Autoimmune disease following the use of silicone gel-filled breast implants: a review of the clinical literature.

The association between the use of silicone breast implants and the later development of connective tissue disease was reviewed. Data from case reports (only 40 in the world literature), case series, case-control studies, surveys of plastic surgeons, and cohort studies provided no evidence of an association. In many studies, the appropriate information was not collected to evaluate the association. The case-control and cohort studies were too small to detect even moderately increased risks should they exist. Further prospective studies are required to determine the risks of connective tissue disease associated with the use of silicone breast implants.

Duration of use of copper releasing IUDs and the incidence of copper wire breakage.

The incidence of copper wire breakage for IUDs (Multiloads) using 0.3 and 0.4 mm diameter copper wire was evaluated by examining 969 devices that had been removed for various reasons. The IUDs were examined by light microscopy to determine the integrity of the copper wire. As expected, the incidence of breakage increased with increasing duration of IUD use. The cumulative breakage rate (life table) was significantly lower (p less than 0.05) for the Multiload 375 that used 0.4 mm diameter wire, compared to the Multiload 250 that used 0.3 mm diameter wire. The cumulative rates were 5.4 per 100 IUDs after 3 years for the Multiload 250, and 3.8 per 100 IUDs after 5 years for the Multiload 375. In only 1 (0.1%) of the 969 Multiloads examined, the breakage of the copper wire was sufficiently extensive to adversely affect the user's risk of pregnancy.

[Larger amounts of copper correspond to greater contraceptive effectiveness. Experiments with the ML Cu 375, the IUD with the highest copper content]. / A plus de cuivre correspond une plus grande efficacité contraceptive. Expérimentations à propos du ML Cu 375, le DIU le plus chargé en cuivre.

PIP: An evaluation of the Cu ML 375 IUD, which has the same structure as the Cu ML 250 but increased copper content, indicates that the greater amount of the copper provides greater protection against accidental pregnancy with no change in the rate of expulsions. The cumulative rates for 1969 insertions of the Cu ML 375 after 12, 24, 36, 48, and 60 months of use respectively were .4, 1.6 2.1, 2.8, and 3.2 for pregnancy; 1.8, 2.3, 2.7, 3.6, and 4.0 for expulsion, 5.9, 10.8, 14.7, 18.5, and 21.2 for removal because of pain and bleeding; .9, 2.3, 3.2, 4.1, and 5.2 for removal because of other medical factors; 5.2, 11.6, 16.0, 19.3, and 22.0 for removal to become pregnant; and 2.7, 5.8, 10.2, 14.0, and 10.4 for removal for other personal reasons. The continuation rates were 85.0, 70.3, 59.5, 51.3, and 44.3 for each of the 5 years. The numbers of cycles covered were 21,762, 39,223, 53,173, 64,567, and 71,818. A simple study of the Cu ML 250 inserted in 877 women gave cumulative rates after 12 and 24 months of 1.2 and 2.0 for accidental pregnancy, 1.3, and 2.1 for expulsion, 5.7 and 10.7 for removal because of pain and bleeding; 3.4 and 3.8 for removal because of other medical factors; 3.0 and 8.5 for removal to become pregnant, and 4.8 and 10.9 for removal for other personal reasons. The continuation rates were 82.7 and 32.3 and the numbers of cycles covered were 9440 and 16,761. The devices were inserted intramenstrually, postpartum, or postabortum in women with no contraindications to IUD use. Another study of the Cu ML 375 2 years later involving 1650 insertions gave cumulative rates of .3 and 1.5 for accidental pregnancy and 1.5 and 2.0 for expulsions. The continuation rates were 85.9 and 71.9. 10,333 and 33,322 cycles were covered respectively. The better contraception offered by the Cu ML 375 appears to result more from the effect of the increased mass of copper than from the increased surface area.^ieng

The intrauterine device and its dynamics.

In the past decade, attention has shifted from family planning (often made available through population programs) to reproductive health--a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity, in all matters related to the reproductive system and its function and processes. Reproductive health has three components: the ability to procreate, regulate fertility and enjoy sex; the successful outcome of pregnancy through infant and child survival and growth; and the safety of the reproductive process. According to Mitchell et al., the following are key elements in a reproductive health program: (a) Family planning services that offer complete and accurate information about all contraceptive methods and that make contraceptive services, supplies and counseling accessible. (b) Antenatal care, which research suggests lowers rates of maternal mortality. (c) Safe delivery services, so that all women deliver under some type of supervised care and so that referral systems are established to provide emergency treatment of life-threatening complications of delivery. (d) Postnatal care that contributes to a woman's ability to have a speedy and complete recovery from the stress of pregnancy and childbirth, to enjoy sexual relations without pain and to have safe pregnancies and deliveries in the future. (e) Management of the complications of abortion where safe abortions are not available. (f) Infertility services that enable women to achieve their reproductive goals; and effective screening for or control of reproductive tract infections (RTIs), because RTIs are the most common preventable cause of involuntary infertility and ectopic pregnancy, as well as of chronic pelvic pain and recurrent infection. (g) Management and treatment of systemic sexually transmitted diseases (STDs), such as HIV and hepatitis B. (h) Symptomatic treatment of urinary tract infections. (i) Detection and treatment of breast and reproductive tract cancers, such as cervical cancer. (j) Attention to and treatment of dysmenorhea, which in some cases is the first sign of other problems, such as pelvic inflammatory disease, endometriosis, fibroids, endometrial cancer and ectopic pregnancy. (k) Nutritional supplementation to meet the special needs of adolescents, pregnant or lactating women, and women older than 50 years. (1) Services for menopause and other health problems that women encounter as they grow older. (m) Services for adolescents, including family planning and STD prevention and treatment. It shall be clear that many institutions delivering reproductive health services operate significantly below their physical capacity to see clients, and that much of the equipment required for expanding reproductive health services may already be available for use in family planning and other health services. In this context, we would therefore like to discuss the dynamics of IUDs.

