ADEPT: feasibility of estimating the risk of adverse pregnancy, neonatal and child outcomes following either in utero ASM exposure through the mother, or peri-conceptional ASM exposure through the father

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Feasibility analysis
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine, other:
  Methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin, paramethadione, trimethadione, ethadione, phensuximide, mesuximide, ethosuximide, combinations, clonazepam, carbamazepine, oxcarbazepine, rufinamide, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, sultiame, phenacemide, lamotrigine, felbamate, topiramate, pheneturide, levetiracetam, zonisamide, stiripentol, lacosamide, carisbamate, retigabine, perampanel, brivaracetam, cenobamate, fenfluramine, ganaxolone, beclamide, gabapentin, pregabalin, mirogabalin.
• Anatomical Therapeutic Chemical (ATC) code:
  (N02BF) Gabapentinoids

  Gabapentinoids

  (N03A) ANTIEPILEPTICS

  ANTIEPILEPTICS

Population studied

• Short description of the study population:
  The source population comprises the 9 included data sources, BIFAP (ES), SIDIAP (ES), VID (ES), CPRD (UK), Finish registries (FI), EFEMERIS (FR), Norwegian registries (NO), PHARMO (NL), and Val Padana LHU (IT) between 01/01/2000 and latest availability. We will assess many different parameters in different groups with the aim to generate indicators for the final fit-for- purpose assessment of different study questions using the Gatto framework (Gatto et al. 2022). For objectives a-c multiple cohorts (all population, mother, father, neonate/child) will be created which depend on the parameter that is being assessed.
• Age groups:
  Neonate

  Infants and toddlers (28 days – 23 months)

  Children (2 to < 12 years)

  Adolescents (12 to < 18 years)

  Adult and elderly population (≥18 years)

  Adults (18 to < 65 years)

  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Elderly (≥ 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Special population of interest:
  Pregnant women
• Estimated number of subjects:
  40000000

Study design details

• Study design:
  Study using four different retrospective cohorts.
• Main study objective:
  To assess the feasibility of estimating the risk of adverse pregnancy, neonatal and child outcomes after periconceptional maternal or paternal exposure to antiseizure medications (ASM), or in-utero ASM exposure, using data from 9 electronic healthcare databases in Europe.
• Setting:
  This study will be conducted using electronic health record data from 9 data sources in 7 countries in Europe comprising a total active population of 49 million persons. This includes BIFAP (ES), SIDIAP (ES), VID (ES), CPRD (UK), Finish registries (FI), EFEMERIS (FR), Norwegian registries (NO), PHARMO (NL), and Val Padana LHU (IT). The source population comprises all individuals, men and women, of childbearing age and their offspring. Data sources vary in the type of data banks that can be accessed. Participation per sub-objective differs based on data availability for the specific objectives and the finite resources/timelines. Some Data Access Partners (DAPs) will re-use the data instance they use for ConcePTION (UiO, CHUT), whereas other DAPs re-extract and All countries (i.e., 7) and DAPS will participate in each sub-objective and more than 2 DAPs (i.e., 6 as UU, THL, CHUT, UiO, PHARMO, INSPIRE) have data completeness for 15 years.;
• Comparators:
  NA
• Outcomes:
  Outcome parameters for Objective 2 are evaluated for each sub-objective using several pre-established parameters. Here are some examples:; Objective 2a: Feasibility Parameters for Women; -Percentage of pregnant individuals with complete ATC codes for each antiepileptic drug by data source, in the year before and during pregnancy. This inspects potential exposure misclassification and compares data sources.; -Proportion of adverse pregnancy outcomes, such as spontaneous pregnancy loss, induced abortion, stillbirth (>20-28 weeks), and preterm birth (<37 weeks’ gestation). This inspects potential outcomes misclassification, benchmarks against national statistics, and compares data sources.; Objective 2b: Feasibility Parameters for Men and Paternal Linkage; -Percentage of men with complete ATC codes for each antiepileptic drug (ATC N03A) by data source, calendar year, and age group. This inspects potential exposure misclassification and compares data sources.; -Percentage of pregnancies identified using the ConcePTION algorithm with a linked father, by linkage method (deterministic, probabilistic), data source, and calendar year. This inspects father-pregnancy linkage and compares data sources.; Objective 2c: Feasibility Parameters for Neonates/Children; -Duration of follow-up after birth among those registered from birth, including the percentage in follow-up at 1, 2, 3, 5, 11, and 15 years. This inspects the length of follow-up.; -Percentage of neonates with recorded major congenital malformations within 90 days, used for descriptive purposes and benchmarking across data sources and against EUROCAT.; -Risk of ADHD at 5, 11, and 15 years using different algorithms in those registered within 1 month after birth, used for descriptive purposes and benchmarking across data sources.; -Percentage of neonates with information on paternal exposure to antiepileptic drugs preconception, used to assess the prevalence of exposure.
• Data analysis plan:
  Feasibility parameters:; For objective 2a-2c we will estimate the 41 feasibility parameters. Descriptive analyses will be used to report as well as graphics to show time trends and comparisons between data sources. Benchmark data will be obtained from the literature (e.g. WHO or EUROPERISTAT), to have an external validation on pregnancies and outcomes. ; ; Feasibility to determine associations of pre conceptional/prenatal parental exposure to antiepileptics and the development of adverse pregnancy and child outcomes:; We will use the parameters from objectives 1-2 plus metadata on the data sources and assess the fitness-for-purpose of the data instance by using, implementing, and adapting the framework from Gatto N, and colleagues. (Gatto et al., 2022). This is an assessment tool aimed at conducting feasibility assessment to determine whether a data source is fit-for-purpose for specific real-world effectiveness and safety study. Gatto´s feasibility assessment framework is composed of three operative steps: i) operationalization and ranking of minimal criteria required to answer the research question; ii) identification and narrowing down data sources options, and iii) conducting detailed feasibility assessment. This third step will allow us to tabulate different evaluation items and therefore to score an overall assessment.;