Human Reproduction Update Advance Access originally published online on April 9, 2008
Human Reproduction Update 2008 14(3):197-208; doi:10.1093/humupd/dmn003
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Intrauterine devices and intrauterine systems
Correspondence address. P.G. Crosignani, Department of Obstetrics and Gynecology, University of Milano, Via Commenda 12, 20122 Milano, Italy. E-mail: piergiorgio.crosignani{at}unimi.it
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Abstract |
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Abstract
IntroductionFrom a public health viewpoint, the intrauterine device (IUD) is the most widely used contraceptive method in the world. Prevalence rates range among countries from 2 to 80% of contraceptive users. During 5 years of IUD use, pregnancy occurs in less than 2 per 100 insertions. Bleeding and pain are the most common reasons for removal rates of 10% in the first year and up to 50% within 5 years. The contraceptive effects of IUDs may be due to a sterile inflammatory reaction in the endometrial cavity which interferes with sperm function, so that fertilization is less likely to occur. IUDs also interfere with implantation but the extent to which this contributes to their contraceptive action is unknown. In nulliparous women rates of expulsion and removal for bleeding and/or pain are higher than in parous women. Effective use of IUDs for up to 10 years has the same pregnancy rate as tubal interruption. Thus, the IUD may be an alternative to female sterilization, especially in younger women who are more likely to experience regret after sterilization. The levonorgestrel intrauterine system (LNG-IUS) reduces bleeding and dysmenorrhoea, provides superior effectiveness to copper IUDs, and may be a useful treatment for endometriosis or an alternative to hysterectomy for menorrhagia.
Key words: contraception / family planning / intrauterine devices / intrauterine system / sterilization
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Introduction |
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The intrauterine device (IUD) is the most frequently used reversible family planning method in the world. The earlier IUDs made of inert plastic materials have largely been superseded in modern practice by products which release copper or levonorgestrel, modifications which substantially enhance the already high efficacy. In 34 randomized controlled trials involving more than 50 000 women and 16 different comparisons between devices, copper IUDs were highly effective in preventing pregnancy, with protection lasting up to 12 years for the TCu380A (Grimes et al., 2007
). Overall, the TCu380A was more effective than alternative devices, including the Multiload 375 (MLCu375), Multiload 250 (MLCu250), Copper T220 (TCu220) and Copper T200 (TCu200). In two studies that compared copper devices and the levonorgestrel intrauterine system (LNG-IUS), pregnancy rates were lower with the LNG-IUS than with copper devices. (Table I).
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Side effects and device-related complications such as expulsions and perforations are comparable between copper IUDs and the LNG-IUS. Proper insertion is the key to preventing complications including perforations, expulsions and pain. Expulsion of an IUD occurs in
1 in 20 women, and is most common in the first 3 months after insertion, often during menstruation (NICE, 2005). The most important adverse effects are dysmenorrhoea and bleeding, which lead to the removal of copper IUDs in 10% of women in the first year of use (Hubacher et al., 2006). The risk of an ectopic pregnancy is lower in women using an IUD (0.1% in 5 years) than in women using no contraception, but if pregnancy occurs with an IUD in situ, 1 in 20 pregnancies is ectopic, indicating that the IUD prevents mainly intrauterine pregnancies (Backman et al., 2004).
Up to 50% of women stop using IUDs within 5 years, most often because of unacceptable vaginal bleeding or pain (NICE, 2005). The frequency of removals for bleeding problems (including amenorrhea) is similar for copper IUDs and the LNG-IUS: 14% in copper T users and 11% in LNG-IUS users after 36 months of use (Luukkainen, 1991). The effects of copper IUDs and the LNG-IUS on menstrual pattern, however, are different. Copper IUDs are associated with an increased volume of menstrual flow and dysmenorrhoea, whereas the LNG-IUS is associated with reduced flow and less painful menstruation (Suhonen et al., 2004). The irregular bleeding or spotting that does occur with the LNG-IUS is usually limited to the initial months of use. Once the endometrial effects are established, the bleeding pattern with the LNG-IUS turns gradually to oligomenorrhea or amenorrhea. Using strict criteria for amenorrhea (90 consecutive days with no bleeding or spotting), 20% of the LNG-IUS users are defined to be in amenorrhea after one year of use.
Given the comparable effectiveness between the LNG-IUS and the high dose copper devices, the reduction in menstrual flow with the LNG-IUS, and its 5-fold higher cost, the LNG-IUS, might be reserved for women who have excess menstrual bleeding or pain (Grimes et al., 2007).
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Societal factors affecting utilization of IUDs |
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Variations in IUD use in the world
Until the 1960s, IUDs and condoms were the only artificial method for the control of fertility. The mix of available methods has greatly expanded and the insertion of an IUD is now the second most prevalent method of family planning used worldwide (13.6%), after female sterilization (20.5%), among women of reproductive age who are married or cohabiting (United Nations, 2006).
The total number of current IUD users is estimated at over 150 million women worldwide, of which 100 million are in China. The majority of devices used are copper devices but reliable data on the use of different types of devices are not available. The LNG-IUS has been used by over 10 million users in 113 countries, since it was first marketed in 1990 (http://www.mirena-us.com/press.html?C=&c=). The proportion of IUD users among married or cohabiting women of reproductive age is nearly 2-fold higher in the developing world (14.5%) than the developed world (7.6%).
Prevalence of IUD use is the greatest in the Democratic People’s Republic of Korea, where it is used by 78% of contraceptive users, in the Central Asian Republics (63–76%), and in certain countries in the Middle East and Latin America (Egypt, 63%; Cuba, 59%) (United Nations, 2006). In contrast, IUD prevalence is below 2% among women of reproductive age in sub-Saharan Africa and in North America.
IUD use also varies within Europe, with the greatest proportions of contracepting women using this method in the northern and eastern parts of the region. In northern Europe, the IUD is used by 30% of contracepting women, with the exception of Denmark (14%). In eastern Europe, it is used by over 55% of contraceptive users in Belarus and Moldova, and by 11–27% of contracepting women in most other countries. In southern Europe, this percentage is between 9 and 17%, with the exception of Albania (1%). In western Europe, it is less than 8% except for France (27%) (United Nations, 2006).
Service delivery and policy factors affecting prevalence of use
At the level of service delivery, IUD uptake is influenced by the views of clinicians: some have received appropriate training and have updated knowledge of the IUD types available in their environment of practice, while others lack the skills and experience for providing adequate counselling and care for safe IUD use.
At the programme level, factors that influence IUD use include costs (the cost of the device, of its insertion and removal, and of clinic services for the management of possible side effects); quality of care; training and supervision of providers; and the geographical distribution and facility of access to these services.
At the country level, the availability of an IUD will depend on each manufacturer’s marketing strategy, which is influenced by the size of the potential market, the financing available in both the public and the private sectors, and the medico-legal environment. Availability also will depend on the licensing of devices by national regulatory agencies, and on the authorization granted by professional bodies to different types of healthcare personnel to provide IUD services. Where programmes have access to foreign aid, method choice may reflect donor preferences; equally, absence of foreign aid may limit method mix and favour provision of the cheapest methods of family planning regardless of effectiveness. The history of the country itself, with its international alliances, relationship with industry, demographic policies and cultural and religious influences, will create an environment more or less favourable to IUD use (Sullivan et al., 2006).
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Clinical factors affecting utilization of IUDs |
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Clinical factors that influence uptake and continuation reflect the experience of individuals and clinicians (Table II). Individuals considering use of the IUD will be influenced by their own familiarity with contraception in general, by the acceptability of family planning in their socio-cultural and religious community, and by their wish to space or limit childbearing. A woman’s attitudes to the IUD also will be shaped by her knowledge of the method, and by her assessment of the relative risks and benefits associated with its use. In some cases, misinformation may dominate, fuelled by reports of severe complications with older IUD types that are no longer available (Hutchings et al., 1985
).
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Acceptability
The acceptability of a contraceptive method is usually inferred from its uptake (prevalence of use) and from continuation rates. Neither uptake nor continuation rates are ideal indicators of acceptability, however, because of the numerous factors that affect these measures. To overcome this shortcoming, trials now may include acceptability questions such as ‘Would you recommend this method to a friend?’ Among 17 914 Finnish women responding to an interview request, 70% chose the LNG-IUS because of dissatisfaction with a previous method and 74% were satisfied with LNG-IUS. Satisfaction was the highest in women given the most information about side effects (Backman et al., 2002).
