Hormonal contraception might increase HIV acquisition risk. A recent systematic review of 20 prospective studies concluded that combined oral contraception (COC) does not increase risk, but that the evidence for progestin-only injectables is conflicting . In 2009, 145 million women worldwide were using hormonal contraception, most commonly COCs or progestin-only injectables, such as depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) . Progestin-only injectables are the most frequently used form of contraception in sub-Saharan Africa, where the HIV burden is highest . Several biological mechanisms have been postulated, but it is unclear which (if any) are clinically relevant. The proposed mechanisms include increased area of cervical ectopy, vaginal epithelial thinning, local immune activation, and changes in the composition of the vaginal microbiome [3,4].
Several prospective cohort studies have shown significant associations between bacterial vaginosis by Amsel  or Nugent criteria  and subsequent HIV acquisition in women, with adjusted hazard ratios (aHRs) ranging from 1.4 to 2.3 . A meta-analysis of individual participant data of 13 African prospective cohort studies showed that intermediate vaginal microbiota (Nugent score 4–6) and bacterial vaginosis (Nugent score 7–10) were each associated with HIV acquisition in multivariable models (aHR 1.54 and 1.69, respectively) . In addition, four studies have shown a positive association between vaginal candidiasis and HIV acquisition, with adjusted relative risks (aRRs) ranging from 1.8 to 3.3 . Taken together, current evidence suggests that any deviation from a normal lactobacilli-dominated vaginal microbiome increases women's susceptibility to HIV. In the last decade, new molecular techniques have become available that can characterize the composition of the vaginal microbiome in much more detail (such as next-generation sequencing and DNA microarrays) , but to date, these have mostly been used in exploratory studies.
We conducted a systematic review of the published literature and reanalysed one of our own studies, to investigate whether hormonal contraception increases the risk of bacterial vaginosis and/or vaginal candidiasis. Both of these conditions could be on the causal pathway between hormonal contraception and HIV acquisition. We also reviewed exploratory studies describing the impact of hormonal contraception on the vaginal microbiome as characterized by molecular methods.
Materials and methods
Our aim was to assess whether women using hormonal contraception had a higher prevalence or incidence of bacterial vaginosis (assessed by Gram stain Nugent scoring or molecular methods) and/or vaginal candidiasis (all Candida species; assessed by culture or KOH wet mount), than women not using hormonal contraception. We could not reliably distinguish vaginal Candida colonization from symptomatic vaginal candidiasis and refer to these outcomes as (vaginal) candidiasis throughout this manuscript. We considered the exposure group inappropriate if hormonal methods and copper intrauterine devices (IUDs) were grouped together, but not when different types of hormonal methods were grouped together. For many studies, we could not be sure that ‘oral contraceptive (OC) users’ included progestin-only pill (POP) users or not. Throughout the manuscript, these study groups are indicated with OC instead of COC. However, in most populations, POPs are used by only a small percentage of pill users, and we therefore analysed the OC and COC studies together . We considered the control group inappropriate if the entire group consisted of users of another contraceptive method (e.g. copper IUD users), but not if users of other methods or pregnant women made up a minority proportion of the larger control group (e.g. copper IUD users combined with women not using any contraception).
We conducted a systematic review according to the PRISMA 2009 guidelines . Two researchers (M.C.V. and J.H.H.M.vdW.) designed the search terms (Fig. 1) and selection criteria (using predefined data extraction tables instead of a protocol), and independently selected and classified the articles. We searched the Medline (US National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA) and Embase (Elsevier B.V., Amsterdam, The Netherlands) databases for articles up to 1 July 2012, using the search terms in Fig. 1, and limiting our search to articles written in English. These searches yielded 1871 articles (883 in Medline and 988 in Embase), including 194 duplicates (Fig. 2). Fourteen additional articles were identified from reference lists. The title and abstract of all 1691 articles were read, and the following articles were eliminated: articles that included an intervention that might interfere with our research question, focused exclusively on the changes of the vaginal microbiome during pregnancy or the peri/postmenopausal period or did not address our research question (n = 1105) and articles published before 1990 (n = 472). A total of 114 articles were deemed of interest. Two of these could not be retrieved. After reading the full text of the remaining 112 articles, a further 86 were rejected because they did not address our research question appropriately (most commonly because bacterial vaginosis was assessed by Amsel criteria, Pap smear cytology or clinical signs and symptoms only; vaginal candidiasis was assessed by Pap smear cytology or clinical signs and symptoms only; there was no appropriate control group; or because the measure of effect was not and could not be calculated due to insufficient data presented in the article). A total of 36 articles were selected and categorized by clinical outcome: bacterial vaginosis only (n = 11), candidiasis only (n = 12), bacterial vaginosis and candidiasis as separate outcomes (n = 9) and the vaginal microbiome using molecular methods (n = 4).
