The prevention of unintended pregnancy leads to substantial health benefits for women and children, including reduced maternal morbidity and mortality and increased infant survival primarily through birth spacing [1,2]. Among HIV-infected women, prevention of unintended pregnancy is also a key strategy in preventing mother-to-child transmission . Although much effort has been focused on providing antiretroviral therapy (ART) to HIV-infected pregnant women, only about 33% of these women in low-income and middle-income countries (as defined by the United Nations) received ART to reduce perinatal transmission in 2007 . Family planning can play a critical role in preventing HIV transmission [5,6], and a recent economic analysis found that, for the same amount of resources, more HIV-positive births would be prevented by increasing contraceptive use than by increasing nevirapine use during pregnancy .
To protect against transmission to sexual partners, people with HIV and their partners should use male latex condoms correctly and consistently (although evidence is limited, female condoms may also reduce the risk of HIV transmission) . Many women and couples also rely on condoms for pregnancy prevention. However, to achieve dual protection against both infection and pregnancy, many women and couples choose to use condoms along with another method of contraception. Although male or female sterilization may be options for people infected with HIV, sterilization is only appropriate for those who are certain that they wish to prevent pregnancy permanently. There is a wide range of highly effective, reversible contraceptive methods available, including hormonal contraceptives and intrauterine devices (IUDs). Although these methods are well tolerated for use by most women, there are theoretical concerns regarding the use of contraception among women with HIV/AIDS. It is possible that contraceptive methods might enhance HIV disease progression, affect the risk of other adverse health outcomes, or increase the likelihood of HIV transmission to uninfected sexual partners. The simultaneous use of antiretrovirals and hormonal contraception may present some challenges with regard to potential drug interactions; however, direct evidence on drug interactions is limited and has been addressed elsewhere [8,9].
Given the importance of contraceptive use among women with HIV/AIDS to prevent unintended pregnancy and perinatal transmission of HIV, evidence-based guidance regarding contraceptive choices for HIV-infected women is urgently needed. We recently conducted systematic reviews of hormonal and intrauterine contraceptive use among women with HIV/AIDS for the World Health Organization (WHO). This report summarizes the scientific evidence we identified and the WHO recommendations.
The PubMed database was searched for all articles published through August 2009 using the following search terms: (((‘Contraceptive Agents, Female’[Mesh]) OR (‘Contraceptive Devices, Female’[Mesh])) AND ((‘HIV’[Mesh] OR ‘HIV Infections’[Mesh]) OR (‘Acquired Immunodeficiency Syndrome’[Mesh]))) OR (((‘HIV’[Mesh] OR ‘HIV Infections’[Mesh]) OR (‘Acquired Immunodeficiency Syndrome’[Mesh])) AND (‘Virus Shedding’[Mesh])). Articles in all languages were accepted. Reference lists of identified articles and relevant review articles were also searched.
We included primary research reports of observational studies or clinical trials that evaluated use of hormonal or intrauterine contraceptive methods [combined oral contraceptives (COCs), combined injectables, combined rings, combined patches, progestin-only injectables, progestin-only pills (POPs), progestin implants, emergency contraceptive pills, levonorgestrel-releasing intrauterine systems (LNG-IUD), or copper IUDs] among HIV-infected women in association with HIV disease progression, other adverse health outcomes, or sexual HIV transmission to uninfected partners (including shedding of HIV DNA or RNA from the genital tract).
All authors participated in assessing the evidence through the use of standard abstract forms . The quality of each individual study was assessed using the system of the United States Preventive Services Task Force . Summaries of each study included in this review can be found in Tables 1–3. We did not calculate summary statistics due to heterogeneity between the studies with regard to study population, study design, exposure measurement, and study outcome.
Throughout this review, we use the term ‘oral contraceptives’ to describe contraceptive exposure in studies that either did not specify the type of contraceptive pill used (combined or progestin-only) or that reported results for all pill users together and not by type of pill.
From the 883 articles identified by our search strategy, 25 met the inclusion criteria for this review. We also included one article that is being published simultaneously with this review in this supplement of AIDS .
