Background
Intrauterine devices are effective and safe, long-acting reversible contraceptives, but the risk of uterine perforation occurs with an estimated incidence of 1 to 2 per 1000 insertions. The European Active Surveillance Study for Intrauterine Devices, 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 at ≤36 weeks after delivery had a higher risk of uterine perforation. The Association of Uterine Perforation and Expulsion of Intrauterine Device (APEX-IUD) study was a Food and Drug Administration–mandated study designed to reflect current United States clinical practice. The aims of the APEX-IUD study were to evaluate the risk of intrauterine device–related uterine perforation and device expulsion among women who were breastfeeding or within 12 months after delivery at insertion.
Objective
We aimed to describe the APEX-IUD study design, methodology, and analytical plan and present population characteristics, size of risk factor groups, and duration of follow-up.
Study Design
APEX-IUD study was a retrospective cohort study conducted in 4 organizations with access to electronic health records: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Washington, and Regenstrief Institute in Indiana. Variables were identified through structured data (eg, diagnostic, procedural, medication codes) and unstructured data (eg, clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors were breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis in the year before 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 (from January 1, 2001 to January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal or reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of the study period (June 30, 2018). Comparisons of levels of exposure variables were made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights.
Results
The study population includes 326,658 women with at least 1 device insertion during the study period (Kaiser Permanente Northern California, 161,442; Kaiser Permanente Southern California, 123,214; Kaiser Permanente Washington, 20,526; Regenstrief Institute, 21,476). The median duration of continuous enrollment was 90 (site medians 74–177) months. The mean age was 32 years, and the population was racially and ethnically diverse across the 4 sites. The mean body mass index was 28.5 kg/m 2 , and of the women included in the study, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% were recent smokers; furthermore, among these women, 79.4% had levonorgestrel-releasing devices, and 19.5% had copper devices. Across sites, 97,824 women had an intrauterine device insertion at ≤52 weeks after delivery, of which 94,817 women (97%) had breastfeeding status at insertion determined; in addition, 228,834 women had intrauterine device insertion at >52 weeks after delivery or no evidence of a delivery in their health record.
Conclusion
Combining 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 the APEX-IUD study results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for intrauterine devices perforation and expulsion for clinicians.
Introduction
Although intrauterine devices (IUDs) are highly effective long-acting reversible contraceptives, their use carries a risk of uterine perforation, with estimated incidences of 1 to 2 perforations per 1000 insertions. , These rates were reported in the prospective observational European Active Surveillance Study for Intrauterine Devices (EURAS-IUD), designed to evaluate the risk of uterine perforation among users of levonorgestrel (LNG)-releasing and copper IUDs used in a routine clinical setting, conducted in 6 European countries, with recruitment from 2006 to 2012. Here, 2 cohorts were included: new users of LNG-releasing IUDs (n=43,078) or copper IUDs (n=18,370), with follow-up after 12 months. The study did not identify a relevant difference in perforation rate by IUD type; however, this study suggested that breastfeeding at the time of IUD insertion was associated with a 6-fold increase in the relative risk of uterine perforation. Furthermore, there was an increased risk of uterine perforation among those with IUD insertions within 36 weeks after the most recent delivery.
Why was this study conducted?
The European Active Surveillance Study for Intrauterine Devices showed an increased risk of uterine perforation among women who were breastfeeding or ≤36 weeks after delivery at intrauterine device (IUD) insertion. The US Food and Drug Administration suspected differences in breastfeeding practices and postpartum timing of IUD placement and mandated a study to assess risks among women in the United States.
Key findings
Retrospective, real-world data can be used to estimate risks with more timely results than are achieved with prospective studies. Pooling data across multiple sites can provide demographic variation and confirm results across sites.
What does this add to what is known?
APEX-IUD study design and patient characteristics are presented. Final study results will provide valuable information for clinical practice based on real-world evidence about the risk of perforation and expulsion.
Consistent with clinical practice in the European countries participating in the study, EURAS-IUD provided little data on IUD placement immediately after delivery, a more accepted practice in the United States. Given the results of EURAS-IUD, the US Food and Drug Administration (FDA) mandated a study to evaluate uterine perforation risks associated with US clinical practices for IUD insertion. Although the FDA initially recommended a prospective observational study, the research team instead suggested that a retrospective study drawing data from electronic health records (EHRs) would provide greater efficiency and more timely results while reflecting current US clinical practice. Following a validation study demonstrating that algorithms could be used to identify uterine perforation and IUD expulsion in proposed data sources and that breastfeeding could be identified in EHRs of women who had given birth, the Association of Uterine Perforation and Expulsion of IUD (APEX-IUD) study was planned in coordination with Bayer and the FDA.
The APEX-IUD study was a multisite, retrospective cohort study that used data from EHRs and a health information exchange to assess the outcomes of uterine perforation and IUD expulsion in association with potential risk factors, including breastfeeding, postpartum timing of IUD insertion, recent history of menorrhagia, and IUD type in the setting of usual healthcare. This manuscript describes the study design, methodology, and characteristics of the study population. In addition, comparisons with the methods of the prospective cohort study, EURAS-IUD, are discussed. The study results of the APEX-IUD study will be described separately.
Materials and Methods
Study population
The study population included all women aged ≤50 years with evidence of an IUD insertion and with ≥12 months of enrollment history preceding IUD insertion (for Kaiser Permanente [KP] sites) or a clinical visit ≥12 months before insertion (for Regenstrief Institute [RI]). Here, the first potential date for a woman’s inclusion varied by research site based in part on when EHR data became available at the beginning of the year at each site, 2001 at the RI, 2007 at KP Washington (KPWA), 2009 at KP Southern California (KPSC), and 2010 at KP Northern California (KPNC); and the last date for inclusion at all sites was on April 30, 2018. All IUD insertions from eligible women have been included.
