Happy Healthy Parents and Babies: Levetiracetam,Lacosamide and Epilepsy Pregnancy Registries

Abstract

Fallik N, Trakhtenbroit I, Fahoum F, Goldstein L. Therapeutic drug monitoring in pregnancy: Levetiracetam. Epilepsia. 2024 May;65(5):1285-1293. Epub 2024 Feb 24. PMID: 38400747. doi:10.1111/epi.17925.

Objective: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. Methods: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020–2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1–2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. Results: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the third trimester, the most significant C/D decrease was observed at the first trimester (slope = .85), with no significant change in the second trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the third trimester. Significance: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period.

Perucca P, Bourikas D, Voinescu PE, Vadlamudi L, Chellun D, Kumke T, Werhahn KJ, Schmitz B. Lacosamide and pregnancy: data from spontaneous and solicited reports. Epilepsia. 2024 May;65(5):1275-1284. Epub 2024 Feb 27. PMID: 38411300. doi:10.1111/epi.17924.

Objective: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. Methods: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. Results: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. Significance: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.

Commentary

In June of 2024, the American Academy of Neurology, American Epilepsy Society, and Society for Maternal-Fetal Medicine collaborated to publish new guidelines on the use of antiseizure medications (ASMs) in people with epilepsy of childbearing potential or PWECP. ¹ Following an extensive literature search, the authors recommended using lamotrigine, levetiracetam or oxcarbazepine when appropriate based on diagnosed epilepsy syndrome in PWECP given the lower risk of major congenital malformations (MCM) compared to other ASMs. Regarding several newer or less utilized antiseizure medications including lacosamide, the group recommended cautioning PWECP that evidence is limited about pregnancy-related outcomes.

A recently estimated 1.3 million PWECP live in the United States ² and many are now treated with levetiracetam given the evidence of low risk for MCM, as stated in the guidelines. Oxcarbazepine is not appropriate for generalized epilepsy and lamotrigine levels can fluctuate significantly during pregnancy and after delivery and for these reasons, levetiracetam may be the preferred choice when effective. Guidance regarding the management of antiseizure medication (ASM) doses during pregnancy included titrating to a dose that minimizes seizures and optimizes fetal outcomes without further details. Fortunately, an article was recently published in Epilepsia in February of 2024 providing additional evidence regarding monitoring of levetiracetam (LEV) levels in pregnancy. ³ This retrospective study investigated a cohort of 38 pregnant people with epilepsy (PWE) on levetiracetam monotherapy or polytherapy and had at least one LEV blood level measurement during pregnancy in a specialized epilepsy center in Israel. A total of 263 samples were collected and LEV concentration/dose (C/D) was calculated. There was an initial decrease in LEV C/D in the first trimester compared to the third and a significant increase post-partum. To address changes in levels over time (measured every 1-2 months during pregnancy), LEV doses were increased by an average of 75%. Of the 38 individuals studied, 5 (17%) had breakthrough seizures during pregnancy. These included two pregnant PWE in the setting of hyperemesis gravidarum with decreased LEV absorption, two whose LEV concentrations decreased in pregnancy, and one during transition from valproic acid to LEV during pregnancy.

These findings emphasize the need to closely monitor LEV levels during pregnancy, particularly in PWE who develop hyperemesis gravidarum or in whom transitioning from one ASM during pregnancy to LEV is deemed medically necessary. These additional findings are in line with the recent published guidelines. ¹ Seizure outcomes could not be meaningfully assessed because study participants on polytherapy were included and may have adjusted the doses of these other treatments during pregnancy as well. However, this study provides additional guidance and emphasis on the importance of monitoring and reacting quickly to blood level changes of levetiracetam frequently during pregnancy.

A second study published in the same issue of Epilepsia, ⁴ focused on the evaluation of 76 PWECP during pregnancy treated with LCM as monotherapy and 159 treated with lacosamide (LCM) as polytherapy in the UCB Pharma global pharmacovigilance database. The study was funded by UCB Pharma. The authors concluded that no new safety issues were identified among these individuals and their offspring.

While these results are reassuring and suggest that lacosamide may be reasonable to add to the list of antiseizure medications safe to use during pregnancy, pharmacovigilance databases are inherently biased in that they rely on self-reporting of pregnant PWE on their medication and are typically sponsored by pharmaceutical companies that produce a specific patented treatment with no comparison group. However, the same can be true for many pregnancy registries as well, which are considered the gold standard for collecting and reporting data on safety of ASMs in pregnancy.^5–7 The definitions of minor and major malformations, which are included in the registry, duration of follow up, whether data are collected prospectively or retrospectively and based on self- or provider-report, and comparison groups vary between studies.

In addition, pregnancy registries and pharmacovigilance databases typically focus on “antiepileptic drugs” and most often do not take into account other treatments used by PWECP including ketogenic diet therapies ⁸ and neurostimulation devices. ² These are relevant as the safety of ketogenic diet therapies used in PWECP is also unknown. ⁹ Ketone bodies produced by following a low fat, high carbohydrate diet can cross the placenta and potentially impact the risk of fetal malformations. Ketogenic diet therapies can also alter the serum concentrations of several antiseizure medications. ¹⁰ Adjustment of neurostimulation devices during pregnancy has the potential to alter seizure control. A reduction in seizures with one or more of these nonpharmacologic therapies could result in fewer or lower doses of antiseizure medications and could potentially lower the risk of ASM associated teratogenicity and adverse cognitive outcomes in offspring of PWECP. Awareness that a PWECP is treated with these therapies as an adjunct to antiseizure medications is essential to classify an ASM as truly a “monotherapy” as these therapies may impact treatment outcomes for a PWE and their offspring.

Design and implementation of a single international pregnancy registry that collects prospective data in PWECP considering pregnancy, while pregnant, and for an agreed-upon duration following delivery, would be ideal. Such a large database would accumulate data more rapidly than separate national registries and industry-sponsored pharmacovigilance studies and allow for earlier discoveries regarding pregnancy risks with newer ASMs. ⁷ Standardization of such a registry would require agreement among investigators regarding data collection, including patient and offspring demographics, recording of doses of ASMs, changes in ASM dose, and serum ASM levels as well as deciding whether this data is collected by provider-report versus self-report or through electronic medical record extraction. There are benefits and disadvantages of each approach and all would require patient consent and/or deidentification in accordance with local laws regarding protection of human subjects. In addition, the definition of and screening process for detecting fetal malformations would need to be clearly defined as well as appropriate comparison cohorts. Finally, inclusion of nonpharmacologic therapies in the registries would be necessary. The greatest anticipated practical barriers to this approach include the cost of staff to collect and analyze data, and determination of who controls and has access to the data. However, the importance of obtaining this information with a rigorous and rapid approach cannot be over-emphasized.