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Prenatal exposure to the antiseizure medications topiramate and valproate may cause a significantly increased risk of neurodevelopmental disorders in offspring, according to a cohort study in JAMA Neurology.
“Women with epilepsy during pregnancy often worry that their disease or treatment will hurt their unborn child,” said principal investigator Marte-Helene Bjork, MD, PhD, a consultant neurologist at Haukeland University Hospital in Bergen, Norway. “These women require answers to which treatment is the least harmful. However, because there is a lack of safety data for newer antiseizure medication, I often could not give them evidence-based information.”
The Nordic register-based study of antiepileptic drugs in pregnancy is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden. Data from 1996 to 2017 was assessed.
Prenatal exposure to antiseizure medication was determined from maternal prescription fills between last menstrual period and birth for 4,494,926 alive-born children, of whom 51.3% were male.
The authors estimated the cumulative incidence of neurodevelopmental disorders at age 8 in exposed and unexposed children to antiseizure medications.
Among the 21,634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of autism spectrum disorder (ASD), and 0.8% had a diagnosis of intellectual disability (ID) by age 8.
This compared to a rate of 4.3% for ASD and 3.1% for ID in children who were exposed to topiramate monotherapy, and 2.7% and 2.4% respectively, for those exposed to valproate monotherapy.
The study also found that the duo-therapies levetiracetam with carbamazepine and lamotrigine with topiramate were linked to increased risks of neurodevelopmental disorders in children of women with epilepsy: an 8-year cumulative incidence of 5.7% and 7.5%, respectively. There was no increased risk for levetiracetam with lamotrigine.
“We were surprised by the strong associations between prenatal exposure to topiramate and neurodevelopmental disorders in the children,” Bjork told Contemporary OB/GYN®. “We knew that valproate was linked to these disorders; however, there were scant data on long-term effects of topiramate exposure.”
Even though there are some signals for increased risk of congenital malformations after exposure to topiramate, the investigators did not expect the associations between autism and ID to be almost as strong as for valproate.
“We were also surprised that the connections between specific duo-therapy combinations to neurodevelopmental disorders were so different, depending on which drugs were used in combination,” Bjork said. “I am personally relieved that the combination of levetiracetam and lamotrigine was not associated with increased risk of neurodevelopmental disorders because it is a combination used by many patients that I care for, when a single drug is not enough to stop their seizures.”
Bjork believes that women of childbearing age should not use topiramate, if other antiseizure medications are effective and tolerated. “If they need to use this drug, they should be very well informed and use safe contraception,” she said. “Also, if they need to use topiramate in pregnancy, the lowest effective dose should be used.”
Bjork, chair of the Bergen Epilepsy Group and an associate professor of clinical medicine at the University of Bergen, is deeply concerned that new antiseizure medications indicated for women in their childbearing years “are not routinely investigated for long-term and short-term safety. For instance, topiramate came on the marked in the 1990s, but we only now have this information. We should have a better system that does not leave investigations of pregnancy drug safety to single research groups or funders.”
Bjork also noted it is unfair that women of childbearing age have fewer treatment options than men for seizures.
Bjork receives advisory board honoraria personal fees from Eisai, consultancy and personal fees from Novartis Norway, and advisory board honoraria personal fees from Jazz Pharmaceuticals and Angelini Pharma.
Bjork M-H, Zoega H, Leinonen MK, et al. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA Neurol. Published online May 31, 2022. doi:10.1001/jamaneurol.2022.1269