By Aleksei Dingel, MD, and Lisa Bayer, MD, MPH
Synopsis: This study reports on the three-year data from an ongoing Phase III study evaluating the efficacy, safety, and tolerability of a new low-dose copper intrauterine device (IUD), demonstrating low rates of expulsion and discontinuation and expanding the nonhormonal IUD options available in the United States.
Source: Creinin MD, Gawron LM, Roe AH; Copper 175mm2 IUD Phase 3 Clinical Investigator Group. Three-year efficacy, safety, and tolerability outcomes from a phase 3 study of a low-dose copper intrauterine device. Contraception. 2025;143:110771.
According to the Centers for Disease Control and Prevention’s (CDC) 2017-2019 National Survey of Family Growth, 65.3% of women aged 15-49 years in the United States use contraception.1 Of those using contraception, 10.4% are using long-acting reversible contraception (LARC), including the implant and intrauterine devices (IUDs).
Although there are five hormonal IUD options available in the United States, until now there has been only one nonhormonal option available for more than 40 years. This new, low-dose copper IUD increases LARC options within the United States. This study is particularly timely, since there has been a shift in women desiring nonhormonal contraceptive options in the past decade. Specifically, there have been growing patient concerns regarding hormone exposure and various side effects affecting mood, sexuality, physical effects, and fertility.2
This article examined the three-year efficacy, safety, and tolerability outcomes of the new Cu 175 mm2 IUD. The authors reviewed the key features of the new IUD. The new device contains a copper surface area of 175 mm2, which is less than half of the copper load of the TCu380A IUD. The Cu 175 mm2 IUD has a novel flexible frame composed of nitinol, which is a nickel-titanium alloy known for its super-elastic and shape-memory properties, eliminating the risk of plastic breaking with other IUD frames. The inserter has other new properties, including the device being preloaded in the inserter, the inserter tip being tapered to allow for easy passage through the cervix, and the strings being precut. The frame of the IUD also allows for a narrower loaded inserter diameter (3.7 mm) compared to the 4.75 mm diameter of the TCu380A IUD. Prior to this Phase III study, the device underwent two Phase II clinical trials (the first in the Dominican Republic and the second in the United States), which demonstrated the efficacy and safety of the Cu 175 mm2 IUD at one year and three years. Based on these results, the device was advanced to a Phase III clinical trial, the results of which are reviewed here.
This was a Phase III, single-arm clinical trial conducted at 42 sites in the United States with enrollment occurring between August 2018 and August 2019. Results from three years are reported here; there is an extension of the trial for up to eight years of follow-up. Inclusion criteria included postmenarchal, premenopausal individuals at risk of pregnancy up to 45 years of age, history of regular menstrual cycles, sexually active with a male partner who had not had a vasectomy, and planning to have intercourse at least once monthly during the study. There were no weight, body mass index (BMI), or uterine cavity dimension limitations for enrollment.
Participants completed a pain rating scale immediately after IUD placement. The investigators rated the ease of placement of the IUD. Participants then used daily electronic diaries to record bleeding, pain, cramping, vaginal intercourse, and other variables. Participants had four scheduled follow-up visits in year 1 and every six months thereafter, where they completed a urine pregnancy test and IUD presence was confirmed by pelvic examination or transvaginal ultrasound.
To determine the sample size of 1,605 participants (1,480 participants aged ≤ 35 years), a Pearl Index (pregnancies per 100 person-years) of 0.191 to 0.280 for a single-year interval was used. The study evaluated both the intention-to-treat (ITT) population (anyone who underwent IUD placement, regardless of success) as well as the evaluable-for-pregnancy (EP) population (those in the ITT, ≤ 35 years of age, successful placement, at least one follow-up visit with pregnancy status and at least one cycle with intercourse).
The primary outcome was contraceptive efficacy through three years of use in the EP population by calculating the Pearl Index. The Pearl Index was calculated as the number of on-treatment pregnancies per 100 person-years among those ≤ 35 years of age, excluding cycles where participants did not have intercourse or used a backup method. The secondary endpoints included pregnancy rates by life-table analysis, placement success, ease of placement, safety, and tolerability.
Of the 1,620 patients enrolled, 1,601 (98.8%) had a successful IUD placement after one or two attempts. Within the 1,397 patients who made up the EP population, 64% were nulliparous, mean age was 26.5 ± 4.7 years, 72.4% were white, and 69% had a BMI < 30 kg/m2. Of the 1,601 participants who received an IUD, 1,263 (78.9%) and 794 (49.6%) continued use through one and three years, respectively. The one-year Pearl Index was 0.94 (95% confidence interval [CI], 0.43% to 1.95%) and the one-year life-table pregnancy rate was 2.47% (95% CI, 1.34% to 3.6%). The cumulative three-year life-table pregnancy rate was 2.47% (1.34% to 3.60%).
