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Review

Intrauterine device and upper-genital-tract infection

David A Grimes Concern about upper-genital-tract infection related to intrauterine devices (IUDs) limits their wider use. In this systematic review I summarise the evidence concerning IUD-associated infection and infertility. Choice of an inappropriate comparison group, overdiagnosis of salpingitis in IUD users, and inability to control for the confounding effects of sexual behaviour have exaggerated the apparent risk. Women with symptomless gonorrhoea or chlamydial infection having an IUD inserted have a higher risk of salpingitis than do uninfected women having an IUD inserted; however, the risk appears similar to that of infected women not having an IUD inserted. A cohort study of HIV-positive women using a copper IUD suggests that there is no significant increase in the risk of complications or viral shedding. Similarly, fair evidence indicates no important effect of IUD use on tubal infertility. Contemporary IUDs rival tubal sterilisation in efficacy and are much safer than previously thought. In 1987, a Scientific Group of WHO concluded that, . . . the currently available copper and hormonereleasing IUDs, when properly used, are probably the most effective and reliable reversible method of fertility regulation.1 Nevertheless, use of the intrauterine device (IUD) is languishing in much of the world today. Concern about upper-genital-tract infection and resultant infertility remains a stubborn obstacle to a wider use of modern IUDs. A re-examination of the evidence nullifies much of that concern. I examine several contemporary questions about IUDs and upper-genital-tract infection (endometritis, salpingitis, oophoritis, and peritonitis). In general, the term pelvic-inflammatory disease (PID) is used interchangeably with the above diagnoses. The subjective nature of PID accounts for both wide variations in rates in different populations and diagnostic bias. I searched for relevant articles in any language in MEDLINE dating back to 1969, with the search terms gonorrhoea, chlamydia, infection, salpingitis, pelvicinflammatory disease, infertility, AND intrauterine device. This yielded 76, 76, 665, 143, 710, and 229 citations, respectively. I also searched POPLINE using the following strategy: keyword gonorrhoea (aetiology) OR chlamydia (aetiology) OR pelvic inflammatory disease (aetiology) OR infertility (aetiology) OR adnexitis (aetiology) AND (global) IUD OR IUDS. This yielded 107 references. An EMBASE search was done with the strategy gonorrhoea (aetiology or complications) OR chlamydia OR salpingitis (aetiology or complications) OR pelvic inflammatory disease (aetiology or complications) OR adnexitis (aetiology or complications) OR infertility (aetiology or complications) AND intrauterine contraceptive device. This resulted in 150 citations. The Cochrane Controlled Trials Register yielded 256 citations with intrauterine device as the search term; no additional citations were identified. Reference lists from articles and texts and
Lancet 2000; 356: 101319
Family Health International, PO Box 13950, Research Triangle Park, North Carolina 27709, USA (D A Grimes MD) Correspondence to: Dr David A Grimes (e-mail: dgrimes@fhi.org)

discussions with investigators supplemented the search, which focuses on currently available IUDs. Lists of citations were sent to IUD investigators seeking citations missed, but this search produced no new references. I used the US Preventive Services Task Force rating system2 to assess the quality of evidence and strength of conclusions possible. Quality of evidence I=evidence obtained from at least one proper randomised controlled trial; II-1=evidence obtained from well-designed controlled trials without randomisation; II-2=evidence obtained from welldesigned cohort or case-control analytic studies, preferably from more than one centre or research group; and II-3=evidence obtained from multiple-time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence; III=opinions of respected authorities, based on clinical experience, descriptive studies, case reports, or reports of expert committees. Strength of recommendations A=good evidence to support the recommendation; B=fair evidence to support the recommendation; C=there is insufficient evidence to recommend for or against; D=fair evidence against the recommendation; and E=good evidence against the recom-mendation. This review gives priority to randomised controlled trials, followed by analytic studies, and then case-series reports.

