USE OF TOPIRAMATE IN PREGNANCY

Topiramate is an antiseizure medication (ASM) used in monotherapy or as adjunctive therapy in the treatment of generalised tonic-clonic seizures, focal seizures with or without secondary generalisation, and seizures associated with Lennox-Gastaut syndrome. Topiramate is also licensed for the prophylaxis of migraine.

Topiramate should not be used for migraine prophylaxis in pregnancy. Following the publication of three recent observational studies, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) now recommend that topiramate should not be used during pregnancy for the treatment of epilepsy unless there is no suitable alternative treatment available. The PRAC have also recommended additional measures in the form of a pregnancy prevention programme. For further information please see the EMA website.

The majority of the available epidemiological data relate to topiramate use in pregnancy for the treatment of epilepsy. Gestational topiramate exposure has been associated with elevated risks of overall malformation (up to 2-fold increased, absolute risk ~6%) and orofacial clefts (up to 6-fold increased, absolute risk ~0.6%). Exposure has also been associated with increased risk of neurodevelopmental impairment (up to 2.3-fold increased, absolute risk ~9%), specifically including autism spectrum disorder (ASD) (up to 2.8-fold increased, absolute risk ~3%), attention deficit hyperactivity disorder (ADHD) (up to 2.4-fold increased, absolute risk ~5%) and intellectual disability (up to 3.9-fold increased, absolute risk ~8%).

Studies have suggested dose-related increased risks of both malformation and neurodevelopmental impairment, with higher risks associated with doses >100mg/day. However, increased risks of any neurodevelopmental disorder have also been described following doses <100mg/day.

There are conflicting data regarding the risk of fetal malformation when topiramate is used in polytherapy regimens. If increased risks exist, it is unclear whether these may be explained by factors such as higher doses of topiramate in polytherapy regimens, synergistic effects between topiramate and other ASMs, or concomitant use of proven teratogenic ASMs (such as valproate). Further research is required to clarify these findings.

Weight loss is a recognised side effect of topiramate use and there is evidence that exposure in pregnancy is associated with reduced infant birth weight. Data relating to rates of miscarriage, stillbirth and premature delivery are too limited to facilitate an accurate assessment of any potential risks. Overall, the available evidence relating to these outcomes does not suggest increased risks. Where the use of topiramate is being considered during pregnancy, women should be made aware of the lack of data for these outcomes.

Use of any medication affecting the central nervous system throughout pregnancy or near delivery may be associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Delivery should be planned in a unit with adequate facilities.

Topiramate is not known to impact maternal folate status. However, UK guidelines state that women who take any ASM should be prescribed high dose folic acid (5mg).

Where topiramate exposure has occurred during the first trimester, detailed ultrasound scans are recommended to check for signs of malformation, particularly of the mouth and palate.

Topiramate should only be used during pregnancy where benefits of treatment are considered to outweigh any potential risks, and where there are no suitable alternatives. Plasma concentrations of topiramate have been shown to decline as pregnancy progresses and regular clinical review of women in whom continued treatment with topiramate is indicated is recommended. The dosage of topiramate may need to be adjusted to maintain seizure control, particularly in the third trimester of pregnancy. Monitoring of maternal weight and fetal growth are also recommended.

Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.