Reasons for low acceptability in England were summarized in a small interview study of women who had never used an IUD. The main reasons for rejecting the method were lack of objective information about the method; influences from friends who reported side effects; infection risk; anxieties about insertion (during menses); and lack of personal control over the method, especially with respect to having it removed (Asker et al., 2006). Acceptability of IUDs is higher in other European countries where ease of use is an attractive feature (den Tonkelaar and Oddens, 2001) and where the amenorrhoea associated with the IUS is regarded by many women as a benefit (Baldaszti et al., 2003). Reasons for low uptake of intrauterine contraception in developing countries include rumours and myths about the method, insufficient emphasis during contraceptive consultations and insufficient provider experience (Katz et al., 2002).
IUD/IUS continuation rates are within the range of continuation rates for other methods of contraception. In a systematic review of the literature for a national guideline on long-acting reversible contraceptives, the National Institute for Health and Clinical Excellence in the UK (NICE, 2005) reported cumulative discontinuation rates as high as 17% after 1 year and 28% after 2 years for the Cu-IUD. For the LNG-IUS, discontinuation rates were as high as 24% after 1 year and 33% after 2 years. Discontinuation rates are up to 50% for all types of IUDs by 5 years. Women using copper IUDs are most likely to discontinue because of bleeding and/or pain. Although these are also common reasons for discontinuation of use of the IUS (Dubuisson et al., 2002), almost 1 in 4 women stop using the LNG-IUS because of amenorrhoea, which other women consider a benefit. Overall, the commonest reason for discontinuation of a Cu-IUD or LNG-IUS is unacceptable bleeding patterns.
Continuation rates are rarely reported from randomized trials because trials of contraceptive methods are rare, since most women have strong views on which method they would like to use—and on which ones they would not consider. One study in four developing countries (Brazil, Guatemala, Vietnam and Egypt) randomized 368 women to either a copper IUD or Depot Medroxy Progesterone Acetate (DMPA): 77% of women were still using the IUD at 12 months of follow-up compared with 58% of women using DMPA (Feldblum et al., 2005).
Prevalence of use is also determined by the prevalence of contraindications to the use of intrauterine contraception. Although many theoretical contraindications are listed, few women actually do have contraindications to use of either the Cu-IUD or the LNG-IUS (Table III).
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In the WHO Medical Eligibility Criteria guidelines, Category 3 conditions (the risks with use outweigh the benefits) and Category 4 conditions (the risks are considered unacceptable to health) relate mainly to increased risks of infection, uterine perforation and vaginal bleeding (World Health Organization, Reproductive Health and Research, 2004
).
With respect to infection, women with increased risk of sexually transmitted infections including HIV/AIDS are in Category 3. The risks of pelvic inflammatory disease (PID) with insertion of an IUD in the presence of existing infection were reported in a systematic review which included six studies. With IUD insertion in the presence of chlamydia infection or gonorrhoea, subsequent PID rates were 0–5%, compared to insertion in the absence of infection (0–2%) (Mohllajee et al., 2006). Of course, PID frequency in comparable women without an IUD is not known.
Although uterine perforation occurs in less than 1 in 1000 insertions (O’Brien and Marfleet, 2003), it is prudent to avoid predisposing conditions, such as a previous recent Caesarean section or distorted uterine anatomy. Although uterine perforation is said to be more likely in the early weeks after childbirth, there were no perforations with insertion at 4 weeks postpartum and no significant differences in the discontinuation rates for any reason between 411 women who had an IUD inserted between 4 and 8 weeks postpartum, and 1197 women who had the IUD inserted more than 8 weeks after a term delivery (Mishell and Roy, 1982).
Unexplained vaginal bleeding is usually a contraindication to most methods of contraception including intrauterine methods. As unwanted bleeding is a common reason for discontinuation of the copper IUD, any pre-existing conditions which predispose to bleeding (such as use of anticoagulant therapy) will contraindicate use of the copper IUD, but not usually the LNG-IUS, which may ameliorate bleeding. For women with serious chronic medical conditions, predominantly cardiovascular disease, the risks of using the LNG-IUS may outweigh the benefits (Category 3). These women, however, may need to use an effective method of contraception, and a copper IUD is often the ideal choice.
Some Category 3 conditions for the IUS exist because of the hormone released, e.g. breast cancer with no recurrence for 5 years. Recent evidence of the lack of associations, such as between LNG-IUS use and breast cancer, may lead to a reconsideration of these Category 3 listings (Backman et al., 2005).
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Mechanisms of action |
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Although the contraceptive effect of rings and other artefacts placed in the uterus of women and the females of other species has been known for over 2000 years, it is still not entirely clear how they prevent pregnancy (Ortiz et al., 1996
). Not unexpectedly they produce signs of a low grade inflammatory response, including leucocyte infiltration in the endometrium, but because the mechanisms of implantation vary between mammals, it has been difficult to identify a convenient animal model with which to study mechanism of IUD action (Ortiz and Croxatto, 2007). Studies in women are inevitably limited by ethical constraints and the results are often inconclusive. Moreover, if it was conclusively shown that the sole or principal mode of action was to prevent the embryo from implanting, then this method, as in the case with emergency contraception, would be considered by the Roman Catholic church as causing an early abortion. As a result many agencies involved in the research, development or delivery of contraception prefer to leave the mechanism of action issue unresolved, which may explain why research into the contraceptive mechanisms of IUDs has been sparse in the last 20 years. Each of the key reproductive processes (ovulation, sperm transport, fertilization and implantation) has been evaluated as a potential locus of the IUD mechanism of action.
Ovulation
Normal ovulatory cycles occur in women with IUDs. Although the levels of levonorgestrel in the blood of LNG-IUS users are similar to those found in women after prolonged use of Norplant, there is no evidence that disruption of ovarian function contributes to their contraceptive effect (Barbosa et al., 1995).
Sperm transport and function
Sperm move from the cervix to the tube and peritoneal cavity within 1 h. In women with copper IUDs or the LNG-IUS, reduced numbers are recovered from the site of fertilization in the ampullary portion of the tube (Tredway et al., 1975; Koch, 1980). Copper ions are toxic to spermatozoa (Jecht and Berstein, 1973) and levonorgestrel concentrations are high enough to alter the quality of cervical mucus, making it hostile to the movement of sperm through the cervix (Kesseru and Camacho-Ortega, 1972; Jonsson et al., 1991). Thus, the number and quality of sperm reaching the site of fertilization in the tube seems to be reduced in IUD and IUS users. Nevertheless, it is unknown whether the remaining high quality sperm that do reach the tube are insufficient to fertilize the oocyte, although the rare failures indicate fertilization capacity.
Oocyte quality and fertilization
A number of studies have attempted to establish whether fertilization occurs and the ovum develops normally by recovering oocytes and pre-implantation embryos from the tubes and uterus of women with and without IUDs during surgical sterilization (Ortiz et al., 1996; Ortiz and Croxatto, 2007). The studies are technically demanding and inevitably the sample sizes are small. In one much quoted study, the recovery of normally cleaving zygotes from the Fallopian tube did not occur in women with copper unlike inert or LNG impregnated or non-IUD users (Alvarez et al., 1988).
In a second series of more recent experiments, oocytes and embryos were recovered from women at varying times after intercourse (Ortiz and Croxatto, 2007).
A total of 10 out of 20 embryos recovered from control women showed normal development. In three, there was no development and in the remaining seven development was uncertain. In contrast none of the 14 oocytes recovered from women with IUDs showed normal development, nine showed no development and the status of the remainder was uncertain. The authors concluded that although fertilization does occur in some women with IUDs, development of the embryo may be impaired.
Implantation
The embryo normally implants in the uterus 6–7 days after fertilization. In women with copper IUDs, inflammatory cells enter the endometrium and prostaglandin production is excessive (Myatt et al., 1975). In women with the LNG-IUS, the endometrium is abnormally thin and contains areas of superficial fragile vessels (Guttinger and Critchley, 2007). These features suggest that the uterus would be hostile to implantation. Expression of genes associated with implantation, such as the genes for glycodelin and leucocyte inhibition factor, is also altered among women with copper IUDs (Horcajadas et al., 2006).
