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Evidence summaries

Levonorgestrel Intrauterine System Vs. other Forms of Reversible Contraceptives

Levonorgestrel intrauterine system (LNG-20 IUS) and copper IUD are highly effective for contraception. The risk of unwanted pregnancy is lower with LNG-20 compared to copper IUD. LNG-IUS, IUD and implants appear to be more effective than contraceptive pills, transdermal patch or vaginal ring. LNG-20 often causes amenorrhoea. Level of evidence: "A"

A Cochrane review [Abstract] 1 included 25 studies. 9 trials were included in meta-analyses, four comparing LNG-20 IUSs with non-hormonal IUDs, one comparing the LNG-20 IUS with Norplant-2, one comparing the LNG-20 IUS with oral contraceptives (COCs), and three comparing Progestasert with non-hormonal IUDs.

There was no significant difference in the pregnancy rates between LNG-20 and IUD >250mm2 or COC users. There was a significantly lower risk of pregnancy when the LNG-20 IUS was compared to IUDs ≤ 250 mm2 . Women using the LNG-20 IUS were more likely to experience amenorrhoea and device expulsion than women using IUDs >250mm2 . LNG-20 users were significantly more likely than all the IUD users to discontinue because of hormonal side effects and menstrual disturbance. When compared to Norplant-2, the LNG-20 users were significantly more likely to experience amenorrhoea and oligomenorrhoea, but significantly less likely to experience prolonged bleeding and spotting. No other significant differences were observed. The contraceptive effectiveness of Progestasert was significantly better than non-medicated IUDs, but no difference was observed when compared to IUDs ≤ 250mm2 .

LNG-20 IUS did not have impact upon breastfeeding performance or the growth and development of breastfed infants in lactating women (1 trial, n=320) nor did the device have an adverse effect on glucose metabolism among insulin-dependent diabetic women (1 trial, n=60).

A prospective observational cohort study 2 (The Contraceptive CHOICE Project, n= 9 256) that provided no-cost contraception to women in the USA assessed 24-month continuation rates of all reversible contraceptive methods. The project promoted the use of long-acting reversible contraception (LARC: IUDs and implants). Twenty-four month continuation rates for LARC and non-LARC methods were 77% and 41%, respectively (n=6 153). Continuation at 24-months for the levonorgestrel intrauterine system (LNG-IUS) and the copper IUD were the highest reported and similar 79%, and 77%, respectively. The implant continuation rate was significantly lower (69%, P<.001) compared with IUDs at 24 months. There was no statistically significant difference in 24-month continuation rates among the 4 non-LARC methods COC 43%, patch 40%, ring 41%, depot medroxyprogesterone acetate 38%; P=.72). Participants with a LARC method were at significantly lower risk of contraceptive method discontinuation (adjusted hazard ratio 0.29, 95% confidence interval 0.26-0.32) compared with women using a non-LARC method.

Another part of the The Contraceptive CHOICE Project 3 compared the rate of failure of different contraceptive methods in the overall cohort and in groups stratified according to age (less than 21 years of age vs. 21 years or older). Among the 7 486 participants 334 unintended pregnancies were identified. Women using contraceptive pills, transdermal patch, or vaginal ring had higher rates of unintended pregnancy than those using LARC: Failure rates for the pills, patch, or ring were 4.8%, 7.8%, and 9.4% in years 1, 2, and 3, respectively; the corresponding rates in the group using IUDs or implants were 0.3%, 0.6%, and 0.9% (P<0.001). The failure rates for depot medroxyprogesterone acetate injection were similar to those for IUDs or implants (0.1%, 0.7%, and 0.7% for years 1, 2, and 3, respectively; P=0.96). The contraceptive failure rate among participants using pills, patch, or ring was 4.55 per 100 participant-years, as compared with 0.27 among participants using LARC (hazard ratio after adjustment for age, educational level, and history with respect to unintended pregnancy, 21.8; 95% confidence interval, 13.7 to 34.9). Among participants who used pills, patch, or ring, those who were less than 21 years of age had a risk of unintended pregnancy that was almost twice as high as the risk among older participants.

A prospective cohort study 4 evaluated the effectiveness of the contraceptive implant and the 52-mg LNG-IUS in women using the method for 2 years beyond the current approved 3 and 5 years of use, respectively. There have been no documented pregnancies in implant users during the 2 years of postexpiration follow-up (n=291 with 444 woman-years). Two pregnancies have been reported in LNG-IUS users (n=496 with 696.9 woman-years). The failure rate in the sixth year of use of the LNG-IUS is calculated as 0.25 (95% CI 0.04 to 1.42) per 100 woman-years; failure rate during the seventh year is 0.43 (95% CI 0.08 to 2.39) per 100 woman-years. Among implant users the median etonogestrel level was 207.7 pg/mL (range 63.8-802.6 pg/mL) at the time of method expiration, 166.1 pg/mL (range 67.9 25.0-470.5 pg/mL) at the end of the fourth year, and 153.0 pg/mL (range 72.1-538.8 pg/mL) at the end of the fifth year. Median etonogestrel levels were compared by body mass index at each time point and a statistical difference was noted at the end of 4 years of use with overweight women having the highest serum etonogestrel (195.9; range 25.0-450.5 pg/mL) when compared to normal (178.9; range 87.0-463.7 pg/mL) and obese (137.9; range 66.0-470.5 pg/mL) women (P = .04).

