The New England Journal of Medicine -- April 9, 1998 -- Vol. 338, No. 15
Since the mid-1970s, 25 percent of American adults have regularly consumed a multivitamin containing 400 µg of folic acid. The current evidence suggests that people who take such supplements and their children are healthier. This evidence raises the question of whether physicians and other health care professionals should recommend that all adults take a multivitamin daily.
"Folate" is the generic term for compounds that have vitamin activity similar to that of pterolymonoglutamic acid (also called folic acid), the chemical that is added to supplements or fortified foods. Folic acid is synthetic, heat stable, and approximately twice as bioavailable as the folate that occurs naturally in food. In nutritional regulations and customary use, the terms "folic acid" and "folate" are interchangeable, but I use "folic acid" in this editorial to mean the synthetic chemical.
Until recently, estimates of the minimal requirements of food-derived folate were based on studies of how much folic acid is needed to cure anemia due to folate deficiency. Extrapolation from these data suggested that the general population needed 200 µg of folic acid daily; therefore, the recommendation was for 400 µg of food-derived folate. Because the incidence of anemia due to folate deficiency was low, in 1989 the Food and Nutrition Board lowered the recommended dietary allowance (RDA) of folate. This lower level was not adopted by the Food and Drug Administration (FDA) for regulatory or labeling purposes; therefore, a product sold in the United States labeled "100% of folate or folic acid" contains 400 µg of folic acid. New evidence that folic acid prevents birth defects, summarized below, suggests that the RDA should be increased.
In a randomized, controlled trial of women consuming their usual diets plus 4000 µg of folic acid in pill form daily, the Medical Research Council Study found that folic acid prevents two common and serious birth defects.  Observational studies of women eating their usual diet and taking a multivitamin supplement containing approximately 400 µg of folic acid found protective associations. On the basis of these data, the U.S. Public Health Service recommended that all women who could become pregnant consume 400 µg of folic acid each day. 
Cuskelly et al. showed that although neither dietary advice nor consumption of food estimated to contain 400 µg of folate significantly increased blood folate, a pill or serving of cold breakfast cereal containing 400 µg of folic acid increased blood folate by about 50 percent.  Daly et al. recently showed the effects on blood folate concentrations of 100, 200, and 400 µg of folic acid, taken in pill form.  Their study found that at least 400 µg of folic acid plus the usual diet is required to achieve blood folate concentrations sufficient for full prevention of birth defects known to be preventable by increasing folic acid intake.
Because the terms "folic acid" and "folate" are often used interchangeably, some professionals recommend that women consume 400 µg of food-derived folate rather than 400 µg of folic acid. Women consuming an average diet containing 200 µg of food-derived folate plus 400 µg of supplemental folic acid in a multivitamin or fortified cereal are consuming the equivalent of approximately 1000 µg of naturally occurring folate. Anyone who chooses to counsel a woman to consume 400 µg of food-derived folate rather than 400 µg of supplemental folic acid will be recommending a strategy that has not been proved to prevent birth defects and that leads to lower blood folate concentrations.
Since January 1, the FDA has required enriched grains to be fortified with folic acid at a concentration that will provide the average woman with an extra 100 µg per day. Thus, the only sure way for most women to achieve the recommended intake of 400 µg of folic acid is to consume a multivitamin or a serving of fully fortified (400 µg of folic acid per serving) breakfast cereal daily.
Plasma homocysteine is a sensitive biomarker of folate deficiency. Lewis et al. showed that at plasma folate concentrations above 15 nmol per liter the homocysteine concentration is on a low, normal plateau.  At lower levels of plasma folate, the plasma homocysteine concentration increases steadily.  A homocysteine concentration above the low, normal plateau has been found in many but not all studies to be a strong, graded, independent risk factor for cardiovascular disease. [7, 8] Rimm et al. recently reported in a large prospective study of women that the 20 percent who had the highest consumption of folate (94.5 percent of whom consumed multivitamins) had significantly less cardiovascular disease than the lowest 20 percent (7.7 percent of whom consumed multivitamins).  There have been no published randomized, controlled trials of the effect of folic acid alone on cardiovascular disease. The predominant cause of homocysteine blood concentrations above the low, normal base line is inadequate blood folate.  Inadequate blood folate is common among those who do not take multivitamin supplements but unusual among those who do. In the Framingham Study cohort, 90 percent of those not consuming multivitamins had homocysteine levels above the low, normal base line associated with adequate blood folate. 
There has been interest in determining how much supplemental folic acid is required to reduce blood homocysteine. Shimakawa et al. reported that people who use multivitamin supplements have significantly lower mean plasma homocysteine concentrations than nonusers.  In this issue of the Journal, Malinow et al. report the results of a randomized, controlled trial of the effects of consuming breakfast cereal fortified with folic acid.  They show that 400 µg of folic acid had as great a homocysteine-lowering effect as 600 µg, but 100 µg had a smaller effect. Ward et al. also found a threshold effect when they gave healthy men pills containing 100, 200, or 400 µg of folic acid.  The third of the study subjects with the highest mean plasma folate concentrations had no change in mean homocysteine at any supplement level. Although the 100-µg supplement did lower mean homocysteine concentrations in the other two thirds of the subjects, maximal reduction required at least 200 µg. Thus, it is likely that the extra 100 µg of folic acid that Americans are consuming in fortified foods will lower plasma homocysteine concentrations, but more will be necessary for full reduction. Another important point of the study by Ward et al. is that 66.7 percent of their sample had plasma folate concentrations low enough that folic acid consumption lowered their homocysteine concentrations.
If food fortification provided enough folic acid to prevent all birth defects known to be preventable by folic acid, homocysteine reduction for the general population would also be accomplished. These new data should provide a rationale for increasing the levels of fortification. 
An intake of 400 µg of folic acid above the dietary level will prevent birth defects. Elevated homocysteine concentrations due to insufficient blood folate concentrations are common. An intake of 400 µg of supplemental folic acid will minimize the blood homocysteine concentrations of most of the population. I agree with Omenn et al. that the evidence that increased consumption of folic acid will prevent cardiovascular disease is strong and that we should recommend consumption of at least 400 µg of folic acid daily.  Consuming a standard multivitamin or a serving of fully fortified breakfast cereal is a convenient, effective, safe, and inexpensive way to increase consumption of folic acid by 400 µg rapidly. Now is the time to recommend these approaches to increasing folic acid consumption while continuing to recommend a healthy diet and working to increase the concentration of folic acid in fortified grains.
Godfrey P. Oakley, Jr., M.D.
Centers for Disease Control and Prevention
Atlanta, GA 30341-3724
The views expressed are the author's and do not necessarily represent the policies of the Centers for Disease Control and Prevention.
Copyright © 1998 by the Massachusetts Medical Society. All rights reserved.