AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies

Abstract

Background Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control. Objective To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels. Design A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out. Setting Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK. Participants Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies. Interventions In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features. Main outcome measures Primary outcome – seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes – pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs. Analysis Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen–Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios. Results A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs. Limitations Fewer women than the original target were recruited. Conclusion There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes. Future work recommendations Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy. Trial registration Current Controlled Trials ISRCTN01253916. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 23. See the NIHR Journals Library website for further project information.

Predicting seizures in pregnant women with epilepsy: Development and external validation of a prognostic model

“…We developed and validated the prognostic model for seizures in the prospective multicentre EMPiRE (AntiEpileptic drug Monitoring in PREgnancy) study, which recruited pregnant women with epilepsy on antiepileptic drugs at first antenatal visit from 50 maternity units in the UK between 4 November 2011 and 17 August 2014 [17]. The UK National Research Ethics Committee approved the EMPiRE study (11/WM/0164), written consent was obtained from participants, and the protocol can be accessed at https://www.journalslibrary.nihr.ac.uk/programmes/hta/095538#/.…”

“…Serum antiepileptic drug levels were assessed every month, but the women and clinicians were blinded to these levels. For women for whom drug levels remained stable, the blinding was maintained (non-randomised cohort) until delivery, and drug doses were adjusted based on clinical features, in line with national recommendations [17,21]. Women whose serum drug levels fell were randomly allocated either to a strategy of adjusting antiepileptic doses based on serum drug levels (after unblinding) or to a strategy of changing the drug doses based on only clinical features (blinding maintained).…”

“…All participants were followed up until 6 weeks after delivery (S1 Appendix). The study is described in detail elsewhere [17]. For model development, we used the cohort of women who were managed without routine serum drug level monitoring (non-randomised and randomised women), which is in line with standard epilepsy care in the UK [17,21].…”

“…The study is described in detail elsewhere [17]. For model development, we used the cohort of women who were managed without routine serum drug level monitoring (non-randomised and randomised women), which is in line with standard epilepsy care in the UK [17,21]. We validated the model in the separate cohort of women managed differently, with routine therapeutic drug monitoring, as practised in some countries such as the US, to determine if the model was transportable across varied healthcare practices [22].…”

A Review of Population Pharmacokinetic Studies of Levetiracetam

“…However, the CL of LEV is higher in pregnant women than in non-pregnant individuals, which could lead to the failure of seizure control [8, 43]. Thus, the TDM of LEV in pregnant patients is necessary to maintain the appropriate concentration [44]. However, the data reported for LEV in pregnant women are insufficient.…”