[From Gräfenberg to the Multiload Cu 250--the development of the so-called spiral]. / Van Gräfenberg tot de Multiload Cu 250--de ontwikkeling van het zgn. spiraaltje.

PIP: A general description of the development and qualities of the IUD is given. The first true IUD was developed by von Graefenberg in 1925, after which physicians in many lands did research to improve the effectiveness and acceptability of these devices. The most common IUDs are made of plastic and covered with a thin layer of copper, which increases the effectiveness of the IUD so that it can be kept smaller, thus causing less uterine irritation. The IUD has been a more important contraceptive for the Third World than in the industrialized nations, where oral contraceptives are preferred. The effectiveness of the IUD in humans is due to an inhibition of implantation: this is caused in part by an increase in macrophagocytes and a disturbance of the synchronization between the movement of the fertilized ovum and the phases of the endometrium. Extreme care must be taken to avoid spreading infection when inserting an IUD. In the case of pregnancy or infection, the IUD should be removed immediately. Pain and bleeding are other side effects of IUD use. IUDs can also cause uterine perforation. If pregnancy occurs with an IUD in situ, the IUD should be removed immediately; if evidence of infection is present, an abortion may be indicated. Most pregnancies with IUD in situ result in spontaneous abortion. In cases where a pregnancy with IUD in situ has been carried to term, no increased instance of birth defects has been established, although the number is not large enough to give unequivocal statistical evidence.^ieng

Fifteen years' experience with the Multiload IUD.

The Multiload IUD with an exposed copper surface area of 250 mm2 (MLCu250) was developed in 1972 and has become one of the most widely used IUDs. Modifications to the MLCu250 include an increase in the area of exposed copper wire to 375 mm2 (the MLCu375) and an increase in the diameter of copper wire from 0.3 to 0.4 mm. The Multiload has been evaluated extensively in noncomparative and comparative clinical trials. In these latter studies the MLCu250 performed better than the Cu-7 and TCu-200, and the MLCu375 performed better than the Fincoid or Nova T and about equally as well as the TCu380. Pooled data from over 26,000 insertions of the MLCu250 gave the following 3-year cumulative event rates (per 100 women): pregnancy, 2.0; expulsion, 3.1; removal for pain/bleeding, 7.1. Comparative studies of the Multiload and other IUDs have shown all IUDs in current use are associated with similar rates of pelvic inflammatory disease. IUDs such as the MLCu375 that have larger copper surface areas appear to be associated with lower ectopic pregnancy rates. Follow-up studies of women who have had their Multiloads removed indicate that use of the device does not impair future fertility or affect pregnancy outcome. All IUD users, regardless of the type of IUD used, are at risk of complications. On balance, the benefits of IUD usage far exceed the associated risks.

Uterine perforation and use of the Multiload IUD.

The English language literature on IUDs was reviewed to evaluate the uterine perforation rate associated with use of the Multiload. No reports of cervical perforation were found, and the uterine perforation rate was 0.12/1000 insertions compared to a rate of 0.68/1000 insertions for other copper-bearing IUDs. This lower rate may reflect an under-reporting of uterine perforations in the medical literature, or may represent a truly lower perforation rate due to factors related to the Multiload design and/or its insertion technique.

Safety of intrauterine contraception.

Some of the risks which have been associated with the use of intrauterine contraception are reviewed. For users of copper-releasing IUDs, such as the Multiload Cu375 and TCu380, uterine perforations are rare, there is no evidence of an increased risk of infertility, and there probably is no increased risk of ectopic pregnancy after IUD removal. Any increased risk of pelvic inflammatory disease may be limited to the initial months of IUD use. The safety of intrauterine contraception needs to be re-evaluated for the newer IUDs, since most of the information relating to IUD safety is based on studies of devices which are no longer used or which are not in widespread use.

When does exposure to agent X cause disease Y?

The concept of 'cause' between exposure to agent X and the subsequent development of disease Y is reviewed briefly in terms of how it is used in experimental and clinical medicine, statistics and epidemiology, and in law. Some of the interrelationships of the definition of cause by these disciplines are considered.

