In July 2022 MHRA issued new guidance on the use of topirimate in women of childbearing age both in the treatment of epilepsy and prevention of migraine
The new safety review was triggered by a large observational study ( Bjørk M et al 2022) reporting that prenatal exposure to topiramate is associated with an increased risk of autism spectrum disorders, intellectual disability, and neurodevelopmental disorders (https://jamanetwork.com/journals/jamaneurology/fullarticle/2793003
Use of Topiramate
- 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
Advice if a pregnancy is planned
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
NB 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
MHRA review 2021
Following a comprehensive national review by the Commission on Human Medicines into the safety of antiepileptic drugs in pregnancy, including topiramate, in January 2021 a new safety advice in Drug Safety Update with patient advice, and a Public Assessment Report were published.
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.
Details on the findings of the Bjørk study
The study by Bjørk and colleagues 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 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).
A range of sensitivity analyses were conducted that broadly showed consistent and statistically significant effect estimates of a greater than 2-fold increase in risk of neurodevelopmental disorders across most of the analyses. The data also showed a dose-dependent effect for topiramate.
Topiramate and current pregnancy prevention requirements
- 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.
- For epilepsy, alternative therapeutic options should be considered for women of childbearing potential. If topiramate is used, a highly effective contraception is strongly recommended, and the discussion with the patient should include information on both the risks associated with taking topiramate and of uncontrolled epilepsy during pregnancy.
- For migraine prophylaxis, topiramate is contraindicated in pregnancy and in women of childbearing potential if not using a highly effective method of contraception. As such, topiramate should not be prescribed for migraine prevention in a patient who is pregnant
Topirimate and Breastfeeding
- Maternal doses of topiramate up to 200 mg daily produce relatively low levels in infant serum. Sedation and diarrhoea have been reported occasionally in breastfed infants, but most infants tolerate the drug in milk well. In a few infants, no long-term adverse effects on growth and development have been seen. Monitor the infant for diarrhoea, drowsiness, irritability, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of anticonvulsant or psychotropic drugs. (https://www.ncbi.nlm.nih.gov/books/NBK501259/
- Öhman et al 2002. observed five babies at delivery and followed three of them through lactation. Two to three weeks after delivery two of the breastfed infants had detectable but unquantifiable levels of topiramate and one had an undetectable concentration; m/p ratios of around 0.86 were determined throughout the study period and no adverse events noted. Observe for sedation, poor feeding and diarrhoea. https://breastfeeding-and-medication.co.uk/fact-sheet/anti-epilepsy-medication-and-breastfeeding
- Topirimate is moderately excreted into breast milk with the infant receiving just over 10% of the maternal weight-adjusted dose. Neither clinical nor psychomotor developmental effects have been observed in infants whose mothers were treated. Only a possibly related case of gastroenteritis that resolved after discontinuation of mother’s medication. Plasma levels of infants whose mothers were treated with topiramate have shown to be undetectable or pretty below (<1 mg / L) the recommended therapeutic level (5-20 mg / L). Check up the occurrence of diarrhoea, irritability and lethargy in infants ( https://www.e-lactancia.org/breastfeeding/topiramate/product/)
Adequate precautions against pregnancy must be used even when breastfeeding exclusively.