Antiseizure Medication Concentrations During Pregnancy: Results From the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study

Abstract

Importance: During pregnancy in women with epilepsy, lower blood concentrations of antiseizure medications can have adverse clinical consequences.

Objective: To characterize pregnancy-associated concentration changes for several antiseizure medications among women with epilepsy.

Design, setting, and participants: Enrollment in this prospective, observational cohort study, Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), occurred from December 19, 2012, to February 11, 2016, at 20 US sites. Enrolled cohorts included pregnant women with epilepsy and nonpregnant control participants with epilepsy. Inclusion criteria were women aged 14 to 45 years, an intelligence quotient greater than 70 points, and, for the cohort of pregnant women, a fetal gestational age younger than 20 weeks. A total of 1087 women were assessed for eligibility; 397 were excluded and 230 declined. Data were analyzed from May 1, 2014, to June 30, 2021.

Exposure: Medication plasma concentrations in women taking monotherapy or in combination with noninteracting medications. The cohort of pregnant women was monitored through 9 months post partum, with similar time points for control participants.

Main outcomes and measures: Dose-normalized concentrations were calculated as total or unbound plasma medication concentrations divided by total daily dose. Phlebotomy was performed during 4 pregnancy study visits and 3 postpartum visits for the pregnant women and 7 visits over 18 months for control participants. The primary hypothesis was to test pregnancy changes of dose-normalized concentrations from nonpregnant postpartum samples compared with those of control participants.

Results: Of the 351 pregnant women and 109 control participants enrolled in MONEAD, 326 pregnant women (median [range] age, 29 [19-43] years) and 104 control participants (median [range] age, 29 [16-43] years) met eligibility criteria for this analysis. Compared with postpartum values, dose-normalized concentrations during pregnancy were decreased by up to 56.1% for lamotrigine (15.60 μg/L/mg to 6.85 μg/L/mg; P < .001), 36.8% for levetiracetam (11.33 μg/L/mg to 7.16 μg/L/mg; P < .001), 17.3% for carbamazepine (11.56 μg/L/mg to 7.97 μg/L/mg; P = .03), 32.6% for oxcarbazepine (11.55 μg/L/mg to 7.79 μg/L/mg; P < .001), 30.6% for unbound oxcarbazepine (6.15 μg/L/mg to 4.27 μg/L/mg; P < .001), 39.9% for lacosamide (26.14 μg/L/mg to 15.71 μg/L/mg; P < .001), and 29.8% for zonisamide (40.12 μg/L/mg to 28.15 μg/L/mg; P < .001). No significant changes occurred for unbound carbamazepine, carbamazepine-10,11-epoxide, and topiramate, although a decrease was observed for topiramate (29.83 μg/L/mg to 13.77 μg/L/mg; P = .18). Additionally, compared with dose-normalized concentrations from control participants, pregnancy dose-normalized median (SE) concentrations decreased significantly by week of gestational age: carbamazepine, -0.14 (0.06) μg/L/mg (P = .02); carbamazepine unbound, -0.04 (0.01) μg/L/mg (P = .01); lacosamide, -0.23 (0.07) μg/L/mg (P < .001); lamotrigine, -0.20 (0.02) μg/L/mg (P < .001); levetiracetam, -0.06 (0.03) μg/L/mg (P = .01); oxcarbazepine, -0.14 (0.04) μg/L/mg (P < .001); oxcarbazepine unbound, -0.11 (0.03) μg/L/mg (P < .001); and zonisamide, -0.53 (0.14) μg/L/mg (P < .001) except for topiramate (-0.35 [0.20] μg/L/mg per week) and carbamazepine-10,11-epoxide (0.02 [0.01] μg/L/mg).

Conclusions and relevance: Study results suggest that therapeutic drug monitoring should begin early in pregnancy and that increasing doses of these anticonvulsants may be needed throughout the course of pregnancy.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Pennell reported receiving research support from the National Institutes of Health and the Karger Foundation; honoraria for grant reviews from Harvard Medical School and the National Institutes of Health; advisory board honorarium from Harvard School of Public Health; speaking honoraria and/or travel reimbursements from the American Epilepsy Society and American Academy of Neurology; and royalties from UpToDate Inc. Dr Karanam reported being employed by Pfizer Inc during the conduct of the study, and his work on this study was during graduate school at the University of Minnesota. Dr Meador reported receiving research support from the National Institutes of Health, Eisai, Sunovion, and Medtronic Inc; receiving university payment for research consultant time from The Epilepsy Study Consortium related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals; being a coinvestigator and director of Cognitive Core of the Human Epilepsy Project for the Epilepsy Study Consortium; and being on the editorial boards for Neurology, Cognitive and Behavioral Neurology, Epilepsy & Behavior, and Epilepsy & Behavior Case Reports. Dr Gerard reported receiving research support from Xenon and Sunovion Pharmaceuticals and speaking honoraria from GW Pharmaceuticals and Neurology Week. Dr Penovich reported receiving support for participation in speakers bureaus and on advisory boards for Neurelis, SK Biopharmaceuticals, UCB Pharma, and for advisory work for Lvis Corporation and Engage Therapeutics; and receiving personal fees from Greenwich Biosciences, Eisai, and Sunovian outside the submitted work. Dr McElrath reported receiving research support from the National Institutes of Health, NxPrenatal Inc, and Mirvie Inc; receiving compensation for service on the scientific advisory boards of NxPrenatal Inc, Mirvie Inc, Hoffman-LaRoache Ltd, and Momenta Pharmaceuticals Inc; and being a paid consultant for Comanche Biopharma Inc. Dr McElrath reported receiving royalties from UpToDate Inc. Dr Birnbaum reported receiving research support from the National Institutes of Health, Epilepsy Foundation, Supernus Pharmaceuticals, and Veloxis Pharmaceuticals and being a coinventor of a patent for intravenous carbamazepine (Lundbeck Pharmaceuticals). No other disclosures were reported.

Figures

Figure 1.. Lamotrigine and Levetiracetam Dose-Normalized Concentrations During Pregnancy and the Postpartum Period

Boxplots showing lower dose-normalized concentrations during pregnancy and the postpartum period for lamotrigine (A) and levetiracetam (B). The midline of the box plots indicates the median, and the box indicates the 25th and 75th percentiles. Whiskers represent 1.5 times the IQR. Circles represent outliers. The postpartum period and the first trimester were used as comparators. aP < .001.

Figure 2.. Zonisamide, Lacosamide, and Topiramate Dose-Normalized Concentrations During Pregnancy and the Postpartum Period

Boxplots showing the median lower dose-normalized concentrations during pregnancy and the postpartum period for zonisamide (A), lacosamide (B), and topiramate (C). The midline of the box plots indicates the median, and the box indicates the 25th and 75th percentiles. Whiskers represent 1.5 times the IQR. Circles represent outliers. The postpartum period was used as a comparator. aP < .001. bP < .05.

Figure 3.. Total and Unbound Oxcarbazepine Dose-Normalized Concentrations During Pregnancy and the Postpartum Period

Boxplots showing statistically significant median lower dose-normalized concentrations during pregnancy and the postpartum period for total (A) and unbound (B) oxcarbazepine (measured as total and unbound monohydroxy derivative). The midline of the box plots indicates the median, and the box indicates the 25th and 75th percentiles. Whiskers represent 1.5 times the IQR. Circles represent outliers. The postpartum period was used as a comparator. aP < .001. bP < .01.