HIV disease progression
HIV disease progression has been examined in eight reports of seven studies of hormonal contraceptive users [12–19] and three studies of copper or LNG-IUDs [18,20,21] (Table 1). Studies used various outcome measures to assess disease progression, including changes in CD4 cell count, HIV RNA levels, and survival.
A randomized controlled trial (RCT) was conducted among 599 postpartum HIV-infected women in Zambia to examine the safety and effectiveness of IUD use among this population . Women were assigned to a copper IUD group (n = 296) or a hormonal contraceptive group [women could choose oral contraceptives or depot medroxyprogesterone acetate (DMPA); n = 303]. Women were followed every 6 months for 2 years, during which 31% of the hormonal contraceptive group and 23% of the IUD group withdrew or were lost to follow-up. A high proportion of women discontinued their assigned method during the study, and some switched to a new method: 49% of women assigned to the IUD discontinued, 76% of whom switched to a hormonal method; 13% discontinued hormonal contraception, of whom 16% switched to the IUD. Within the hormonal group, 34% of women switched between oral contraceptives and DMPA. The rate of death among those assigned to hormonal contraception was 2.89 per 100 woman-years [95% confidence interval (CI) 1.80–4.65], whereas the rate of falling below a CD4 cell count of 200 cells/μl was 11.2 per 100 woman-years (95% CI 8.64–14.6). The rate of death among those assigned to IUDs was 2.01 per 100 woman-years (95% CI 1.17–3.47), whereas the rate of falling below a CD4 cell count of 200 cells/μl was 7.48 (95% CI 5.51–10.2). Therefore, hormonal contraceptive users experienced a nonsignificant increased risk of death (hazard ratio 1.4, 95% CI 0.7–3.0) and a significant increased risk of falling below a CD4 cell count of 200 cells/μl (hazard ratio 1.6, 95% CI 1.04–2.3) compared with IUD users. When both outcomes of death or CD4 cell count below 200 cells/μl were combined, the hazard ratio for the hormonal contraceptive group compared with the IUD group was 1.6 (95% CI 1.1–2.3) in the intent-to-treat analysis and 1.7 (95% CI 1.1–2.5) for the actual-use analysis. A secondary analysis of these data examined the effects of oral contraceptives and DMPA separately compared with IUD use . Significant associations of similar magnitude to the findings from the primary analysis were reported for oral contraceptive use with the outcomes of CD4 cell count less than 200 cells/μl and the composite outcome of CD4 cell count less than 200 cells/μl or death, as well as for DMPA use with the outcomes of CD4 cell count less than 200 cells/μl and the composite outcome of CD4 cell count less than 200 cells/μl or death.
None of the six prospective cohort studies observed an association between hormonal contraceptive use and risk of HIV disease progression [12–17]. A large, multicountry study included 4109 HIV-infected women from 12 clinical sites in Africa and one in Asia and accumulated 5911 person-years of follow-up (median time per participant was 379 days) . Participants used oral contraceptives, implants/injectables, or no hormonal method (including nonhormonal method users and women using no method). Outcomes were becoming eligible or starting ART (as defined by local program criteria) or death. In time-varying adjusted analyses, neither oral contraceptives nor implants/injectables were associated with either of the outcomes individually or with the outcomes considered together when compared with no hormonal method (eligible for ART or death: hazard ratio 0.8, 95% CI 0.6–1.1 for oral contraceptives and hazard ratio 1.0, 95% CI 0.8–1.1 for implants/injectables). A study of HIV-infected female sex workers in Thailand followed 112 oral contraceptive users and 55 DMPA users at 3-month intervals for a median of 15–24 months . There were no differences in the proportion of women with a rapid decline in CD4 cell count, the time to first CD4 cell count less than 200 cells/μl, or survival for oral contraceptive users compared with nonoral contraceptives users and DMPA users compared with non-DMPA users. The Women's Interagency HIV Study analyzed 1721 HIV-infected women, 50 years of age or less, with regard to hormonal contraceptive use and CD4 cell count or HIV RNA levels . Of these women, 87 reported oral contraceptive use, 77 DMPA use, 13 levonorgestrel implant use, and 1544 were nonusers; women were followed up for up to 17 months. At baseline, hormonal contraceptive users had higher CD4 cell counts than nonusers (median 371 vs. 325 cells/μl, P = 0.046), but both groups had similar HIV RNA levels (median 23 000 vs. 21 000 copies/ml, P = 0.58). After the follow-up, hormonal contraceptive use was not associated with changes in HIV RNA levels (P = 0.526). CD4 cell counts increased slightly over time among hormonal contraceptive users (mean