Background: biases in observational studies

Observational research has commonly found an increased risk of salpingitis or tubal infertility among IUD users. For example, the apparent increased risk of upper-genital-tract infection in some observational studies3,4 suggested a causal association. However, this was because of the consistent presence of three types of bias: use of an inappropriate comparison group (women using contraceptives that lower the risk of PID), systematic overdiagnosis of salpingitis among IUD users, and inability to control for confounding factors (such as number of sexual partners).1,3 The Oxford Family Planning Association study showed just how strong these biases can be. In 1981, this large cohort study5 reported a ten-fold, highly

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statistically significant increase in the risk of salpingitis among IUD users compared with women using other contraception. After the WHO Scientific Group called attention1,3 to these three biases, the Oxford investigators updated their analysis, excluding users of the Dalkon Shield and using as the reference group women using other or no method of contraception. In the update,6 the relative risk of salpingitis with older non-medicated devices decreased to 33 (95% CI 2350), and for medicated devices (mostly copper IUDs) to 18 (95% CI 0840). Probable diagnostic bias, residual confounding, and chance could explain the small remaining risk associated with medicated IUDs. Large randomised controlled trials from around the world79 have shown low rates of salpingitis associated with IUD use, even in populations with substantial rates of sexually transmitted diseases (STDs).7,8 In lower-risk populations, salpingitis is rarer still. For example, a randomised controlled trial9 in Los Angeles County, USA, found a rate of salpingitis in the early months of copper IUD use of one per 1000, regardless of whether prophylactic antibiotics were used.

remain the best available. In addition, women who volunteer for trials tend to be healthier than other women, so the ability to generalise trial results needs to be considered.

The IUD tailstring and infection

The Dalkon Shields multifilament tailstring could carry bacteria cephalad by capillary action.16 This has raised the possibility that monofilament tails might facilitate ascent of bacteria as well. Though numerous physical17 and bacteriological18 studies of monofilament tailstrings have been done, their relevance to the risk of infection is unknown. Clinical studies provide a better assessment of the potential risk of the tailstring. Two types of evidence exist: the temporal relationship between insertion and infection; and direct comparisons of IUDs with and without tailstrings. First, as discussed above, if the tailstring facilitated infection, then the risk would remain increased throughout use. This is not the case.7,13,14 Second, randomised controlled trials of IUDs with and without tailstrings have shown no increased risk associated with the appendage. One trial19 compared infection risks associated with a TCu 200B IUD with and without a string. More than 600 women were allocated to each group. Gross cumulative rates of PID at 12 months were similar with and without a string (33% and 35%, respectively). Although the power of this study was limited, the study was able to exclude a large effect of the tailstring. Another trial20 compared a Multiload 250 with the tailstring placed in the endometrial cavity versus the usual position. No case definition of salpingitis was provided, no blinding of evaluators was done, and the random allocation yielded disparate sample sizes; hence, this trial is difficult to interpret. Other trials from China21,22 randomly assigned women to different IUDs, some of which had tailstrings and others of which did not. Over 3300 women were enrolled in these two trials, and no case of infection occurred. Thus, level I evidence supports a class A recommendation2 that the IUD tailstring does not substantially increase the risk of infection. A review of published studies23 and meta-analysis24 on this topic reached the same conclusion.

The IUD as a cause of PID

Foreign bodies in the skin dramatically reduce the bacterial inoculum required to cause infection. By analogy, some researchers have concluded that the presence of an IUD in the uterus lowers host resistance to infection.10 However, the uterus and the skin are very different organs. If an IUD increases a womans risk of upper-genitaltract infection and if her exposure to infection remains constant, then her risk of PID should remain raised throughout the duration of her IUD use. Evidence indicates otherwise. 30 years ago, investigators showed that insertion of an IUD contaminates the endometrial cavity with bacteria.11 Epidemiological studies have confirmed that the risk of upper-genital-tract infection associated with IUDs is temporally linked to insertion. The first large cohort study in the USA in the 1960s showed an inverse relation between risk and time since insertion.12 Since then, a large case-control study from the USA13 found the increase in risk limited to the first 4 months after IUD insertion; by 5 months and thereafter, the risk was not significantly increased. Among married or cohabiting women with only one sex partner in the past 6 months, the risk of salpingitis in the first 4 months of use was increased, but not significantly so.14 Investigations by the WHO7 showed that the increase in risk is confined to the first 20 days after insertion. Importantly, these studies did not compare the risk of PID to that of sexually active women not using contraception. Nevertheless, ascertainment bias related to visits is unlikely to account for this temporal clustering, which is not seen among women initiating other contraceptives or in IUD users around the time of scheduled visits.15 In summary, evidence from large cohort studies,12 case-control studies,13 and randomised controlled trials7 supports a class-A recommendation that any risk of upper-genital-tract infection after the first month is small (table). Because the randomised controlled trials did not allocate women to an IUD or no contraception, these data are analogous to those of a cohort study (level II-2 evidence).2 Of note, trials such as this are unlikely to be done, so level II-2 evidence will

