Design of the Association of Uterine Perforation and Expulsion of IUD (APEX-IUD) Study: A Multisite Retrospective Cohort Study.

Abstract

BACKGROUND\nIntrauterine devices (IUDs) are effective and safe, long-acting reversible contraceptives, but risk of uterine perforation occurs with an estimated incidence of 1-2 per 1,000 insertions. EURAS-IUD, a European prospective observational study that enrolled 61,448 participants (2006-2012), found that women breastfeeding at the time of device insertion or with the device inserted ≤36 weeks postpartum had higher risk of uterine perforation. APEX-IUD (Association of uterine Perforation and EXpulsion of IUD) is a Food and Drug Administration-mandated study designed to reflect current United States clinical practice. The aims of APEX-IUD are to evaluate risk of IUD-related uterine perforation and device expulsion among women who are breastfeeding or within 12 months postpartum at insertion.\n\n\nOBJECTIVE\nWe describe the APEX-IUD study design, methodology, and analytic plan and present study population characteristics, size of risk-factor groups, and duration of follow-up.\n\n\nSTUDY DESIGN\nAPEX-IUD is a retrospective cohort study conducted in four organizations with access to electronic health records: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), Kaiser Permanente Washington (KPWA), and Regenstrief Institute (RI) in Indiana. Variables were identified through structured data (e.g., diagnostic, procedural, medication codes) and unstructured data (e.g., clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors are breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis within the year prior to insertion. Covariates include demographic characteristics, clinical characteristics, and procedure-related variables, such as difficult insertion. The first potential date of inclusion for eligible women varies by research site (January 1, 2001-January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal/reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of study period (June 30, 2018). Comparisons between levels of exposure variables will be made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights.\n\n\nRESULTS\nThe study population includes 326,658 women with at least one device insertion during the study period (KPNC: 161,442; KPSC: 123,214; KPWA: 20,526; RI: 21,476). Median duration of continuous enrollment was 90 (74-177) months. Mean age was 32 years, and the population was racially and ethnically diverse across the four sites. Mean body mass index was 28.5 kg/m2, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% of women were recent smokers; 79.4% had levonorgestrel-releasing devices and 19.5% had copper devices. Across sites, 97,824 women had an insertion ≤52 weeks postpartum, of which 94,817 (97%) had breastfeeding status determined at insertion; 228,834 women had device insertion >52 weeks postpartum or no evidence of a delivery in their health record.\n\n\nCONCLUSION\nCombining retrospective data from multiple sites allowed for a large and diverse study population. Collaboration with clinicians in the study design and validation of outcomes ensured that APEX-IUD results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for IUD perforation and expulsion for clinicians.