Study design
The APEX-IUD study was a retrospective cohort study. Among women with an IUD insertion identified within EHR data, this study has evaluated the association of 2 primary potential risk factors, breastfeeding status at the time of IUD insertion and timing of IUD insertion during the postpartum period, and the outcomes of IUD-related uterine perforation and IUD expulsion in the usual healthcare setting (ie, the data were abstracted from patient care records rather than data collected for a clinical trial). In addition, the association of 2 secondary potential risk factors, recent history of menorrhagia and IUD type, and said outcomes were evaluated. Women were observed from IUD insertion date (index date) to the earliest date of IUD-related uterine perforation, IUD expulsion, IUD removal, IUD reinsertion, pregnancy, hysterectomy or other sterilization procedures, IUD expiration, disenrollment from the healthcare system (KP sites), last clinical encounter (RI), end of the study period (June 30, 2018), or death. All person-time at risk data were included with no requirement for minimum or maximum follow-up time.
All participating research sites received an approval or a waiver to conduct this study from their respective institutional review boards. In addition, KPSC received approval from the California Health and Human Services Agency and the California Department of Public Health Center for Health Statistics and Informatics (state birth and death files). Each site submitted data for analysis in a deidentified, standard format in accordance with the data structure template for variables ( Table 1 ).
| Variable | Definition | Categories | Format |
|---|---|---|---|
| Potential risk factor variables | |||
| Postpartum time of IUD insertion | Time since most recent delivery date ≤index date a |
| 4 categories; 5 categories; binary |
| Breastfeeding status | Breastfeeding status at index date b , c , d |
| 3 categories |
| IUD type | IUD type at the time of the index date c , d |
| 3 categories |
| Menorrhagia | Menorrhagia before or on index date c |
| Binary |
| Outcome variables | |||
| Uterine perforation | Uterine perforation event during person-time at risk c , d |
| Binary |
| IUD expulsion | IUD expulsion event during person-time at risk c , d |
| Binary |
| Covariates | |||
| Demographic | |||
| Age | Age in years at IUD insertion f |
| Integer; 3 categories |
| Race and ethnicity | Race and ethnicity f |
| 8 categories |
| Smoking | Smoked within 365 d of index date b , c , d |
| 3 categories |
| Calendar year of IUD insertion | Calendar year of IUD insertion c , d |
| Categorical |
| Duration of lookback period | Duration of lookback period a |
| Continuous; 4 categories; 2 categories |
| Clinical | |||
| BMI | BMI (kg/m 2 ) at index date or closest date c , d |
| Continuous; 5 categories |
| Dysmenorrhea | Dysmenorrhea before or on index date c |
| 4 categories |
| Menorrhagia | Menorrhagia before or on index date c |
| 4 categories |
| Uterine fibroids | Fibroids before or on index date c |
| Binary |
| Parity | Cumulative number of viable pregnancies (ie, carried to at least 20 wk gestation) before the index date c , d , f |
| Integer; 2 categories; 2 categories; 5 categories |
| Cesarean delivery | Any cesarean delivery during the lookback period (summarized only if a woman had one or more parity) c |
| Binary |
| Cesarean delivery for most recent delivery | Cesarean delivery for most recent delivery (summarized only if there was a recorded delivery within 52 wk before or on the index date) c |
| Binary |
| Concomitant gynecologic procedure | Any of the following procedures at insertion a |
| Binary |
| Abortion procedure | Abortion c |
| Binary |
| Aspiration and curettage | Aspiration and curettage c |
| Binary |
| Dilation and curettage | Dilation and curettage c |
| Binary |
| Biopsy of the cervix or uterus | Biopsy c |
| Binary |
| Ablation | Ablation c |
| Binary |
| Colposcopy and other cervical procedures | Colposcopy and cervical procedures c |
| Binary |
| Hysteroscopy procedure | Hysteroscopy at insertion c |
| Binary |
| Laminaria procedure | Laminaria c |
| Binary |
| Laparoscopy | Laparoscopy c |
| Binary |
| Lysis adhesions | Lysis adhesions c |
| Binary |
| Myomectomy | Myomectomy c |
| Binary |
| Nerve procedure | Nerve procedure c |
| Binary |
| Salpingectomy or oophorectomy | Salpingectomy or oophorectomy c |
| Binary |
| Indicator of a difficult IUD insertion | Any of the following indicators at insertion a |
| Binary |
| Dilation | Cervical dilation c , d |
| Binary |
| Ultrasound guidance | Ultrasound guidance c , d |
| Binary |
| Paracervical block | Paracervical block c , d |
| Binary |
| Provider noted difficult insertion | Provider noted difficult insertion d |
| Binary |
| Misoprostol | Misoprostol before insertion c , d |
| Binary |
| Clinician-related characteristics (available in KPNC, KPSC, and KPWA but not in RI) | |||
| Number of IUD insertions performed | Number of IUD insertions performed f |
| Continuous; 3 categories |
| Annualized number of insertions in previous year | Annualized number of insertions in previous year a |
| Continuous; 5 categories; 3 categories |
| Length of employment in previous year | Length of employment in previous year, in days f | Continuous and missing | |
| Other | |||
| Live birth | Live birth for the most recent delivery within the past 52 wk of the index date (summarized only among women who had a delivery within 1 y before the index date) c , f |
| Binary |
| Site | Study site f |
| 4 categories |
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