Temporal Trends Show Increased Use of Antiseizure Medications With Lower Teratogenic Risk

Valproic acid, which had been associated with a variety of major and minor malformations in pregnancy, remained barely unchanged in terms of use, dropping slightly from 12.4% to 10.1% over the 5-year period.

In a Japan-based cohort study of pregnant outpatient women with epilepsy who visited hospitals between 2016 and 2020, findings showed a temporal trend toward antiseizure medications (ASMs) with lower teratogenic risk, such as levetiracetam (Keppra; UCB Pharma) and lamotrigine (Lamictal; GlaxoSmithKline), whereas prescriptions for valproic acid remained relatively unchanged.1

Over the 5-year stretch, the numbers of pregnant women with epilepsy were 404, 421, 368, 378, and 386. The data showed that the proportions of levetiracetam and lamotrigine prescriptions significantly increased from 19.1% to 30.8% and from 12.1% to 18.4%, respectively, during that time period. In contrast, there was no temporal change in the proportion of valproic acid prescriptions, which was 12.4% in 2016 and 10.1% in 2020.1

Previous literature has shown that valproic acid is associated with a variety of major and minor malformations, including a 20-fold increase in neural tube defects, cleft lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay, endocrinology disorders, limb defects, and autism.2 In Japan, newer ASMs such as perampanel (Fycompa; Eisai) and lacosamide (Vimpat; UCB Pharma) have been available since 2016; however, changes in ASMs over time have not been identified after 2016. Led by Daisuke Kikuchi, PhD, department of pharmacy, Tohoku Medical and Pharmaceutical University Hospital, the study aimed to clarify the temporal trends in prescribed ASMs for Japanese pregnant women outpatients with epilepsy since 2016, using administrative data of hospital outpatients.

As of 2020, levetiracetam had the highest proportion of prescriptions in nonpregnant women with epilepsy, increasing from 15.3% to 24.7%, whereas the proportions of those on valproic acid or carbamazepine significantly decreased from 31.1% to 24.0% and from 18.1% to 14.2%, respectively.1 Similar to valproic acid, carbamazepine has previously been found to increase the rate of congenital anomalies, mainly neural tube defects, cardiovascular and urinary tract anomalies, and cleft palate.3

Among other notable findings showed the increased number of prescriptions for perampanel and lacosamide, 2 of the more recently approved ASMs. Despite the increase, Kikuchi et al wrote, "the proportion of prescriptions of these drugs for pregnant women outpatients with epilepsy in 2020 was still low: 2.8% for perampanel and 3.1% for lacosamide. The guidelines for the treatment of epilepsy indicate that there is insufficient data on pregnant women and childbirth for perampanel and lacosamide, and this may be why their use in pregnant women with epilepsy has not advanced."

There were several limitations to the study, including the fact that the pregnancy period during which ASM was prescribed was unknown in the database, and the ICD-10 codes related to pregnant women were extracted monthly. Additionally, ASMs can be indicated for migraine, mood disorders, and pain, in addition to epilepsy. Although the analysis excluded patients with migraine, mood disorders and pain were not excluded because of a wide variety of disease names, ensuing the possibility that ASMs were prescribed for conditions other than epilepsy.

A previous study showed that the most frequently prescribed drug for Japanese pregnant women was valproic acid before 2016.4 Despite this, levetiracetam was the most frequently prescribed drug in pregnant women outpatients with epilepsy during this study period, and its proportion has increased over time, Kikuchi et al noted.1 The reason for the increase in levetiracetam use may have been because of its lowered risk of teratogenicity than valproic acid in pregnant women with epilepsy.

The study investigators added, "Lamotrigine, like levetiracetam, is considered an ASM with a low risk of teratogenicity. One reason why the proportion of lamotrigine prescriptions was lower than of levetiracetam prescriptions in this study may be that the Pharmaceuticals and Medical Devices Agency in Japan warns about lamotrigine-related serious skin rashes."

1. Kikuchi D, Obara T, Miura R, et al. Trends in the prescription of anti-seizure medicines for pregnant women outpatients with epilepsy during 2016-2020 in Japan. Seizure. 2022;98:101-104. doi:10.1016/j.seizure.2022.04.007
2. Alsdorf R, Wyszynski DF. Teratogenicity of sodium valproate. Expert Opin Drug Saf. 2005;4(2):345-353. doi:10.1517/14740338.4.2.345
3. Matalon S, Schechtman S, Goldzweig G, Ornoy A. The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures. Repord Toxicol. 2002;16(1):9-17. doi:10.1016/s0890-6238(01)00199-x.
4. Ishikawa T, Obara T, Jin K, et al. Examination of the prescription of antiepileptic drugs to prenatal and postpartum women in Japan from a health administrative database. Pharmacoepidemiol Drug Saf. 2019;28(6):804-811. doi:10.1002/pds.4749.
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