Correspondence

Folate Supplementation in Sickle Cell Anemia

N Engl J Med 2003; 349:813August 21, 2003

Article

To the Editor:

The case report by Dhar et al. (May 29 issue)1 serves as a useful reminder that patients for whom high-dose folic acid is prescribed should have their vitamin B₁₂ status checked periodically. However, the report errs in two ways.

First, it recommends that routine folate supplementation be discontinued in patients with sickle cell disease because of its unproven clinical benefit. Instead, what needs to be proved is that the lack of supplementation is innocuous. Dietary folate intake is often borderline, and intake is commonly further diminished in persons with chronic diseases. The folate requirement in patients with hemolytic anemia is known to be higher than normal. Until there is proof to the contrary, patients in this situation may be presumed to require supplemental folate.

Second, by failing to specify the dose of folic acid that their patient received, the authors leave the impression that any folic acid supplementation can conceal the hematologic signs of vitamin B₁₂ deficiency. Their patient's serum folate level was off the scale, suggesting that she was probably ingesting 5 mg per day. Yet a dose of 1 mg per day will probably prevent folic acid deficiency in this setting and has never been reported to mask vitamin B₁₂ deficiency.

L. John Hoffer, M.D., Ph.D.
McGill University, Montreal, QC H3T 1E2, Canada

1 References

1. 1

   Dhar M, Bellevue R, Carmel R. Pernicious anemia with neuropsychiatric dysfunction in a patient with sickle cell anemia treated with folate supplementation. N Engl J Med 2003;348:2204-2207
   Full Text | Web of Science | Medline

Author/Editor Response

The burden of proof concerning the efficacy and innocuousness of folate supplementation in patients with sickle cell disease rests on the advocates of this treatment, because the clinical benefits of routine folate supplementation in sickle cell disease have never been proved and are unsupported by the only prospective, randomized study of the subject.1 Others2 besides us have questioned routine supplementation. A dispassionate reassessment is overdue.

Second, our patient used only 1 mg or occasionally 1.4 mg of folic acid, not 5 mg. Taken regularly, either of these doses can raise folate levels above 20 μg per liter. Furthermore, even 1 mg or less sometimes masks the anemia of cobalamin deficiency.3,4 No known dose of folate can be considered to be safe indefinitely in patients with a cobalamin deficiency.3 Incidentally, our patient's anemia was overlooked rather than masked; blunting of anemia is often variable and transient at any dose.3

Ralph Carmel, M.D.
New York Methodist Hospital, Brooklyn, NY 11215
rac9001@nyp.org

4 References

1. 1

   Rabb LM, Grandison Y, Mason K, Hayes RJ, Serjeant B, Serjeant GR. A trial of folate supplementation in children with homozygous sickle cell disease. Br J Haematol 1983;54:589-594
   CrossRef | Web of Science | Medline

2. 2

   Wang WC. Role of nutritional supplement in sickle cell disease. J Pediatr Hematol Oncol 1999;21:176-178
   CrossRef | Web of Science | Medline

3. 3

   Chanarin I. The megaloblastic anaemias. 2nd ed. Oxford, England: Blackwell Scientific, 1979:293-5.
   

4. 4

   Rothenberg SP. Increasing the dietary intake of folate: pros and cons. Semin Hematol 1999;36:65-74
   Web of Science | Medline