A post-authorization safety study (PASS) to evaluate the paternal exposure to valproate and the risk of neurodevelopmental disorders including autism spectrum disorders as well as congenital abnormalities in offspring - a population-based retrospective study

Study type

• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (N03A) ANTIEPILEPTICS
• Medical condition to be studied:
  Multiple congenital abnormalities

  Neurodevelopmental disorder

  Autism spectrum disorder

  Bipolar disorder

  Epilepsy

  Migraine

  Pregnancy

Population studied

• Age groups:
  Preterm newborn infants (0 – 27 days)

  Term newborn infants (0 – 27 days)

  Infants and toddlers (28 days – 23 months)

  Children (2 to < 12 years)
• Estimated number of subjects:
  4080

Study design details

• Main study objective:
  To investigate the risk of NDD, including ASD, in offspring paternally exposed to valproate (monotherapy), compared to lamotrigine or levetiracetam (composite monotherapy) treatment at the time of conception.
• Outcomes:
  The primary outcome of interest is NDD, including ASD in offspring up to twelve years of age based on ICD-10 diagnostic codes, as recorded in the National Patient Registries, The secondary outcome of interest is a composite of CM diagnosed in offspring up to twelve years of age, stillbirths and spontaneous abortions based on ICD-10 diagnostic codes, as recorded in the National Patient Registries and Medical Birth Registries.
• Data analysis plan:
  For NDD and CM cohort by country, demographic and clinical characteristics of father at conception date, mother and offspring at delivery (index date) will be described overall and by paternal exposure group. Paternal AED exposure and maternal AED exposure will be characterised by cluster analysis. For NDD, risk and time to onset will be described overall and by paternal exposure group. A propensity-score (PS) matched Cox proportional hazards regression model will estimate a hazard ratio (+95%CI) between offspring paternally exposed to valproate and offspring paternally exposed to lamotrigine/levetiracetam. ; For CM, a PS-matched logistic regression model will estimate the odds ratio (+95%CI) of CM between offspring paternally exposed to valproate and offspring paternally exposed to lamotrigine/levetiracetam. Incidence % (+95%CI) will be calculated both for the composite CM endpoint and specific CM target body system organ groups (Norway/Denmark only). Data may be pooled via meta-analyse.