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      ORIGINAL ARTICLE Year : 2023  |  Volume : 71  |  Issue : 5  |  Page : 928-932

Anti-Seizure Monotherapy and Early Abortion Under Real-World Conditions

Yuanyuan Chen1, Junhong Wu1, Hui Zhang1, Hongnian Chen1, Xin Tian1, Wei Jing2, Xuefeng Wang1
1 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
2 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing; Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China

Date of Submission08-Feb-2022Date of Decision06-Sep-2022Date of Acceptance15-Apr-2023Date of Web Publication18-Oct-2023

Correspondence Address:
Wei Jing
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing; Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan
China
Xin Tian
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing
China
Xuefeng Wang
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/0028-3886.388098

Background: Most pregnant epilepsy patients need to continue using anti-seizure medications (ASMs) to control epileptic seizures.
Objective: This study aimed to evaluate the risk of early abortion in pregnant epilepsy patients exposed to anti-seizure monotherapy.
Methods and Material: We prospectively followed up pregnant epilepsy patients treated with anti-seizure monotherapy in our epilepsy center between January 2010 and January 2020 under real-world conditions. Early abortion (spontaneous abortion in the first trimester of pregnancy) was the endpoint.
Results: Of 211 pregnancies exposed to monotherapy, including 40% (n = 85) to lamotrigine (LTG), 28% (n = 58) to oxcarbazepine (OXC), 15% (n = 32) to sodium valproate (VPA), 9% (n = 19) to levetiracetam, and 8% (n = 17) to carbamazepine, six ended in early abortion. The overall risk of early abortion in pregnant patients exposed to ASM monotherapy was 2.8% (n = 6) [95% confidence interval (CI) = 0.013–0.073]. The risk of early abortion was 2.4% (n = 2) (95% CI = 0.003–0.082) in women treated with LTG, 3.5% (n = 2) (95% CI = 0.004–0.115) in women treated with OXC, and 6.3% (n = 2) (95% CI = 0.008–0.208) in women treated with VPA. The relative risk of early abortion in the LTG, OXC, and VPA groups did not reach statistical significance.
Conclusions: Although the sample size of our study was small, these results indicate that the use of anti-seizure monotherapy in pregnant epilepsy patients may not increase the risk of early miscarriage. Larger prospective studies are needed for sufficient statistical analysis.

Keywords: Anti-seizure medication, early abortion, epilepsy, monotherapy, pregnancy
Key Message: The use of anti-seizure monotherapy in pregnant epilepsy patients may not increase the risk of early miscarriage. Larger prospective studies are needed for further research.

How to cite this article:
Chen Y, Wu J, Zhang H, Chen H, Tian X, Jing W, Wang X. Anti-Seizure Monotherapy and Early Abortion Under Real-World Conditions. Neurol India 2023;71:928-32

Yuanyuan Chen and Junhong Wu contributed to this work equally and share first authorship.

Epilepsy is a common disease of the central nervous system, with a prevalence rate of 7%.[1] There are more than 70 million patients with epilepsy worldwide, spanning all age ranges.[2] Studies have indicated that approximately 0.3–0.7% of pregnant women suffer from epilepsy,[3] and approximately 19–38% of pregnant women with epilepsy have an increased frequency of seizures during pregnancy.[4],[5] Seizures during pregnancy may have a significant impact on the growth and development of the fetus and may even lead to maternal death.[6] Therefore, most patients with epilepsy continue to use anti-seizure medications (ASMs) during pregnancy to control epileptic seizures.[7]

The first trimester of pregnancy is important for the growth and development of the fetus, and drugs have a great impact during this period. To date, there have been many studies on the use of ASMs in patients with epilepsy during pregnancy and pregnancy outcomes,[8],[9],[10] but few studies have been conducted to evaluate the risk of early spontaneous abortion with ASM monotherapy. Therefore, this study aimed to evaluate the risk of early abortion in patients with epilepsy using ASM monotherapy during pregnancy.

  Materials and Methods 

Patients

The study population included all pregnant patients using ASM monotherapy who were treated in the epilepsy specialist clinic of the First Affiliated Hospital of Chongqing Medical University from January 2010 to January 2020.

The inclusion criteria were as follows: (1) only women with epilepsy already followed up in the center and seeking a pregnancy, (2) patients who were seizure-free for at least 9 months before pregnancy, and (3) patients with pregnancies exposed to ASM monotherapy at the time of conception.

