Background
Intrauterine devices are effective instruments for contraception, and 1 levonorgestrel-releasing device is also indicated for the treatment of heavy menstrual bleeding (menorrhagia).
Objective
To compare the incidence of intrauterine device expulsion and uterine perforation in women with and without a diagnosis of menorrhagia within the first 12 months before device insertion
Study Design
This was a retrospective cohort study conducted in 3 integrated healthcare systems (Kaiser Permanente Northern California, Southern California, and Washington) and a healthcare information exchange (Regenstrief Institute) in the United States using electronic health records. Nonpostpartum women aged ≤50 years with intrauterine device (eg, levonorgestrel or copper) insertions from 2001 to 2018 and without a delivery in the previous 12 months were studied in this analysis. Recent menorrhagia diagnosis (ie, recorded ≤12 months before insertion) was ascertained from the International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. The study outcomes, viz, device expulsion and device-related uterine perforation (complete or partial), were ascertained from electronic medical records and validated in the data sources. The cumulative incidence and crude incidence rates with 95% confidence intervals were estimated. Cox proportional hazards models estimated the crude and adjusted hazard ratios using propensity score overlap weighting (13–16 variables) and 95% confidence intervals.
Results
Among 228,834 nonpostpartum women, the mean age was 33.1 years, 44.4% of them were White, and 31,600 (13.8%) had a recent menorrhagia diagnosis. Most women had a levonorgestrel-releasing device (96.4% of those with and 78.2% of those without a menorrhagia diagnosis). Women with a menorrhagia diagnosis were likely to be older, obese, and have dysmenorrhea or fibroids. Women with a menorrhagia diagnosis had a higher intrauterine device–expulsion rate (40.01 vs 10.92 per 1000 person-years) than those without, especially evident in the first few months after insertion. Women with a menorrhagia diagnosis had a higher cumulative incidence (95% confidence interval) of expulsion (7.00% [6.70–7.32] at 1 year and 12.03% [11.52–12.55] at 5 years) vs those without (1.77% [1.70–1.84] at 1 year and 3.69% [3.56–3.83] at 5 years). The risk of expulsion was increased for women with a menorrhagia diagnosis vs for those without (adjusted hazard ratio, 2.84 [95% confidence interval, 2.66–3.03]). The perforation rate was low overall (<1/1000 person-years) but higher in women with a diagnosis of menorrhagia vs in those without (0.98 vs 0.63 per 1000 person-years). The cumulative incidence (95% confidence interval) of uterine perforation was slightly higher for women with a menorrhagia diagnosis (0.09% [0.06–0.14] at 1 year and 0.39% [0.29–0.53] at 5 years) than those without it (0.07% [0.06–0.08] at 1 year and 0.28% [0.24–0.33] at 5 years). The risk of perforation was slightly increased in women with a menorrhagia diagnosis vs in those without (adjusted hazard ratio, 1.53; 95% confidence interval, 1.10–2.13).
Conclusion
The risk of expulsion is significantly higher in women with a recent diagnosis of menorrhagia. Patient education and counseling regarding the potential expulsion risk is recommended at insertion. The absolute risk of perforation for women with a recent diagnosis of menorrhagia is very low. The increased expulsion and perforation rates observed are likely because of causal factors of menorrhagia.
Introduction
Abnormally heavy or prolonged menstrual bleeding in women, also known as menorrhagia, affects 10%–30% of women, especially those in the reproductive age group. Heavy menstrual bleeding (HMB) continues to be the foremost reason for conducting a hysterectomy, accounting for approximately 45% of all hysterectomy procedures in the United States. HMB has long been considered to affect the social and emotional well-being and the quality of life of those affected. It has been suggested that HMB may be an effect of morphologic and hemodynamic changes of the uterus and heightened uterine contractility. , HMB has been associated with uterine fibroids, adenomyosis, endometrial polyps, and coagulopathy.
Why was this study conducted?
Many women use levonorgestrel-releasing intrauterine devices (LNG-IUDs) to decrease bleeding. The risk of LNG- and copper-IUD-related uterine perforation and IUD expulsion in women with a recent diagnosis of menorrhagia has not been investigated. We investigated these outcomes by menorrhagia status in 228,834 US women—most of them with an LNG-IUD—who were >12 months postpartum or nulliparous at IUD insertion.
