Cervical carcinogenesis must involve the presence of additional promoting factors, since only a minority of patients harbouring HPV develop cervical dysplasia 
. BV has been suggested as an intriguing possible co-factor in cervical carcinogenesis. Previous studies examining the relationship between BV and CIN, however, have rendered conflicting results. This meta-analysis with over 10.000 women and in addition a database of more than one million cervical smears, is to our knowledge the first study confirming a positive association between BV and cervical pre-cancerous lesions, with a significant overall estimated odds ratio of 1.51.
The role of BV as a co-factor in the natural history of HPV infection and related disease remains largely elusive. A putative explanation might be the fact that BV promotes – as noted for most sexually transmitted infections 
– the acquisition and persistence of HPV infection. In a previous meta-analysis a positive association between BV and cervical HPV infection was confirmed (OR 1.43; 95% CI, 1.11–1.84) (Gillet et al, in press). Furthermore, BV is associated with profound changes in the physicochemical and immunological environment of the vaginal niche. It has been suggested that an elevated vaginal pH, as present in BV, may arrest squamous metaplasia in the post-pubertal cervix and prolong the period in which the transformation zone is vulnerable to agents promoting dysplasia such as HPV 
. Da Silva et al. described an increased frequency of BV and Chlamydia trachomatis in pregnant women with HPV infection 
. Biochemical changes in vaginal secretions of women with BV include production of metabolic by-products, such as propionate and butyrate, capable of damaging epithelial cells. In addition, the BV-associated anaerobes release volatile amines (especially putrescine, trimethylamine and cadaverine) 
, responsible for the characteristic fishy malodour 
. Amines appear in the vaginal environment after conversion of amino acids produced by abundance of anaerobes, and form in combination with nitrites (produced by nitrate reducing bacteria) nitrosamines 
. These carcinogenic compounds are capable of forming DNA adducts and consequently mutagenic events 
. Previous investigations suggest that local accumulation of nitrosamines during episodes of BV may induce cell transformation of the cervical epithelium, in concert with other oncogenic agents like HPV infection 
Alternatively, alterations in inflammatory cytokine profile present in a disturbed vaginal environment could promote development of cervical lesions 
. In a prospective study of Tavares-Murta and colleagues, patients with BV and CIN presented a similar local cervical immune profile, as assessed by cytokine (IL-6, IL-8 and IL-10) and nitric oxide (NO) concentrations 
. On the other hand, it has been reported that cervical inflammation (leading to genotoxic damage through oxidative metabolites) is associated with CIN, and may be a cofactor for high-grade cervical lesions in HPV-infected women 
. Since BV frequently coexists with cervicitis 
, a disturbed vaginal microflora might therefore indirect predispose to cervical dysplasia.
Another important additional co-factor in cervical carcinogenesis could be the relative absence of hydrogen peroxide (H2
)-producing lactobacilli. Bauer et al elaborated a hypothetical model for lactobacilli-mediated control of cancer, in which selective apoptosis induction represents the key element of the lactobacilli-mediated antitumor defense 
. He suggested that H2
-producing lactobacilli and peroxidase in the vagina of healthy women and the consequently generation of hypochlorous acid (HOCl), is responsible for creating a balanced microbicidal vaginal environment and represents a natural antitumor system. If transformed cells appear in the vaginal mucosa, they will be driven into selective apoptosis by interaction of the preformed HOCl with target cell-derived reactive oxygen species (superoxide anions), which leads to the site-specific generation of highly reactive hydroxyl radicals 
Some methodological limitations need to be considered. First of all, most included studies had a cross-sectional design, where data on prevalence of BV and cervical lesions were gathered simultaneously, rather than longitudinally. Therefore, this analysis is liable to reverse causation bias and prohibits concluding that BV plays a causal role in cervical carcinogenesis. BV may influence onset and progression to cervical pre-cancerous lesions, but it is also plausible that cervical dysplasia favours conditions for disruption of the normal vaginal environment and promotes an abundant growth of anaerobes. Since the vaginal environment is considered to be influenced by various factors, such as hormones and the state of the vaginal mucosa, gynaecological diseases may affect the growth of the vaginal microflora. Only a cohort study can determine which condition precedes the other. In this systematic review, only two incidence studies were found. In a study conducted by Lehtovirta et al 
BV was associated with a significantly increased risk of CIN in univariate analysis (Hazard ratio (HR) 1.85, 95% CI 1.04–3.28, p
0.04) and approached significance in multivariate analysis (HR 2.32; 95% CI 0.95–5.65). In another retrospective cohort-study of Engberts et al 
, women with dysbacteriosis were significantly more likely to have LSIL and HSIL in their follow-up smear (OR 1.89, 95% CI 1.42–2.52).