Indirect clinical evidence is supportive of the hypothesis that the effect of the copper IUD on the endometrium plays a role in its contraceptive action (Spinnato, 1997). Insertion of an IUD in the early luteal phase is a highly effective emergency contraceptive, suggesting that the IUDs act after fertilization (Cheng et al., 2007). Also, several long-term studies have established that when pregnancy occurs in IUD users the embryo is more likely to be ectopic than in control women using no contraception or in those who become pregnant while taking oral contraceptives (Sivin and Tatum, 1981; World Health Organization, 1994). The ratio of ectopic to intrauterine implantations is 1 in 6–8 among IUD pregnancies compared to 1 in 20 control pregnancies. The most plausible explanation for these findings is that IUDs are more effective at preventing pregnancy when it implants in the uterus rather than the tube, implying that with an IUD in place some embryos reach the uterine cavity but fail to implant.
Thus, both clinical and experimental evidence suggests that IUDs can prevent and disrupt implantation. It is unlikely, however, that this is the main IUD mode of action, although the evidence showing that fewer normally developed preimplantation embryos reach the uterus of IUD bearers in the second half of the cycle is inconclusive. The embryo produces a number of specific factors around the time of implantation, some of which can be detected in peripheral blood. Studies in the 1980s detected transiently elevated levels of hCG (Huang et al., 1984) and Early Pregnancy Factor in the luteal phase in up to 50% of sexually active women with an inert IUD (Smart et al., 1982). In contrast, hCG and pregnancy specific beta 1-glycoprotein PSBG) both were raised in only 0.7%; in fact hCG was detected in only 3 of 214 copper IUD users (Ylikorkala et al., 1980). Other studies using highly specific and more sensitive assays found hCG in less than 1% of IUD users (Wilcox et al., 1987). It is now thought that many of the early positive findings were due to cross reaction of the assays with pituitary LH (Segal et al., 1985). The best evidence indicates that in IUD users it is unusual for embryos to reach the uterus.
In conclusion, IUDs may exert their contraceptive action at different levels. Potentially, they interfere with sperm function and transport within the uterus and tubes. It is difficult to determine whether fertilization of the oocyte is impaired by these compromised sperm. There is sufficient evidence to suggest that IUDs can prevent and disrupt implantation. The extent to which this interference contributes to its contraceptive action is unknown. The data are scanty and the political consequences of resolving this issue interfere with comprehensive research.
The LNG-IUS directly targets the endometrium by releasing levonorgestrel into the uterine cavity. The cylinder containing 52 mg of LNG is covered by a rate-controlling membrane which regulates the daily release rate of the hormone. The initial release rate is 20 µg/day, declining to 11 µg/day at the end of 5 years. The mean release rate over 5 years is 14 µg/day (Luukkainen et al., 1990).
Local administration of LNG results in high endometrial concentrations, ranging from 470 to 1500 ng/g of tissue weight and sustained over the 5 years of use (Nilsson et al., 1986). The LNG concentrations in myometrial and Fallopian tube tissues are much lower (1.8–2.4 ng/g) (Nilsson et al., 1982). The high local LNG concentrations achieve uniform suppression of endometrial proliferation, and decidualization of the stroma (Critchley, 2003). The result is a thin decidualized endometrium, an environment that is unsuitable for sperm survival and fertilization, as noted above, this represents a key mechanism of contraceptive action.
Local delivery of LNG results in low but detectable serum levels of LNG (0.1–0.4 ng/ml), much lower than peak levels observed with other combined or progestin-only contraceptives containing levonorgestrel (Table IV). The low serum levels are insufficient to affect ovulation, but this systemic exposure is responsible for some of the hormonal adverse effects women sometimes experience during the use of the LNG-IUS. Corresponding to the higher release rate in early months of use, these adverse effects are more pronounced during the initial use.
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By inactivating the endometrium and suppressing proliferation, LNG-IUS also decreases menstrual blood loss (MBL) and pain. The steady continuous release of low doses of LNG is effective over 5 years. The LNG-IUS is well suited during the menopause transition because it can remain in place during the peri-menopausal years and protect the endometrium when estrogen therapy is initiated at menopause (Sturdee et al., 2004
; Hampton et al., 2005). |
Special contraceptive applications |
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IUD for nulliparous women
Clinicians’ reservations about the use of IUDs in nulliparous women arise from the concern about the smaller size of the uterine cavity in women who have never been pregnant. In vivo and in vitro measurements have shown the uterine cavity of nulligravid women to be smaller, both in depth and width, than that of parous women (Kurz et al., 1984). Whether nulliparity is truly a contraindication to the IUD, however, depends on the comparative effectiveness, acceptability and safety in nulliparous and parous women. Also important is the size of the IUD (mini IUDs, short IUDs), and whether it is copper releasing or hormone releasing.
Effectiveness of the IUD in nulliparous women
There are few randomized controlled trials of the effectiveness of IUDs in nulliparous women, and those that do include nulliparous women usually do not provide the data for an interaction analysis in the nulliparous subgroup. In a Mexican randomized controlled trial that compared three different IUDs in nulliparous women cumulative 12 month pregnancy rates were 1.0, 0.5 and 0 in 5961, 10 839 and 10 974 months of use, respectively, for the standard TCu 380, the TCu 380 Nul and the ML Cu 375 sl (P < 0.05) but the study has been criticized because of the unusually high rate of removals for bleeding (Otero-Flores et al., 2003). In another study, pregnancy rates in nulliparous women using the ML-Cu250 device were 0.5–0.9% in the first 12 months (Thiery, 1979). A Cochrane review concluded that IUDs are effective methods of long-term contraception, that the TCu380A is more effective than other IUD’s, but that the optimum device for nulliparous women remains to be established (Kulier et al., 2006). With respect to the LNGIUS there is less than 1 pregnancy per 100 woman-years of use regardless of parity (Prager and Darney, 2007).
Acceptability
One measure of acceptability is the percentage of removals for complaints, usually bleeding or pain. In general, nulliparous women experience higher rates of expulsion and removals for bleeding or pain compared with parous women (Hubacher, 2007). In the first 12 months follow-up of 2254 nulliparous women, expulsion rates were 6% for the T380A and 9% for the T200, and removal rates for bleeding or pain were 12% for the T200 and 14% for the T380A (Sivin and Stern, 1979). In the Mexican randomized controlled trial among nulliparous women, removal rates for bleeding or pain were less 4% with a smaller T-device (T380Nul) and 59% with the regular T380A (Otero-Flores et al., 2003), but the 59% rate is disproportionately higher than the corresponding 14% rate in the Sivin and Stern (1979) study. The discontinuation rate in the first year of the LNG-IUS is 20%, indicating that acceptability is similar among nulliparous and parous women (Prager and Darney, 2007).
Safety
Infection risk is a relative contraindication to fitting any woman with an IUD, it is only present for a few weeks after insertion and probably arises from an undiagnosed cervical infection at the time of insertion. The risk of developing PID following IUD insertion is less than 1% when the risk of sexually transmitted disease is low, as in women who are in a stable, monogamous relationship. Nulliparous women often are notin a stable marital relationship, and may be at higher risk of contracting STDs, especially Chlamydia trachomatis. Usually in monogamous nulliparous women the risk of PID with IUD insertion is safe. Although trial results do not indicate the need to screen for and treat STDs before inserting an IUD (Grimes et al., 2007), the question has not been specifically addressed in young women who may wish to have a child in the future and clinicians are divided on routine use of prophylactic antibiotics.
Return of fertility is a key concern among nulliparous women. Among 558 nulliparous women, 54% of those discontinuing a barrier method delivered within 12 months, compared to 39% of those who had used an IUD and 32% of those stopping the pill (Doll et al., 2001). In a secondary analysis, 46% of 51 women who discontinued the IUD after use for less than 42 months delivered within 12 months, compared to 28% of the 57 women who had used it for more than 78 months (Doll et al., 2001) (Fig. 1).
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The safety of the LNG-IUS seems similar in nulliparous and parous women. There is no greater risk of perforation or expulsion in nulliparous women, although the bulkier frame may interfere with easy insertion in a small nulliparous uterus (Prager and Darney, 2007
). There is also a protective effect against PID similar to that ascribed to other hormonal contraceptives (Toivonen et al., 1991; Prager and Darney, 2007).
