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Quality Improvement Data Report:Prescription of valproate to patients of childbearing potential

Introduction

Valproate is associated with a significant risk of birth defects and developmental disorders inchildren born to women who take valproate during pregnancy.

This report has been produced as part of the programme of RCGP/CPRD Quality Improvementreports, which focus on prescribing and patient safety.

The table below shows patients who meet the following criteria:

• Female, Indeterminate or Unknown gender• Age 12-55 years in 2019• Any valproate prescription (sodium valproate, valproic acid or valproate semisodium) issued

in 2019

The code list used to identify valproate prescriptions is available on the project page on the CPRDwebsite1.

The search included only currently registered patients that have not dissented from secondary useof their clinical data. The analysis is based on our latest database build, for which data wereextracted from your practice on Sunday 22nd September, 2019.

The following pages give the rationale for this report and suggested next steps.

Patient Birth Number of Date ofIdentifier year prescriptions last issue

issued in 20195629 2006 9 29/09/201991250 1986 2 25/05/20190838 1994 1 10/08/20197772 1970 8 05/09/201915020 2000 16 30/09/20193948 1973 3 16/05/2019

1Project page on CPRD websitehttps://www.cprd.com/generalpractitioner/QualityImprovementProject.asp

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Rationale

In women who take valproate while pregnant, around 1 in 10 babies will have a birth defect. Birthdefects seen when mothers take valproate during pregnancy include:

• spina bifida (where the bones of the spine do not develop properly)• facial and skull malformations (including cleft lip and palate, where the upper lip or facial

bones are split)• malformations of the limbs, heart, kidney, urinary tract and sexual organs

In women who take valproate while pregnant, about 34 children in every 10 may havedevelopmental problems. The long-term effects are not known. The effects on child developmentcan include:

• being late in learning to walk and talk• lower intelligence than other children of the same age• poor speech and language skills• memory problems

Children exposed to valproate in the womb are three times more likely to have autism or autisticspectrum disorders. There is also some evidence children may be more likely to be at risk ofdeveloping symptoms of attention deficit hyperactivity disorder (ADHD)2.

Following regulatory changes, new restrictions were introduced to prevent valproate exposure inpregnancy in April 2018. Valproate is now banned for use in women of childbearing age unless theconditions of the Pregnancy Prevention Programme (PPP) are met3. It has also been the subjectof a follow-up letter to pharmacists from the four UK Chief Pharmaceutical Officers4. For Englishpractices, the Prescribing Safety module of the Quality Improvement domain of the 2019/20 QOFhas a focus on this issue5.

Current advice

Valproate must not be used in any woman or girl able to have children unless there is a PPP inplace this is also known as PREVENT6.

In girls and women of childbearing potential, valproate should be initiated and supervised by aspecialist and only when other medications have not been tolerated or have been found to beineffective.

2Valproate use by women and girls, MHRAhttps://www.gov.uk/guidance/valproate-use-by-women-and-girls

3Valproate medicines (EpilimH, DepakoteH): contraindicated in women and girls of childbearing potential unlessconditions of Pregnancy Prevention Programme are methttps://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met

4Valproate Pregnancy Prevention Programme letterhttps://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAttachment.aspx?Attachment id=103118

5Guidance for GMS Contract 2019/20 in Englandhttps://www.england.nhs.uk/wp-content/uploads/2019/05/gms-contract-qof-guidance-april-2019.pdf

6Guidance Document on Valproate Use in Women and Girls of Childbearing Yearshttps://www.rcog.org.uk/globalassets/documents/guidelines/valproate-guidance-march-2019.pdf

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What next?

The recommendation is that you review the list of patients on the front page of this report andarrange a recall if the patient is not on the PPP and an appropriate reason is not documented.The MHRA has produced a template letter for use with patients, which can be accessed from theproject page on the RCGP website7.

The MHRA’s Guide for Healthcare Professionals provides a comprehensive list of actions for GPsand pharmacists8. The following actions are highlighted as being the responsibility of generalpractice when implementing a PPP:

• Ensure continuous use of highly effective contraception in all women of childbearingpotential (and consider the need for pregnancy testing if not a highly effective method)

• Check that all patients have an up to date, signed, Annual Risk Acknowledgment Form(ARAF) each time a repeat prescription is issued

• Ensure the patient is referred back to the specialist for review, annually• Refer back to the specialist urgently (within days) in case of unplanned pregnancy or where a

patient wants to plan a pregnancy

These actions should be documented within the patient record, using the appropriate SNOMEDcodes. To help you with this, we have included a section on Standardised SNOMED coding, whichis taken from draft MHRA guidance.

