Regular monitoring of antiepileptic drug levels in pregnant women with epilepsy does not improve seizure control compared with clinical features-based monitoring. This NIHR-funded study was conducted across 50 UK hospitals and is the largest randomised trial in pregnant women with epilepsy.
Just over 260 pregnant women with unstable antiepileptic drug levels were assigned to ongoing monthly blood checks or clinical features monitoring. There were no differences in seizures or other pregnancy outcomes between the two strategies. But umbilical cord blood showed that babies whose mothers received blood checks were exposed to higher levels of antiepileptic drugs.
The study provides important information about the utility of monitoring blood levels of antiepileptic drugs, which previously was standard clinical practice. NICE guidelines advised against routine monitoring in 2012 and this trial gives support to this recommendation.
Why was this study needed?
Epilepsy is thought to affect 0.6% of pregnant women in the UK. Uncontrolled epilepsy during pregnancy is associated with increased risk of maternal death in addition to risks to the fetus such as lack of oxygen and miscarriage. By contrast, certain antiepileptic drugs are harmful to the unborn baby, causing congenital abnormalities. However, there is general consensus that controlling seizures in the mother outweighs risk to the fetus, provided the most suitable drugs are used.
During pregnancy, the level of antiepileptic medication in the blood may decrease, and consequently, seizures may occur. American guidelines recommend monitoring blood levels of antiepileptic drugs, and this practice has been used in the UK. But UK guidelines now recommend being guided by clinical features and adjusting medication accordingly.
To date, no randomised controlled trials had compared which method was better at preventing seizures and minimising side effects, and this study meets that need.
What did this study do?
The EMPiRE trial recruited 560 pregnant women (under 24 weeks) with epilepsy from 50 hospitals across the UK. Women who had a 25% or greater decrease in their blood antiepileptic levels compared with pre-pregnancy (263 women) were then randomised to either therapeutic drug monitoring (blood levels measured monthly) or to monitoring of clinical features only.
Researchers had calculated that they needed to recruit at least 660 and the under-recruitment has caused the confidence intervals to be wider than ideal. Therefore a possible small benefit from monitoring can’t be excluded. The study couldn’t analyse seizure risks by individual antiepileptic drug, because the numbers for each were too small. Women taking sodium valproate (no longer recommended during pregnancy) were excluded, as were women taking a combination of drugs unless it involved lamotrigine.
What did it find?
- Thirty-eight percent of women in both the therapeutic drug monitoring (48/127) and clinical features monitoring (50/130) groups experienced at least one seizure during pregnancy or up to six weeks after birth.
- There was no difference in the main outcome of time to first seizure which was 28 days after randomisation in the therapeutic monitoring group versus 27 days in the clinical features group (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.55 to 1.20). Neither was there difference when restricting the analysis to time until more serious tonic-clonic seizures (HR 0.80, 95% CI 0.43 to 1.50).
- There were no differences between groups in pregnancy outcomes of average gestational age at delivery, preterm birth rate, type of delivery, infant birth weight, Apgar scores, rate of maternal haemorrhage, or admission to a neonatal unit. There was also no difference in breastfeeding rates.
- Lamotrigine, levetiracetam and carbamazepine were the drugs taken by all but one recruited individual (taking phenytoin). Infants whose mothers received therapeutic monitoring had higher cord blood levels of lamotrigine (mean difference [MD] 0.55 mg/l, 95% CI 0.11 to 1.0) and levetiracetam (MD 7.8mg/l, 95% CI 0.86 to 14.8) compared with clinical features monitoring. There was no difference between groups in levels of carbamazepine.
What does current guidance say on this issue?
In the UK, NICE and SIGN guidelines advise not to routinely monitor antiepileptic drug levels during pregnancy. Instead, they suggest that monitoring may be useful to guide dose adjustments if seizures increase or are expected to increase, particularly if lamotrigine and phenytoin are being used.
The Royal College of Obstetrics and Gynaecology 2016 guidance on Epilepsy in pregnancy states: “Based on current evidence, routine monitoring of serum antiepileptic levels in pregnancy is not recommended although individual circumstances may be taken into account”.
A review of the NICE guideline Epilepsies in adults: diagnosis and management is currently underway, with an expected publication date of 20 January 2021.
What are the implications?
This study supports the change in national guideline recommendations against routine monitoring of antiepileptic levels during pregnancy. It suggests therapeutic monitoring gives little or no benefit while increasing fetal exposure to potentially harmful antiepileptic drugs.
The insufficient recruitment is a limitation, which does mean the researchers have not ruled out a small benefit. One reason for this is that a number of UK centres declined participation as treating doctors considered one strategy to be preferable to the other. This trial may provide evidence to standardise practice and help women to be fully informed around appropriate treatment of epilepsy during pregnancy.
Citation and Funding
Thangaratinam S, Marlin N, Newton S, et al. AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies. Health Technol Assess. 2018;22(23).
This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 09/55/38).
NICE. Epilepsies: diagnosis and management. CG137. London: National Institute for Health and Care Excellence; 2012, updated April 2018.
RCOG. Epilepsy in pregnancy. Green-top Guideline No. 68. London: Royal College of Obstetricians and Gynaecologists; 2016.
SIGN. Diagnosis and management of epilepsy in adults. SIGN Publication No. 143. Edinburgh: Scottish Intercollegiate Guidelines Network; 2015.
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