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International Notes Valproic Acid and Spina Bifida: A Preliminary Report -- France

Valproic acid use during the first trimester of pregnancy has been reported among an unusually high proportion of mothers of infants with spina bifida. During 1976 and from 1978 through September 1982, the birth defects surveillance system at the Institut Europeen des Genomutations in Lyon, France, ascertained 146 cases of spina bifida aperta. Among these cases, nine (6.2%) of the mothers had epilepsy and had taken valproic acid during the first trimester at dosages between 400 mg and 2,000 mg per day. Five of the nine patients with spina bifida were exposed to valproic acid alone, and four were exposed to additional anticonvulsants. Twenty-one (0.32%) of the mothers of the 6,616 infants in the surveillance system with other malformations had taken the drug (Table 1). These data show a highly statistically significant odds ratio of 20.6.* To isolate the effect of valproic acid from the possible effects of seizure disorders and other drug therapy, the analysis was then confined to the 71 epileptic mothers. Nine (90%) of the 10 such mothers of spina bifida infants had taken valproic acid, compared with 21 (34.4%) of the 61 mothers of infants with other defects (Table 2). The odds ratio of 17.1 is statistically significant. Reported by E Robert, MD, Institut Europeen des Genomutations, Lyon, France; Epidemiology Development Br, Div of Drug Experience, Food and Drug Administration; Birth Defects Br, Chronic Diseases Div, Center for Environmental Health, CDC. *The odds ratio is an estimation of relative risk in case-control studies.

Editorial Note

Editorial Note: A woman who requires treatment for epilepsy during pregnancy is at increased risk of having a baby with a birth defect. The American Academy of Pediatrics Committee on Drugs offers the following recommendation on alerting women to the risk: "When a woman who has epilepsy and requires medication asks about pregnancy, she should be advised that she has a 90% chance of having a normal child, but that the risk of congenital malformations and mental retardation is two to three times greater than average because of her disease or its treatment" (1). The new data from Lyon do not change this general advice.

While the Lyon data suggest that valproic acid taken during the first trimester of pregnancy is associated with spina bifida, other anticonvulsants (phenytoin and trimethadione) have also been associated with increased risk of specific congenital defects (2,3). Selection of therapy for a seizure patient who may become pregnant is a complex decision and requires careful consideration of the clinical situation. All anticonvulsants, including valproic acid, carry a warning of potential human teratogenicity in their labeling.

It has been estimated that, in the United States, 700-1,000 pregnant women take valproic acid each year. Given the United States' spina bifida rate of approximately six per 10,000 births (4) and a relative risk of 20.6 (as indicated by the French data), the estimated risk of valproic acid-exposed women having children with spina bifida is approximately 1.2%. This risk is similar to that for women who have had previous children with neural-tube defects (anencephaly or spina bifida). The United States has prenatal counseling centers for women at increased risk of having children with spina bifida. Women who may be exposed to valproic acid during pregnancy should contact their physicians for further counseling.

A registry of women currently taking valproic acid during pregnancy is being established in order to better define the risk of such therapy. Physicians of women who are taking valproic acid during pregnancy are urged to report to this registry as soon as possible by calling (404) 452-4080 on weekdays between 8:00 a.m. and 4:30 p.m., Eastern time, or by writing Birth Defects Branch, Center for Environmental Health, Centers for Disease Control, Atlanta, Georgia 30333.


  1. American Academy of Pediatrics Committee on Drugs. Anticonvulsants and pregnancy. Pediatrics 1979;63:331-3.

  2. Hanson JW, Myrianthopoulos NC, Harvey MA, Smith DW. Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 1976;89:662-8.

  3. Zackai EH, Mellman WJ, Neiderer B, Hanson JW. The fetal trimethadione syndrome. J Pediatr 1975;87:280-4.

  4. CDC. Congenital malformations surveillance, January-December 1980. Atlanta: CDC, February 1982:8.

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