Type of device
Smaller devices such as the miniCu7, the shortML250 and the T380Nul were designed to minimize expulsions and removals among nulliparous women, but the findings are not consistent. In a systematic review that identified 20 comparisons of nulliparous and parous women from 15 individual studies, there were more expulsions among nulliparous women in 13 of 20 comparisons, and more removals for bleeding/pain in 15 of 20 comparisons (Hubacher, 2007). In eight studies comparing different IUD types in nulliparous women, no type or size of IUD had consistently better expulsion rates or lower removal rates for bleeding or pain (Hubacher, 2007). Since the efficacy and safety of the LNG-IUS in nulliparous women is at least equal but possibly superior to copper releasing IUDs, the LNG-IUS is not contraindicated in nulliparous women of any age (NICE, 2005).
The risks and benefits of the copper IUDs and the LNG-IUS in nulliparous women, including the return of fertility after long-term use, are based on relatively few studies and few subjects and need further investigation.
Postcoital contraception with IUD and IUS
The IUD was first proposed for postcoital contraception by Tatum and Lippes in 1975 and the first clinical study was published in 1976 (Lippes et al., 1976). In that study, no pregnancies were reported in 96 IUD insertions for emergency contraception. A 1989 review of the literature summarized nine studies that involved 879 postcoital insertions of an IUD, with only one pregnancy (Fasoli et al., 1989). The estimated pregnancy rates for postcoital contraception were 0.1% for the IUD, 1.5% for single dose levonorgestrel (von Hertzen et al., 2002), 1.8% for ethinyl estradiol with levonorgestrel and 2.0% for danazol.
Although copper IUDs are a highly effective emergency contraceptive, the hormone releasing IUS is not recommended for emergency contraception and limited experience suggests it is not effective. The absence of embryotoxic copper ions is one factor; also, the serum levels of levonorgestrel obtained immediately following insertion of an IUS are not as high as those achieved with standard hormonal emergency contraception.
Effectiveness of the copper IUD for postcoital contraception
Effectiveness of the IUD for emergency contraception has not been evaluated in level I studies because of difficulties in conducting the necessary randomized trials. In one trial which randomized 200 subjects to a copper IUD and 100 women to no method there were four pregnancies (2%) in the IUD group and 22 pregnancies (22%) in the non-intervention group (Askalani et al., 1987). In an observational study in China reporting on postcoital insertion of a high copper load IUD (Multiload 375) in 1013 women, there was one pregnancy in parous and one in nulliparous women, giving an overall pregnancy rate of 0.2 per 100 women (Zhou and Xiao, 2001).
In addition to immediate effectiveness, when a copper IUD is used for emergency contraception, a major benefit is that the device can be left in situ as an ongoing method of contraception.
Mode of action
The mechanism of action for the copper IUD as a method of emergency contraception has not been extensively studied. It is very likely that the high degree of efficacy is related in part to the embryotoxic effect of high copper ion concentrations. The associated inflammatory changes also make the endometrium unfavourable for implantation (Stanford and Mikolajczyk, 2002). Studies in mouse models suggest that copper concentrations of 2.5 x 10–5 mol/l are embryotoxic in the genital tract. Copper IUDs with a 200 mm2 copper surface area have 4000-fold higher concentrations (9 x 10–4 mol/l) (Haspels, 1994).
Timing of insertion
An emergency IUD ideally should be fitted within the first 5 days following unprotected sex. If ovulation could be timed accurately, insertion could be up to 5 days after the day of ovulation (that is, up to day 19 in an ideal 28 day cycle) despite multiple episodes of unprotected intercourse (Emergency contraception. Guidance from the CEU, 2006). Later insertion increases the risk of embryo-toxicity if the device fails to prevent implantation.
Complications and risks
In the Chinese case series, the emergency IUD was inserted with ease in 96% of the parous women and 82% of the nulliparous women (Zhou and Xiao, 2001). As would be expected, more nulliparous women required cervical dilatation (21 versus 13%); also, pain and bleeding were more frequent in the nulliparous group during the insertion procedure. The total discontinuation rate of the IUD for all reasons was significantly higher (15%) in nulliparous women compared with 4% in parous women. Spontaneous expulsion rates were similar in both groups.
Among 98 women with IUDs fitted for emergency contraception, pregnancy rates (3%), expulsion rates (9%) and removals for medical reasons (6%) were similar to the rates in controls with electively inserted IUDs (Gottardi et al., 1986). There were, however, more removals for personal reasons in the emergency IUD group (13 versus 6%,) all within 30 days after insertion.
The infection risk with emergency IUD insertion should be assessed as with any IUD insertion although the circumstances surrounding unprotected intercourse may mean that infection risk is higher.
Barriers to use of IUD for emergency contraception
An audit of emergency contraceptive consultation practices in the UK found that only 10 of 718 women (median age 24 years) were informed about IUDs and only 2 had an IUD inserted for emergency contraception (Bannister et al., 2007). Possible reasons were suggested by an earlier study which questioned 100 family planning doctors and 100 family physicians about the potential barriers to insertion of an IUD for emergency contraception. The main drawback was the physicians’ perception that they had insufficient time during the consultation to offer IUDs to the majority of women requesting emergency contraception (Reuter, 1999). The study also highlighted that many physicians overestimated the risk of PID associated with insertion of an emergency IUD.
Cost effectiveness
The majority of women requesting emergency contraception are at low risk of conceiving, having missed only one oral contraceptive pill or having had intercourse at a time of the cycle when their risk was low. Thus, use of a more expensive emergency contraceptive such as the copper IUD will be more wasteful than hormone pills, unless the majority of users continue to use the IUD for long-term contraception (Trussell et al., 1997).
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Intrauterine contraception as an alternative to sterilization |
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Sterilization prevalence is still high (Table V) but the decline seen in some areas may be the result of increased use of long-acting contraceptive methods (DASH Project, 2005
), now that copper IUDs are licensed for up to 10 years and the LNG-IUS is licensed for 5 years. Female sterilization is still the most commonly used modern method of fertility control and sterilization has traditionally been used by couples whose families are complete. However, given the reported five year effectiveness (Table VI) for many couples either the copper IUD or the LNG-IUS may be a better choice.
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The potential for increased IUD/IUS use in place of sterilization is huge: in all 180 million women and 43 million men in the world rely on sterilization. One-fifth of couples use female sterilization in Brazil and India and one-third in China. The potential also extends into Europe: five European countries (UK, The Netherlands, Switzerland, Denmark and Norway) are among the 20 countries with the highest rates of male sterilization, although no western European country features in the list of the 20 countries with the highest rates of female sterilization (Engender Health, 2002
). The proportion of acceptors may be indicated by a UK study of women referred to a clinic to discuss sterilization, fewer than half of whom had heard of the LNG-IUS. Given the opportunity to discuss alternatives to sterilization in detail, one-third of the women chose a long acting contraceptive method in preference to going ahead with sterilization (Mattison and Mansour, 2003). A significant drawback to sterilization is that many couples regret being sterilized; between 7% (in the USA and Colombia) and 17% (in the Dominican Republic). Women undergoing sterilization at age 30 years or younger were about twice as likely as those over 30 to express regret. Younger women were also 18-fold more likely to request information about reversing the procedure and 8-fold more likely to actually undergo reversal or have an evaluation for IVF. The outstanding difference between sterilization and intrauterine contraception is the reversibility of the method.
For many women, the attraction of sterilization lies in the need for no further action after the procedure has been completed. In contrast up to 24% of IUDs are removed after 1 year (NICE, 2005). Other factors to take into consideration when comparing sterilization with intrauterine contraception include the risks associated with IUD insertion versus the sterilization operation. IUD complications include uterine perforation (1 in 1000 insertions) (O’Brien and Marfleet, 2003), expulsion (1 in 20) (NICE, 2005) and PID (1–2 per 1000) (Farley et al., 1992). Sterilization complications among 9475 women included a 1.5% rate of unintended major surgery or re-hospitalization (Jamieson et al., 2000). A further consideration is the non-contraceptive benefits such as amenorrhoea associated with the LNG-IUS (Suhonen et al., 2004). For policy makers cost is a consideration; the incremental cost of each failure prevented with tubal sterilization compared to the LNG-IUS would be US$1150 in 2001 (Chiou et al., 2003). Finally, service providers must be concerned about the availability of facilities and service delivery issues.
