Seizure control and treatment in pregnancy: Observations from the EURAP Epilepsy in Pregnancy Registry
The Eurap Study Group;
Commented by , 22 Mar 2006
Background
Endocrine/metabolic changes during pregnancy may affect seizure susceptibility as well as the pharmacokinetics of antiepileptic drugs (AEDs) (ref. 1; ref. 2).
Aim
To investigate changes in seizure control and AED treatment during pregnancy in women with epilepsy (WWE).
Methods
- Non-interventional prospective observation of 1,956 pregnancies in 1,882 WWE enrolled in a multinational pregnancy registry (ref. 3) within gestation week 16. All women were on AEDs at enrolment.
- Seizures were classified as generalized tonic-clonic (convulsive) or other seizure types (non-convulsive) and categorized in each trimester by frequency (no seizures, <1/month, monthly, weekly, more than weekly, daily). AED changes were recorded.
Results
- 58.3% of women were seizure-free during the entire observation period. Using the first trimester as reference, seizure frequency remained unchanged throughout pregnancy in 63.6%, increased in 17.3% and decreased in 15.9%. Seizures during deliver occurred in 3.3%.
- Seizure occurred more commonly in patients with partial epilepsy and on polytherapy.
- 36 cases of status epilepticus (12 convulsive) resulted in one case of stillbirth but no other cases of miscarriage or adverse maternal outcome.
- Number or doses of AEDs increased more often in women with seizures and in those on monotherapy with lamotrigine or oxcarbazepine. Women on oxcarbazepine monotherapy were also more likely to have convulsive seizures and to show seizure deterioration.
Professor Perucca's comments
Prior to this work, the largest prospective studies on seizure control in pregnancy enrolled less than 160 patients (ref. 4; ref. 5; ref. 6; ref. 7; ref. 8). The strengths of this study are its uniquely large sample size, its prospective design and a population drawn from a wide range of settings (>300 reporting physicians from 30 countries in 4 continents). The fact that 60% of WWE were seizure-free throughout and 80% were on monotherapy suggests that, compared with most previous studies, the population was less biased towards severe epilepsy cases.
The study, however, is not free from drawbacks:
- it was not population-based
- there was no control group of non-pregnant WWE
- seizure frequency was recorded by categories rather than quantitated precisely
- changes in seizure control were assessed versus the first trimester, not versus a pre-pregnancy baseline. Drawbacks derive in part from the fact the registry is primarily designed to investigate birth defects (ref. 3), rather than seizure frequency.
In agreement with previous reports (ref. 2; ref. 4; ref. 5; ref. 9; ref. 10; ref. 11), the data indicate that most WWE do not show major changes in seizure control during pregnancy. This is a reassuring message for WWE planning pregnancy.
Perhaps the most interesting finding is that only one of 36 cases of status epilepticus was associated with stillbirth, and none with maternal mortality. This contrasts with the commonly held view, based on retrospective and probably biased case reports (ref. 12), that status epilepticus during pregnancy results in high fetal and maternal mortality.
Another interesting finding was that increases in AED number or doses after the first trimester occurred more often in patients on oxcarbazepine or lamotrigine monotherapy. Women on oxcarbazepine were also more likely to show seizure deterioration during pregnancy. Although interpretation should be cautious due to non-randomized treatment allocation, these findings could be related to pharmacokinetic changes.
Although the blood levels of most AEDs decrease during pregnancy (ref. 13; ref. 14), pharmacokinetic changes are known to be especially prominent for lamotrigine (ref. 15; ref. 16; ref. 17; ref. 18). Similarly to lamotrigine, the active mono-hydroxy-derivative (MHD) of oxcarbazepine is cleared by glucuronide conjugation (ref. 19), and preliminary data suggest that MHD concentrations may also fall markedly during pregnancy (ref. 20). Follow-up studies correlating seizure frequency changes with alterations in AED levels during pregnancy are clearly required.
References
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