R01 Study Further Exploring Antiseizure Drug Exposure to The Fetus During Pregnancy and Breastfeeding

UPMC and University of Pittsburgh Department of Neurology Chair, Page B. Pennell, MD, is the co-principal investigator of a new National Institutes of Health R01 grant that will continue to expand upon prior studies of antiseizure medications used during pregnancy and breastfeeding and their effect on the mother, developing fetus and newborn child.

Dr. Pennell is joined on the investigation by Angela K. Birnbaum, MD, from the University of Minnesota. Drs. Pennell and Birnbaum and other colleagues have collaborated previously on the long-running study “Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study (MONEAD)”. With their new research, they will continue to build upon that investigation's pioneering evidence-base on the effects of antiseizure medications (ASMs) during pregnancy.

The new investigation, “Physiological-based Pharmacokinetics Approach to Determine the Extent of Drug Exposure of Antiseizure Medications During Pregnancy and Breastfeeding,” under NIH project number 1R01HD105305, in essence, picks up the line of investigation where the MONEAD study left off and incorporates many of its findings into the aims of the new project.

"This new study has two main priorities," says Dr. Pennell. "The first aim is to further explore and predict precise fetal exposure levels to antiseizure medications during pregnancy using the two most commonly prescribed agents – lamotrigine and levetiracetam. This work will be conducted in animal models led by my colleague Dr. Birnbaum, who has extensive expertise in modeling drug clearance in the mother and how these agents cross the placenta to the developing fetus or from breastmilk to the newborn. The end goal result will be a much more thorough understanding of fetal and fetal brain exposure.”

These physiological-based pharmacokinetic studies will then be combined with other data from the second part of the study that Dr. Pennell is leading. The second aim of the investigation will enroll a new cohort of women planning pregnancy and taking one of the two medications mentioned above to control their seizures.

"This new cohort of women will allow us to fill in some of the gaps in our knowledge relative to early pregnancy and the early postpartum period. Our goal is to develop a clearer understanding of how early in pregnancy we need to begin making ASM dosage adjustments, and also how to make postpartum dosage adjustments more precisely," says Dr. Pennell.

Dr. Pennell's study will also employ new technology to obtain blood samples from women while at home, avoiding frequent clinic visits. Study participants will be able to self-collect blood samples in much the same way a person with diabetes checks their glucose levels – through a finger stick. Samples will then be sent to the study team to obtain measurements of ASM levels. This approach will allow for more frequent testing and characterization of drug levels at a more granular level of time.

By combining the animal modeling pharmacokinetic data with the human cohort samples, Drs. Pennell, Birnbaum, and colleagues will work to develop an algorithmic approach that can be applied to individual patients in a precision medicine approach to monitoring and adjusting ASM drug dose levels prior to, during, and after pregnancy in order to optimize the health of the mother and limit exposure to the developing fetus and newborn child to levels as low as possible.

“The way we adjust ASM dosage in pregnancy right now is more art than science because we just have not had the evidence available to make it a clear-cut decision-making process. If we are successful, we will turn that paradigm on its head. The evidence and science will guide our decision-making process but also simplify how patients are monitored," says Dr. Pennell.

At present, because of the need to get lab testing of medication levels and the lag time associated with getting the readings, in the setting of dramatically increasing drug clearance during pregnancy, there is always a "catch-up" game being played by the clinician in terms of adjustments. This approach, if successful, will allow clinicians to work more proactively through the use of modeling techniques.

"There is still far too much we do not understand relative to having epilepsy during pregnancy and how the ASMs we prescribe to our patients to control their seizures affect the developing fetus and newborn child, and importantly how those effects may play out in the long-term as the child develops. Our continuing research has made great strides in this area, and our new grant will help us further understand how to optimally treat epilepsy during pregnancy to ensure the long-term health of the mother and baby,” says Dr. Pennell.

Learn more about the study and read the entire abstract on the NIH RePORTER site.

Learn more about the MONEAD study, its aims and history, and findings through the following references and links.

• Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) (NIH RePORTER - Project Number: 5U01NS038455.)
• 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.
• 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.
• 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.
• 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.
• Pennell PB, Karanam A, Meador KJ, Gerard E, Kalayjian L, Penovich P, Matthews A, McElrath TM, Birnbaum AK; MONEAD Study Group. Antiseizure Medication Concentrations During Pregnancy: Results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study. JAMA Neurol. 2022 Feb 14:e215487. Epub ahead of print.