Valproate, women, and exceptional circumstances
BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3625 (Published 28 August 2018) Cite this as: BMJ 2018;362:k3625
- Heather Angus-Leppan, consultant neurologist1,
- Rohit Shankar, consultant in adult developmental neuropsychiatry2,
- Hannah Cock, professor of epilepsy and medical education3
- on behalf of Royal College of Psychiatrists Intellectual Disability Section, the United Kingdom Learning Disability Professional Senate, and 62 signatories
- 1Epilepsy Initiative Group, Royal Free London NHS Foundation Trust, London, UK
- 2Cornwall Partnership NHS Foundation Trust, Bodmin, UK
- 3Atkinson Morley Regional Epilepsy Network, St George’s University Hospital NHS Foundation Trust, London, UK
- heather.angus-leppan{at}nhs.net
The Medicines and Healthcare Products Regulatory Agency (MHRA) now requires women of childbearing potential who take valproate to provide annual signed confirmation of adherence to the pregnancy prevention programme. The detail that for “for some women with epilepsy, it may not be possible to stop valproate, and they may have to continue treatment (with appropriate specialist care) in pregnancy”1 is crucial and from our experience seems to be sometimes overlooked.
There is international consensus that valproate is a major teratogen, that alternatives should be offered where possible and safe, and that all women for whom it is considered should undergo specialist review. There is also broad acceptance that the decisions should be individualised and that “there are likely to be some women who, even after informed consultation, choose to carry a pregnancy while taking valproate.”234 The MHRA recognises that some women with epilepsy cannot stop taking valproate before or during pregnancy without major risk to the person and the unborn child—frequent convulsions and convulsive status epilepticus are potentially dangerous to both.
In an open letter to the MHRA (box), we have outlined guidance for the exceptional circumstances in which a pregnancy prevention programme is not appropriate, although a risk acknowledgment form would still be required. These include emergency situations; those who make a fully informed decision and whose treating professionals agree that pregnancy prevention is not appropriate; and those with impaired capacity (such as some people with intellectual disability), where a bests interest process has been followed supporting the continuation of valproate. This guidance is endorsed by the Royal College of Psychiatrists Intellectual Disability Section, the United Kingdom Learning Disability Professional Senate, and 62 epilepsy clinicians working in tertiary, secondary, and community care across the country.
MHRA new regulations on valproate use: suggested guidance on exceptional circumstances
The MHRA has issued new regulations regarding the use of valproate (https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-pregnancy-prevention-programme-materials-online).
Its use will be banned in women and girls of childbearing potential unless they adhere to the pregnancy prevention programme, to prevent the development of fetal abnormalities. There is international consensus that valproate is a major teratogen, that alternatives should be offered where possible and safe, and that all women in whom it is considered need specialist review.
The MHRA recognises that in some women with epilepsy valproate cannot be stopped during pregnancy without major risk to the person and the unborn child (both frequent convulsions and convulsive status epilepticus are potentially dangerous to mother and child). This paper outlines the situations in which a child or woman, or her authorised representative, may decide that she will continue valproate even though she might be, or may become, pregnant, and those in which the pregnancy prevention programme is not appropriate, although a risk acknowledgement form would still be required.
1. Emergency situations: status epilepticus or serial seizures in a female of childbearing potential when valproate is considered by her medical specialists to be the most effective medication to control her seizures
In this situation discussion with the patient is usually not possible so treatment is given on a best interest basis under mental capacity legislation. Informed discussions about continuation of valproate and the associated risks would be undertaken on recovery with the patient, her advocates, or both, where capacity is impaired. Consent would be sought from the patient later.
2. Epilepsy in a female of childbearing potential in whom valproate is the most effective medication and the fully informed woman decides it is the best option for her, and for whom the pregnancy prevention programme is not appropriate.
This may follow unsuccessful trials of other medication
It may be in women who are currently seizure free on valproate as first line monotherapy and who, after fully informed discussion, do not want to change to another medication because of the risks to their personal safety of switching to an alternative
Women who are not able to become pregnant for health related or physical reasons
Women who, after fully informed discussion, do not want to use the forms of contraception recommended by the MHRA for personal, religious, or health reasons
3. In those who may lack capacity, such as some women with intellectual disability, an individual assessment of abilities to make informed choices on epilepsy management and medication issues is needed.
