A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls

Hum Reprod. 2015 Nov;30(11):2527-38. doi: 10.1093/humrep/dev221. Epub 2015 Sep 25.


Study question: Is there any difference in the clinical performance of the 3-year one-rod etonogestrel (ENG)- and the 5-year two-rod levonorgestrel (LNG)-releasing contraceptive implants during 3 years of insertion, and between implant and intrauterine device (IUD) contraception, in particular complaints possibly related to hormonal contraceptives?

Summary answer: The cumulative contraceptive effectiveness after 3 years and method continuation through 2.5 years were not significantly different between ENG and LNG implants, but both outcomes were significantly worse in the non-randomized age-matched group of IUD users than in the combined implant group.

What is known already: ENG- and LNG-releasing implants are safe and highly efficacious contraceptives with pregnancy rates reported to be 0.0-0.5 per 100 women-years (W-Y). No head-to-head comparative study of the two implants has been undertaken, and little information is available on comparisons of complaints of side effects of implant and copper IUD users.

Study design, size, duration: This was an open parallel group RCT with 1:1 allocation ratio of the ENG and the LNG implants with non-randomized control group of women choosing TCu380A IUD to address lack of reliable data on common side effects typically attributed to the use of progestogen-only contraceptives. After device(s) placement, follow-ups were at 2 weeks, 3 and 6 months, and semi-annually thereafter for 3 years or until pregnancy, removal or expulsion of the implant/IUD occurred.

Participants, setting, methods: The study took place in family planning clinics in Brazil, Chile, Dominican Republic, Hungary, Thailand, Turkey and Zimbabwe. Women seeking long-term contraception were enlisted after an eligibility check and informed consent, and 2982 women were enrolled: 1003, 1005 and 974 in the ENG-implant, LNG-implant and IUD groups, respectively; 995, 997 and 971, respectively, were included in the per protocol analysis reported here.

Main results and the role of chance: ENG and LNG implants each had the same 3-year cumulative pregnancy rate of 0.4 per 100 W-Y [95% confidence interval (CI) 0.1-1.4]. A weight of ≥70 kg at admission was unrelated to pregnancy. Method continuation rates for ENG and LNG implants at 2.5 years were 69.8 (95% CI 66.8-72.6) and 71.8 per 100 W-Y (68.8-74.5), and at 3 years 12.1 (95% CI 5.2-22.0) and 52.0 per 100 W-Y (95% CI 41.8-61.2), respectively. Bleeding disturbances, the most frequent reason for method discontinuation, were significantly more common in the ENG group [16.7 (95% CI 14.4-19.3)] than in the LNG group [12.5 (95% CI 10.5-14.9)] (P 0.019). The 3-year cumulative loss to follow-up was lower in the ENG- than in the LNG-implant group, 8.1 (95% CI 6.4-10.2) and 14.4 per 100 W-Y (95% CI 12.1-17.1), respectively. The median duration of implant removal was 50 s shorter among women with ENG than among women with LNG implant (P < 0.0001). In the observational comparison between IUD and implant users, the 3-year relative risk for pregnancy in IUD group compared with the combined implant group was 5.7 per 100 W-Y (95% CI 4.4-7.3) (P = 0.0003). The 3-year expulsion rate of the IUD was 17.8 per 100 W-Y (95% CI 14.5-21.9), while the discontinuation rate for bleeding disturbances was 8.5 (95% CI 6.7-10.9). Frequency of complaints of headache and dizziness was not significantly different between implant and IUD users (P = 0.16 and 0.77, respectively), acne and bleeding irregularities were more frequent among implant users (P < 0.0001), while heavy bleeding and lower abdominal pain occurred more often among IUD than implant users (P < 0.0001).

Limitations, reasons for caution: Few women were ≤19 years old or nulligravida, the proportion of implant users ≥70 kg was <20% and <8% were obese.

Wider implications of the findings: Findings of the study can inform policy makers and clinicians about choice of implant, but also about TCu380A IUD in relation to implants.

Study funding/competing interests: UNDP/UNFPA/WHO/UNICEF/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization (WHO). This report contains the views of an international expert group and does not necessarily represent the decisions or the stated policy of the WHO.

Trial registration: ISRCTN33378571 registered on 22 March 2004. The first participant was enrolled on 12 May 2003.

Keywords: Jadelle; TCu380A IUD; contraception; etonogestrel; implanon; implants; levonorgestrel; randomized clinical trial.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Contraceptive Agents, Female / administration & dosage
  • Contraceptive Agents, Female / adverse effects
  • Contraceptive Agents, Female / pharmacology*
  • Desogestrel / administration & dosage
  • Desogestrel / adverse effects
  • Desogestrel / pharmacology*
  • Drug Implants / adverse effects
  • Drug Implants / pharmacology*
  • Female
  • Humans
  • Intrauterine Devices, Copper* / adverse effects
  • Levonorgestrel / administration & dosage
  • Levonorgestrel / adverse effects
  • Levonorgestrel / pharmacology*
  • Outcome Assessment, Health Care*
  • Pregnancy
  • Pregnancy, Unplanned*
  • Time Factors
  • Young Adult


  • Contraceptive Agents, Female
  • Drug Implants
  • etonogestrel
  • Levonorgestrel
  • Desogestrel

Associated data

  • ISRCTN/ISRCTN33378571