Page B. Pennell, MD, on Changes in Antiepileptic Drug Dose and Seizure Frequency Among Pregnant Women With Epilepsy

Among pregnant women with epilepsy, changes in antiepileptic drug dose appear to be more common than among nonpregnant women with epilepsy, according to new findings published in the New England Journal of Medicine.

The authors of the study arrived at their conclusion after performing a prospective, observational, multicenter cohort study of 351 pregnant women and 109 nonpregnant controls with epilepsy. The frequency of seizures among participants during pregnancy through the first 6 weeks post-birth (epoch 1) was compared with that of the subsequent 7.5 months following pregnancy (epoch 2). Follow-up lasted 18 months.

The primary outcome of the study was defined as the percentage of women with a higher frequency of seizures associated with decreased awareness during epoch 1 compared with epoch 2. Changes in antiepileptic drug dose in both groups during the first 9 months of epoch 1 were also compared.

A total of 299 pregnant women and 93 controls had a history of seizures associated with impaired awareness, and had available data for both epochs. The results of the study indicated that, among these women, the frequency of seizures was higher in epoch 1 compared with epoch 2 among 70 pregnant women and 23 controls (23% and 25%, respectively; odds ratio [OR] 0.93). Approximately 74% of pregnant women had their dose of an antiepileptic drug changed at least once during pregnancy compared with 31% of controls (OR 6.36).

Neurology Learning Network (NLN) discussed these findings and their significance further with lead study author Page B. Pennell, MD, who is a professor of neurology at Harvard Medical School, vice-chair of Academic Affairs in the Department of Neurology, and director of research for the Division of Epilepsy at Brigham and Women’s Hospital in Boston, Massachusetts.

NLN: Could you discuss the design for your study and its key findings regarding seizure frequency?

Dr Pennell: The study design involved enrolling women with epilepsy who were pregnant, as well as nonpregnant women with epilepsy. We matched them on many key covariates, including the type of seizures they had, the baseline seizure frequency, and the medications they were prescribed. Subsequently, we followed them throughout the study to compare the percentage of participants who had seizure worsening during pregnancy with that of controls during comparable time periods, which we labeled as epoch 1.

During epoch 1, 23% of women had an increase in seizure frequency compared with epoch 2, which is their nonpregnant baseline. The controls demonstrated similar findings: 25% of them had seizure worsening during epoch 1. Another notable finding is that 14% of pregnant women had seizure improvement during pregnancy compared with 11% of controls followed over the same time period. With that, we were able to show that variability and seizure frequency is the same among pregnant women with epilepsy as nonpregnant women with epilepsy who had similar clinical features to the pregnant women enrolled in this study.

NLN: You found that during pregnancy, the doses of antiepileptic drugs were changed at least once in the majority of pregnant women compared with controls. Could you discuss the significance of this finding in more detail?

Dr Pennell: A total of 74% of women had a change in their antiepileptic drug dose during pregnancy compared with 31% of controls. Overall, 70% of pregnant women had a dose increase compared with 24% of controls. Clinically, what does this mean? We can reassure our pregnant patients with epilepsy that we can get them through their pregnancy safely and without increased risk of seizure worsening, but we must also be mindful that we will need to monitor their medication blood levels carefully during pregnancy and make adjustments for the changes that occur in the clearance of the medications during pregnancy to be able to keep their seizures stable.

NLN: Will the findings from this study inform future guidelines?

Dr Pennell: Yes. The American Academy of Neurology and American Epilepsy Society are now working on updating the guidelines, though the first guideline being developed will address other issues including the risk of major congenital malformation (or birth defects) in the offspring of mothers with epilepsy, as well as the effects of the medications on the neurodevelopment of the fetus. When the group develops the guideline addressing seizure control and frequency during pregnancy, the data from the present study will be incorporated into the new guidelines.

NLN: What areas of future research are still needed in this field?

Dr Pennell: My colleagues and I will perform a secondary analysis to look more specifically at the blood concentrations and the patterns of dose adjustments/increases to determine whether changes in seizures are related to the changes in antiepileptic drug blood concentrations. In addition, as new medications are approved for use and begin to be used more among pregnant women with epilepsy, we must be mindful if dose adjustments are also needed with the new medication to help keep seizures under control.

Our overall study, called “Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD),” is looking at 6 primary outcomes. We are also evaluating the rates of depression and anxiety among pregnant women with epilepsy compared with pregnant women without epilepsy and nonpregnant women with epilepsy, and we are following children born to pregnant women with epilepsy vs without epilepsy to determine whether there are any differences in learning, development, and rates of autism between these 2 groups. These data will be published in the near future.

NLN: What key takeaways about this topic do you hope to leave with neurologists and related clinicians?

Dr Pennell: One key reason why we advocated for publication of this study in The New England Journal of Medicine is that approximately 30% of adults with epilepsy in the United States are not followed by neurologists but instead are followed by primary care providers. Because of this, we thought it was really important to have these findings published in a journal that would be seen by all types of health care providers. Especially if a patient’s seizures are well-controlled, they are less likely to be seen in a subspecialty epilepsy center. Other providers including primary care providers, obstetricians, general neurologists, and epilepsy specialists, will be able to counsel that woman that, if she wants to start a family, it can be done safely, and she has that option just like any other women of reproductive age. This will also help enable clinicians to carefully manage their patients with epilepsy during pregnancy, and to consider adjusting the doses of antiepileptic medications to maintain blood concentration for optimal seizure control.

—Christina Vogt

Pennell PB, French JA, May RC, et al. Changes in seizure frequency and antiepileptic therapy during pregnancy. N Engl J Med. 2020;383:2547-2556. doi:10.1056/NEJMoa2008663