Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy
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).
References (27)
- et al.
Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry
Lancet Neurol
(2011) - et al.
Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts
Epilepsy Res
(2008) - et al.
Seizure deterioration in women treated with oxcarbazepine during pregnancy
Epilepsy Res
(2009) - et al.
Individual changes in lamotrigine plasma concentrations during pregnancy
Epilepsy Res
(2005) - et al.
Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin
Epilepsy Res
(2002) - et al.
Effect of levetiracetam on the pharmacokinetics of antiepileptic drugs: a pooled analysis of data from randomized clinical trials
Epilepsy Res
(2005) - et al.
Serum concentration/dose ratio of levetiracetam before, during and after pregnancy
Seizure
(2008) - et al.
Long-term developmental outcome of children of women with epilepsy, unexposed or exposed prenatally to antiepileptic drugs
Drug Saf
(2010) - et al.
The effect of pregnancy on seizure control and antiepileptic drugs in women with epilepsy
Rev Neurol Dis
(2011) Antiepileptic drug pharmacokinetics during pregnancy and lactation
Neurology
(2003)