Depression risk in users of different doses of levonorgestrel intrauterine systems: a nationwide prospective cohort study

Background Use of the high -dose levonorgestrel-releasing intrauterine system (LNG-IUS) has been associated with increased risk of incident depression. Evidence is lacking on the influence of use of two recently marketed lowdose LNG-IUS on risk of depression. This study aims to examine associations between use of different doses of LNG-IUS and risk of depression. Methods We conducted a nationwide prospective cohort study involving all first -time users of an LNG-IUS among all Danish nulliparous women aged 15-34 years with no medical history of depression, major psychiatric diseases, endometriosis, heavy menstrual bleeding, polyp, myoma, dysmenorrhoea, iron supplement use, abortion, and infertility treatment. Findings A total of 46,565 first -time users of LNG-IUS were followed for 80,516 person-years with 1,531 incident initiations of antidepressant use observed during follow-up. Use of the high -dose LNG-IUS containing 52 mg levonorgestrel was initiated by 9,902 (21%) women, while 20,665 (44%), and 15,998 (34%) initiated use of the lowdose LNG-IUS containing 19.5 mg and 13.5 mg levonorgestrel, respectively. The age-, calendar-time-, and education-standardised incidence rates of first -time depression per 1,000 person-years at full LNG-IUS duration were 30.8 (95% CI 23.6-39.5) for the 52 mg LNG-IUS, 19.8 (95% CI 16.1; 24.0) for the 19.5 mg LNG-IUS, and 17.7 (95% CI 14.4-21.5) for the 13.5 mg LNG-IUS-. Compared to the high -dose 52 mg LNG-IUS, the adjusted number of avoided depressions per 1,000 person-years were 11.0 (95% CI 7.1-14.9) for the 19.5 mg LNG-IUS and 13.1 (95% CI 9.6-16.6) for the 13.5 mg LNG-IUS. The corresponding adjusted rate ratios were 0.77 (95% CI 0.68; 0.88) and 0.85 (95% CI 0.75-0.96). The reduced risk of depression with low-dose LNG-IUS compared to high -dose LNG-IUS was observable throughout duration of use. Interpretation Use of low-dose LNG-IUS containing 19.5 mg and 13.5 mg levonorgestrel, respectively, were associated with a reduced risk of incident depression compared to use of the high -dose 52 mg LNG-IUS. The study suggests that low-dose LNG-IUS should be preferred over the high -dose LNG-IUS for contraceptive purpose. Funding Sygeforsikringen "Danmark" grant: 2021-0128. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).