By Alexandra Morell, MD
Synopsis: This Phase III randomized clinical trial demonstrated a three-year cumulative pregnancy rate of 4.8% (95% confidence interval, 2.75 to 6.86) for the NTCu380 mini intrauterine device (IUD), with similar discontinuation rates between the mini copper IUD and the TCu380A standard copper IUD (51.3% vs. 57.3%, P = 0.07), but fewer discontinuations for bleeding and pain for the mini copper IUD (14.5% vs. 27.3%, P < 0.001).
Source: Schreiber CA, Nanda K, Hubacher D, et al. Contraceptive efficacy and comparative side effects of a mini copper intrauterine device. NEJM Evid. 2025;4(8):EVIDoa2400480.
There are two main categories of intrauterine devices (IUDs): hormonal IUDs containing levonorgestrel and nonhormonal IUDs containing copper.1 Copper IUDs, first introduced in 1988, are approved for up to 10 years of contraceptive use. Their contraceptive effect is achieved through the continuous release of copper ions, which create a hostile intrauterine environment for sperm and thereby impair fertilization.2 Beyond their role in long-term contraception, copper IUDs also are the most effective method of emergency contraception. In the United States, the first Food and Drug Administration (FDA)-approved nonhormonal IUD was the TCu380A, marketed as Paragard. Recently, Miudella, a three-year nonhormonal IUD, was approved in the United States.3 Internationally, there are several other copper IUDs available.
This was a multicenter, participant-masked, Phase III randomized clinical trial conducted at 16 sites in the United States to evaluate the contraceptive efficacy of the NTCu380 mini IUD (mini Cu IUD) and to compare safety and discontinuation rates with the standard TCu380A copper IUD (standard Cu IUD). The mini Cu IUD measures 2.4 cm across the horizontal arms and 3.0 cm along the vertical stem, with copper wire applied exclusively to the stem, providing a total copper surface area of 380 mm2. In contrast, the standard Cu IUD measures 3.2 cm by 3.6 cm, with copper distributed on both the arms and the stem, also totaling 380 mm2 of copper surface area.
Eligible participants were women aged 16 to 40 years with regular menstrual cycles (12 to 35 days), heterosexual vaginal intercourse at least once per month, and no concurrent use of other contraceptives. Exclusion criteria included abnormal cervical cytology requiring treatment, human immunodeficiency virus (HIV) infection, known infertility, prior tubal ligation, contraindications to copper IUD use, or intention to conceive within 37 months. At the time of enrollment, participants found to have a uterine length < 5.5 cm also were excluded.
Participants were randomized 4:1 to the mini Cu IUD or standard Cu IUD, with all providers trained in placement of both devices. Following insertion, pain was assessed using visual analog scales (VAS) immediately and 10 minutes post-procedure. Clinical follow-up occurred at six weeks and at three, six, 12, 24, and 37 months, with urine pregnancy testing performed at each visit. Mini Cu IUDs were removed at 37 months, while participants randomized to the standard Cu IUD arm could continue use under the discretion of their own care provider.
The primary endpoint was contraceptive efficacy of the mini Cu IUD, expressed as the Pearl Index (number of pregnancies per 100 woman-years), overall and by year of use. Secondary endpoints included adverse events (pelvic pain and bleeding), continuation rates, expulsion rates, and accidental IUD removal. Statistical analyses included Fisher’s exact or Cochran-Mantel-Haenszel tests for categorical variables, Mann-Whitney or analysis of variance (ANOVA) for continuous measures, and Kaplan-Meier with log-rank tests for discontinuation rates.
A total of 1,105 participants were enrolled (887 mini Cu IUD; 218 standard Cu IUD), with 15 not undergoing attempted insertion (10 mini Cu IUD; five standard Cu IUD). The majority (83.9%) were nulliparous in both groups. The three-year cumulative Pearl Index for the mini Cu IUD was 1.86 pregnancies per 100 woman-years (95% confidence interval [CI], 1.20 to 2.74), with yearly rates of 0.98 (95% CI, 0.36 to 2.13) in year 1, 1.65 (95% CI, 0.66 to 3.39) in year 2, and 3.91 (95% CI, 2.02 to 6.84) in year 3.
Among women ≤ 35 years of age, the three-year cumulative pregnancy rate for the mini Cu IUD was 4.80% (95% CI, 2.75 to 6.86). Although the trial was not powered for direct comparison, the cumulative three-year pregnancy rate for the standard Cu IUD was 2.52% (95% CI, 0.00 to 6.06). Post-hoc analysis regarding menstrual cup use demonstrated three-year Pearl indices of 1.67 (95% CI, 0.97 to 2.67) and 2.18 (95% CI, 0.88 to 4.49) for mini Cu IUD users who did not use vs. used menstrual cups, respectively. On post-hoc analysis regarding uterine cavity length, three-year Pearl indices were 1.56 for cavity length ≤ 8 cm (95% CI, 2.75 to 6.86) vs. 4.98 (95% CI, 2.75 to 6.86) for > 8 cm.
