Correspondence

Fortification of Foods with Folic Acid

N Engl J Med 2000; 343:970-972September 28, 2000

Article

To the Editor:

In his Sounding Board article (May 11 issue),1 Mills points out that some have called for an increase in the level of fortification of foods with folic acid,2 even though the effect of the current level of fortification of 140 μg of folic acid per 100 g of grain products is still unknown. Our data from Kaiser Permanente members showed an increase in median serum folate levels, from 12.6 ng per milliliter in 1994 to 18.7 ng per milliliter in 1998.3 It is of interest to know whether serum folate levels stabilized beginning in 1998 or whether they continued to rise. As Table 1Table 1Serum Folate Levels, 1994 through 1999. shows, the median serum folate level rose from 18.7 ng per milliliter in 1998 to more than 20.0 ng per milliliter in 1999 while the prevalence of folate deficiency (defined as a level of less than 2.7 ng per milliliter) declined. The median serum folate value could not be assessed in 1999, since it exceeded the maximal value (20.0 ng per milliliter) of the method used to measure serum folate in our laboratory (Advia Centaur immunoassay system, Bayer Diagnostics). The median serum folate value for women 18 to 45 years of age increased from 10.8 ng per milliliter in 1994 to 17.3 ng per milliliter in 1998 and to 19.0 ng per milliliter in 1999.

Jean M. Lawrence, Sc.D., M.P.H.
Vicki Chiu, M.S.
Diana B. Petitti, M.D., M.P.H.
Kaiser Permanente Southern California, Pasadena, CA 91101

3 References

1. 1

   Mills JL. Fortification of foods with folic acid -- how much is enough? N Engl J Med 2000;342:1442-1445
   Full Text | Web of Science | Medline

2. 2

   Oakley GP Jr. Prevention of neural-tube defects. N Engl J Med 1999;341:1546-1546
   Full Text | Web of Science | Medline

3. 3

   Lawrence JM, Petitti DB, Watkins M, Umekubo MA. Trends in serum folate after food fortification. Lancet 1999;354:915-916
   CrossRef | Web of Science | Medline

To the Editor:

Fortification of breakfast cereal with folic acid was begun in Victoria, Australia, in 1996. In 1997, other foods, including some types of bread, began to be fortified. The State Government Department of Human Services includes a Birth Defects Register, which was established in 1982 and covers a population with approximately 62,000 births annually (Figure 1Figure 1Prevalence of Neural-Tube Defects in Victoria, Australia, 1983 through 1999.). The prevalence of neural-tube defects, including terminated pregnancies, was 1.39 per 1000 for the 15-year period up to 1997. This figure dropped to 0.98 per 1000 in 1998 and was even lower in 1999. In 1999 there were 53 reported cases of neural-tube defects (including 31 cases in which the pregnancy was terminated before 20 weeks of gestation), for a prevalence of 0.9 per 1000.

This recent decline cannot be explained by the periconceptional use of supplements by women and raises the question whether food fortification is having a role. However, it is highly unlikely that the full recommended dose of 400 μg is being obtained through the ingestion of fortified foods, since a woman would have to eat four servings of breakfast cereal per day to consume this much folic acid. Therefore, we support the idea proposed by Mills that a lower dose of folic acid may indeed be instrumental in bringing about a significant reduction in the incidence of neural-tube defects, as has been seen in Victoria.

Jane L. Halliday, Ph.D.
Murdoch Children's Research Institute, Parkville 3052, Victoria, Australia

Merilyn Riley, B.App.Sc.
Victorian Perinatal Data Collection Unit, Melbourne 3001, Victoria, Australia

To the Editor:

In his Sounding Board article, Mills recommends against increasing the current level of fortification of 140 μg of folic acid per 100 g of grain products. This level was projected to increase the average daily intake of folic acid by only 100 μg, which is one fourth the intake of 400 μg of synthetic folic acid recommended by the Institute of Medicine for all women of reproductive age.1 A national panel in the United Kingdom reviewed the data available to Mills and came to a different conclusion. This committee recently recommended that flour be fortified with folic acid at nearly double the current level in the United States: “On scientific, medical and public health grounds, the Committee concluded that universal folic acid fortification of flour at 240 μg/100 g in food products as consumed would have a significant effect in preventing NTD [neural-tube–defect]-affected conceptions and births without resulting in unacceptable high intakes in any group of the population.”2 Mills notes that in an analysis of data from Ireland, he and his colleagues estimated that consuming 200 μg of synthetic folic acid daily would prevent nearly twice as many neural-tube defects as would a dose of 100 μg a day.3 I was surprised that he does not argue that the level of fortification should be doubled, so that the average woman would consume 200 μg of synthetic folic acid a day.

Russell S. Kirby, Ph.D.
University of Wisconsin Medical School, Milwaukee, WI 53201-0342

3 References

1. 1

   Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline: a report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients. Washington, D.C.: National Academy Press, 1998. (See http://www.nap.edu/openbook/0309065542/html.)
   

