Reassuring New Data on In Utero Exposure to Antiseizure Meds

Verbal abilities in children at age 6 years who were exposed to antiseizure medication (ASM) in utero were similar to their counterparts who were not exposed, new research showed.
However, exposure-dependent outcomes were more nuanced, with lamotrigine exhibiting positive and levetiracetam potential negative associations at certain blood concentrations.
“Because all ASMs are potential teratogens and teratogens act in an exposure-dependent manner, the clinical challenge is to provide a dose sufficiently high to protect the mother and fetus from seizures but at the lowest effective concentration to minimize fetal risks,” the investigators, led by Kimford J. Meador, MD, with Stanford University School of Medicine, Palo Alto, California, wrote.
Of note, folate supplementation early in pregnancy, including higher doses, was associated with improved cognitive and behavioral outcomes.
“Concern has been raised that higher folate doses may have adverse effects, but our study found no indication of adverse effects at higher folate doses,” the researchers noted.
The study was published online on November 25 in JAMA Neurology.
Positive Effect of Folate
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) is a prospective, observational, nonrandomized multicenter study examining pregnancy outcomes for both mother and child.
The primary neurodevelopmental outcome for children at age 6 years was a measure of verbal abilities as measured using the Verbal Index Score (VIS) because previous studies have suggested that verbal abilities might be more susceptible to fetal ASM exposure, the investigators noted.
They compared scores on this measure between 298 children of women with epilepsy and 89 children of healthy women, adjusting for multiple potential confounding factors.
Overall, the investigators found no significant difference in the VIS of 6-year-old children of women with epilepsy compared with those of healthy women (adjusted difference, −0.6; P = .64).
Women with epilepsy were primarily on monotherapy (74%). The most common monotherapies were lamotrigine (44%) and levetiracetam (35%). The most common polytherapy was lamotrigine plus levetiracetam (45%).
Looking at exposure-specific outcomes, lamotrigine exposure in the third trimester showed a positive association with verbal abilities at therapeutic blood levels, although this association did not appear to continue above 5.8 μg/mL.
Third-trimester levetiracetam exposure had a potential negative association with verbal abilities, predominantly at concentrations above 24.0 μg/mL, and this association was no longer significant after further adjusted analyses.
Importantly, neuropsychological outcomes for all children exposed to levetiracetam did not differ from lamotrigine-exposed children or unexposed children, suggesting that levetiracetam is a “relatively safe” ASM for pregnancy, the investigators wrote.
Children of women with epilepsy showed no significant differences from those of healthy women in key behavioral outcomes.
Folate supplementation in the first 12 weeks of pregnancy demonstrated positive associations with cognitive and behavioral outcomes across all children, with no indication of harm at higher doses (> 4.0 mg).
Fetal acetaminophen exposure was associated with poorer cognitive outcomes, a finding that expands on prior studies reporting adverse effects of fetal acetaminophen exposure.
Reassuring Data 
Commenting on this research for Medscape Medical News, Torbjörn Tomson, MD, PhD, professor of neurology, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden, noted that maintaining seizure control is important for the safety and well-being of the pregnant woman with epilepsy and her fetus.
“Hence, effective treatment with ASMs is needed during pregnancy despite the potential teratogenic risks. It is therefore reassuring that the MONEAD study confirms the safety with regards to cognitive outcomes with lamotrigine and probably also with levetiracetam. Unfortunately, there were too few pregnancies with exposure to other newer ASMs to permit any firm conclusions,” Tomson said.
Brian Lee, PhD, professor of epidemiology, Drexel University Dornsife School of Public Health, Philadelphia, who also was not involved in the study, said it is “comforting to see that higher lamotrigine concentrations in third trimester — the most commonly prescribed ASM during pregnancy — were not associated with adverse neuropsychological outcomes at age 6. In my opinion, the picture is less clear with levetiracetam, and I think more study is warranted there.”
Lee said it is also “nice to see that higher folate doses did not seem to be associated with adverse effects.”
Tomson agreed. “Folate supplementation in early pregnancy was associated with better cognitive and behavioral outcomes. Interestingly, this improvement appeared to be similar regardless of dose (from < 0.4 mg to > 4 mg daily), which is important since other studies have suggested an association between high-dose folate supplementation and maternal and childhood cancer,” he said.
Meador reported receiving grants from the National Institutes of Health, VA, Eisai, and Medtronic during the conduct of the study. A complete list of author disclosures for the MONEAD investigator group is available with the original article. Lee reported receiving consulting fees for literature reviews performed for Beasley Allen Law Firm, Patterson Belknap Webb & Tyler LLP, and AlphaSights. Tomson is chair of the central project commission of EURAP, the international antiepileptic drugs and pregnancy registry.
 
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