Valproate is used for treating epilepsy but also for bipolar disorder and, off-label, to prevent
migraine. Valproate is associated with a significantly higher risk of physical birth defects and developmental disorders including autistic spectrum disorders in children exposed via their mothers during pregnancy. Therefore, valproate should not be prescribed to girls or females of childbearing age unless they are part of the pregnancy prevention programme. Despite this, a number of women continue to be prescribed valproate while pregnant. There is also evidence of changes to the testes in young male mice and effects in the babies born to animals who had been exposed in pregnancy although evidence in humans is limited. A recent study also reported an increased risk of developmental disorders in children born to fathers taking valproate, compared to those taking lamotrigine and levetiracetam, around the time of conception. Topiramate is also used to treat epilepsy although it is licenced to prevent migraine for which it is used more widely. There is also growing evidence of risks with topiramate, with a recent large study suggesting an increased risk of developmental disorders in children born to women taking topiramate during pregnancy. The purpose of this study is to describe the use of valproate and topiramate in different groups, to understand the impact of, , and potential need for further, regulatory action to ensure their safe use for all patients and to explore the rate of diagnosed and recorded birth defects and developmental disorders in children exposed via their mothers.
Valproate is associated with an 11% risk of congenital malformations and a 50% risk of neurodevelopmental disorders in children born to mothers exposed during pregnancy. Despite introduction of a pregnancy prevention programme, exposures continue to occur. Further, there are data showing changes to the testes in juvenile mice and potential transgenerational effects and a recent study reported an increased risk of developmental disorders in children born to fathers taking valproate around the time of conception, raising further concern about the safety of valproate. The Commission on Human Medicines (CHM) also highlighted data for topiramate that raises concerns that its use during pregnancy may be associated with poorer developmental outcomes. Evidence from a large cohort study, suggests a 3-fold increased risk of autistic spectrum disorders and a 4-fold increased risk of intellectual disability. The CHM therefore considered new regulatory recommendations to support safe prescribing for both drugs. The purpose of this descriptive study is to quantify the use of valproate and topiramate and trends over time to understand the impact of regulatory action. The primary exposure will be a prescription for valproate or topiramate, and overall and new-user prescribing rates over time will be calculated. Stratifications will include by sex, age, ethnicity, deprivation index, region, pregnancy status, daily dose and potential indication for treatment. Alternative treatments before initiating valproate/topiramate, stopping or switching to alternative drugs, and switching prior to or during pregnancy will also be assessed. The rate of GP referrals to appropriate specialists and proportion of exposed women with relevant medical codes indicating that a risk acknowledgement form has been completed, will also be evaluated. The number of children born after maternal exposure, with and without recorded neurodevelopmental disorders will also be quantified to inform evaluation of the feasibility of exploring the risks with topiramate in the UK population.
Patients prescribed valproate, topiramate and other antiepileptic drugs or migraine prophylaxis drugs (for topiramate cohort) or bipolar disorder drugs (for valproate cohort); new-users of valproate and topiramate and other anti-epileptic drugs or migraine prophylaxis drugs (for topiramate cohort) or bipolar disorder drugs (for valproate cohort); Pregnancies exposed to valproate or topiramate; Child outcomes following maternal exposure; GP referrals to specialists; completion of ARAF
Katherine Donegan - Chief Investigator - MHRA
Katherine Donegan - Corresponding Applicant - MHRA
Jenny Wong - Collaborator - MHRA
Preeti Datta-Nemdharry - Collaborator - MHRA
Sophie Scanlon - Collaborator - MHRA
HES Admitted Patient Care;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation;CPRD Aurum Ethnicity Record;CPRD Aurum Mother-Baby Link;CPRD Aurum Pregnancy Register;CPRD GOLD Ethnicity Record;CPRD GOLD Mother-Baby Link;CPRD GOLD Pregnancy Register