Abstract
Background and Objectives To assess whether increased seizure frequency during pregnancy and postpartum is influenced by epilepsy type, seizure location, and antiseizure medications.
Methods Clinical data were collected in a longitudinal prospective database of pregnant women with epilepsy at Brigham and Women's Hospital. Within each individual participant, baseline seizure frequency was calculated for the 9 months before conception, and whether seizure frequency increased during pregnancy or the postpartum period was determined. Seizure frequency was calculated for each 4-week interval during pregnancy. Generalized estimating equations for logistic regression were applied.
Results Ninety-nine patients contributing 114 pregnancies were included from 2013 to 2018. Increased seizure frequency occurred more often during pregnancies of women with focal vs generalized epilepsy (21.1% vs 5.3%, odds ratio [OR] 4.70, 95% confidence interval [CI] 1.00–22.00; p = 0.0497). Among women with focal epilepsy, increased seizure frequency occurred more often in those with frontal lobe epilepsy (OR 8.00, 95% CI 2.19–29.21; p = 0.0017). There was no difference in seizure worsening in the postpartum period between the focal and generalized (11.1% vs 9.1%; p = 0.4478) or frontal and other focal (18.8% vs 6.0%; p = 0.1478) epilepsy groups. Pregnancies on polytherapy had higher odds of seizure worsening compared to monotherapy (OR 8.36, 95% CI 2.07–33.84; p = 0.0029), regardless of the medication or epilepsy type. A lack of preconception seizure freedom was also associated with increased seizure frequency during pregnancy (OR 6.418; p = 0.0076).
Discussion Women with focal epilepsy have higher likelihood of seizure worsening during pregnancy compared to women with generalized epilepsy; frontal lobe epilepsy poses an especially elevated risk. Polytherapy and lack of preconception seizure freedom are additional predictors for an increased likelihood of seizure worsening.
Glossary
- ASM=
- antiseizure medication;
- CI=
- confidence interval;
- OR=
- odds ratio;
- RTC=
- ratio-to-target concentration;
- WWE=
- women with epilepsy
Prior studies suggest that seizure frequency in the 9 months before pregnancy is a good predictor of seizure frequency during pregnancy, although focal epilepsy syndromes and treatment with specific antiseizure medications (ASMs) may be associated with a higher rates of seizure worsening during pregnancy.1,-,4 These studies did not incorporate analyses of localization or details about ASM concentrations. Studies of postpartum seizure frequency are scarce.4
We examined the effect of the epilepsy type and seizure onset localization and ASM regimen and concentrations on seizure frequency during pregnancy and the postpartum period.
Methods
Study Design
Women with epilepsy (WWE) followed up at Brigham and Women's Hospital (by P.B.P. and P.E.V.) with pregnancies completed between 2011 and 2019 were included. Exclusion criteria included abortions, seizure onset during pregnancy, unclear preconception seizure frequency, nonepileptic seizures, poor adherence, enrollment in another epilepsy study, and ASM discontinuation during pregnancy.
WWE were followed up with at least 1 visit per trimester, 1 to 2 postpartum visits, and monthly phone calls/electronic patient messaging for therapeutic drug monitoring. Information related to ASM dose adjustments, serum concentrations, seizure types/frequency, and pregnancy outcome was prospectively recorded in a clinical database (created in 2011 by P.B.P.).
Seizure Frequency Analysis
Seizures were recorded prospectively over the 9 months before conception, during pregnancy, and during 6 to 9 months postpartum. Patients presenting to our practice later reported their seizure frequency for the same interval until their first visit date.
Average 4-week seizure frequency was calculated for the 9 preconception months and used as baseline seizure frequency. Seizure frequency was recorded for each 4-week interval during pregnancy; if 1 or more 4-week intervals had any increase above baseline seizure frequency, then the pregnancy was categorized as increased seizure frequency. Postpartum analysis included only pregnancies with ≥6 months of seizure tracking. Average 4-week seizure frequency was calculated for the available 6 to 9 postpartum months and compared with the baseline seizure frequency.
Myoclonic jerks were excluded from this analysis given the difficulty in quantifying them. All other seizure types, including focal aware seizures, within an individual patient were summed together for this analysis.