Inserting an IUD in the presence of gonorrhoea or chlamydial infection

In settings where STDs are uncommon, upper-genitaltract infection associated with an IUD is rare. For example, in the large WHO report,7 4031 women in China had IUDs inserted but no case of PID occurred during 9197 woman-years of observation. By contrast, in Africa, where STDs are more prevalent, eight cases of PID occurred during 1292 woman-years of follow-up. Carrying out an abortion in the presence of Neisseria gonorrhoeae or Chlamydia trachomatis increases the risk of postabortal endometritis about three-fold compared with the risk for uninfected women.25,26 By analogy, some studies27 have concluded that inserting an IUD through a cervix infected with these pathogens may be especially risky. However, a common error in logic here is use of the wrong comparison group. The usual comparison group is uninfected women having an IUD inserted; by contrast, the appropriate comparison group is

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Issue

Highest level of evidence II-2 I II-2

Strength of Conclusion conclusion A A C Risk related to insertion process Monofilament tailstring not a vector for infection Limited data, but no evidence of increased risk compared with gonorrhoea or chlamydia without an IUD insertion No significant effect on overall complications or viral shedding No increase in risk Limited data Conflicting data on protection against PID No impaired response to antibiotic therapy No substantial increase in risk

IUD as cause of PID Tailstring as cause of PID IUD insertion in presence of gonorrhoea or chlamydia IUD use by women with HIV infection Acquisition of chlamydia by IUD user Acquisition of gonorrhoea by IUD user Levonorgestrel-releasing IUD and upper-genital-tract infection Treatment of PID with IUD in situ Infertility after discontinuation

II-2 II-2 II-2 II-2

B B C C

I II-2

B B

Clinical issues and available evidence

asymptomatic infected women not having an IUD inserted. The latter address the key question: given asymptomatic cervical infection, does IUD insertion increase the risk? provided One randomised controlled trial20 information about chlamydia. Among 445 women randomised to receive a Mutiload 250 device with the string left in the endometrial cavity or in usual position, 13 had chlamydia at insertion. All were successfully treated with the IUD in place; none developed PID (95% CI 025). Several observational studies have addressed this issue. A case-series report from Brazil27 found that 19 of 327 women who had Copper T380A IUDs inserted had unsuspected chlamydial infection at insertion. Two of 19 women returned within 2 weeks because of lower abdominal pain. One had a clinical diagnosis of PID and had the IUD removed; the other was afebrile and reported only mild pelvic pain during bimanual vaginal examination. The IUD was not removed from this woman, and since she did not meet minimal criteria for diagnosing typical PID.28,29 One (5%) in 19 (95% CI 026) developed symptomatic PID within 2 weeks of insertion. A similar case-series report from Norway found no case of PID among five women (052) who had IUD insertions through a cervix infected with chlamydia.30 Another case-series from England31 reported no PID among nine women with IUD insertions in the presence of chlamydial cervicitis (034). Without a comparison group, these studies do not allow cause-and-effect conclusions27 to be drawn. Two Kenyan studies used uninifected women as the comparison group. In a cohort study,32 women infected with either gonorrhoea or chlamydia had a significant increase in the risk of early complications compared with those not infected with these pathogens. The relative risk of overall complications was 285 (130627) and for infection-related complications 276 (115662). A randomised controlled trial of antibiotic prophylaxis before IUD insertion in Kenya8 showed the important role of gonorrhoea. Physicians and patients were masked as to treatment groups (doxycycline vs placebo), and culture results were not available to clinicians for several weeks. Physicians used uniform diagnostic criteria for PID29 for all patients. In the placebo group, two (2%) of 90 women with chlamydial infection at insertion

