New expert guidance to help clinicians manage the treatment of patients with epilepsy during pregnancy has been released.
Issued by the American Academy of Neurology, the American Epilepsy Society, and the Society for Maternal-Fetal Medicine, the new practice guideline covers the use of antiseizure medications (ASMs) and folic acid supplementation before conception and during pregnancy.
“Most children born to people with epilepsy are healthy, but there is a small risk of pregnancy-related problems, partly due to seizures and partly due to the effects of antiseizure medications,” the guidelines’ lead author Alison M. Pack, MD, MPH, professor of neurology and chief of the Epilepsy and Sleep Division, Columbia University, New York City, said in a news release.
“This guideline provides recommendations regarding the effects of antiseizure medications and folic acid supplementation on malformations at birth and the development of children during pregnancy, so that doctors and people with epilepsy can determine which treatments may be best for them,” she added.
The guideline was published online on May 15 in Neurology.
Why Now?
The new guideline updates 2009 guidance on epilepsy management during pregnancy. Since then, Pack told Medscape Medical News, there has been a wealth of new data on differential effects of different ASMs — notably, lamotrigine and levetiracetam — the most commonly prescribed medications in this population.
“In this guideline, we were able to assess differential effects of different ASMs on outcomes of interest, including major congenital malformations [MCMs], perinatal outcomes, and neurodevelopmental outcomes. In addition, we looked at the effect of folic acid supplementation on each of these outcomes,” she said.
The overarching goals of care for patients are to “optimize health outcomes both for individuals and their future offspring,” the authors wrote. Shared decision-making, they add, leads to better decision-making by providing a better understanding of the available treatment options and their potential risks, resulting in enhanced decision-making that aligns with personal values.
Clinicians should recommend ASMs that optimize seizure control and fetal outcomes, in the event of a pregnancy, at the earliest possible preconception time, the guideline authors note.
“Overall, treating clinicians need to balance treating the person with epilepsy to control convulsive seizures (generalized tonic-clonic seizures and focal-to-bilateral tonic-clonic seizures) to minimize potential risks to the birth parent and the possible risks of certain ASMs on the fetus if pregnancy occurs,” they wrote.
If a patient is already pregnant, the experts recommend that clinicians “exercise caution” in removing or replacing an ASM that controls convulsive seizures, even if it’s “not an optimal choice” for the fetus.
In addition, they advise that ASM levels should be monitored throughout the pregnancy, guided by individual ASM pharmacokinetics and an individual patient’s clinical presentation. ASM dose, they note, should be adjusted during pregnancy in response to decreasing serum ASM levels or worsening seizure control.
The authors point out that there are limited data on “pregnancy-related outcomes with respect to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin.”
Patients should be informed that the birth prevalence of any major congenital malformation in the general population ranges between 2.4% and 2.9%.
If Feasible, Avoid Valproic Acid
“One of the most important take-home messages is that valproic acid has the highest unadjusted birth prevalence of all major congenital malformations — 9.7% — and the highest unadjusted birth prevalence of neural tube defects at 1.4%,” Pack said. As a result, the guideline authors advise against using valproic acid, if clinically feasible.
Valproic acid also has the highest prevalence of negative neurodevelopmental outcomes, including a reduction in global IQ and an increased prevalence of autism spectrum disorder (ASD). Patients should be counseled accordingly and advised of the increased risk for ASD and decreased IQ resulting from valproic acid.
Clinicians should consider using lamotrigine, levetiracetam, or oxcarbazepine when appropriate. Serum concentrations of most ASMs have a “defined therapeutic window” for effective seizure control and that concentration may decrease during pregnancy, particularly with lamotrigine and levetiracetam, the authors note.
Phenobarbital, topiramate, and valproic acid should because of the increased risk for cardiac malformations, oral clefts, and urogenital and renal malformations.
Fetal screening for major congenital malformations is recommended to enable early detection and timely intervention in patients treated with any ASM during pregnancy Patients receiving phenobarbital during pregnancy should also undergo fetal cardiac screenings.
Valproic acid and topiramate are also associated with children who are small for their gestational age. To enable early identification of fetal growth restriction, patients taking valproic acid or topiramate should be monitored. In addition, children exposed to these medications in utero should be monitored during childhood to ensure they are meeting age-appropriate developmental milestones.
Folic acid taken during pregnancy can reduce the prevalence of negative neurodevelopment outcomes, but not major congenital malformations, Pack noted.
“Due to limited available data, we were unable to define an optimal dose of folic acid supplementation beyond at least 0.4 mg/d,” Pack said. “Future studies, preferably randomized clinical trials, are needed to better define the optimal dose.”
She emphasized that epilepsy is one of the most common neurologic disorders, and 1 in 5 of those affected are people of childbearing potential. Understanding the effects of ASMs on pregnancy outcomes is critical for physicians who manage these patients.
Uncertainty Remains
Commenting for Medscape Medical News, Kimford Meador, MD, a professor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine , Stanford Neuroscience Health Center, Palo Alto, California, noted that the new guidelines reflect the gains in knowledge since 2009 and that the recommendations are “reasonable, based on available data.”
However, “one very important point is how much remains unknown,” said Meador, who was not involved in writing the current guideline. “Many ASMs have no data, and several have estimates based on small samples or a single observational study.” Thus, “the risks for the majority of ASMs are uncertain.”
Given that randomized trials “are not possible in this population, and that all observational studies are subject to residual confounding, a reliable signal across multiple studies in humans is required to be certain of findings,” he stated.
This practice guideline was developed with financial support from the American Academy of Neurology. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the National Institutes of Health for serving as coinvestigator and site principal investigator for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin intrauterine device. One of Pack’s immediate family members has received personal compensation for serving as an employee of REGENEXBIO. The other authors’ disclosures are listed on the original paper. Meador has received research support from the National Institutes of Health, Veterans Administration, Eisai, Inc, and Suno Medtronic Navigation, Inc, and the Epilepsy Study Consortium pays Meador’s university for his research on the Human Epilepsy Project and consultant time related to Eisai, UCB Pharma, and Xenon.
Batya Swift Yasgur MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).
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