Prenatal antiseizure medication (ASM) exposure is not associated with increased epilepsy risk in children, according to a recent study published in JAMA Network Open.
Takeaways
- Despite its efficacy in treating seizures, prenatal exposure to valproate, a commonly prescribed antiseizure medication (ASM), may be linked to higher epilepsy risk in children.
- Children exposed to valproate in polytherapy had a higher risk of epilepsy compared to those exposed to monotherapy or no ASMs during prenatal development.
- The study found that the risk of epilepsy wasn't significantly influenced by the dose of valproate exposure during pregnancy, suggesting that even low doses could pose a similar risk as higher doses.
- While valproate showed an increased risk, other ASMs such as lamotrigine, mazepine, and oxcarbazepine did not exhibit heightened risks of epilepsy in children when exposed prenatally.
- The study highlights that factors beyond prenatal ASM exposure, such as the heritability of maternal epilepsy, may contribute to observed associations between specific ASMs like valproate and epilepsy risk in children.
While valproate has been indicated as one of the most effective ASMs, concerns have arisen over adverse outcomes when pregnant women use the drug. Studies have linked prenatal valproate exposure to poorer outcomes for intellectual functioning, developmental milestones, language and memory functioning, and autism spectrum disorder.
Epilepsy risk may rise from aberrations in fetal brain development. Since valproate and other ASMs may alter fetal brain development, investigators have hypothesized changes caused by ASMs may increase epilepsy risk among offspring. Data has also indicated increased epilepsy risk among children of mothers with epilepsy vs fathers with epilepsy.
To evaluate the association between valproate and other ASM use among pregnant women with epilepsy and child epilepsy risk, investigators conducted a prospective, population-based cohort study. Data was obtained from nationwide health and social registers from Denmark, Iceland, Finland, Sweden, and Norway.
Participants included live-birth singletons of mothers with epilepsy from 1997 to 2017 in Denmark, 2004 to 2017 in Iceland, 1996 to 2016 in Finland, 2006 to 2017 in Sweden, and 2005 to 2017 in Norway. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes were used to determine maternal epilepsy.
National prescription registers were assessed for data about maternal ASM use. This included dispensing date, Anatomical Therapeutic Chemical (ATC) classification code, and number of dose units per pack.
Children whose mothers redeemed a prescription for any medication with ATC codes N03A, N05BA09, or S01EC01 from 30 days before their last menstrual period until delivery were classified as having been exposed to prenatal ASMs. Pregnancies with only 1 type of ASM prescription redeemed were considered monotherapy.
Pregnancies with 1 or more prescriptions for 1 or more different ASMs were considered polytherapy and divided into combinations with and without valproate. The mean daily dose of monotherapy was measured as the sum of all defined daily doses from prescriptions filled divided by the number of days in the exposure window.
ICD-10 codes were also used to determine epilepsy in children. The administration date of the child’s first hospital contact with an epilepsy diagnosis was considered the date of epilepsy.
There were 38,663 children included in the final analysis, with a mean follow-up duration of 7.2%. Monotherapy valproate exposure was reported in 5% of children, valproate exposure in polytherapy in 2.1%, and no ASM exposure in 57.4%.
Children with no prenatal ASM exposure had a cumulative epilepsy risk when aged 15 years of 3.2%, vs 9.1% in those with monotherapy valproate exposure and 8.5% in those with polytherapy valproate exposure. In fully adjusted models, monotherapy valproate exposure had an adjusted hazard ratio (AHR) of 1.28 and polytherapy valproate exposure 2.10.
Additional AHRs included 2.32 for topiramate monotherapy, 1.90 for clonazepam monotherapy, and 1.39 for polytherapy without valproate. Children with prenatal lamotrigine, mazepine, or oxcarbazepine did not have increased risks of epilepsy.
Risks were not dose dependent, with low, medium, and high prenatal valproate dose exposures having similar AHRs of 2.18, 2.19, and 2.14, respectively. An AHR of 1.69 was reported for epilepsy risk among children of mothers who continued valproate use into pregnancy vs those who discontinued valproate before pregnancy.
Of mothers with epilepsy, 1% used valproate in at least 1 pregnancy and no ASM in at least 1 other pregnancy. Epilepsy risk did not differ between children with prenatal exposure and their unexposed offspring.
Additionally, sensitivity analyses indicated other factors such as the heritability of maternal epilepsy may explain the association with valproate and topiramate observed in the initial assessment. Investigators concluded prenatal ASM exposure may not increase epilepsy risk in children.
Reference
Dreier JW, Christensen J, Igland J, et al. Prenatal exposure to antiseizure medications and risk of epilepsy in children of mothers with epilepsy. JAMA Netw Open. 2024;7(2):e2356425. doi:10.1001/jamanetworkopen.2023.56425
