Epilepsy and Pregnancy: A Prospective Study of Seizure Control in Relation to Free and Total Plasma Concentrations of Carbamazepine and Phenytoin

Abstract

Seizure control and plasma concentrations of antiepileptic drugs (AEDs) were determined in a prospective, population-based study of 93 pregnancies (cases) of 70 patients with epilepsy. Seventy-seven cases were treated with monotherapy, which in 70 cases consisted of carbamazepine (CBZ) or phenytoin (PHT). Dosage was kept constant unless poor seizure control prompted an increase. Plasma concentrations were determined at monthly intervals throughout pregnancy and compared with baseline levels obtained at least 10 weeks postpartum. Both free and total CBZ and PHT concentrations were analyzed. Seizure frequency during pregnancy for the group as a whole was not different as compared with the 9 pregestational months and was unaltered or improved in 85% of cases. Total CBZ concentration was slightly lower during the third trimester as compared with baseline, whereas free concentration was unchanged. In contrast, PHT levels decreased steadily as pregnancy progressed. Total plasma concentration was 39% of baseline during the third trimester, whereas free PHT concentration decreased far less, being 82% of baseline level during the third trimester. No clear-cut relation could be demonstrated between seizure control and plasma concentrations, which may be explained by the limited changes in free AED concentrations and the small number of cases with an increased seizure frequency. Our results indicate that total plasma concentrations may be misleading and that monitoring of free concentrations, in particular of PHT concentrations, may be advantageous during pregnancy.

Management issues for women with epilepsy—Focus on pregnancy (an evidence‐based review): I. Obstetrical complications and change in seizure frequency

“…In one study, 38 of 45 (84%; CI 0.71-0.92) of pregnant WWE remained seizurefree (Gjerde et al, 1988), and in the other study, 47 of 51 (92%; CI 0.82-0.97) of pregnant WWE remained seizurefree (Tomson et al, 1994).…”

“…In a third Class IV study, which evaluated 93 pregnancies (Tomson et al, 1994), seizure frequency as a whole was not different in pregnancy compared to baseline (p = 0.42). The exact numbers were not provided, but the percent change was reported as the following: 61% unchanged, 24% decreased, 15% increased.…”

“…Hence, all studies were graded Class IV (Table S2). Three articles (Bardy, 1987;Gjerde et al, 1988;Tomson et al, 1994) used each patient's nonpregnant seizure frequency (per pregnancy) as its own control. In one study, which evaluated 154 pregnancies (Bardy, 1987), seizure frequency was unchanged in 54% (95% CI 0.46-0.62) [including 48 (31%) seizure-free patients], decreased in 14% (95% CI 0.10-0.21), and increased in 32% (95% CI 0.25-0.40) compared to prepregnancy seizure frequency.…”

“…This comparison suggests status epilepticus does not occur more frequently during pregnancy. However, the absence of a comparison group of nonpregnant WWE within these studies makes it impossible to determine the relative risk of status epilepticus during pregnancy.Conclusion There is insufficient evidence to support or refute an increased risk of status epilepticus in pregnant WWE.Seizure recurrence in previously seizure-free WWE Two Class II articles (Gjerde et al, 1988;Tomson et al, 1994) showed that for WWE who were seizure-free for 9 months prior to pregnancy, 84-92% remained seizurefree during pregnancy (Table S4). In one study, 38 of 45 (84%; CI 0.71-0.92) of pregnant WWE remained seizurefree (Gjerde et al, 1988), and in the other study, 47 of 51 (92%; CI 0.82-0.97) of pregnant WWE remained seizurefree (Tomson et al, 1994).…”

“…Hence, all studies were graded Class IV (Table S3). Three population-based studies reported a frequency of status epilepticus in WWE during pregnancy of 0-1.3% [0/154, 0%, 95% CI 0.00-0.3 (Bardy, 1987); 1/78 convulsive status epilepticus, 1.3%, 95% CI 0.00-0.07 (Gjerde et al, 1988); and 0/89, 0%, 95% CI 0.00-0.04 (Tomson et al, 1994)]. Similarly, a large prospective, but not population-based, study of nearly 2,000 pregnancies (EURAP Study Group, 2006) found status epilepticus in 36/1,956 (1.8%, 95% CI 0.01-0.03) pregnancies.…”