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Mortality Rates and Causes of Death in Children with Epilepsy Prescribed Antiepileptic Drugs

A Retrospective Cohort Study using the UK General Practice Research Database

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Abstract

Background: Patients with epilepsy, including children, have an increased risk of mortality compared with the general population. Antiepileptic drugs (AEDs) were the most frequent class of drugs reported in a study looking at fatal suspected adverse drug reactions in children in the UK.

Objective: The objective of the study was to identify cases and causes of death in a paediatric patient cohort prescribed AEDs with an associated epilepsy diagnosis.

Methods: This was a retrospective cohort study supplemented with general practitioner-completed questionnaires, post-mortem reports and death certificates. The setting was UK primary care practices contributing to the General Practice Research Database. Participants were children and adolescents aged 0–18 years prescribed AEDs between 1993 and 2005. Causality assessment was undertaken by a consensus panel comprising paediatric specialists in neuropathology, neurology, neuropsychiatry, paediatric epilepsy, pharmacoepidemiology and pharmacy to determine crude mortality rate (CMR) and standardized mortality ratios (SMRs), and the likelihood of an association between AED(s) and the event of death.

Results: There were 6190 subjects in the cohort (contributing 26 890 person-years of data), of whom 151 died. Median age at death was 8.0 years. CMR was 56.2 per 10000 person-years and the SMR was 22.4 (95% CI 18.9, 26.2). The majority of deceased subjects had severe underlying disorders. Death was attributable to epilepsy in 18 subjects; in 9 the cause of death was sudden unexpected death in epilepsy (SUDEP) [3.3 per 10 000 person-years (95% CI 1.5, 6.4)]. AEDs were probably (n = 2) or possibly (n = 3) associated causally with death in five subjects. Two status epilepticus deaths were associated causally with AED withdrawal.

Conclusions: Children prescribed AEDs have an increased risk of mortality relative to the general population. Most of the deaths were in children with serious underlying disorders. A small number of SUDEP cases were identified. AEDs are not a major cause of death but in a small proportion of cases, a causal relationship between death and AEDs could not be excluded.

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Acknowledgements

We sincerely thank the following members of the study steering committee: Kathleen and Kevin Bramley (parents of a child with epilepsy), Jane Hanna (Director of Epilepsy Bereaved), Dr Henry Smithson (GP, Former Chair of the Epilepsies Guidelines Group at the National Institute for Health and Clinical Excellence [NICE]) and Dr Lynda Wilton (Pharmacoepidemiologist). We are also grateful to Professor Tim Cole at the Institute for Child Health, London, for his statistical advice, the GPRD verification team and staff at the Office for National Statistics for providing the additional data for this study, and to all the GPs who contributed data to the GPRD.

Contributors: Ian C.K. Wong, Frank M.C. Besag, Ruth Ackers and Macey L. Murray conceived the idea of the study. All authors were involved in the study design. Ruth Ackers and Ian C.K. Wong analysed the data, and Ruth Ackers, Frank M.C. Besag, Elaine Hughes, Waney Squier and Ian C.K. Wong interpreted the data. All authors had full access to the study data and can take responsibility for the integrity of the data and the accuracy of the data analysis. All authors drafted, revised and approved the final manuscript. Ian C.K. Wong and Frank M.C. Besag supervised the study. Ian C.K. Wong is the guarantor.

Competing interest statement: Ian C.K. Wong is a member of the NICE Epilepsy Guideline Group, and has received funding from various pharmaceutical companies, including GlaxoSmithKline, Janssen-Cilag, Pfizer and Therakind (manufacturers of lamotrigine, topiramate, gabapentin and midazolam, respectively); however, none of the funding is related to this study. Frank M.C. Besag has received lecture fees, consultancy fees, research grants and equipment grants from and has been sponsored to conferences by various pharmaceutical companies. He was previously Editor-in-Chief of a journal sponsored by GlaxoSmithKline. None of these monies have been paid directly to him; all monies since 2001 paid to NHS Trust. No monies are currently being received from pharmaceutical companies, nor from any source other than his employer, the NHS in the UK. Frank M.C. Besag has recently been sponsored to attend international epilepsy conferences by Eisai, the company that markets rufinamide in the UK. In addition, he is shortly to receive an unrestricted educational grant from Janssen-Cilag to hold a non-profit educational conference at the Royal College of Physicians on the Use of Psychotropic Drugs in Child and Adolescent Psychiatry. Elaine Hughes has received payment for teaching at educational meetings supported by Eisai, UCB Pharma and Janssen-Cilag. Ruth Ackers, Waney Squier and Macey L. Murray have no competing interests.

Funding: The protocol and methodology had also been peer reviewed and approved by the MHRA as the funder of this project. The MHRA reviewed and commented on the results and final report; however, they had no control of the conduct of the project.

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Authors and Affiliations

  1. Centre for Paediatric Pharmacy Research, School of Pharmacy, University of London, Level 1, BMA House, Tavistock Square, London, WC1H 9JP, UK

    Ruth Ackers, Frank M.C. Besag, Macey L. Murray &  Ian C.K. Wong

  2. Institute of Child Health, University College London, London, UK

    Ruth Ackers, Frank M.C. Besag, Macey L. Murray &  Ian C.K. Wong

  3. Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

    Ruth Ackers

  4. Twinwoods Health Resource Centre, SEPT: South Essex Partnership NHS Trust, Bedford, UK

    Frank M.C. Besag

  5. Paediatrics Department, Kings College Hospital, London, UK

    Elaine Hughes

  6. Neuropathology Department, John Radcliffe Hospital, Oxford, UK

    Waney Squier

  7. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong

    Ian C.K. Wong

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  1. Ruth Ackers
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  2. Frank M.C. Besag
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  3. Elaine Hughes
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  4. Waney Squier
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  5. Macey L. Murray
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  6. Ian C.K. Wong
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Correspondence to Ian C.K. Wong.

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Ackers, R., Besag, F.M., Hughes, E. et al. Mortality Rates and Causes of Death in Children with Epilepsy Prescribed Antiepileptic Drugs. Drug-Safety 34, 403–413 (2011). https://doi.org/10.2165/11588480-000000000-00000

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