New Research Provides Evidence-Based Dosing Strategies for Managing Epilepsy in Pregnancy

ARTICLE IN BRIEF:

A large, multicenter analysis of antiseizure medications used during pregnancy provides clinicians with clear guidance on how to adjust dosing across gestation and into the postpartum period to minimize seizures and risk to unborn babies.

New research provides medication-specific guidance for safely increasing antiseizure medication (ASM) doses during pregnancy, delivering real-world evidence the neurology community has long needed to inform care for pregnant women with epilepsy.

Earlier studies have shown that pregnancy profoundly alters the metabolism of ASMs, often necessitating dose increases two or three times over baseline pre-pregnancy levels to maintain therapeutic blood concentrations. Maintaining these levels is essential, as allowing them to fall below roughly 65 percent of baseline sharply increases the risk of breakthrough seizures.

Until recently, however, clinicians have relied largely on anecdotal experience to guide ASM dose adjustments during pregnancy. Findings from this new multicenter, prospective trial—published online Dec. 29 in Neurology—provide much-needed data to inform dosing strategies and support more systematic, evidence-based clinical decision-making, however.

This latest research was driven by a very simple question, said Page B. Pennell, MD, FAAN, chair of neurology at the University of Pittsburgh School of Medicine and the study's senior author: “How do we take what we know about drug clearance in pregnant women with epilepsy and provide guidance on medication dose adjustments based on real-world evidence that clinicians everywhere can actually adopt?”

Dr. Pennell, who has led numerous studies in pregnant women with epilepsy, added that by systematically examining how 20 expert epilepsy-pregnancy centers managed medication changes, the study “moves the field beyond pharmacokinetic theory toward practical, reproducible strategies that can be applied well outside tertiary referral centers.”

Multi-Center Study Overview

The study was part of the ongoing Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study group, which previously demonstrated favorable maternal seizure control and child outcomes when ASMs were actively managed during pregnancy. The new analysis included 299 participants who had a median gestational age at enrollment of 14 weeks.

During pregnancy, dose increases were implemented for 246 of 363 ASM prescriptions (67.8 percent), beginning a median of 32 days after enrollment. During the postpartum period, dose reductions occurred within six weeks of delivery for 171 of 357 ASMs (47.9 percent), with adjustments initiated a median of three days after childbirth and quickly lowered to pre-pregnant dosing.

Among the participants, 363 ASMs were prescribed for at least seven days after conception, including 61 individuals who received polytherapy with two or more ASMs. The most commonly used agents were lamotrigine and levetiracetam, prescribed to 146 participants (48.8 percent) and 125 participants (41.8 percent), respectively. These were followed by oxcarbazepine (18 participants), carbamazepine (17), zonisamide (17), and topiramate (12). Eleven other ASMs were used in fewer than 10 individuals each.

Dr. Pennell and colleagues focused not on outcomes alone but rather on how medications were adjusted in real-world clinical practice across leading epilepsy centers. During gestation, researchers adjusted dosing as follows for the two most commonly used ASMs: 87.7 percent of patients taking lamotrigine saw their doses increased by 100 mg/d (median) each time, with dose increases occurring approximately every four weeks; they reached 191 percent of the conception dose by delivery. For levetiracetam, 56 percent of participants saw their doses increased by 500 mg/d (median) each time, with dose increases happening approximately every six weeks; they reached 177 percent of the conception dose by delivery.

“All 20 sites had epileptologists experienced in managing pregnancy,” Dr. Pennell said. “But rather than just telling people what we do in lectures, we wanted to provide scientific evidence so a neurologist in a rural community, or even a primary care clinician, could use it as a roadmap.”

The latest research provides clinicians with medication-specific information for adjusting doses throughout pregnancy and the postpartum period, offering practical guidance that can be applied even in settings without immediate access to therapeutic drug monitoring.

“For a long time, everyone has essentially been doing this based on experience and trends rather than data,” said Sarita Maturu, DO, associate professor of neurology at The Ohio State University Wexner Medical Center, who authored an accompanying editorial in Neurology. “It is reassuring to see what larger academic centers are actually doing and how that can be translated to other facilities.”

A central takeaway of the study is that pregnancy-related declines in ASM serum concentrations are common, predictable, and clinically meaningful. Rather than aiming for population-based “normal” levels, the authors emphasized targeting each patient's individual pre-pregnancy baseline.

“Women often worry when they hear they may need a two- or even threefold increase in dose,” Dr. Pennell said. “But what matters is the blood concentration—not the milligram number. If levels drop below about 65 percent of a woman's baseline, seizure risk rises substantially.”

She added that “this finding reframes counseling conversations with patients, shifting focus away from absolute dose size toward maintaining stable exposure throughout pregnancy.”

When Monitoring Matters Most

Frequent drug level monitoring proved essential in capturing the dynamic changes of pregnancy. Based on observed practice patterns, the study supports checking ASM levels approximately every four to six weeks, a schedule that may be more intensive than what many clinicians currently employ.

“This paper really reinforces that less-frequent monitoring, once per trimester, or only early and late in pregnancy, is probably insufficient,” Dr. Maturu said. “It gives us a much clearer sense of how often we should be checking levels and making adjustments.”

Importantly, metabolic changes begin early. Although women in MONEAD were enrolled up to 20 weeks' gestation, prior work by Dr. Pennell and colleagues has shown significant clearance changes as early as five weeks—prompting her to advise patients to contact their neurologist immediately after a positive pregnancy test.

