This systematic review examined the association between use of hormonal contraceptives and detection of BV and supports the hypothesis that women using HC have a decreased risk of BV, compared to women not using a hormonal method of contraception. This negative association was robust and present regardless of the HC-type reported, and was evident across all three BV outcome measures (prevalent, incident and recurrent BV), with the exception of unspecified HC-use and incident BV, for which there was only one study. Most data were available from prevalence compared to incidence studies, and there were few studies examining recurrence; however HC-use was associated with a statistically significant reduced risk of BV for each of these outcomes when separately examined. Hormonal contraceptive use was associated with a 32% reduction in the odds of prevalent BV (pooled reES
0.68, 95%CI:0.63–0.73), an 18% reduction in the relative risk of incident BV (reES
0.82, 95%CI:0.72–0.92), and a 31% reduction in the risk of recurrent BV (reES
0.69, 95%CI:0.59–0.91). Unexpectedly, when stratified by reported HC-type, combined HC-use and POC methods were associated with a similar magnitude reduction in prevalent BV risk. When all estimates were converted to RRs, the meta-analysis showed that individuals using any HC-type had a significant overall reduction in risk of the composite BV outcome (reES
0.78, 95%CI:0.74–0.82). This meta-analysis provides compelling evidence that HC-use influences a woman’s risk of BV, with important implications for clinicians and researchers in the field. Importantly, these data encompassed high and low BV prevalence populations in geographically diverse settings, and had a low level of publication bias indicated by funnel plot and Eggers bias tests, and were not influenced by a number of varied sensitivity analyses.
The negative association between HC-use and BV may be somewhat surprising in light of recent data implicating HC, particularly POC, with possible increased risk of HIV transmission 
. However, over the last 30 years evidence has been emerging from observational studies of a negative association between HC-use and BV. Although the observed association could be due to confounding, it is evident across a large number of studies, many of which attempted to control for the confounding effects of behaviours, including condom use and recent sexual practices. A number of possible biological mechanisms may underlie this observed reduction in BV risk. One plausible hypothesis, that is more relevant to oestrogen-containing contraceptives, is that they may reduce the risk of BV by increasing the glycogen-content of epithelial cells, which is metabolised to lactic acid by epithelial cells and lactobacilli. Lactic acid is thought to be the primary vaginal acidifier and a known potent inhibitor of BV
. Higher lactic acid abundance has been reported in women with a vaginal microbiome dominated by L.crispatus
, which appear able to produce more lactic acid than other species 
. Furthermore, lactic acid has also been shown to elicit a favourable cytokine response in the female genital tract 
, which may further assist in reducing the risk of BV.
While the glycogen-lactic acid theory may explain a protective effect from oestrogen, it seems unlikely to be relevant to progesterone-only contraceptives, which often result in an oestrogen-deficient state. Interestingly, however, both progesterone and oestrogen appear to regulate a number of important immune mechanisms in genital tract epithelial and immune cells, with mid-cycle immunological suppression allowing for fertilization and pregnancy. There is direct and indirect cyclical regulation of soluble immune mediators, such as immunoglobulins (in particular IgA and IgG), secretory leukocyte protease inhibitor (SLPI), and defensins, which have antimicrobial actions against bacteria, fungi and viruses. Both sex steroids also influence recruitment of lymphocytes, natural killer cells, macrophages and Langerhans cells and production of cytokines 
. The actions of these hormones are complex and appear to vary depending on concentration, and to also differ between the vagina and the endometrium 
. Oestrogen exerts pro-inflammatory effects at low concentrations, and anti-inflammatory effects at high concentrations 
. The concentrations and cyclical pattern of expression of β-Defensins have been reported to differ during the phases of the menstrual cycle and between combined HC users compared to non-users 
A further mechanism by which HC, particularly progesterone-containing HC, may protect against BV is by reducing the frequency of menstruation, and therefore the volume and presence of haemoglobin in the genital tract. A number of studies have reported that BV is detected more commonly at the beginning of the menstrual cycle when oestradiol levels are lowest 
. Iron is essential for growth for most bacteria, including BVAB. Experiments have shown that G.vaginalis
is capable of both utilizing iron-containing compounds from sources including haemoglobin, and producing siderophores to acquire iron from the environment 
. Furthermore, quantities of L.jensenii
have been shown to decrease and G.vaginalis
concentrations to increase with the onset of menses 
. It is possible that through reduction in menstrual loss, HC-use influences susceptibility to colonization with BVAB, and that this effect may be particularly relevant to progesterone-only methods that commonly produce amenorrhoea.
