Women of childbearing age: What antiseizure medications are they taking?

Abstract

For a chronic disease such as epilepsy, management of seizures often involves lifelong medication use. The choice of antiseizure medication (ASM) prescribed to patients of childbearing age is important as patients are not always aware of when they will become pregnant; therefore, fetal exposure may not be avoidable. ASMs are also used for conditions other than epilepsy, thus the distribution of use may vary according to indication as management of non-epilepsy conditions may not be similar. Determining the ideal ASM target doses for a patient often involves identification of the concentration that balances seizure control and adverse events, thus maximizing efficacy whilst minimizing fetal exposure to drug. The primary aim of the study by Clavenna et al. was to examine the prescribing trends of ASMs in women of childbearing age and pregnant women in the Lombardy region of Italy.1 Data from four local health units were collected between 1 January 2010 and 31 December 2019, which included three databases containing outpatient drug prescription information, hospital discharge and birth certificates. Patient data from drug prescription and hospital discharge databases were matched using unique alphanumeric codes associated with every patient. The inclusion criterion for determination of the overall prevalence of ASM use was at least one prescription of an ASM during the study period with an ASM defined according to the N03A subgroup of the Anatomical Therapeutic Chemical (ATC) classification system. Women of childbearing age were defined as those women of ages 15–49 years, the age range mirroring the ages of women who gave birth in the authors' dataset. Men belonging to the same age group were included to provide a comparison control group. Several comparisons were made with the combined databases to understand the prevalence of ASM prescriptions in different groups. In women of childbearing age in 2019, approximately 15% received at least one ASM with a similar prevalence of use over the whole study period. The most frequent ASMs identified were pregabalin, valproate, topiramate and levetiracetam, ranging from 22.3% to 13.1%. In comparison to 2010, the prescription of valproate decreased by approximately 10% by 2019. This decreased trend in valproate use has been reported in other countries. For example, a nationwide outpatient study that included approximately 5.3 million permanent residents of Finland reported a decline in the use of valproate in women of child-bearing age.2 Interestingly the distribution of ASMs was similar in men except for topiramate, which was present in only 3.9% of men compared to 13.3% of women. It is well known that ASMs are used for multiple indications. It is difficult to speculate the distribution of ASM use since data pertaining to indication for each prescription was not reported in this study. Pregabalin, for instance, is classified as an ASM, but it is also indicated for neuropathic pain. Pregabalin is usually not reported as the most frequently prescribed medication in treating epilepsy patients. How a drug is used (as needed vs. every day) and what doses are used can vary across indications and can affect overall cumulative fetal exposure. The increased use in women compared to men of topiramate could reflect its use for migraine and not epilepsy since migraine has shown to be more prevalent in women.3 Initial and maintenance treatment of conditions with topiramate is not the same, thus it is difficult to predict overall fetal exposure without more information on the indication for ASM use. Additionally, the study does not provide data on the duration of ASM therapy. The decision to use only a single dispensing of ASM may skew results as it includes patients who may try a medication and discontinue it for lack of effectiveness. Including only women who received multiple months of therapy may have been useful as an indicator of chronic therapy. Additional criteria from hospital records were used in the Clavenna et al. study to determine ASM use during pregnancy as each participant needed to have evidence of giving birth, providing confirmation of a pregnancy. Use of ASM was determined at two time points: 12 and 24 months prior to birth, the 12-month period before birth being an indicator of fetal exposure. It appears that in 2019, only 139 individuals were included in the pregnancy portion of the study providing a relatively small sample size. For pregnant women receiving an ASM, levetiracetam (16.6%) and lamotrigine (16.6%) were the most frequently prescribed drugs, which is a similar distribution as other studies reporting ASM use in pregnant patients. The Maternal Outcomes and Neurodevelopmental Effects of anti-epileptic Drugs (MONEAD) study, one of the largest