The exclusion criteria were as follows: (1) patients who received ASM polytherapy during pregnancy; (2) patients who required long-term drugs, other than ASMs, that could affect the development of the fetus; (3) patients who had co-morbidities that could increase the risk of abortion, such as a history of habitual abortion, diabetes, toxoplasmosis, or human immunodeficiency virus infection; (4) patients who had chromosomal or genetic abnormalities; (5) patients who had induced abortion; (6) patients or their husbands who had congenital malformations; (7) pregnant epilepsy patients who smoked or drank; and (8) patients who were lost to follow-up.

This study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. All patients or their families were informed of the study, and signed informed consent allowing the use of patient medical record data for research was obtained.

Research process

Upon the patient's first consultation, a specially trained physician conducted a detailed on-site interview of the patients and the witness (if possible), and the demographic information (living area, occupation education level), clinical characteristics (age at onset, type of epilepsy), and related auxiliary examination results [electro-encephalogram (EEG) and magnetic resonance imaging (MRI)] were recorded. Finally, the experienced epilepsy physician team diagnosed the patient according to the diagnostic criteria of the International League Against Epilepsy (ILAE) in 2010.[11] For all diagnosed patients, the epilepsy team selected an appropriate ASM after considering the efficacy and safety of the medication. Subsequently, the patient was instructed to consult the outpatient clinic of our center for the evaluation of the treatment effect after 4 weeks and then at least every 3 months for evaluation through the outpatient clinic. The patients started preparing for pregnancy after a 9-month absence of seizures and were supplemented with folic acid at 5 mg/day at least 3 months before the planned pregnancy. All individuals were regularly followed up by the same experienced epilepsy team at our epilepsy specialist clinic and at the obstetrics and gynecology department every month.

Definitions

Our data collection began in 2010; therefore, we classified epilepsy as general, focal, and unknown according to the 2010 ILAE revised edition.[11] Early abortion was defined as spontaneous abortion in the first trimester of pregnancy.[12] Patients' educational levels were categorized as illiteracy or primary school, secondary school, senior school, and college or above.

Statistical analysis

Statistical analysis was performed using SPSS statistical software version 26.0 (IBM, Armonk, New York). For non-normally distributed quantitative data, the median and inter-quartile range [M (P25, P75)] were used for statistical analysis. The risk of early abortion was compared between drugs using risk ratios (RRs), 95% confidence intervals (CIs), and P values from two-tailed tests.

  Results 

After excluding 17 patients lost to follow-up, ten patients with induced abortion, nine patients with chromosomal or genetic abnormalities, 12 patients with diseases that can cause early abortion, and 11 patients who had taken drugs other than ASMs that can influence abortion, a total of 211 patients treated with ASM monotherapy were included in our study [Figure 1]. Among them, 151 (71.6%) were in urban areas, 60 (28.4%) were in rural areas, 142 (67.3%) were employed, and 69 (32.7%) were unemployed. Twenty-one (10.0%) patients had an education level of illiterate or primary school, 97 (46.0%) had secondary school, 63 (30.0%) had senior school, and 30 (14.0%) had college or above level. There were 173 (82%) primiparous and 38 (18%) multiparous women. The median age of seizure onset was 13 years. The median maternal age was 26 years. A total of 66 (31.3%) people had focal epilepsy, 118 (55.9%) people had generalized epilepsy, and 27 (12.8%) people had unknown epilepsy. One hundred and fifty-eight (74.9%) people did not have seizures, 43 (21.8%) people had seizures less than three times, and 10 (4.3%) people had seizures more than three times during pregnancy; 74 (35.1%) and 137 (67.9%) people had normal and abnormal EEGs, respectively. Fifty-nine people (28.0%) had abnormal MRI, and 152 (72.0%) people had normal MRIs. The demographic data and clinical characteristics of the patients are shown in [Table 1].

Table 1: Demographic characteristics and clinical information of study participants (n=211)

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In our study, 40% of patients received lamotrigine (LTG) (n = 85), 28% received oxcarbazepine (OXC) (n = 58), 15% received sodium valproate (VPA) (n = 32), 9% received levetiracetam (LEV) (n = 19), and 8% received carbamazepine (CBZ) (n = 17). The average daily doses of LTG, OXC, VPA, LEV, and CBZ were 165.00 mg/d, 837.93 mg/d, 1226.56 mg/d, 1434.21 mg/d, and 852.94 mg/d, respectively [Table 2].

