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Medicines regulators urge caution as new evidence links paternal valproate use and autism risk

The UK and European medicines regulators are considering new evidence suggesting that children whose fathers took valproate during the three months before conception are at increased risk of neurodevelopmental disorders such as autism.

A new study, commissioned by the European Medicines Agency (EMA), found that around five in 100 children born to fathers treated taking valproate around conception were diagnosed with a disorder, compared with three in 100 children with fathers who took other antiseizure drugs.

The Medicines and Healthcare products Regulatory Agency (MHRA) has confirmed that these results will be ‘rigorously analysed’, but in the meantime urged caution for male patients who want to have children.

‘As a precaution, male patients on valproate who are planning a family in the next year should talk to their healthcare professional about their treatment,’ the MHRA said.

PRAC, the EMA’s safety committee, is also recommending precautionary measures, including that valproate treatment in male patients is started and supervised by a specialist in the management of epilepsy, bipolar disorder or migraine.

’Doctors should inform male patients who are taking valproate about the possible risk and discuss the need to consider effective contraception, for both the patient and their female partner,’ the PRAC said.

It also advised the regular review of valproate treatment in male patients to consider whether it remains the most suitable treatment, particularly when the patient is planning to conceive a child.

’The potential risk of neurodevelopmental disorders and the precautionary measures will be reflected in updates to the product information and educational material for valproate medicines,’ the PRAC concluded, adding that ’a direct healthcare professional communication will be sent in due course to healthcare professionals prescribing, dispensing or administering the medicine’.

Previous recommendations to avoid exposure to valproate medicines in women during pregnancy due to the risk of congenital malformations and neurodevelopmental disorders remain in place.

Meta-analysis results

The PRAC reviewed data from a retrospective observational study carried out by companies that market valproate as an obligation following a previous review of valproate use during pregnancy.

The study used data from multiple registry databases in Denmark, Norway and Sweden and focused on birth outcomes in children born to men who were taking valproate or taking lamotrigine or levetiracetam around the time of conception.

A meta-analysis of data resulted in a pooled adjusted hazard ratio (HR) of 1.50 (95% CI: 1.09-2.07) for neurodevelopmental disorders in children of fathers treated with valproate in the three months prior to conception compared with lamotrigine or levetiracetam.

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The adjusted cumulative risk of neurodevelopmental disorders was estimated to be around 5% in the valproate group versus around 3% in the lamotrigine and levetiracetam group. No difference in the risk of congenital malformations was seen between the two groups.

The study did not evaluate the risk of neurodevelopmental disorders in children born to fathers who stopped using valproate more than three months before conception.

The study data on male patients had limitations, including differences between the groups in the conditions for which the medicines were used and in follow-up times.

The PRAC could therefore not establish whether the increased occurrence of these disorders suggested by the study was due to valproate use.

In addition, the study was not large enough to identify which types of neurodevelopmental disorders children could be at increased risk of developing.

Nonetheless, the PRAC considered precautionary measures were warranted to inform patients and healthcare professionals of the potential risks.

MHRA tightening valproate prescribing rules

In December, the MHRA urged healthcare organisations to prepare for new tightened rules on prescribing valproate which are due to come in later this month. 

Under these rules, the epilepsy drug must not be started in new patients – male or female – under the age of 55 unless two specialists have agreed and documented that there are no other effective or tolerated treatments.

In August, when the study on paternal risk was first submitted, the brand leader for valproate informed the MHRA of errors in the study which forced the researchers to conduct a full re-analysis. 

After re-submission, the MHRA confirmed it will review the results as part of its ‘ongoing monitoring of the safety of valproate’.

But this will not have ‘implications’ for the new strengthened safety rules coming in this month, according to the MHRA.

Any further guidance resulting from the study’s findings, based on the MHRA’s review and independent advice from the Commission on Human Medicines, will be communicated to healthcare professionals ‘as soon as possible’.

In June last year, NHS England launched a new tool to help with decisions on whether sodium valproate should be prescribed for epilepsy or bipolar disorder by weighing up the benefits and potential harms. 

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