A multinational, prospective, non-interventional cohort study 5 of new users of LNG-IUS and copper IUDs included 61 448 women in 6 European countries. The copper IUD cohort contained more than 30 different types. Validated 1-year follow-up information for 58 324 users between 18 and 50 years of age (70% using LNG-IUS, 30% using copper IUDs) was collected. A total of 118 contraceptive failures occurred (26 LNG, 92 copper). Both types of IUD were highly effective, with overall Pearl indices of 0.06 (95% CI 0.04 to 0.09 for LNG-IUS and 0.52 (95% CI 0.42 to 0.64) for copper IUDs. The adjusted hazard ratio for LNG-IUS vs. copper IUDs was 0.16 (95% CI 0.10 to 0.25). 21 pregnancies (7 LNG IUS, 14 copper IUD) were ectopic, yielding an adjusted hazard ratio for ectopic pregnancy of 0.26 (95% CI 0.10 to 0.66).

An open-label randomized controlled multi-centre trial 6 including 7735 women assessed rates of unintended pregnancy with LNG-IUS and TCu380A contraception. The cumulative 7-year pregnancy rate of the LNG-IUS was 0.5 (standard error 0.2) per 100, significantly lower than 2.5 (0.4) per 100 of the TCu380A. Cumulative method discontinuation rates at 7 years were 70.6 (1.2) and 40.8 (1.3) per 100, respectively. Dominant reasons for discontinuing the LNG-IUS were amenorrhea (26.1 [1.3] per 100) and reduced bleeding (12.5 [1.1] per 100), particularly in Chinese women and, for the TCu380A, increased bleeding (9.9 [0.9] per 100), especially among non-Chinese women.

A multicenter phase 3 trial 7 including 1751 nulliparous and multiparous participants evaluated the efficacy and safety of the 52 mg LNG-IUS for up to 10 years. Overall, 569 participants started year 7, 478 completed year 7 and 343 completed year 8 (257 aged≤39 years at beginning of year); 77 completed 10 years of use. 11 pregnancies occurred over 8 years, 7 of which were ectopic. Two pregnancies occurred in year 7 (Pearl Index, 0.49; 95% CI 0.06 to 1.78), 1 in a participant with implantation 4 days after a desired removal; no pregnancies occurred in year 8. The cumulative life-table pregnancy rate in the primary efficacy population through year 8 was 1.32 (95% CI 0.69 to 2.51); without the postremoval pregnancy, the rate was 1.09 (95% CI 0.56 to 2.13). Only 44 (2.6%) participants overall discontinued because of bleeding complaints (4 total in years 7 and 8) with rates per year of 0.1% to 0.5% for years 3 to 8. Amenorrhea rates were 39% at both years 7 and 8.

A multicenter, single-arm commercially funded study 8 enrolled 362 existing users of the 52-mg LNG-IUS, who have had the system for 4.5 to 5 years. 243 women entered and 223 completed 8 years, all were aged ≤36 years at the end of year 8. For years 6 to 8, the 3-year Pearl Index was 0.28 (95% CI 0.03 to 1.00) with a 3-year cumulative failure rate of 0.68% (0.17 to 2.71). Pearl Indexes for years 6, 7, and 8 were 0.34 ( 95% CI 0.01 to 1.88), 0.40 (0.01 to 2.25), and 0.00 (0.00 to 1.90), respectively. The 3-year (years 6-8) ectopic pregnancy Pearl Index was 0.14 (95% CI 0.00 to 0.77). The discontinuation rate was 38.4% (139/362), most commonly because of desire for pregnancy (44/362).

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    References

    • French R, Van Vliet H, Cowan F, Mansour D, Morris S, Hughes D, Robinson A, Proctor T, Summerbell C, Logan S, Helmerhorst F, Guillebaud J. Hormonally impregnated intrauterine systems (IUSs) versus other forms of reversible contraceptives as effective methods of preventing pregnancy. Cochrane Database Syst Rev 2004;(3):CD001776 [Last assessed as up-to-date: 14 July 2009]. [PubMed]
    • O'neil-Callahan M, Peipert JF, Zhao Q et al. Twenty-four-month continuation of reversible contraception. Obstet Gynecol 2013;122(5):1083-91. [PubMed]
    • Winner B, Peipert JF, Zhao Q et al. Effectiveness of long-acting reversible contraception. N Engl J Med 2012;366(21):1998-2007. [PubMed]
    • McNicholas C, Swor E, Wan L et al. Prolonged use of the etonogestrel implant and levonorgestrel intrauterine device: 2 years beyond Food and Drug Administration-approved duration. Am J Obstet Gynecol 2017;216(6):586.e1-586.e6. [PubMed]
    • Heinemann K, Reed S, Moehner S et al. Comparative contraceptive effectiveness of levonorgestrel-releasing and copper intrauterine devices: the European Active Surveillance Study for Intrauterine Devices. Contraception 2015;91(4):280-3. [PubMed]
    • Rowe P, Farley T, Peregoudov A et al. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception 2016;93(6):498-506. [PubMed]
    • Creinin MD, Schreiber CA, Turok DK, et al. Levonorgestrel 52 mg intrauterine system efficacy and safety through 8 years of use. Am J Obstet Gynecol 2022;227(6):871.e1-871.e7 [PubMed]
    • Jensen JT, Lukkari-Lax E, Schulze A, et al. Contraceptive efficacy and safety of the 52-mg levonorgestrel intrauterine system for up to 8 years: findings from the Mirena Extension Trial. Am J Obstet Gynecol 2022;227(6):873.e1-873.e12 [PubMed]

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