Elsevier

Epilepsy & Behavior

Volume 29, Issue 1, October 2013, Pages 13-18
Epilepsy & Behavior

Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy

https://doi.org/10.1016/j.yebeh.2013.06.026Get rights and content

Highlights

  • We studied antiepileptic drug (AED) clearance in pregnancy in women with epilepsy.

  • Significant changes in AED clearance during pregnancy were observed.

  • When AED levels fell > 35% from preconception, seizures worsened significantly.

  • Monitoring of AED levels with dose adjustment is recommended during pregnancy.

Abstract

The aims of the study were to characterize the magnitude of clearance changes during pregnancy for multiple antiepileptic drugs (AEDs) and to assess seizure frequency and factors increasing seizure risk in pregnant women with epilepsy. A retrospective analysis was performed for 115 pregnancies in 95 women with epilepsy followed at the Emory Epilepsy Center between 1999 and 2012. Antiepileptic drug blood levels (ABLs) obtained during routine clinical practice were used to calculate AED clearance at multiple points during pregnancy. Antiepileptic drug doses and seizure activity were also recorded. The data were analyzed for changes in clearance and dose across pregnancy and for an association between ABL and changes in seizure frequency. Significant changes in clearance during pregnancy were observed for lamotrigine (p < 0.001) and levetiracetam (p < 0.006). Average peak clearance increased by 191% for lamotrigine and 207% for levetiracetam from nonpregnant baseline. Marked variance was present across individual women and also across repeat pregnancies in individual women. Despite increased AED dose across most AEDs, seizures increased in 38.4% of patients during pregnancy. Seizure deterioration was significantly more likely in patients with seizures in the 12 months prior to conception (p < 0.001) and those with localization-related epilepsy (p = 0.005). When ABL fell > 35% from preconception baseline, seizures worsened significantly during the second trimester when controlling for seizure occurrence in the year prior to conception. Substantial pharmacokinetic changes during pregnancy occur with multiple AEDs and may increase seizure risk. Monitoring of AED serum concentrations with dose adjustment is recommended in pregnant women with epilepsy. Further studies are needed for many AEDs.

Introduction

Management of epilepsy during pregnancy presents substantial challenges. Fetal antiepileptic drug (AED) exposure is associated with a dose-dependent increase in the risk of congenital malformations [1] and neurocognitive deficits [2], [3]. These risks must be balanced against the adverse health effects of seizures for both mother and fetus [4], [5].

Maintaining seizure control is complicated by pharmacokinetic alterations during pregnancy, including increased volume of distribution, elevated renal clearance, and induction of hepatic metabolism [4], [6]. These changes may result in decreased serum AED concentrations, although the degree of decline differs across medications and individuals [4], [6], [7].

Reductions in AED concentrations are associated with increased seizure frequency during pregnancy. This relationship has been shown most clearly for lamotrigine [8], with a similar trend observed for oxcarbazepine [9]. Accordingly, the American Academy of Neurology has recommended therapeutic drug monitoring for several AEDs during pregnancy, with the goal of maintaining serum levels near preconception baseline [10]. However, insufficient data are available to justify a recommendation for many AEDs currently in use [10], [11].

In this study, we aim to further characterize clearance changes across pregnancy for multiple AEDs by presenting a large series of pregnancies managed with periodic measurements of AED serum concentrations. Additionally, we present information on seizure control in women whose AED levels were used as a guide for dose adjustment.

Section snippets

Study population and design

This is a retrospective study of 135 women with epilepsy on AED therapy during pregnancy seen at the Emory Epilepsy Center (February 1999–February 2012). The Institutional Review Board of Emory University School of Medicine approved the study. Charts were reviewed for AED blood levels (ABLs) obtained through routine clinical practice, and patients were selected if they had at least one ABL for each trimester of pregnancy. Patients were excluded if any AEDs were added or removed during the

Results

One hundred fifteen pregnancies (113 singletons and two sets of twins) in 95 women were included in the study. In women with multiple pregnancies, each pregnancy was analyzed separately. Antiepileptic drug monotherapy was employed in 100 pregnancies, while 15 required two AEDs, and one required three (Table 1). Nine different AEDs were represented, with LTG used most frequently. Data from 22 pregnancies on LTG monotherapy have previously been included in a report of a prospective study

Discussion

This study demonstrates that changes in AED pharmacokinetics are common during pregnancy. We used apparent oral clearance as a dose- and weight-corrected measure of plasma AED concentrations and found significant increases in Cl that would produce large drops in AED serum concentration if not counteracted by dose adjustments, particularly for LTG and LEV monotherapies. We also observed significant variability across AEDs and individuals.

The most common AED examined in this study was LTG, which

Conclusions

Significant changes in AED clearance during pregnancy in women with epilepsy were observed in this retrospective study. Considerable variability was seen across AEDs and across individual women. Seizures worsened when AED levels fell > 35% from preconception levels. We recommend monitoring of AED levels during pregnancy with dose adjustment if indicated to maintain AED levels near preconception levels.

Conflicts of interest

Dr. Meador reports receiving research support from GlaxoSmithKline, EISAI Medical Research, Myriad Pharmaceuticals, Marinus Pharmaceuticals, NeuroPace, Pfizer, SAM Technology, Schwartz Biosciences, UCB Pharma, the Epilepsy Foundation, and the NIH; received salary support to Emory University from the Epilepsy Consortium for research consultant work related to NeuroPace, Novartis, Upsher-Smith, and Vivus; served as a consultant for Eisai, GlaxoSmithKline, Johnson and Johnson (Ortho McNeil),

Acknowledgments

This work was supported by the National Institutes of Health (NS038455-11 to KJM and PBP).

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