New directions in IUCD development.

In recent years, the development of improved intrauterine devices has focused on finding methods to reduce expulsion and the need for medical removal for better intrauterine retention and devices. Efforts also have been directed towards developing intracervical devices. Some of the more recent developments in intrauterine and intracervical devices are discussed.

Breast cancer risk among women using silicone gel breast implants.

Since their introduction in 1962, silicone gel-filled breast implants have been used by an estimated one to two million women. Questions concerning an increased cancer risk to these women have been raised. A review of the medical literature, including case reports, case series, physician surveys, case-control studies, and cohort studies, failed to turn up any evidence which associated the use of silicone breast implants with either an increased risk of breast cancer or an increased risk of a more advanced stage of cancer at the time of cancer diagnosis. The available data do not indicate any significant difference between the characteristics of the breast cancers of women with breast implants and those of women in control populations.

Contraceptive development and testing in the United States of America.

Contraceptive development, including the development of IUDs, is discussed in light of the changing regulatory role of the FDA. The paper considers how the FDA and the government affect contraceptive development. Events that led to the demise of IUD use in the United States probably will have long-lasting effects on all future contraceptive development by the pharmaceutical industry in the United States.

PIP: The changing regulatory role of the FDA has affected the development of contraceptives including the IUD. This work attempts to discuss how the FDA and the government influence contraceptive development. Particular government actions led to the demise of the IUD in the US and will have long lasting effects in the US on the future of all contraceptive development by the pharmaceutical industry. This work traces the history of government regulation of contraceptives from the Pure Food and Drug Act of 1906 through the 1976 Medical Device Amendments to the Food Drug and Cosmetic Act of 1962. This act required manufactures of nonmedicated IUDs, and any other contraceptives, to conduct similar clinical trials that are required for the development of other drugs. In the US, IUD contraception has become a legal battle ground and its future is that of a condemned product. Currently no manufacturer of IUDs is marketing products in the US. This deprives US women of a safe and effective form of contraception. This work also discusses Depo-Provera and RU-486. The author's final conclusion is that the future of contraceptive research and development in the US is in doubt. The pharmaceutical companies of Western Europe have proven their commitment and ability in this area in the last decade and will continue to do so for the next.

Medical removals of the Multiload IUD.

In a follow-up evaluation of 3721 Multiload IUD users, the removal rate for medical reasons other than bleeding/pain was only 2.6 per 100 women at three years. Most of these removals were for reasons that appeared to be unrelated to IUD use. The removal rate for pelvic inflammatory disease was 0.3 per 100 woman years. Women were followed up for up to three years after removal of their IUDs. Among women with PID at least 70% of those who desired pregnancy subsequently became pregnant, a rate similar to that of women who had their IUDs electively removed to become pregnant. The study provides further data on the safety of intrauterine contraception.

Effects of intrauterine devices on the surface ultrastructure of human endometrium before and after removal.

The effects of copper-releasing IUDs on the endometrial ultrastructure were evaluated in 101 women. Endometrial samples were obtained in the secretory phase of the menstrual cycle, both during and after IUD use, and were evaluated using both scanning and electron microscopy. The degree and extent of changes to the surface ultrastructure of the endometrium were found to be related to the copper surface area of the IUD. Regardless of the duration of IUD use, by one month after IUD removal the endometrial ultrastructure had returned to its normal state. The results of this study show that the effects of copper-releasing IUDs on the endometrial ultrastructure are essentially limited to the time the IUD is in utero.

Oral contraceptives and breast cancer risk.

Because of the continuing controversy on the breast cancer risks associated with the use of combined oral contraceptives (OCs), the medical literature was reviewed to assess the risks of this cancer to OC users. This review found that the medical literature supports the view that OC use is associated with small increased risks of premenopausal breast cancer. There is no consensus as to which subgroups of women might be at an increased risk.

Scanning electron microscopy of the IUD tail.

PIP: The surface ultrastructure of the tails of various IUDs (Multiload, Copper 7, Copper T-Device, Nova-T, FDI, Lippes Loop, and Dalkon Shield) was studied with the scanning electron microscope. The parts of the IUD tail exposed to the vaginal, cervical, and uterine milieu showed strikingly different surface characteristics. The surface ultrastructure of these 3 parts is influenced by the duration of use, nature of microbiological contaminants, pregnancy with the IUD in situ, and pelvic inflammatory disease (PID). Duration of use and PID alter the surface ultrastructure most drastically. In comparing tails of the different IUDs, the IUDs with relatively smooth tails became less rapidly contaminated during the 1st few months of use. The surface ultrastructure of the IUD tail was formed through a coat of material which consists of cellular debris, dead bacteria, mucus, etc. The thickness of the coat was found to be largely dependent on the duration of IUD use. The thicker the coat, the more likely bacteria were found on the intrauterine part of the tail. The possible significance of these findings with respect to the development of PID is discussed.^ieng