Valproate is a known human teratogen. First-trimester exposure is associated with an approximately three-fold increased risk of major congenital malformations, most commonly spina bifida (absolute risk, 6–9%). Phenobarbital use during pregnancy is also associated with an elevated risk of major congenital malformation, most often cardiac defects. First-trimester in utero exposure to topiramate is associated with an approximately 10-fold increase in oral clefts risk (absolute risk, 1.4%). If possible, valproate, phenobarbital, and topiramate should be avoided in women of childbearing potential, and if the drugs cannot be eliminated, they should be used at the lowest dose possible because the risk, at least for valproate, has been shown to be dose-dependent. Other antiseizure drugs may present a lower risk of major congenital malformations (or the risk is poorly understood), but the risk for most drugs, including carbamazepine, phenytoin, and levetiracetam is not zero. In addition to congenital malformations, there is evidence that first-trimester exposure is associated with cognitive impairment. In particular, fetal exposure to valproate is associated with a dose-dependent reduction in cognitive abilities across a range of domains including IQ. Fetal exposure to lamotrigine or levetiracetam may be safer with regard to cognition than other antiseizure drugs, and these two agents also have the lowest risks of major congenital malformations. Polytherapy may increase the risk of neurodevelopmental deficits, particularly when one of the drugs is valproate. In addition, there is evidence that valproate exposure may be associated with an increased risk of autism spectrum disorder.
Some antiepileptic drugs such as primidone, levetiracetam, gabapentin, lamotrigine, and topiramate penetrate into breast milk in relatively high concentrations. For example, in one study, plasma concentrations of lamotrigine in breastfeeding infants were 18.3% of maternal plasma concentrations. Other antiseizure drugs that are highly protein bound, such as valproate, phenobarbital, phenytoin, and carbamazepine, do not penetrate into breast milk substantially. Case series have not reported adverse effects on the newborn of antiseizure drug exposure via breast milk, although there are some reports of sedation with the barbiturates and benzodiazepines. As a general rule, breastfeeding should not be discouraged given the lack of evidence of harm and the known positive benefits.
An analysis of suicidal behavior during clinical trials of antiseizure drugs was carried out by the US Food and Drug Administration in 2008. The presence of either suicidal behavior or suicidal ideation was 0.37% in patients taking active drugs and 0.24% in patients taking placebo. This led to an alert of an increased risk of suicide in people taking antiseizure drugs. Following the report, several studies have addressed the issue in various ways but have not provided convincing data that, as a class, antiseizure drugs induce suicide-related behaviors. Some data suggest a possible association of lamotrigine, levetiracetam, and topiramate with suicidality, but further research is needed. Patients treated with antiseizure drugs and their families should be informed of the risk of suicidality.