Valproate medicines and serious harms in pregnancy: new Annual Risk Acknowledgement Form and clinical guidance from professional bodies to support compliance with the Pregnancy Prevention Programme

Ongoing patient survey data suggest that more effort is needed by clinicians to achieve full and timely compliance with the valproate Pregnancy Prevention Programme and meet the goal to rapidly reduce and eventually eliminate the harms of valproate in pregnancy in view of its serious teratogenicity. We have updated the Annual Risk Acknowledgement Form, which should be used during annual specialist review of all women and girls of childbearing potential on valproate medicines (irrespective of indication). Specialists should comply with guidance given on the form if they consider the patient is not at risk of pregnancy, including the need for regular review in case her risk status changes.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 16 April 2019

• Therapeutic area: Neurology, Obstetrics, gynaecology and fertility, Paediatrics and neonatology, Pain management and palliation, Pregnancy and Psychiatry

Post-publication note - January 2024

New measures have been implemented to reduce the harms of valproate treatment, including new safety and educational materials. See Drug Safety Update January 2024 for more information and the valproate guidance page for safety and educational materials.

Advice for healthcare professionals:

• use the revised Annual Risk Acknowledgement Form(at initiation and annual review of all girls and women of childbearing potential on valproate medicines (irrespective of indication)
• specialists should comply with guidance on the form if they consider there to be compelling reasons to indicate their patient is not at risk of pregnancy, including the need to document reasons for this and for the patient or responsible person to sign to confirm these are correct
• if the absence of pregnancy risk may change (for example, the patient is pre-menarchal), the date for the next annual discussion of the risks must be documented and the patient or the patient’s family or caregivers asked to contact the prescriber rapidly if the situation changes
• there is no safe dose of valproate that can be used in pregnancy – see reminder below for key facts about the risks if pregnancies are exposed to valproate

Revised Annual Risk Acknowledgement form

Children exposed to valproate in utero have a very high risk for congenital malformations (10% risk) and neurodevelopmental disorders (30–40% risk). See below for a Reminder of key facts about the risks of valproate.

It is the prescriber’s responsibility to ensure women and girls of childbearing potential (from menarche to menopause) who are taking a valproate medicine, irrespective of indication, fulfil all the requirements of the Pregnancy Prevention Programme. These responsibilities include that the patient (or responsible person) and their specialist must complete the Annual Risk Acknowledgement Form at each year’s annual review.

The Annual Risk Acknowledgement Form has been updated following feedback from healthcare professionals and stakeholders and should be used for all future reviews of female patients on valproate.

The form can now be used to record when the specialist considers the patient not to be at risk of pregnancy, either permanently or until the date of the next annual review. Patients or their responsible person must countersign this section to confirm details given are correct.

NICE guidance summary

To support healthcare professionals to understand their clinical responsibilities for valproate, NICE has produced a summary of their guidance and safety advice.

Pan-college guidance

Experts from 13 national healthcare bodies, including 7 Royal Colleges, have produced clinical guidance to support healthcare professionals involved in the care of women on valproate. The ‘pan-College’ guidance advises on the more challenging issues that clinicians across primary and specialist care might encounter in daily practice. These include transition from paediatric to adult services, competence to consent to treatment, and confidentiality.

Paediatric guidance

The British Paediatric Neurology Association (BPNA) and the Royal College of Paediatrics and Child Health (RCPCH) have developed joint guidance to provide recommendations about the use of valproate in female patients under 18 years of age.

Reminder of key facts about the risks of valproate in pregnancy

• 1 in 10 babies (10%) exposed to valproate in pregnancy are born with a congenital malformation – for the general population, the risk is about 2–3%^{[footnote 1]}
• Folic acid supplementation may decrease the general risk of neural tube defects but there is evidence that it does not reduce the risk of birth defects associated with valproate exposure
• There is no safe dose of valproate that can be used in pregnancy – in a comparative study, all doses of valproate increased the risk of major congenital malformations^{[footnote 2]}
• Around 3 to 4 in 10 children (30–40%) exposed to valproate in pregnancy have delays in their development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding), and memory problems^{[footnote 3]}
• IQ in school-aged children (age 6 years old) with a history of valproate exposure in pregnancy was recorded to be on average 7–10 points lower than children exposed to other antiepileptic drugs ^{[footnote 4]}
• Children with a history of valproate exposure in pregnancy have a 3-fold risk of autistic spectrum disorder and 5-fold risk of childhood autism compared with general population^{[footnote 5]}
• Children exposed to valproate in pregnancy may be at increased risk of attention deficit/hyperactivity disorder (ADHD)^{[footnote 6]}

Post-publication note

The date on the Annual Risk Acknowledgement Form has been amended from March 2019 to November 2019 to be consistent with other valproate educational Pregnancy Prevention Programme materials. As of January 2024, these materials have now been superseded by new safety and educational materials which are on the valproate guidance page for safety and educational materials.

Article citation: Drug Safety Update volume 12, issue 9: April 2019: 2.

1. Weston J, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 2016 Nov 7;11: CD010224. ↩

2. Thompson, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol 2018; 17: 530–38. ↩

3. Bromley RL, et al. [Early cognitive development in children born to women with epilepsy: a prospective report]https://doi.org/10.1111/j.1528-1167.2010.02668.x). Epilepsia 2010; 51: 2058–65. ↩

4. Meador KJ, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013 12: 244–52. ↩

5. Christensen J et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013; 309: 1696–703. ↩

6. Cohen MJ et al. Fetal antiepileptic drug exposure: motor, adaptive and emotional/ behavioural functioning at age 3 years. Epilepsy Behav 2011; 22: 240–246. ↩

Published 16 April 2019