increase 27.6 cells/μl, P = 0.01), although this change was not likely to be clinically significant. A study in Kenya enrolled 213 women with HIV who were initiating hormonal contraception, including 101 DMPA, 53 low-dose COC, seven high-dose COC, and 52 POP users, and measured plasma HIV-1 RNA concentrations at baseline and 1–2 months after initiating hormonal contraception . No changes were observed in plasma HIV-1 RNA concentrations for all hormonal contraceptive users (4.84 log10 copies/ml at baseline and 4.88 log10 copies/ml at follow-up, P = 0.47) or for the contraceptive groups individually. A prospective cohort study conducted in Kenya followed 319 HIV-infected postpartum women for up to 24 months and assessed immediate and long-term effects of oral contraceptives and DMPA . Among 193 women who visited twice after the first postpartum month, 41 had initiated oral contraceptives, 43 had initiated DMPA, and 109 were not using hormonal contraception. Visits were approximately 3 months apart. There were no significant differences in the change in HIV RNA levels or CD4 cell counts when comparing oral contraceptive users or DMPA users with women not using hormonal contraception. Similarly, among the 283 women who were followed up to 24 months, no significant differences were seen in HIV RNA levels or CD4 cell counts among the three groups. In a prospective cohort study from Rwanda, investigators followed 460 HIV-infected women, ages 15–35 years, every 6 months for up to 6 years to assess HIV-related mortality . Use of neither oral contraceptives nor DMPA affected the survival when compared with women not using these methods.
Two, small, descriptive studies from Finland examined HIV disease progression among LNG-IUD users [20,21]. In the first study, 12 HIV-infected women were followed for 1 year after LNG-IUD insertion ; the second study enrolled six HIV-infected women and followed them for a mean of 45 months . No statistically or clinically significant changes in CD4 cell count were noted.
Other adverse health outcomes
Four studies have examined the risk of acquiring a sexually transmitted infection (STI) among HIV-infected women using hormonal contraception [22–25] (Table 2). A prospective cohort study followed 242 HIV-infected commercial sex workers in Kenya for a median of 35 months to assess the risk of cervical infections among hormonal contraceptive users . DMPA users were at increased risk of Chlamydia trachomatis infection (hazard ratio 3.1, 95% CI 1.0–9.4) and cervicitis (hazard ratio 1.6, 95% CI 1.0–2.3), but not Neisseria gonorrhoeae infection (hazard ratio 1.0, 95% CI 0.6–1.7), adjusted for the presence of cervical ectopy, when compared with women who were sterilized or used no method. A similar pattern was found for oral contraceptive users compared with sterilized women or those using no method (C. trachomatis: hazard ratio 2.2, 95% CI 0.7–7.3; cervicitis: hazard ratio 2.3, 95% CI 1.4–3.8; N. gonorrhoeae: hazard ratio 0.6, 95% 0.3–1.3). Another prospective cohort study of female sex workers in Kenya enrolled 157 HIV-seropositive women and 145 seronegative women in order to examine risk factors for genital ulcer disease (GUD) . The mean duration of follow-up was 24.3 months. Among HIV-infected women, any use of oral contraceptives during follow-up was associated with a small increased risk of GUD compared with nonusers [relative risk (RR) 1.4, 95% CI 1.0–1.9]. However, it is not known whether oral contraceptives were used at the time of incident GUD, and there was no adjustment for condom use and other sexual behavior variables. A retrospective cohort study enrolled 241 women with HIV, of whom 30 were using oral contraceptives, 47 were using DMPA or Norplant, 91 were using condoms only, and 73 had undergone tubal ligation . Women received semi-annual gynecologic evaluations, including STI screening. The outcome measure was incident STI, including incident infection with N. gonorrhoeae, C. trachomatis, syphilis, or trichomonas. Oral contraceptive users had a nonsignificant increased risk of incident STI (RR 1.5, 95% CI 0.6–3.6) compared with the rest of the cohort (i.e., the other hormonal contraceptive users were included in the comparison group). DMPA and Norplant users had a three-fold increased relative risk of STI (95% CI 1.4–6.6) compared with the rest of the cohort. It is unclear whether contraceptive use was measured over time or only at baseline, and therefore actual contraceptive use at the time of STI acquisition might have been misclassified. The final study was a retrospective cohort of 304 HIV-infected women in the United States, which found no differences in rates of chlamydial infections, gonorrhea, or trichomoniasis when comparing DMPA users with nonhormonal users, even though DMPA users more often reported having multiple partners and less condom use . No adjusted analyses were reported.
