Copper

Copper-containing intrauterine contraceptive devices

Copper-containing intrauterine contraceptive devices [ ] became popular because local inflammatory reactions in the endometrium are more marked and the contraceptive effect is thus more pronounced [ ]. In addition, copper ions released from intrauterine contraceptive devices reach concentrations in the luminal fluids of the genital tract that are toxic to spermatozoa and embryos. The ability of copper to induce the generation of free radicals and the formation of malonaldehyde may be involved in its contraceptive effect.

There is a positive correlation between high copper loss from an intrauterine contraceptive device and the development of menorrhagia or pathological lesions, such as cervical dysplasia and endometrial cytopathology [ ]. Evidence of endometrial carcinoma was not found in endometrial aspirates from 189 women who had used Copper-T-200 devices for 1–10 years, but five cases of endometrial hyperplasia (2.67%) were encountered in women in the series, all of whom had worn copper devices for 6 years or more. Inflammatory changes in the endometrial cells were found in 12 cases (6.2%), 11 of 12 having worn the device for over 3 years. It is possible that constant exposure to copper may be responsible for persistence of chronic inflammatory changes in endometrial cells, which could be the precursors of hyperplastic changes. It is not clear whether the dissolved copper is also responsible for the temporarily increased predisposition to bacterial contamination and the somewhat increased risk of pelvic inflammatory disease, seen especially in young nulliparous women using this type of contraceptive method.

Migration of intrauterine contraceptive devices is relatively rare, although they have been found in the omentum, rectosigmoid, peritoneum, bladder, appendix, small bowel, adnexa, and iliac vein. Most authors have recommended removal of copper-containing devices, because of the potential for inflammatory reactions, which can cause bowel obstruction and perforation [ ]. Two cases of migration of intrauterine contraceptive devices to the bowel have been reported.

• A Copper-T intrauterine contraceptive device migrated to the rectal lumen in a 36-year-old woman with menorrhagia for 3 months and a history of Copper-T insertion 6 years before [ ].

• A 28-year-old pregnant woman developed an ileal perforation 4 weeks after the insertion of a Multiload-Cu 375 intrauterine contraceptive device [ ].

The second report documents the shortest interval between insertion and proven bowel injury by an intrauterine contraceptive device.

Immunological and hypersensitivity reactions beyond the uterus are uncommon, but they can occur. Rashes, including generalized urticaria and eczematoid eruptions, have occurred as a result of allergy to the copper released from intrauterine contraceptive devices, although they are extremely rare [ , ]. One woman who had worn a copper-containing device for 12 months developed widespread urticaria and angioedema of the eyelids and the labia majora and minora for about 6 months [ ]. She also had persistent symptoms of premenstrual and postmenstrual spotting and leukorrhea for about 6 months. A patch test was positive with 1% copper sulfate, as was an in vitro lymphocyte stimulating test with copper. An endometrial biopsy showed vulvovaginitis, with hyperplasia of the cervical canal and T cell and eosinophilic granulocyte infiltration. Removal of the device caused complete remission.

Genital tract actinomycosis has come increasingly to the fore [ , ]. In one study in Britain, the pelvic smears of nearly one-third of women using plastic devices were positive for Actinomyces - like organisms, compared with two of 165 women using copper-loaded IUCDs and none in a series of oral contraceptive users. There was a highly significant correlation between the presence of these organisms on smear and pain and other symptoms of pelvic inflammatory disease.

• A 32-year-old woman, who had had a copper intrauterine contraceptive device for more than 5 years, developed acyclic menstrual bleedings and had a uterine biopsy after removal of the intrauterine device [ ]. Histology of the abraded tissue showed an actinomycotic endometritis, with brown to black deposits in or around typical Actinomyces druses , but there was no carcinoma. Electron microscopy showed copper deposits in the shell and matrix of the druses and inside the bacteria. Electron-dense accumulations showed high signals for copper and sulfur, and to a lesser extent also for phosphorus and oxygen.

Copper accumulation in this case may have been caused by active uptake and concentration by the Actinomycetes .

If copper-containing fragments of intrauterine contraceptive devices perforate the uterine wall and enter the peritoneal cavity, acute inflammatory reactions and peritoneal adhesions can occur. Laparoscopic removal is then not only as a rule impossible but may also be dangerous because of the marked peritoneal reaction surrounding the copper part of the device. Laparotomy has therefore been suggested as the primary measure in such cases. Whether copper devices result more commonly in perforation than non-copper devices is not entirely clear, nor is the question answered whether copper increases the risk of extrauterine pregnancies, although older evidence suggested this as a risk [ ].

Although copper-containing intrauterine contraceptive devices are very effective, pregnancies do occur and the question of possible second-generation effects has to be considered. In one case the neonate showed significantly increased copper and ceruloplasmin concentrations, whereas maternal concentrations were within the reference range. Whether such exposure to copper can cause harm is not clear; because of the pharmacological effects of copper, it has been suspected of having mutagenic and carcinogenic potential. Until now, there is no clear evidence that harm is actually done. Five published cases scattered throughout the literature in which incomplete closure of the neural tube was found [ ] could have been coincidental, bearing in mind the large number of pregnancies in which exposure to copper must occur in this way. In various species of animals which have been studied (rat, rabbit, hamster, sheep) no teratogenicity of intrauterine copper was detected [ ].

Systematic reviews

A meta-analysis of 35 randomized controlled studies of the effectiveness and adverse effects of copper-containing intrauterine contraceptive devices (IUCDs) has been published [ ]. There were 18 comparisons of 10 different IUCDs in about 48 000 women. TCu380A was more effective in preventing pregnancy than MLCu375 (RD = 1.70%; 95% CI = 0.07, 2.95%) after 4 years of use. TCu380A was also more effective than MLCu250, TCu220, and TCu200. There tended to be fewer pregnancies with TCu380S than with TCu380A after the first year of use, a difference that became statistically significant in the fourth year (RD = − 1.62%; 95%CI = − 3.00, − 0.24%). This occurred despite more expulsions with TCu380S (RD = 3.50%; 95% CI = 0.36, 6.63% at 4 years). MLCu375 was no more effective than TCu220 at 1 year of use or than MLCu250 and NovaT up to 3 years. Compared with TCu380A or TCu380S, none of the IUCDs showed any benefits in terms of bleeding or pain, or any of the other reasons for early withdrawal. None of the trials that reported events at insertion showed that one IUCD was easier to insert than another or less painful. There is no evidence that uterine perforation rates vary by type of device. The authors concluded that TCu380A or TCu380S are more effective than other IUCDs. No IUCD had consistently lower removal rates for bleeding and pain than any other. There is no evidence that any particular framed copper device is better suited to women who have not had children.