Additionally, there are a number of PPP materials online9, including:

• Patient Card: to be given by pharmacists to all female patients who are dispensed valproatemedicines to inform them of the risks

• Patient Guide: to be provided to patients of childbearing potential taking any medicinecontaining valproate (or their parent/caregiver/responsible person)

• Guide for Healthcare Professionals: for all prescribers, pharmacists, and other healthcareproviders involved in the care of patients of childbearing potential using valproate medicines

• Annual Risk Acknowledgement Form (ARAF): for the specialist and patient (or theirparent/caregiver/responsible person) to sign at initiation and at treatment reviews at leastevery year.

7Project webpage on RCGP websitehttps://www.rcgp.org.uk/clinical-and-research/our-programmes/quality-improvement/quality-improvement-prescribing-and-patient-safety-reports.aspx

8Guide for Healthcare Professionals: Information on the risks of valproate, MHRA.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment data/file/708850/123683 Valproate HCP Booklet DR15.pdf

9Valproate medicines (EpilimH, DepakoteH): Pregnancy Prevention Programme materials onlinehttps://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-pregnancy-prevention-programme-materials-online

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Further information about valproate in pregnancy

The Medicines and Healthcare products Regulatory Agency (MHRA) has published a number ofdocuments and resources around the use of valproate with women of childbearing age, including:

• Guidance on valproate use by women and girlshttps://www.gov.uk/guidance/valproate-use-by-women-and-girls

• Valproate medicines: Pregnancy Prevention Programme materials onlinehttps://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-pregnancy-prevention-programme-materials-online.

The RCGP and the Royal College of Physicians have published guidelines for clinicians, which areendorsed by all the medical Royal Colleges. The guidance is intended to provide practicalinformation and guidance for healthcare professionals when there may be problems or questionsabout following the MHRA regulations, and sources of further support, for clinicians involved withvalproate: it gathers data, where available, on best practice and summarises consensus opinionfrom seventeen national bodies across the UK:

• https://www.rcgp.org.uk/-/media/Files/CIRC/Epilepsy/RCGP-pan-college-valproate-march-2019.ashx

The National Institute for Health and Care Excellence (NICE) has produced a summary of itsguidance and safety advice on valproate, which includes links to the relevant documentation:

• https://www.nice.org.uk/guidance/qs115/resources/valproate-in-children-young-people-and-adults-summary-of-nice-guidance-and-safety-advice-pdf-6723784045

The MHRA has been monitoring trends in the prescribing of valproate to assess the impact ofevolving regulatory recommendations and introduction of the pregnancy prevention programmeusing primary care data from the Clinical Practice Research Datalink GOLD database:

• CPRD study monitoring the use of valproate in girls and women in the UK: January 2010 toJune 2018https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment data/file/765558/CPRD-valproate-usage-17122018.pdf

• CPRD study monitoring the use of valproate in girls and women in the UK: January 2010 toDecember 2018https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment data/file/811041/CPRD valproate usage report -2nd revision Jun 2019 clean.pdf.

The regulatory position on valproate in pregnancy has been endorsed by the European MedicinesAgency:

• https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0

The Summary of Product Characteristics (SPCs) for valproate includes advice for prescribers:

• https://www.medicines.org.uk/emc/search?q=valproate

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Standardised SNOMED Coding10

Standardised coding is critical to evaluate adherence and effectiveness of the risk minimisationmeasures for valproate and the different aspects of the valproate pregnancy prevention programme(PPP, also known as PREVENT).

The SNOMED codes provided below enable standardised recording of the key elements of the PPPand reason why a female patient would not meet the conditions of the PPP while taking valproate.It is also important to record if a patient no longer adheres to the conditions of the PPP whilecontinuing to take valproate. This level of granularity is needed to understand if valproate is usedsafely as per regulatory recommendations and understand under what circumstance a patient maynot be on the PPP. Use of the recommended codes will enable healthcare professionals to trackfemale patients on valproate, document if this medicine is used safely and recall them for theirannual review where applicable. This will be important for GPs to document their adherence to theQI indicator in the new GP contracts under Prescribing Safety for valproate pregnancy prevention.

Valproate prescribing should be documented in prescription records.

Please select from the appropriate SNOMED codes provided below to document management ofwomen 12-55 years on valproate. The PPP codes are being introduced from October 2019; pleasecontact your commissioning support unit for help if you are unable to find them within yourpractice system.