ASM Serum Concentration Analysis
All WWE included in the study were similarly managed with monthly blood draws and dose adjustments to compensate for pregnancy-related clearance changes and to maintain an individualized target concentration, established from the patient's preconception/baseline concentration. A ratio-to-target concentration (RTC) was calculated, as described previously (trimester average/target ASM serum concentration)5,-,7 for patients with seizure worsening to assess for inadequate dose adjustments (RTC <0.65). We excluded patients without a target ASM serum concentration.
Data Analysis
Generalized estimating equations for logistic regression evaluated the differences between categories of interest (focal vs generalized, frontal lobe vs other focal epilepsies, monotherapy vs polytherapy, seizure status preconception, and focal localization–ASM regimen combined). Clinical covariates included were age and race. The Fisher exact test was used to test the relationship between frontal epilepsy and polytherapy.
Standard Protocol Approvals, Registrations, and Patient Consents
Mass General Brigham Institutional Review Board approved the analysis of patients' epilepsy-related clinical information and determined that the study was exempt from obtaining informed consent because the information collected was used primarily for clinical purposes.
Data Availability
Individual deidentified data and the statistical analysis will be shared on request over the next 2 years.
Results
Clinical Characteristics
Ninety-nine women 20 to 44 years of age and 114 pregnancies were included (Table 1). Adequate postpartum seizure frequency was available for 102 pregnancies.
Clinical Characteristics of Patients Included in the Study
At conception, 3 WWE were on no ASMs, 11 were on ASM polytherapy, and 100 were on ASM monotherapy with lamotrigine (n = 62) followed by levetiracetam (n = 25) as the most common ASMs (Table 1). Two patients had an ASM added during pregnancy (1 on monotherapy and 1 on no ASMs).
Age was not a significant covariate for seizure worsening during pregnancy (p = 0.7865). Given the disproportionately White-predominant population, we could not assess the influence of race (Table 1).
Seizure Outcome During Pregnancy as It Corresponds to Preconception Seizure Status in Women With Focal Epilepsy
Differential Risk of Increased Seizure Frequency During Pregnancy or Postpartum With Different Epilepsy Types
Increased seizure frequency occurred in 21.1% pregnancies of women with focal epilepsies compared to 5.3% with generalized epilepsy (odds ratio [OR] 4.70, 95% confidence interval [CI] 1.00–22.00; p = 0.0497). No differences were noted between the 2 groups during the postpartum period (9.1% vs 11.1%, respectively; p = 0.4478) (Figure 1A).
Comparison between groups with seizure worsening during pregnancy and during first 9 months postpartum for (A) generalized epilepsies (blue) and focal epilepsies (red) and (B) frontal epilepsies (purple) and all other focal epilepsies (orange). *Significant differences are noted only during pregnancy months.
Seizure worsening occurred in 52.9% of pregnancies of women with frontal lobe epilepsy compared to 11.9% of women with other focal epilepsies (OR 8.000, 95% CI 2.191–29.210; p = 0.0017) (Figure 1B). Most women with other focal epilepsy had temporal lobe epilepsy; thus, further dividing by seizure onset localization was not meaningful. In the postpartum period, the frontal vs other focal seizure worsening groups did not differ significantly (18.8% vs 6.0%; p = 0.1478).
Due to concerns that baseline seizure freedom status might be confounding the observed relationship between frontal lobe epilepsy and increased seizures during pregnancy, we added baseline seizure freedom into our generalized estimating equation model estimating increased seizures during pregnancy by frontal lobe epilepsy vs other focal epilepsies (Table 2). In this updated model, frontal lobe epilepsy was still associated with increased seizure frequency during pregnancy (OR 8.68; p = 0.002). In addition, a lack of baseline seizure freedom was associated with increased seizure frequency (OR 6.42; p = 0.008). The absence of a statistically significant interaction between these 2 variables (p = 0.90) suggests that each variable contributes independently to increased seizure risk during pregnancy.
For the pregnancies with seizure worsening during pregnancy, seizure frequency increased by >50% in all cases, with the exception of 1 patient who experienced <50% increase in her absence seizures.
In plotting the number of pregnancies with increased seizure frequency for each 4-week intervals during pregnancy, we observed a trend for more patients with frontal lobe epilepsy to experience seizure worsening starting at 20-week gestational age (Figure 2).
Note different units chosen for the vertical axes. Pregnancies of patients with frontal epilepsy (purple, n = 9) are represented on the right axis; those of patients with other focal (orange; n = 7) and generalized (blue; n = 2) epilepsy, as well as all together (black, n = 18), are represented on the left axis.
