels (Rimm EB, et al. JAMA 1998;279:359-364). Why might folate be so important? As Giovannucci et al point out, folate is essential for regenerating methionine, the methyl donor for DNA methylation. Also, it is needed for producing purines and pyrimidines for DNA synthesis. Inadequate availability of folate may contribute to aberrations in DNA methylation and may lead to abnormalities in DNA synthesis and repair. Hypomethylation of DNA is reported to be one of the earliest events in colon carcinogenesis. It is estimated that 88% of the population has folate intake of less than 400 g/d, the amount currently recommended and generally contained in multivitamin preparations. While foods naturally high in folate contain important micronutrients and the goal of obtaining most nutrients from food should not be abandoned, multivitamin use or increased intake of fortified foods is recommended to ensure adequate folate status.

Comment by Elizabeth Morrison, MD, MSEd

We already know that all American women of reproductive age should be taking supplementary folate because it prevents neural tube defects in their offspring.1 Data from the Nurses’ Health Study, published in the JAMA earlier this year,2 indicate that women who take multivitamin supplements with folate may decrease their risk of coronary artery disease by up to 25%. Now, we have compelling evidence of yet another benefit of multivitamin supplements and folic acid for women—reducing the risk for colon cancer.

Giovannucci et al skillfully handled possible confounders. Women who take multivitamin and folate supplements are likely to pursue other "health-seeking behaviors" such as low-fat and high-fiber diets. Giovannucci et al searched for confounding ties between these behaviors and colon cancer risk but found none that altered the substantial relationship between folate, multivitamins, and colon cancer.

It is interesting that even high intake of dietary folate did not seem to decrease colon cancer risk, while folate and multivitamins in supplement form did. Giovannucci et al point out that dietary folate is not as bioavailable as folate supplements, which may account for this difference. One also wonders why no benefit resulted when women took the supplements for less than 15 years. Could other dosages or forms of these nutrients provide more rapid or more powerful benefits?

Giovannucci et al discuss the study’s main flaw—its inability to separate the effects of folate from the multivitamins in the supplements. It is certainly possible that unknown nutrients in the multivitamin supplements, and not the folate, are ultimately responsible for the reduced risk of colon cancer. Clearly, we need to see data from a randomized, controlled trial, preferably one that separately analyzes folate and other nutrients contained in multivitamin supplements. Since such data will not be available any time soon, if ever, this study’s meticulous analysis provides useful interim findings. I will add this study to my repertoire as I encourage women to pursue "health-seeking behaviors" that include daily folate-containing multivitamin supplements. (Dr. Berga is Associate Professor, Departments of Obstetrics, Gynecology, Reproductive Sciences, and Psychiatry, University of Pittsburgh, Pittsburgh, PA. Dr. Morrison is Assistant Clinical Professor of Family Medicine, University of California, Irvine.)

References

1. Czeizel AE. Ann N Y Acad Sci 1993;678:266-275.

2. Rimm EB, et al. JAMA 1998;279:359-364.