Subdermal implants vs. levonorgestrel intrauterine devices outcomes in reproductive-aged women: a systematic review and meta-analysis

Subdermal implants are linked to a higher incidence of acne, weight gain, device removal due to side effects, and overall dissatisfaction compared to LNG-IUS. Additionally, subdermal implants effect might influence negatively irregular bleeding in women with gynecological conditions and in healthy women in use of Norplant-2

The Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement recommendations were followed for the design of this systematic review and meta-analysis [ 10 ]. The protocol was registered in International Prospective Register of Systematic Reviews (PROSPERO) in April 2024 (ID CRD42024516472). Studies were included in this meta-analysis if they met all the following eligibility criteria: (1) randomized controlled trials (RCT); (2) comparing intrauterine devices to subdermal implants; and (3) reporting any of the outcomes of interest. Follow-up duration was not restricted. We excluded studies with (1) no control group and (2) no follow-up. We conducted a systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to April 2024 using the following search terms and their alternative terms: “Etonogestrel”, “levonorgestrel” and “randomized controlled trials”. No filters or language restrictions were applied. We also manually searched the references of all included studies for additional relevant studies. Screening of studies was performed using Rayyan. The authors initially reviewed papers based on their titles and included any that were uncertain for further evaluation. This approach was consistently applied to both abstract and full-text screenings. Two authors independently extracted the data following predefined search criteria and quality assessment. Efficacy outcomes included: (1) maintenance of the device inserted; (2) discontinuation due to side effects; (3) amenorrhea or infrequent bleeding; and (4) irregular bleeding. Satisfaction outcomes included three categories of satisfaction: (1) very satisfied; (2) satisfied; and (3) dissatisfied. Side effects were also evaluated, such as (1) weight gain, (2) acne and (3) detection of a new ovarian cyst. We performed subgroups analyses on: (1) women with endometriosis or adenomyosis and (2) type of subdermal implanted device—Norplant-2 and Implanon. The subgroup analysis explores whether the effects vary across different study characteristics, claryfing the robustness of the findings and whether certain subgroups are driving the overall effect. We used the Cochrane risk-of-bias for randomized trials (RoB 2) tool to appraise the quality of the included studies. Two authors completed the risk of bias assessment tool independently, and disagreements were resolved by consensus between them. The Cochrane Collaboration and the PRISMA statement guidelines were used to guide the statistical analysis [ 10 ].Odds-ratios (OR) with 95% confidence intervals were used to compare treatment effects for categorical endpoints. Cochran Q test and I 2 statistics were used to assess for heterogeneity; P values inferior to 0.10 and I 2  > 25% indicated substantial heterogeneity. A DerSimonian and Laird random-effects model was used for the outcomes. We aimed to perform sensitivity analyses using the leave-one-out strategy, which systematically excludes one study at a time, assessing the stability of the results. This approach helps to identify if any single study disproportionately influences the meta-analytic findings. R statistical software version 4.2.1 (R foundation for Statistical Computing) was used for statistical analysis. The Cochrane Handbook advises that at least 10 studies are needed for statistical tests of publication bias to be reliable. As our meta-analysis did not meet this threshold, we were unable to perform a statistical assessment of publication bias.

