Correspondence

Folic Acid Fortification

N Engl J Med 1999; 341:922-924September 16, 1999

Article

To the Editor:

Jacques and colleagues (May 13 issue)1 report data showing that the 30 percent of the Framingham Offspring Study cohort who took B vitamin supplements had a substantially lower mean plasma homocysteine concentration that the members of the cohort who did not take such vitamins, even after the fortification of grain products with folic acid was introduced by the Food and Drug Administration (FDA). Furthermore, the upper tail of the distribution of homocysteine concentrations remained skewed in those who did not take supplements after fortification as compared with those who did take them. This distribution suggests that the homocysteine concentration remains too high in those who do not take supplements. Thus, approximately 70 percent of the adult population in the United States is exposed to a risk factor for cardiovascular disease — an elevated plasma homocysteine concentration — that can be easily avoided simply by consuming a B vitamin supplement. It seems strange that the authors suggest neither supplements nor increased fortification of food.

Ward and colleagues gave male hospital workers 100, 200, or 400 μg of synthetic folic acid daily.2 They reported that in order for the one third with the highest plasma homocysteine concentrations (those who were the most vitamin deficient) to reduce their plasma homocysteine concentrations to a level as low as the one third with the lowest concentration (those with enough vitamins), 400 μg of synthetic folic acid daily was required. Thus, Americans who are not taking supplements should begin taking 400 μg of synthetic folic acid daily. Since the Framingham Offspring Study cohort is middle-aged or older, it is likely that some of the increased homocysteine concentrations among those not taking supplements were due to the fact that they did not consume enough synthetic vitamin B₁₂. In April 1998, the Institute of Medicine recommended that adults 50 years of age or older consume 2.4 μg of synthetic vitamin B₁₂ daily.3

Most Americans who consume B vitamin supplements take a multivitamin that contains 400 μg of synthetic folic acid and 6 μg of synthetic vitamin B₁₂. The studies by Jacques et al.1 and Ward et al.2 suggest that hundreds of thousands of Americans who do not take B vitamin supplements will be exposed unnecessarily to a cardiovascular risk factor until the FDA increases the amount of synthetic folic acid in the diet so that almost all Americans — not just the average American — are consuming 400 μg of synthetic folic acid and 2.4 μg of synthetic vitamin B₁₂ daily.4 Until the FDA gets the amount of fortification right, adults can largely avoid the cardiovascular risk associated with high plasma homocysteine concentrations by eating well and taking a multivitamin.

Godfrey P. Oakley, Jr., M.D., M.S.P.M.
Emory University, Atlanta, GA 30322

4 References

1. 1

   Jacques PF, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-1454
   Full Text | Web of Science | Medline

2. 2

   Ward M, McNulty H, McPartlin J, Strain JJ, Weir DG, Scott JM. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM 1997;90:519-524
   CrossRef | Medline

3. 3

   Institute of Medicine, Food Nutrition Board. Dietary reference intakes: thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, D.C.: National Academy Press (in press).
   

4. 4

   Oakley GP Jr. Let's increase folic acid fortification and include vitamin B-12. Am J Clin Nutr 1997;65:1889-1890
   Web of Science | Medline

To the Editor:

In their article on the effect of folic acid fortification on plasma folate and total homocysteine concentrations, Jacques et al. concluded that the recent introduction of folic acid fortification was associated with a substantial improvement in folate status in a population of middle-aged or older adults.

In order to evaluate the effect of folic acid fortification on the risk of neural-tube defects, vascular diseases, and cancer, however, researchers will need to conduct additional studies that relate these outcomes to changes in concentrations of blood folate.

One key point in the evaluation of the success of the national folic acid fortification program is the ability to compare serum and whole-blood folate results obtained by different laboratories and methods. In an international, interlaboratory study, Gunter et al.1 reported that folate concentrations measured by different methods varied by factors of two to nine, with the greatest variation occurring at critical, low concentrations of folate.

If we want to be able to use data on folate generated by many studies and laboratories in a meaningful way, we need to ensure the comparability and accuracy of folate measurements. This can be achieved only if high-quality reference methods and definitive means of analyzing serum and whole-blood folate are developed and validated and if properly characterized reference materials are introduced through a standardization program. The need for such a standardization program has been recognized,1,2 but no such program has been established. The emerging understanding of the relation between folate concentrations and the risks of vascular disease and cancer makes it imperative that we begin to establish a standardization program now. This program will be essential for ensuring the comparability of data from future studies and for evaluating the effectiveness and safety of folic acid fortification and supplementation as a public health intervention.

Christine M. Pfeiffer, Ph.D.
Elaine W. Gunter, M.T.(A.S.C.P.)
Dayton T. Miller, Ph.D.
Centers for Disease Control and Prevention, Atlanta, GA 30341

2 References

1. 1

   Gunter EW, Bowman BA, Caudill SP, Twite DB, Adams MJ, Sampson EJ. Results of an international round robin for serum and whole-blood folate. Clin Chem 1996;42:1689-1694
   Web of Science | Medline

2. 2

   Jacobsen DW. Serum and erythrocyte folates: a matter of life and premature death. Clin Chem 1996;42:1579-1581
   Web of Science | Medline

To the Editor:

The increases in blood folate concentrations and the declines in homocysteine values attributed to the fortification of cereal-grain products with folic acid presented by Jacques et al. are encouraging. However, we urge caution in concluding that “the job is done,” as many in the media imply, by claiming, for example, that “folic acid deficiency has all but vanished.”1 Folate “deficiency” was defined on the basis of megaloblastic anemia, not on the prevention of neural-tube defects. The mechanism by which folic acid prevents neural-tube defects is unknown but could be related to compensating for individual variations in folate metabolism rather than to correcting a folate “deficiency.” In addition, it is premature to interpret the findings as proof that the intake of folic acid among women of childbearing age is currently optimal and will maximize reductions in the occurrence of neural-tube defects. Higher red-cell folate concentrations have been shown to be associated with lower rates of neural-tube defects, with continuous rate decreases well past clinically normal folate concentrations.2

Ultimately, the effectiveness of folic acid fortification will be determined by its effect on the occurrence of neural-tube defects independent of the effects of the increasing use of prenatal diagnosis and termination of pregnancy, which has already lowered the birth prevalence of neural-tube defects by at least 32 percent.3 The Centers for Disease Control and Prevention monitors the rates of neural-tube defects closely. It is too early to assess the effect of fortification on the occurrence of neural-tube defects. Although many targeted foods were probably fortified with folic acid before the FDA's January 1998 deadline,4 there may have been some lag time owing to the consumption of products that were stored before the fortification requirement was in place. If most targeted items consumed in January 1998 were fortified, the earliest term infants of mothers who were “exposed” to fortification early in pregnancy would be those born in late 1998.

If the increase in folate concentrations found among older adults in the Framingham Offspring Study applies to women of childbearing age, and if this increase translates to more healthy babies born without major disabling birth defects, we will have strong evidence that fortification is successful. In the meantime, we think it is most appropriate to continue to advocate that all women capable of becoming pregnant take 400 μg of a synthetic fo-lic acid supplement daily. Achieving the recommended 400 μg daily by consuming fortified grains alone requires a substantial change in behavior; the estimated average daily intake of folic acid from fortified grains by women is 100 μg.4

Margaret L. Watkins, M.P.H., B.S.N.
J. David Erickson, D.D.S., Ph.D.
Joseph Mulinare, M.D., M.S.P.H.
Centers for Disease Control and Prevention, Atlanta, GA 30341-3724

4 References

1. 1

   Haney DQ. Study: adding vitamin to flour has made folic acid deficiency drop. Boston: Associated Press, May 12, 1999.
   

2. 2

   Wald NJ, Law M, Jordan R. Folic acid food fortification to prevent neural tube defects. Lancet 1998;351:834-834
   CrossRef | Web of Science | Medline

3. 3

   Cragan JD, Roberts HE, Edmonds LD, et al. Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis — United States, 1985–1994. MMWR CDC Surveill Summ 1995;44(SS-4).
   

4. 4

   Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist 1996;61:8781-8797
   

Author/Editor Response

The authors reply:

To the Editor: Dr. Oakley blurs the distinction between the effect of folic acid fortification on folate status and the effect of vitamin-supplement use on vitamin B₁₂ status. Rather than consider all the evidence that we presented relating fortification to the improved folate status of Americans, he chooses to select a single confounded observation to support his belief that fortification levels are too low. Dr. Oakley considers only the difference in mean homocysteine concentrations after fortification between the participants who used multivitamin supplements and those who did not. However, he ignores the evidence presented in our paper that showed that this difference was due to a better vitamin B₁₂ status among those who used supplements. Furthermore, Dr. Oakley ignores the finding that the prevalence of homocysteine concentrations of more than 13 μmol per liter after fortification among those who did not use multivitamin supplements was not significantly different from the prevalence among those who did. Finally, he ignores the observation that the prevalence of folate concentrations of less than 3 ng per milliliter dropped from greater than 20 percent before fortification to 1.7 percent after fortification in those who did not use supplements and that this latter prevalence was not significantly different from that for those who used vitamin supplements.

We also believe that Dr. Oakley's comment that approximately 70 percent of the adult population of the United States has an elevated risk of cardiovascular disease as a result of increased plasma homocysteine concentrations is unsupported by any evidence. Furthermore, his recommendation that the entire population use multivitamin supplements to protect against elevated homocysteine concentrations seems unwarranted in the absence of any data from randomized, controlled clinical trials indicating that treatment of mild hyperhomocysteinemia with B vitamins actually reduces the incidence of cardiovascular disease.

Pfeiffer and colleagues present their case for the standardization of folate measures, but the lack of standardization had no effect on our results, since all the measurements were performed in the same laboratory with the use of the same methods.

In response to the comments of Watkins and colleagues: we did not conclude or intend to imply that the job is done. Since folic acid fortification was mandated by the FDA as a means of reducing the incidence of neural-tube defects, we agree that the effectiveness of fortification will only be demonstrated through its effect on the prevention of such defects. Given that fortification has been largely in place for almost two years, we anticipate that such evidence will soon be forthcoming. In the meantime, it seems only prudent to await the data before deciding on the adequacy of the current fortification level.

Paul F. Jacques, Sc.D.
Jacob Selhub, Ph.D.
Irwin H. Rosenberg, M.D.
Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111

Citing Articles (2)

Citing Articles

1. 1

   Laura Pickell, Katharine Brown, Deqiang Li, Xiao-Ling Wang, Liyuan Deng, Qing Wu, Jacob Selhub, Li Luo, Loydie Jerome-Majewska, Rima Rozen. (2011) High intake of folic acid disrupts embryonic development in mice. Birth Defects Research Part A: Clinical and Molecular Teratology 91:1, 8-19
   CrossRef

2. 2

   Rebecca Schmidt, Janine LaSalle. 2010. Interactions between Folate, Other B Vitamins, DNA Methylation, and Neurodevelopmental Disorders. , 317-361.
   CrossRef