2. 2

   Folic acid and the prevention of disease: report of the committee on medical aspects of food and nutrition policy. Report on health and social subjects: 50. London: Her Majesty's Stationery Office, 2000:11.
   

3. 3

   Daly S, Mills JL, Molloy AM, et al. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 1997;350:1666-1669
   CrossRef | Web of Science | Medline

To the Editor:

We recently cared for a 34-year-old woman in the third trimester of pregnancy who had been taking a supplement of 350 μg of folic acid per day since conception. A complete blood count was obtained at 36 weeks' gestation after the development of fatigue, lethargy, glossitis, and painful feet. The hemoglobin level was 7.3 g per deciliter, the white-cell count was 6.4×10⁹ per liter, the platelet count was 177×10⁹ per liter, and the mean corpuscular volume was 110 μm³ (normal range, 86 to 96). Examination of a peripheral-blood film showed macro-ovalocytes, hypersegmentation of the neutrophil nuclei, and occasional erythroblasts. A marrow aspirate confirmed the presence of megaloblastic erythropoiesis. The vitamin B₁₂ level was 75 pg per milliliter (normal range, 150 to 1000). Parenteral vitamin B₁₂ supplementation was promptly initiated, and hematologic variables approached normal at term. A baby boy with no evidence of neurodevelopmental abnormalities was delivered without complications. However, his mother continues to have severe peripheral neuropathy.

This case highlights the dangers of indiscriminate folic acid fortification and supplementation, as outlined by Dr. Mills. Clearly, folic acid fortification and supplementation have enormous benefits in preventing neural-tube defects. However, those dealing with pregnant women should be vigilant for the development of a peripheral neuropathy, particularly in patients with a history of an autoimmune disorder.

Catherine Flynn, M.B., M.R.C.P.(Edin.)
Helen Enright, M.D., F.R.C.P.I., F.R.C.Path.
Adelaide and Meath Hospital, Dublin 24, Ireland

Author/Editor Response

Dr. Mills replies:

To the Editor: The increase in serum folate levels reported by Lawrence et al. provides support for recent claims that manufacturers are overfortifying foods. Rader et al.1 have shown that fortified foods often contain folate levels that are 150 to 200 percent of the listed value. This could be a problem because those who consume large amounts of enriched grain products, particularly young children, may exceed the upper level of intake established by the Institute of Medicine.2

Halliday and Riley report a drop of more than 30 percent in the rate of neural-tube defects after the initiation of a food-fortification program. It is not clear exactly how much folic acid women are receiving from this fortification program; however, these data suggest that the current U.S. fortification program will substantially decrease the incidence of neural-tube defects.

Flynn and Enright's letter makes several important points: the diagnosis of vitamin B₁₂ deficiency must be considered in patients younger than 50 years of age, the presenting symptoms are varied and sometimes subtle, and the neurologic damage may be irreversible despite therapy. As would be expected, the dose of folic acid their patient received (350 μg per day) did not complicate the diagnosis by correcting the anemia.

Dr. Kirby seems to have missed my main point. We know that higher levels of fortification will mean that more women will reach the target intake of 400 μg per day; we do not know whether higher levels of fortification are safe for everyone who is exposed to the additional folic acid. The Food and Drug Administration (FDA) came down firmly on the side of safety. It selected 140 μg per 100 g of grain products as the fortification level precisely because at that level, almost no one would be exposed to total folate levels of more than 1 mg per day — levels at which data on safety are lacking.3 If the true fortification level is 140 μg per 100 g of grain products, the risk that children will exceed the upper intake level recommended by the Institute of Medicine2 will be modest. The United Kingdom panel recommended fortification at a level of 240 μg per 100 g of grain products despite evidence4 that 1 percent of all adults over the age of 50 years (including 2.2 percent of men 50 to 64 years of age) would exceed the total folate limit of 1 mg per day that the FDA considers safe. I, like the FDA, prefer to err on the side of conservatism until higher doses are proved safe.

James L. Mills, M.D.
National Institute of Child Health and Human Development, Bethesda, MD 20892-7510

4 References

1. 1

   Rader JI, Weaver CM, Angyal G. Total folate in enriched cereal-grain products in the United States following fortification. Food Chem 2000;70:275-289
   CrossRef | Web of Science

2. 2

   Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline: a report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients. Washington, D.C.: National Academy Press, 1998. (See http://www.nap.edu/openbook/0309065542/html.)
   

3. 3

   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
   

4. 4

   Folic acid and the prevention of disease: report of the committee on medical aspects of food and nutrition policy. Report on health and social subjects: 50. London: Her Majesty's Stationery Office, 2000.
   

