Levonorgestrel intrauterine system associated amenorrhea: a systematic review and metaanalysis

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. 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. 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. 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. Approximately 20% of levonorgestrel intrauterine system users experience amenorrhea during at least 1 90-day interval by the first yea