Key findings
Women with menorrhagia had higher incidence rates of IUD expulsion (40.01 vs 10.92/1000 person-years) and slightly higher rates of uterine perforation (0.98 vs 0.63/1000 person-years) than women without menorrhagia.
What does this add to what is known?
A recent diagnosis of menorrhagia is associated with an increased IUD expulsion risk after adjusting for potential confounding factors.
In addition to being a highly effective, long-acting, and reversible contraceptive method, levonorgestrel-releasing intrauterine devices (LNG-IUDs) (20 μg LNG/day) are an effective US Food and Drug Administration (FDA)-approved treatment for HMB. It has been suggested that women with HMB are at increased risk of IUD expulsion, with potential mechanisms including brisk bleeding and clotting. Furthermore, it is unknown whether the morphologic changes that occur with HMB along with the underlying uterine pathology may predispose women to potential uterine perforation during IUD use. Therefore, given the relatively high prevalence of HMB among women of childbearing age and the common use of LNG-releasing IUDs for HMB, further investigation is warranted to assess the risks of IUD expulsion and uterine perforation associated with HMB to inform appropriate counseling.
To better understand the outcomes associated with IUD use as reflected in US clinical practice, we conducted the APEX-IUD (Association of uterine Perforation and EXpulsion of Intrauterine Device) study—a multisite, retrospective US cohort study of >325,000 women—to evaluate the incidence and risk factors associated with IUD expulsion and uterine perforation as observed in real-world treatment settings. The objective of the analysis reported here was to estimate the crude incidence rate, the cumulative incidence, and the risk of IUD expulsion and uterine perforation among women with a diagnosis of menorrhagia in the 12 months before IUD insertion compared with women without such a diagnosis in this time frame.
Materials and Methods
The data for APEX-IUD were obtained from electronic health records (EHRs) within 3 integrated healthcare systems, viz, Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), and Kaiser Permanente Washington (KPWA), and Regenstrief Institute (RI)—a healthcare information exchange in Indiana. The study methods for APEX-IUD and validation of the IUD expulsion and uterine perforation outcomes have been previously described in detail. , All the participating research sites received approval or exemption for the conduct of this study by their respective institutional review boards. KPSC also received approval from the California Health and Human Services Agency and the California Department of Public Health Center for Health Statistics and Informatics (ie, state birth and death files).
Study population
The full APEX-IUD population included 326,658 women aged ≤50 years with evidence of an IUD insertion from 2001 to 2018 and who had EHR data available for analysis for a minimum of 12 months before IUD insertion. If a woman had >1 IUD insertion during this time period, only the first insertion was used. Only women without evidence of a delivery in the 12 months preceding IUD insertion (n=228,834) were included in the analysis ( Figure 1 ). Women who were <12 months postpartum were excluded, because menorrhagia is less likely to occur in women who have recently given birth and are breastfeeding.
The first year for inclusion in the study varied by the research study site (2001 at RI, 2007 at KPWA, 2009 at KPSC, and 2010 at KPNC), and the last date for inclusion was April 30, 2018 at all sites. The date of IUD insertion is referred to as the index date. Women were followed from the index date to the earliest outcome date (device expulsion or uterine perforation) or the first of the following censoring events: IUD expulsion (if perforation was the outcome), removal, reinsertion, or expiration; uterine perforation (if expulsion was outcome); pregnancy, hysterectomy, or other sterilization procedure; disenrollment from the healthcare system (KP sites); last clinical encounter (RI); end of the study period (June 30, 2018); or death.
Exposure and covariates
The variables for this study were ascertained from the EHR systems or a health information exchange, utilizing a mixture of structured data (National Drug Codes, International Classification of Diseases, Ninth Revision and Tenth Revision, Clinical Modification [ICD-9-CM/10-CM], Healthcare Common Procedure Coding System [HCPCS], and Current Procedural Terminology [CPT] codes) and unstructured data (clinical notes via natural language processing). Operational definitions were initially developed centrally for all study variables and then tailored to each site using combinations of structured and unstructured data. The primary exposure of interest, ie, menorrhagia, was identified via ICD codes (626.2, 626.3, 627.0, N92.0, N92.2, or N92.4) within 12 months before the date of IUD insertion.