We scored the quality of each study as follows: the exposure group consisted of only one hormonal method (1 point); the control group did not include any hormonal contraceptive users or consisted of the same women prior to exposure (1 point); the control group did not include any pregnant women (1 point); the study did not target symptomatic women (1 point); the study was prospective (1 point); and the measure of effect was adjusted in multivariable analysis (1 point). When studies had the same score, we ordered them in the tables from largest to smallest sample size.
When the number of cases and controls in each exposure group were presented in an article but no measure of effect was given, we calculated a crude odds ratio (OR), 95% confidence interval (CI) and two-sided P value by Fisher's exact test using STATA version 12 (StataCorp, College Station, Texas, USA).
We also reanalysed data from the Hormonal Contraception and HIV Acquisition (HC-HIV) Study. The HC-HIV study was implemented in Zimbabwe, Uganda and Thailand between 1999 and 2004 . The HC-HIV study methodology, including bacterial vaginosis and candidiasis assessments, was described in a related article by van de Wijgert et al.. The study was found to be well positioned to answer our research questions due to its study design (participants were selected based on their contraceptive method use), large study size (6109 women), long duration of follow-up (15–24 months per woman) and close attention paid to contraceptive method switches and pregnancies during follow-up. The HC-HIV study was approved by the ethics committees of all eight collaborating institutions in the United States, Uganda, Zimbabwe and Thailand . All participants provided written informed consent.
In the current HC-HIV analysis, we used data from all three study countries and compared bacterial vaginosis (Nugent score 7–10) and intermediate microbiota (Nugent score 4–6) with normal microbiota (Nugent score 0–3) in separate multivariable binomial regression models with generalized estimating equations (GEEs). The same methodology was used to evaluate the vaginal candidiasis outcome. Contraceptive method switches during the study were taken into account and pregnant person-time was excluded. The following variables were considered for inclusion in the multivariable models (starting with the full model but removing variables that confounded the effect of hormonal contraception on the outcome of interest by less than 10%): study country, age, education, parity, living with a steady partner, current breastfeeding, any vaginal practices in previous interval, condom use in previous interval (consistent, inconsistent or none), age at first sex, sexual risk taking by the woman (composite variable), sexual risk taking by male partners (composite variable), self-reported lifetime history of sexually transmitted disease, any use of antimicrobials in previous interval and current HIV status (all women were HIV-negative at enrolment but 213 women acquired HIV infection during follow-up).
Hormonal contraception and risk of bacterial vaginosis and intermediate microbiota by Nugent scoring
Eleven out of the 19 selected studies had a sample size larger than 200 (Table 1) [13–23]. Seven of these studies provided a measure of effect for COCs and/or DMPA separately or provided sufficient data for us to calculate the measure of effect [13–17,20,22]. Four studies combined all hormonal contraceptive methods into one exposure group [18,19,21,23]. Out of the six studies that evaluated COCs as a separate exposure group, five found a statistically significant reduction of bacterial vaginosis [13,14,17,20,22] and one found no effect . All four studies that evaluated DMPA as a separate exposure group found a significant reduction of bacterial vaginosis [13–15,17]. One study also evaluated NET-EN as a separate exposure group and found a reduction in bacterial vaginosis in that group as well . Two out of the four studies that grouped all hormonal methods into one exposure group found a reduction of bacterial vaginosis [18,19] and the other two studies found no association [21,23].
