The Medicines and Healthcare products Regulatory Agency (MHRA) is to undertake a safety review into topiramate, triggered by a study reporting an increased risk of neurodevelopmental disabilities in children whose mothers took the drug during pregnancy.

The review will assess the benefits and risks of topiramate and consider whether further measures are required to reduce the risk of harm associated with topiramate use during pregnancy. The MHRA said it would communicate the outcomes of this review once it had concluded.

Topiramate (Topamax) is used to prevent migraine headaches and treat seizures. It is available as tablets, a liquid oral solution, or as capsules that can be swallowed whole or sprinkled on soft food.

The drug is known to be associated with an increased risk of congenital malformations and effects on foetal growth if used during pregnancy.

Healthcare professionals were encouraged to continue counselling patients who can become pregnant on the known and emerging risks of topiramate for an unborn baby and on the need to use effective contraception throughout use.

The review was triggered by a large observational study reporting that prenatal exposure to topiramate or valproate was associated with an increased risk of autism spectrum disorders, intellectual disability, and neurodevelopmental disorders. These risks are known for valproate.

The Commission on Human Medicines considered the findings and advised that it provided robust evidence to support the association.

Prescribers were reminded to:

  • Not to prescribe topiramate during pregnancy for migraine prophylaxis
  • Ensure any patients of childbearing potential know to use highly effective contraception throughout treatment and the reduced effectiveness topiramate may have on steroidal contraceptives, including oral contraceptives
  • Counsel patients on the importance of avoiding pregnancy during use

Before the initiation of topiramate in a woman of childbearing potential, pregnancy testing should be performed.

For migraine prophylaxis, topiramate can be withdrawn in pregnancy by an appropriate prescriber ‘but alternative treatments should be considered’, said the MHRA.

For epilepsy, alternative options should be considered, it added. Anyone on topiramate who was planning a pregnancy or was pregnant should be urgently referred for specialist advice on their antiepileptic treatment.

Healthcare professionals should continue to use the data provided by the Medicines and Pregnancy Registry - Antiepileptic use in females aged 0 to 54 in England - to review comparative use of antiepileptic medicines in pregnancy.

2021 review

The latest data showed that while prescribing of valproate had declined substantially in girls and women of childbearing age, as well as during pregnancy, a number of pregnancies continued to be exposed.

Conversely, total prescribing of topiramate was increasing, and had become one of the more commonly prescribed antiepileptics in women younger than 55, including during pregnancy.

This is despite safety advice published by the MHRA in January 2021, following a comprehensive national review by the Commission on Human Medicines into the safety of antiepileptic drugs in pregnancy – including topiramate.

The review showed topiramate exposure in-utero to be associated with an increased risk of congenital malformations (approximately four or five cases per 100 babies, compared with two or three in the general population).

It was also shown to be associated with an increased risk of the baby being born of low birth weight and small for gestational age.

At the time of the 2021 review, some data had raised concerns that topiramate use during pregnancy may be associated with an increased risk of autism spectrum disorder and poorer developmental outcomes. However, the numbers in the available studies were limited and further data was needed to reach firm conclusions.

Clinicians were advised to continue to consult the wider findings of the review when considering prescribing of epilepsy medicines in female patients.

Lamotrigine (Lamictal) and levetiracetam (Keppra) were not associated with an increased risk of birth defects compared with the general population, the review also found.

Healthcare professionals were urged to continue to report any suspected adverse drug reactions (ADRs) associated with topiramate or any other medicines via the Yellow Card scheme.