By Emily Wolverton, MD, and Lisa Bayer, MD, MPH
Synopsis: This secondary analysis compares the incidence of hormone-related side effects of the levonorgestrel 52-mg intrauterine device (IUD) between users who previously were using combined hormone contraceptives vs. nonhormonal contraceptives to understand which side effects can be directly attributed to the IUD and which are more likely secondary to discontinuation of combined hormonal contraceptives.
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
Clinical trials for new contraceptives require that participants are sexually active and desire prevention of pregnancy. This means these participants often discontinue an alternative contraceptive method before starting the trial medication. This discontinuation of contraceptives may introduce a confounding variable, since there are side effects associated with stopping certain contraceptives. This study analyzes differences in side effects experienced by participants who discontinued combined hormonal contraceptives (CHCs) compared to those previously using nonhormonal contraceptive (NHC) methods before starting use of the levonorgestrel 52-mg intrauterine device (IUD). The aim of this review is to discern which nonbleeding and non-expulsion hormone-related side effects are caused by the initiation of the IUD vs. the discontinuation of a different hormonal contraceptive.
This report is a secondary analysis from data collected in a multicenter (29 sites) prospective trial of healthy nonpregnant 16- to 45-year-old women interested in initiation of a hormonal IUD. Participants collected information in daily diaries to record symptoms and attended clinical visits at one, three, six, and 12 months, with a phone visit at nine months. Exclusion criteria included the use of a prior progestin-only method. Data analysis focused primarily on nonbleeding-related and non-expulsion adverse events that could represent a hormone-related side effect in the first 180 days of levonorgestrel IUD use. Secondary evaluation through 12 months from placement was performed for all events with a P-value of < 0.2. Adverse effect frequency also was reviewed and correlated to IUD discontinuation to understand how bothersome these side effects were to affected individuals.
To compare proportions, Fisher exact and chi-square tests were used. Multivariable regression models evaluated the correlation between adverse effects and the use of prior CHC or NHC based on age, body mass index (BMI), parity, race, and ethnicity. Statistical significance was determined to be a P-value of 0.05.
Overall, 644 participants used CHC prior to IUD placement and 855 used NHC. When examining the results, it is important to note the statistically significant difference in demographics between populations using CHCs and NHCs, which may introduce confounding factors. NHC users were more likely to be non-white (26.9% vs. 15.4%) and have a BMI higher than 30 kg/m2 (28.3% vs. 20.2%) compared to CHC users. A larger proportion of CHC users were nulliparous compared to NHC users (72.4% vs. 51.6%) as well as younger than age 25 years at the time of enrollment (41.6% vs. 36%).
The five most frequently reported side effects over the first 180 days of IUD use included acne (10.5%), nonmigraine headache (5.7%), mood changes (4.5%), breast pain/tenderness (4.5%), and dyspareunia (4.3%). Of all the side effects examined after initiation of the levonorgestrel IUD, only acne had a statistically significant difference between prior CHC vs. NHC users (13.0% vs. 8.5%, P = 0.006). Orgasm/libido problems almost reached statistical significance between prior CHC vs. NHC users (2.0% vs. 0.8%, P = 0.07). Multivariable modeling subsequently was performed to evaluate factors associated with reporting acne or orgasm/libido issues during the first six months of IUD use. When adjusted odds of acne were examined for CHC vs. NHC users, there no longer was a significant difference (odds ratio [OR], 1.40; 95% confidence interval [CI], 0.99-1.98). However, there were significantly higher adjusted odds of acne in both obese (70%) and nulliparous participants (60%). No factors were associated with orgasm/libido issues.
Side effects with a P < 0.2 between CHC and NHC users at 180 days also were examined at 360 days: acne (12.8%), breast pain/tenderness (5.3%), mood changes (5.2%), weight increase/poor weight loss (3.6%), orgasm/libido problems (2.1%), and alopecia (1.7%). During this time, rates increased for acne (10.5% to 12.8%), with more CHC than NHC users reporting acne at 360 days (15.7% vs. 10.6%, P = 0.005). Rates also increased for orgasm/libido problems (1.3% to 2.1%) at 360 days, with more CHC than NHC users reporting orgasm/libido problems (3.1% vs. 1.4%, P = 0.03).
Beyond incidence alone, the authors of this review also examined the number of days affected individuals experienced any given side effect. Among the first 180 days, CHC users reported acne on average for 13 days (7.4%) and NHC users (P < 0.001) reported it for nine days. However, those who experienced acne noticed it for more than half of the first 180 days of IUD use (CHC [n = 84], 99.2 days and NHC [n = 73], 100.4 days). This was not statistically different.
Although reported by few, some individuals did experience other side effects for 100 or more days within the first 180 days of IUD use. These side effects include alopecia in CHC users (n = 12, 102.9 days), anxiety/panic in CHC users (n = 9, 100.9 days), orgasm/libido problems (CHC [n = 12], 106.1 days and NHC [n = 7], 110.6 days), and weight increase/poor weight loss in NHC users (n = 27, 110.3 days).