Another eight studies reporting on the association between hormonal contraception and bacterial vaginosis by Nugent scoring had a sample size below 200 participants [24–31]. Most of these showed no statistically significant results [24–27,29–31], but two showed a trend towards a reduction in bacterial vaginosis prevalence for COC use [25,27] and none showed a trend towards an increase in prevalence for either COC or DMPA use. A small prospective study  conducted in Mombasa, Kenya, including only 10 OC users and 43 DMPA users, found no statistically significant association between OC use and bacterial vaginosis but did find a significant reduction in bacterial vaginosis prevalence among DMPA users.
The three studies with a maximum quality score of 6 (Table 1) showed consistent results, reporting adjusted measures of effect for the association with bacterial vaginosis by Nugent scoring ranging from 0.80 to 0.90 for COC use and from 0.70 to 0.82 for DMPA use [13–15]. All associations were statistically significant. The HC-HIV study also evaluated the effects of COC and DMPA use on intermediate microbiota by Nugent scoring and found aRRs of 0.89 for each (COC: 95% CI 0.84–0.96, P = 0.002; DMPA: 95% CI 0.83–0.95; P < 0.001).
One large Italian study (n = 27 172) using stored electronic microbiology records deserves mention, even though this study evaluated cultures of Gram-negative and Gram-positive bacteria rather than Nugent scores for bacterial vaginosis diagnosis . Women who were using COCs were less likely to have a positive culture for Gram-negative (aOR = 0.75; 95% CI 0.57–0.99) as well as Gram-positive bacteria (aOR = 0.86; 95% CI 0.68–1.09) than women who were not using any hormonal contraception, although the latter did not reach statistical significance.
Seven studies in Table 1, including all three studies with a maximum quality score of 6, recruited women on the basis of their contraceptive choices or HIV status, and not because they sought care for vaginal symptoms [13–16,18,20,21]. The other four studies recruited from gynaecology clinics [17,19,22,23], but only one study targeted women reporting vaginal symptoms . None of the studies in Table 1 except for one  included postmenopausal women, but four studies did not exclude pregnant women [18,20–23]. All except for three studies in Table 1[13,16,17] compared a Nugent score of 7–10 (bacterial vaginosis) with a Nugent score of 0–6 (which includes both intermediate and normal microbiota). Our analysis of the HC-HIV study is the only one providing measures of effect for intermediate microbiota separately. Four articles explicitly mentioned that the microscopist who conducted the Nugent scoring was blinded to the exposure status of the participant [13,17,18,20] and three articles explicitly mentioned that external quality control of Nugent scoring was implemented [13,15,17]. All except for one study  presented adjusted measures of effect, but it was not always clear which adjustments were made and whether use of antibiotics or other antimicrobial drugs was taken into account.
Hormonal contraception and risk of vaginal candidiasis
Thirteen of the 21 selected studies had a sample size larger than 200 (Table 2): the presence of Candida species was assessed by culture in nine studies [32–40] and by KOH wet mount in four studies [13,14,21,41]. Only one study combined COC and injectables into one exposure group ; this study found no statistically significant effect (Table 2). All other studies evaluated COCs as the exposure group, and four studies also evaluated DMPA or injectables as a separate exposure group [13,14,33,35]. Of the 12 studies that evaluated COCs as a separate exposure group, seven found a statistically significant increase in vaginal candidiasis prevalence or incidence [14,34–36,38–40], two found a positive association that was close to significance [32,37], two found no association [33,41] and one found a statistically significant reduction of candidiasis by KOH wet mount . Of the four studies that evaluated DMPA as a separate exposure group, one found a statistically significant increase in candidiasis , one found a statistically significant reduction  and two found no association [14,35].
Another eight studies reporting on the association between hormonal contraception and culture-positive candidiasis had a sample size below 200 participants [24,29–31,42–45]. Only one of these showed statistically significant results, reporting a significant increase in culture-positive candidiasis for COC use .
The three studies with a maximum quality score of 6 showed inconsistent results [13,14,33]. The one study using culture-positive candidiasis as the outcome found no association with COC use and an increased risk with DMPA use . Of the two studies with Candida on KOH wet mount as the outcome, one found reduced risks in COC and DMPA users  and the other one an increased risk in COC users and no effect in DMPA users .
