By Rebecca H. Allen, MD, MPH
Assistant Professor,
Department of Obstetrics and Gynecology,
Warren Alpert Medical School of Brown University,
Women and Infants Hospital,
Providence, RI

Dr. Allen reports she is a consultant for Actavis and Bayer and receives grant/research support from Bayer.

Synopsis: In this small prospective cohort study, use of the etonogestrel implant and the levonorgestrel intrauterine device for an additional year past their FDA-approved duration was associated with an acceptably low failure rate.

Source: McNicholas C, et al. Use of the etonogestrel implant and levonorgestrel intrauterine device beyond the U.S. Food and Drug Administration-approved duration. Obstet Gynecol 2015;125:599-604.

This is a prospective cohort study of 237 etonogestrel implant users and 263 52 mg levonorgestrel intrauterine device (LNG-IUD) users who were enrolled between January 2012 and November 2014. The participants were recruited through advertising (12%) and also through previous participation in the Contraceptive CHOICE project (88%) in the St. Louis, MO, area. Women were eligible if they were English- or Spanish-speaking, aged 18 to 45 years, sexually active with a male partner, wanted to avoid pregnancy for at least 12 months, and were within 3 months of or beyond the current FDA-approved duration of use of their device. Method expiration date was validated in 91.8% of the sample through medical records. After initial enrollment, participants were followed with telephone surveys every 6 months and, for those with the implant, etonogestrel assays annually, at the time of method removal, or if pregnancy occurred.

For this analysis, 123 of the 237 implant users had the implant for an additional year and 34 for an additional 2 years. Among these users, there have been zero pregnancies for a failure rate of 0 (one-sided 97.5% confidence interval [CI], 0-1.61). The median etonogestrel level at 3 years of use was 188.8 pg/mL (range 63.8-802.6 pg/mL) and at 4 years of use, 177.0 pg/mL (range 67.9-470.5 pg/mL). There were no differences in etonogestrel levels at year 3 or 4 by body mass index class (29% normal weight, 25% overweight, 46% obese). Of the 263 LNG-IUD users, 108 had the device for an additional year. One pregnancy has been documented in the LNG-IUD group for a failure rate of 0.51 (95% CI, 0.01-2.82) per 100 women-years.

COMMENTARY

Use of long-acting reversible contraceptives (LARC) has been shown to reduce unintended pregnancy.1 The failure rate of the etonogestrel implant is 0.05% and the failure rate of the LNG-IUD is 0.2%.2 Therefore, many national organizations have endorsed the use of LARC for adolescent and adult women who seek highly effective contraception.3 Barriers to LARC still exist, however, including knowledge and misperceptions among patients and providers, as well as financial costs. If the devices could be used for longer than their FDA-approved duration, then women would not have to worry about access or payment for a replacement immediately upon expiration. This would save the health care system money overall and has many implications for global use. My main criticism of this study is the failure to confirm method expiration dates through medical records in 100% of the participants. To me, that would be part of the eligibility criteria since the primary outcome of the study is efficacy after the FDA-approved duration.

Nevertheless, the authors of this study report that the etonogestrel implant maintained its effectiveness up to 4 years, even in women who were overweight or obese. Traditionally, a level of 90 pg/mL of etonogestrel has been judged sufficient to suppress ovulation.4 The median etonogestrel level at 4 years among the 47 women who underwent venipuncture was well above this threshold. Even if the level drops below 90 pg/mL, the authors speculated that other mechanisms of action may provide contraception besides ovulation suppression such as thickening cervical mucus. As they continue to recruit and follow participants, they will be able to assess the relationship between etonogestrel level and contraceptive efficacy by clinical outcome (unintended pregnancy).

Levonorgestrel levels were not measured in IUD users, as the mechanism of action for the device is locally on the uterus and cervix. A previous systematic review of extending LNG-IUD use beyond 5 years concluded that based on previous studies, extending the device to 7 years was safe and effective.5 However, this review was criticized, as two of the four studies cited used 60 mg LNG-IUDs.6 Since the rate-controlling membrane is proprietary, it is unknown if this device would function like the currently marketed 52 mg LNG-IUD product. In addition, the two other studies cited were small prospective studies of 109 and 67 women, respectively. In a timely fashion, this current analysis answers the call for more prospective data with the currently marketed U.S. product.

This report is definitely reassuring, although I doubt the manufacturers will want to apply to the FDA to change their labeling, as that would not make business sense. Therefore, we cannot rely on the FDA to inform us when and if we can counsel our patients about extended use. Personally, I would like to see more data, especially in younger women before I recommend routinely extending use. I don’t think patients can be told that the LNG-IUS is good for 7 years at this point (although some providers are doing just that), especially if failure would be devastating to the patient. The only population that I may use this information in would be perimenopausal women who have a low likelihood of pregnancy. Either way, certainly documenting a discussion with the patient about the limitations of the current evidence and the off-label nature of the recommendation is necessary. Hopefully, we will have more data in the future from these investigators to allow us to confidently extend the duration of use.

References

  1. Peipert JF, Madden T, Allsworth JE, Secura GM. Preventing unintended pregnancies by providing no-cost contraception. Obstet Gynecol 2012;120:1291-1297.
  2. Trussell J. Contraceptive efficacy. In: Hatcher RA, et al. Contraceptive Technology: 20th revised edition. New York NY: Ardent Media, 2011.
  3. ACOG Committee Opinion no. 450: Increasing use of contraceptive implants and intrauterine devices to reduce unintended pregnancy. Obstet Gynecol 2009;114:1434-1438.
  4. Diaz S, et al. Clinical trial with 3-keto-desogestrel subdermal implants. Contraception 1991;44:393-408.
  5. Wu J, Pickle S. Extended use of the intrauterine device: A literature review and recommendations for clinical practice. Contraception 2014;89:495-503.
  6. Creinin MD. Extended use of the intrauterine device: A literature review and recommendations for clinical practice. Contraception 2014;90:104.