In Utero Antiepileptic Drug Exposure
In Utero Antiepileptic Drug Exposure
Meador KJ, Baker GA, Browning N, et al
N Engl J Med. 2009;360:1597-1605
Animal studies suggest that in utero exposure to antiepileptic drugs (AEDs) at lower than teratogenic doses may produce cognitive and behavioral abnormalities, but possible cognitive effects of fetal exposure of humans to antiepileptic drugs are still unknown. In a prospective, observational, multicenter US and UK study, pregnant women with epilepsy treated with a single antiepileptic drug (carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled between 1999 and 2004. The investigators plan to compare neurodevelopmental outcomes at age 6 years after fetal exposure to different AEDs.
In a planned interim analysis of cognitive outcomes in 309 children at 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than did those exposed to other AEDs. Mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate, after adjusting for maternal IQ, maternal age, dose of antiepileptic drug, gestational age at birth, and maternal use of folate before conception.
Average IQ score was 9 points lower in children exposed to valproate than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1-14.6; P = .009), 7 points lower vs phenytoin (95% CI, 0.2-14.0; P = .04), and 6 points lower vs carbamazepine (95% CI, 0.6-12.0; P = .04). There was a dose-dependent association between valproate use and IQ. Among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate, there was a significantly relationship between children's IQs and maternal IQs.
In this study, fetal exposure to valproate was associated with an increased risk for impaired cognitive function at 3 years of age, and this risk was dose-dependent as compared with fetal exposure to other commonly used AEDs. A recommendation against using valproate as a first-choice drug in women of childbearing potential is supported by this finding, as well as by the results of previous studies.
Study limitations include relatively small sample, lack of randomization, possible confounding factors, lack of a control group of children not exposed to AEDs, and relatively young age of the children at this planned interim analysis.
Epileptic women of childbearing age should consider the possible adverse fetal effects in AED selection. For women in whom valproate is the only medication that adequately controls seizures, consideration and discussion of the risks of valproate should be balanced against those of uncontrolled seizures.
Abstract
Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs
Meador KJ, Baker GA, Browning N, et al
N Engl J Med. 2009;360:1597-1605
Summary
Animal studies suggest that in utero exposure to antiepileptic drugs (AEDs) at lower than teratogenic doses may produce cognitive and behavioral abnormalities, but possible cognitive effects of fetal exposure of humans to antiepileptic drugs are still unknown. In a prospective, observational, multicenter US and UK study, pregnant women with epilepsy treated with a single antiepileptic drug (carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled between 1999 and 2004. The investigators plan to compare neurodevelopmental outcomes at age 6 years after fetal exposure to different AEDs.
In a planned interim analysis of cognitive outcomes in 309 children at 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than did those exposed to other AEDs. Mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate, after adjusting for maternal IQ, maternal age, dose of antiepileptic drug, gestational age at birth, and maternal use of folate before conception.
Average IQ score was 9 points lower in children exposed to valproate than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1-14.6; P = .009), 7 points lower vs phenytoin (95% CI, 0.2-14.0; P = .04), and 6 points lower vs carbamazepine (95% CI, 0.6-12.0; P = .04). There was a dose-dependent association between valproate use and IQ. Among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate, there was a significantly relationship between children's IQs and maternal IQs.
Viewpoint
In this study, fetal exposure to valproate was associated with an increased risk for impaired cognitive function at 3 years of age, and this risk was dose-dependent as compared with fetal exposure to other commonly used AEDs. A recommendation against using valproate as a first-choice drug in women of childbearing potential is supported by this finding, as well as by the results of previous studies.
Study limitations include relatively small sample, lack of randomization, possible confounding factors, lack of a control group of children not exposed to AEDs, and relatively young age of the children at this planned interim analysis.
Epileptic women of childbearing age should consider the possible adverse fetal effects in AED selection. For women in whom valproate is the only medication that adequately controls seizures, consideration and discussion of the risks of valproate should be balanced against those of uncontrolled seizures.
Abstract
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