developed PID in the first month (95% CI 08). Similarly, three (11%) of 27 women with untreated gonorrhoea at insertion developed PID in 1 month (95% CI 229). By comparison, 1% (13) of women with neither pathogen had PID within that time period. Stated alternatively, women with chlamydial infection at insertion had a small, statistically insignificant, increase in risk of PID compared with uninfected women (relative risk 17; 95% CI 0475). By contrast, women with gonorrhoea had a significant increase in risk (83; 24288). In this trial, administration of prophylaxis had a statistically insignificant protective effect against PID overall but a strong effect among women with gonorrhoea. Since STD status was not the exposure of interest in the Kenya trial, this evidence can be considered level II-2. As shown in the Kenyan studies,8,32 women infected with cervical gonorrhoea or chlamydia have an increased risk of PID compared with uninfected women. The unresolved question is whether infected women having an IUD inserted have a higher risk of PID than infected women not having an insertion. Background rates of PID among women infected with gonorrhoea or chlamydia provide an indirect assessment. Many women with untreated chlamydia or gonorrhoea develop ascending infection without instrumentation of the cervix. For example, a study33 of gonorrhoea treatment found that 67 (52%) of 129 patients were also infected with chlamydia. After treatment with penicillin or ampicillin (ineffective against cervical chlamydia), 11 (9%) of the 129 women (95% CI 415) developed PID within 35 days (mean 15 days). A similar study34 found that 6 (30%) of 20 women (95% CI 1254) with gonorrhoea and chlamydia who received penicillin treatment (ineffective against chlamydia) developed PID. Another35 found that 9 (47%) of 19 women (2471) with gonorrhoea developed PID a median of 11 days after infection. Thus, rates of PID associated with IUD insertion8,27,30,32 in the presence of these two STDs fall within or below the reported ranges without IUD insertion.3335 Stated alternatively, the risk does not appear as large as many would anticipate. Nevertheless, the available imperfect evidence does not allow a definitive conclusion about the potential role of the IUD (table). In the absence of laboratory testing for STDs, identifying IUD candidates with cervical infection is difficult. Failure to identify infected women may pose avoidable risks. One studys recommendation for routine bacteriological screening is undermined by its use of historical controls and lack of case definitions.36 Conversely, inappropriately labelling women at high risk for infectious complications of IUD use may deprive them of safe and effective contraception. Use of dataderived STD risk algorithms37 may help to identify appropriate candidates for IUDs.

IUD use by women with HIV infection

Based on theoretical concerns, several international medical organisations38,39 advise against IUD use by HIV-infected women. Two concerns predominate: a possible increased risk of PID because of immunosuppression; and a theoretical increase in the risk of female-to-male transmission of HIV via increased viral shedding or menstrual blood loss. A cohort study in Nairobi, Kenya, suggests that IUDs may be safe in HIV-infected women who have access to

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care.32 Investigators followed 156 women with HIV infection who began using IUDs and compared their outcomes to 493 IUD new users without infection. Physicians assessing the patients were unaware of patients HIV status. At 4 months after IUD insertion (the maximum period of insertion-related infection risk), the overall complication rates were similar for women in both groups (adjusted odds ratio 080; 95% CI 038168). The same held true for infection-related complications (102; 046227). By contrast with HIV infection, cervical infection with gonorrhoea or chlamydia significantly increased the risk of overall complications (risk ratio 285; 95% CI 130627) and infection-related complications (276; 115662). In this study, the comparison group was suboptimal: women without infection having IUDs inserted, rather than women with infection not having IUDs inserted. In summary, infection with gonorrhoea or chlamydia increased risk, whereas HIV infection did not. In this study,40 IUD use remained safe after 2 years of use. Multivariate analysis at 24 months revealed a similar risk of overall complications with and without HIV infection (hazard ratio 10; 95% CI 0616). Infection-related complications were also comparable (13; 0724). Incident PID was infrequent in both groups but higher in those infected with HIV (20% in women infected with HIV and 04% in uninfected women (p=009). With longer IUD use (>5 months), women infected with HIV tended to have more infection-related complications than did uninfected women. Moreover, use of a copper IUD does not appear to increase cervical viral shedding of HIV.41 A before-after study of HIV-infected women from this Nairobi cohort identified infected cells with PCR amplification of HIV-1 gag DNA sequences. The prevalence of shedding before insertion was 50%, and was 43% 4 months after insertion (odds ratio 08; 95% CI 0512). After controlling for potential confounding in a multivariate model, the lack of association persisted (06; 0311). One study42 has examined the potential role of the IUD in female-to-male HIV-1 transmission and found no effect.