Neurologists should resist narrowing surveillance based on seizure type or ASM and instead adopt a broadly conservative approach to pregnancy management, according to Jennifer L. Hopp, MD, FAAN, director of the Women's Epilepsy Program at the University of Maryland.

“What this paper really shows is that we don't want to exclude certain patient populations from surveillance,” she said.

Postpartum: Rapid Reversal Requires Rapid Action

The postpartum period has emerged as one of the most critical, and underappreciated, phases of ASM management. As pregnancy-related metabolic changes rapidly normalize, serum drug levels can rebound within days.

“In this study, the average time to dose reduction was about three days after delivery,” Dr. Maturu noted. “That's a very practical signal that we need to reassess medications almost immediately after childbirth.”

Dr. Pennell added that while doses often need to be reduced quickly, they may still remain slightly higher than pre-pregnancy levels to account for sleep deprivation, stress, and seizure vulnerability during early parenthood.

A key takeaway for Dr. Hopp was that monitoring must continue soon after birth, when ASM pharmacokinetics begin reverting toward baseline.

“We need to check early and at regular intervals and then continue to ensure clinical follow-up in the postpartum period,” she said.

Dr. Pennell cautioned that ASM clearance can normalize rapidly after birth, creating a narrow window in which patients are vulnerable to supratherapeutic levels and toxicity if pregnancy-adjusted doses are continued too long. At the same time, she acknowledged gaps in the evidence base: “While the study captured real-world postpartum dose reductions, we don't have as much detailed pharmacokinetic data after delivery because the changes happen so fast.”

In her practice, Dr. Pennell does not obtain serum drug levels in the early postpartum period; instead, she makes empiric dosage adjustments. Her prior work with lamotrigine, for example, demonstrated that empiric postpartum dose adjustments were effective for seizure control and minimizing side effects. She applies this to all ASMs, given that the clearance changes so quickly that the medication concentrations are not in steady-state, and cannot wait to get the blood level results in time to make dosage adjustments. Perhaps more importantly, it is difficult for women with newborns to go to the lab every few days.

“This variation in practice highlights that further research is needed on this topic,” Dr. Pennell said.

Counseling Implications

Both Drs. Pennell and Maturu stressed that these findings reinforce the need for routine, proactive pregnancy counseling for all patients of childbearing potential.

“About half of pregnancies in women with epilepsy are unplanned,” Dr. Maturu said. “That means these conversations can't wait until someone says they're trying to conceive.”

Preconception counseling should include establishing baseline ASM levels, explaining the likelihood of dose increases, and outlining a postpartum adjustment plan. Clear expectations improve adherence and reduce anxiety when changes become necessary, Dr. Pennell emphasized.

Dr. Hopp noted that counseling should help patients understand the rationale behind frequent monitoring and dose adjustments.

“By explaining why this monitoring is necessary, we can address patients' concerns and reduce anxiety around medication changes,” she said.

“For patients planning pregnancy, counseling can now more explicitly frame drug monitoring as a cornerstone of successful pregnancy outcomes rather than a reactive safety measure,” said P. Emanuela Voinescu, MD, PhD, director of the Women's Epilepsy Program at Brigham and Women's Hospital. “Preparing patients in advance for frequent, scheduled blood draws, and explaining that dose adjustments are anticipated and protective, helps normalize this process and reduces anxiety when changes become necessary.”

Although seizure type itself did not emerge as a differentiating factor, baseline seizure control and medication class mattered. Patients with unstable epilepsy or prior convulsions require especially close monitoring.

“If someone enters pregnancy with poor seizure control, I may check levels and adjust doses every two weeks,” Dr. Pennell said. “Convulsions pose risks to both mother and fetus, so we're particularly aggressive in those cases.”

She likened ASM management in pregnancy to insulin titration in gestational diabetes: frequent adjustments guided by physiologic change.

Implications for Future Studies and Guidelines

Dr. Pennell and other epilepsy experts emphasized that the findings reflect practice at large academic centers, potentially limiting generalizability to community-level clinical practice. Monthly monitoring requires infrastructure, lab access, and clinician time, resources not uniformly available across the country.

In addition, although the study included women with drug-resistant epilepsy, it excluded women with intellectual disability. Data were also strongest for a limited number of commonly used ASMs, leaving many newer or less frequently prescribed agents understudied.

“Out of more than 30 antiseizure medications available, we have robust pregnancy safety data for only a handful of drug options,” Dr. Pennell said.

Dr. Pennell is now collaborating with pharmacologist Angela Birnbaum, PhD, FAES, MLS(ASCP), of the University of Minnesota, on physiologically based pharmacokinetic modeling aimed at developing protocols, and eventually digital tools, that could guide dosing without relying solely on serum levels.

Current clinical guidelines recommend regular ASM monitoring during pregnancy but do not specify intervals. Dr. Pennell, who served on the most recent guidelines committee, expects future updates to become more granular as additional evidence emerges.

Dr. Hopp said future research must focus on implementation and access in addition to gathering pharmacokinetic data.

“We need studies that help us understand how to integrate this level of monitoring into routine practice, particularly in settings without pharmacists, specialty clinics, or easy access to frequent blood-level testing,” she said.

For now, clinicians may view the study as a pragmatic bridge between theory and practice. As Dr. Maturu summarized, “It replaces a lot of anecdotal decision-making with evidence and gives neurologists more confidence that they're doing the right thing for a very vulnerable population.”

Disclosures

Dr. Voinescu has received a speaker honorarium from SK Life Science. Drs. Hopp, Maturu, and Pennell had no disclosures.

Source: https://neurologytoday.aan.com/doi/10.1097/01.wnt.0001189220.34776.35