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Treating women with epilepsy during pregnancy is an often challenging and complex clinical endeavor. In decades past, women with epilepsy who desired to become pregnant were counseled or advised not to attempt having children because of the potential dangers to the mother and developing fetus, and ultimately the child after birth.
The modern efficacious drug therapies that currently exist to treat epilepsy and the clinical evidence base that has accumulated on management strategies have informed clinical providers on effective management to achieve optimal maternal/fetal outcomes and the long-term health of the child while minimizing potential complications resulting from poorly controlled seizures during pregnancy.
While much progress has been made, too much is still unknown about how epilepsy and its treatment during pregnancy affect maternal and child outcomes. Far too little is currently known about the potential structural teratogenic effects and other long-term impacts on the neurocognitive health of the developing fetus and child for most of the approved antiepileptic drugs currently used to treat various forms of epilepsy.
Moreover, these same medications are used in three times as many women during pregnancy for other indications such as mood disorders, substance use disorders, and migraine and other pain disorders.
In June 2021, the research team conducting the long-running Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)1 longitudinal study published their data on two-year-old cognitive outcomes in children born to women with epilepsy. The study2 was published in the journal JAMA Neurology.
University of Pittsburgh School of Medicine Department of Neurology chair Page B. Pennell, MD, was a senior author of the paper* and she has been a principal investigator of this landmark study since it began enrolling participants in 2012.
The MONEAD study1, a multicenter prospective, observational, cohort investigation, began recruiting participants in 2012 and has been continually funded by the National Institutes of Health (NIH) since that time. Since its inception, the study has been led by principal investigators Kimford J. Meador, MD, from Stanford University, and Dr. Pennell. The MONEAD study was designed to probe six specific aims to significantly improve the evidence base and better understand the relationship between antiepileptic drug exposure and maternal/fetal/child outcomes across various measures.
Additionally, it is the first multi-center study to evaluate outcomes with blood level measurements of antiepileptic drugs and assess the relationship between the amount of drug exposure and maternal and fetal outcomes, as well as optimal drug dosing strategies. The ultimate goal is to find the perfect balance between reduced drug exposure to the developing fetus to prevent potential teratogenic or neurocognitive effects related to antiepileptic agent exposure throughout all of pregnancy while maintaining a woman’s optimal seizure control.
The specific aims of the MONEAD study center on three maternal outcomes and three child outcomes. Control groups include healthy pregnant women and nonpregnant women with epilepsy.
Maternal aims include determining whether seizure frequency increases during pregnancy and what factors may drive such an increase; assessing the prevalence of Caesarean section and other obstetric complications in pregnant women with epilepsy; and determining if rates of postpartum depression or depression during pregnancy are higher in pregnant women with epilepsy compared to control groups.
Child aims include determining rates of neonatal complications compared to control groups, ascertaining whether specific neurocognitive outcomes in children are impacted by their exposure to antiepileptic drugs in utero and to what degrees; and understanding whether infants who breastfeed are affected neurocognitively by antiepileptic drug use in the mother. Children enrolled in the study are followed from birth up to six years of age with detailed neurobehavioral testing.
“I became interested in studying epilepsy during pregnancy early in my career precisely because there was a profound lack of data available to inform evidence-based care for this incredibly vulnerable and complex patient population," says Dr. Pennell. "Studies like our MONEAD investigation and its predecessor, the NEAD trial, have greatly expanded what we know about many aspects of pregnancy and child outcomes for women with epilepsy. We have learned a great deal but still have a tremendous amount of work to assess long-term outcomes, drug interactions and toxicities, optimal dosing schedules based on how individual patients process specific agents, and much more. We will make progress, but it will require additional studies with varying designs to propel the field forward."
Indeed, the impact of this work to date has been profound in more ways than one. The initial and preceding study by this group, Neurodevelopmental Effects of Antiepileptic Drugs (NEAD), was designed with the main primary goal to examine neurodevelopmental outcomes in children born to women with epilepsy who were taking the four most commonly prescribed antiepileptic drugs at the time (1999-2004).
A significant discovery from the NEAD study was that the children exposed to valproate in utero had lower full-scale IQ, reduced verbal abilities, and a higher risk for attention-deficit hyperactivity disorder.2 These findings led to a major labeling change by the U.S. Food and Drug Administration and the European Medicines Agency for valproate that led to restrictions on its use globally in women of childbearing age.3
One of the first papers4 from the MONEAD study team to report on its findings was published in the New England Journal of Medicine in December 2020, and in which Dr. Pennell was the first and corresponding author.