Female sterilization and the copper IUD are equally effective in preventing pregnancy and the LNG-IUS is similarly effective and more beneficial if menorrhagia is a symptom. Both sterilization and intrauterine contraception are associated with ectopic pregnancy if they fail, probably less with IUD and less still with IUS. IUDs and IUS can last for a very long time and perhaps long enough to allow women to become menopausal. Overall, the LNG-IUS is arguably the best method, and should be made available at low cost in developing countries where sterilization is so common and where rates of regret can be high.
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Gynecological treatment |
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The LNG-IUS has been approved in many countries not only for contraception, but also for treatment of menorrhagia and for endometrial protection during menopause hormone treatment. Since the LNG-IUS also decreases dysmenorrhoea, it may be indicated in gynaecological conditions that involve the symptom.
LNG-IUS for treatment of dysmenorrhea associated with endometriosis
Dysmenorrhea is the most frequent symptom in women with endometriosis and this symptom is decreased in most women using the LNG-IUS. After the first year of use 20–30% of users have amenorrhea and in the remainder there is a 70–90% reduction in MBL (Shulman et al., 2004). Levonorgestrel induces endometrial glandular atrophy, causes extensive decidual transformation of the stroma, down regulates endometrial cell proliferation, increases apoptotic activity, and has anti-inflammatory and immunomodulatory effects. These changes suggest a biological rationale for use of the LNG-IUS in women with endometriosis to relieve pelvic pain symptoms (Grimes et al., 2007). The alternatives (danazol and GnRH agonists) are costly and associated with significant side effects. Moreover, they generally must be withdrawn after a few months, in contrast to the potential for long-term treatment with the LNG-IUS (Vercellini et al., 2005). In four small studies involving 20–34 patients with endometriosis, pain relief was satisfactory in 60–96% of patients treated for six to 36 months (Vercellini et al., 1999; Lockhat et al., 2004, 2005b; Petta et al., 2005). In the latter study pain relief was similar for six months with the LNG-IUS and a GnRH agonist (Fig. 2). The LNG-IUS also appeared to reduce the risk of recurrence of dysmenorrhoea after conservative surgery for endometriosis; dysmenorrhoea recurred in 2 of 20 LNG-IUS patients and 9 of 20 who had surgery only (Vercellini et al., 2003).
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A systemic effect due to the low levels in serum of LNG absorbed from the uterus may explain why the LNG-IUS appears to relieve pain caused by peritoneal and recto-vaginal endometriosis (Lockhat et al., 2005a). Eleven symptomatic patients with recto-vaginal endometriosis had greatly reduced dysmenorrhoea, pelvic pain and deep dyspareunia over 12 months of LNG-IUS use; trans-rectal and trans-vaginal ultrasonography showed that the size of the endometriosis lesions was significantly reduced by treatment (Fedele et al., 2001
).
The LNG-IUS also was used in a small series of women who had menorrhagia associated with adenomyosis (Fedele et al., 1997). Among 25 patients aged 38–45 years with menorrhagia and an ultrasonographic diagnosis of adenomyosis, 1-year follow-up was completed by 23 women, who had reduced average monthly blood loss and reported amenorrhea (2), oligomenorrhea (3), spotting (2) and regular periods (16).
Results in one trial and small case series are promising, but more trials are needed to determine whether the IUD-IUS as a treatment for endometriosis or adenomyosis is effective.
The LNG-IUS as an alternative to hysterectomy for treatment of excessive menstrual bleeding
Hysterectomy is one of the most common surgical procedures performed in gynaecological practice and the most common indication for hysterectomy is excessive menstrual bleeding. Almost 500 000 hysterectomies are performed each year in the USA because of menstrual disorders and more than 18 000 hysterectomies were performed in England each year solely because of menorrhagia (Rees, 1989) but in the last 15 years this number has been halved. Approximately 10–15% of fertile women have menorrhagia, defined as MBL > 80 ml (Hallberg et al., 1966).
Various forms of medical treatment have been advocated as initial treatment of idiopathic menorrhagia because hysterectomy involves not insignificant morbidity and mortality. Effective medical treatments include (with the percentage MBL reduction): anti-fibrinolytic agents (40–50% reduction), prostaglandin synethetase inhibitors (20–25%), oral contraceptives (40–50%) and LNG-IUS (86–97% reduction) (Milsom et al., 1991; Hurskainen et al., 2007; Milsom, 2007). The greatest reduction in MBL was achieved with the LNG-IUS (Andersson and Rybo, 1994) (Fig. 3).
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The superiority of the LNG-IUS among medical treatments of idiopathic menorrhagia was shown in an randomized controlled trial comparing LNG-IUS and mefenamic acid. At the 6th cycle of treatment, both treatment groups had a reduction in MBL, total menstrual fluid loss and pictorial blood loss, but the reduction with LNG-IUS was significantly greater (Reid and Virtanen-Kari, 2005
). The LNG-IUS has also been shown to be effective in women with menorrhagia due to inherited bleeding disorders (Kingman et al., 2004). The evidence suggests that the LNG-IUS would be a logical alternative to hysterectomy for treating menorrhagia.
An unblinded randomized controlled trial tested LNG-IUS as a means of avoiding hysterectomy in 56 women aged 33–49 years who had excessive uterine bleeding and were scheduled for hysterectomy (Lahteenmaki et al., 1998). The women either continued their current medical treatment or had an LNG-IUS inserted. At 6 months 64% (95% CI 44–81) of the LNG-IUS group cancelled their hysterectomy appointment compared with 14% (4–32) of the control group.
A second RCT directly compared the LNG-IUS (119 women) with hysterectomy (117 women). Only 50 (42%) in the LNG-IUS group subsequently underwent a hysterectomy during the 5-year observation period. Overall quality of life was similar in the two groups and LNG-IUS costs were 40% lower than hysterectomy costs (Hurskainen et al., 2004).
Endometrial ablation is another effective alternative to hysterectomy as a treatment for heavy menstrual bleeding (Lethaby et al., 1999). The LNG-IUS has not fared as well when compared to endometrial destruction in five trials. Endometrial ablation caused significantly greater reduction in menstrual flow in two trials and higher rates of successful treatment in three trials, although the rates of satisfaction with LNG-IUS and ablation treatment were similar. In addition, endometrial ablation does not guarantee contraception (Lethaby et al., 2005).
Strong, consistent level I evidence indicates that use of the LNG-IUS is the best medical alternative to hysterectomy.
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Summary |
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IUDs that release copper or levonorgestrel are extremely effective contraceptives. The LNG-IUS also reduces menorrhagia and dysmenorrhoea. The major barrier to long-term effectiveness is the discontinuation rate, mainly for menstrual problems. Although IUDs are the most widely used reversible method of family planning in the world, utilization would be greater still if not for limitations in device and provider availability and misplaced concern about the risk of infection.
Both copper IUDs and levonorgestrel releasing IUSs may interfere with implantation, although this may not be the primary mechanism of action. The devices also create barriers to sperm transport and fertilization, and sensitive assays detect hCG in less than 1% of cycles, indicating that significant prevention must occur before the stage of implantation.
The copper IUD, but not the LNG-IUS, is an effective emergency contraceptive. The copper IUD would be a cost-effective emergency contraceptive if it were left in place for continuing contraception. The copper IUD is, however, inconvenient for clinicians to insert in an emergency, and the alternative treatments are simple and cheap.
Surprisingly little robust research evidence exists to support IUD use in nulliparous women, although nulliparity is not a contraindication in many guidelines. Although effectiveness is similar in nulliparous and parous women, insertion is more difficult, there are more expulsions and removals, some nulliparous women are not monogamous and therefore at higher risk of PID. Research on smaller devices is inconclusive.
Intrauterine contraception provides a contraception which is just as effective as, and arguably safer than, female sterilization.
In patients with endometriosis small studies indicate that the LNG-IUS may reduce dysmenorrhoea and other pelvic pain symptoms. Trials are needed to confirm these effects. As there are proven alternative treatments the trials cannot include a placebo arm, active controls could be the proven continuous and cyclic use of oral contraception. Trials also could verify whether the results are maintained for up to 5-years and evaluate the effectiveness of the LNG-IUS for treatment of dyspareunia and dyschezia.
