DARWIN EU® – Benzodiazepine use during pregnancy: a descriptive study characterising exposure, pregnancy loss, and covariates to inform future safety studies

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Disease epidemiology

  Drug utilisation
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Medicinal product name, other:
  Commonly used benzodiazepines
• Anatomical Therapeutic Chemical (ATC) code:
  (N05BA) Benzodiazepine derivatives

  Benzodiazepine derivatives

  (N05CD) Benzodiazepine derivatives

  Benzodiazepine derivatives

Population studied

• Short description of the study population:
  Participants in the study will be required to fulfil the following criteria: ; Inclusion criteria (Table 5): ; 1) Observation period within the study period (1st January 2010-31st December 2023, or latest data availability). ; 2) Female sex at birth. ; 3) At least one year of prior history recorded before start of pregnancy episode. ; 4) A pregnancy episode recorded during the study period (defined by the pregnancy start date), with a pregnancy start date on or before December 31, 2022 (to allow sufficient time between index date and last date of database data availability to cover a full-term pregnancy).(29); 5) Pregnancy end date follows pregnancy start date (in time). ; 6) Pregnancy duration (in days) is greater than 1 but less than 308 days (equivalent to 44 weeks of gestation). ; Exclusion criteria (Table 6): ; 1) Molar and ectopic pregnancies will be excluded (concept ids: 439083 and 437611). ; Disease Epidemiology (objective 5): Two approaches will be used: ; • No exclusion for prior history of pregnancy ; • Excluding anyone with a history of pregnancy in the -365 days.; • Excluding anyone with an unknown pregnancy outcome.;
• Special population of interest:
  Pregnant women

Study design details

• Study design:
  Population-level cohort; Drug/s user cohort; Population-level cohort; Cohort analysis;
• Main study objective:
  1. To characterise users of benzodiazepine and alternative treatments (SSRIs, SNRIs, Z-hypnotics, and Melatonin) during pregnancy in terms of demographics, prior medications, history of mental illness and other comorbidities. ; 2. To characterise treatments with benzodiazepine and alternative treatments during pregnancy in terms of duration, posology, and indication of prescription during pregnancy.; 3. To describe the prevalence of benzodiazepine and alternative treatments’ use during pregnancy ; 4. To describe trajectories of prescriptions fills for benzodiazepine and alternative treatments throughout the year before pregnancy, pregnancy period, and one month following pregnancy end date. ; 5. To estimate the incidence of pregnancy loss among all pregnancies and in benzodiazepines and alternative treatment users during pregnancy (when numbers allow). ; 6. To characterise individuals with pregnancy loss in terms of demographics, comorbidities, and treatments of interest. ;
• Setting:
  This study was conducted using routinely collected data from primary care, specialist care, hospital, and birth registry data sources in the DARWIN EU® network of data partners from two European countries in one EU member state. All data had been previously mapped to the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) prior to this study.
• Outcomes:
  Objective 1: Characteristics of benzodiazepine and alternative treatment users.; Objective 2: Benzodiazepine and alternative treatment first era’s treatment duration, posology (dose), and ; indication.; Objective 3: Prevalence of benzodiazepine and alternative treatments use.; Objective 4: Prescription trajectories of benzodiazepine and alternative treatments use, categorised into:; • Restarting the same treatment.; • Switching to a different treatment.; • Restarting the same treatment while also switching to another.; • Discontinuing treatment altogether (neither the original treatment nor any potential switch), relative to the entire period analysed.; Objective 5:; Pregnancy loss: Date of pregnancy end date, comprising any of the following events: miscarriage/abortion ; (spontaneous), stillbirth (death of foetus, foetal loss, intrauterine death, dead born), as recorded in the PET. ; (20) Additionally, miscarriage and stillbirth were assessed separately.; Objective 6: Characteristics of individuals with pregnancy loss.; ; Exploratory outcome: ; Objective 7: Incidence of potential negative control outcomes among benzodiazepine and alternative treatment users during pregnancy. The outcome was based on the presence of at least one diagnostic code (SNOMED) code to identify the first occurrence of the following conditions:; • Musculoskeletal injuries ; • Skin conditions; • Urinary tract infection