The analysis examined whether seizure frequency in pregnant women changed compared to the non-pregnant baseline. The control group of non-pregnant women with epilepsy was followed prospectively with the same protocol, and both groups used a customized daily seizure and medication app. The paper also examined how dose changes occurred in a participant's antiepileptic medication regimen during pregnancy.
The study showed no significant differences in the proportion of women with increased seizure frequency during pregnancy in the study cohort compared to the control cohort of nonpregnant women with epilepsy followed over the same time frame.
However, the groups differed dramatically in how they were clinically managed. During pregnancy, 74% of the women experienced dose changes of their antiepileptic drugs, while only 31% of the nonpregnant group had dose increases made by their treating clinicians. Furthermore, the majority of pregnant women whose drug dose changed during pregnancy saw an increase in their dose – 70% of women.
The study also did not find any relevant differences in seizure frequency based on the trimester of the pregnancy or by individual seizure types.
"What our analysis shows is that during pregnancy, we could maintain a women's seizure stability if we are proactive about making necessary dosage adjustments over time, but this also ties into our work in the study looking at how increasing doses of antiepileptics affect the developing brain of the fetus," says Dr. Pennell. "It is a very delicate balance we have to strike as clinicians. We must maintain a patient's seizure stability during pregnancy by increasing their dose due to the metabolic and drug clearance increases that happen in women during pregnancy with keeping doses as low as possible to limit the risks to the developing fetus and possible long-term complications later in life.”
In the recent study5 published in JAMA Neurology, the MONEAD team assessed the cognitive outcomes in 2-year-old children of women with epilepsy who used some form of antiepileptic medication during pregnancy. This analysis was designed to uncover any associations between exposure to antiepileptics in utero by the fetus and any subsequent neurocognitive deficits at two years of age.
The primary findings from the study showed no difference in neurocognitive abilities – language domain scores – using the third edition of the Bayley Scales of Infant and Toddler Development.
However, the study did find that children of women who had increased doses and levels of some antiepileptic drugs during the third trimester showed an association with lower scores on the Bayley Scale related to motor domain and general adaptive domain.
"While these results are encouraging, measures at longer-term follow-up points are crucial to more robustly assess neurobehavioral effects on the children," says Dr. Pennell. "Given how little we know about the long-term developmental effects of virtually all of the antiepileptic medications in use, we must be diligent in 1) continuing these studies to expand our evidence base, and 2) remain vigilant in using the lowest dose possible while still affording the mothers optimal control of seizures to protect both their health and that of their developing fetus.”
Read more about the MONEAD study and the two papers summarized in this article using the below references.
1. Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) (NIH RePorter site link. Project Number: 5U01NS038455.
2. Meador KJ, Baker GA, Browning N, et al. Fetal Antiepileptic Drug Exposure and Cognitive Outcomes at Age 6 Years (NEAD Study): A Prospective Observational Study. Lancet Neurol. 2013; 12(3): 244-252.
3. Cohen MJ, Meador KJ, Browning N, May R, Baker GA, Clayton-Smith J, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; NEAD Study Group. Fetal Antiepileptic Drug Exposure: Adaptive and Emotional/Behavioral Functioning at Age 6 Years. Epilepsy Behav. 2013 Nov; 29(2): 308-15.
4. Pennell PB, French JA, May RC, Gerard E, Kalayjian L, Penovich P, Gedzelman E, Cavitt J, Hwang S, Pack AM, Sam M, Miller JW, Wilson SH, Brown C, Birnbaum AK, Meador KJ; MONEAD Study Group. Changes in Seizure Frequency and Antiepileptic Therapy During Pregnancy. N Engl J Med. 2020 Dec 24; 383(26): 2547-2556.
5. Meador KJ, Cohen MJ, Loring DW, May RC, Brown C, Robalina CP, Matthews AG, Kalayjian LA, Gerard EE, Gedzelman ER, Penovich PE, Cavitt J, Hwang S, Sam M, Pack AM, French J, Tsai JJ, Pennell PB, for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Investigator Group. Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study. JAMA Neurol. 2021; 78(8): 927-936.
*Note: This study and papers were conducted and published prior to Dr. Pennell joining UPMC and the University of Pittsburgh School of Medicine Department of Neurology in July 2021.