Six patients experienced early abortion during the follow-up period. Two patients taking LTG experienced early abortions in the 8th and 11th weeks of pregnancy, two patients taking OXC experienced early abortions in the 9th and 11th weeks of pregnancy, and two patients taking VPA experienced early abortions in the 7th and 11th weeks of pregnancy.

The total risk of early abortion with ASM monotherapy in our study was 2.8% (6/211) (95% CI = 0.013–0.073). The risk of early abortion was 2.4% (95% CI = 0.003–0.082), 3.4% (95% CI = 0.004–0.115), and 6.3% (95% CI = 0.008–0.208) in women receiving LTG, OXC, and VPA, respectively [Table 3].

Thereafter, we analyzed the RR of early abortion, 95% CI, and P values among patients in the LTG, OXC, and VPA groups with early abortion. The results showed that the RR of the three groups did not reach statistical significance (P > 0.05; Fisher's exact test) [Table 4].

  Discussion 

Abortion caused by drugs generally occurs during the organ formation period (18–60 days after conception), during which embryos undergo rapid growth, proliferation, migration, and maturation, especially in the central nervous system; moreover, they are most sensitive to drug toxicity during this period, and a higher drug dose results in a greater risk of early abortion.[13] Most patients with epilepsy continue to use ASMs during pregnancy to control epileptic seizures.[7] In this context, it is surprising that the current research focuses only on the risk for the overall outcome of the use of different ASMs in pregnant epilepsy patients,[8] and few studies have evaluated the risk of early abortion with antiepileptic monotherapy during pregnancy.

In our study, among the pregnant women with epilepsy who received the four most frequently used ASM monotherapies, the overall risk of early miscarriage was 2.8%, which is much lower than the risk of spontaneous miscarriage in the population.[14],[15],[16],[17],[18],[19] This may be partly explained by the small sample size of our study and the younger age of the pregnant women enrolled in the group. Previous studies have shown that maternal age has a strong relationship with the risk of miscarriage. The review performed by Quenby et al.[19] suggested that risk of miscarriage increased in women younger than 20 years and older than 35 years. Magnus et al.[20] and Frick et al.[21] also reported similar findings. Furthermore, our results also indicated that there was no significant difference in the risk of early abortion among the four groups, which may partially indicate that ASM monotherapy may not increase the risk of spontaneous miscarriage in pregnant women with epilepsy, which is consistent with the results of previous studies. EURAP's study found that intrauterine mortality was similar for different ASM monotherapies during pregnancy,[22] and Pariente et al.[23] also found no association between prenatal LTG monotherapy and variables associated with adverse pregnancy outcomes. Moreover, Annegers et al.[24] found that in utero ASM exposure was not associated with recognized fetal loss. However, some studies have also shown that more adverse pregnancy outcomes, such as major congenital malformations or fetal death, can occur after exposure to VPA monotherapy in utero,[8],[25] which can also exhibit a dose-dependent effect. Although clinicians avoid prescribing VPA for pregnant women with epilepsy, some patients still insist on using it because of the drug cost and intolerance to other drugs.[26]

The advantages of our study include a prospective design and the diagnosis and follow-up of the patients being performed by the same experienced epilepsy physician team. Moreover, before pregnancy, our subjects were all supplemented with folic acid, which is important for the development of the fetus.[27] However, our research also has certain limitations. First, our sample sizes were small and we did not study the influence of various factors on early abortion in pregnant epilepsy patients. For example, the concentration of various drugs is vital during pregnancy. A previous study showed that a high dose of some ASMs, especially LTG, is associated with major congenital malformations.[25] Ding et al.[28] found that LTG metabolism changes during pregnancy. To determine whether the concentrations of ASMs affect early abortion, larger prospective studies are needed for sufficient statistical analysis. Second, a control group consisting of untreated women with epilepsy was lacking because this is not achievable for women with active epilepsy. Third, because of ethical issues, the relevant autopsy data of aborted fetuses were lacking.

In conclusion, our research shows that the use of ASM monotherapy in pregnant epilepsy patients may not increase the risk of early miscarriage. Larger prospective studies are needed for sufficient statistical analysis. However, the specific mechanism leading to early abortion is still unclear, and additional research is needed in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

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  [Figure 1]
 
 
  [Table 1], [Table 2], [Table 3], [Table 4]