The results of a study headed by researchers at the French National Agency for Medicines and Health Products Safety (ANSM), indicate that children born to mothers who took the antiepileptic drug sodium valproate (VPA) during pregnancy may have a four- to fivefold increased risk of developing neurodevelopmental disorders in early childhood. Rosemary Dray-Spira, PhD, and colleagues used anonymized medical records from more than 1.5 million children born in France, to investigate the incidence of neurodevelopmental disorders (NDs) in young children exposed to antiepileptic drugs (AEDs). Their results suggested that the highest risks were associated with VPA, and that the risk of neurodevelopmental disorders were much lower in children whose mothers took other types of AED.

Reporting on their findings in Scientific Reports, “Risk of early neurodevelopmental disorders associated with in utero exposure to valproate and other antiepileptic drugs: a nationwide cohort study in France,” the authors concluded. “The results for VPA confirm published data concerning both the level of increased risk NDs associated with exposure during pregnancy, the nature of these disorders and the dose-dependent nature of this risk.”

Epilepsy is one of the most common conditions affecting women of reproductive age, and most need antiepileptic drugs to avoid the harmful effects of uncontrolled seizures on themselves and on their children, the authors wrote. However, in utero AED exposure has been linked with congenital malformations of varying degrees of severity, and with neurodevelopmental disorders, they continued. In utero exposure to VAP, in particular, is associated with poorer educational attainment, poorer cognitive skills, and various neurodevelopmental disorders, including motor disorders, attention-deficit/hyperactivity disorder and autism spectrum disorders.

“These disorders may affect 30 to 40% of exposed children, and their frequency increases with the dose of VPA administered to the mother,” the scientists wrote. Information on the risks is limited, however. “Although a number of studies have been conducted on this topic, it is difficult to draw firm conclusions given the variety of methods and outcomes considered, related to cognitive skills (e.g. IQ or language skills), NDs (e.g. autism spectrum disorders, or attention-deficit/hyperactivity disorder) or school performance … previous studies have failed to determine whether the risk differs according to the period of exposure during pregnancy. Data concerning other AEDs are heterogeneous and insufficient to allow any definitive conclusions concerning the risk of NDs.”

For their studies, the team turned to the French National Health Data System, and followed infants who were born between January 2011 and December 2014, from birth up until December 2016. Mean follow-up was 3.6 years. The cohort included 1,721,990 children. Of their mothers, 11,549 had been treated with one of several common antiepileptic drugs during pregnancy, and 15,458 (0.9%) of children were identified as having neurodevelopmental disorders by the end of 2016. Of those AED-exposed children, 50 of the 991 (5%) who were exposed to VPA in utero were diagnosed with neurodevelopmental disorders in their first five years, compared with 15,270 of 1,710,441 children (0.89%) who hadn’t been exposed to any antiepileptic drugs.

Overall, children exposed to sodium valproate before birth had a 5.1 times higher likelihood of intellectual disability, a 4.7 times higher likelihood of language, learning and motor disorders and a 4.6 times higher risk of autism spectrum disorders, than children who hadn’t been exposed to AEDs. Increased risk was not observed in children exposed to sodium valproate during the first trimester only, and the risk was lower among children exposed to lower doses of the drug, than it was among those exposed to higher VPA doses.

Children born to mothers treated with the antiepileptic drugs lamotrigine, carbamazepine and pregabalin were 1.6 times, 1.9 times, and 1.5 times more at risk of developing neurodevelopmental disorders, respectively. No increased risk of neurodevelopmental disorders was observed in children born to mothers treated with the antiepileptic drugs clonazepam, gabapentin, levetiracetam or oxcarbazepine.

The scientists suggested that their results provide new information on the risks of early NDs associated with in utero exposure to VPA and to other AEDs. “ … it shows a four to fivefold higher risk of early NDs following exposure to VPA, more specifically concerning pervasive developmental disorders, mental retardation and disorders of psychological development,” they wrote. “Exposure to VPA, which was found to have a dose–response relationship with occurrence of NDs, also had a different impact according to the period of exposure: children exposed during the second and/or third trimesters of pregnancy had a markedly increased risk of early NDs, unlike children exposed to VPA only during the first trimester.”

The study also provides new insights into the ND risks to offspring of in utero exposure to other AEDs. “Almost no data concerning the risks of NDs associated with the other AEDs considered in our study are available in the literature,” the team noted. “The results of the present study do not suggest an increased risk of a diagnosis of NDs associated with exposure to clonazepam, gabapentin, levetiracetam or oxcarbazepine during pregnancy. However, our finding of an increased risk of mental retardation and utilization of orthoptic services among children exposed to pregabalin constitutes a signal that needs to be further investigated.”

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