Two studies reported no adverse health outcomes among HIV-infected Norplant users [26,27]. A study of 41 Thai Norplant users with asymptomatic HIV-1 infection, who were within 4 weeks postpartum or postabortion, found no adverse changes in mean blood pressure, body weight, or hemoglobin levels over 12 months . A similar study of 88 asymptomatic HIV-1-infected Thai women, who received Norplant within 48 h postpartum, followed participants for 24 weeks . Although 62% reported irregular bleeding, none of the 80 women who completed follow-up discontinued Norplant use, and most reported no other side effects.
Two studies examined the risk of infectious complications, particularly pelvic inflammatory disease (PID), among IUD users [18,28,29]. A prospective cohort study in Nairobi, Kenya, followed 156 HIV-infected women and 493 noninfected women from the insertion of an IUD to 4 months  and 24 months of use . Prevalence of overall and infectious complications was low, and there were no statistically significant associations between HIV-infection status and overall complications [odds ratio (OR) 0.80, 95% CI 0.38–1.68] or infectious complications (OR 1.02, 95% CI 0.46–2.27) at 4 months . At 24 months of use, the lack of association persisted for overall complications (hazard ratio 0.98, 95% CI 0.59–1.60) . The same was true for infectious complications, although there was a nonsignificantly increased risk of infection among women with HIV after 155 days or more of follow-up (hazard ratio 1.84, 95% CI 0.77–4.39) that was not seen for less than 155 days of follow-up (hazard ratio 0.79, 95% CI 0.35–1.76). There were no differences in infectious complications or overall complications by level of immunosuppression. The rates of PID were low in this study population; the proportions of HIV-infected women and noninfected women with PID at the 4-month visit were 1.4 and 0.2%, respectively,  and at the 24-month visit were 2.0 and 0.4%, respectively (P = 0.09) . The RCT conducted in Zambia, described earlier, reported one case of PID, which occurred in an IUD user, for a rate of 0.16 per 100 woman-years (95% CI 0.004–87) .
Two, small, descriptive studies from Finland described earlier reported no adverse health effects among LNG-IUD users [20,21]. In the study with 12 HIV-infected women followed for 1 year after LNG-IUD insertion, no statistically or clinically significant changes were found in serum hemoglobin or ferritin, or in abnormal Pap smear results; women reported less menstrual bleeding over time . The second study enrolled six women with HIV and followed them for a mean of 45 months, and found that Pap smear results remained unchanged, whereas menstrual bleeding decreased and hemoglobin levels increased (mean increase of 12 g/l) .
HIV transmission to partners, including HIV-1 DNA and RNA shedding
Only one study was identified that directly examined the influence of oral contraceptive and copper IUD use on risk of female to male HIV transmission  (Table 3). A European cohort study that included 151 male partners of HIV-infected women found similar percentages of male seroconversion among those whose partners used oral contraceptives compared with those who used no regular contraception (18 and 12%, respectively) and for copper IUD users compared with no regular contraception (10 and 12%, respectively). The study was underpowered and results were unadjusted for sexual behavior or condom use. Of the total 19 HIV-infected men, 16 were seropositive at baseline; therefore, the temporal sequence for contraceptive use and HIV transmission, as well as the direction of transmission (male-to-female or female-to-male), remain unclear.
