Contraception year in review 2025

In this update, we will focus on important new studies of copper intrauterine devices (IUDs) that have been published in the past year. The copper 380mm² IUD (TCu380A, Paragard), has been the only non-hormonal long-acting reversible contraception available in the United States, first marketed in 1988. TCu380A use can be limited by side effects of increased bleeding and cramping, leading to discontinuation rates of up to 21% within 12 months and 36% within 24 months of placement.¹ Patients with the highest discontinuation rates are young, nulliparous users.² The TCu380A is the largest copper IUD available worldwide (32mm wide and 36mm long), and its frame, a Tatum-T design, is less flexible than other similar frames, like the Nova-T.³ One or both of these frame characteristics may be responsible for these side effects.

In contrast to the United States, there is a vast array of other copper IUDs available worldwide. This discrepancy is related to regulatory approval requirements. In Europe, the European Medicines Agency considers IUDs as devices which means that approval and marketing can occur based on known similarities with established devices without product-specific efficacy and safety trials.⁴ However, the FDA considers an IUD as a combination drug/device and requires clinical trials to prove outcomes, limiting the speed of approval. As a result, the TCu380A has been the only non-hormonal IUD available in the United States until this year.

Pregnancy rates with the TCu380A with both older and more contemporary studies are demonstrated in Table 1.^{2-3, 5-11} Early studies consistently demonstrate pregnancy rates of <1% per year as reported in the product label with rates of 0.7%, 0.3%, and 0.6% in years 1, 2, and 3, respectively.¹² However, these studies have some limitations, most importantly lack of specified inclusion of nulliparous patients (2 did not specify how many nulliparous patients they included but reported participants’ mean live births which exceeded 1 in both studies). They also all have an average age of participants of more than 25 years. These characteristics limit their generalizability in contemporary IUD users, which include young, nulliparous persons. A systematic review including these studies compared different types of copper IUDs and concluded that TCu380A is more effective than other copper IUDs.¹³ However, this review grouped TCu380Ag (a different copper IUD) results together with TCu380A, making these results difficult to interpret. Given the limitations of earlier studies, clinicians need to be aware of more recent efficacy data when counseling patients.

More contemporary studies have consistently demonstrated higher pregnancy rates with TCu380A use than previously reported. A 2016 trial included 1871 parous TCu380A users with pregnancy rates of 1.53% and 2.45% at 3 and 7 years, respectively.² Several additional recent studies demonstrate the pregnancy rates with TCu380A to be even higher. A recent trial in nulliparous United States users demonstrated a cumulative 3-year pregnancy rate of 2.52% for TCu380A, the only study in the past 5 years with data on TCu380A efficacy.³ This rate aligns with the results of another large international study reported in 2015 with mostly multiparous patients estimating 1- and 3- year cumulative pregnancy rates of 1.1% and 2.8% respectively.¹¹ These 3 more contemporary studies demonstrate a higher pregnancy rate with TCu380A use than previously reported. They also show that TCu380A is less effective than hormonal IUDs, especially the levonorgestrel 52mg IUDs, which have a reported cumulative 8-year pregnancy rate of 1.3%.¹⁴ A meta-analysis of randomized controlled trials comparing copper vs levonorgestrel IUDs also showed lower rates of pregnancy with levonorgestrel IUDs.¹⁵

In this past year, two studies reported outcomes with two novel copper IUDs, both smaller and with a different frame shape than the TCu380A (Figure 1). Both studies were performed with the hopes of finding alternatives to the TCu380A that maintained efficacy but with fewer side effects.

The copper 380mm² Mini IUD

The copper 380mm² Mini (NTCu380 Mini, Mona Lisa Mini) is available in Europe and Canada. It is smaller (24mm horizontal by 30mm vertical) than the TCu380A and uses a more flexible Nova-T frame. The copper exposure (380mm²) is the same as the TCu380A; however, whereas a significant portion of the copper for the T380A is in bands on the IUD arms, the NTCu380 Mini localizes all of the copper on the IUD stem.¹⁶ A randomized trial comparing the NTCu380 Mini with the TCu380A showed lower rates of discontinuation due to side effects in nulliparous users (especially bleeding and cramping) for the NTCu380 Mini compared to the TCu380A, with similar safety outcomes and insertion pain of the two devices.¹⁷ However, the NTCu380 Mini had a 3-year cumulative pregnancy rate of 4.8% compared to 2.5% for the TCu380A, although the study was not powered to detect a difference.³ This higher pregnancy rate likely presents a significant limitation of the device, despite the benefit of the improved side effect profile.

Prior to this study, no clinical trial efficacy and safety data specifically for this IUD was available even though it is marketed outside the United States. The manufacturers cite a pregnancy rate of 1.9% to 4.4% at 5 years based on two efficacy studies from the early 2000s from a different IUD (NTCu380, Mona Lisa Standard).¹⁶ Given the type of approval process outside the United States, patients and clinicians may not be able to make an informed choice that takes side effects and efficacy into account. These studies demonstrate the importance of clinical trials for patients and clinicians to accurately compare efficacy and side effects between products.

