During pregnancy, women with epilepsy (WWE) rely on anti-seizure medication (ASM) to prevent seizure-related harm to themselves and their babies. Balancing the risk of uncontrolled seizures during pregnancy against potential birth anomalies, neurodevelopmental conditions and other health problems in babies exposed to ASM in utero is difficult, given the implicit ethical issues which preclude randomised controlled trials of ASM in pregnancy and infancy, and the countless confounders in observational studies.
Thomas et al.[1] describe a project from the Kerala Registry of Epilepsy and Pregnancy, a prospective observational registry tracking outcomes of pregnancy in WWE. Developmental paediatricians, blinded to antenatal ASM exposure, assessed motor and mental development for 1357 infants aged 12-24 months. They found both developmental indicators were favourable for ASM-unexposed babies compared to those exposed to ASM monotherapy, whose outcomes were in turn better than those exposed to ASM polytherapy. Analysis for valproate (VPA) showed scores were worst among cases with VPA-containing polytherapy regimens and VPA monotherapy compared to polytherapy without valproate. Levetiracetam exposure had similar outcomes for ASM-unexposed babies.
In an observational cohort study based in Scandinavia, Vegrim et al.[2] report an increased risk of malignancy among children of WWE prescribed high-dose folic acid just before or during pregnancy, compared to children of WWE who did not take high-dose folic acid (adjusted hazard ratio of 2.7). A strength of this study lies in the use of population-based data from mandatory, nationwide healthcare and administrative registries, providing a sample size sufficient to explore associations between rare combinations of exposures and outcomes. Although this is a single study and explanatory mechanisms have not been delineated, this finding should be considered when discussing perinatal folic acid supplementation.
Shawahna et al.[3] conducted a robust review of 15 observational studies considering the excreted concentrations of 8 ASMs in the breastmilk of WWE. The authors estimated the relative ASM doses for breastfeeding babies (highest for lamotrigine and lowest for carbamazepine). Most ASMs did not produce short-term adverse effects sufficient to stop breastfeeding but long-term neurodevelopmental outcome data for infants exposed to ASMs by breastfeeding was not available.
Tomson et al.[4] intentionally sought to review a broader range of studies for practical clinical purposes. Of the 73 studies analysed, the15 papers reviewed by Shawahna and colleagues were included. Although data suggested very low levels of ASMs in infants were only rarely associated with side effects, this information was only available for a relatively small number of ASMs and prospective long-term outcomes are missing for most ASMs.
A literature review by King et al.[5] highlights that almost 60% WWE are estimated to be at risk of unplanned pregnancies and that improved counselling is needed in relation to pregnancy planning and contraception. Current data regarding potential impacts of ASM on fertility and birth rates among WWE is conflicting. There is an increased prevalence of adverse outcomes in obstetrics and perinatal care for WWE which must be addressed.
Key points
- Recent population registry data offers further insights into the risks of developmental problems in children due to in utero valproate exposure.
- The potential risks and benefits of high-dose folic acid supplementation in pregnancy should be carefully considered.
- ASMs can be detected in the breastmilk of WWE and in the serum/plasma of breastfed babies. However, data pertaining to short-term adverse effects is available for only a limited selection of ASMs and long-term neurodevelopmental outcomes for most ASMs is missing.
- Improvements are needed in pre-pregnancy counselling and obstetric/perinatal care for WWE
References
- Thomas S, Jeemon P, Jose M, et al. Differential impact of antenatal exposure to antiseizure medications on motor and mental development in infants of women with epilepsy. Epileptic Disord 2022;24:531–40. doi:10.1684/epd.2022.1414. PMID: 35770752.
- Vegrim H, Dreier J, Alvestad S, et al. Cancer Risk in Children of Mothers With Epilepsy and High-Dose Folic Acid Use During Pregnancy. JAMA Neurol. 2022;79(11):1-10. doi: 10.1001/jamaneurol.2022.2977. PMID: 36156660.
- Shawahna R, Zaid L. Concentrations of antiseizure medications in breast milk of lactating women with epilepsy: A systematic review with qualitative synthesis. Seizure 2022;98:57–70. doi:10.1016/j.seizure.2022.03.017. PMID: 35427849.
- Tomson T, Battino D, Bromley R, et al. Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force. Epileptic Disord 2022;24:1020–32. doi:10.1684/epd.2022.1492. PMID: 36193017.
- King A, Gerard EE. Contraception, fecundity, and pregnancy in women with epilepsy: an update on recent literature. Curr Opin Neurol 2022;35:161–8. doi:10.1097/WCO.0000000000001039. PMID: 35191408.
Publish on behalf of the Scientific Panel Epilepsy