The initial search yielded 2862 results. Duplicate records and ineligible studies were removed and 23 studies were fully reviewed based on inclusion criteria. Of these, a total of 6 RCTs were included, comprising 1503 patients, of which 741 (49.3%) were from the subdermal implant group (Suppl. Material Fig. S1 ). Additional study characteristics are reported in Table  1 . Table 1 Included studies characteristics Author/year Country Number of patients Type of devices Gynecological conditions Age (years)ª BMI (kg/m 2 )ª Apter 2016 Australia, Finland, France, Norway, Sweden, and UK Implant: 381 LNG-IUS: 378 Nexplanon and LNG-IUS 13.5 mg (Jaydess/Skyla) None 24.9 ± 2.89 23.95 ± 4.97 Black 2021 Australia Implant: 60 LNG-IUS: 76 NA None NA NA Carvalho 2018 Brazil Implant: 52 LNG-IUS: 51 Implanon and Mirena Endometriosis 34.04 ± 1.12 27.45 ± 0.81 Modesto 2014 Brazil Implant: 98 LNG-IUS: 99 Implanon and Mirena None 30.65 ± 5.94 26.51 ± 5.42 Wang 1992 China Implant: 100 LNG-IUS: 100 Norplant-2 and 20ug/day of LNG-IUS c None 30.05 b NA Wei 2024 China Implant: 50 LNG-IUS: 58 ENG 68 mg and 52 mg LNG-IUS c Adenomyosis 38.57 ± 3.99 NA BMI Body mass index; DR Dominican Republic; ENG Etonogestrel; LNG-IUS Levonorgestrel intrauterine system; NA Not available; Nexplanon: a bioequivalent to Implanon, both cointaining 68 mg of ENG); UK : United Kingdom; USA United States of America a Mean ± standard deviation b Standard deviation not available c Not labelled Included studies characteristics Implant: 381 LNG-IUS: 378 Implant: 60 LNG-IUS: 76 Implant: 52 LNG-IUS: 51 Implant: 98 LNG-IUS: 99 Implant: 100 LNG-IUS: 100 Implant: 50 LNG-IUS: 58 BMI Body mass index; DR Dominican Republic; ENG Etonogestrel; LNG-IUS Levonorgestrel intrauterine system; NA Not available; Nexplanon: a bioequivalent to Implanon, both cointaining 68 mg of ENG); UK : United Kingdom; USA United States of America a Mean ± standard deviation b Standard deviation not available c Not labelled There were no statistical differences between the subdermal implant and LNG-IUS groups regarding bleeding patterns of amenorrhea or infrequent bleeding (OR 0.86; 95% CI 0.14–5.36; p  = 0.873; I2 = 94%; Suppl. Material Fig. S2). Similarly, irregular bleeding was not significantly different between groups (OR 1.41; 95% CI 0.67–2.97; p  = 0.361; I2 = 82%; Suppl. Material Fig. S3). There was a significantly higher incidence of device removal due to side effects in the subdermal implant group, as compared with the LNG-IUS group (OR 2.02; 95% CI 1.20–3.41; p  = 0.008; I2 = 24%; Fig.  1 ). Similarly, there was also a trend towards lower maintenance of the device in the subdermal implant group compared with LNG-IUS, although this was not statistically significant (OR 0.53; 95% CI 0.27–1.03; p  = 0.063; I2 = 52%; Suppl. Material Fig. S4). Fig. 1 Subdermal implant users were more prone to remove the device due to side effects when compared to women in use of hormonal intrauterine devices Subdermal implant users were more prone to remove the device due to side effects when compared to women in use of hormonal intrauterine devices We assessed three categories of satisfaction. Dissatisfaction was significantly higher in patients treated with subdermal implants (OR 2.42; 95% CI 1.47–3.98; p  < 0.001; I2 = 0%; Fig.  2 ). Fig. 2 Subdermal implant users were significantly more dissatisfied with treatment when compared to reproductive aged women using LNG-IUS Subdermal implant users were significantly more dissatisfied with treatment when compared to reproductive aged women using LNG-IUS There was a higher incidence of acne (OR 2.21; 95% CI 1.21–4.04; p  = 0.01; I2 = 0%; Fig.  3 ) and weight gain (OR 4.63; 95% CI 1.96–10.63; p  < 0.001; I2 = 0%; Fig.  4 ) in patients treated with subdermal implants. Although we observed a lower rate of detection of new ovarian cyst in women using subdermal implants compared to those using intrauterine devices (4.8% vs. 8.6%), this difference was not statistically significant (OR 0.52; 95% CI 0.17–1.57; p  = 0.247; p 0.17; Suppl. Material Fig. S7). Fig. 3 Patients in use of subdermal implants had higher odds of developing acne when compared with women in use of hormonal intrauterine devices Fig. 4 Reproductive aged women in use of subdermal implants had higher risk of gaining weight compared with women in use of hormonal intrauterine devices Patients in use of subdermal implants had higher odds of developing acne when compared with women in use of hormonal intrauterine devices Reproductive aged women in use of subdermal implants had higher risk of gaining weight compared with women in use of hormonal intrauterine devices Two studies included exclusively women with endometriosis or adenomyosis. We performed a subgroup analysis stratifying patients according to the presence or absence of these gynecological conditions [ 11 , 12 ]. There was a significant subgroup difference in the outcome of irregular bleeding, with a favorable effect of