Non-contraceptive benefits, particularly the effect of the LNG-IUS on menstrual bleeding patterns and the option for prolonged duration of use add to its acceptability as an alternative to sterilization.
The LNG-IUS is a proven alternative to hysterectomy and endometrial ablation. Many surgical procedures are still performed without first evaluating the LNG-IUS or other medical treatments. Not only is the LNG-IUS highly effective in reducing MBL, it is well tolerated, has a high user satisfaction rate and is cost effective.
Given these potential applications, the priority is for a low cost progestogen IUS to provide effective contraception and reduce reliance on surgical sterilization and hysterectomy in both developed and developing countries.
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Funding |
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The meeting was organized with an unrestricted educational grant from Bayer Schering Pharma Italia. University of Milano provided the secretarial support for the manuscript preparation.
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Appendix |
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A meeting was organized by ESHRE to discuss the above subjects. The speakers included: D.T. Baird (Centre for Reproductive Biology, University of Edinburgh, UK), C. D’Arcangues (Department of Reproductive Health and Research World Health Organization, Geneva, Switzerland), J.L.H. Evers (Department of Obstetrics and Gynecology, Academic Hospital Maastricht, The Netherlands), A. Gebbie (Consultant Gynaecologist, Family Planning and Well Woman Service, Edinburgh, UK), A. Glasier (Family Planning and WW Services, Edinburgh, UK), I. Milsom (Department of Obstetrics and Gynecology, Sahlgrenska Academy at Göteborg University and Sahlgrenska University Hospital, Göteborg, Sweden), R. Sitruk-Ware (Rockefeller University and Population Council, New York, USA), P. Vercellini (II Department of Obstetrics and Gynecology, University of Milano, Italy). The discussants included: G. Benagiano (Dipartimento di Scienze Ginecologiche, Università di Roma, Italy), D. Cibula (Department of Obstetrics and Gynecology, Charles University Prague, Czech Republic), J. Collins (McMaster University, Hamilton, Canada), P.G. Crosignani (II Department of Obstetrics and Gynecology, University of Milano, Italy), E. Diczfalusy (Karolinska Institutet, Stockholm, Sweden), A. Lanzone (Clinica Ostetrica e Ginecologica, Policlinico A. Gemelli, Roma, Italy), S.O. Skouby (Department of Obstetrics and Gynecology, University of Copenhagen, Denmark) and A. Volpe (Dipartimento Integrato Materno Infantile, Università di Modena, Italy). The report was prepared by J. Collins and P.G. Crosignani.
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Acknowledgements |
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The secretarial assistance of Mrs Simonetta Vassallo is gratefully acknowledged.
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References |
|---|
Alvarez F, Brache V, Fernández E, Guerrero B, Guiloff E, Hess R, Salvatierra AM, Zacharias S. New insights on the mode of action of intrauterine contraceptive devices in women. Fertil Steril (1988) 49:768–773.[Web of Science][Medline]
Andersson KJ, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynecol (1990) 97:690–694.[Web of Science][Medline]
Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception (1994) 49:56–72.[CrossRef][Web of Science][Medline]
Askalani AH, Sentity AL, Al-Agizy AM, Salam HI, Al-Masry GI, El-Sadek SM. Evaluation of copper T200 as a post-coital contraceptive. Egypt Obstet Gynaecol (1987) 13:63–66.
Asker C, Stokes-Lampard H, Beavan J, Wilson S. What is it about intrauterine devices that women find unacceptable? Factors that make women non-users: a qualitative study. J Fam Plan Reprod Healthcare (2006) 32:89–94.[CrossRef]
Backman T, Huhtala S, Luoto R, Tuominen J, Rauramo I, Koskenvuo M. Advance information improves user satisfaction with the levonorgestrel intrauterine system. Obstet Gynecol (2002) 99:608–613.[CrossRef][Web of Science][Medline]
Backman T, Rauramo I, Huhtala S, Koskenvuo M. Pregnancy during the use of levonorgestrel intrauterine system. Am J Obstet Gynecol (2004) 190:50–54.[CrossRef][Web of Science][Medline]
Backman T, Rauramo I, Jaakkola K, Inki P, Vaahtera K, Launonen A, Koskenvuo M. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol (2005) 106:813–817.[Web of Science][Medline]
Baldaszti E, Wimmer-Puchinger B, Loschke K. Acceptability of the long term contraceptive levonorgestrel-releasing intrauterine system (Mirena®): a 3-year follow-up study. Contraception (2003) 67:87–91.[CrossRef][Web of Science][Medline]
Bannister L, Macve J, Pinkey B, Webberley H. Is the faculty of family planning and reproductive health care guidance on emergency contraception being followed in general practice? An audit in the West Midlands, UK. J Fam Plann Reprod Health Care (2007) 33:195–198.[CrossRef][Web of Science][Medline]
Barbosa I, Olsson SE, Odlind V, Goncalves T, Coutinho E. Ovarian function after seven years’ use of a levonorgestrel IUD. Adv Contracep (1995) 11:85–95.[CrossRef]
Cheng L, Gulmezoglu AM, Van Oel CJ, Piaggio G, Ezcurra E, Van Look PFA. Interventions for emergency contraception [Reviews]. The Cochrane Library (2007) Vol. 2.
Chiou CF, Trussell J, Reyes E, Knight K, Wallace J, Udani J, Oda K, Borenstein J. Economic analysis of contraceptives for women. Contraception (2003) 68:3–10.[CrossRef][Web of Science][Medline]
Critchley H. Endometrial effects of progestogens. Gynecol Forum (2003) 8:6–10.
DASH Project. Key Clinical Indicators for Sexual Health: Action 12 Report on the Baseline Data for 2005 (2005) National Health Services Scotland. 19. http://www.scotland.gov.uk/Resource/Doc/924/0044637.pdf.
Den Tonkelaar D, Oddens BJ. Factors influencing women’s satisfaction with birth control methods. Eur J Reprod Health Care (2001) 6:153–158.[CrossRef]
Doll H, Vessey M, Painter R. Return of fertility in nulliparous women after discontinuation of the intrauterine device: comparison with women discontinuing other methods of contraception. Br J Obstet Gynaecol (2001) 108:304–314.[CrossRef][Web of Science]
Dubuisson JB, Mugnier E, The Mirena Study Group. Acceptability of the levonorgestrel-releasing intrauterine system after discontinuation of previous contraception: results of a French clinical study in women aged 35–45 years. Contraception (2002) 66:121–128.[CrossRef][Web of Science][Medline]
Emergency contraception. Guidance from the CEU. J Fam Plan Reprod Health Care (2006) 32:121–128.[CrossRef]
Engender Health. Contraceptive Sterilization: Global Issues and Trends (2002) New York, USA: Engender Health.
Farley TM, Rosenberg MJ, Rowe PJ, Chen JH, Meirik O. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet (1992) 339:785–788.[CrossRef][Web of Science][Medline]
Fasoli M, Parazzini F, Cecchetti G, La Vecchia C. Postcoital contraception: an overview of published studies. Contraception (1989) 39:459–468.[CrossRef][Web of Science][Medline]
Fedele L, Bianchi S, Raffaelli R, Portuese A, Dorta M. Treatment of adenomyosis-associated menorrhagia with a levonorgestrel-releasing intrauterine device. Ferti Steril (1997) 68:426–429.[CrossRef][Web of Science][Medline]
Fedele L, Bianchi S, Zanconato G, Portuese A, Raffaelli R. Use of a levonorgestrel-releasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril (2001) 75:485–488.[CrossRef][Web of Science][Medline]
Feldblum PJ, Caraway J, Bahamondes L, El-Shafei M, Quan Ha D, Morales E, Wevill S, Condon S. Randomized assignment to copper IUD or depot medroxy-progesterone acetate: feasibility of enrolment, continuation and disease ascertainment. Contraception (2005) 72:187–191.[CrossRef][Web of Science][Medline]
Gottardi G, Spreafico A, De Orchi L. The postcoital IUD as an effective continuing contraceptive method. Contraception (1986) 34:549–558.[CrossRef][Web of Science][Medline]
Grimes DA, Lopez LM, Manion C, Schulz KF. Cochrane systematic reviews of IUD trials: lessons learned. Contraception (2007) 75:S55–S59.[CrossRef][Web of Science][Medline]
Guttinger A, Critchley HO. Endometrial effects of intrauterine levonorgestrel. Contraception (2007) 75:S93–S98.[CrossRef][Web of Science][Medline]
Hallberg L, Högdahl AM, Nilsson L, Rybo G. Menstrual blood loss—a population study. Acta Obstet Gynecol Scand (1966) 45:25–56.
