Dr Emma VoinescuP. Emma Voinescu, MD, PhD
According to the findings of a preliminary study of antiepileptic drug (AED) clearance during pregnancy, levetiracetam clearance changes significantly by the first trimester, while the same is seen by the second trimester for topiramate and oxcarbazepine.

Mean maximal clearances were reached for levetiracetam at 1.71-fold the baseline clearance (P = .0001), oxcarbazepine at 1.63-fold baseline (P = .0001), and topiramate at 1.39-fold baseline (P = .025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower ratio to target concentrations (P <.05).

Led by P. Emma Voinescu, MD, PhD, an epileptologist and instructor at Brigham and Women’s Hospital and Harvard Medical School, the study included 44 women with 44 pregnancies on either AED monotherapy or polytherapy. Study therapies included levetiracetam, oxcarbazepine, phenytoin, topiramate, and valproic acid.

"There are many physiological changes in pregnancy that alter drug metabolism, leading to significant fluctuations in the blood concentration for most of our antiepileptic medications which may influence seizure control during pregnancy," Voinescu told NeurologyLive. "Yet, there continues to be some debate whether therapeutic drug monitoring in pregnancy is necessary, in part because full characterization of the time-course of pregnancy-related clearance changes is lacking for many of our antiepileptic medications."

Voinescu added that in previous work, co-author Paige B. Pennell, MD, and collaborators revealed that the patterns of gestational age-dependent clearance changes may be very different among antiepileptic medications. For example, she noted, lamotrigine clearance increases steadily during pregnancy while carbamazepine clearance changed very little. "Knowledge about these pattern of clearance changes can help guide the timing and range of AED dose adjustments, and contribute to maintaining seizure stability during pregnancy,"  she said.

For levetiracetam, clearance values were found to remain significantly above baseline for the remainder of pregnancy past the first trimester. In the second trimester, the clearance was 1.421-fold baseline (95% CI, 1.68 to 1.73; P = .0001), and was 1.367-fold baseline (95% CI, 1.15 to 1.63; P = .001) in the third trimester. In a comparison of those with more than 5 observations, there was a notably large interindividual variability (peak, 1.6- to 4.4-fold baseline clearance).

"While other studies previously reported levetiracetam clearance changes during pregnancy, they focused on third-trimester values or did not reach statistical significance to draw conclusions on earlier changes,"  Voinescu said. "We demonstrate clearance changes early in the first trimester, with an estimated increase to 1.42- to 2.02-fold baseline clearance. This is important information for clinicians who manage women on levetiracetam as they may opt to begin therapeutic drug monitoring as early as possible in pregnancy."

For phenytoin and valproic acid, no significant clearance changes were observed, for free or total. The peak clearance for total phenytoin was in 1.002-fold baseline (95% CI, 0.69 to 1.46; P = .993) in the first trimester, and for free phenytoin was 1.112-fold baseline (95% CI, 0.76 to 1.62; P = .582). For total valproic acid, peak clearance was in the third trimester, at 1.142-fold baseline (95% CI, 0.926 to 1.408; P = .214), while for free valproic acid, peak clearance occurred in the first trimester, at 1.288-fold baseline (95% CI, 071 to 2.35; P = .41).

Voinescu and colleagues identified 15 patients on AED monotherapy (levetiracetam, n = 1; oxcarbazepine, n = 1; phenytoin, n = 2; topiramate, n = 3; valproic acid, n = 5). Seizure frequency worsened in 40% (n = 6) of patients during at least 1 trimester. Increased seizure frequency was found to be associated with lower ratio to target concentrations in the first trimester (P = .012), second trimester (P = .042), and for the full length of pregnancy (P = .004). This association was not found during the third trimester.

Ratio to target concentrations <0.65 was associated with worsening seizures, while ratio to target concentrations >0.65 were linked with stable and improved seizure frequency. Mean ratio to target concentration in the stable or improved group was 0.82 overall, and 0.77, 0.78, and 0.76 in the first, second, and third trimesters, respectively. Comparatively, in the worsening group, the overall ratio to target concentration was 0.55, while in the first, second, and third trimesters was 0.49, 0.53, and 0.69, respectively.

"Seizure worsening was observed when blood levels fell by >35%, regardless of antiepileptic medication used," Voinescu said. "This was a prospective, observational cohort study of pregnant women with epilepsy with modest numbers and the findings will need to be confirmed by further larger studies. [However,] neurologists can use medication levels to proactively adjust doses to maintain seizure stability and improve pregnancy outcomes."
REFERENCE
Voinescu PE, Park S, Chen LQ, et al. Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy. Neurology. 2018;00:e1-e9.
doi: 10.1212/WNL.0000000000006240.