Levonorgestrel intrauterine system associated amenorrhea: a systematic review and metaanalysis

Abstract

Objective data: Amenorrhea is a polarizing noncontraceptive effect of the levonorgestrel intrauterine system. Composite amenorrhea prevalence estimates that summarize all clinical data for the first-year after insertion currently are not available. The purpose of this study was to investigate the validity of existing prevalence estimates by the systematic calculation of amenorrhea measures for a general population of levonorgestrel intrauterine system users and to provide 90-day interval point estimates for the first year of use.

Study: We identified clinical trials, randomized controlled trials, and randomized comparative trials that were published in English between January 1970 and September 2017 through electronic searches of 12 biomedical and scientific literature databases that included MEDLINE and ClinicalTrials.gov.

Study appraisal and synthesis methods: We considered studies that clearly defined amenorrhea per World Health Organization standards (the complete cessation of bleeding for at least 90 days), collected data from written daily bleeding diaries (the gold standard data collection technique on menstrual bleeding changes), and evaluated levonorgestrel intrauterine system devices that released 20 μg of levonorgestrel per day. We assessed study quality using guidelines established by the US Preventive Services Task Force and Cochrane handbook for systematic reviews of interventions. Two reviewers independently conducted all review stages; disagreements were resolved by a third reviewer. Where possible, data were pooled with the use of a random-effects model.

Results: Of 2938 potentially relevant studies, we included 9 in our meta-analysis. We calculated amenorrhea prevalence, which was weighted for inter- and intrastudy variance, for 4 90-day intervals and months 0-12. Our results demonstrated few levonorgestrel intrauterine system users (0.2%; 95% confidence interval, 0.0-0.4) experienced amenorrhea during the first 90 days after insertion; however, prevalence increased to 8.1% (95% confidence interval, 6.6-9.7) on days 91-180. Finally, 18.2% (95% confidence interval, 14.9-21.5) of users experienced amenorrhea for at least 1 90-day interval during the first year. Although interstudy heterogeneity limited reliability of days 181-271 and 272-365 measures, prevalence increased from 13.6% (95% confidence interval, 9.3-18.0) to 20.3% (95% confidence interval, 13.5-27.0), respectively.

Conclusion: Approximately 20% of levonorgestrel intrauterine system users experience amenorrhea during at least 1 90-day interval by the first year after insertion. This composite estimate is consistent with the product labeling and demonstrates that most users do not experience amenorrhea during the first year. These results provide accurate summary measures to facilitate counselling and informed method selection.

Keywords: amenorrhea; levonorgestrel intrauterine system.

Figure 1

Days 0–90 Weighted percentage of levonorgestrel intrauterine system users who experienced amenorrhea, defined as the proportion of users who reported complete cessation of bleeding or spotting for at least 90 days among total users with completed menstrual bleeding diaries, for the first interval after insertion. CI, confidence interval; Pct, percentage. Sergison and Maldonado. Amenorrhea associated with LNG-IUS use. Am J Obstet Gynecol 2019.

Figure 2

Days 91–180 Weighted percentage of levonorgestrel intrauterine system users who experienced amenorrhea, defined as the proportion of users who reported complete cessation of bleeding or spotting for at least 90 days among total users with completed menstrual bleeding diaries, for the second interval after insertion. CI, confidence interval; Pct, percentage. Sergison and Maldonado. Amenorrhea associated with LNG-IUS use. Am J Obstet Gynecol 2019.

Figure 3

Days 181–271 Weighted percentage of levonorgestrel intrauterine system users who experienced amenorrhea, defined as the proportion of users who reported complete cessation of bleeding or spotting for at least 90 days among total users with completed menstrual bleeding diaries, for the third interval after insertion. CI, confidence interval; Pct, percentage. Sergison and Maldonado. Amenorrhea associated with LNG-IUS use. Am J Obstet Gynecol 2019.

Figure 4

Days 272–365 Weighted percentage of levonorgestrel intrauterine system users who experienced amenorrhea, defined as the proportion of users who reported complete cessation of bleeding or spotting for at least 90 days among total users with completed menstrual bleeding diaries, for the fourth interval after insertion. CI, confidence interval; Pct, percentage. Sergison and Maldonado. Amenorrhea associated with LNG-IUS use. Am J Obstet Gynecol 2019.

Figure 5

Days 0–365 Weighted percentage of levonorgestrel intrauterine system users who experienced amenorrhea, defined as the proportion of users who reported complete cessation of bleeding or spotting for at least 90 days among total users with completed menstrual bleeding diaries, for any 90-day interval during the first 12 months after insertion. CI, confidence interval; Pct, percentage. Sergison and Maldonado. Amenorrhea associated with LNG-IUS use. Am J Obstet Gynecol 2019.

Figure A1

Study selection process The selection process followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. ^aStudies included in 90-day interval analysis (n=6); studies included in 0–12 month analysis (n=3). Sergison and Maldonado. Amenorrhea associated with LNG-IUS use. Am J Obstet Gynecol 2019.

Figure A2

Days 181–271 Weighted percentage of levonorgestrel intrauterine system users who experienced amenorrhea, excluding Darney et al, for the third interval after insertion. CI, confidence interval; Pct, percentage. Sergison and Maldonado. Amenorrhea associated with LNG-IUS use. Am J Obstet Gynecol 2019.

Figure A3

Days 272–365 Weighted percentage of levonorgestrel intrauterine system users who experienced amenorrhea, excluding Modesto et al, for the fourth interval after insertion. CI confidence interval; Pct, percentage. Sergison and Maldonado. Amenorrhea associated with LNG-IUS use. Am J Obstet Gynecol 2019.