Seven studies have examined the influence of hormonal contraceptive use on the risk of HIV-1 DNA or RNA shedding from the genital tract, as a proxy measure for infectivity, among HIV-infected women [14,31–36]. A prospective study examined HIV-1 DNA and RNA cervical shedding among hormonal contraceptive users enrolled 213 women at the time of initiation of COCs, POPs, or DMPA . After a median follow-up of 64 days, the proportion of women with HIV-1 DNA cervical shedding increased from 42 to 52% (OR 1.62, 95% CI 1.03–2.63); however, the proportion of women shedding HIV-1 RNA only changed slightly from 82% at baseline to 86% at follow-up (OR 1.56, 95% CI 0.83–3.03). Another prospective study found no differences in HIV-1 RNA genital tract shedding between hormonal contraceptive users (mostly DMPA) and nonusers at baseline (adjusted OR 0.60, 95% CI 0.16–2.29) or after 3 months (adjusted OR 0.59, 95% CI 0.13–2.72) . Three cross-sectional studies in Kenya evaluated the correlation between hormonal contraceptive use and cervical shedding of HIV DNA. Two of these studies found significant associations between OC use and cervical shedding (OR 11.6, 95% CI 1.7–77.6 and OR 4.9, 95% CI 2.1–11.8) [31,33], whereas one did not (OR 0.6, 95% CI 0.3–1.3) . One of these studies also found an association between DMPA use and cervical HIV DNA shedding (OR 2.9, 95% CI 1.5–5.7) . Neither of the two studies examining vaginal HIV DNA shedding observed an association with hormonal contraceptive use [31,33]. A cross-sectional study in Senegal reported no association between hormonal contraceptive use and HIV-1 or HIV-2 RNA cervicovaginal shedding; however, this study had few hormonal contraceptive users . A cross-sectional study conducted in the United States found no association between hormonal contraceptive use and HIV-1 RNA cervical shedding (OR 0.5, 95% CI 0.2–1.9) .
None of the four studies that examined copper or LNG-IUDs found an association with shedding of HIV-infected cells [20,33,34,37]. In the Nairobi prospective cohort described earlier [28,29], cervical swab samples were taken from 98 HIV-infected women before insertion of an IUD and then 4 months later . There was no significant association between IUD use and shedding (OR 0.6, 95% CI 0.3 – 1.1). In a cross-sectional study in Mombasa, Kenya, swabs of endocervical and vaginal cells of 318 women were analyzed for the presence of HIV-1 DNA . There was no association between IUD use and shedding of HIV-1 DNA in endocervical cells (OR 0.2, 95% CI 0.0 – 2.2, P = 0.2) compared with noncontraceptive users; none of the IUD users were positive for HIV-1 DNA from vaginal swabs. Another cross-sectional study of 311 HIV-infected women conducted in the United States found no association between IUD use and HIV-1 RNA cervical shedding, after adjusting for plasma RNA; the number of IUD users included in the analysis and the actual risk estimates for IUD use were not reported . One small study of HIV-infected women using LNG-IUDs also examined cervical shedding of HIV RNA and found no statistically or clinically significant changes over 12 months .
Of 10 reports of nine studies that examined the effects of hormonal or intrauterine contraceptive use on risk of HIV disease progression [12–21], eight observational studies found no effect on various measures of HIV disease progression, including changes in CD4 cell count, HIV RNA levels, and survival [12–17,20,21]. The only RCT, which examined postpartum women with HIV in Zambia and whose primary outcomes were incidence of pregnancy and PID among IUD users, is the first study to observe adverse effects of hormonal contraception on CD4 cell counts and risk of death [18,19]. Compared with copper IUD users, hormonal users (OC and DMPA) had a significantly increased risk of falling below a CD4 cell count of 200 cells/μl or death, with a hazard ratio of 1.6 (95% CI 1.1–2.3); similar associations were reported when oral contraceptive and DMPA use were examined separately. There are several limitations to this body of evidence. Most studies were not randomized, and thus subject to selection bias and confounding. They also had relatively small sample sizes or few contraceptive users, and the reports generally did not discuss whether there was enough power to detect differences between groups (although most of the point estimates were right around or less than 1.0). Few of the studies were designed to distinguish between the effects of different types of hormonal contraceptives (most commonly oral contraceptives and DMPA); it is possible that these methods may have different effects given their different doses and hormones (combined estrogen/progestin or progestin alone). Although most studies had a relatively long follow-up time (≥2 years), it is not clear whether it was sufficient to observe changes in women with HIV who were generally otherwise healthy at baseline. Although the results of the RCT are concerning, a large number of women either did not complete the study (32% assigned to hormonal contraception, 23% assigned to IUDs) or discontinued their assigned contraceptive method during the study (13% assigned to hormonal contraception, 49% assigned to IUDs) . These losses were differential by study group and, therefore, may have biased the results. The authors conducted an actual-use analysis as well as the intent-to-treat analysis, but were unable to control for any potential confounders associated with method choice and disease progression. ART became available in the community during the study, but was not accounted for in the analysis.
