Article In Brief
An analysis of pregnancies in women with epilepsy found an association between two antiseizure medications, valproate and topiramate monotherapy, and a twofold increased risk of major congenital malformations in children.
The choice and dose of antiseizure medications (ASMs) for women who are pregnant or planning a pregnancy are critical given the teratogenic potential of certain therapies. Now, results from a large, population-based study comparing the safety and potential risk of ASMs on fetal development of major congenital malformations provides some clarity on both concerns.
The analysis, published online Nov. 26 in Annals of Neurology, found that both valproate and topiramate monotherapy were associated with a twofold increased risk of major congenital malformations. Prior evidence from systematic reviews indicated that children exposed prenatally to valproate had a threefold increased risk of developing a congenital malformation, but the risk with topiramate had been less clear. The current study suggests that topiramate may not be a safer alternative to valproate.
The study also confirmed data from prior research showing that lamotrigine and levetiracetam confer a low risk of major congenital malformations and that carbamazepine and oxcarbazepine are relatively safe in terms of risk for major congenital malformations.
Using national health register data from 1996 to 2020 from five Nordic countries—Denmark, Finland, Iceland, Norway, and Sweden—investigators constructed a population-based cohort of nearly 5 million pregnancies to examine the comparative safety of common ASMs. Nearly 16,000 women (0.3 percent) used an ASM monotherapy in the first trimester of their pregnancy compared with 4,866,362 women who did not use any ASM.
Most women were treated with lamotrigine monotherapy (8,339); other treatments included carbamazepine (2,674 women), valproate (2,031), oxcarbazepine (1,313), levetiracetam (1,040), and topiramate (509). The study did not include gabapentin and pregabalin or older agents, such as phenytoin and phenobarbital, that are no longer frequently used in Nordic countries.
The investigators found no difference between those taking lamotrigine monotherapy and women taking no ASM after adjusting for such confounding factors as country, year of delivery, maternal age, indications for ASMs, and other chronic conditions, including diabetes, other medication use in the first trimester, and indicators of health care use before pregnancy.
Investigators compared the safety of lamotrigine monotherapy with monotherapies for carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate. They also stratified the monotherapy groups by dose and compared each with low-dose lamotrigine.
Both valproate and topiramate increased the risk of congenital malformations by twofold in a dose-dependent manner compared with lamotrigine monotherapy. Both agents were associated with the potential for increased risk for multiple malformations. Valporate was associated with cardiac and nervous system malformations as well as oral clefts, clubfoot, and hypospadias.
The study found no increased risk of congenital malformations with carbamazepine, oxcarbazepine, and levetiracetam monotherapies compared with lamotrigine monotherapy.
“Based on our study, we did not find any meaningful differences in the major congenital malformation risk between these drugs,” said the lead author of the study, Jacqueline Cohen, PhD, senior researcher in the department of chronic diseases and Center for Fertility and Health at the Norwegian Institute of Public Health in Oslo. Dr. Cohen said she was reassured by the comparable safety findings on carbamazepine given that the assessment was based on a higher number of infants exposed to the drug prenatally than assessed in previous studies.
“Our findings, in the context of previous research, suggest that neurologists should avoid prescribing valproate and topiramate to people who may become pregnant unless other treatment options are not effective or not tolerated,” Dr. Cohen said.
“Oxcarbazepine, a medication that had not reached the numbers to allow us to confidently assess its structural risk, is now confirmed to be equally safe to lamotrigine and levetiracetam by analyzing over 1,000 exposed pregnancies.”—DR. PAULA VOINESCU
“The best time for counseling women with epilepsy of childbearing age is at least six months prior to pregnancy so that the seizure medication regimen can be simplified with fewer medications at the lowest possible dose to keep the patient seizure-free.”—DR. MONA SAZGAR
“Major congenital malformations occur very early in pregnancy, and therefore it is best to consider these risks before a patient becomes pregnant,” she said. “All patients with the capacity for pregnancy using these drugs should also use effective contraception and be well informed about the risk associated with using the drugs during pregnancy.”
Paula Voinescu, MD, PhD, a neurologist and director of the Women's Epilepsy Program at Brigham and Women's Hospital in Boston, said the study reinforces that lamotrigine and levetiracetam are associated with the best structural outcomes during pregnancy.
What excites her, she added, is that the study also establishes oxcarbazepine as an equally safe medication.
“Oxcarbazepine, a medication that had not reached the numbers to allow us to confidently assess its structural risk, is now confirmed to be equally safe to lamotrigine and levetiracetam by analyzing over 1,000 exposed pregnancies,” Dr. Voinescu said.
She noted that the study also reinforced that valproate should be the “last resort for women planning for pregnancy given its highest rate for congenital malformations.” It also confirms prior suspicions that topiramate carries a significant risk and should be avoided, she said.
The results showing that carbamazepine was associated with a lower rate of congenital malformation than previously shown should be “comforting” to women who are pregnant or planning a pregnancy, Dr. Voinescu added.
Mona Sazgar, MD, a neurologist in the Comprehensive Epilepsy Program at UC Irvine Health, said she the results of the study reassure her, as they align with prospective pregnancy registry data worldwide, including the North American Antiepileptic Drug Pregnancy Registry.
“The results increase my confidence in counseling women with epilepsy,” Dr. Sazgar said.
She advises pregnant women to stay on their ASMs because not controlling seizures during pregnancy carry potential risks to the fetus.
“I attempt to simplify the medication regimen, aim for monotherapy if possible, and select medications with more favorable side effect profiles,” Dr. Sazgar said. “The good news is that the vast majority of these medications, at least as monotherapy, are considered safe, and most women with epilepsy give birth to healthy babies.”
Dr. Sazgar noted that lamotrigine, oxcarbazepine, and levetiracetam (all included in the current study) have a comparable risk profile with the general population. When using zonisamide, gabapentin, and lacosamide, she checks for baseline pregnancy levels as well as obtains monthly blood draws to guide dosing during pregnancy.
In line with the study results and previous findings, she avoids valproate and topiramate as well as phenobarbital. “If the patient has to be on valproate or phenobarbital and has no other choice, then I will try to use a dose lower than 700 mg for valproate and 150 mg for phenobarbital to minimize risk,” she said.
Dr. Sazgar emphasized that gaps remain in understanding the safety of myriad new ASMs, including perampanel, brivaracetam, clobazam, esclicarbazepine, lacosamide, cenobamate, and cannabidiol. Many women use these therapies to control their seizures, but no adequate data on their safety during pregnancy are available.
Counsel Women Before Pregnant
Dr. Sazgar said she tries to discuss the risks of ASMs during pregnancy before a patient becomes pregnant. “The best time for counseling women with epilepsy of childbearing age is at least six months prior to pregnancy so that the seizure mediation regimen can be simplified with fewer medications at the lowest possible dose to keep the patient seizure-free,” she said.
Once a woman becomes pregnant, she said, it usually is not safe to lower the medication dose or simplify the antiseizure medication regimen. “The goal is to keep the patient seizure-free so both mother and the baby will stay healthy.”
Along with using medications with a low risk of birth defects, Prachi Parikh, MD, assistant professor of neurology at Duke University School of Medicine, said it is critical to check blood levels of medications before pregnancy and then every month. “Medication levels typically drop in the first and second trimester and can lead to breakthrough seizures if not accounted for,” she said.
Drs. Cohen and Sazgar had no disclosures. Dr. Voinescu has received speakers' fees from Neurodiem, Stony Brook University, and Physicians' Education Resources.