By Jeffrey T. Jensen, MD, MPH, Editor

Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland

Dr. Jensen reports he is a consultant for and receives grant/research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed; and is a consultant for Teva Pharmaceuticals and Microchips.

SYNOPSIS: Data from a large randomized study conducted by the World Health Organization demonstrate that pregnancy rates do not increase after year five, and support the continued use of the levonorgestrel intrauterine system 52 mg for contraception through seven years.

SOURCE: 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;93:498-506.

Since experience with the levonorgestrel intrauterine system (LNG IUS) was limited in the 1990s, the World Health Organization initiated a multicenter, randomized clinical trial to compare the safety, efficacy, and acceptability of the LNG IUS 52 mg to the TCu380A copper IUD. The study took place in 20 centers in nine countries; 11 of the sites were in China. This paper provides details on pregnancy rates and continuation through seven years of use. The investigators recruited 3,836 healthy parous women age < 40 years at risk for pregnancy and randomized 1,914 to receive the copper device and 1,972 to receive the LNG IUS. A total of 682 copper IUD users and 398 LNG IUS users completed seven years of follow-up.

Although both methods were highly effective, more pregnancies occurred each year in the copper IUD cohort. The cumulative pregnancy rate at seven years was 0.53 for the LNG IUS and 2.45 for the TCu380A (7-year rate difference 1.91; 95% confidence interval [CI], 0.97-2.86). Of particular interest, no additional pregnancies occurred between year five and seven in the LNG IUS group compared with five new pregnancies in the copper IUD group. There was no difference in the risk of expulsion (7-year rate difference 0.67; 95% CI, 1.58-2.91). Bleeding complaints were significantly lower among users of the TCu380A (7-year rate difference -25.45; 95% CI, -28.83 to -22.08). Most were complaints of amenorrhea and reduced bleeding in users of the LNG IUS. Overall, the risk of discontinuation was significantly lower in subjects randomized to the TCu380A group (7-year rate difference -29.81; 95% CI, -33.19 to -26.43). These data provide the first estimates from an international randomized study of the comparative effectiveness of the LNG IUS 52 mg system beyond five years of use, and support continued use of the hormonal system for pregnancy prevention for up to seven years.

COMMENTARY

Use of intrauterine contraception continues to increase in the United States. The most recent estimates from the National Survey of Family Growth show that the use nearly doubled (from 3.5% to 6.4%) between the 2006-2010 and 2011-2013 sample cycles, with increases every year since 1994.1 While most of the increase has been due to the widespread acceptance of the LNG IUS, use of copper devices also has increased. Although many women view the reduction or elimination of menstrual bleeding associated with the LNG IUS system as an additional health benefit, increasing numbers of women would like to avoid hormonal contraception and they pick the copper device as a highly effective, non-hormonal, long-acting method.

Whether all women who desire continuing to use LNG IUS should undergo replacement at five years has been controversial. This paper provides the best data to date that extended use of the LNG IUS through seven years provides continuing low pregnancy rates. Prior studies have suggested that pregnancy rates do not increase in years six and seven, but have been too small to sufficiently evaluate the question2,3 or studied a LNG IUS with a greater LNG load (60 mg) in the reservoir.4,5 The fact that no additional pregnancies occurred during years six and seven is impressive. But, it is important to note the differential loss to follow-up. The product discontinuation was much higher in the LNG IUS group. The authors did not report the characteristics of the population of each cohort finishing seven years of use. Although this was a randomized study at onset, at seven years the groups may differ in important ways with respect to risk of pregnancy. So we should interpret the results with caution.

Still, no additional pregnancies occurred within this group of more than 300 LNG IUS users who contributed data beyond five years of use, and this is important. Other ongoing studies likely will confirm these findings. The developers of the new 52 mg LNG IUS (Liletta) currently are accumulating data to submit to the FDA to change the product label from three years to seven years for the indication of contraception. The Mirena 52 mg LNG IUS is approved for five years of use, and no plans exist to change this indication. Keep in mind that labeling only reflects data as submitted to the FDA. Both products show similar release rates, and the data from the Rowe paper (that used the 52 mg LNG IUS marketed as Mirena) strongly support that users of either device will enjoy low pregnancy rates through seven years.

What are the other clinically important pearls from this paper? First, this was a randomized study, so women did not select a device based on their personal preference for bleeding profile or hormone use. Similar to all of the early studies of the LNG IUS, the rates of discontinuation for amenorrhea was high. This was particularly true at the Chinese centers that contributed more than half of the enrollment. In the Americas and Europe, education and counseling have improved the acceptability of contraception-related amenorrhea, and reduction in bleeding is a primary reason most women pick the LNG IUS in our clinic. While greater acceptability of bleeding changes associated with the LNG IUS should reduce method discontinuation, in this randomized trial, the seven-year rate of discontinuation was significantly lower among copper IUD users (-29.81; 95% CI, 33.19-26.43).

Even with lower discontinuation, the risk of pregnancy was much higher in subjects randomized to the copper IUD (2.45% at 7 years) compared to LNG IUS users (0.53%), and this was true of every year of participation. Granted, both of these rates are impressively low compared to oral contraceptives, but women need to be aware of the risks. Recent data from the EURAS IUD study support this conclusion (adjusted hazard ratio for failure for LNG IUS vs. copper IUDs 0.16; 95% CI, 0.10-0.25).6

Keep in mind that the mean age of participants in this study was 30 years at enrollment, and some were as old as 39 years. The risk of pregnancy at 37 or 46 years of age is certainly lower than at age 25 years. We need more data to conclude that pregnancy risk is not increased after five years of use in younger women. Since placement of the LNG IUS in teenagers is routine at many centers, this question of timely replacement will become common. In my opinion, replacement at five years should remain the standard for women younger than 30 years of age until more reassuring information is available. Another important factor to consider is bleeding patterns. Rates of amenorrhea peak at year three; many women who have resumed cyclic bleeding or a return to heavier bleeding will benefit from early replacement.

REFERENCES

  1. Daniels K, Daugherty J, Jones J, Mosher WD. Current Contraceptive Use and Variation by Selected Characteristics Among Women Aged 15–44: United States, 2011–2013. National Health Statistics Reports. Hyattsville, MD: National Center for Health Statistics; 2015.
  2. Hidalgo MM, Hidalgo-Regina C, Bahamondes MV, et al. Serum levonorgestrel levels and endometrial thickness during extended use of the levonorgestrel-releasing intrauterine system. Contraception 2009;80:84-89.
  3. Rönnerdag M, Odlind V. Health effects of long-term use of the intrauterine levonorgestrel-releasing system, A follow-up study over 12 years of continuous use. Acta Obstet Gynecol Scand 1999;78:716-721.
  4. Sivin I, Mahgoub SE, McCarthy T, et al. Long-term contraception with the levonorgestrel 20 mcg/day (LNG 20) and the Copper T 380Ag intrauterine devices: A five-year randomized study. Contraception 1990;42:361-378.
  5. Diaz J, Faundes A, Diaz M, Marchi N. Evaluation of the clinical performance of a levonorgestrel-releasing IUD, up to seven years of use, in Campinas, Brazil. Contraception 1993;47:169-175.
  6. Heinemann K, Reed S, Moehner S, Minh TD. Comparative contraceptive effectiveness of levonorgestrel-releasing and copper intrauterine devices: The European Active Surveillance Study for Intrauterine Devices. Contraception 2015;91:280-283.