Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry

Abstract

SUMMARYPurpose: To analyze seizure control, dose adjustments, and other changes of antiepileptic drug (AED) treatment during pregnancy in a large cohort of women with epilepsy entering pregnancy on monotherapy with carbamazepine, lamotrigine, phenobarbital, or valproate. Methods: Seizure control and AED treatment were recorded prospectively in 3,806 pregnancies of 3,451 women with epilepsy taking part in European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), an international AED and pregnancy registry. Key Findings: Of all cases, 66.6% remained seizure-free throughout pregnancy. Generalized tonic-clonic seizures (GTCS) occurred in 15.2% of the pregnancies. Women with idiopathic generalized epilepsies were more likely to remain seizure-free (73.6%) than women with localization-related epilepsy (59.5%; p < 0.0001). Worsening in seizure control from the first to second or third trimesters occurred in 15.8% of pregnancies. The AED dose was increased during pregnancy in 26.0% and a second AED added to the initial monotherapy in 2.6% of all pregnancies. Seizures were more likely to occur in the first trimester in pregnancies with an increased drug load (35%; increased dose and/or addition of another AED) than in pregnancies without an increased drug load (15.3%) (p < 0.0001). Compared with other monotherapies, pregnancies exposed to lamotrigine were less likely to be seizure-free, 58.2% (p < 0.0001); had more GTCS, 21.1% (p < 0.0001); had a greater likelihood of deterioration in seizure control from first to second or third trimesters, 19.9% (p < 0.01), and were more likely to require an increase in drug load, 47.7% (p < 0.0001). The mean dose increases from the first to third trimesters were 26% for lamotrigine, 5% for carbamazepine, 11% for phenobarbital, and 6% for valproate. There were 21 cases of status epilepticus (10 convulsive): none with maternal mortality and only one with a subsequent stillbirth. Significance: Although the majority of women remain seizure-free throughout pregnancy, our data suggest that a more proactive approach to adjusting the dose of all AEDs in pregnancy should be considered, in particular for those pregnancies with seizures occurring in the first trimester and those exposed to lamotrigine, to reduce the risk of deterioration in seizure control.

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

“…Despite increasing doses across most AEDs, seizures still increased in 38.4 % of women during pregnancy, and seizure deterioration was significantly more likely in patients during the second trimester when the AED concentration fell to < 65 % of preconception baseline (after controlling for baseline seizure occurrence). Other factors associated with seizure deterioration during pregnancy were the presence of seizures in the 12 months prior to conception and focal seizure types, similar to reports from the EURAP study [34].…”

“…One finding that stood out for women on CBZ in these prior studies was that they had a very low rate of worsened seizure control (0-14.6 %) and were less likely to have dosage adjustments during pregnancy [34,40]. A more recent analysis helped to clarify the pharmacokinetic changes of CBZ during pregnancy compared with the 2009 AAN/AES pregnancy parameter update [29], and findings provide an explanation for these observations.…”

“…The major elimination pathway for OXC is also glucuronidation. EURAP followed up these findings with a more recent study comparing seizure control from the first to the second and third trimesters [34]. Preconceptional baseline seizure frequency was not available, nor was information on AED blood levels.…”

“…Preconceptional baseline seizure frequency was not available, nor was information on AED blood levels. The authors reported that compared with other AED monotherapies, pregnant women on LTG monotherapy were less likely to be seizure-free (58.2 %), had more generalized tonic-clonic seizures (21 %), and had a greater likelihood of deterioration in seizure control from the first trimester to later trimesters (19.9 %), and were more likely to require an increase in drug load (47.7 %) [34]. However, the mean dose increase from the first to third trimesters was only 26 % for LTG, and the authors suggested that a more proactive therapeutic drug monitoring approach should be considered, especially for those on LTG.…”

The Croatian Model of Integrative Prospective Management of Epilepsy and Pregnancy

“…Th e increased volume of distribution and the hepatic metabolism of AEDs, along with decreased compliance during pregnancy and self-initiative interruption of AED intake because of concerns about their eff ects on the fetus, lead to an increase in seizure frequency during pregnancy in women with epilepsy. Seizures in women with epilepsy are observed in as many as 17%-40% of pregnancies 22,23 . In our study, 40% of women with epilepsy had seizures during pregnancy, but owing to close drug monitoring, AED increase (especially LTG) or therapy switch we had no epileptic status and no signifi cantly increased percentage of complications in women with seizures during pregnancy, except for the higher number of cesarean sections.…”