Overall, side effects leading to discontinuation of the levonorgestrel IUD in the first 180 days were rare and not different between CHC and NHC users (5.6% vs. 5.5%, P = 1.0). The highest discontinuation rates for side effects included mood changes (n = 17, 1.1%), acne (n = 15, 1.0%), pelvic pain/discomfort (n = 13, 0.9%), weight increase/poor weight loss (n = 10, 0.7%), and nonmigraine headache (n = 5, 0.3%).
Commentary
Clinicians and patients often place different values on the benefits and risks of various contraceptives. Some clinicians may prioritize contraceptive effectiveness, resulting in coercive practices that compromise reproductive autonomy.1 Clinicians also can bring bias to their contraceptive counseling based on patient, cultural, and other factors.2 On the other hand, patients value a shared decision-making conversation with their clinician regarding contraception, reporting increased satisfaction over selecting a method alone or being assigned a method by their clinician.3 The American College of Obstetricians and Gynecologists echoes this value, stating, “OB/GYNs should adhere to the recommended ethical approach of shared decision-making through patient-centered contraceptive counseling.”4
A critical aspect of contraceptive counseling is providing a comprehensive discussion of side effects to allow patients to choose the best contraceptive for their individual needs. Clinicians can seek to understand the priorities of their patient when counseling about contraceptive options by asking a question such as, “What is important for you in a birth control method?” Hormonal side effects play an important role in the patient’s contraceptive decision-making.5 However, it can be difficult to discern discontinuation vs. initiation side effects when individuals transition from one type of contraception to another.
It is well established that CHCs can be used effectively for the treatment of acne.6,7 Thus, it can be postulated that new side effects related to acne after transitioning from CHCs to another form of birth control may, in fact, be secondary to CHC discontinuation. One retrospective analysis of a commercial claims database showed similar rates of acne among patients who switched from CHCs to either the levonorgestrel or copper IUD, supporting this idea.8
This study can help clinicians better counsel patients about expected hormonal side effects when starting the levonorgestrel 52-mg IUD, specifically for those who are switching from a CHC or NHC. In this study, acne was the most common nonbleeding side effect, with rates increasing over time from 180 to 360 days, especially for prior CHC users. However, the discontinuation rate of the IUD because of acne was relatively low, implying low severity of symptoms. Moreover, non-obese and parous participants had ~40% lower odds of reporting acne with levonorgestrel IUD use, indicating that characteristics other than prior contraceptive method may play a more important role. Other hormonal side effects were less common (occurring < 6%) in this study and did not result in discontinuation of the IUD for most individuals. However, patients prioritize side effects in individual ways, and these priorities should be explored with the patient and addressed by the clinician. Clinicians can use this research when counseling patients about hormonal side effects of the levonorgestrel 52-mg IUD and provide anticipatory guidance of side effects during the first six to 12 months of use.
Emily Wolverton, MD, is a resident physician, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR.
Lisa Bayer, MD, MPH, is Associate Professor, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR.
References
1. Higgins JA, Kramer RD, Ryder KM. Provider bias in long-acting reversible contraception (LARC) promotion and removal: Perceptions of young adult women. Am J Public Health. 2016;106(11):1932-1937.
2. Soin KS, Yeh PT, Gaffield ME, et al. Health workers’ values and preferences regarding contraceptive methods globally: A systematic review. Contraception. 2022;111:61-70.
3. Dehlendorf C, Grumbach K, Schmittdiel JA, Steinauer J. Shared decision making in contraceptive counseling. Contraception. 2017;95(5):452-455.
4. The American College of Obstetricians and Gynecologists. Patient-centered contraceptive counseling. Published February 2022. https://www.acog.org/clinical/clinical-guidance/committee-statement/articles/2022/02/patient-centered-contraceptive-counseling
5. Le Guen M, Schantz C, Régnier-Loilier A, de La Rochebrochard E. Reasons for rejecting hormonal contraception in Western countries: A systematic review. Soc Sci Med. 2021;284:114247.
6. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: A randomized, placebo-controlled trial. Obstet Gynecol. 1997;89(4):615-622.
7. Koltun W, Maloney JM, Marr J, Kunz M. Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 μg plus drospirenone 3 mg administered in a 24/4 regimen: A pooled analysis. Eur J Obstet Gynecol Reprod Biol. 2011;155(2):171-175.
8. Barbieri JS, Mitra N, Margolis DJ, et al. Influence of contraception class on incidence and severity of acne vulgaris. Obstet Gynecol. 2020;135(6):1306-1312.
This secondary analysis compares the incidence of hormone-related side effects of the levonorgestrel 52-mg intrauterine device (IUD) between users who previously were using combined hormone contraceptives vs. nonhormonal contraceptives to understand which side effects can be directly attributed to the IUD and which are more likely secondary to discontinuation of combined hormonal contraceptives.
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