In the ITT population, pain with insertion was rated as none (5.3%), some pain (22.7%), moderate pain (41.3%), painful (25.4%), or very painful (5.3%). Most investigators reported the placement as very easy (52.5%) or easy (31.2%). Mechanical dilation with the first placement attempt was required in 17.5%, most frequently in nulliparous participants (P < 0.001). Nine participants were later found to have embedded IUDs.
The most reported adverse effects (AEs) were heavy menstrual bleeding (77.9%), dysmenorrhea (73.3%), pelvic discomfort (34.6%), and intermenstrual bleeding (30.7%). The participants reporting pain, bleeding, or both AEs decreased over time, with 88.2% in the first three months, 57.9% in months 4 to 12, 27% in year 2, and 17.7% in year 3. Over three years, 353 (22%) participants discontinued the study as the result of an AE. Overall, 15% of participants reported bleeding, pain, or both as the primary reason for discontinuation, with the frequency of discontinuation decreasing over time. Expulsions were low at 2.2% at year 1 and 3.9% overall. There were eight serious AEs, including five ectopic pregnancies, one uterine hemorrhage, one anemia, and one uterine perforation.
Commentary
The Cu 175 mm2 IUD was approved by the U.S. Food and Drug Administration (FDA) in February 2025 under the name Miudella. There are several features of the IUD that are appealing to both patients and clinicians. Although a head-to-head trial with the TCu380A is not available, one can draw some conclusions. Pregnancy rates appear to be similar between the two nonhormonal IUDs. For the Cu 175 mm2 IUD, the life-table pregnancy rate was 1.26% (95% CI, 0.57% to 1.95%) and 2.47% (95% CI, 1.34% to 3.60%) over one and three years, respectively. These pregnancy rates for the TCu380A IUD are reported at 0.7% in the first year and 1.8% cumulatively at three years.3 Although bleeding, pain, or both commonly were reported in the first year of use for the Cu 175 mm2, the rate of discontinuation for these reasons during this first year were low at 8.6%, which is lower than that reported for the TCu380A (11.9%).
It is plausible that the lower copper exposure results in a more favorable side effect profile. The Cu 175 mm2 IUD also has a smaller inserter and has the potential to cause a less painful placement than the TCu380A. However, the fact that 17.5% of patients required mechanical dilation was higher than cited previously in the literature for IUD insertions and bears further study for this device. Lastly, unlike the TCu380A device, which is made of a plastic frame and needs to be loaded by the clinician, the Cu 175 mm2 IUD comes preloaded and is made from material that is not at risk of fracturing or breaking during the removal process, a trend that is rare but is reported increasingly.4
There still is much to learn about this new IUD. It is important to note that only the TCu380A IUD is approved to be used for emergency contraception. In addition, the Cu 175 mm2 is only approved for three years of use, while the TCu380A is FDA-approved for 10 years. However, it is likely that the Cu 175 mm2 IUD’s duration of use will be extended with the ongoing trial. Secondary analyses from this trial still are underway and will provide additional insights into the Cu 175 mm2 IUD, such as trends in bleeding patterns over time.
The Cu 175 mm2 IUD brings a new nonhormonal LARC option to the United States, which is desired by patients. Nonhormonal contraceptives provide important options for patients with contraindications to hormones, such as hormone-sensitive cancers.5 They also provide options for patients who are wary of hormonal contraceptive side effects or who want to maintain their natural hormone levels. Most nonhormonal contraceptive options, such as barrier methods or spermicide, carry a higher failure rate. It is exciting that a new nonhormonal option that also is highly effective is available in the United States.
Aleksei Dingel, MD, is an OB/GYN Resident Physician, 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. Daniels K, Abma JC. Current contraceptive status among women aged 15-49: United States, 2017-2019. NCHS Data Brief. 2020;(388):1-8.
2. 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.
3. CooperSurgical, Inc. Paragard (intrauterine copper contraceptive) prescribing Information. Revised February 2020. https://www.paragard.com/pdf/PARAGARD-PI.pdf
4. Latack KR, Nguyen BT. Trends in copper versus hormonal intrauterine device breakage reporting within the United States’ Food and Drug Administration Adverse Event Reporting System. Contraception. 2023;118:109909.
5. Nguyen AT, Curtis KM, Tepper NK, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2024. MMWR Recomm Rep. 2024;73(4):1-126.
