Major malformations associated with antiepileptic drugs

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The most common major malformations associated with traditional antiepileptic drug therapy (phenytoin, phenobarbital, primidone, benzodiazepine, valproate, carbama-zepine) are cleft palate and cleft lip, cardiac malformations, neural-tube defects, hypospadias and skeletal abnormalities. Unfortunately, because most studies have been of women on multiple drug therapy, the risks of individual drugs are not fully established.

The risk of spina bifida has been particularly well studied. The background population risk of spina bifida is approximately 0.2-0.5% with geographical variation. Valproate is associated with a 1-2% risk of spina bifida aperta, a risk that is strongly dose-related. Carbamazepine carries a risk of spina bifida aperta of about 0.5-1%. It is instructive to note that the induction of neural-tube defects by valproate (and to a lesser extent carbamazepine) was not noticed in animal toxicology. The mechanism of production of drug-induced spina bifida may be different from that in unexposed populations. Both carbamazepine and valproate have been associated also with hypospadias.

The overall risk of malformations due to exposure with antiepileptic drugs are best studied using pregnancy registers. The UK register reports the following monotherapy malformations rates: overall 3.7%; carbamazepine 2.2%; valproate 6.2%; lamotrigine 3.2%; phenytoin 3.7%. The rates on valproate are lower at doses of < 100 mg; and at this dose approximate to rates on lamotrigine at doses > 200 mg. The major malformation rate on polytherapy was 6% overall, and 9% with combinations involving valproate and 4.5% with combinations involving carbamazepine.

One study purported to demonstrate smaller head circumference in babies of mothers on carbamazepine, but the statistical basis of this observation was not well founded. Small increases in rates of pre- and postnatal growth retardation have been found in controlled studies of mothers taking antiepileptics, but the growth differences had disappeared by the time the offspring were 5 years old.

It is not clear whether or not the benzodiazepines have any teratogenic potential, although there are case reports of facial clefts, and cardiac and skeletal abnormalities.

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