The most common teratogenic effects have been cleft lip and cleft palate, but infrequently also a subtle facial dysmorphism (“fetal anticonvulsant syndrome”), similar to the fetal alcohol syndrome. In general, the risk of major congenital defects is low; it increases to 4 to 5 percent in women taking antiepileptic drugs during pregnancy, in comparison to 2 to 3 percent in the overall population of pregnant women. These statistics have been essentially confirmed in the large study by Holmes and colleagues, conducted among several Boston hospitals. When all types of malformations were included, both major and minor, 20 percent of infants born to mothers who took antiepileptics during pregnancy showed abnormalities, compared to 9 percent of mothers who had not taken medications. These authors identified “midface hypoplasia” (shortened nose, philtrum, or inner canthal distance) and finger hypoplasia as characteristic of anticonvulsant exposure; these changes were found in 13 and 8 percent of exposed infants, respectively. However, it should be emphasized that in large surveys, major malformations have occurred in only 5 percent of infants exposed to antiepileptic drugs. The infants born of a group of women with epilepsy who had not taken anticonvulsants during pregnancy showed an overall rate of dysmorphic features comparable to that in control infants, but there was still a 2 to 3 percent rate of facial and finger hypoplasia. This risk is shared more or less equally by all the major antiepileptics again, with valproate associated with a higher rate. Aggregating eight databases, Jetnik and colleagues found a number of malformations of the nervous and somatic systems to be increased in comparison to other antiepileptic drugs.
Of equal or greater concern has been the findings by Meador and colleagues that in utero exposure to valproate was associated with lower IQs (by 9 points) compared to lamotrigine in children at the age of 4. It is not clear if the effect persists after this age. Children who had been exposed to phenytoin or to carbamazepine also had slightly lower IQs but this difference was ostensibly accounted for by lower maternal IQ. Some studies, including the one by Meador and colleagues suggest that folate may have an ameliorating effect on this detrimental effect at age 3, whereas there is an uncertain benefit of folate in preventing fetal malformations due to the drugs.
The risk of neural tube defects is also slightly increased by anticonvulsants during pregnancy, and greatest for the use of valproate. It had been considered to be reduced by giving folate before pregnancy has begun (it is not clear if this is true for valproate), but epilepsy experts avoid the use of valproate during pregnancy altogether. These risks are greater in women taking more than one anticonvulsant, so that monotherapy is a desirable goal. Furthermore, the risk is disproportionately increased in families with a history of these defects. Some of the newer anticonvulsants should probably be used cautiously until greater experience has been obtained. As each new drug has been introduced over the years, there has usually been a tentative claim of reduced teratogenic effects, often proven later to be incorrect. Claims have been made of safety in this regard for lamotrigine, causing many specialists to change from the more conventional drugs to this one in women who anticipate becoming pregnant, but lamotrigine levels tend to fall precipitously during pregnancy. A report by Cunnington and colleagues using registry information suggests that the incidence of major birth defects in the fetuses exposed to lamotrigine during the first trimester is just under 3 percent, similar to risk estimates for the general population but also close to the 3 to 4 percent risk derived from most registries of women on anticonvulsants. Polytherapy with lamotrigine and valproate raised the estimate of risk to 12 percent. For all the drugs, polytherapy has the highest risk and there is a significant dose effect for an individual drug on the likelihood of fetal malformation.