Elevated Risk of Bacterial Vaginosis Among Users of the Copper Intrauterine Device: A Prospective Longitudinal Cohort Study

Peebles K; Kiweewa FM; Palanee-Phillips T; Chappell C; Singh D; Bunge KE; Naidoo L; Makanani B; Jeenarain N; Reynolds D; S L Hillier; Brown ER; Jared M Baeten; Balkus JE; MTN-020/ASPIRE study team

doi:10.1093/cid/ciaa703

General Gynecology · Infections

Elevated Risk of Bacterial Vaginosis Among Users of the Copper Intrauterine Device: A Prospective Longitudinal Cohort Study

Peebles K, Kiweewa FM, Palanee-Phillips T, Chappell C, Singh D, Bunge KE, Naidoo L, Makanani B, Jeenarain N, Reynolds D, Hillier SL, Brown ER, Baeten JM, Balkus JE, MTN-020/ASPIRE study team

Published August 2, 2021 Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73(3), 513-520

DOI 10.1093/cid/ciaa703 PMID 32505132 PMC PMC8326546

Abstract

Background

Limited evidence suggests that the nonhormonal contraceptive copper intrauterine device (Cu-IUD) may increase bacterial vaginosis (BV) risk, possibly due to increased volume and duration of menses, a common side effect of Cu-IUD use. Although increases in bleeding typically resolve within 6-12 months following initiation, evaluations of the association between Cu-IUD and BV have not included more than 6 months of follow-up.

Methods

This secondary analysis of a human immunodeficiency virus type 1 prevention trial included 2585 African women ages 18-45 followed for up to 33 months. Women reported contraceptive use each month. BV was evaluated by Nugent score in 6-monthly intervals and, if clinically indicated, by Amsel criteria. Andersen-Gill proportional hazards models were used to (1) evaluate BV risk among Cu-IUD users relative to women using no/another nonhormonal contraceptive and (2) test changes in BV frequency before, while using, and following Cu-IUD discontinuation.

Results

BV frequency was highest among Cu-IUD users at 153.6 episodes per 100 person-years (95% confidence interval [CI]: 145.2, 162.4). In adjusted models, Cu-IUD users experienced 1.28-fold (95% CI: 1.12, 1.46) higher BV risk relative to women using no/another nonhormonal contraception. Compared to the 6 months prior to initiation, BV risk was 1.52-fold (95% CI: 1.16, 2.00) higher in the first 6 months of Cu-IUD use and remained elevated over 18 months of use (P < .05). Among women who discontinued Cu-IUD, BV frequency was similar to pre-initiation rates within 1 year.

Conclusions

Cu-IUD users experienced elevated BV risk that persisted throughout use. Women and their providers may wish to consider BV risk when discussing contraceptive options.

Topics

By this author

Reproductive Genetics · Epigenetics

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Johnson J et al., 2025 Journal of Assisted Reproduction and Genetics

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Adverse Effects · Cardiovascular Effects

Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis

Morrison CS et al., 2015 PLoS Med Free full text on PubMed Central

Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. Findings: Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I(2) < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (p(interaction) = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Adverse Effects · Cardiovascular Effects

Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study

Heffron R et al., 2012 Lancet Infect Dis Free full text on PubMed Central

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Oral Contraceptives · Cancer Risk

Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women

Baeten JM et al., 2007 AIDS

Studies of the effect of hormonal contraceptive use on the risk of HIV-1 acquisition have generated conflicting results. A recent study from Uganda and Zimbabwe found that women using hormonal contraception were at increased risk for HIV-1 if they were seronegative for herpes simplex virus type 2 (HSV-2), but not if they were HSV-2 seropositive. To explore the effect of HSV-2 infection on the relationship between hormonal contraception and HIV-1 in a high-risk population. Hormonal contraception has previously been associated with increased HIV-1 risk in this population. Data were from a prospective cohort study of 1206 HIV-1 seronegative sex workers from Mombasa, Kenya who were followed monthly. Multivariate Cox proportional hazards analyses were used to adjust for demographic and behavioral measures and incident sexually transmitted diseases. : Two hundred and thirty-three women acquired HIV-1 (8.7/100 person-years). HSV-2 prevalence (81%) and incidence (25.4/100 person-years) were high. In multivariate analysis, including adjustment for HSV-2, HIV-1 acquisition was associated with use of oral contraceptive pills [adjusted hazard ratio (HR), 1.46; 95% confidence interval (CI), 1.00-2.13] and depot medroxyprogesterone acetate (adjusted HR, 1.73; 95% CI, 1.28-2.34). The effect of contraception on HIV-1 susceptibility did not differ significantly between HSV-2 seronegative versus seropositive women. HSV-2 infection was associated with elevated HIV-1 risk (adjusted HR, 3.58; 95% CI, 1.64-7.82). In this group of high-risk African women, hormonal contraception and HSV-2 infection were both associated with increased risk for HIV-1 acquisition. HIV-1 risk associated with hormonal contraceptive use was not related to HSV-2 serostatus.

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Spotnitz ME et al., 2020 Obstet Gynecol Free full text on PubMed Central

To evaluate the relative risk of cervical neoplasms among copper intrauterine device (Cu IUD) and levonorgestrel-releasing intrauterine system (LNG-IUS) users. We performed a retrospective cohort analysis of 10,674 patients who received IUDs at Columbia University Medical Center. Our data were transformed to a common data model and are part of the Observational Health Data Sciences and Informatics network. The cohort patients and outcomes were identified by a combination of procedure codes, condition codes, and medication exposures in billing and claims data. We adjusted for confounding with propensity score stratification and propensity score 1:1 matching. Before propensity score adjustment, the Cu IUD cohort included 8,274 patients and the LNG-IUS cohort included 2,400 patients. The median age for both cohorts was 29 years at IUD placement. More than 95% of the LNG-IUS cohort used a device with 52 mg LNG. Before propensity score adjustment, we identified 114 cervical neoplasm outcomes. Seventy-seven (0.9%) cervical neoplasms were in the Cu IUD cohort and 37 (1.5%) were in the LNG-IUS cohort. The propensity score matching analysis identified 7,114 Cu IUD and 2,174 LNG-IUS users, with covariate balance achieved over 16,827 covariates. The diagnosis of high-grade cervical neoplasia was 0.7% in the Cu IUD cohort and 1.8% in the LNG-IUS cohort (2.4 [95% CI 1.5-4.0] cases/1,000 person-years and 5.2 [95% CI 3.7-7.1] cases/1,000 person-years, respectively). The relative risk of high-grade cervical neoplasms among Cu IUD users was 0.38 (95% CI 0.16-0.78, P<.02) compared with LNG-IUS users. By inspection, the Kaplan-Meier curves for each cohort diverged over time. Copper IUD users have a lower risk of high-grade cervical neoplasms compared with LNG-IUS users. The relative risk of cervical neoplasms of LNG-IUS users compared with the general population is unknown.

Anti-Infective and Anti-Inflammatory Agents · Nonsteroidal Anti-Inflammatory Drugs

Preventing copper intrauterine device removals due to side effects among first-time users: randomized trial to study the effect of prophylactic ibuprofen

Hubacher D et al., 2006 Hum Reprod

Increased menstrual bleeding and pain are the primary side effects that lead to early removal of the copper intrauterine device (IUD). Ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs) are proven treatments for such IUD-induced problems, but their effect on early IUD removal is unknown. A total of 2019 first-time IUD users were recruited in Chile for this double-blind, randomized, placebo-controlled trial. Half of the participants were given ibuprofen and instructions to take 1200 mg daily during menses (for up to 5 days each cycle) for the first 6 months of IUD use. The other half were asked to take an identical appearing placebo in the same manner. The primary outcome was IUD removal within 12 months of insertion. A total of 1011 and 1008 women were randomly assigned to ibuprofen and placebo, respectively. During 12 months of observation, 190 had the device removed because of dysmenorrhoea and/or increased menstrual bleeding: 85 in the placebo group and 105 in the ibuprofen group. For ibuprofen users, the hazard ratio for removal for these IUD-induced side effects was 1.0 and 1.2 at 6 and 12 months, respectively (both not significant). Although increased menstrual bleeding and pain are common reasons for early IUD removal, prophylactic use of ibuprofen, at the dosage used here, does not reduce removal rates.

