Correspondence

Vitamins to Prevent Neural-Tube Defects

N Engl J Med 1993; 328:1641-1642June 3, 1993

Article

To the Editor:

The vitamin supplement used in the study by Czeizel and Dudas of the prevention of first occurrences of neural-tube defects (Dec. 24 issue)1 contained calcium pantothenate. Pantothenate supplementation may be particularly important for women receiving valproic acid in the first trimester of pregnancy for the control of epileptic seizures refractory to other anticonvulsant drugs. The Centers for Disease Control and Prevention estimated that the risk of having a fetus with spina bifida in these women is 1.2 percent,2 almost 30 times the incidence in the general population. The explanation for this adverse association may lie in the fact that in developing and adult animals,3,4 valproic acid causes a profound reduction in hepatic levels of free coenzyme A, an end product of pantothenic acid metabolism. Coenzyme A serves as substrate or cofactor for numerous enzymatic reactions involved in fatty-acid oxidation, fatty-acid synthesis, citric acid cycle oxidation, and acetylation reactions. In addition, pantothenic acid itself is a prosthetic group for acyl carrier protein, which is involved in fatty-acid synthesis.

Exencephaly is highly characteristic of fetuses of rats deficient in pantothenic acid5. Therefore, periconceptional supplementation of this essential vitamin in humans might have an additional protective effect against neural-tube defects.

Jean Holowach Thurston, M.D.
Richard E. Hauhart, M.S.
Washington University School of Medicine at St. Louis Children's Hospital, St. Louis, MO 63110

5 References

1. 1

   Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-1835
   Full Text | Web of Science | Medline

2. 2

   Valproic acid and spina bifida: a preliminary report -- FranceMMWR Morb Mortal Wkly Rep 1982;31:565-566
   Medline

3. 3

   Thurston JH, Carroll JE, Hauhart RE, Schiro JA. A single therapeutic dose of valproate affects liver carbohydrate, fat, adenylate, amino acid, coenzyme A, and carnitine metabolism in infant mice: possible clinical significance. Life Sci 1985;36:1643-1651
   CrossRef | Web of Science | Medline

4. 4

   Becker C-M, Harris RA. Influence of valproic acid on hepatic carbohydrate and lipid metabolism. Arch Biochem Biophys 1983;223:381-392
   CrossRef | Web of Science | Medline

5. 5

   Lefebvres-Boisselot J. Role teratogene de la deficience en acide pantothenique chez le rat. Ann Med 1951;52:225-298
   

To the Editor:

Trimethoprim and sulfamethoxazole are known to act synergistically to inhibit bacterial synthesis of tetrahydrofolic acid, and increased toxicity of these drugs in folate-deficient patients has been reported. It would be most interesting to know whether any of the women who had babies with neural defects had ingested drugs that may have inhibited tetrahydrofolic acid synthesis.

Stephen M. Golden, M.D.
State University of New York at Buffalo, Buffalo, NY 14222

Author/Editor Response

The authors reply:

To the Editor: In response to Dr. Thurston and Mr. Hauhart, we cannot be sure that the preventive effect was due to folic acid alone or in association with the other components of the multivitamin. Folic acid, vitamin B₆, vitamin B₁₂, vitamin C, and zinc interact with one another in many metabolic pathways; thus, folic acid may have a synergistic effect with other vitamins. It is also possible that pantothenic acid (vitamin B₅) has some protective effect against neural-tube defects. In the Medical Research Council Vitamin Study, the recurrence of neural-tube defects was lower, although not significantly so, after supplementation with “other vitamins” (but no folic acid) (8 of 302 women, 2.6 percent) than after the use of “no folic acid and no other vitamins” (13 of 300, 4.3 percent)1. However, “other vitamins” did not include vitamin B₅.

Dr. Golden raises an important issue about the pathogenesis of neural-tube defects. The mothers of the six fetuses with neural-tube defects in our study had not ingested trimethoprim or sulfamethoxazole. The data base of the Hungarian Case-Control Surveillance of Congenital Anomalies (1980-1984)2 showed that of 534 mothers who had offspring with neural-tube defects, 8 (1.5 percent) were treated with co-trimoxazole (trimethoprim-sulfamethoxazole), as compared with 124 (1.25 percent) of 9893 control mothers who had healthy babies. McNemar analysis of 348 subjects with neural-tube defects and 348 healthy controls matched for age, sex, and residence showed an odds ratio of 2.0 for trimethoprim-sulfamethoxazole use (95 percent confidence interval, 0.43 to 13.29; P>0.75).

Andrew E. Czeizel, M.D.
Istvan Dudas, M.D.
National Institute of Hygiene, 1097 Budapest, Gyali u. 2-6, Hungary

2 References

1. 1

   MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-137
   CrossRef | Web of Science | Medline

2. 2

   Czeizel A. A case-control analysis of the teratogenic effects of co-trimoxazole. Reprod Toxicol 1990;4:305-313
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Kathryn Bauerly, Robert Rucker. 2007. Pantothenic Acid. .
   CrossRef

2. 2

   Paddy Jim Baggot, Jeremy A. Kalamarides, James D. Shoemaker. (1999) Valproate-Induced Biochemical Abnormalities in Pregnancy Corrected by Vitamins: A Case Report. Epilepsia 40:4, 512-515
   CrossRef

3. 3

   Tetsuji NAGAO, Mariko SHIROTA, Masako SATO. (1996) Carnitine and Coenzyme A Decrease Valproic Acid-Induced Neural Tube Defects in Mice. Congenital Anomalies 36:2, 65-74
   CrossRef

4. 4

   Masako Sato, Mariko Shirota, Tetsuji Nagao. (1995) Pantothenic acid decreases valproic acid-induced neural tube defects in mice (I). Teratology 52:3, 143-148
   CrossRef