Hampton NR, Rees MC, Lowe DG, Rauramo I, Barlow D, Guillebaud J. Levonorgestrel intrauterine system (LNG-IUS) with conjugated oral equine estrogen: a successful regimen for HRT in perimenopausal women. Hum Reprod (2005) 20:2653–2660.
Haspels AA. Emergency contraception: a review. Contraception (1994) 50:101–107.[CrossRef][Web of Science][Medline]
Horcajadas JA, Sharkey AM, Catalano RD, Sherwin JR, Dominguez F, Burgos LA, Castro A, Peraza MR, Pellicer A, Simon C. Effect of an intrauterine device on the gene expression profile of the endometrium. J Clin Endocrinol Metab (2006) 91:3199–3207.
Huang SC, Chen HC, Chen RJ, Hsieh CY, Wei PY, Ouyang PC. The secretion of human chorionic gonadotropin-like substance in women employing contraceptive measures. J Clin Endocrinol Metab (1984) 58:646–653.
Hubacher D. Copper intrauterine device use by nulliparous women: review of side effects. Contraception (2007) 75:S8–S11.[CrossRef][Web of Science][Medline]
Hubacher D, Reyes V, Lillo S, Pierre-Louis B, Zepeda A, Chen PL, Croxatto H. Preventing copper intrauterine device removals due to side effects among first-time users: randomized trial to study the effect of prophylactic ibuprofen. Hum Reprod (2006) 21:1467–1472.
Hurskainen R, Teperi J, Rissanen P, Aalto A-M, Grenman S, Kivelä A, Kujansuu E, Vuorma S, Yliskoski M, Paavonen J. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia. JAMA (2004) 291:1456–1463.
Hurskainen R, Grénman S, Komi I, Kujansuu E, Luoto R, Orrainen M, Patja K, Penttinen J, Silventoinen S, Tapanainen J, et al. Diagnosis and treatment of menorrhagia. Acta Obstet Gynecol Scand (2007) 86:749–757.[CrossRef][Web of Science][Medline]
Hutchings JE, Benson PJ, Perkin GW, Soderstrom RM. The IUD after 20 years: a review of worldwide experience. Int Fam Plann Persp (1985) 11:77–86.[CrossRef]
Jamieson DJ, Hillis SD, Duerr A, Marchbanks PA, Costello C, Peterson HB. Complications of interval laparoscopic tubal sterilization: findings from the United States Collaborative Review of Sterilization. Obstet Gynecol (2000) 96:997–1002.[CrossRef][Web of Science][Medline]
Jecht E, Berstein G. The influence of copper on the motility of human spermatozoa. Contraception (1973) 7:381–401.[CrossRef][Web of Science]
Jonsson B, Landgren B-M, Eneroth P. Effects of various IUDs on the composition of cervical mucus. Contraception (1991) 43:447–458.[CrossRef][Web of Science][Medline]
Katz KR, Johnson LM, Janowitz B, Carranza JM. Reasons for the low level of IUD use in El Salvador. Int Fam Plan Perspect (2002) 28:26–31.[CrossRef][Web of Science]
Kesseru E, Camacho-Ortega P. Influence of metals on in vitro sperm migration in the human cervical mucus. Contraception (1972) 6:231–240.[CrossRef][Web of Science][Medline]
Kingman CEC, Kadir RA, Lee CA, Economides DL. The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG (2004) 111:1425–1428.[Web of Science][Medline]
Kives S, Hahn PM, White E, Stanczyk FZ, Reid RL. Bioavailability of the Yuzpe and levonorgestrel regimens of emergency contraception: vaginal vs. oral administration. Contraception (2005) 71:197–201.[CrossRef][Web of Science][Medline]
Koch UJ. Sperm migration in the human female genital tract with and without intrauterine devices. Acta Eur Fertil (1980) 2:33–60.[Medline]
Kulier R, Helmerhorst FH, O’Brien P, Usher-Patel M, d’Arcangues C. Copper containing, framed intra-uterine devices for contraception. Cochrane Database Syst Rev (2006) Art. No.:CD005347.
Kurz KH, Tadesse E, Haspels AA. In vivo measurements of uterine cavities in 795 women of fertile age. Contraception (1984) 29:495–510.[CrossRef][Web of Science][Medline]
Lahteenmaki P, Suhonen S, Elomaa K. Use of post-coital contraception in Finland is increasing. Plan Parent Eur (1995) 24:13–14.[Medline]
Lahteenmaki P, Haukkamaa M, Puolakka J, Riikonen U, Sainio S, Suvisaari J, Nilsson CG. Open randomised study of use of levonorgestrel-releasing intrauterine system as alternative to hysterectomy. BMJ (1998) 316:1122–1126.
Lethaby A, Shepperd S, Cooke I, Farquhar C. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev (1999) Art. No.: CD000329. DOI: 10.1002/14651858.CD000329.
Lethaby AE, Cooke I, Rees M. Progesterone/progestogen releasing intrauterine systems versus either placebo or any other medication for heavy menstrual bleeding. Cochrane Database Syst Rev (2005) Art. No.: CD002126. DOI: 10.1002/14651858.CD002126.pub2.
Lippes J, Malik T, Tatum HJ. The postcoital copper T. Adv Planned Parenthood (1976) 11:24–29.
Lockhat FB, Emembolu JO, Konje JC. The evaluation of the effectiveness of an intrauterine-administered progestogen (levonorgestrel) in the symptomatic treatment of endometriosis and in the staging of the disease. Hum Reprod (2004) 19:179–184.
Lockhat FB, Emembolu JE, Konje JC. Serum and peritoneal fluid levels of levonorgestrel in women with endometriosis who were treated with an intrauterine contraceptive device containing levonorgestrel. Fertil Steril (2005) a 83:398–404.[CrossRef][Web of Science][Medline]
Lockhat FB, Emembolu JO, Konje JC. The efficacy, side-effects and continuation rates in women with symptomatic endometriosis undergoing treatment with an intra-uterine administered progestogen (levonorgestrel): a 3 year follow-up. Hum Reprod (2005) b 20:789–793.
Luukkainen T, Lahteenmaki P, Toivonen J. Levonorgestrel-releasing intrauterine device. Ann Med (1990) 22:85–90.[Web of Science][Medline]
Luukkainen T. Levonorgestrel-releasing intrauterine device. Ann NY Acad Sci (1991) 626:43–49.[CrossRef][Medline]
Mattison A, Mansour D. Female sterilization: is it what women really want? J Fam Plann Reprod Health Care (2003) 28:136–139.
Milsom I. An important Finnish contribution to the advancement of womens reproductive health. Acta Obstet Gynecol Scand (2007) 86:645–647.[CrossRef][Web of Science][Medline]
Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamc acid and a levonorgestrel-releasing intrauterine device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol (1991) 164:879–883.[Web of Science][Medline]
Mishell DR Jr, Roy S. Copper intrauterine contraceptive device event rates following insertion 4 to 8 weeks post partum. Am J Obstet Gynecol (1982) 143:29–35.[Web of Science][Medline]
Mohllajee AP, Curtis KM, Peterson HB. Does insertion and use of an intrauterine device increase the risk of pelvic inflammatory disease among women with sexually transmitted infections? A systematic review. Contraception (2006) 73:145–153.[CrossRef][Web of Science][Medline]
Myatt L, Bray MA, Gordon D, Morley J. Macrophages on intrauterine contraceptive devices produce prostaglandins. Nature (1975) 257:227–228.[CrossRef][Medline]
NICE. National Institute for Health and Clinical Excellence. Long-acting Reversible Contraception (2005) www.nice.org.uk (25 September 2007, date last accessed).
Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin Endocrinol (1982) 17:529–536.[Medline]
Nilsson CG, Lahteenmaki PL, Luukkainen T, Robertson DN. Sustained intrauterine release of levonorgestrel over five years. Fertil Steril (1986) 45:805–807.[Web of Science][Medline]
O’Brien PA, Marfleet C. Frameless versus classical intrauterine device for contraception (Cochrane Review). In: The Cochrane Library (2003) Vol. 4. Chichester, UK: John Wiley and Sons Ltd.
Ortiz ME, Croxatto HB. Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception (2007) 75:S42–S51.
Ortiz ME, Croxatto HB, Bardin CW. Mechanisms of action of intrauterine devices. Obstet Gynecol Surv (1996) 51:S42–S51.[CrossRef][Medline]
Otero-Flores JB, Guerrero-Carreno FJ, Vazquez-Estrada LA. A comparative randomised study of three different IUD’s in nulliparous Mexican women. Contraception (2003) 67:273–276.[CrossRef][Web of Science][Medline]
Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E Silva JC, Podgaec S, Bahamondes L. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod (2005) 20:1993–1998.
Prager S, Darney PD. The levonorgestrel intrauterine system in nulliparous women. Contraception (2007) 75:S12–S25.[CrossRef][Web of Science][Medline]
Raudaskoski TH, Tomas EI, Paakkari IA, Kauppila AJ, Laatikainen TJ. Serum lipids and lipoproteins in postmenopausal women receiving transdermal oestrogen in combination with a levonorgestrel-releasing intrauterine device. Maturitas (1995) 22:47–53.[CrossRef][Web of Science][Medline]
Rees MCP. Heavy, painful periods. Clin Obstet Gynecol (1989) 3:341–356.
Reid PC, Virtanen-Kari S. Randomised comparative trial of the levonorgestrel intrauterine system and mefenamic acid for the treatment of idiopathic menorrhagia: a multiple analysis using total menstrual fluid loss, menstrual blood loss and pictorial blood loss assessment charts. BJOG (2005) 112:1–5.[Web of Science][Medline]
Reuter S. Barriers to the use of IUDs as emergency contraception. Br J Fam Plann (1999) 25:63–68.[Web of Science]
Segal SJ, Alvarez-Sanchez F, Adejuwon CA, Brache de Mejia V, Leon P, Faundes A. Absence of chorionic gonadotropin in sera of women who use intrauterine devices. Fertil Steril (1985) 44:214–218.[Web of Science][Medline]
Shulman LP, Nelson AL, Darney PD. Recent developments in hormone delivery system. Am J Obstet Gynecol (2004) 190:S39–S48.[CrossRef][Web of Science][Medline]
Sivin I. Utility and drawbacks of continuous use of a copper T IUD for 20 years. Contraception (2007) 75:S70–S75.[CrossRef][Web of Science][Medline]
Sivin I, Stern J. Long-acting, more effective copper T IUD’s: a summary of US experience 1970–1975. Stud Fam Plann (1979) 10:263–281.[CrossRef][Web of Science][Medline]
Sivin I, Tatum HJ. Four years experience with the TCu380A intrauterine contraceptive devices. Fertil Steril (1981) 36:159–163.[Web of Science][Medline]
Sivin I, Stern J, Coutinho E, Mattos CE, el Mahgoub S, Diaz S, Pavez M, Alvarez F, Brache V, Thevenin F, et al. Prolonged intrauterine contraception: a seven-year randomized study of the levonorgestrel 20 mcg/day (LNg 20) and the Copper T380 Ag IUDS. Contraception (1991) 44:473–480.[CrossRef][Web of Science][Medline]
Sivin I, Viegas O, Campodonico I, Diaz S, Pavez M, Wan L, Koetsawang S, Kiriwat O, Anant MP, Holma P, et al. Clinical performance of a new two-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls. Contraception (1997) 55:73–80.[CrossRef][Web of Science][Medline]
Smart YC, Fraser IS, Clancy RL, Roberts TK, Cripps AW. Early pregnancy factor as a monitor for fertilization in women wearing intrauterine devices. Fertil Steril (1982) 37:201–204.[Web of Science][Medline]
Spinnato JA. Mechanism of Action of intrauterine contraceptive devices and its relation to informed consent. Am J Obstet Gynecol (1997) 176:503–506.[CrossRef][Web of Science][Medline]
Stanford JB, Mikolajczyk RT. Mechanisms of action of intrauterine devices: update and estimation of postfertilization effects. Am J Obstet Gynecol (2002) 187:1699–1708.[CrossRef][Web of Science][Medline]
Sturdee DW, Rantala ML, Colau JC, Zahradnik HP, Riphagen FE. The acceptability of a small intrauterine progestogen-releasing system for continuous combined hormone therapy in early postmenopausal women. Climacteric (2004) 7:404–411.[CrossRef][Web of Science][Medline]
Suhonen S, Haukkamaa M, Jakobsson T, Rauramo I. Clinical performance of a levonorgestrel-releasing intrauterine system and oral contraceptives in young nulliparous women: a comparative study. Contraception (2004) 69:407–412.[CrossRef][Web of Science][Medline]
Sullivan TM, Bertrand JT, Rice J, Shelton JD. Skewed contraceptive method mix: why it happens, why it matters. J Biosoc Sci (2006) 38:501–521.[CrossRef][Web of Science][Medline]
Thiery M. Three years experience with the ML Cu250, a new copper-wired intrauterine contraceptive device. Br J Fam Plann (1979) 5:36–38.
Toivonen J, Luukkainen T, Allonen H. Protective effect of intrauterine release of levonorgestrel on pelvic infection: three years’ comparative experience of levonorgestrel- and copper-releasing intrauterine devices. Obstet Gynecol (1991) 77:261–264.[Web of Science][Medline]
Tredway DR, Umezaki CU, Mishell DR Jr, Settlage DS. Effect of intrauterine devices on sperm transport in the human being: preliminary report. Am J Obstet Gynecol (1975) 123:734–735.[Web of Science][Medline]
Trussell J, Koenig J, Ellertson C, Stewart F. Preventing unintended pregnancy: the cost effectiveness of three methods of emergency. Contraception (1997) 87:932–937.
United Nations. Department of Economic and Social Affairs. Population Division. World contraceptive use 2005. (2006) United Nations publication (ST/ESA/SER.A/253).
Vercellini P, Aimi G, Panazza S, De Giorgi O, Pesole A, Crosignani PG. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril (1999) 72:505–508.[CrossRef][Web of Science][Medline]
Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril (2003) 80:305–309.[Web of Science][Medline]
Vercellini P, Vigano P, Somigliana E. The role of the levonorgestrel-releasing intrauterine device in the management of symptomatic endometriosis. Curr Opin Obstet Gynecol (2005) 17:59–65.
von Hertzen H, Piaggio G, Ding J, Chen J, Song S, Bártfai G, Ng E, Gemzell-Danielsson K, Oyunbileg A, Wu S, et al, WHO Research Group on Post-ovulatory Methods of Fertility Regulation. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet (2002) 360:1803–1810.[CrossRef][Web of Science][Medline]
Wilcox AJ, Weinberg CR, Armstrong EG, Canfield RE. Urinary human gonadotropin among intrauterine device users: detection with a highly specific and sensitive assay. Fertil Steril (1987) 47:265–269.[Web of Science][Medline]
World Health Organization. UNDP/UNFPA/WHO/World Bank, Special Programme of Research, Development and Research Training in Human Reproduction: IUD Research Group. A randomized multicentre trial of the Multiload 375 and TCu380A lUDs in parous women: three-year results. Contraception (1994) 49:543–549.[CrossRef][Web of Science][Medline]
World Health Organization, Reproductive Health and Research. Medical Eligibility Criteria for Contraceptive Use (2004) 3rd edn. Geneva: World Health Organization. http://www.who.int/reproductive_health/publications/mec/index.htm.
Ylikorkala O, Siljander M, Huhtaniemi I, Kauppila A, Seppala M. Trophoblastic markers in women using intrauterine contraception. Obstet Gynecol (1980) 55:329–332.[Web of Science][Medline]
Zhou L, Xiao B. Emergency contraception with Multiload Cu 375: a multicentre clinical trial. Contraception (2001) 64:107–112.[CrossRef][Web of Science][Medline]
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