By Rebecca H. Allen, MD, MPH, Editor
Synopsis: In this secondary analysis of the ACCESS IUS trial, participants who used combined hormonal contraceptives compared to nonhormonal contraceptives prior to enrolling were more likely to complain of acne in the first six months (13% vs. 8.5%, P = 0.006) and 12 months (15.7% vs. 10.6%, P = 0.005) of levonorgestrel intrauterine device use. Overall, the rate of discontinuation in the first six months because of adverse events was 5.5%, with no difference between the two groups.
Source: Kerns JL, Keder LM, Cwiak CA, et al. Hormone-related side effects in new users of a levonorgestrel 52-mg intrauterine device. Am J Obstet Gynecol. 2024;231(6):628.e1-628.e10
The amount of systemic exposure to levonorgestrel while using the 52-mg intrauterine device (IUD) is low. Nevertheless, some patients report hormonal side effects. The authors of this study sought to estimate the rate of these adverse events.
This was a secondary analysis of data from A Comprehensive Contraceptive Efficacy and Safety Study of an Intrauterine System (ACCESS IUS) trial, which was a multicenter U.S. study evaluating a novel 52-mg levonorgestrel (LNG) IUD (brand name: Liletta).1 In this study, healthy, sexually active women aged 16 to 45 years with regular menstrual cycles who desired contraception were included. Over the course of the first year after IUD placement, participants were followed with paper diaries, in-person visits (at one, three, six, and 12 months), and a phone call (at nine months). Each time, patients were asked about any health concerns or adverse events. The primary aim of this analysis was to assess adverse events unrelated to bleeding or expulsion in the first 180 and 360 days of IUD use.
Participants who used progestin-only contraception in the month prior to enrollment were excluded. The primary outcome was the rate of hormone-related adverse events among all participants, with a comparison between those who had used a combined hormonal contraceptive (CHC) in the month prior to enrollment to those who had used no contraception or nonhormonal contraception (NHC) in the month prior to enrollment. Complaints of upper respiratory or gastrointestinal illness, vulvovaginal infections or pruritis, cervical dysplasia, contusion, insomnia, back pain, dizziness, and presyncope were excluded as nonhormonally related.
Overall, 1,499 subjects were included in this analysis. Of those, 1,369 (91.3%) and 1,237 (82.5%) continued IUD use at six and 12 months, respectively. A total of 644 participants had used CHC in the month before enrollment (pill, 77.5%; ring, 21.1%; patch, 1.4%). Those who used NHC were more likely to be older (age 25-45 years, 65% vs. 58.4%) and parous (48.4% vs. 27.6%).
For the entire study population, at six months, the most common side effects reported were acne (10.5%), headache (5.7%), breast tenderness (4.5%), mood changes (4.5%), dyspareunia (4.3%), pelvic pain (4.1%), and vaginal odor (3.7%). Over the first six months, acne was the only side effect that statistically differed between subjects who had used CHC prior to enrollment and those who had used NHC (13% vs. 8.5%, P = 0.006). At 12 months, prior CHC users continued to report more acne (15.7% vs. 10.6%, P = 0.005) and orgasm/libido problems (3.1% vs. 1.4%, P = 0.03). Discontinuation because of side effects in the first six months occurred in only 83 (5.5%) subjects, with no difference between those who used CHC and those who used NHC. The only side effects where discontinuation rates were 1% or more were mood changes (1.1%) and acne (1.0%).
Commentary
The 52-mg LNG-IUD is a highly effective contraceptive with high satisfaction and continuation rates.2 The authors of this study hypothesized that some early hormonal side effects of the LNG-IUD may be the result of the recent discontinuation of combined hormonal contraceptives. They ultimately found that only acne at six months and acne and libido at 12 months were statistically significantly different between those who had used CHC prior to study enrollment and those who had used NHC prior to study enrollment. The authors hypothesized that while using CHC, the patient’s acne had been treated, and when they switched to the LNG-IUD, they were more likely to notice a return of their acne. This makes clinical sense.
Overall, the study had strengths with prospective data collection of side effects and a diverse patient population across the United States. These data can help clinicians counsel patients who are considering the 52-mg levonorgestrel IUD for contraception. As per the study, the most common hormonal side effects reported were acne, headache, breast tenderness, mood changes, dyspareunia, pelvic pain, and vaginal odor. But only 5.5% of subjects thought these side effects were bothersome enough to request IUD removal.
Other important factors to counsel patients about when considering IUD insertion are the risks of bleeding, infection, uterine perforation, expulsion, and failure.3 The 52-mg levonorgestrel IUD also can be associated with unscheduled bleeding in the first three to six months of use. Ultimately, however, it reduces menstrual blood loss significantly for most patients by 79% to 97%. Limitations of the study include the fact that the populations of former CHC and NHC users were very different at baseline.
In sum, patients can be reassured that the risk of systemic hormonal side effects with the 52-mg LNG-IUD is low. For patients who end up being bothered by side effects, they could opt to switch to a lower dose LNG-IUD, such as the 19.5-mg LNG-IUD (Kyleena) or the 13.5-mg LNG-IUD (Skyla), or to the copper IUD.
References
1. Teal SB, Turok DK, Chen BA, et al. Five-year contraceptive efficacy and safety of a levonorgestrel 52-mg intrauterine system. Obstet Gynecol. 2019;133(1):63-70.
2. American College of Obstetricians and Gynecologists. Long-acting reversible contraception implants and intrauterine devices. Practice Bulletin No. 186. November 2017. (Replaces Practice Bulletin Number 121, July 2011. Reaffirmed 2024.) https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2017/11/long-acting-reversible-contraception-implants-and-intrauterine-devices
3. Varma R, Sinha D, Gupta JK. Non-contraceptive uses of levonorgestrel-releasing hormone system (LNG-IUS) — a systematic enquiry and overview. Eur J Obstet Gynecol Reprod Biol. 2006;125(1):9-28 .
In this secondary analysis of the ACCESS IUS trial, participants who used combined hormonal contraceptives compared to nonhormonal contraceptives prior to enrolling were more likely to complain of acne in the first six months (13% vs. 8.5%, P = 0.006) and 12 months (15.7% vs. 10.6%, P = 0.005) of levonorgestrel intrauterine device use. Overall, the rate of discontinuation in the first six months because of adverse events was 5.5%, with no difference between the two groups.
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