subdermal implants in patients with endometriosis or adenomyosis, but not in patients without these gynecological conditions (Fig.  5 ). The development of ovarian cysts was significantly reduced in women without endometriosis or adenomyosis (OR 0.27; 95% CI 0.09–0.84). Fig. 5 Odds of irregular bleeding when in use of subdermal implants or LNG-IUS might depend on the presence of gynecological conditions ( A ), while the odds of finding a new ovarian cyst was lower in healthy women in use of subdermal implants ( B ) Odds of irregular bleeding when in use of subdermal implants or LNG-IUS might depend on the presence of gynecological conditions ( A ), while the odds of finding a new ovarian cyst was lower in healthy women in use of subdermal implants ( B ) In the subgroup of women with and without gynecological conditions, the test for subgroup differences was not significant for the outcomes of: amenorrhea or infrequent bleeding (Suppl. Material Fig. S8), acne (Suppl. Material Fig. S9), side effects (Suppl. Material Fig. S10), and weight gain (Suppl. Material Fig. S11). There was a significant subgroup difference for irregular bleeding and amenorrhea or infrequent bleeding, with a worse effect of Norplant-2 in reproductive-aged women, but not in women in use of ENG 68 mg implants (Fig.  6 ). No difference was observed for the outcomes of continuation of the chosen method (Suppl. Material Fig. S12), being “dissatisfied” (Suppl. Material Fig. S13), “satisfied” (Suppl. Material Fig. S14), or “very satisfied” with the chosen method (Suppl. Material Fig. S15), or diagnosis of a new ovarian cyst (Suppl. Material Fig. S16). Fig. 6 Use of subdermal implant was associated with a higher risk of irregular bleeding ( A ) and lower risk of amenorrhea or infrequent bleeding ( B ) relative to LNG-IUS in studies that used Norplant-2 subdermal implant, but not in studies that used ENG 68-mg implants Use of subdermal implant was associated with a higher risk of irregular bleeding ( A ) and lower risk of amenorrhea or infrequent bleeding ( B ) relative to LNG-IUS in studies that used Norplant-2 subdermal implant, but not in studies that used ENG 68-mg implants All observational studies were evaluated through the RoB 2 tool (Suppl. Material Fig. S17). The overall risk of bias was considered low risk for four studies [ 12 – 15 ]. One study exhibited bias from the randomization process due to lack of reporting concealment, [ 11 ] and two studies had bias in selecting reported results due to the inability to retrieve clinical registry data. Both studies were categorized with a general risk level of "some concerns" for this matter [ 11 , 16 ]. We also conducted the leave-one-out analysis (Suppl. Material Figs. S18–S27). Heterogeneity was well distributed among studies during all outcomes evaluation except for the new ovarian cyst (Suppl. Material Fig. S22) and side effects outcome (S25). We observed that the adenomyosis study [ 13 ] increased heterogeneity in the new ovarian cyst assessment, while the endometriosis study [ 12 ] lowered the heterogeneity in the side effects outcome assessment. No impact on Odds Ratio was observed in both scenarios.

In this systematic review and meta-analysis of six randomized controlled trials involving 1503 women, we compared subdermal implants to LNG-IUS (Mirena) in reproductive-aged women. Our findings indicate that subdermal implants are associated with a significantly higher risk of dissatisfaction, acne, weight gain, and device removal due to side effects when compared to the LNG-IUS. No statistical significance was found for the outcomes of amenorrhea or infrequent bleeding, irregular bleeding, maintenance of the inserted device, being “satisfied” and “very satisfied” with treatment, and detection of a new ovarian cyst. Although both methods are highly effective for long-term contraception, these differences in side-effect profiles could play a crucial role in patient decision-making, particularly for individuals who are more sensitive to physical changes, such as weight gain or acne. Previous studies have highlighted that subdermal implants offer high confidence in their correct use, with rates surpassing those of methods, such as copper IUDs (92.4% vs. 82.5%) [ 17 ]. However, our analysis shows that up to one-quarter of patients using subdermal implants would not choose to use them again [ 18 ]. One in five patients reported being “unsatisfied” or “very unsatisfied”, and up to 17% of patients would not recommend the method to others [ 18 ]. The reasons may be several-fold, including weight gain, menstrual irregularities, headaches, or loss of libido. In contrast, only 2% of women using hormonal IUDs are “somewhat dissatisfied” or “very dissatisfied”, and approximately 5% would not recommend the method. As expected, this rate is higher in women with higher pain scores [ 20 ]. Additional side effects that may lead to LNG-IUS discontinuation include bleeding and/or