Isotretinoin, Contraception, and Pregnancy Outcomes

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Drug utilisation

  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  ISOTRETINOIN
• Anatomical Therapeutic Chemical (ATC) code:
  (D10BA01) isotretinoin

  isotretinoin
• Medical condition to be studied:
  Pregnancy

  Stillbirth

  Abortion spontaneous

  Abortion induced

  Live birth
• Additional medical condition(s):
  Termination of pregnancy for fetal anomaly; Congenital malformations

Population studied

• Short description of the study population:
  The study population will include female patients aged between 12 and 48 years old (18 years and older in Alberta) who initiated treatment with isotretinoin between 1997 and 2023.
• Age groups:
  • Adolescents (12 to < 18 years)
  • Adults (18 to < 65 years)

    • Adults (18 to < 46 years)
    • Adults (46 to < 65 years)
• Special population of interest:
  Pregnant women

  Women of childbearing potential not using contraception

  Women of childbearing potential using contraception

Study design details

• Study design:
  Multicentre retrospective cohort study
• Main study objective:
  1) To estimate the frequency and change in frequency over time of contraception use in individuals of childbearing age prescribed isotretinoin from 1997 to present.; 2) To examine the frequency and change in frequency over time of pregnancy and pregnancy outcomes in individuals of childbearing age prescribed isotretinoin from 1997 to present including:; a. Pregnancies overlapping isotretinoin exposure and quantification of the extent of overlap by trimester; b. Pregnancies with isotretinoin exposure that reached live birth with and without congenital abnormalities; c. Pregnancies with isotretinoin exposure that ended with induced abortion, spontaneous abortion, or stillbirth; 3) Describe prescriber specialty (e.g., family physician, dermatologist) of the health professionals who prescribe isotretinoin.
• Setting:
  We will use administrative health care data from 5 Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, and Saskatchewan). In each province, the source population will include all female residents who registered for provincial medical services coverage between January 1, 1996, and December 31, 2024. From the source population, we will identify female patients aged between 12 and 48 years old, inclusive, who initiated treatment with isotretinoin between January 1, 1997 (or one year after the earliest data of data availability in each province) and December 31, 2023 (the latest accrual date that will allow adequate follow-up time for outcome ascertainment). The date of the first dispensing will be the cohort entry date. We will exclude patients who received a prescription for isotretinoin in the previous 365 days and those with less than 12 months of health plan enrollment. Patients will be allowed to enter the cohort multiple time provided they meet the eligibility criteria. ; ; For each pregnancy identified among isotretinoin users, we will estimate the pregnancy start date (estimated last menstrual period) and the pregnancy end date (date of outcome, described subsequently) using a validated algorithm (Dormuth, 2021). We will then assess the estimated pregnancy period overlap (by trimester) with isotretinoin treatment duration. An isotretinoin exposure will be considered to overlap with a pregnancy if any day of the isotretinoin episodes (including the days supply and a pre-specified grace period) falls within the estimated gestation period. Preconception exposure will be defined as isotretinoin exposure that occurred within 30 days prior to the estimated last menstrual period. For pregnancies ending in live birth, we will follow infants for 365 days to capture congenital malformations.
• Comparators:
  Not applicable
• Outcomes:
  We will study the following outcomes:; 1) Occurrence of seven pregnancy outcomes, where the duration of isotretinoin treatment overlaps with estimated gestational period. These will include: a composite pregnancy outcome, stillbirth subset (includes birth type mixed subset), spontaneous abortion subset, induced abortion subset, live birth only subset, termination of pregnancy for fetal anomaly only subset, and congenital malformations.; 2) Overall utilization of contraceptives before, during, and after treatment with isotretinoin. Contraceptives will include (when feasible with the available data): contraceptive pills, intrauterine devices (IUDs) – hormonal and copper, hormonal implant, hormonal vaginal ring, hormonal patch, and contraceptive injection.; 3) Overall utilization of other anti-acne medications (systemic antibiotics, topical antibiotics, topical retinoids, and miscellaneous agents) before, during, and after treatment [AS6.1][AS6.2]with isotretinoin.
• Data analysis plan:
  Analyses will be completed in each provincial database with results combined where appropriate. We will describe patient demographics, prescribing characteristics, and other medication use at treatment initiation. We will estimate the utilization of contraception use before, during, and after therapy, expressed as the number of users per 100 isotretinoin episodes, overall, by age category, and by calendar year. We will estimate pregnancy incidence during and shortly after isotretinoin therapy. Among pregnancies with overlap, we will summarize the timing of exposure (i.e., duration of overlap by trimester and evidence of contraception use). We will quantify preconception exposure as well as pregnancies by age category. We will also examine trends over time to assess changes in contraception use and pregnancy incidence annually. Secondary analyses will further explore pregnancy outcomes (described previously) per 1,000 users, patterns of contraceptive use, isotretinoin prescriber patterns, and repeat isotretinoin episodes.