Correlations Between ASMs and Seizure Frequency During Pregnancy
ASM polytherapy was associated with 8-fold higher risk of seizure worsening compared with monotherapy (OR 8.3637, 95% CI 2.0672–33.8351; p = 0.0029), even after adjustment for epilepsy type. However, the effect did not remain statistically significant (OR 8.3012, 95% CI 0.9470–72.7770; p = 0.0560). After polytherapy was added to the model, women with frontal lobe epilepsy were still more likely to have increased seizure frequency during pregnancy than the rest (adjusted OR 8.3964, 95% CI 2.0614–34.1991; p = 0.0030). There was no significant relationship between frontal epilepsy type and polytherapy (p = 0.3674). Both polytherapy and frontal focal epilepsy were independently associated with increased seizure frequency in pregnancy.
There was no significant correlation between an increase in seizure frequency during pregnancy for any ASM monotherapy compared to the rest of monotherapies: levetiracetam (p = 0.3693, n = 28), lamotrigine (p = 0.5617, n = 61), and carbamazepine/oxcarbazepine (p = 0.0814, n = 11).
A secondary analysis of 157 laboratory values from women with seizure worsening showed values >0.65 for 100% ASM RTCs of the women with frontal lobe epilepsy and 82.4% of the other women, demonstrating adequate efforts for dose adjustments.
Discussion
Our study suggests that the localization of seizure onset may be a determinant of seizure frequency worsening during pregnancy. We found that patients with focal epilepsy, especially those with frontal epilepsy, are at a higher risk of seizure worsening, despite adequate therapeutic dose monitoring.
In our relatively small group of women with frontal lobe epilepsy, seizure frequency during pregnancy had 2 peaks: one in the first trimester and another late in the second trimester, consistent with a prior report for women with focal epilepsy.4 Pennell et al.8 in a multicenter study recently showed that the rate of seizure frequency worsening in WWE during pregnancy is not different from that of nonpregnant WWE over a similar time interval. Our single-center study does not have a nonpregnant control cohort, and our analysis is based only on within-patient seizure variation. It has, however, the advantage of a consistent management strategy. Of note, the rate of seizure worsening within patients with focal seizures is similar in our study compared with this larger multicenter study (21.1% vs 23.9%). Our analysis included all seizure types combined and did not test for differences between different seizure types (aware, impaired awareness, progressing to bilateral tonic-clonic).
Frontal lobe seizures are frequently sleep disruptive, and sleep deprivation may play a role in the difference observed. The apparent improvement during postpartum compared with pregnancy goes against this explanation. Future studies should include measures of sleep.
Patients with frontal lobe epilepsy tend to be refractory and require polytherapy.9 Our women with frontal lobe epilepsy are similarly less likely to be seizure-free and are more frequently on polytherapy compared with the rest. We were able to show that frontal lobe epilepsy is a strong predictor for an increased seizure frequency during pregnancy independently of polytherapy and preconception seizure status. Larger studies will be needed to validate these findings.
There may be an underestimation of the true rate of seizure worsening during the postpartum period because we taper the ASM dose in the first few weeks postpartum to a dose higher than the preconception dose. Similar adjustments were performed for all postpartum women in the study. Thus, the comparison between different epilepsy types remains valid.
Despite its limitations, our study offers important information to recommend closer monitoring of pregnant patients with focal and, in particular, frontal lobe epilepsy.
Study Funding
This study was supported in part by the NIH, National Institute of Neurologic Disorders and Stroke (U01-NS038455) (P.B.P.), the Brigham Women's Brain Initiative and Building Interdisciplinary Research Careers in Women's Health Associate Scholarship (P.E.V.), and the Karger Foundation (A.E.).funding
Disclosure
P.E. Voinescu received honoraria for lectures from Brainwork. A.N. Ehlert, C.P. Bay, and S. Allien report no disclosures relevant to the manuscript. P.B. Pennell reports grants from the National Institute of Neurologic Disorders and Stroke, National Institute of Mental Health, and Karger Fund during the conduct of the study, as well as personal fees from UpToDate, Inc and Wolters Kluwer, outside the submitted work. Go to Neurology.org/N for full disclosures.
Appendix Authors
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
See page e876
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- Received January 17, 2021.
- Accepted in final form October 25, 2021.
- © 2021 American Academy of Neurology
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