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Short-Term Treatment of Bothersome Bleeding for Etonogestrel Implant Users Using a 14-Day Oral Contraceptive Pill Regimen

A Randomized Controlled Trial

Guiahi, Maryam, MD, MSc; McBride, Madeline, MD; Sheeder, Jeanelle, PhD; Teal, Stephanie, MD, MPH

doi: 10.1097/AOG.0000000000000974
Original Research

OBJECTIVE: To understand whether using oral contraceptive pills (OCPs) results in temporary interruption of bleeding for etonogestrel contraceptive implant users during a 14-day course.

METHODS: In this double-blind trial, we randomly assigned etonogestrel implant users reporting 7 consecutive days or more of bothersome bleeding to receive 14 pills of study drug (150 microgram levonorgestrel and 30 microgram ethinyl estradiol combined OCPs) or an identical-appearing placebo. The primary outcome was the proportion of women in each group who stopped bleeding during therapy and continued to report no bleeding at the end of therapy. Prespecified secondary outcomes were number of days until temporary interruption of bleeding occurred, number of days without bleeding during therapy, and number of days to recurrence of bleeding after discontinuation of therapy. We hypothesized that temporary interruption of bleeding would occur in 80% of the treatment group compared with 20% in the control group; using 80% power, we needed a sample size of 26 women. We performed intent-to-treat analysis.

RESULTS: From November 2013 through December 2014, 66 women were screened and 32 were randomized: OCPs (n=16) or placebo (n=16). The majority was young, Caucasian women with reported bleeding as extremely or very annoying; groups had similar baseline characteristics. Participants randomized OCPs were more likely (14 of 16 [87.5%±16.2%] compared with six of 16 [37.5%±23.7%]) to have a temporary interruption of bleeding during the study drug period (odds ratio 11.7, 95% confidence interval 1.9–70.2). Of women in the OCP arm who had a temporary interruption, 85.7% had bleeding recurrence within 10 days after treatment.

CONCLUSION: Bothersome bleeding in etonogestrel contraceptive implant users will usually stop with 14-day OCP treatment, but bleeding most often resumes within days of treatment cessation.



Bothersome bleeding in etonogestrel contraceptive implant users usually stops with 14-day combined oral contraceptive pill treatment, but bleeding most often resumes within days of treatment cessation.

Department of Obstetrics and Gynecology, Section of Family Planning, University of Colorado Anschutz Medical Center, Aurora, Colorado.

Corresponding author: Maryam Guiahi, MD, MSc, 12631 E. 17th Avenue, Room 4203, Mailstop B192-2, Aurora, CO 80045; e-mail:

Supported by the American College of Obstetricians and Gynecologists/Ferring Pharmaceuticals Inc. Research Award on Menstrual Bleeding Disorders (2013–14) and a Society of Family Planning Trainee grant.

Presented at the North American Forum on Family Planning Annual meeting, November 14–16, 2015, Chicago, Illinois.

The authors thank the professional research assistants Sandra Cano and Maryke Swartz for their work with this study and Dr. Molly Richards and Jennifer Johnson, providers at Children's Hospital Colorado, for their help with recruitment.

Financial Disclosure Dr. Teal serves on advisory boards for Actavis and Bayer Pharmaceuticals, receives honoraria for service on a Data Safety and Monitoring Board for studies sponsored by Merck & Co., receives research funding from Medicines360, and is a consultant to Microchips. The other authors did not report any potential conflicts of interest.

The etonogestrel contraceptive implant is a silicone-free, single-rod, subdermal contraceptive implant that contains 68 mg etonogestrel and is approved for use for 3 years. It is one of the most effective forms of contraception available with a failure rate of 0.05%1,21,2 and 2-year continuation rates are high ranging from 53% to 90%.3,43,4 Like other contraceptive methods, many implant users discontinue before the 3 years of intended use for reasons other than desiring pregnancy. One of the most common reasons for lower contraceptive satisfaction is “bleeding problems” such as prolonged bleeding and frequent episodes, which may be termed “bothersome bleeding.”5–85–85–85–8 Up to 11.3% of women in clinical trials report discontinuation for bothersome bleeding that is ultimately considered unacceptable.6 In a qualitative study by Hoggart et al,9 implant users reported irregular bleeding as the “tipping point” for removal.

Because bothersome bleeding is a common complaint that results in discontinuation of the etonogestrel contraceptive implant, it is imperative to find therapies that are effective in stopping bleeding episodes and preventing bleeding recurrence. We set out to understand whether a 14-day course of a combined oral hormonal steroid as compared with a placebo would interrupt a bleeding episode such that users were no longer bleeding at the end of the therapy.

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This was a double-blind randomized controlled trial that aimed to recruit etonogestrel implant users who reported bothersome bleeding with a current bleeding–spotting episode of at least 7 consecutive days. Bothersome bleeding was based on patient complaint and no attempt was made to quantify the amount of blood loss. Women were invited to participate after being seen at one of our institution's clinics with this complaint or after responding to advertisements that were posted on the Internet through social media platforms, in the local newspaper, or around public venues such as a local university.

