Epilepsy
Aiya Almogaber, PharmD
As clinicians strive to safeguard the health of pregnant women with epilepsy and their unborn children, it’s important to balance effective seizure control with any risks associated with antiseizure medications. A new guideline, developed by experts from the American Academy of Neurology, the American Epilepsy Society, and the Society for Maternal-Fetal Medicine, offers crucial recommendations for managing epilepsy in individuals of childbearing potential.
The updated guideline, published in Neurology on May 15, 2024, is the result of a systematic review of studies conducted between June 2007 and August 2022. The panel of experts evaluated data from 69 key studies, which encompassed thousands of cases of in-utero exposure to antiseizure medications in individuals of childbearing potential. In refining the recommendations using these findings, experts aimed to balance seizure control with minimizing risks associated with antiseizure medications to both the mother and fetus.
Key findings and recommendations
The systematic review revealed that certain antiseizure medications, particularly valproic acid, are associated with a significantly higher risk of major congenital malformations, such as neural tube defects and cardiac anomalies, as well as adverse neurodevelopmental outcomes, including autism spectrum disorder and lower IQ. In response, the guideline authors recommend the use of safer antiseizure medications, such as lamotrigine, levetiracetam, and oxcarbazepine, which present a lower risk to the fetus.
Among the most critical recommendations is the avoidance of valproic acid during pregnancy, unless it is the only viable option for maintaining seizure control.
Additionally, folic acid supplementation is advised before and during pregnancy to potentially improve neurodevelopmental outcomes, though it may not significantly reduce the risk of major congenital malformations.
“The good news is most children born to people with epilepsy are healthy,” said Mark R. Keezer, MD, PhD, senior author of the guideline. “It is important to note that the safety profile between antiseizure medications varies dramatically.”
He highlighted the importance of optimizing the choice of antiseizure medication prior to pregnancy. He further noted that while the findings from the systematic review were largely expected, “what was not necessarily expected was how strong the final guideline recommendations were.”
This is a reflection of the seriousness of the risks, the low cost of choosing an optimal antiseizure medication, and the shared goal of both clinicians and parents to minimize any risks to a child, according to Keezer.
Guideline development and evidence review
In response to significant advancements in understanding the safety of newer antiseizure medications and their potential effects on fetal neurodevelopment, a multidisciplinary panel undertook the task of updating the 2009 guidelines.
“With such new information, the three organizations that collaborated on this project agreed that updating the 2009 guideline was a priority,” said Keezer, who is from the Department of Neurosciences and School of Public Health of the Université de Montréal.
The evidence from the systematic review was graded using a modified version of the GRADE process, which assessed the risk of bias, consistency, directness, precision, and potential publication bias in the studies reviewed.
The guideline specifically focused on four clinical questions related to the prevalence of major congenital malformations, adverse perinatal outcomes, and neurodevelopmental outcomes associated with antiseizure medications.
Reflecting Keezer’s hope for “an increasing appreciation for the importance of neurodevelopmental safety with antiseizure medications during pregnancy,” the recommendations were formulated based on the strength of the evidence, with a clear emphasis on optimizing both maternal and fetal outcomes in individuals with epilepsy who are pregnant or could become pregnant.
Practical applications in clinical settings
The updated guidelines provide clinicians with clear, actionable steps for managing epilepsy in individuals of childbearing potential, particularly during pregnancy. Additionally, shared decision making is emphasized, ensuring that patients are fully informed about their treatment options, especially when planning for or managing pregnancy.
“These guidelines conclude with a section of suggested future research,” said Keezer. He points out that while much research has focused on physical malformations due to in-utero exposure to antiseizure medications, there are still significant gaps in knowledge and understanding, particularly regarding the neurodevelopmental safety of the medications. Keezer also stressed the need for future studies to include more people from underrepresented groups to better serve all individuals with epilepsy. ■