In utero exposure to valproate was associated with poorer cognitive outcomes than was exposure to other commonly used antiepileptic drugs. The effect of valproate was dose dependent. As in previous population studies,9
maternal IQ was strongly related to child IQ except for mothers who took valproate during pregnancy, a result suggesting that valproate disrupted this normally robust relationship.
The strengths of our study include its prospective design, blinded cognitive assessments with the use of standardized measures, and detailed monitoring of multiple potential confounding factors. Its limitations include its relatively small sample, lack of randomization, and lack of a control group of unexposed children. The relatively young age of the children at this planned interim analysis is an additional limitation, and we plan to obtain more detailed assessments of the children at the age of 6 years.
Because the NEAD study is not a randomized trial, a potential concern is that the results may be due to confounding factors related to baseline characteristics that might affect the child’s IQ. For example, antiepileptic-drug assignment was not randomized, and therefore the largest proportion of mothers taking valproate had idiopathic generalized epilepsy. However, the association between maternal valproate use and poor cognitive outcomes in the children persisted in analyses adjusted for many baseline characteristics, including the propensity analyses.
Our results are consistent with those of previous investigations. Retrospective studies in the United Kingdom found poorer outcomes among children exposed to valproate in utero as compared with children who were unexposed and with those exposed to other antiepileptic-drug monotherapies.5,25
These poor outcomes for valproate included increased developmental delays in a cohort younger than 6 years of age, increased special-education needs in a cohort 5 to 18 years of age, and reduced verbal IQ in a cohort 6 to 16 years of age, as compared with unexposed children (7 points), children exposed to carbamazepine (10 points), and children exposed to phenytoin (15 points). A prospective Finnish study reported a reduction in verbal IQ among children exposed to valproate as compared with unexposed controls (13 points) and with children exposed to carbamazepine (14 points).26
This prospective study was limited by a small sample of subjects exposed to valproate monotherapy (13 children) and lack of information on maternal IQ.26
Several studies have also shown that valproate is associated with an increased risk of congenital malformations24,27–32
; this association is dose-dependent.24–26,28,30
A recent meta-analysis indicated that of various antiepileptic drug monotherapies, valproate was associated with the highest incidence of malformations (10.7%; 95% CI, 8.2 to 13.3).33
The results of several studies showing an increased incidence of anatomical or behavioral teratogenesis in children exposed to valproate as compared with other antiepileptic drugs raise serious concern that valproate poses a particular risk to the unborn child.
Additional studies are needed to better define the risks associated with antiepileptic drugs and to understand the underlying mechanisms. Data currently being collected in registries of pregnant women taking antiepileptic drugs (e.g., the North American Antiepileptic Drug Pregnancy Registry and the International Registry of Antiepileptic Drugs and Pregnancy [EURAP]) should provide further information on the risks associated with antiepileptic drugs and modifiers of these risks.
The present results, together with other data, suggest that valproate should not be used as a first-line antiepileptic drug in pregnant women or — since data indicate that half of pregnancies are unplanned34
— in women of childbearing potential. Our finding that associations between the use of valproate in pregnancy and lower IQ in the offspring are dose-dependent suggests that lower doses may be safe. However, it should be recognized that there is considerable individual variability among children exposed to similar doses.
For some patients, valproate is the only medication that adequately controls seizures. Such women should be informed of the potential risks associated with the use of this medication in pregnancy. If a woman taking valproate is already pregnant, it is critical that she not stop valproate without consultation with her physician, since stopping an antiepileptic drug could lead to seizures and serious consequences for both the woman and her fetus.
Fewer than half of antiepileptic-drug prescriptions are written for epilepsy or seizures; the majority are intended for pain management and psychiatric indications. Although our study did not include women who were prescribed antiepileptic drugs for indications other than seizure, a previous report suggested that the risk of malformations in the offspring of these women is similar to that of children of women taking antiepileptic drugs for epilepsy.35
In summary, our interim analysis of the NEAD study indicates that the maternal use of valproate during pregnancy is associated with an increased risk of cognitive impairment in children at 3 years of age. This information is relevant to counseling women of reproductive age regarding this drug class.