In some women with moderate to profound intellectual disability consent to sexual intercourse may be unlikely, so pregnancy is not likely to occur (in these women, pregnancy would raise concerns of abuse, sexual exploitation, or rape)
Pregnancy prevention may be part of the care plan to manage psychological distress arising from menstruation in women with moderate to profound intellectual disability lacking mental capacity to understand the natural physiological changes
Those with mild intellectual disability should be managed as other women are, but will need particular care to support their decisions in this area and may require augmented communication to enable them to make informed decisions on using medication. There may need to be involvement of special parenting services in addition to other key stakeholders such as social care
Acknowledgments
Individual signatories Heather Angus-Leppan, consultant neurologist and lead, Epilepsy Initiative Group, Royal Free London NHS Foundation Trust; Rohit Shankar, consultant in adult developmental neuropsychiatry, Cornwall Partnership NHS Foundation Trust, and honorary associate clinical professor, Exeter Medical School; Hannah Cock, professor of epilepsy and medical education and consultant neurologist, Atkinson Morley Regional Epilepsy Network, St George’s University Hospital NHS Foundation Trust; Julia Aram, epilepsy lead and consultant neurologist, Royal Sussex County Hospital, Brighton; Nina Barnett, visiting professor, Institute of Pharmaceutical Science, Kings College London; John Bowler, consultant neurologist, Royal Free London NHS Foundation Trust; Alice Brockinton, consultant epileptologist, Sheffield University Hospitals NHS Trust; Alison Carr, epilepsy nurse specialist, Bradford Epilepsy Service, West Yorkshire; Elizabeth Carunia-Galizia, consultant neurologist, Atkinson Morley Regional Epilepsy Network, St George’s University Hospitals NHS Foundation Trust; Christine Cole, epilepsy clinical nurse specialist, Harrow Neurology Specialist Nursing Service; Paul Cooper, consultant neurologist, Greater Manchester Neuroscience Centre, and honorary senior lecturer, University of Manchester; Alison Corp, learning disability epilepsy specialist nurse, NHS Greater Glasgow and Clyde; Helen Cross, Prince of Wales’s chair of childhood epilepsy and honorary consultant in paediatric neurology, UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, London, and Young Epilepsy, Lingfield; Shane Delamont, consultant neurologist, King’s College Hospital NHS Trust, London; Gary Denis, consultant neurologist and epileptologist and training programme director, Royal Hallamshire Hospital, Sheffield; Susan Duncan, consultant neurologist/senior clinical lecturer, Department of Clinical Neurosciences and East of Scotland Epilepsy Service, Western General Hospital, Edinburgh; Robert Elwes, consultant neurologist, Centre for Epilepsy, King’s College NHS Foundation Trust, London; Penny Fallon, consultant in paediatric neurology, St George’s University Hospitals NHS Foundation Trust, London; Howard Faulkner, consultant neurologist and epileptologist, North Bristol NHS Trust, Southmead Hospital, Bristol; Andrew Gale, consultant neurologist, Royal Free London NHS Foundation Trust; Melesina Goodwin, clinical nurse specialist in epilepsy, Northampton General Hospital NHS Trust; Roberto Guiloff, professor of clinical neurology, Santiago, Chile, and senior lecturer, Imperial College London; Irene Hadjikoumi, consultant in paediatric neurodisability and epilepsy, St George’s University Hospitals NHS Foundation Trust, London; Andy Hansen, GP with a special interest in epilepsy, Bradford Epilepsy Service, West Yorkshire; Dominic Heaney, consultant neurologist, University College Hospitals NHS Foundation Trust, London; Michael Johnson, professor of neurology and genomic medicine and deputy head, Centre for Clinical Translation, Division of Brain Sciences, Imperial College London; Kirsten Kammen, stroke and neurology consultant, Ashford and St Peter’s Hospital, Surrey; Andrew Kelso, consultant neurologist