Biological Responses to Metal Implants

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USFDA Publication

September 1, 2019

Section on Copper IUDs

Copper-containing intrauterine devices (IUD)
Although the exact mechanism of action of copper-IUDs is difficult to elucidate, these reversible contraception devices are characterized as “functional spermicides” designed to prevent the formation of viable embryos by inducing local change in the endometrium (Ortiz and Croxatto 2007).

Copper (Cu) ions released from a copper-containing IUD (which can be made from up to 99.9% pure Cu wire) are thought to exert contraceptive effects via inflammatory response that is usually limited to the uterus and genital tract, but in some cases, may affect distant organs (Ortiz and Croxatto 2007).

Similar to NiTi-based Essure, copper-IUDs have been reported to be associated with pain and heavy bleeding and in rare cases, with uterine perforation and device expulsion/migration (Nelson and Massoudi 2016). Suggesting the role of hormonal factors in the IUD-related tissue changes and subsequent perforation, a meta-analysis on copper-IUDs found that uterine perforation with IUD insertion was 6 to 10 times more likely in breastfeeding vs. non-breastfeeding women('Intrauterine Copper Contraceptive' 2006). In the large EURAS-IUD 5-year extension study (Barnett et al. 2017), the overall perforation rate for copper-IUD users was estimated as 1.6 per 1000 insertions (95% CI: 0.9-2.5), which was lower than the corresponding estimate for users of hormone (levonorgestrel)-releasing IUDs. In rare cases, IUD-related perforations were reported to result in injuries to intra-abdominal and pelvic structures, such as in the case report on a copper-IUD that was located in the abdominal wall, resulting in a foreign body granuloma and mimicking acute appendicitis (Ansari et al. 2009).

No difference in serum Cu levels was found in an earlier study on women using specific copper-IUDs up to one year (Arowojolu, Otolorin, and Ladipo 1989). However, in a study of different product, IUD users, regardless of age or length of use, had blood Cu levels above normal concentrations and significantly higher compared to non-users (De la Cruz et al. 2005).

Some reports on copper- IUDs described reactions suggesting involvement of adaptive immunity. There have been at least 5 documented cases where women with copper-IUDs developed systemic ACD with metal sensitivity confirmed by patch testing and symptom resolution upon device removal (Teo Wendy and Schalock 2016). As an example, Purello D'Ambrosio et al. (1996) reported a case of copper-IUD-related endometritis and vulvovaginitis accompanied by treatment-resistant urticaria and angioedema. Patch testing and lymphocyte-stimulating test (LST) showed strong positivity to Cu sulfate and the Cu spiral applied to the patient's forearm also provoked a positive reaction with erythema, itching, and rash; device removal resulted in complete symptom resolution (Purello D'Ambrosio et al. 1996).

Some small studies explored potential immune and inflammatory markers in relation to copper-IUDs. In a study on a copper versus non-copper IUDs, women using the copper-based device for <1 year had higher increases of serum acute-phase reactants and immunoglobulins G and M (Shaarawy et al. 1981).

Circulating IL6 levels were elevated in 20% of women using another copper-IUD for 10-24 months (Woolley et al. 1996); however, it remained unclear whether the increased circulating levels of this proinflammatory interleukin was a result of "overspill" from local inflammatory response or an indication of possible IUD-related systemic immune activation. A copper-IUD was also reported to precipitate familial Mediterranean fever (FMF) attacks one week after insertion in a 23-year-old Turkish woman who was diagnosed with FMF at 12 years old and was symptom-free on colchicine treatment for at least 4 years(Kurultak et al. 2015); the clinical reoccurrence of an autoinflammatory disease such as FMF suggested to the authors that a copper-IUD may trigger a systemic inflammatory response in the presence of predisposing factors such as a mutation (M694V) in the autoinflammation-causing gene (MEFV).

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