Antiepileptic drug exposure in pregnancy linked to neurodevelopmental disorders

Use of the antiepileptic valproate during pregnancy was associated with an increased risk for neurodevelopmental disorders in offspring during early childhood, according to research published in Scientific Reports.

“Epilepsy is one of the most common conditions affecting women of reproductive age, and most of them need antiepileptic drugs (AED) to avoid the harmful effects of uncontrolled seizures on themselves and their offspring,” Joël Coste, MD, PhD, of the department of public health studies at French National Health Insurance, and colleagues wrote. “However, in utero AED exposure is associated with congenital malformations of varying degrees of severity and with neurodevelopmental disorders.”

Coste and colleagues evaluated the incidence of neurodevelopmental disorders in children of women who used sodium valproate or other AEDs during their pregnancy using data from the French national health data system. They included singleton livebirths that occurred from January 2011 through December 2014.

They identified 1,721,990 children born during the study period. A total of 11,549 mothers used AEDs during pregnancy, including the following: 3,862 used lamotrigine, 1,491 used valproate, 1,777 used pregabalin, 1,559 used clonazepam, 1,210 used levetiracetam, 791 used carbamazepine, 697 used topiramate, 467 used gabapentin, 250 used oxcarbazepine and 154 used phenobarbital.

Among the children included in the study, 0.9% were found to have a neurodevelopmental disorder during follow-up.

Coste and colleagues determined that compared with unexposed children, children exposed to valproate during pregnancy were at a higher risk for neurodevelopmental disorders (aHR = 3.7; 95% CI 2.8–4.9).

They found that children exposed to valproate were more likely to have pervasive developmental disorders (aHR = 4.6; 95% CI, 2.9–7.5) like autism spectrum disorders and psychological development disorders (aHR = 4.7; 95%, CI 3.5–6.4) compared with children who were not exposed.

Coste and colleagues reported that the risk for neurodevelopmental disorders among children exposed to valproate varied based on the period they were exposed. For instance, they found that exposure from the first trimester through the second or third trimester was associated with higher risks for neurodevelopmental disorders, while exposure only during the first trimester was not.

According to the researchers, the only other AED that was consistently associated with an increased risk for neurodevelopmental disorders was pregabalin (aHR = 1.5; 95% CI, 1.0–2.1).

“This study confirms a four- to five-fold increased risk of early [neurodevelopmental disorders] (before the age of 6 years), especially pervasive developmental disorders and mental retardation, associated with exposure to [valproate] indicated in epilepsy during pregnancy, with a marked dose effect,” Coste and colleagues wrote. “It also provides new data suggesting that the exposure period associated with an increased risk of early [neurodevelopmental disorders] is more particularly situated during the second and/or third trimesters of pregnancy.”