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

Background:
Pregnant women with epilepsy on antiepileptic drugs (AED) may experience a fall in serum AED levels, with potential to worsen seizure control.
Objective:
To determine whether in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring (TDM) reduces seizure deterioration compared to monitoring based on clinical features alone (CFM) after a fall in serum AED levels.
Design:
A multicentre double blind randomised control trial embedded within a cohort study, alongside a qualitative study.
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, levetiracetam. Women with a 25 percent or more fall in AED level from baseline were randomised to TDM or CFM strategies.
Interventions:
In the TDM strategy arm, in addition to clinical findings, clinicians had access to monthly AED levels to guide adjustment of AED dosage for seizure control. In the CFM arm, the decision to adjust the AED dose was based on only clinical features.
Outcome:
Primary outcome: Seizure deterioration defined as time to seizure per woman until six weeks postpartum.
Secondary outcome: Pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable AED level, AED dose exposure and adverse events related to AED.
Analysis:
Analysis of time to seizure was performed using a Cox proportional hazard model, and multivariate failure time analysis by the Anderson-Gill model. The effects were reported as hazard ratios (HR) with 95% confidence intervals (CI). Secondary outcomes were reported as mean differences or odds ratios.
Results:
Of 560 women recruited, 267 with a fall in AED level in pregnancy were randomised, and 257 (98% complete data) were included in primary analysis. There were no significant differences in time to first seizure (HR 0.82; 95% CI 0.55,1.2), or time to subsequent seizures (HR 1.3, 95% CI 0.70,2.5) between both strategies. Compared to the group with stable AED levels, there were no significant increases in seizures in the CFM (OR 0.93; 95% CI 0.56,1.5) or TDM group (OR 0.93; 95% CI 0.56,1.5) with fall in AED levels. Maternal and neonatal outcomes were similar in both arms, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l; 95% CI 0.11,1), levetiracetam (MD 7.8 mg/l; 95% CI 0.86,14.8) in TDM than CFM 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.
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.
Trial registration: 01253916
Funding: The National Institute for Health Research-Health Technology Assessment programme.
Word Count: 486
Key words: Epilepsy, pregnancy, maternal, fetal, seizure, anti-epileptic drug, monitoring