Clearly, further research is needed to understand the complex multifaceted effects of both oestrogen and progesterone on the vaginal environment. However, one could reasonably postulate that increased and sustained circulating levels of sex hormones could potentially act in a number of favourable ways to promote and support a healthy vaginal state and reduce the risk of BV. This may include facilitating growth of protective Lactobacillus species, and supporting sustained high levels of lactic acid and favourable alterations to immune mechanisms in the female genital tract, that promotes vigorous host responses and clearance of BVAB. While more research is needed to disentangle the biological mechanisms that may underlie this association, clearly only a randomised controlled trial (RCT) will determine whether HC-use does exert a protective effect against BV.
A number of important limitations were present in this meta-analysis. First, the meta-analysis was limited to published studies, which could overestimate the overall estimates if there has been publication bias resulting from the tendency to publish and present only statistically significant findings. We only searched studies which were published in English, which may limit the generalizability of our findings; however included studies represented women in all continents and from diverse ethnicities. Importantly, no evidence of publication bias was seen in either funnel plot or in the Eggers test for bias, and in a number of studies where raw data was presented, we included derived associations that were not mentioned in the manuscript. A potential limitation is the inclusion of clinical trials and quite specific sub-populations. While this may have also contributed to bias, we conducted sensitivity analyses and showed that their inclusion did not significantly affect the overall effect size. Although we included adjusted estimates where possible, unmeasured confounding may have contributed to the pooled estimates i.e. there may have been other unmeasured biases contributing to women’s choice of HC, which was not adjusted for in analyses and may have resulted in an overestimation of the effect. One of the strengths of this meta-analysis was that it included highly diverse studies from many different geographical locations, and women with diverse risks from various recruitment settings, but there were more women recruited from sexual/reproductive health services compared to broader population-based studies. This may somewhat limit the generalizability of the findings, and could be a source of bias, however, as the negative association is robust across these heterogeneous studies, this indicates the impact of selection bias is minimal. A significant proportion of studies did not specify type of HC-use. This may have disproportionately affected the associations between POC-use and BV outcomes in for instance African settings, and combined HC-use in developed nation settings, where each of these methods is, respectively, more commonly used. Overall, however, this is likely to have limited impact on the pooled estimates. Finally, the control groups varied between studies and often contained IUD-users, users of other HC-types and condom users. IUD-use, which predominantly reflected non-hormonal IUDs, has importantly been associated with increased risk of BV 
. For this reason, we excluded any studies that exclusively had IUD-users as the control population as this would lead to an overestimation of the effect, but importantly, for the majority of other studies, IUD-users represented only a minority of the control population. It is reasonable to assume that many HC-users may use condoms less consistently than non-HC users. However, a previous meta-analysis has shown that condom use is associated with a 20% reduced risk for BV 
, and therefore the inclusion of a greater proportion of consistent condom users in control populations, is more likely to underestimate, rather than overestimate, an observed protective effect of HC against BV. Importantly, we included ratios that had been adjusted for condom use when provided. The most striking observation from these data is that the negative association between HC-use and BV was robust and consistent when stratified by HC-type and across the three outcome measures.
In conclusion, this meta-analysis demonstrates a negative association between HC-use and the risk of BV, and raises the tantalizing potential role of exogenous steroid hormones in influencing the vaginal environment in a protective manner against the development of BV. With over 50% of women experiencing BV recurrence following first-line antibiotic therapies, and no significant improvement in the management of BV in the last 20 years, identifying potential modifiable sexual and contraceptive practices that influence susceptibility to infection and recurrence are integral to progressing prevention and management approaches for this important and common genital tract infection. Crucially, there are no data from RCTs evaluating a hormonal intervention, and the mechanism(s) by which hormonal contraception may exert a protective effect against BV requires further investigation.