detection rates in users of copper T IUDs and in nonusers (14% vs 20%). Another cross-sectional study47 found the prevalence of chlamydial antibodies in IUD users (17%) to be lower than that in oral contraceptive users (39%) and similar to that in women using periodic abstinence or barrier methods of contraception (21%). Another study48 found that geometric mean serum antibody titres for C trachomatis for women with a history of IUD use were not significantly different from those of pregnant women who had never used contraception (1047 vs 617). In addition, lower mean titres among copper IUD users compared with nonmedicated IUD users suggested a possible protective effect of the former against chlamydial infection or against antibody development. Rates of chlamydial infection in these cross-sectional studies may reflect selection bias or confounding. Although level II-2 evidence supports a B recommendation that IUD use does not increase the risk of chlamydial infection, information about gonorrhoea is inadequate.

Levonorgestrel-releasing IUD and upper-genital-tract infection

Unlike other IUDs, the levonorgestrel-releasing intrauterine system may lower the risk of pelvic inflammatory disease, although data are inconsistent. A multicentre randomised controlled trial from Europe compared the levonorgestrel IUD and the Nova T, a copper device. The cumulative 36-month gross discontinuation rates for PID were 05 and 20 per 100 women (p<002)49 and the 60-month rates were 08 and 22 per 100 women, respectively (p<001).50 Another large randomised controlled trial51 compared the levonorgestrel IUD with the Copper T 380A. In this multicentre study, the incidence of PID was low and nearly identical in both groups after 7 years of use. Finally, in WHO trials,7 no case of PID occurred among 1552 women who received the levonorgestrel IUD. Impenetrable cervical mucus, endometrial changes, or reduced retrograde menstruation might be responsible for a protective effect.49 Thus, conflicting Level I evidence does not establish whether the levonorgestrel IUD is associated with a lower risk of PID than other IUDs.

Acquisition of gonorrhoea or chlamydial infection

Little is known about the potential for the IUD to influence the acquisition of cervical STD pathogens. A study from Sweden43 examined the risk of PID among women with cervical gonorrhoea. Even without controlling for potential confounding, the investigators found no significant increase in the risk of PID (confirmed by laparoscopy) among IUD users compared with women using neither an IUD nor oral contraceptives. However, in a cross-sectional study such as this, the timing of STD acquisition in relation to IUD insertion is unknown. Chlamydia studies have been reassuring. A 1988 review of 16 reports44 found no higher risk of cervical chlamydial infection among IUD users than among women using no method of contraception. Since that review,44 a cohort study45 found a significantly lower risk of cervical chlamydia among IUD users than among oral contraceptive users (08 vs seven per 100 woman-years). A cross-sectional study46 using the direct fluorescent antibody test for the C trachomatis antigen found similar

Treatment of upper-genital-tract infection in IUD users

Based on the foreign-body analogy, some have theorised that the presence of an IUD will impair treatment of an upper-genital-tract infection. A laparoscopy study from Sweden52 found no significant difference in the degree of inflammation of the fallopian tubes among IUD users compared with women using neither an IUD nor oral contraception. The same held true for erythrocyte-sedimentation rate and fever. Others have confirmed that the severity of PID is not related to use of an IUD.53 The limited available evidence suggests no important effect of an IUD on the response to antibiotic treatment. A small randomised controlled trial54 found responses to therapy with the IUD left in place or removed to be similar, as seen by declines in erythrocyte sedimentation rate. The investigators concluded that the IUD should generally be left in place during treatment. Because of the limited power of this trial, more evidence is needed.