observational studies in pregnant women with epilepsy in the United States (351 pregnant women with epilepsy), showed that lamotrigine and levetiracetam were more frequently received by pregnant women with epilepsy between 2012 and 2016.4 Pregnancy registries established across the globe in the late twentieth century collect data on the prescribing trends of ASMs in pregnant women with epilepsy as well as rates of major congenital malformations (MCMs) in babies born to pregnant women with epilepsy. The North American pregnancy registry and EURAP International Registry of Antiepileptic Drugs and Pregnancy are two of the largest registries available. MCMs and negative effects on the cognitive development of infants born to women with epilepsy have been associated with the use of valproate.5 Lamotrigine (LTG) and levetiracetam (LEV) have a better safety profile in terms of rates of MCMs as well as long-term exposure outcomes and thus have become the most commonly prescribed ASMs in this population.6-8 The Nordic register, which included approximately 100,000 births, demonstrated no increase in the risk of autism spectrum disorder and/or intellectual disability associated with monotherapy of lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, gabapentin, pregabalin, clonazepam and phenobarbital.9 The Clavenna paper reports MCM rates among 1324 newborns exposed to ASMs during the 2012–2019 period irrespective of type of therapy (mono- vs. polytherapy). A decline in the incidence of MCMs in the Lombardy region was observed, which mirrors the outcomes from the EURAP pregnancy registry in women with epilepsy on monotherapy.10 Clavenna et al. found an MCM rate of 6.1% in newborns exposed to lamotrigine, which is high compared to data from the pregnancy registries. However, pertinent information needed to assess this finding is not available and the sample size for this conclusion is small, especially at the individual drug level. The NAAPR and EURAP show MCM rates of 2% and 2.9%, respectively, with LTG monotherapy exposure, similar to the general MCM risk in pregnant women without epilepsy.6-8 The association between MCM rates and lamotrigine appears to be dose dependent (i.e., 4.5% for doses ≥300 mg/day and 2.0% for doses <300/day).10 As dose was not available in the Clavenna et al., study, it is possible that higher doses of lamotrigine were being used in the mothers of infants who experienced MCMs. Therefore, information on dose of ASM prescription would improve the relevance of the study as there is a dose-dependent association between MCM and other ASMs including valproate, carbamazepine and phenytoin. The use of newer ASMs with a lower teratogenic potential such as levetiracetam and lamotrigine has increased.4 It is well established that the pharmacokinetics of some ASMs change significantly over the course of a pregnancy, increasing the potential for unanticipated issues; however, data are limited to the more frequently prescribed drugs with an emphasis on lamotrigine and levetiracetam. Data are sparse for medications that are prescribed in smaller numbers of individuals and the long-term effects due to in utero exposure is not well characterized. One medication that does show a negative outcome in children born to mothers who are receiving chronic ASM therapy are those infants who are exposed to valproate. Although the use of valproate is declining in women of childbearing age after the issuance of a black box warning by the United States Food and Drug Administration due to valproate's increased teratogenic potential, there are still patients where its use may be beneficial (i.e., most efficacious). If valproate is found to be the best choice, then a dose reduction should be considered. Starting long-term treatment with safer ASMs should be considered in people of childbearing age as it is difficult to anticipate pregnancy or switch treatment during pregnancy. There are several gaps in the current knowledge regarding use of ASMs during pregnancy, making the choice of ASM therapy in individuals of childbearing age challenging as they can affect the outcomes of both mother and child. Several factors such as age, duration of use, monotherapy vs. polytherapy, pregnancy status and the potential for drug interactions should be considered when prescribing chronic medication. Knowing prescribing patterns are important as they indicate the extent of exposure of a certain medication to a population. Equally important is how to describe the appropriate population for comparison through relevant inclusion and exclusion criteria in order to allow applicable conclusions. Use of medications for multiple indications can complicate analyses as criteria are more difficult to define especially as some effects are dose dependent. The authors do not have any conflicts of interest to declare.