Impact of antiepileptic medications and sex hormones on maternal and child outcomes in epilepsy

Paula Emanuela Voinescu, MD, PhD

Credit: Brigham and Women's Hospital

Studies show that sex steroid hormone concentrations significantly increase throughout the duration of pregnancy. These concentrations and their neuroactive steroid metabolites may influence fetal neurodevelopment and seizure control among pregnant women with epilepsy. Enzyme-inducing (EI) antiseizure medications (ASMs) have been known to alter sex steroid hormone concentrations in the nonpregnant state. In a recent analysis of the MONEAD study presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, EI-ASMs did not significantly affect progesterone and estradiol concentrations, 2 endogenous steroid hormones, in pregnant women with epilepsy.¹

Conducted by Paula Emanuela Voinescu, MD, PhD, MONEAD is a prospective, observational, multi-center study of pregnant women with epilepsy who were enrolled no more than 20 weeks of gestation. Investigators measured serum progesterone, estradiol, and estrone concentrations at enrollment, at trimesters 2 and 3, and delivery. Participants were categorized into the EI-ASM group, where they were on at least 1 EI-ASM, (n = 30), or nonEI-ASM group (n = 169). Estrone concentrations for the EI-ASM group were consistently lower, most notably in the second (median: 1572pg/mL [IQR: 621, 2690] vs 3030 [1820, 5040]) and third trimesters (3025 [1460, 4510] vs 5095 [3605, 7025]).

Voinescu, director of the Women's Epilepsy Program at Brigham, had a conversation with NeurologyLive® at the meeting to discuss how different antiepileptic drugs influence the concentration of sex hormones in pregnant women with epilepsy. She also spoke about the correlations that exist between sex hormone levels and seizure outcomes in women with epilepsy. In addition, Voinescu, who also serves as an assistant professor of neurology at Harvard Medical School, talked about how neuroactive steroids might affect the neurodevelopmental outcomes of children born to mothers with epilepsy.

For those who are interested in learning more about your presentation, could you provide a brief overview of the data?

Paula Emanuela Voinescu, MD, PhD: These data come from a study called MONEAD, which stands for maternal outcomes and neurodevelopmental effects of antiepileptic drugs. It looks both at maternal outcomes and children outcomes for women, mothers, with epilepsy. It was conceived by Kimford Meador, MD, who is now a professor of neurology and neurosciences at Stanford University, and Page B. Pennell, MD, FAES, who was my research mentor at Brigham and Women's but is now the Henry B. Higman Professor of Neurology at the University of Pittsburgh School of Medicine. This study in particular is looking at the sex hormone concentrations for those mothers with epilepsy enrolled in the study.

The motivation behind the study—we know that sex hormones and their metabolites, the so-called neuro active steroids, can influence neuronal excitability. We also know that some antiseizure medications, specifically those called EI medication, can affect the levels of sex hormones, most obviously their metabolites. The reason behind it is to see if sex hormones are associated with seizure outcomes in this patient population. The study is only in the first phase of looking at how the sex hormones concentration differ between women who are on EI medications versus those who are on nonEI medication or no medication at all. The first findings, as shown in my abstract and presentation, are that EI medication indeed decreased the concentration of some sex hormones. Interestingly, it did not decrease the concentration of progesterone, but it did decrease the concentration of estradiol and estrone.

What do you think are the implications of these results for this patient population?

That's going to be the next question for us to answer. Looking at the seizure outcomes and seeing whether there's any correlation between seizures and subsequent levels is going to be another study to be done in the future. At the same time, we know that psychiatric comorbidities may have shared our neurobiology and sexual concentrations play a role in postpartum depression. Another analysis that's being done is trying to understand if the level of sex hormones play a role for the prevalence of the psychiatric comorbidities in pregnant women with epilepsy.

These first phase only looked at few sets of sex hormones, but all neuroactive steroids could be measured. Another future study could look in more detail on those neuroactive steroids I was mentioning earlier to see whether there is any difference in how those models correlate with these maternal outcomes. I should also mention that there is some evidence that neurotic theories also influence neuronal development of children. MONEAD is a study that, as I mentioned, also looks at the children's of mothers with epilepsy with thorough neurodevelopmental tasks. The cognitive performance of these children could be also analyzed—keeping in mind the mother's sex hormone concentrations—to see whether those levels influence global concentrations influence the neurodevelopmental outcomes of their children. A lot of possible implications but unfortunately, I don't have results to talk about any of them.

Do you believe there is a lot to look forward to with investigating these sex hormones in this patient population?

Definitely. MONAED is one of these studies that very thoroughly collected a lot of information about these patients. Many questions will hopefully be answered in the future.

Is there anything else you wanted to add about what you're looking forward to in this realm of maternal health and epilepsy?

Studies like MONEAD, they just aren’t enough of them. We have over 30 medications and the information we have about their use in pregnancy is reliable for only less than a handful of patients. The data we accumulated was on 2 antiseizure medications, in particular lamotrigine and levetiracetam. The majority of patients in MONEAD are on these medications, but way less is known about some of the newer antiseizure medications. It's important that this type of work is continued so that we have as good of an understanding of the other medications that we frequently use for our patients. We have no insight. Studies like this one that we talked about today may shed some insight into other ways in which medications may influence maternal and possibly fetal outcomes for pregnant women with epilepsy.

Transcript edited for clarity. Click here for more coverage of AAN 2024.

This article was originally published by our sister publication Neurology Live.

REFERENCES
1. Voinescu P, Pennell P, Pack A, et al. Sex Steroid Hormone Serum Concentrations in Pregnant Women with Epilepsy in MONEAD. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO.