Use of the etonogestrel contraceptive implant (Nexplanon, formerly Implanon) continues to increase in the United States, especially among young adults and adolescents.1,2 The etonogestrel implant has a relatively high continuation rate (65–91% at 1 year of use); however, 11.3% of women ultimately discontinue this method owing to bothersome bleeding irregularities.3–5 Prolonged periods of bleeding and frequent irregular bleeding were the most common bleeding patterns associated with discontinuation.5 In the St. Louis-based contraceptive CHOICE project, the majority of women who discontinued the contraceptive implant within the first 6 months of use (53%) reported “Irregular or Frequent bleeding” as a reason.6 Though many treatments have been studied to treat bothersome bleeding with the etonogestrel implant (eg, oral contraceptive pills, nonsteroidal antiinflammatory drugs, tamoxifen), these treatments often provide only short-term benefits with resumption of abnormal bleeding after treatment cessation.7–9
Despite ample data on the prevalence of abnormal bleeding patterns with the contraceptive implant, few published data exist on how individual patient characteristics influence a woman's risk for experiencing bleeding-associated side effects. In addition to the wide variability in bleeding profiles, several studies have demonstrated wide variability in interindividual serum etonogestrel concentrations among women using the etonogestrel implant for identical periods of time.10,11 The two largest published cohorts of contraceptive implant users found a range of serum etonogestrel concentrations of 55.8–802.6 pg/mL, a greater than 14-fold difference between the highest and lowest values.10,11 We do not know the extent to which variability in serum drug levels, for the implant and other hormonal contraceptive methods, contributes to the variability in bleeding side effects.12,13
Given that bleeding-related side effects are some of the most common reasons for contraceptive method discontinuation, there is an urgent need to understand what factors may contribute to an individual woman's risk for these side effects, including potential pharmacologic factors.3,4,6 As such, we aimed to evaluate the relationship between serum etonogestrel concentrations and both bleeding patterns and related side effects in contraceptive implant users. Etonogestrel contraceptive implant users are ideal candidates for pharmacokinetic variability studies because they achieve relative steady-state serum concentrations owing to the steady drug release nature of the implant. This avoids any confounding stemming from protocol adherence.4,14 We hypothesized that increased serum etonogestrel concentrations would be associated with increased odds of experiencing abnormal or bothersome bleeding with the contraceptive implant.
The underlying methodology for this study has previously been published, including all inclusion and exclusion criteria.10 Participants were English or Spanish speaking reproductive age women (18–45 year old) with an etonogestrel contraceptive implant in place for at least 12 and no more than 36 months. Women had to have an implant in place for at least 12 months to be in the relative steady-state period of the implant's pharmacokinetics.14 From the available pharmacokinetic data, the amount of etonogestrel released from the implant decreases by only 15% on average between 1 and 2 years of use (40 micrograms/d vs 34 micrograms/d), as compared with a decrease of up to 33% between 4 weeks (60–70 micrograms/d) and 1 year of use.14 We chose 36 months as our upper enrollment limit for duration of implant use because this is the current U.S. Food and Drug Administration approved duration of use.4 We excluded women using any medications or supplements that could affect serum etonogestrel levels through inhibition or induction of cytochrome P450 (CYP) enzymes (specifically CYP3A4).15 We also excluded women who reported any medical conditions that could affect baseline liver function (eg, hepatitis, cirrhosis) or measured body mass indexes (BMIs, calculated as weight in kilograms divided by height in meters squared) less than 18.5, because low BMI has been associated with abnormal metabolism. The hypothesis tested in this analysis was a prespecified outcome of a broader pharmacogenomic study.10 The protocol was approved by the Colorado Multiple Institutional Review Board and all participants gave written informed consent before study initiation. This study was also registered on ClinicalTrials.gov (NCT03092037). We recruited participants through community advertising and contraceptive clinics at the University of Colorado Anschutz Medical Campus and compensated participants with a $20 gift card for their participation.
For eligible participants, we determined the length of implant use by participant self-report and confirmed presence of the implant by physical exam. We excluded women who could not remember when they had the implant placed, unless there was documentation of the date of insertion in their medical record. Participants completed a questionnaire to obtain self-reported demographics and side effect information (Appendix 1, available online at http://links.lww.com/AOG/B522). To specifically assess subjective bleeding patterns and side effects, we asked participants whether they had experienced “abnormal bleeding” (yes or no) while using their contraceptive implant. We also assessed whether participants experienced monthly periods (yes or no) at the time of enrollment, and, if not, roughly how many days of bleeding or spotting they had over the previous 90-day (3-month) period before enrollment. When defining bleeding patterns, we designated participants who reported 0 days of bleeding or spotting over a 90-day period as experiencing amenorrhea. For participants who were recruited during a routine visit with their health care provider at our institution, we also reviewed their medical record to determine whether they had received a prescription for combined oral contraceptive pills for treatment of bothersome breakthrough bleeding at any time during use of their contraceptive implant. We specifically evaluated combined oral contraceptive pill prescription because this is the standard treatment for bothersome breakthrough bleeding with the contraceptive implant at our recruitment sites.