The covariates for this analysis included demographics (age, race, and ethnicity) and risk factors at the time of IUD insertion on the basis of all available information during the look-back period, which extended to the earliest enrollment date (KP sites) or clinical encounter (RI) for each woman (12 months minimum). The potential risk factors included smoking status during the past 12 months, body mass index (BMI, kg/m 2 ), parity, gynecologic factors (eg, diagnosis of dysmenorrhea using ICD codes, diagnosis of uterine fibroids using either the ICD or CPT code or both), cesarean delivery (for women with a delivery before the index date), and indicators of a difficult IUD insertion (eg, dilation, ultrasound guidance, paracervical block, provider noted difficult insertion, or use of misoprostol), year of index insertion, and IUD type (LNG-IUD or copper [Cu]-IUD).
Outcomes
The outcomes of interest were any IUD expulsion and any uterine perforation. IUD expulsion was either complete (ie, IUD located in the vagina, not present in the uterus or abdomen on imaging, or patient reported that the IUD fell out) or partial (ie, any portion of IUD in the cervix on imaging, documented IUD visualization by a clinician at the cervical os, or IUD malpositioned on imaging and removed by the clinician). Uterine perforation was either complete (ie, clinical evidence of IUD in the pelvis, abdominal cavity, or adjacent organs) or partial (ie, IUD removed after being visualized as partially embedded in the myometrium on imaging or hysteroscopy, or partial perforation noted by clinician at the time of removal). Algorithms to identify these outcomes were previously validated in the data sources; during development of the algorithms, a sample of up to one-third with a maximum of 100 possible cases of uterine perforation and possible cases of IUD expulsion identified by the algorithm underwent medical record review to determine the case status.
Statistical analysis
The descriptive analyses for all the variables of interest are presented overall and by menorrhagia status. For the categorical variables, the frequencies and percentages were calculated for each level. For the continuous variables, the mean, standard deviation, minimum, maximum, median, and quartiles were examined. Missing data were treated as missing, and no imputations were performed. The variables included a “missing” category for analyses, wherever appropriate.
The crude incidence rates were calculated as the number of IUD expulsions and uterine perforations divided by the total person-time at risk (in person-years) and were reported as point estimates (number of cases per 1000 person-years) and 95% confidence intervals (CIs). The crude cumulative incidence, defined as the number of women with IUD expulsions and uterine perforations occurring up to a time point out of the number of IUD insertions, was estimated using the Kaplan-Meier method.
Cox regression models were used to estimate the crude hazard ratios (HRs), and they are reported as point estimates with 95% CIs. The proportional hazards assumption between each exposure and outcome pairing was assessed. Adjusted HRs were estimated using a Cox model with propensity score overlap weighting. Propensity score models were developed separately for IUD expulsion and uterine perforation, and correspondingly, separate weighting was applied for IUD expulsion and uterine perforation. The standardized differences before and after overlap weighting were calculated to evaluate balance in the exposure groups; the groups were considered balanced if the standardized difference was <0.20 (generally considered small). , Details for the propensity score models and the overlap weights have been described previously and are presented in Supplemental Appendix A . The following variables were included in the final propensity score models: IUD type, age (continuous for perforation, tertiles for expulsion), race/ethnicity, recent smoker (only for perforation), duration of look-back period (quartiles, only for perforation), calendar year of index date, BMI (categorical), dysmenorrhea, uterine fibroids, parity (0, > 0, or missing), any cesarean delivery (only for perforation), cesarean delivery for the most recent delivery, live birth for the most recent delivery, concomitant gynecologic procedure, indicator of difficult IUD insertion, provider experience (quartiles of number of procedures in most recent calendar year), research site, and age (continuous for perforation and tertile for expulsion) × site interaction. Balance between the 2 exposure groups among the weighted population of women who had no delivery in the previous 12 months was assessed and confirmed. All standardized differences were <0.2 after weighting.
