Long-Term Outcomes of Implanon in Managing Adenomyosis: A 3-Year Prospective Study

Introduction

The radiopaque Implanon etonogestrel implant (Implanon) is a relatively new type of subcutaneous contraceptive implant. It was first approved by the European Union in 2010, the United States in 2011, and China in December 2013. This implant consists of a slow-release ethylene vinyl acetate polymer that contains 68 mg of etonogestrel. It sustains an ovulation-inhibiting concentration for up to 24 hours after subdermal insertion, ensuring efficacy for a period of 3 years [1]. Subdermal implants are internationally acknowledged as a convenient, efficient, long-acting, and reversible contraceptive method [2,3]. The etonogestrel subcutaneous implant, a progesterone-based contraceptive, also offers non-contraceptive benefits [4–6]. However, a study spanning 204 countries and territories between 1970 and 2019 showed that the proportion of implants among total contraceptive methods varied worldwide, with China’s usage rate ranging only about 4.3–9.3% [7]. Moreover, although progestins are effectively used in the treatment of adenomyosis, the low utilization rate of implants in China has limited research on the effect of Implanon for this condition, particularly in the absence of controlled studies and long-term follow-up research [4,8].

Adenomyosis is a relatively common condition encountered in gynecology clinics. In recent years, there has been a notable increase in its incidence, and the age of onset has been decreasing, indicating a trend towards younger patients. This gynecological disorder lacks ideal conservative treatment options, with surgical resection being the primary therapeutic approach. However, hysterectomy for women of childbearing age not only leads to infertility and disrupts endocrine balance but also has adverse psychological impacts and diminishes overall quality of life [9,10]. Consequently, the selection of an appropriate reversible contraceptive method is of crucial importance.

To delve into the contraceptive efficacy, safety, and satisfaction associated with the Implanon implant, and to provide a foundation for its clinical application, particularly in patients with adenomyosis, we conducted this research.

Material and Methods

STUDY DESIGN AND PARTICIPANTS:

This observational research was conducted at the gynecological clinic of the only third-class A maternal and child health hospital in Qingdao. The inclusion criteria for participants were as follows: aged above 18 years, engaged in regular sexual activity, in need of contraception, and voluntarily choosing Implanon as a long-acting contraceptive method. Exclusion criteria included confirmed or suspected pregnancy, postpartum within 42 days of lactation period, no transvaginal ultrasound examination results, contraindications to use of Implanon such as active venous thromboembolic disease, abnormal liver or kidney function, known or suspected hormone-sensitive malignancies, unexplained vaginal bleeding, and allergies to implant components. All patients received subcutaneous implantation on the left upper arm during the first to fifth days of menstruation, during amenorrhea while lactating, or immediately after induced abortion. Participation in the study was voluntary, and written informed consent was obtained from each participant. All subjects were followed up for clinical observation until the removal of the subcutaneous implant. The follow-up period was more than 3 years. The study was approved by the Institutional Review Board of Qingdao Women and Children’s Hospital Ethics (No. GL2016.2-214).

SAMPLE SIZE:

The sample size was determined using the Freedman estimation method for survival analysis [11]. We conducted a 2-sided test with a statistical power of 90% and an alpha (α) level of 0.05. In the absence of prior 3-year follow-up studies on the utilization analysis of Implanon categorized by adenomyosis in China, we referenced a continuation rate of 30% from Luton for the group without adenomyosis [12], and a rate of 66% [13] reported for the levonorgestrel-releasing intrauterine system among women with adenomyosis as the estimated rate for the adenomyosis group. The calculated minimum required sample size was 85 participants. Considering loss to follow-up, we enrolled all eligible subjects (N=124) who presented at our hospital from June 12, 2016 to December 5, 2018.

DIAGNOSIS OF ADENOMYOSIS:

Adenomyosis is characterized by the presence of endometrial glands and stroma within the myometrium, presenting with various clinical and/or imaging phenotypes [14]. In this study, experienced clinicians diagnosed adenomyosis based on the following criteria: progressive dysmenorrhea, transvaginal ultrasonography showing diffuse heterogeneous myometrial echogenicity; includes striations and indistinct endomyometrial junction, anechoic lacunae and/or cysts, focal abnormal myometrial echotexture; indistinct borders, globular and/or asymmetric uterus unrelated to leiomyomata. Of all participants, 45 patients were diagnosed with adenomyosis and 79 were not.

DATA COLLECTION:

Detailed information on demographic characteristics (age, height, weight), menstrual history, and fertility history was collected at enrollment and upon discontinuation. Body mass index (BMI) was calculated from self-reported height and weight and categorized as low (BMI <18.5 kg/m2), normal (BMI: 18.5–24 kg/m2), overweight (BMI: 24.0–29.9 kg/m2), and obese (BMI ≥30.0 kg/m2) according to Chinese recommendations [15]. Menstrual cycle and periods were classified as normal or abnormal based on a scale of 21–45 days and 3–7 days, respectively [16].