We performed serum etonogestrel concentration analysis using the previously published methodology that used a previously validated liquid chromatography-mass-spectrometry assay protocol.10,16 All liquid chromatography-mass-spectrometry procedures were performed at the Biomarkers Core Laboratory of the Irving Institute of Clinical and Translational Research at Columbia University Medical Center.
We used IBM SPSS 25 statistical software for all statistical analyses. We performed descriptive frequencies for reported abnormal bleeding and bleeding patterns. We also performed multivariable logistic regression to identify predictors for abnormal bleeding, for the bleeding patterns of monthly periods and amenorrhea, and for the provision of oral contraceptive pills for treatment of bothersome bleeding. We chose the pertinent patient characteristics of age, months of implant use, BMI, race, ethnicity, and serum etonogestrel concentration as independent variables for our logistic regression analyses. We used a backward conditional approach to create our logistic regression model for our selected outcomes of interest. The sample size was determined by the primary pharmacogenomic study size.10
We recruited 350 participants over the course of 15 months (March 2016–May 2017). Table 1 shows pertinent patient characteristics. The median age of participants was 22.5 years with a median duration of etonogestrel implant use of 26.0 months. The most frequent self-reported race was white or Caucasian (46.6%) and 51.4% of participants reported Hispanic or Latina ethnicity. Amongst the 77 participants who responded with “No response or Unknown” in relation to self-identified race, all identified their ethnicity as “Hispanic or Latina.” The median serum etonogestrel concentration was 137.4 pg/mL (range 55.8–695.1) with an interquartile range of 63.5 pg/mL.
The majority of participants (59.4%) reported experiencing abnormal bleeding and 37.7% of participants responded that they currently have a monthly period. Table 2 demonstrates the full breakdown of reported bleeding patterns. Using the definition of amenorrhea as outlined in the methods, 52 of the 205 participants without a monthly period were designated as having amenorrhea (25.4%). Overall, a large majority of participants without monthly periods reported less than 16 days of bleeding or spotting over a 90-day period (71.7%), with only 10.2% of participants reporting bleeding in excess of 45 days.
Almost three-fourths of participants were recruited during routine health care visits (72.3% [253/350]). Among this group, 20.9% (53/253) had received a prescription for combined oral contraceptive pills for management of bothersome bleeding during the time they had an etonogestrel contraceptive implant in place. No participants were prescribed oral contraceptive pills containing progestins that are metabolized into or directly related to etonogestrel (eg, desogestrel).
For the multivariable logistic regression analysis, we included the participant characteristics and demographics of age, months of implant use, BMI, race, ethnicity, and serum etonogestrel concentration as our variables of interest based on availability and plausible associations with bleeding profiles. The crude odds ratios (ORs) for all variables of interest and our bleeding side effect outcomes are shown in Table 3. The final multivariable logistic regression models and adjusted ORs (aORs) are presented in Table 4. Overall, serum etonogestrel concentrations were significantly associated with two outcomes. For every 1-pg/mL increase in serum etonogestrel concentration, participants had 1.005 times the odds of having experienced abnormal bleeding (P=.015) and 1.008 times the odds of having received a prescription for oral contraceptive pills for bothersome bleeding (P=.002). No other variables remained in the logistic regression model for abnormal bleeding.
Two other variables were significantly associated with receiving a prescription for oral contraceptive pills, but with competing effects. For every 1 month of implant use past 12 months, participants had 0.95 times the odds of having received a prescription for oral contraceptive pills, but participants who self-reported as black or African American had 4.5 times the odds of having been prescribed oral contraceptive pills as participants of any other race or ethnicity (Table 3). Black or African American race was also the only variable significantly associated with reporting a monthly period (aOR 2.22, 95% CI 1.14, 4.32). After accounting for oral contraceptive pill prescription, the association between black or African American race and reporting a monthly period remained (aOR 2.33, 95% CI 1.02, 5.31). For amenorrhea, only Asian or Pacific Islander race remained as a significant predictor in the regression model (aOR 3.25, 95% CI 1.15, 9.22).