The question remains whether there is a causal relation between BV and cervical pre-cancerous lesions, or whether both conditions co-occur in sexually active women. It is known that a number of socio-demographic and lifestyle behavioural factors influence the risk of BV and cervical pre-cancerous lesions in a similar fashion. Although not considered an STI in its usual sense, BV mirrors this profile 
, and is associated with sexual activity and thus a candidate for an epidemiological association with CIN. Most studies examining the association between BV and CIN failed to take into account confounding factors, such as presence of HPV, sexual habits and cigarette smoking. Only three included studies performed multivariate analysis and adjusted for confounding factors in examining the association between BV and CIN (Castle et al 
, Schiff et al 
, Spinillo et al 
). However, these few studies yielded conflicting results.
Although meta-regression could not clarify heterogeneity of results, a number of variables could contribute to the variety of association between BV and cervical lesions. Most prominent, BV prevalence varied according to the study population. Various social habits and ethno-geographical risk factors may explain the wide BV prevalence range observed (3 to almost 50%). It is well recognized that prevalence of BV in African women is among the highest worldwide. Therefore, it would be interesting to evaluate the association between BV and cervical lesions in African women, since we may expect a more pronounced effect. Only one study included in this meta-analysis (Kharsany et al, 1993) was conducted in South-Africa. Indeed, BV prevalence, diagnosed by Amsel criteria, was high (37.5%) and although the sample size was rather small, the estimated odds ratio was the second highest of all included studies (OR 4.0; 95% CI, 1.07–15.1) 
. Technical biases, subjectivity, sensitivity and specificity of diagnostic methods could also contribute to detected heterogeneity. Especially for diagnosing BV, criteria varied strong among the studies. Two included studies conducted in the Netherlands used a unique coding system (KOPAC), defining BV as dysbacteriosis 
. Although dysbacteriosis is associated with the clinical syndrome BV, differences between the two entities certainly exist, since dysbacteriosis is a 100% morphological (light microscopic) diagnostic method as opposed to the clinical Amsel criteria. However, this meta-analysis was also conducted without these studies using the KOPAC system, yielding still a positive and more pronounced association (OR 1.62; 95% CI 1.10–2.38).
Further, this meta-analysis was limited to that of published studies, which could have caused publication bias, resulting from tendency to selectively publish results that are statistically significant. However, half of the included studies showed no significant association between BV and cervical pre-cancerous lesions, and Beggs rank correlation test did not give any indication of a possible publication bias either. In addition, the literature review was limited to English language studies found in two major databases, i.e. Pubmed and Web of Science.
In conclusion, this meta-analysis confirms a positive association between BV and cervical pre-cancerous lesions and emphasizes the potential role of a disturbed vaginal microflora in gynaecologic complications. BV is one of the most common conditions of child-bearing aged women worldwide, and considering a possible synergy of an imbalanced vaginal environment with cervical pre-neoplasia, it is clear that greater attention needs to be given to this condition. These results support the need for prospective cohort-studies addressing the interrelationships between BV and CIN, where sensitive and specific diagnostic methods are used, and were confounding factors, are taken into account. If BV plays a promoting role in the development of cervical cancer, then women with a history of recurrent or persistent BV should be eligible for closer follow-up, and restoring the vaginal microflora should in that case be a promising answer.