Interested, eligible women were screened by phone and subsequently invited for a visit. At the screening visit, the potential participant completed a health questionnaire; her height, weight, and blood pressure were measured by the research assistant; and a pregnancy test and rapid urine chlamydia test were performed. Participants completed questions specific to their use of the etonogestrel implant and their recent bleeding pattern. A physician–investigator then performed a speculum examination and recorded any abnormal findings.

We included women ages 18–44 years who were English- or Spanish-speaking with a bleeding episode of at least 7 consecutive days at the time of enrollment. Women were excluded if they met category 3 or 4 contraindications to receive estrogen therapy according to the Centers for Disease Control and Prevention 2010 Medical Eligibility Criteria,10 had a body mass index (calculated as weight (kg)/[height (m)]2) greater than 35, a systolic blood pressure greater than 135 mm Hg or a diastolic blood pressure greater than 85 mm Hg on more than two occasions separated by an interval of at least 15 minutes, a positive pregnancy test, a positive chlamydia test, were unable or unwilling to swallow pills, had a medical condition deemed severe by a physician investigator, were taking a hepatic enzyme inducing medication, had a known allergy to levonorgestrel or ethinyl estradiol (E2), had findings on speculum examination indicating an anatomic source of bleeding, (eg, polyp, cervicitis), was not up to date with current cervical screening guidelines according to the American Society for Colposcopy and Cervical Pathology, had a cervical procedure done in the past 3 months, were on a concurrent hormonal contraceptive, or were illiterate. This study was approved by the Colorado multiple institutional review board.

Eligible participants provided written informed consent. All investigators, participants, and research assistants were blinded to treatment allocation. Arm assignment was determined by computer-generated randomization ( of study IDs in a ratio of eight to one by one of the authors (J.S.) who did not have any contact with the study drug or participants. The list was sent by this author to another research assistant not associated with participant recruitment to prepare corresponding study drug bottles for each study ID. After informed consent was obtained, participants were sequentially assigned to their study ID. The research assistant involved with participant study procedures would then retrieve the study drug with the corresponding study ID from a locked storage cabinet.

Participants were given their assigned nonlabeled pill bottle containing 14 pills of the study drug (150 micrograms levonorgestrel and 30 micrograms ethinyl E2 oral contraceptive pill [OCP]) or the identically appearing placebo. The participant was instructed to start the study drug that day and to take pills consecutively for the next 13 days. During this time, participants completed a bleeding and pill-taking diary. In the diary, the participants noted if the pill was taken on the appropriate day, the time the pill was taken, and the amount of bleeding experienced that day (none, spotting, light, normal, or heavy).

After 14 days, the research assistant contacted participants by phone to review the diary and query for side effects or changes in health status. Participation was complete for any patient who reported bleeding on study day 14. If the participant's bleeding episode had stopped and she was not bleeding on the last day of the study drug, she was contacted weekly for the first 30 days and then monthly until she reported bleeding.

Our primary outcome was the proportion of women in each group who stopped bleeding during therapy and continued to report no bleeding at the end of the 14-day treatment period (temporary interruption of bleeding). To calculate our sample size, we used Alvarez-Sanchez et al's study11 that examined the use of a 50-microgram ethinyl E2 and 250 microgram levonorgestrel combined OCP compared with a placebo in levonorgestrel implant users. His study demonstrated that 91% of levonorgestrel implant users with prolonged or irregular bleeding stopped bleeding within 3 days of use of OCPs compared with 15% of placebo users. To test whether our intervention resulted in 80% of those randomized to a 30-microgram ethinyl E2 OCP having their bleeding episode interrupted and terminated during the remainder of treatment compared with 20% of placebo users with a 5% probability of type I error and 20% probability of type II error (80% power), we calculated that 13 participants were required in each group. Accounting for 20% anticipated loss to follow-up or dropout, we enrolled 32 women.

Data analysis was performed in accordance with the intention-to-treat principle. We compared proportions using the χ2 test and Fisher's exact test given small cell sizes.

Our secondary outcomes included the number of days until temporary interruption of bleeding during therapy occurred, number of days without bleeding during therapy, and number of days to recurrence of bleeding after discontinuation of therapy. We compared medians using the nonparametric independent sample test and report ranges. We used IBM SPSS Statistics 21.0.0 for all analyses.

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From November 2013 through December 2014, 66 women were screened and 32 were randomized (Fig. 1): OCP (n=16) or placebo (n=16). The most common reasons for ineligibility were no longer bleeding (n=11) and migraines with aura (n=8). Table 1 demonstrates their baseline characteristics; groups were similar on all measured demographic and reproductive characteristics. The majority of the participants (78%) reported their bleeding as extremely or very annoying, and more than half of the participants (53%) had considered removal of the implant because of their bleeding pattern; these characteristics did not differ between groups. None of our participants reported any adverse events.

