Medicines Healthcare Products Regulatory Agency
Advice for healthcare professionals:
- we have started a new safety review to assess the benefits and risks of topiramate and to consider whether further measures are required to reduce the risk of harm associated with topiramate use 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
- of the antiepileptic medicines reviewed for use in pregnancy, lamotrigine and levetiracetam continue to be considered the safer for the baby since they were not associated with an increased risk of birth defects see advice following comprehensive safety review of antiepileptic drugs in pregnancy
- it remains vital that the strict restrictions for valproate prescribing in women and girls of childbearing potential are followed given the known significant risks if valproate is used in pregnancy (see dedicated section below
Reminder of current advice for topiramate:
- do not prescribe topiramate during pregnancy for migraine prophylaxis
- ensure any patients of childbearing potential know to use highly effective contraception throughout treatment with topiramate
- counsel patients on the importance of avoiding pregnancy during topiramate use due to these emerging data and also the established increased risks of major congenital malformations and fetal growth restriction in babies exposed to topiramate in-utero
- topiramate may reduce the effectiveness of steroidal contraceptives, including oral contraceptives, therefore consider alternative or concomitant methods (see section on Advice on contraceptive interactions in the article)
- for migraine prophylaxis, topiramate can be withdrawn in pregnancy by an appropriate prescriber but alternative treatments should be considered
- for epilepsy, urgently refer anyone on topiramate who is planning a pregnancy or who is pregnant for specialist advice on their antiepileptic treatment
Advice to provide to patients:?
- do not stop taking topiramate without first discussing it with your doctor
- topiramate can harm the way an unborn baby grows and develops during pregnancy see advice on epilepsy medicines and pregnancy
- a new study has also linked topiramate to an increased risk of autism spectrum disorders and intellectual disabilities (effects on learning and development) in children exposed to it during pregnancy
- the MHRA and its independent experts are investigating whether there needs to be changes to how topiramate can be used in UK patients we will communicate the outcomes of this review once it has concluded
- if you are taking topiramate for epilepsy and are planning a pregnancy, urgently talk to your doctor for a specialist review there are other epilepsy medicines that are not associated with an increased risk of birth defects in pregnancy
- if you are taking topiramate for migraine and planning a pregnancy, talk to your prescriber about alternative treatments that can be used in pregnancy as soon as possible
- anyone who is able to get pregnant should have a pregnancy test before they start topiramate treatment and use effective contraception while taking topiramate
- topiramate can reduce the effectiveness of hormonal contraception in preventing unplanned pregnancy talk to a healthcare professional about the best contraception for you while you are taking topiramate
Topiramate and known harms if used in pregnancy
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
It is available as tablets, a liquid oral solution, or as capsules that can be swallowed whole or sprinkled on soft food. The brand name of topiramate is Topamax, and so this may also appear on the box.
Following a comprehensive national review by the Commission on Human Medicines into the safety of antiepileptic drugs in pregnancy, including topiramate, in January 2021 we published new safety advice in?Drug Safety Update with?patient advice, and a?Public Assessment Report.
The review showed topiramate exposure in-utero to be associated with an increased risk of congenital malformations (approximately 4 or 5 cases per 100 babies, compared with 2 or 3 in the general population). Topiramate was also shown to be associated with an increased risk of the baby being born of low birth weight and small for gestational age (fetal growth restriction).
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 were needed to reach firm conclusions.
Clinicians should continue to consult the wider findings of the review when considering prescribing of epilepsy medicines in female patients, particularly that lamotrigine (Lamictal) and levetiracetam (Keppra) were not associated with an increased risk of birth defects compared with the general population.
New national safety review of topiramate
The MHRA regularly reviews any emerging data relating to the safety of topiramate, as for all medicines.
A recently published study (Bjrk and colleagues[footnote 1]) reported prenatal exposure to topiramate to be associated with an increased risk of autism and intellectual disability. 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 (see study for definition).
We have now started 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. More about the review is available on our website.
While the review is ongoing, we are alerting healthcare professionals to the findings of this new study and reminding you of the important risks and precautions to take when prescribing or dispensing topiramate in women of childbearing potential.
Further details on the findings of the new study
The study by Bjrk and colleagues[footnote 1] is a large, well-conducted study using established data sources from 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). It reports that children whose mothers use topiramate or valproate during pregnancy are at an increased risk of autism spectrum disorder, intellectual disability, and a composite outcome of any neurodevelopmental disorder. These risks are known for valproate (see section on valproate below).
Data from around 4.5 million mother-child pairs were examined 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. These data were analysed to estimate the risk of autism spectrum disorder and intellectual disability 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 chil