MHRA Update – Risk of Topiramate (Topamax) in children with prenatal exposure

On 21 July 2022, Medicines and Health care products Regulatory Agency (MHRA) released a drug safety update stating, initiation of new safety review into topiramate because of increased risk of neurodevelopmental disabilities in children whose mothers took topiramate during pregnancy.

The new safety review was triggered by a large observational study reporting that prenatal exposure to topiramate is associated with an increased risk of autism spectrum disorders, intellectual disability, and neurodevelopmental disorders.

Topiramate is used:

• to prevent migraine headaches in adults after consideration of possible alternative treatment options
• alone to treat seizures in adults and children aged older than 6 years
• with other medicines to treat seizures in adults and children aged 2 years and older

As per the published observational study results, prenatal exposure to topiramate to be associated with an increased risk of autism and intellectual disability. The data for the study was collected from around 4.5 million mother-child pairs and this included 24,825 children (0.6%) who were prenatally exposed to antiepileptic drugs. Of these, 16,170 were born to mothers who had epilepsy.

This data was analyzed to estimate the side effects after exposure to the 10 most frequently used antiepileptic drugs when used as monotherapy (one medicine) and the 5 most frequently used antiepileptic drugs when used as duotherapy (two medicines at the same time). In unexposed children of mothers with epilepsy, the 8-year cumulative incidence of autism spectrum disorder and intellectual disability were 1.5% and 0.8% respectively compared with 4.3% and 3.1% in children of mothers with epilepsy exposed to topiramate. The adjusted hazard ratios for autism spectrum disorder and intellectual disability were 2.8 (95% CI 1.4 to 5.7) and 3.5 (95% CI 1.4 to 8.6). 

The Commission on Human Medicines considered the findings of this new study and advised that it provides robust evidence to support an association between prenatal exposure to topiramate and an increased risk of autism spectrum disorder, intellectual disability and the composite outcome of any neurodevelopmental disorder.

MHRA has initiated a safety review to evaluate these findings in the context of the accumulating data relating to the benefits and risks of use of topiramate, with a particular focus on women of childbearing potential and during pregnancy. The review will also explore the need for additional risk minimisation measures to reduce the potential harms associated with the use of topiramate during pregnancy. 

Additional drug monitoring measures:

• Before the initiation of topiramate in a woman of childbearing potential, pregnancy testing should be performed, and the patient should be fully informed of the risks if used during pregnancy.
• Topiramate should not be prescribed for migraine prevention in a patient who is pregnant.
• Topiramate may reduce the effectiveness of steroidal contraceptives, including oral contraceptives, therefore consider alternative or concomitant methods

References:

https://www.gov.uk/drug-safety-update/topiramate-topamax-start-of-safety-review-triggered-by-a-study-reporting-an-increased-risk-of-neurodevelopmental-disabilities-in-children-with-prenatal-exposure#new-national-safety-review-of-topiramate

https://jamanetwork.com/journals/jamaneurology/fullarticle/2793003