Prevention of neural tube defects The neural tube defects, which include anencephaly and spina bifida, are common and well-known birth defects. In several recent studies, 1-3 the issue of the prevention of these malformations has been debated. Most pediatricians probably did not see the published letters to the editor in which were presented the reasons that each study did not confirm the prevention of these malformations by perinatal supple, mentation with vitamins. The report of the Medical Research Council Vitamin Study Research Group, published in July 1991, 4 was widely regarded as having presented convincing proof that perinatal vitamin supplementation works. The report by Mills et al., in this issue of THE JOURNAL, shows us that prevention is not so simple. This should not be a surprise, because the Medical Research Council study actually showed a reduction in the recurrence risk from 3.5% for pregnancies of the women who were not given supplements to 1% for those given supplements. Seeing this significant reduction in the rate of recurrence, one would postulate logically that many NTDs were prevented because added amounts of folic acid ingested by the mother prevented the occurrence of these fetal abnormalities. Mills and his associates tested one aspect of this hypothesis by asking whether the occurrence of anencephaly or spina bifida was associated with a decreased maternal serum level of vitamins and folate. They found no evidence of this in the samples obtained, There are several potential explanations. First, the serum samples might not have been obtained early enough in pregnancy, that is, before the occurrence of the NTD in the fourth week after conception. Second, the maternal serum level might not be a good marker of vitamin deficiencies that "cause" spina bifida. This explanation was also suggested by the observation of Holzgreve et al. 5 that erythrocytic folate levels in blood from fetuses with NTDs between 16 and 22 weeks o f gestational age were normal. Third, the women studied might not have been a group at risk for having infants with vitamin-responsive anencephaly or spina bifida. The last explanation seems to be most relevant, because Finland is an area with a low prevalence of anencephaly and spina bifida. This could mean that the occurrence of spina bifida and anencephaly in this Finnish population is like that in the affected infants born to the women given vitamin supplements in the Medical Research Council trial; that is, these NTDs would not
have been prevented by adding more folic acid to the microenvironment of the embryo. The findings reemphasize the fact that there are many causes of NTDs, only some of which may be responsive to vitamins and folate. Previous clinical studies have suggested etiologic hererogeneity for spina bifida; families with several affected individuals have had patterns suggestive of dominant inheritance 6 in some and X-linked inheritance 7 in others. The level of the lesion has been implicated as an indicator of the cause; some 8 (but not all 9) studies have suggested that high lesions are more likely to recur in siblings than are low lumbosacral lesions. Several mutant genes in See related article, p. 863.
Neural tube defect
the mouse have been shown to cause anencephaly or spina bifida.l~ One of these mouse mutants, the curly-tail mouse, has been shown to have an interrelationship with vitamin A: maternal intake early in pregnancy is associated with a decreased rate of occurrence of NTDs. Perhaps some of the mouse's mutant genes that cause anencephaly and spina bifida are responsive to folic acid and some are not, as in human beings. What, then, do we recommend to parents who have had a child with anencephaly or spina bifida? For the rare couples who plan pregnancies successfully, we can recommend, as does the Centers for Disease Control, 11 that the woman take 4 mg of folic acid a day for 2 months before and after conception. Because most pregnancies are not planned, we recommend that the woman who has had one affected child, and who is in the childbearing age group, continue to take a daily vitamin preparation that contains 0.4 mg folic acid per tablet, an amount present in many commercial brands. However, the report by Mills et al. reminds us to tell these parents that periconceptional vitamin supplementation is unlikely to prevent all recurrences of NTDs.
Lewis B. Holmes, MD Massachusetts General Hospital Boston, MA 02114-2696 REFERENCES
1. Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260:3141-5. 2. Mills JL, Rhoads GG, Simpson JL, et al. The absence of a re-
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lation between the periconceptionat use of vitamins and neural tube defects. N Engl J Med 1989;321:430-5. Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989;262:2847-52. MRC Vitamin Study Research Group: Prevention of neural tube defects: results of the Medical Research Council on Vitamin Study. Lancet 1991;338:131-7. Holzgreve W, Tercanli S, Pietrzik K. Vitamins to prevent neural tube defects. Lancet 1991;2:639-40. Fineman RM, Jorde LB, Martin RA, Hasstedt SJ, Wing SD, Walker ML. Spinal dysraphia as an autosomal dominant defect in four families. Am J Med Genet 1982;12:457-64. Jensson O, Arnason A, Gunnarsdotter H, Petursdottir I, Fossdal R, Hreidarsson S. A family showing apparent X-linked
inheritance of both anencephaly and spina bifida. J Med Genet 1988;25:227-9. Hall JG, Friedman JM, Kenna BA, Popkin J, Jawanda M, Arnold W. Clinical, genetic and epidemiological factors in neural tube defects. Am J Hum Genet 1988;43:827-37. Frecker MF, Fraser FC, Heneghan WD. Are "upper" and "lower" neural tube defects actiologically different? J Med Genet 1988;25:503-4. Copp A J, Brook FA, Estiberio JP, Shum ASW, Cockroft DL. The embryonic development of mammalian neural tube defects. Prog Neurobiol 1990;35:363-403. Centers for Disease Control. Use of folic acid for prevention of spina bifida and other neural tube defects--1983-1991. MMWR 1991;40:513-6.
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