Rates of serious adverse events were similar between the two groups, with 3.5% (n = 31) in the mini Cu IUD group vs. 1.9% (n = 4) in the standard Cu IUD group, P = 0.28. Median VAS pain scores immediately after insertion were 4.9 in both groups. Prolonged bleeding episodes occurred in 60.1% of mini Cu IUD users and 59.7% of standard Cu IUD users (P = 0.70). At three years, discontinuation rates were 51.3% for the mini Cu IUD and 57.3% for the standard Cu IUD (P = 0.07). The most common reason for discontinuation was adverse effects, reported in 20.8% (95% CI, 17.4 to 24.2) of mini Cu IUD users and 33.2% (95% CI, 25.3 to 41.1) of standard Cu IUD users. Discontinuation specifically for bleeding or pelvic pain was significantly lower among mini Cu IUD users compared with standard Cu IUD users (14.5% vs. 27.3%, P < 0.001).
Commentary
The T380A standard copper IUD is a highly effective form of contraception, with a 10-year failure rate of 1.9 per 100 women and is effective immediately after placement.4 It is FDA-approved for 10 years in the United States, but there is evidence that its contraceptive efficacy extends beyond the approved time duration.5 In addition, the standard copper IUD remains the most effective option for emergency contraception and can be placed up to five days after unprotected intercourse.4 Contraindications to using a copper IUD include uterine cavity anomalies, active pelvic inflammatory disease, postpartum or post-abortal endometritis within 12 weeks of placement, known cervical or uterine cancer, and Wilson’s disease.6
The current study evaluated the NTCu380 mini copper IUD and reported a three-year cumulative pregnancy failure rate of 4.8%. Notably, the 2.52% three-year cumulative pregnancy rate for the standard copper IUD in this trial is higher than previously published rates for the TCu380A, which generally have reported less than 1% annual failure.1,4 In addition, the study was not powered for direct head-to-head comparison, so although these findings suggest the mini Cu IUD may have a higher failure rate than the standard Cu IUD, the difference should be interpreted with caution given the study design. An adequately powered study comparing the efficacy of both devices could be helpful in the future.
Interestingly, although overall discontinuation rates did not differ significantly between the two copper IUDs (51.3% mini Cu IUD vs. 57.3% standard Cu IUD), discontinuation due to bleeding or pelvic pain was significantly less frequent in the mini Cu IUD group. The American College of Obstetricians and Gynecologists (ACOG) recommends that women are counseled regarding the possibility of worsening bleeding and menstrual cramping after placement of a copper IUD, but that these symptoms typically decrease over time.4 Irregular bleeding is thought to result from increased prostaglandin and fibrinolytic activity in the endometrium and a transient “burst” in copper concentration immediately following insertion.2 Nonsteroidal anti-inflammatory medications are considered first-line for therapy. These medications inhibit COX-1 and COX-2 to decrease prostaglandin release.2 Other potential options for treatment include tranexamic acid or combined oral contraceptive pills.
Although the NTCu380 mini copper IUD currently is not available in the United States, in February 2025, the FDA approved Miudella, a three-year copper IUD, for use in the United States.6 Miudella contains 175 mm2 of copper surface area compared to the 380 mm2 in both the mini and standard Cu IUDs. The cumulative three-year pregnancy rate of Miudella was 2.47% and a clinical trial is ongoing to evaluate efficacy up to eight years.6 Compared to Paragard, Miudella is smaller in size, has lower copper content, and is approved for shorter duration of use. It is not clear if Miudella offers the same potential benefit of fewer discontinuations related to irregular bleeding as the NTCu380 mini Cu IUD, but this warrants further investigation. Nonetheless, Miudella represents the only additional nonhormonal IUD option available in the United States beyond Paragard and may provide a valuable alternative in select clinical scenarios, although its specific advantages over Paragard have yet to be established.
Alexandra Morell, MD, is Adjunct Instructor, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY.
References
1. Whaley NS, Burke AE. Intrauterine contraception. Womens Health (Lond). 2015;11(6):759-767.
2. Castillo K, Zambrano K, Barba D, et al. Long-acting reversible contraceptives effects in abnormal uterine bleeding, a review of the physiology and management. Eur J Obstet Gynecol Reprod Biol. 2022;270:231-238.
3. [No authors listed]. Miudella — a lower-dose copper IUD. Med Lett Drugs Ther. 2025;67(1730):89-90.
4. Committee on Practice Bulletins–Gynecology, Long-Acting Reversible Contraception Work Group. Practice Bulletin No. 186: Long-acting reversible contraception: Implants and intrauterine devices. Obstet Gynecol. 2017;130(5):e251-e269.
5. Dethier D, Qasba N, Kaneshiro B. Society of Family Planning clinical recommendation: Extended use of long-acting reversible contraception. Contraception. 2022;113:13-18.
6. Paragard prescribing information. CooperSurgical, Inc.;2024. https://www.paragard.com/pdf/PARAGARD-PI.pdf
