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Valproate: A New Cause of Birth Defects -- Report from Italy and Follow-Up from France

Studies by the Indagine Policentrica Italiana sulle Malformazioni Congenite (IPIMC) in 1980-1982 found a significant association between valproic-acid exposure during the first trimester of pregnancy and spina bifida (Table 2). Among 118 infants with spina bifida, two (1.7%) were exposed to valproic acid; in the group with other malformations, three (0.1%) of 4,489 were exposed.

Further data from France on the association between spina bifida aperta among infants with birth defects and valproic-acid use during the first trimester update the preliminary report from Lyon (Tables 3 and 4) (1). An infant with spina bifida, who had intrauterine exposure to valproic acid, has been added, and an infant with spina bifida, whose mother had not been recognized as having epilepsy, has been properly classified. These data represent the cumulative experience during 1976 and from 1978 to December 1982. Reported by Bolletino Epidemiologica Nazionale (November 25, 1982); E Robert, MD, Institut Europeen des Genomutations, Lyon, France; Birth Defects Br, Chronic Diseases Div, Center for Environmental Health, CDC.

Editorial Note

Editorial Note: In addition to these new data from Italy and France, a United Kingdom researcher has reported that, of infants born to 196 pregnant women treated with valproic acid, 157 (80%) were normal and nine (5%) had spina bifida (2). The remaining 30 infants had other structural defects, including cardiovascular defects, orofacial clefts, and digital abnormalities. Since most of the pregnancies were reported either to the U.K. researcher or to a drug company and since normal pregnancies would tend not to be reported, there is probably some bias in the direction of reporting abnormal pregnancies. Given that these data were collected before the report from France and that spina bifida accounted for 23% (9/39) of the reported abnormalities, the 10-fold excess reported from the United Kingdom is probably not due entirely to reporting bias.

With these new data, valproic acid and sodium valproate should be considered human teratogens. CDC has estimated that a pregnant woman in the United States treated with these drugs would have a 1%-2% risk of having a child with spina bifida.* Since this risk is similar to the risk of spina bifida recurrence in subsequent pregnancies, women exposed in the first trimester should consult their physicians about further prenatal counseling. A pregnant woman undergoing treatment for epilepsy should not change her drug therapy without first consulting her physician.

Little is known about the relationship between valproic acid and other birth defects. To better define the risk of such therapy, CDC is assembling a registry of women taking valproic acid during pregnancy. Physicians caring for such women are urged to report these pregnancies to the CDC registry as soon as possible by calling (404) 452-4035 on weekdays between 8 a.m. and 4:30 p.m., Eastern time, or by writing the Birth Defects Branch, Chronic Diseases Division, Center for Environmental Health, Centers for Disease Control, Atlanta, Georgia 30333.

References

  1. CDC. Valproic acid and spina bifida: a preliminary report--France. MMWR 1982;31:565-6.

  2. Jeavons PM. Sodium valproate and neural-tube defects (letter). Lancet 1982;2:1282-3.

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