Though having a monthly period or amenorrhea were not associated with serum etonogestrel concentrations, increases in serum etonogestrel concentration were associated with both increased subjective reporting of abnormal bleeding and increased objective prescription of combined oral contraceptive pills for bothersome bleeding. To put these associations into more clinically relevant terms, for every 100 pg/mL increase in serum etonogestrel concentration, a woman had 1.6 times the odds of reporting having experienced abnormal bleeding and 2.3 times the odds of having received a prescription for oral contraceptive pills for management of bothersome bleeding. At our clinical setting, first-line treatment for bothersome bleeding with the etonogestrel implant is prescription of oral contraceptive pills. Thus, these findings support a clinically significant association between serum etonogestrel concentrations and bothersome bleeding side effects, because patients with higher serum etonogestrel concentrations were more likely to have received a medical intervention. Though higher BMI and longer duration of implant use are associated with small decreases in serum etonogestrel concentrations, we did not find that these two patient characteristics were associated with bothersome bleeding side effects.17 Given that discontinuation of the contraceptive implant and other hormonal contraceptive methods are often a result of bothersome bleeding, understanding the role and sources of pharmacokinetic variability may lead to more individualized interventions.10
In this large cohort of etonogestrel contraceptive implant users, we found similar bleeding patterns as demonstrated in prior studies.5 The percentage of participants in our study experiencing amenorrhea (15.4%) was somewhat lower than the rate found by Mansour et al5 (22.2%), but that analysis included six studies conducted in Southeast Asian countries. We found that participants who self-reported their race as Asian or Pacific Islander had more than three times increased odds of reporting amenorrhea as compared with all other participants, which could account for some of this discrepancy.
The only other self-reported race that was associated with a bleeding pattern was black or African American; these participants had more than two times the odds of reporting current monthly periods. However, it remains unclear from our findings why participants who self-reported as black or African American had more than four times the odds of having received a prescription for oral contraceptive pills. Because we did not assess the temporality of abnormal bleeding with our survey, it may be that these participants had bothersome bleeding patterns earlier in the use of the contraceptive implant, which then may have resolved for some of these women after prescription of oral contraceptive pills or were more likely to report a desire for treatment of bothersome bleeding. Given this unresolved potential contradiction, research on bleeding patterns with other hormonal contraceptive methods may help elucidate the pertinence of our findings.
In this study, we were able to recruit a large and diverse cohort. Within this cohort, we were able to detect significant associations between our outcomes of interest and serum etonogestrel concentrations. Another strength of the study was recruiting participants using a medication with a controlled-release rate and steady-state pharmacokinetics, which allowed us to efficiently capture each individual's pharmacokinetic profile with only a single etonogestrel measurement during the relative steady-state period between 12 and 36 months.4,14 Our study population was also relatively young with a median age of 22.5 years, which is representative of the general population of etonogestrel implant users.4 Thus, the prevalence of bothersome bleeding and overall bleeding patterns of our study cohort are more likely to be representative of the general population of contraceptive implant users that continue past the first year of use.
The primary limitation of our study was that we used only a brief questionnaire to assess side effects and bleeding profiles. We designed this questionnaire to be short to reduce participant fatigue but our data lack some of the complexity in bleeding profiles demonstrated in prior studies.5 We were not able to obtain sufficient detail to categorize bleeding patterns according to the accepted World Health Organization Belsey criteria.18,19 We also assessed only for the experience of abnormal bleeding at any time during contraceptive implant use and so recall bias may have affected participants' responses. However, we supported these data with our chart review to obtain objective information regarding treatment for bothersome bleeding. Though 97 participants did not have past medical records available for review, we were able to review records of more than 72% of our total participants for this objective analysis. Finally, we only enrolled participants with implants past 12 months of use, and thus did not capture those who discontinued use of this method early who may have different side effect and bleeding profiles.
The amount of circulating hormone from a contraceptive method can influence the side effects women experience with that method. For the etonogestrel contraceptive implant, high concentrations of the progestin are associated with higher rates of abnormal bleeding and bothersome bleeding requiring medical management. Because discontinuation of a contraceptive method places a woman at potential risk for unintended pregnancies, it is imperative to understand all of the clinical factors that contribute to bothersome side effects with hormonal contraception. Our findings highlight that more research is needed on the relationship between pharmacokinetic variability and side effect profiles so that clinicians can continue to improve individualized medication selection and patient counseling on contraceptive options, thereby improving patient satisfaction.
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