Increased levetiracetam clearance in pregnancy: Is seizure frequency affected?

Emerging data on the teratogenic potential of antiepileptic drugs (AEDs), in particular valproate, have resulted in a prescribing shift towards lamotrigine and levetiracetam in women of childbearing age with epilepsy. Over the last 20 years prescription of lamotrigine to women of childbearing potential has increased tenfold in the UK, with a reduction in valproate prescription of one third. However, use of lamotrigine and levetiracetam during pregnancy can be associated with other difficulties. It is widely documented that lamotrigine clearance increases by up to 330% in pregnancywith studies showing an increase in seizure frequency in 39–45% of women. Early studies have also shown that serum levels of levetiracetam fall by 40–62% during the second and third trimesters of pregnancy. In contrast to lamotrigine very little is known about whether this is clinically significant. To date, the largest report of seizure control in women taking levetiracetam during pregnancy included only 19 patients. Although increased seizure frequency was observed in seven women, the authors felt that no definite conclusion could be drawn between declining levetiracetam dose/concentration ratios and seizure breakthrough. Two other small studies are complicated by inclusion of women taking both lamotrigine and levetiracetam as part of polytherapy regimens. In a cohort of 39 women in Northern Ireland identified through the UK Epilepsy and Pregnancy Register, who took levetiracetam as monotherapy during pregnancy, we observed deterioration or relapse of seizures in 30.8% (12) of women. Seizure control was unchanged in twenty women (51.3%) and improved in seven (17.9%). Five women discontinued AED treatment on confirmation of pregnancy and have not been included in this study. Eleven (91.7%) of the twelve women whose seizures deteriorated had active epilepsy prior to pregnancy. In contrast 21 of 27 (77.8%) of those noting an improvement in seizure control or no change in seizure frequency had active epilepsy prior to pregnancy. Active epilepsy is defined as a person whose most recent seizure has occurred within the last 2 years.One patient who had been seizure free for four years prior to pregnancy had a relapse of simple partial seizures at 35 weeks gestation. The mean number of previous AEDs was 2.1, 1.78 and 1.57 for those whose seizure control deteriorated, did not change and improved respectively. Mean levetiracetam dose was 1596 mg prior to pregnancy. Levetiracetam dose was increased during pregnancy in 48.7% of patients (mean dose increase of 592 mg). Serum drug levels were checked in 41% of women but these were one off levels taken routinely at the time of first antenatal appointment in the majority of cases. This report raises some concerns about deteriorating seizure control in women taking levetiracetam during pregnancy, particularly for those women with active epilepsy prior to pregnancy. The number with a deterioration in seizure control at over 30% of women is towards the upper end of the expected range of 15–32%. In