Fig. 1

Fig. 1

Table 1

Table 1

Participants randomized to receive OCPs were 11.7 times more likely (95% confidence interval 1.9–70.2) to have a temporary interruption of bleeding during the study drug period: 14 (87.5%±16.2%]) in the OCP group compared with six (37.5%±23.7%) in the placebo group (P<.01; Table 2). Participants randomized to placebo continued to report unpredictable bleeding patterns on their 14-day diaries. One participant randomized to OCPs was noncompliant with pill-taking; the participant took additional pills after realizing she missed, outside the protocol. She reported interruption of bleeding starting on day 4. She missed pills on days 11 and 12, took two pills on day 13 and two pills on day 14, and subsequently experienced light bleeding on day 13 and spotting on day 14.

Table 2

Table 2

Our secondary outcomes are also demonstrated in Table 2. The median number of days to the start of the temporarily interrupted episode (if one occurred) was 5.0 for the intervention group compared with 9.0 for the placebo group (P=.05). Regardless of whether a temporary interruption of bleeding was achieved, the median number of days without bleeding during the 14-day therapy period was higher in the treatment group than in the placebo group (9.0 compared with 3.0, P=.03). Of women in the OCP arm who had a temporary interruption of bleeding during therapy, the median time to recurrence of bleeding was 5.5 days (range 1–131 days); 12 of 14 (85.7%) had a bleeding recurrence 10 days or less after treatment ended.

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Most irregular bleeding associated with progestin-only contraceptives is secondary to endometrial atrophy. Estrogen supplementation opposes the progestin effects on the endometrium. We chose to test a commonly prescribed low-dose OCP rather than E2 alone because OCPs are familiar to women and health care providers, widely accessible, and inexpensive.12 Many women select the implant because it is a nondaily method without estrogen side effects. Because the intervention of OCPs includes both daily use and estrogen, we chose to test a short period of therapy (14 days).

We found that etonogestrel contraceptive implant users who present with bothersome bleeding patterns are more likely to have a temporary interruption of bleeding and less days of bleeding during a 14-day course of OCPs as compared with placebo. The median time to the start of a temporary interruption of bleeding episode for women in the OCP arm was 5 days. When OCP therapy was discontinued, 85.7% of women experienced their next bleeding episode within 10 days. Among our participants, treatment was very well tolerated and there were no adverse events.

Weisberg and colleagues have previously conducted a pilot13 and larger trial14 to evaluate time to interruption of bleeding using various regimens. In both studies, they found a decrease in time to interruption of a bleeding episode with 25 mg mifepristone twice daily on day 1 followed by 4 days of 20 micrograms ethinyl E2 compared with placebo (mean time 4.0–4.3 days compared with 6.4–7.5 days). The larger trial also demonstrated that 25 mg mifepristone twice daily on day 1 followed by 100 mg doxycycline twice daily for 5 days was more effective than doxycycline alone or in combination with ethinyl E2 or placebo (mean time 4.4 compared with 6.4 days for all other regimens). None of these therapies resulted in improvement in subsequent bleeding patterns. Mifepristone is difficult and expensive to obtain in the United States as a result of prescribing restrictions and is only available as a 200-mg formulation, the dose for medication abortion.15 We used an inexpensive, widely available medication that resulted in shortened time to interruption of bleeding and temporary interruption during a longer treatment course.

Although most women who report heavier or more frequent bleeding on the implant still say they are very satisfied, they are less likely to be highly satisfied than other implant users and more likely to discontinue.5,65,6 Although the overall continuation rates of implants are very good compared with short-acting methods, continuation beyond 1 year of use appears lower for implants than other long-acting methods, often secondary to unacceptable bleeding.3,163,16 Interventions such as the one tested in this study may be of benefit to women seeking temporary cessation of bleeding episodes and possibly avoid early removal.

Our study has several limitations. According to our protocol, the first day of bleeding after therapy was the end of that participant's study participation, because our secondary aim was time to resumption of bleeding. Therefore, we cannot report on the characteristics of the first posttreatment bleeding episode or the long-term bleeding pattern after a single 14-day treatment. We also did not assess potential causes of bothersome bleeding such as intracavitary polyps of myomas and, as such, cannot comment on the effect of such structural lesions on therapy. However, the mean age of our patients was 21–22 years, and we assessed for common causes of bleeding in this age group such as ectropion and cervicitis.

Based on the findings of this study, use of a low-dose combination OCP for patients with etonogestrel implants who report bleeding and have no estrogen contraindications will likely result in temporary bleeding cessation with minimal risk or side effects. However, optimal dosing (oral compared with parenteral), length of treatment, frequency of treatments, and safety of repeat dosing remain unknown. Alternative therapies that are available in the United States such as ethinyl E2 alone may also provide benefit. For women who have contraindications for estrogen therapy, tamoxifen may be a potential therapy. Furthermore, a larger study is needed to confirm the results of this sample, to better evaluate secondary outcomes, and to allow subgroup analyses to better understand if any patient characteristics influence success.

Future studies should also evaluate the acceptability of the bleeding pattern after treatment and the effect of treatment on discontinuation of the contraceptive implant. Before undertaking a study of method satisfaction and continuation, however, other regimens that may cause bleeding to stop in more women and produce a more durable effect than that described in this study should be evaluated.

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