EMPIRE 

Full title: Antiepileptic drug (AED) management in Pregnancy: An evaluation of effectiveness, cost effectiveness and acceptability of dose adjustment strategies

Acronym: EMPIRE

Research Funder: National Institute for Health Research, Health Technology Assessment Programme 

Research status: Recruiting

OVERVIEW

Antiepileptic drug (AED) management in pregnancy: an evaluation of effectiveness, cost effectiveness, and acceptability of dose adjustment strategies (EMPIRE)

Background: Epilepsy affects 0.5-1% of the general population. About a third of women with epilepsy are of childbearing age. There is a 10-fold increase in death rate among pregnant women with epilepsy, which greatly exceeds the two to three-fold rate of deaths observed in all people with epilepsy. One in 250 pregnancies are exposed to anti-epileptic drugs. Whilst for all patients a diagnosis of epilepsy results in a drastic life change, many more concerns are raised for women of childbearing age.                                                                                              .

For a woman with epilepsy there is a consideration of medication choice, risk of seizures to her and the baby whilst pregnant, risk of any anti-epileptic drugs to unborn child, and the increased monitoring and attendance at maternity clinics. Both seizures during pregnancy and the effects of anti-epileptic drugs are thought to influence poorer outcomes in children born to mothers with epilepsy.

The levels of anti epileptic drugs have been shown to be reduced in pregnancy. This decrease in blood level has been associated with an increased risk of seizure. Currently there is uncertainty as to how to manage such fall in blood levels, as identified by our survey of clinicians managing such women. Some doctors increase the dose of the drug in response to falling blood levels, in attempts to maintain pre-pregnancy levels at which seizures were well controlled (therapeutic drug monitoring). Other doctors increase the dose of drugs on clinical features alone, like worsening of seizures (Clinical features monitoring).

There is very little research on the type of management that is beneficial to the mother and baby. To date there are no randomised controlled trials comparing these two strategies and the immediate and long term effects to both mother and baby. Consequently doctors find it difficult to reliably advise as to the best way to treat and manage such patients during this time. Doctors are responsible for minimising the risk of seizure whilst ensuring that the drugs do not adversely affect the developing baby. Our survey of pregnant women with epilepsy showed an overwhelming support for a randomised controlled trial in this area. These women showed great awareness and understanding of the complexities and uncertainties currently facing doctors managing their care and welcomed research into this area.

Aim: Through the proposed study we plan to compare the clinical and cost effectiveness, safety and acceptability of Therapeutic drug monitoring vs Clinical features monitoring strategies.

Study conduct: We will be studying the four commonly used anti epileptic drugs in pregnancy. Pregnant women with epilepsy on treatment will be randomised to either receive the reactive or preventative strategy, as outlined above. Eligible women will be consented for participating in the study when they come to the hospital for their first appointment at 12 -14 weeks of pregnancy.

If women agree they will be randomised (this is like flipping a coin) to receive either care based on drug levels in blood (Group A) or clinical features alone (Group B). Women without any fall in blood levels will continue to be monitored regularly (Group C). Women will have equal chance of being allocated to both strategies if they choose to take part in the project and their blood levels of the drug fall. Mothers and doctors in Group A will be aware of the drug levels in blood. Doctors will not use blood levels to manage women in Group B. Both women and clinicians will not be informed of the results of blood level testing in Groups B and C. All women will undergo regular blood tests for drug levels.

The main outcome of this study is the severity of seizures in the two groups ascertained by a seizure diary completed by the mother. This will help doctors and pregnant women with epilepsy on drugs decide whether it is better to use the preventative strategy or the reactive strategy. We shall collect data on the health of the mother and baby in pregnancy and up to 6 weeks after childbirth. We will also obtain information on the Quality of Life regularly. The potential benefits/risks to foetus will be measured using EURCAT definition of major and minor congenital malformations either detected at scan or birth, admission to the neonatal unit, as well as any other complications such as intrauterine growth restriction.

Trial Team

We have assembled a well balanced team with expertise and experience in carrying out large trials of this nature. The team is comprised of

  • obstetricians, who look after the mother and baby in pregnancy
  • neurologists: these professionals look after patients with epilepsy or suspected epilepsy
  • clinical epidemiologists, who design and conduct such trials
  • epilepsy specialist nurse, who looks after the management and wellbeing of patients with epilepsy
  • pharmacologist, who has expertise in medication, its use and properties
  • neuropsychiatrist, who specialises in the mental health and wellbeing of patients with illnesses like epilepsy that effect the brain
  • health economist, who considers and assess the costs of health services and treatments
  • statistician, who analyses the data
  • qualitative researcher, who considers the experiences of women during the trial on an individual basis e.g. participation, acceptability of treatment and concerns about medication or seizures.