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Infertility after IUD use

Many studies have examined fertility after IUD discontinuation. Numerous case-series reports5559 have suggested a negligible effect of IUD use on fertility after discontinuation. However, without contemporaneous comparison groups, this evidence is weak. Two large case-control studies60,61 from the USA found an overall increase in the risk of confirmed tubal infertility of 20 to 26 fold after use of all types of IUDs, including Dalkon Shields. However, women who had used only a copper IUD had no significant increase in the risk of primary tubal infertility, even if they had the device removed because of complications.61 7 years after this publication, the investigators reanalysed the data62 and found the risk associated with copper IUDs to be significantly increased. As expected, sexual behaviour was an important risk factor: women who had only one partner had no significant increase in tubal infertility regardless of their choice of contraceptive.60 Other case-control studies have been inconsistent. An Indian case-control study of PID and infertility63 used a suboptimal control group (women having tubal sterilisation operations) and found a significant reduction in risk associated with use of a copper IUD. A Swedish case-control study64 used pregnant women as controls and found no significant effect of IUD use. Using fertile women as controls, French investigators65 found a significant association between tubal infertility and IUDs. A preliminary analysis of another large case-control study of tubal infertility in Mexico66 found a significant association between antibodies to C trachomatis and infertility but not between prior IUD use and infertility. Finally, a Norwegian case-control study of tubal infertility67 used an inappropriate control group (infertile women without tubal obstruction), which precludes interpretation. Cohort studies and a randomised controlled trial have been reassuring. The Oxford Family Planning Association cohort study68 showed no substantial impairment of fertility in parous women after discontinuing IUDs in order to conceive or because of medical problems, compared with women discontinuing other contraceptive methods. Two cohort studies compared fertility rates in women who discontinued copper IUDs; the exposed groups were those who discontinued because of complications, and the unexposed were those who had their IUDs removed so that they could conceive. In New Zealand,69 conception rates were similar during the next 4 years. However, those who had the IUD removed because of problems had a significantly higher induced abortion rate thereafter, reflecting the return of undesired fertility. The Norwegian study70 confirmed these results: no impairment of fertility even after removal because of complications, and a higher rate of induced abortion in this group. In these recent cohort studies, the common theme has been undesired fertility, rather than subfertility. Another small cohort study71 with inadequate power noted no apparent effect of the IUD on fertility. A small randomised controlled trial with inadequate power compared two IUDs and found no apparent effect on fertility.72 One cohort study73 found a faster return of fertility after discontinuation of copper as compared with non-medicated IUDs. Fair evidence indicates no important effect of IUD use on infertility.

Balancing risks and benefits

Unlike barrier contraceptives, IUDs do not protect women against STDs. Unlike combination oral contraceptives, most IUDs do not protect against PID that requires admission to hospital. Protection against infection, however, is not the purpose of contraception. The usual counselling for women at risk of acquiring an STD, independent of contraceptive choice, is to use condoms as needed. This is prudent advice for IUD users as well. Modern IUDs, such as the copper T 380A and levonorgestrel-releasing IUD, are highly effective methods of contraception. Indeed, the efficacy of both IUDs rivals that of tubal sterilisation. The cumulative 12year failure rate with the copper T 380A (22%)74 resembles the cumulative 10-year failure rate for tubal sterilisation (19%).75 By contrast with sterilisation, the IUD is simpler, safer, less expensive, and immediately reversible, but discontinuations are more frequent.76 IUDs may confer non-contraceptive health benefits as well. Five of six case-control studies7782 found protection against endometrial cancer associated with IUD use. In two of these,78,82 the protection was statistically significant. In addition, two studies83,84 suggest modest protection against cervical cancer. Women free of cervical infections seem to have the lowest risk of upper-genital-tract infections associated with IUD. Screening candidates can be done by demographical37 or by bacteriological36 methods. In settings of high STD prevalence, a single oral dose of doxycycline (200 mg) may lower the risk of PID.85 Scheduling the first follow-up visit about 7 days later may allow detection of early infection; the traditional visit after the first menses may miss this opportunity. Methodological flaws in early observational research exaggerated the risk of PID associated with IUD use.1,3,86 This misunderstanding has inadvertently affected womens health around the world by limiting access to a highly effective contraceptive and thus indirectly adding to the burden of unintended pregnancy with its associated risks.76,87 Moreover, IUDs, especially the copper-bearing devices, appear to be the most costeffective modern contraceptive available.88 Extensive evidence now underlines the WHOs Scientific Group assessment1 that todays copper and hormone-releasing IUDs are not only very effective but also very safe.
Support for this study was provided by Family Health International with funds from the U S Agency for International Development under Cooperative Agreement CCP-A-00-95-00022-02. The views expressed in this article do not necessarily reflect those of Family Health International or USAID.

References
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