The majority of the studies in Table 2 were clinic-based, including five studies that only included symptomatic women [34,37–40]. All except one study with candidiasis by culture as the outcome  were cross-sectional or case–control studies, whereas three out of the four studies using Candida on KOH wet mount as the outcome were prospective cohort studies [13,14,41]. In contrast to the bacterial vaginosis studies presented in Table 1, the majority of the candidiasis studies in Table 2 did not present adjusted measures of effect. None of the articles except for one  described quality control procedures for the Candida assessments.
Our search yielded only four studies investigating the relationship between female sex hormones (but not hormonal contraceptives) and the vaginal microbiome characterized by molecular methods [46–49]. Two of these studies investigated the vaginal microbiome of women at various time points during an in-vitro fertilization (IVF) procedure [46,47] and two at various time points during the menstrual cycle [48,49]. The studies showed that high oestrogen levels favour a vaginal microbiome dominated by ‘healthy’ Lactobacillus species, but that data on progesterone levels are limited and not clear (Table 3). Three additional longitudinal menstrual cycle studies showed that the Lactobacillus crispatus load declines about 100-fold during menses, whereas the bacterial loads of Lactobacillus iners, Gardnerella vaginalis and Atopobium vaginae increase, thereby making women more vulnerable for bacterial vaginosis during and after menses [50–52].
We conclude that COCs and DMPA (and most likely also NET-EN) reduce the prevalence and incidence of bacterial vaginosis in women, and that COCs (but not DMPA) may increase the prevalence of vaginal candidiasis. This is the first comprehensive review of these relationships, and our findings have not been widely recognized before. Therefore, the hypothesis that DMPA use may increase HIV acquisition risk by increasing bacterial vaginosis or vaginal candidiasis risk is not supported by the evidence. However, the potential role of candidiasis in HIV transmission among hormonal contraceptive users, and vaginal microbiome imbalances other than bacterial vaginosis or candidiasis, cannot yet be ruled out. Now that molecular methods have become more accessible, they should be incorporated into larger epidemiological studies to investigate these relationships more fully.
The evidence for a reduction of bacterial vaginosis risk in hormonal contraceptive users is much stronger than the evidence for a potential increased candidiasis risk in COC users. First, the results of the large bacterial vaginosis studies (with at least 200 participants) are consistent, and none of the smaller studies report a trend in the opposite direction. The three bacterial vaginosis studies with the highest quality score report bacterial vaginosis risk reductions of 10–20% for COCs and 18–30% for DMPA. The data on COCs and vaginal candidiasis are less consistent and in some cases even contradictory, and limited data are available for DMPA. Second, the results of the candidiasis studies were more difficult to interpret because it was not possible to differentiate between high and low levels of Candida species in the vagina, the quality of the candidiasis studies (in the context of our research questions) was low and Candida species were not assessed in the molecular studies. The mean quality score of the candidiasis studies with a sample size of at least 200 participants was 3.3, compared with 4.2 for the bacterial vaginosis studies. Candidiasis studies, compared with bacterial vaginosis studies, were less often prospective (31 vs. 55%), more often targeted symptomatic women (38 vs. 8%), less often presented adjusted measures of effect (38 vs. 91%) and less often described at least one aspect of laboratory quality control procedures (8 vs. 45%). It should be noted, however, that most prospective studies did not describe how contraceptive switches and repeat incident infections were handled, and that it was not always clear what adjustments were made in multivariable analyses.
The outcome of the bacterial vaginosis studies was more robust than the outcomes of the candidiasis studies, because the Nugent score is well standardized and takes quantities of three bacterial morphotypes into account (albeit crudely, by counting number of cells in microscopic fields). However, eight of the 11 bacterial vaginosis studies compared bacterial vaginosis (defined as a Nugent score of 7–10) with ‘no bacterial vaginosis’ (Nugent score 0–6), thereby including women with intermediate microbiota (Nugent score 4–6) in the negative outcome group. This most likely diluted the protective effect of hormonal contraception on bacterial vaginosis because molecular studies show that vaginal microbiome compositions associated with Nugent scores of 4–6 are more closely related to bacterial vaginosis than to a normal lactobacilli-dominated microbiome composition . Our own analysis of the HC-HIV study data showed that COC and DMPA use was negatively associated with bacterial vaginosis as well as intermediate microbiota, and that the measures of effect were of similar magnitudes.