Three of four observational studies found increased risks of some STIs among HIV-infected women who were using hormonal contraception [22–25]. In particular, the study of commercial sex workers in Kenya reported increased risks for cervical chlamydial infection and cervicitis, but not for gonorrhea . These findings are consistent with those from a report of HIV-uninfected women from this same cohort , as well as with the literature among HIV-uninfected women that generally shows increased risks of cervical chlamydial infection with hormonal contraceptive use and mixed results for gonorrhea . Among women with HIV, STIs have been reported to increase HIV viral load, possibly leading to faster HIV disease progression, and cervical STIs increase HIV viral shedding, potentially enhancing infectivity [24,39,40]. Neither of the two studies that examined pelvic infections among HIV-infected copper IUD users was adequately powered to detect differences in rates between groups; however, very low rates of PID and other infectious complications were observed [18,28,29].
With regard to HIV transmission to uninfected partners, the one study of female-to-male transmission that was identified found no effect of oral contraceptive or copper IUD use, although there was strong potential for bias due to temporal sequence as well as misclassification of the direction of transmission . The bulk of the evidence regarding the risk of female-to-male transmission is indirect, coming from studies of HIV-1 DNA or RNA shedding in the genital tract. These studies provide conflicting results regarding whether the use of oral contraceptives or DMPA increase the risk of shedding. However, the relationship between the amount of shedding needed for sexual transmission, and the relative importance of HIV-1 DNA compared with HIV-1 RNA for predicting risk of transmission, is not yet understood. Most of these studies are of cross-sectional design, limiting any ability to assess causality or temporal association. The cross-sectional studies used ORs to estimate their measure of effect. However, because of the relatively high prevalence of shedding in these study populations, it has been noted that the prevalence ratio may be a better measure of effect [41,42]. Recalculation of the associations between oral contraceptive use and cervical HIV shedding, from ORs to prevalence ratios, decreased the strength of the associations by one-third to one-half [41,42]. None of the three studies of copper IUD users showed any increased risk in viral shedding [33,34,37]; only one study was adequately powered to detect any possible differences .
Overall, there is limited evidence on the effects of hormonal or intrauterine contraceptive use among women with HIV, and no information on the combined patch or ring, the injectable norethisterone enantate (NET-EN), or Implanon. None of these studies examined differences in effects according to ART use. Finally, few of these studies included women with advanced disease. For example, the Zambian RCT excluded women with WHO stage III and IV disease , and in the Kenyan study of IUD users only 11 of 109 HIV-infected women were ‘severely immunocompromised’ .
This body of evidence suggests that hormonal and intrauterine contraceptives are well tolerated for use by women with HIV, although some theoretical concerns remain. WHO recommends that women with HIV/AIDS can use hormonal contraception and can generally use intrauterine contraception, with the exception that women with AIDS, who are not clinically well on ART, generally should not undergo IUD insertion (Table 4) [43,44]. This global guidance should be incorporated into the many on-going efforts to integrate HIV and reproductive health services in order to provide the best healthcare for women with HIV.
K.M.C. developed and executed the search strategy, identified articles for inclusion in the review, reviewed individual articles, and wrote the manuscript. K.N. reviewed individual articles and provided substantial revision to the manuscript. N.K. reviewed individual articles and provided substantial revision to the manuscript.
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the World Health Organization.
This review was supported by resources from the World Health Organization, the US Centers for Disease Control and Prevention (CDC), US Agency for International Development (USAID) and the US National Institute of Child Health and Human Development (NICHD).
Conflicts of interest: None.
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