The copper 175mm² IUD

The copper 175mm² IUD (Miudella, study name Veracept) was approved by the FDA in February 2025¹⁸ with plans for marketing in late 2025 or early 2026. The frame is composed of Nitinol (a nickel and titanium alloy), the same material used for cardiac stents, which has a forever memory, allowing the IUD to be pre-loaded in an inserter narrower than other marketed IUDs.¹⁸ The frame shape is similar to Nova-T frames and contains copper beads strategically in the areas of the internal cervical os and uterine cornua, resulting in a copper surface area less than half of the TCu380A. The thread is pre-cut so that when the IUD inserter is removed, few clinicians will need to cut the thread. The developers hoped that this frame design with less copper would lead to high efficacy with decreased side effects.

A single-arm phase 3 trial of 1620 patients was conducted in the United States which demonstrated a 3-year cumulative pregnancy rate of 1.26% with 15.4% discontinuing the device over 3 years due to side effects of bleeding and pain, a lower rate of discontinuation than has been historically reported for TCu380A.¹⁹ The device is currently FDA approved for 3 years (18), although research is ongoing to extend its efficacy with the study planned for 8 years.²⁰

The copper 175mm² IUD is approved under a Risk Evaluation and Mitigation Strategy (REMS) program, requiring providers to undergo product-specific training and become certified prior to use and requires pharmacies to only dispense it to a certified provider,¹⁸ which may present a barrier to access. The FDA required this training program because the inserter, which uses sliders like other currently available IUDs, has one extra step to release the IUD as compared to other inserters. For other IUDs, when the slider(s) are moved to the bottom of the inserter handle, the IUD is released within the uterine cavity, and the inserter can be safely removed. However, because the copper 175mm² IUD is pre-loaded and has a pre-cut thread, a separate retention thread is present to hold the IUD within the insertion tube (pre-loading) and is attached to a cap at the bottom of the inserter. Thus, once the sliders are moved to the bottom of the insertion handle, the cap needs to be rotated one-quarter turn, pulled off the end of the insertion handle, and the retention thread pulled out completely before removing the inserter from the uterus. The FDA believes this training is necessary to decrease the likelihood of having a failed insertion (pulling the IUD out with the inserter), which could result in the need for multiple procedures or, if not recognized, pregnancy. Requiring training mimics the phase 3 trial where all investigators were trained and certified on placement.¹⁹ Unfortunately, this requirement may limit access for patients; while some other long-acting reversible contraceptives have training programs designed by the manufacturer with the FDA, none are limited by a REMS.

The initial approval for the copper 175mm² IUD is based on 3-year data.¹⁸ Overall, however, the copper 175mm² IUD compares favorably to TCu380A; although pain and bleeding remain negative side effects for the copper 175mm² IUD, the lower rates compared to historical data for the TCu380A combined with high efficacy at 3 years suggest that this is a safe and effective additional option for long-acting non-hormonal contraception. For both clinicians and patients, the phase 3 study is still ongoing with all enrolled participants through 5 years of follow-up and plans to continue through 8 years.²⁰

What does this new data mean for copper IUDs?

While the copper 175mm² IUD will be marketed in the United States soon, it is less likely we will also see the NTCu380 Mini, primarily because of the higher-than-expected pregnancy rate. Understanding the findings from these studies and the design differences among all 3 of these copper IUDs provides important lessons to guide investigation and device development as well as clinical use.

The high efficacy of both the copper 175mm² and TCu380A IUDs in which both have copper concentrated at the cornual regions, compared to the NTCu380 Mini, which has the same amount of copper as the TCu380A but only on the stem, implies that the location of the copper is potentially more important for efficacy than the dose/exposure area. This conflicts with prior thoughts that there is a direct correlation between copper dose and efficacy. Of note, higher copper content IUDs typically had additional copper on the arms.

Both the NTCu30 Mini and copper 175mm² IUD users had less cramping and bleeding complaints compared to TCu380A users. Several feature differences could account for these differences in side effects. Both of the newer IUDs are smaller and have a Nova-frame design. Because we see no difference in uterine cramping complaints among users of different size levonorgestrel IUDs,²¹ it is reasonable to assume these differences between the copper IUDs are related more to the Nova-T frame design rather than the size differences.

Finally, the Tatum-T design is stiffer than the Nova-T design and has sharp angles at the junction of the stem and arms. The stiffer frame and sharp angles lead to higher stress on the junction during removal as compared to Nova-T frames,²² which is believed to be the reason breakage during removal is reported more frequently in the United States with the TCu380A than hormonal IUDs.²³ The frames with the copper 175mm² IUD and the NTCu30 Mini, which are Nova-T in shape, may, accordingly, have lower breakage rates during removal than the TCu380A; this relationship will need to be studied as the device is used more. Future device development may therefore focus on Nova-T designs with the copper located on the arms of the device to optimize efficacy while decreasing side effects and removal complications.

References

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