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Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort

Kleinschmidt I et al., 2007 Contraception

To investigate whether the incidence of HIV infection is higher among sexually active women using depot medroxyprogesterone acetate (DMPA) or noresthisterone enanthate (NET-EN) injections for contraception than among women using nonhormonal or no contraception. Five hundred and fifty-one initially HIV-negative women were followed up for a total of 491 person-years. Participants were interviewed, counselled, examined, tested for HIV and other STIs, and treated, at three monthly intervals for 1 year. There was no significant association between progestin contraceptive use and HIV infection (rate ratio 1.1, 95% CI 0.5 to 2.8; log-rank test, p=.73). In proportional hazards regression, the only significant hazard ratios for HIV acquisition were prevalent Neisseria gonorrhoea (5.2; 95% CI 1.1 to 23.7, p=.035) and Trichomonas vaginalis (4.8; 95% CI 1.0 to 22.8, p=.049); bacterial vaginosis was marginally significant (2.8; 95% CI 1.0 to 8.3, p=.057). The adjusted hazard ratios for NET-EN and DMPA were 1.76 (95% CI 0.64 to 4.84) and 0.46 (95% CI 0.06 to 3.79), respectively, relative to nonuse. Five hundred and twelve of 551 women had one or more confirmed STIs during the study. There is no evidence of an association between HIV infection and injectable contraceptives. Due to the limited power of this study and because similar studies have not included young women using NET-EN, we recommend that further research be carried out to focus on the use of NET-EN and HIV acquisition in high risk groups.

Adverse Effects · Mood and Libido

Side effects from the copper IUD: do they decrease over time?

Hubacher D et al., 2009 Contraception Free full text on PubMed Central

The copper intrauterine device (IUD) can cause side effects in some women; increased uterine bleeding and pain may cause early removal. Because of simplified reporting from previous research, little is known about how side effects might change over time. This is a secondary analysis of a prospective study of 1947 first-time copper IUD users. Over a 1-year period, we collected detailed information on side effects and looked for trends using generalized mixed-effects regression modeling. During menses, most bleeding and pain side effects were found to decrease over time (p<.05). During intermenstrual intervals, overall spotting and pain complaints remained unchanged, but the number of days with these problems increased (p<.05). Serious side effects that prompted either a clinic visit or IUD removal had varied patterns over time, depending on the type of problem. Side effects from the copper IUD can be troubling for both user and clinician. Some problems improve over time, while others do not. This information may be helpful in counseling women who are considering IUD use and current users who are contemplating IUD removal due to side effects.

General Gynecology › Infections › Vaginal and Cervical Infections · Contraception › Long Acting Methods › Intrauterine Devices · Infections and the Reproductive Microbiome › Vaginal and Cervical Flora › Bacterial Vaginosis

Jared M Baeten

J Baeten

PMID 32505132 32505132 DOI 10.1093/cid/ciaa703 10.1093/cid/ciaa703 Peebles et al. 2021, Peebles 2021

Cite this article

Peebles, K., Kiweewa, F. M., Palanee-Phillips, T., Chappell, C., Singh, D., Bunge, K. E., Naidoo, L., Makanani, B., Jeenarain, N., Reynolds, D., Hillier, S. L., Brown, E. R., Baeten, J. M., Balkus, J. E., & MTN-020/ASPIRE study team (2021). Elevated Risk of Bacterial Vaginosis Among Users of the Copper Intrauterine Device: A Prospective Longitudinal Cohort Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73(3), 513-520. https://doi.org/10.1093/cid/ciaa703

Keywords

bacterial vaginosis, copper intrauterine device, long-acting reversible contraception