The patient is adherent to ‘PREVENT’ (the valproate pregnancy prevention programme)SNOMED Code Description1129771000000103 Pregnancy prevention programme started (situation)

• Patient on valproate and on effective contraceptionSNOMED Code Description413116005 Transdermal contraception (finding)268464009 Depot contraception (finding)449038007 Uses hormone releasing intrauterine device contraception312082008 Contraceptive coil (physical object)714594000 Copper-containing intrauterine device (product)428987008 Subcutaneous contraceptive implant present (finding)

• Patient had a negative pregnancy test prior to initiating valproateSNOMED Code Description250425007 Pregnancy test negative (finding)

• The patient had her annual review to discuss the risk of valproate with a specialistThere are no specific codes to record a complete Annual Risk Acknowledgement Form(ARAF), however the more general code below can be used to document this The signedARAF should be uploaded and added to the patient record.

SNOMED Code Description381351000000107 High risk drug monitoring annual review (procedure)

10This section is taken from draft MHRA guidance.

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The patient is not adherent to ‘PREVENT’SNOMED Code Description1129841000000102 Pregnancy prevention programme discontinued (situation)1129791000000104 Pregnancy prevention programme not needed (situation)

If the patient is not adherent to PREVENT please document the reason using the appropriateSNOMED codes. Some examples are provided below, however the list is not exhaustive11.

• Absence of pregnancy risk is permanentSNOMED Code Description161800001 History of hysterectomy (situation)289903006 Menopause present (finding)287664005 Bilateral tubal ligation (procedure)275572005 History of female sterilization (situation)373717006 Premature menopause (finding)

• Not yet reached menarcheSNOMED Code Description14302001 Amenorrhea (finding)

• RefusedSNOMED Code Description1129801000000100 Pregnancy prevention programme declined (situation)1129821000000100 Pregnancy prevention programme declined by parent

(situation)1129811000000103 Pregnancy prevention programme declined by caregiver

(situation)

Infant exposed to valproate in-utero

Please use the SNOMED code provided below to document the impact of valproate prescribing inpregnancy on an infant.

SNOMED Code Description1129511000000101 Exposure to anticonvulsant in utero (event)

11For instance, a woman who is of childbearing potential should be on Prevent whether or not they are currentlysexually active. However, there may be circumstances where a prescriber is confident that a woman who is not currentlysexually active will not subsequently become so and appropriate codes should be used to document this.

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Further information about the QI report programme

This report has been produced as part of the Quality Improvement collaboration between RCGPand Clinical Practice Research Datalink (CPRD), which produces confidential data reports onprescribing and patient safety for all practices signed up to the CPRD data extract.

Along with this report on valproate, there are two other reports, covering:

• Heart and Circulatory System• Patients with Learning Disabilities or Autism or both.

There is further detail about the reports on the RCGP and CPRD project webpages:

• https://www.rcgp.org.uk/clinical-and-research/our-programmes/quality-improvement/quality-improvement-prescribing-and-patient-safety-reports.aspx

• https://www.cprd.com/generalpractitioner/QualityImprovementProject.asp

Clinicians who have used these reports have told us that they use them in the following ways:

1. To review the care of individual patients highlighted in the reports where necessary, patientshave their treatment changed

2. As the starting-point for discussions involving all clinicians within the practice around safeprescribing

3. As evidence for annual appraisals and revalidation, under Domain 2 Safety and Quality4. To flag all patients with the identified conditions in order to ensure that they will not be

prescribed potentially unsafe drugs in future5. As part of locality or cluster quality improvement meetings6. As part of the practice’s work for the Quality and Outcomes Framework (QOF)

If you know of colleagues who would like to receive Quality Improvement reports for their practice,they can sign up via the CPRD website12.

Please help us to make the reports better by filling in our short online survey13. We are writing upcase studies of how the reports are used by practices, so please get in touch if you’d like your workto be shared and help other practices across the UK.

A write-up of the pilot phase of this Project has been published in the British Journal of GeneralPractice14. The paper describes the development of the reports and our success in using routinedatasets to provide quality improvement resources that impact directly on patient care.

12CPRD joining formhttps://www.cprd.com/joiningform

13Online Surveyhttps://www.surveymonkey.co.uk/r/QIReport Valproate

14Quality improvement of prescribing safety: a pilot study in primary care using UK electronic health recordshttps://doi.org/10.3399/bjgp19X704597

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