Dr Alison Cave, chief safety officer at the Medicines and Healthcare products Regulatory Agency (MHRA), asks healthcare professionals to work together to better protect patients from the unnecessary harms of valproate, and to prescribe safer alternatives. New guidance was launched on 31 January

The teratogenic effects of valproate, prescribed in the UK to treat epilepsy and bipolar disorder, are uncontested.

To put this into context, the risk of physical birth defects is estimated to be around 11% but this can increase to 25.2% at high maternal doses (compared to a background rate of 2-3% in the general population). The risk of neuro-developmental disorders, which can range from poor educational attainment to autism spectrum disorders and may prevent those affected from leading independent lives, is estimated to be even higher at 30-40%.

In 2018, new safety measures were introduced across Europe that meant valproate could no longer be used in individuals of child-bearing potential unless a Pregnancy Prevention Programme (PPP) was in place. The aim was that this would rapidly reduce and eventually eliminate prescribing in pregnancy and for women who could become pregnant unless they had no other treatment options.

It’s of great concern that this has not yet been the case. While the number of women exposed to valproate during pregnancy has indeed been declining since the introduction of the PPP, this decline has plateaued and in the last 6 months an average of 3 babies a month in England continue to be born following exposure to valproate in utero.

Unfortunately, the risks of valproate don’t stop there. Valproate carries a known risk to male fertility (which has been in the product information since 2011 and is thought to be reversible on dose reduction or discontinuation) and there are signals from animal data of juvenile testicular toxicity and transgenerational effects, the clinical relevance of which is currently unknown.

As the evidence for valproate accumulates so does our understanding of its harmful effects, and there are compelling reasons why valproate should not be prescribed where other effective options are available.

This is why the MHRA has introduced important regulatory changes. Healthcare professionals are urged to promptly introduce these into their clinical practice.  

From 31 January 2024, valproate must not be started in new patients (male or female) younger than 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment, or there are compelling reasons that the reproductive risks do not apply. For the majority of patients, other effective treatment options are available.

All women who could become pregnant and girls who are currently taking valproate should be reviewed at their next annual specialist review, using a revised valproate Annual Risk Acknowledgement Form, which will include the need for a second opinion’s signature if the patient is to continue with valproate.

Further measures are being considered for male patients currently taking valproate with advice from an independent expert group of the Commission on Human Medicines, which includes representation from across the healthcare system.

New safety and educational materials have been introduced for patients and healthcare professionals to support the implementation of these measures. Healthcare professionals should review the new measures and materials and integrate them into their clinical practice to aid in discussions concerning the risks of valproate with patients.

We understand that for some people with uncontrolled epilepsy, valproate may be the only effective treatment option and for these individuals valproate will continue to remain available.

But for most people it’s not, and so we are asking you to help us better protect patients from the harms of this powerful medicine and ensure it is only used when no other treatment is effective. Our new regulatory measures and educational materials should support you in achieving this.

For more information on the regulatory measures, please see the MHRA's Drug Safety Update.