The main strength of the work described in this article is that we investigated the research questions in a comprehensive manner, using multiple assessments of the vaginal microbiome. We did not limit ourselves to bacterial vaginosis, but also included candidiasis and vaginal microbiome assessments using modern molecular methods. The most important limitation of the systematic review was that hardly any of the eligible studies were designed to investigate our research questions. We therefore had to work with different study designs, outcomes (see previous paragraph), exposure groups, control groups and analysis strategies. This is also the reason why we decided not to do meta-analyses. Although we found that the HC-HIV study was one of the best positioned studies to answer our research questions, that study had limitations too, most notably the fact that we did not assess candidiasis by culture but by KOH wet mount. In general, studies with large sample sizes and multiple follow-up visits tend to not use cultures for diagnosis due to the time-sensitive and labour-intensive nature of this procedure. Other limitations of our work include that we may have missed eligible studies, and that many of the eligible studies cannot firmly establish temporal sequences or rule out (residual) confounding.
Several hypotheses have been postulated to explain why oestrogen may inhibit bacterial vaginosis associated micro-organisms. The dominant hypothesis is that oestrogen increases the levels of available glycogen in epithelial cells, which facilitates lactobacilli growth and lactic acid production, thus lowering the vaginal pH . Glycogen also provides a favourable environment for the growth of other micro-organisms, including Candida albicans. However, these hypotheses do not explain why DMPA users and postmenopausal women, who have much lower levels of oestrogen, are also protected against bacterial vaginosis. It has been hypothesized that this may be due to a lack of menses . As mentioned above, women are more vulnerable for bacterial vaginosis during and after menses due to lower L. crispatus loads and higher loads of bacterial vaginosis associated bacteria [50–52].
The effects of DMPA on HIV acquisition may be mediated by a high progesterone level, a low oestrogen level or the induction of a hypoestrogenic state . Potential mechanisms include effects on physiological properties of the cervix (cervical ectopy) and vaginal wall (epithelial thinning or atrophy, reduced cornification of epithelial cells, increased availability of target cells for HIV) and immunomodulatory effects [3,4,58]. High-quality studies are needed to further investigate the role of these processes in HIV transmission.
In the last decade, the second-generation progestin levenorgestrel has become popular in family planning, and a recent report of the Initiative for Multipurpose Prevention Technologies endorsed the use of levenorgestrel in products that are being developed to prevent both HIV/sexually transmitted infections (STIs) and pregnancy . The effect of levenorgestrel on the vaginal microbiome, cervix and vaginal wall and genital mucosal immune system therefore also needs to be studied as a matter of priority. In the meantime, women at risk of HIV using hormonal contraception, particularly progestin-only injectables, should be advised to also use condoms.
The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The content of this publication does not necessarily reflect their views or policies, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.
The authors thank the HC-HIV Study team for implementation of the HC-HIV study between 1999 and 2004, Pai-Lien Chen for providing input in the reanalysis of the HC-HIV data and Hanneke Borgdorff and Marc Bonten for critical review of the manuscript.
J.H.H.M.vdW. designed the study. A.N.T., J.H.H.M.vdW., C.S.M. analysed the HC-HIV data. M.C.V., J.H.H.M.vd.W. conducted the systematic review. J.H.H.M.vdW., M.C.V. wrote the first draft of the article. A.N.T., C.S.M. contributed to the writing of the article. J.H.H.M.vdW., M.C.V., A.N.T., C.S.M. read and met the ICMJE criteria for authorship. J.H.H.M.vdW., M.C.V., A.N.T., C.S.M. agreed with the manuscript's results and conclusions.
Ethics review was not required for the systematic review. The HC-HIV study was approved by the institutional review boards and/or ethics committees of all eight collaborating institutions in the United States, Uganda, Zimbabwe and Thailand. The approval letters are available upon request. All study participants provided written informed consent.
The HC-HIV study was funded with U.S. federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services through a contract with Family Health International (contract N01-HD-0-3310).
Conflicts of interest
The authors have declared that no competing interests exist.
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