Our group has been significantly strengthened by inclusion of Epilepsy Action. The participants will be able to access the charity Help Line for any queries about epilepsy generally or the trial and these communications are always logged. We have the support of 50 units in the UK for participation in the trial. 

STAFF

Investigators

Chief investigator:

Professor Khalid S Khan, Professor of Women's Health and Clinical Epidemiology, Centre for Primary Care and Public Health, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Chief investigator:

Dr Shakila Thangaratinam, Professor of Obstetrics and Maternal Medicine, Centre for Primary Care and Public Health, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London. Email: This email address is being protected from spambots. You need JavaScript enabled to view it., Tel: 0044 (0)20 7882 5635

Co-investigator:

Dr Dougall McCorry, Consultant Neurologist, Queen Elizabeth Hospital Email: This email address is being protected from spambots. You need JavaScript enabled to view it. 

Alexander Pirie, National Lead Obstetrician, Birmingham Women's Hospital Foundation Trust  Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Shakila Thangaratinam, Professor of Obstetrics and Maternal Medicine, Centre for Primary Care and Public Health, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Lynette Greenhill, Epilepsy Specialist Nurse Practitioner and Prescribe, Birmingham & Solihull Mental Health Trust. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Kelly Hard, R&D manager, Birmingham Women's NHS Foundation Trust. Email This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Rajat Gupta, Consultant Paediatric Neurologist, Birmingham Children’s Hospital. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Elaine Denny, Professor of Health Sociology, Birmingham City University. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Jamie Coleman, Senior Lecturer in Clinical Pharmacology, University of Birmingham. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Professor Tracy Roberts, Director of MSc Health Economics and Health Policy, University of Birmingham. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Naghme Adab, Consultant Neurologist special interest Epilepsy, University Hospital Coventry and Warwickshire. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Khaled Ismail, Senior Lecturer/Consultant in Obstetrics & Gynaecology, Keele University Medical School & University Hospital of North Staffordshire. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Manny Bagary, Consultant Neuropsychiatric, Queen Elizabeth Hospital. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Lee Middleton, Medical Statistician, Birmingham University. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Tracey Baker, Service User

 

Staff

Sally KerryShakila ThangaratinamKhalid KhanRachel RikunenkoEwelina RogozińskaAmy Hoon.

OTHER INFORMATION

Scientific Summary

Design: An RCT embedded within a comprehensive cohort study. We will also undertake a qualitative study, a decision-analysis and an economic evaluation.

Setting: Joint epilepsy obstetric clinics and antenatal clinics in secondary and tertiary care units in the UK.
Pregnant women with confirmed diagnosis of epilepsy on lamotrigine (LTG) monotherapy or polytherapy (with carbamazepine CBZ, phenytoin PHT, levetiracetam LEV), CBZ monotherapy, PHT monotherapy and LEV monotherapy

Intervention: The management of patients this group will involve discussion with the patient of potential risks of reduced serum levels and the risks and benefits of increase in AED dose to mother and baby. The treatment options include more frequent monitoring, increase in dosage of the AED immediately or delayed pending early testing.

Control: Women and clinicians will be blinded to serum AED levels. The dose of AED will depend on the clinical features like frequency and severity of seizures according to local clinical practice.

Primary Outcome: The seizure diaries will provide the primary outcome data. Time to seizure in pregnancy will be analysed taking into account the time to each individual seizure per woman over the whole period of monitoring until birth.
Secondary Outcomes: Maternal- Neurological: Serum levels of AED in each trimester, daily dose exposure by trimester, cumulative dose exposure for pregnancy, adverse events as measured by the Liverpool Adverse Events Profile.
Obstetric: Maternal death, mode of delivery, preterm labour, induction of labour, pre-eclampsia, antepartum and postpartum haemorrhage, admission to high dependency/ intensive care unit, breast feeding.
Quality of Life: Epilepsy specific QoL as measured by QOLIE-31, generic QoL as measured by EQ-5D.
Fetal and neonatal: Major and minor congenital malformation: major congenital malformations defined as structural abnormalities with surgical, medical, or cosmetic importance. 45 Apgar score at 1’ and 5’, admission to neonatal unit, birth weight, head circumference, fetal growth, stillbirths, neonatal deaths.