cramping (5%), acne, and weight change (3%) [ 20 ]. Our findings also align with the European Society of Human Reproduction and Embryology (ESHRE) guidelines, which recommend both ENG implants and LNG-IUS for managing pain associated with endometriosis [ 23 ]. These methods have been shown to reduce pain severity and improve menstrual symptoms, leading to higher satisfaction among women who use them for pain management in endometriosis [ 12 , 24 , 25 ]. However, the limitations of previous studies, such as small sample sizes and variability in pain assessment methods, suggest that further research is needed to clarify the comparative effectiveness of these methods in women with endometriosis. The analysis also highlighted a key distinction between Norplant and Implanon. While both implants are associated with menstrual changes, Norplant tends to result in more frequent and irregular bleeding, leading to a higher discontinuation rate, whereas Implanon is more frequently associated with amenorrhea [ 26 , 27 ]. ENG implants, specifically, have been recognized as a significant aid in reducing pain in women with endometriosis [ 12 , 24 , 25 ]. A systematic review highlighted that they are effective in this scenario, assessed through the visual analog scale (VAS) pain scores, and improving quality of life [ 24 ]. However, the review did not include a comparison group or statistical analysis, and it noted that the small sample sizes and high variability among studies were significant limitations [ 24 ]. This distinction is important for clinicians when counseling patients on long-term contraceptive options, as individual preferences for managing menstrual changes may impact method choice and adherence. This study has several limitations. First, the number of RCTs directly comparing subdermal implants to LNG-IUS was limited, preventing us from conducting meta-regression to explore factors associated with differences between the methods. In addition, most of the included studies did not provide data using standardized bleeding assessment tools, such as the Pictorial Blood Loss Assessment Chart (PBAC), and did not fully elucidate the reasons for treatment discontinuation. Finally, the exclusion of adolescents (patients under 18 years) limits the generalization of our findings to younger populations, who may have different satisfaction profiles and tolerances to side effects. Future research should focus on expanding the comparison between contraceptive methods in adolescent populations and those with specific gynecological conditions, such as severe endometriosis. In addition, studies should adopt standardized tools for assessing menstrual bleeding and pain to provide more robust data for clinical decision-making. Long-term studies are also needed to evaluate the continuation rates and side effects of both methods over a period of 5 or more years.

In 2021, the World Health Organization reported that nearly 900 million women worldwide were in use of modern contraceptive methods [ 1 ]. The most popular methods globally include female sterilization (24%), intrauterine devices (IUDs) (17%), male condoms (21%), and contraceptive pills (16%) [ 2 ]. Although subdermal implants account for only 2% of contraceptive use, they represent a promising option for long-acting reversible contraception (LARC) that does not require frequent maintenance or regular exams [ 3 ]. Consequently, their use is increasing across all regions, with particularly high rates in Sub-Saharan Africa and Oceania (2019).[ 2 ]. Subdermal implants suppress ovulation, enhance cervical mucus thickness, and induces endometrial atrophy [ 4 ]. They have lower 1-year pregnancy rates compared to IUDs (0.6 vs. 2.3 per 100 woman-years) [ 5 ]. Additional advantages include different formulations and doses, being estrogen-free, providing continued protection for 3–5 years [ 3 , 6 ], and the potential for a rapid return to fertility [ 7 ]. Side effects related to subdermal implants may be influenced by prior use of estrogen-containing contraceptive methods, which could result in acne. Furthermore, common side effects include changes in menstrual bleeding, such as amenorrhea, higher risk of noncancerous ovarian cysts, lower sex drive, mood swings, sore breasts, and weight gain [ 7 ]. Subdermal implants and levonorgestrel IUDs are hormone-based methods that offer LARC without the need for daily or monthly attention. They may also be recommended for women with particular gynecological conditions, such as endometriosis [ 8 , 9 ]. While they are attractive for women seeking LARC, a comprehensive comparison between both devices has not yet been conducted. In the absence of contraindications, the choice between methods can be challenging. Thus, we aimed to conduct a systematic review and meta-analysis to compare the outcomes of subdermal implants and levonorgestrel intrauterine system (LNG-IUS).

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