Follow-up data were collected at 10 days, 3 months, 12 months, 24 months, and 36 months after implantation, including the incidence of unintended pregnancies, extraction time, menstrual changes, hormonal adverse effects, and other adverse clinical events. A survey of satisfaction and reasons for discontinuation was administered at the time of implant removal. The evaluation indicators of the treatment’s effectiveness included the contraceptive efficacy rate, as well as the continuation rate at 1, 2, and 3 years. Additionally, we documented all discomfort reported by the patients, such as amenorrhea, breast tenderness, and weight gain. Overall satisfaction [17], intention to recommend [18], and willingness to reuse Implanon as a contraception method were assessed using a 5-point Likert scale. The total satisfaction score, which is the sum of the responses to these 3 questions, could reach a maximum of 15 points, with higher scores denoting greater satisfaction with Implanon.

STATISTICAL ANALYSIS:

Continuous variables are reported as mean±standard deviation (SD) and were compared using the t test; non-normal distributed continuous variables are described as median with interquartile range (IQR) and were compared with the Mann-Whitney U test, whereas categorical variables are presented as number and percentage and were testing using chi-square tests, and the Kruskal-Wallis test for used categorical variables. Kaplan-Meier chart and log-rank test were used to compare the continuation rates of patients with and without adenomyosis. Univariate and multivariate Cox proportional hazards models were used to further analyze the risk factors of implant removal. All results were two-sided, with statistical significance considered at P<0.05. Statistical analyses were conducted using R software (version 4.2.2).

Results

SUBJECTS’ CHARACTERISTICS:

A total of 124 participants were enrolled in the study, including 45 with adenomyosis. The mean patient age was 35.53 years (range 18.50–52.79). Implantation occurred at 1–5 days after menstruation for 104 patients, during postpartum lactation amenorrhea for 10, immediately after induced abortion for 4, and after implant replacement for 6. The follow-up rate was 100%. Apart from age and reproductive history, no significant differences were observed in other baseline characteristics between patients with and without adenomyosis. The age of patients with adenomyosis was significantly older than for those without. Although most subjects were multiparous, among those with adenomyosis, most had had 1 child, in contrast to those without adenomyosis, who had typically delivered more than 2 children (Table 1).

EFFICACY AND ADVERSE EFFECTS:

None of the 124 subjects became pregnant during the treatment period, yielding a contraceptive effectiveness of 100%. The main adverse effect at 10 days after implantation was pruritus at implant position, and the second most common was abnormal uterine bleeding (Table 2). The incidence of adverse effects was 66.13% within the first 3 months, but decreased over time. This trend was consistent for both groups with and without adenomyosis. While the adverse effect rate was higher in the adenomyosis group than in the non-adenomyosis group within the first 6 months, it decreased more significantly between 6–12 months and remained persistently lower until extraction. A similar trend was observed for the incidence of bleeding-related issues, excluding amenorrhea (Figure 1).

REASONS FOR DISCONTINUATION AND SATISFACTION WITH IMPLANON:

Two subjects had their Implanon removed due to hypermenorrhea, prolonged menstrual bleeding, and hypogastrium distension in the first and third months. The primary reason for discontinuation was the expiration of the implant after more than 3 years of use, accounting for 58.06% of cases, with a higher percentage of 75.56% for subjects with adenomyosis. The main reason for premature removal was bleeding-related problems, including amenorrhea, constituting 32.26% of cases, with a lower percentage for subjects with adenomyosis. Over 60% of subjects reported being satisfied or very satisfied with Implanon and would recommend it to others. Seventy-one (57.26%) subjects expressed a desire to reuse the implant for contraception. Overall satisfaction with Implanon was higher among subjects with adenomyosis compared to those without (Table 3).

CONTINUATION RATE ANALYSIS:

The continuation rates at 1 year, 2 years, and 3 years were 75.81%, 66.94%, and 54.84%, respectively. For subjects without adenomyosis, the rates were 68.4%, 57.0%, and 41.8%, while for those with adenomyosis, they were 88.9%, 84.4%, and 75.6%, respectively. The continuation rate for subjects with adenomyosis was higher than for those without, and was particularly significant after 12 months of implantation (Table 4). Age was also significantly associated with the continuation rate of Implanon. Subjects aged 35 years or older were more likely to maintain their implant than younger individuals.