Sample Size: we have to recruit 1000 eligible women.

Paeticipating Centres: 

There are 50 centres taking part in the EMPiRE study across England and Wales. 

Patient Acceptability:To gain insight into the way pregnant women with epilepsy rationalise and make sense of the management of AED, we will undertake a qualitative study of patient perspective in a sample of women who enter the trial and in a sample who do not wish to participate in the trial but agree to discuss their experience of epilepsy and pregnancy.

More information please see EMPiRE Road Show slides.

EMPiRE Steering groups

EMPIRE Trial Management Group (TMG) meetings are held on the 2nd Wednesday of the month.
The EMPIRE Data monitoring Committee (DMC) and Trial Steering Committee (TSC) meet every 6 months.

Trial Management Group (TMG)

Professor Khalid Khan: Professor of Women’s Health and Epidemiology, QMUL
Professor Shakila Thangaratinam: Professor of Obstetrics and Maternal Medicine, QMUL
Dr Dougall McCorry: Consultant Neurologist, Queen Elizabeth Hospital, Birmingham
Alexander Pirie: Consultant Obstetrician and Gynaecologist, Birmingham Women’s Hospital
Rachel Rikunenko: Trial Co-ordinator, QMUL
Professor Elaine Denny: Professor of Health Sociology, Birmingham City University
Annalise Weckesser: Qualitative Assistant, Birmingham City University
Professor Tracy Roberts: Director of MSc in Health Economist and Health Policy
Louise Jackson: Research Assistant, University of Birmingham, University of Birmingham 
Dr Manny Bagaory: Neuropsychiatrist, Birmingham and Solihull Mental Health Foundation Trust 
Lynette Greenhill: Epilepsy specialist Nurse, Birmingham and Solihull Mental Health Foundation Trust
Emily Denness: EMPIRE coordinating research midwife, Barts Health NHS Trust
Liz Quinlan – Jones: EMPIRE co-ordinating research midwife, Birmingham Women’s Hospital
Professor Sandra Eldridge / Nadine Marlin: Statisticians, QMUL
Natasha Stevens: PCTU Manager, QMUL
Sandy Smith: Data Manager, QMUL
Ewelina Rogozinska: Data Assistant, QMUL

Trial Steering Committee (TSC)

Professor Ben Willem Mol: Professor of Obstetrics and Gynaecology, Academic Medical centre at the University of Amsterdam
Professor Khalid Khan: Professor of Women’s Health & Epidemiology, QMUL
Professor Shakila Thangaratinam: Professor of Obstetrics and Maternal Medicine, QMUL                                             

Dr Dougall McCorry: Consultant Neurologist, Queen Elizabeth Hospital, Birmingham

Alexander Pirie: Consultant Obstetrician and Gynaecologist, Birmingham Women’s Hospital    
Rachel Rikunenko: Trial Coordinator, QMUL
Professor Elaine Denny: Professor of Health Sociology, Birmingham City University
Dr John Craig: Consultant Neurologist, Queen Elizabeth Hospital, Birmingham
Dr David Williams: Consultant Obstetrician, UCL
Lynette Greenhill: Epilepsy specialist Nurse, Birmingham and Solihull Mental Health Foundation Trust
Professor Sandra Eldridge / Nadine Marlin: Statisticians, QMUL

Data Monitoring Committee (DMC)

Professor Carl Clarke: Professor of Neurology, University of Birmingham 
Professor Javier Zamora: Professor of Biostatistics, Unidad de Bioestadistica Clinica Madrid
Bill Martin: Consultant Obstetrician, Birmingham Women’s Hospital
Professor Sandra Eldridge / Nadine Marlin: Statisticians, QMUL

Regional Lead Consultants/ Physicians
Neurology Leads

Midlands – Dr Dougall McCorry, Queen Elizabeth Hospital, Birmingham
South Wales – Dr Khalid Hamandi, University Hospital of Wales, Cardiff
Yorkshire – Dr Gary Dennis, Royal Hallamshire Hospital, Sheffield
London – Dr Andrew Kelso, The Royal London Hospital, Whitechapel

Obstetrics Leads

National – Alexander Pirie, Birmingham Women's Hospital Foundation Trust
Midlands – Professor Shakila Thangaratinam, Professor of Obstetrics and Maternal Medicine, QMUL
London – Professor Catherine Nelson Piercy, Consultant Obstetrics Physician, St Thomas' Hospital Westminster