and divisional director specialist medicine, Barts Health NHS Trust, London; Mike Kerr, professor of learning disability psychiatry, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University; Lucy Kinton, consultant neurologist, Hampshire Hospitals NHS Foundation Trust; Matthias Koepp, professor of neurology, UCL Institute of Neurology, and consultant neurologist, National Hospital for Neurology and Neurosurgery, London and Epilepsy Society, Chalfont Centre for Epilepsy; Rebecca Liu, consultant neurologist and clinical governance lead, Royal Free London NHS Foundation Trust, honorary consultant, Institute of Neurology, London, and member, Epilepsy Initiative Group, Royal Free London; Bridget MacDonald, consultant neurologist, Atkinson Morley Regional Epilepsy Network, Croydon University Hospitals and St George’s University Hospitals NHS Foundation Trust; Laura Mantoan, consultant neurologist, Centre for Epilepsy, King’s College NHS Foundation Trust, London; Dougall McCorry, consultant neurologist, University Hospital Birmingham; Brendan McClean, consultant neurologist, NIHR PENCLRN clinical lead for neurology, The Royal Cornwall Hospitals NHS Trust, Treliske; Marco Mula, consultant epileptologist, Atkinson Morley Regional Epilepsy Network, St George’s University Hospitals NHS Foundation Trust, London; Adina Nash, epilepsy clinical nurse specialist, Royal Free London NHS Foundation Trust, honorary consultant, Institute of Neurology, London, member, Epilepsy Initiative Group, Royal Free London,; Lina Nashef, consultant neurologist and reader, King’s College Hospital NHS Trust, London; Aiden Neligan, consultant neurologist with an interest in epilepsy, Homerton University Hospital Foundation Trust, London; Niran Nirmalananthan, consultant neurologist and clincial lead for neurology, St George’s University Hospitals NHS Foundation Trust, London; Linda Parsons, consultant neurologist, Royal Free London NHS Foundation Trust; Jane Pritchard, consultant neurologist, Imperial College Healthcare NHS Trust, London; Wojtek Rakowicz, consultant neurologist, Hampshire Hospitals NHS Foundation Trust; Ashok Roy, consultant psychiatrist, Coventry and Warwickshire Partnership NHS Trust, chair, Intellectual Disability Faculty, Royal College of Psychiatrists; Lomalan Reddy, GP with a special interest in epilepsy, Bradford Epilepsy Service, West Yorkshire; Leone Ridsdale, professor of neurology and general practice, King’s College London; Amanda Ronaldson, epilepsy nurse specialist, Bradford Epilepsy Service, West Yorkshire; Martin Sadler, consultant neurologist and epilepsy service lead, University Hospitals Plymouth NHS Trust, Plymouth; Romi Saha, consultant neurologist, Royal Sussex County Hospital, Brighton; Violeta Sanchez, neurology consultant, lead clinician for neurology, Royal London Hospital, Barts Health NHS Trust, London; Maithilli Srikantha, consultant neurologist, Surrey and Sussex Healthcare NHS Trust and St George’s University Hospitals NHS Foundation Trust; Amelia Steward, epilepsy nurse specialist, Bradford Epilepsy Service, West Yorkshire; Singhal Sumeet, consultant neurologist, Nottingham University Hospitals NHS Trust; Evangelina Theochari, consultant neurologist with an interest in epilepsy, Neuroscience Department, King’s College Hospital NHS Foundation Trust, London; Rhys Thomas, consultant in epilepsy, Royal Victoria Infirmary Newcastle; Goska Trubshaw, associate specialist in epilepsy, Atkinson Morley Regional Epilepsy Network, St George’s University Hospitals NHS Foundation Trust; Vasiliki Tsirka, consultant in clinical neurophysiology and neurology, Royal London Hospital, Barts Health NHS Trust; Lance Watkins, higher trainee, Psychiatry of Learning Disability, Wales; Heather Wilson, consultant neurologist, Royal Free London NHS Foundation Trust; Mahinda Yogarajah, locum consultant neurologist, Atkinson Morley Regional Epilepsy Network, St George’s University Hospitals NHS Foundation Trust; John Young, consultant neurologist, Royal Sussex County Hospital, Brighton.
Footnotes
Competing interests: None declared.