All analyses were performed using SAS software version 9.3 or higher (SAS Institute Inc, Cary, NC).
Results
Cohort characteristics
Of 228,834 nonpostpartum women, 31,600 (13.8%) had a recent diagnosis of menorrhagia, and 197,234 women had no such recent history of diagnosis. Among women without a recent diagnosis of menorrhagia, 10,135 (5.1%) had a diagnosis of menorrhagia >12 months before IUD insertion. Among women with a recent diagnosis of menorrhagia, 96.4% had an LNG-releasing IUD and 2.3% had a Cu-IUD; among women without a recent diagnosis, 78.2% had an LNG-releasing IUD and 20.5% had a Cu-IUD. In both the groups, 1.3% of women had an IUD of unknown type.
Women with a recent diagnosis of menorrhagia were more likely than women without one to have had a previous cesarean delivery (19.1% vs 11.0%), dysmenorrhea (4.7% vs 1.2%), and uterine fibroids (24.4% vs 3.1%) ( Table 1 ). They were also more likely than women without a recent diagnosis to be aged 37 to 50 years (74.9% vs 33.3%) and be obese (48.0% vs 29.7%). They were also less likely to be nulliparous (14.9% vs 29.0%).
Characteristic | Recent menorrhagia diagnosis | Unweighted absolute standardized differences a | |
|---|---|---|---|
| Yes (N=31,600) | No (N=197,234) | ||
| Person-years at risk | 62,405.4 | 390,598.3 | |
| Age, mean (SD), y | 40.1 (7.64) | 32.0 (8.62) | 0.987 |
| Age category, n (%), y | |||
| ≤28 | 2832 (9.0) | 74,660 (37.9) | 0.726 |
| 29–36 | 5112 (16.2) | 56,956 (28.9) | 0.308 |
| 37–50 | 23,656 (74.9) | 65,618 (33.3) | 0.918 |
| Race or ethnicity, n (%) | |||
| Asian or Pacific Islander | 3060 (9.7) | 23,284 (11.8) | 0.069 |
| Hispanic Black | 89 (0.3) | 392 (0.2) | 0.017 |
| Hispanic Other | 6433 (20.4) | 34,312 (17.4) | 0.076 |
| Hispanic White | 4031 (12.8) | 18,119 (9.2) | 0.114 |
| Non-Hispanic Black | 3680 (11.6) | 17,047 (8.6) | 0.100 |
| Non-Hispanic White | 12,571 (39.8) | 88,975 (45.1) | 0.108 |
| Other or multiple | 1293 (4.1) | 10,221 (5.2) | 0.052 |
| Unknown | 443 (1.4) | 4884 (2.5) | 0.078 |
| Body mass index (kg/m 2 ), n (%) | |||
| Underweight | 183 (0.6) | 2940 (1.5) | 0.090 |
| Normal weight | 7431 (23.5) | 76,860 (39.0) | 0.338 |
| Overweight | 8618 (27.3) | 54,075 (27.4) | 0.003 |
| Obese | 15,156 (48.0) | 58,577 (29.7) | 0.381 |
| Missing | 212 (0.7) | 4782 (2.4) | 0.142 |
| Recent smoker, n (%) | 3349 (10.6) | 21,349 (10.8) | 0.007 |
| Previous history of cesarean delivery, n (%) | 6031 (19.1) | 21,612 (11.0) | 0.229 |
| Nullipara, n (%) | 4698 (14.9) | 57,217 (29.0) | 0.347 |
| IUD type, n (%) | |||
| LNG | 30,455 (96.4) | 154,278 (78.2) | 0.567 |
| Copper | 728 (2.3) | 40,395 (20.5) | 0.597 |
| Unknown | 417 (1.3) | 2561 (1.3) | 0.002 |
| Dysmenorrhea, n (%) | 1498 (4.7) | 2340 (1.2) | 0.211 |
| Previous history of fibroids, % | 7705 (24.4) | 6031 (3.1) | 0.652 |
| Any difficult insertion, % | 3699 (11.7) | 23,098 (11.7) | 0.000 |
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