New data support an old adage: Remember to take your vitamins
By Harold C. Sox, FACP
This month, instead of focusing on public policy, I would like to talk about clinical policy. The subject is folic acid, a vitamin that may offer a powerful way to prevent disease.
Of all the new uses for folic acid, the best-established is for the prevention of neural tube defects in the developing fetus. In several randomized clinical trials and case-control studies, it was found that the use of supplemental folic acid during pregnancy reduced the incidence of neural tube defects.
The 1995 United States Preventive Services Task Force report recommends that women of childbearing age supplement their diet with folic acid in order to reduce the incidence of neural tube defects. The amount required is uncertain, however; while randomized trials in high-risk women used 4-5 mg per day, nonrandomized studies have shown similar risk reductions in women taking less than 0.5 mg of folic acid a day.
The crucial period of susceptibility is the first trimester, when many women do not know they are pregnant. And since many pregnancies are unplanned, most expert panels recommend that all women of childbearing age supplement their diet with 0.4 mg of folic acid. The U.S. Preventive Services Task Force recommends that women who have given birth to a child with a neural tube defect take 4 mg of folic acid per day, starting one month before conception and extending at least through the first trimester.
Coronary heart disease
Evidence for other potential uses of folic acid comes from the Nurses' Health Study, a cohort study that has been following a group of female registered nurses since 1976. Every two years, in order to identify new cases of coronary heart disease (CHD) and other diseases, the women in the study receive a follow-up questionnaire.
A recent report from the Nurses' Health Study provides the best direct evidence that folic acid can reduce the risk of CHD. (See "Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women" in the Feb. 4, 1998, issue of JAMA.) In women whose folic acid intake was in the top quintile (an average intake of 696 µg per day), the risk of nonfatal myocardial infarction or sudden death was 69% that of women whose folic acid intake was in the bottom quintile (an average intake of 158 µg per day). When calculating these odds ratios, the authors corrected for interquintile differences in many predictors of heart disease.
Interestingly, folate intake had only a small effect on CHD risk in women who did not consume alcohol. The risk of CHD in women with the highest folate intake and who drank more than one alcoholic drink per day was 22% of that found in women who did not drink alcohol and had the lowest folate intake. The research suggests that folic acid has the largest effect on women who drink about 22 gm of alcohol per day.
One weakness of cohort studies is that they can demonstrate an association but not a causal relationship between two variables. In the case of folic acid intake and CHD incidence, adjusting for interquintile differences in predictors of CHD does not eliminate the possibility that an unknown variable and not folic acid is responsible for the reduced incidence of CHD. Such "confounders" will cause some physicians to wait for stronger evidence from randomized, controlled trials before they recommend routine supplemental folic acid.
When faced with suggestive but not fully convincing evidence, physicians must ask several questions in order to decide whether to recommend an intervention that might turn out to be ineffective or wait for definitive evidence of effectiveness. First, does the putative effect make good biological sense? In the case of folic acid and cardiovascular disease, the biological link is quite strong. Several observational studies have shown that elevated plasma homocysteine is associated with an increased risk of coronary heart disease. Since folic acid lowers plasma homocysteine, an effect of folic acid on CHD seems plausible.
Second, what is the cost and risk of the intervention? Folic acid is inexpensive and safe. Third, how high is the risk of developing the disease in question? The balance of harms and benefits shifts toward net benefit as the risk of disease increases. Putting all these factors together, it is reasonable to recommend that women at high risk of CHD take supplementary folic acid.
When discussing folic acid intake, physicians should also consider its possible effect on reducing the risk of colon cancer. In the Nurses' Health Study, women who consumed >400 µg of folic acid per day saw their risk of colon cancer reduced by 69% (95% confidence interval, 52% to 93%, p=.01) over women who consumed <200 µg per day. (The data were adjusted for differences in the variables noted above and family history of colon cancer.)
In women who had taken folic acid for 15 years or more, the relative risk of colon cancer was 0.25 (95% confidence interval 0.13 to 0.51). Shorter periods of folic acid intake were associated with smaller, statistically nonsignificant effects (See "Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study " in the Oct. 1, 1998, issue of Annals of Internal Medicine.)
These findings suggest that the average adult woman's dietary intake of approximately 225 µg per day isn't nearly enough. In 1998, the Institute of Medicine recommended a daily allowance of 400 µg per day of folic acid for both men and women. This can be achieved by eating food supplemented with folic acid or taking a multivitamin capsule.
In 1998, the FDA mandated that all enriched grains (enriched bread, pasta, flour, breakfast cereal and rice) must contain 140 µg folic acid per 100 grams of grain produce. One serving of an enriched grain product should increase the average person's folic acid intake by 40 µg per day. As a result, meeting the recommended daily allowance requires individuals to eat either five servings of enriched grain product per day to supplement their existing folic intake or to take one multivitamin per day.
ACP-ASIM has gotten involved in the effort to make patients and physicians aware of the importance of folic acid by joining the National Council on Folic Acid, a coalition to promote awareness of the importance of adequate folic acid intake and the means to achieve it. Stay tuned for more information. Meanwhile, take your vitamins.
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