Characterization of neurodevelopmental disorders in children exposed in utero to valproate and/or other antiepileptic drugs with long-term follow-up: retrospective study of multiple European data sources (AVALON)

Study type

• Study topic:
  Human medicinal product
• 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

• Study drug International non-proprietary name (INN) or common name:
  VALPROIC ACID

  VALPROMIDE
• Anatomical Therapeutic Chemical (ATC) code:
  (N03AG01) valproic acid

  valproic acid

  (N03AG02) valpromide

  valpromide
• Medical condition to be studied:
  Neurodevelopmental disorder

  Multiple congenital abnormalities

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)

  Adolescents (12 to < 18 years)
• Special population of interest:
  Pregnant women
• Estimated number of subjects:
  18253

Study design details

• Main study objective:
  Investigate the risk and the course of NDD (including ASD and ADHD), in infants, children and adolescents exposed in utero to valproate and other antiepileptic drugs, with a long-term follow-up from birth (until maximum 17 years). And to investigate the incidence and characteristics of mCM in children exposed to valproate in utero.
• Outcomes:
  NDD as a composite outcome, defined as at least one diagnosis of NDD during the follow-up within any of the NDD categories, the date associated to the event will be the date of the first NDD diagnosis after birth. ; All NDD sub-types (ASD, ADHD, ID, CD, DPD, MD), defined as at least one diagnosis of each sub-type, the date associated to the event will be when the NDD subtype diagnosis after birth. NDD characteristics (severity, attending specialized school, receiving special needs support at school, education level, treatments received) and characteristics of NDD course (changes in NDD pharmacotherapeutic treatments, healthcare resources consumption) and disease pathway (time-interval between consecutive NDD-related events). ; Minor congenital malformations.
• Data analysis plan:
  Descriptive and comparative analysis will be performed according to the study objectives. ; Categorical variables will be presented as counts (n), proportions (%) with confidence interval where relevant. Continuous variables will be presented as means with standard deviation and as medians with interquartile range, where appropriate. ; Incidence rates and cumulative incidence of the main outcomes will be estimated. Hazard ratios from a Cox proportional hazards regression model (with propensity score weighting) will be calculated to estimate the effect of exposure in utero to valproate vs comparator drugs on NDD composite – all types and NDD sub-types. Summary statistics for time-to-event outcomes will be estimated using the Kaplan-Meier estimator. ; The results related to the primary outcomes and incidence of mCM will be meta-analysed across all eligible databases. ; Different sensitivity analysis will be performed to test the robustness of the results obtained in the main analysis.