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. 2002 Apr 13;324(7342):918.

Fortification of flour with folic acid

Fortification has several potential risks

Edward Reynolds 1
PMCID: PMC1122855  PMID: 11950755

Editor—Wharton and Booth recommend caution and carrying out a field trial before a policy of fortifying flour with folic acid is implemented, but both they and the Department of Health's report understate the potential risks of the policy to the nervous system.1

In people with vitamin B-12 deficiency, giving folic acid does much more than mask any anaemia. The response of pernicious anaemia to folic acid is usually suboptimal and temporary and often followed by relapse. The vitamin precipitates not only neurological complications, sometimes after some initial temporary improvement, but also anaemia, although not necessarily to the same degree or in the same time scale.2,3

Can these problems with usually pharmacological doses of folic acid (1-50 mg daily) be avoided with minimum food fortification? The only evidence I know of is a review of 38 patients with vitamin B-12 deficiency treated with ⩽1 mg folic acid, 30% of whom showed a significant haematological response. None of 25 patients treated for 7-19 days developed nervous system disorder, whereas six of 12 treated for 90-930 days did. Isolated examples of a reticulocyte response and neurological deterioration occurred with doses as low as 0.3-0.5 mg daily.4 Because of the very active blood-brain barrier for folate the vitamin enters the nervous system slowly and the duration of treatment is just as important as the dose, which is highly relevant to food fortification.3,5

Folic acid does much more than interfere with the metabolism of antiepileptic drugs. Experimental studies have confirmed that folates are highly convulsant if the blood-brain barrier is circumvented. The risk to patients is small because of the barrier mechanism, but the bigger the dose, the longer the duration, and the greater the damage to the blood-brain barrier then the higher the risk.

I do not agree that the benefits of fortification are clear. They may be relatively clear with respect to the prevention of neural tube defects, but not all such defects are preventable with folic acid. The Department of Health's report estimates that fortification with 240 μg folic acid/100 g flour would prevent a further 74 cases (41%) in the United Kingdom. Given the potential risks to others, the policy of universal food fortification seems disproportionate.

Other, potentially much greater benefits of food fortification exist (including in vascular disease and to mental health), which have yet to be clarified. The possible benefits for mood, cognitive function, and ageing are considerable but have not been evaluated.3,5

For all these reasons field trials are advisable before the whole population is exposed to a prolonged increase in folate intake.

References

  • 1.Wharton B, Booth I. Fortification of flour with folic acid. BMJ. 2001;323:1198–1199. doi: 10.1136/bmj.323.7323.1198. . (24 November.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Will JJ, Mueller JF, Brodine C, Kiely CE, Freidman B, Hawkins VR, et al. Folic acid and vitamin B12 in pernicious anaemia. Studies on patients treated with these substances over a ten year period. J Lab Clin Med. 1959;53:22–38. [PubMed] [Google Scholar]
  • 3.Reynolds EH. Neurological aspects of folate and vitamin B12 metabolism. In: Hoffbrand AV, editor. Clinics in haematology, 5. London: Saunders; 1976. pp. 661–696. [PubMed] [Google Scholar]
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BMJ. 2002 Apr 13;324(7342):918.

Fortification is needed now

Mark Sillender 1

Editor—Wharton and Booth raised several points about the safety of fortifying food with folic acid to prevent neural tube defects.1-1 In my opinion, the negative effects of food fortification are overstated.

The risk of folate masking B-12 deficiency leading to spinal cord degeneration is probably low.1-2 It is well known that neuropathies due to B-12 or folate deficiency can occur without megaloblastic anaemia. Surely an increase in cord degeneration would have been seen by now in the United States, where food has been fortified since 1998. Even if it was increased, this risk could be abrogated by food fortification with vitamin B-12 in addition to folate.1-3

Interference with antiepileptic drugs is unlikely to occur at the levels of fortification proposed. As the risk of fetal abnormality is increased in people with epilepsy who are taking drugs, especially in those taking sodium valproate, folate supplementation in this group is even more important.

Although it is mentioned in the editorial, not enough weight is given to the effect of folic acid in reducing plasma homocysteine concentration, an emerging risk factor for atherosclerosis. Many case-control studies show that patients with high homocysteine concentrations are at increased risk from ischaemic heart disease and stroke, probably because of direct vascular endothelial damage.1-4 The potential positive effects of folate on the vascular endothelium have been shown in recent short term randomised controlled trials in high risk groups.1-5

More extensive trials are ongoing, but they will probably show a magnitude of benefit similar to that estimated by case-control studies. As 10-20% of the population have high homocysteine concentrations, and this proportion increases with age, the potential health improvements are large and are likely to much outweigh the theoretical negative effects mentioned in the editorial.

A controlled trial of folate fortification, as suggested, would have to be conducted over an extended period to show the positive and negative effects adequately. During this time, preventable morbidity and death from atherosclerotic disease would be likely and many women would have unnecessary second trimester terminations. Folic acid fortification should be started as soon as possible.

References

  • 1-1.Wharton B, Booth I. Fortification of flour with folic acid. BMJ. 2001;323:1198–1199. doi: 10.1136/bmj.323.7323.1198. . (24 November.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Dickenson J. Does folic acid harm people with vitamin deficiency? A critical examination of the evidence, relevant to fortification of cereal grain. Q J Med. 1995;88:357–364. [PubMed] [Google Scholar]
  • 1-3.Oakley GP, Adams M, Dickenson CM. More folic acid for everyone, now. J Nutr. 1996;126:751–75S. doi: 10.1093/jn/126.suppl_3.751S. [DOI] [PubMed] [Google Scholar]
  • 1-4.Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, et al. Plasma homocysteine as a risk factor for vascular disease. The European concerted action project. JAMA. 1997;277:1775–1781. doi: 10.1001/jama.1997.03540460039030. [DOI] [PubMed] [Google Scholar]
  • 1-5.Vermeulen EG, Stehouwer CD, Twisk JW, van den Berg M, de Jong SC, Mackaay AJ, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet. 2000;355:517–522. doi: 10.1016/s0140-6736(99)07391-2. [DOI] [PubMed] [Google Scholar]

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