Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study.
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam during their pregnancy, or a combination of the two.
However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes — worse outcomes with higher exposure levels — with levetiracetam.
The results have been released ahead of their presentation at the American Academy of Neurology (AAN) 2021 Annual Meeting being held virtually April 17 to 22, 2021.
“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” lead investigator, Kimford J. Meador, MD, told Medscape Medical News. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.
“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Meador said.
In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability.
“In the secondary analysis there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Meador, professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California. “We saw some signal in the children when they were 2 years old and this was still there but not as striking at 3 years old.”
He said these secondary results should be interpreted with extreme caution.
“We don’t want to over emphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this as I am still not sure whether this is a real association or not,” Meador commented.
He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an artform than science, and as the children get older these signals often dissipate. We will know more by the time they are 6 when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.
“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Meador said.
He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”
Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.
He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
He explained that risk for adverse effects with antiseizure medication always needed to be balanced with risk for seizures if the medication was not used.
“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs such as valproate which poses a serious risk to cognitive and behavioral development.”
He also advised that women should be taking folic acid regularly as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.
The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.
The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 versus 102.1).
Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n=265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).
General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.
In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Meador reported.
However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.
The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.
“Information on use in pregnancy for most antiseizure medications are still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions since teratogens act on a susceptible genotype.”
American Academy of Neurology (AAN) 2021 Annual Meeting. To be presented April 17-22, 2021.
The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.