Valproate poses by far the greatest teratogenic risk of all the commonly prescribed antiepileptic drugs, according to Dr. Kimford J. Meador of the University of Florida, Gainesville, and his associates in the Neurodevelopmental Effects of Antiepileptic Drugs Study Group.
“We advise that [valproate] not be used as the AED of first choice for women of childbearing potential, and, when used, its dose should be limited, if possible,” the group wrote (Neurology 2006;67:407–12).
Current guidelines from the American Academy of Neurology advise a variety of ways to minimize the risk of teratogenicity with AEDs, including use of monotherapy if possible, use of the lowest effective dose, supplementation with folate, and treatment of the infant with vitamin K at birth (Neurology 1998;51:944–8). However, no current recommendation addresses the differential teratogenetic risk associated with individual AEDs, Dr. Meador and his associates noted.
The data come from an ongoing prospective observational study of mother/child pairs across 25 epilepsy centers in the United States and United Kingdom. A total of 323 mothers and 333 children were available for analysis. Mean gestational ages at the time of enrollment were 17 weeks for the 69 infants exposed to valproate, 18 weeks for the 98 lamotrigine-exposed infants, and 19 weeks for both the 110 whose mothers who used carbamazepine and for the 56 infants exposed to phenytoin. Mean age of the children at the time of analysis ranged from 2.7 years with lamotrigine to 3.5 years for valproate and carbamazepine.
Major congenital malformation or fetal death occurred in 20.3% with valproate, 10.7% with phenytoin, 8.2% carbamazepine, and 1.02% with lamotrigine. Not only was the valproate risk approximately twice that of the other AEDs, but valproate was the only one to show a dose-response relationship: The mean valproate dose for the pregnancies with serious adverse fetal outcomes was 1,268 mg/day compared with just 844 mg/day for those without serious adverse outcomes.
The differences in risk between the AEDs were accounted for by congenital malformation rather than death. Indeed, death rates were actually slightly higher for both carbamazepine and phenytoin (3.6%) than for valproate (2.9%). There were no deaths with lamotrigine. Congenital malformations, on the other hand, occurred in 17.4% with valproate compared with 7.1% with phenytoin, 4.5% carbamazepine, and 1.0% lamotrigine.
Clinicians are urged to encourage their pregnant patients on AEDs to join one of the pregnancy registries around the world that are seeking additional information on AED risk for anatomic teratogenesis. The North American Pregnancy Registry has a toll-free number, 1-888-AED-AED4. The EURAP registry, covering Europe and elsewhere, is online at www.eurapinternational.org