Citing Articles (19)

Citing Articles

1. 1

   Samanthi Abeywardana, Carol Bower, Jane Halliday, Annabelle Chan, Elizabeth A. Sullivan. (2010) Prevalence of neural tube defects in Australia prior to mandatory fortification of bread-making flour with folic acid. Australian and New Zealand Journal of Public Health 34:4, 351-355
   CrossRef

2. 2

   Robert Berry, Joseph Mulinare, Heather Hamner. 2009. Folic Acid Fortification. , 179-204.
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3. 3

   Caron Molster, Carol Bower, Peter O'Leary. (2007) Australian survey on community knowledge and attitudes regarding the fortification of food with folic acid. Birth Defects Research Part A: Clinical and Molecular Teratology 79:9, 664-670
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4. 4

   Indu B. Ahluwalia, Jean M. Lawrence, Lina Balluz. (2006) Psychosocial Factors Associated With Use Of Multivitamins By Women Of Childbearing Age. Journal of Community Health 32:1, 57-69
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5. 5

   Lorenzo D. Botto, Alessandra Lisi, Carol Bower, Mark A. Canfield, Nirupa Dattani, Catherine De Vigan, Hermien De Walle, David J. Erickson, Jane Halliday, Lorentz M. Irgens, R. Brian Lowry, Robert McDonnell, Julia Metneki, Simone Poetzsch, Annukka Ritvanen, Elisabeth Robert-Gnansia, Csaba Siffel, Claude Stoll, Pierpaolo Mastroiacovo. (2006) Trends of selected malformations in relation to folic acid recommendations and fortification: An international assessment. Birth Defects Research Part A: Clinical and Molecular Teratology 76:10, 693-705
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6. 6

   Carol Bower. (2006) Primary prevention of neural tube defects with folate in Western Australia: the value of the Western Australian Birth Defects Registry. Congenital Anomalies 46:2, 118-121
   CrossRef

7. 7

   Jean M. Lawrence, Margaret L. Watkins, Vicki Chiu, J. David Erickson, Diana B. Petitti. (2006) Do racial and ethnic differences in serum folate values exist after food fortification with folic acid?. American Journal of Obstetrics and Gynecology 194:2, 520-526
   CrossRef

8. 8

   K de Meer, Y M Smulders, J R Dainty, D E C Smith, R M Kok, C D A Stehouwer, P M Finglas, C Jakobs. (2005) [6S]5-methyltetrahydrofolate or folic acid supplementation and absorption and initial elimination of folate in young and middle-aged adults. European Journal of Clinical Nutrition 59:12, 1409-1416
   CrossRef

9. 9

   Jean M. Lawrence, Margaret L. Watkins, Vicki Chiu, J. David Erickson, Diana B. Petitti. (2004) Food fortification with folic acid and rate of multiple births, 1994-2000. Birth Defects Research Part A: Clinical and Molecular Teratology 70:12, 948-952
   CrossRef

10. 10

    Carol Bower, Fiona J. Stanley. (2004) Case for mandatory fortification of food with folate in Australia, for the prevention of neural tube defects. Birth Defects Research Part A: Clinical and Molecular Teratology 70:11, 842-843
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11. 11

    Elizabeth A Yetley, Jeanne I. Rader. (2004) Modeling the Level of Fortification and Post-Fortification Assessments: U.S. Experience. Nutrition Reviews 62, S50-S59
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12. 12

    James M Shikany, Douglas C Heimburger, Chandrika J Piyathilake, Renee A Desmond, Paul G Greene. (2004) Effect of folic acid fortification of foods on folate intake in female smokers with cervical dysplasia. Nutrition 20:5, 409-414
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13. 13

    Kelley Scanlon, Lisa Bodnar, Mary Cogswell. 2003. Nutritional Anemias. , 213-242.
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14. 14

    Lynn L. Moore, M. Loring Bradlee, Martha R. Singer, Kenneth J. Rothman, Aubrey Milunsky. (2003) Folate Intake and the Risk of Neural Tube Defects: An Estimation of Dose-Response. Epidemiology 14:2, 200-205
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15. 15

    Caterina Canavese, Daniela Bergamo, Giulio Mengozzi, Giuseppe Aimo, Luisa Sandri, Antonio Marciello. (2003) The statement that folate supraphysiological levels in uremic patients do not cause harm should not go unchallenged. Kidney International 63:2, 771-771
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16. 16

    H.E.K. De Walle, L.T.W. De Jong-Van Den Berg. (2002) Insufficient folic acid intake in the Netherlands: What about the future?. Teratology 66:1, 40-43
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17. 17

    Lyndsey F. Watson, Maxwell J. Watson, Jane L. Halliday, Robin J. Bell. (2002) Consequences of surveying folate awareness. Health Expectations 5:1, 38-46
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18. 18

    Maxwell Watson, Lyndsey Watson, Robin Bell, Jane Halliday. (2001) The increasing knowledge of the role of periconceptional folate in Victorian women of child-bearing age: follow-up of a randomised community intervention trial. Australian and New Zealand Journal of Public Health 25:5, 389-395
    CrossRef

19. 19

    T. J. Owen, J. L. Halliday, C. A. Stone. (2000) Neural tube defects in Victoria, Australia: potential contributing factors and public health implications. Australian and New Zealand Journal of Public Health 24:6, 584-589
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