The Kaplan-Meier survival curves showed that the continuation rate of patients with adenomyosis was significantly higher than those without (χ2=6.6, P=0.01) (Figure 2). Cox proportional hazards regression model analysis was used to estimate the adjusted hazards ratio (HR) and 95% confidence interval (95% CI) for Implanon removal. The univariate model indicated an HR of removal for the adenomyosis group of 0.62 compared to the non-adenomyosis group. Compared to the group under age 35 years, the HRs and CIs for removal rate in the 35 years and older group were 0.68 (0.54–1.49); and compared to nulliparous women, the HRs and CIs for the other 2 groups (women with 2 or more children and women with 1 child) were 0.30 (0.11–0.78) and 0.46 (0.18–1.14), respectively. The multivariate model, adjusted by age, parities, and BMI at the time of implantation, yielded an HR for adenomyosis of 0.55 (0.36–0.85). Adenomyosis and parity were inversely associated with the risk of Implanon removal (Table 5).

Discussion

Our study confirms that Implanon is an effective contraception method, particularly for patients with adenomyosis, as demonstrated by this observational follow-up study over a period of 3 years. The most common adverse effect was related to bleeding issues. The overall incidence of adverse effects decreased over time, with a more significant decline observed in the adenomyosis group at 6–12 months, and this lower rate was maintained until the implant was removed.

The radiopaque Implanon is a flexible cylinder, 40 mm long and 2 mm in diameter, that contains a drug core and a membrane controlling the steady release of etonogestrel. Each implant holds 68 mg of etonogestrel, which is slowly released after insertion. The contraceptive mechanism involves inhibiting the hypothalamic-pituitary-ovarian axis, thus inhibiting ovulation, increasing cervical mucus viscosity to impede sperm penetration, and thinning the endometrium, which creates a synergistic effect that inhibits the development of adenomyosis. This is akin to how ulipristal acetate treats submucosal fibroids [19], providing additional therapeutic benefits while simultaneously serving as a contraceptive method.

Our research confirms a 100% contraceptive efficacy with no unintended pregnancies, consistent with the findings of a previous review of Implanon [2, 20]. This efficacy is higher than other contraceptive methods, including levonorgestrel-releasing implants (LNG implant and Norplant) [21], even when used perfectly [22]. In our clinic, we have observed patients switching from Mirena to subcutaneous implants due to issues with IUD shedding and descent. The subcutaneous implant, unlike the intrauterine Mirena, rarely falls out and offers superior contraceptive effects [22].

Bleeding-related problems, including amenorrhea and prolonged menstrual bleeding, were the most frequent adverse events. The incidence of adverse effects in our study (66.13% at 3 months) was lower than reported in other studies conducted in Chongqing and Shanghai, China (73.85% and 74.2%) [18,23]. We found that the incidence of bleeding-related problems decreased from 62.90% at 3 months to 10.84% at 24 months, supporting previous findings of a decline over time [21].

Our findings showed that 58.06% of the subjects used the implant for the full 3 years. Bleeding-related problems, including amenorrhea, accounted for 30.26% of removals, similar to the 38.1% rate reported in another study [1]. Other medical reasons such as acne and weight gain accounted for less than 4% of removals. The 1-year continuation rate in our study was 75.81%, which is lower than rates reported in other studies (96.21% [18] and 86% [24]), while the 2-year continuation rate of 66.94% is consistent with rates from these studies (66.35% [18] and 67.9% [24]). The 3-year continuation rate of 54.84% is higher than the 38.10% reported elsewhere [1], and there are limited data on 3-year continuation rates in China.

Interestingly, our study found that the rate of adverse reactions decreased more rapidly in the adenomyosis group within 6–12 months, suggesting that the mechanisms of Implanon’s action on adenomyosis differ over time, warranting further research. The satisfaction survey indicated that patients with adenomyosis were most satisfied with Implanon, more likely to recommend it to others, and to continue using the implant after expiration. Both univariate and multivariate Cox proportional hazards model analysis, as well as the Kaplan-Meier chart, confirmed that the continuation rate was higher for patients with adenomyosis.

A key strength of our study is the extended prospective follow-up period, which reduces the effects of recall bias. Furthermore, our survival analysis revealed promising insights into the potential therapeutic effects of Implanon on adenomyosis, offering a valuable perspective for further clinical investigation and consideration in treatment protocols. However, several limitations should be acknowledged. We did not utilize the daily menstrual diary cards to document bleeding problems, and reliance on patient-reported information may have introduced bias. Although significant differences in continuation rates were noted between participants with and without adenomyosis, we did not do subgroup analysis about the concurrent presence of other conditions, such as endometriosis. In addition, the mechanism’s non-contraceptive benefits warrant further study.

Conclusions

In conclusion, Implanon is an effective and safe contraceptive method that is particularly well-suited for women with adenomyosis. The presence of adenomyosis appears to be associated with a reduced likelihood of having the Implanon implant removed, suggesting that it can offer additional benefits for this group of patients. The primary adverse reaction observed was related to bleeding issues, with a relatively high incidence at the start of use. However, this rate significantly decreased over time. Healthcare providers should thoroughly explain the potential adverse effects to patients before and during the subcutaneous implantation process to manage expectations and prevent anxiety and dissatisfaction that could arise from lack of understanding.