Skip to main content
Download PDF

Probiotics are a good choice for the treatment of bacterial vaginosis: a meta-analysis of randomized controlled trial

Reproductive Health volume 19, Article number: 137 (2022) Cite this article

Abstract

Background

Bacterial vaginosis (BV) is one of the most common vaginal infectious diseases in female reproductive period. Although the existing view is that probiotic treatment may be one of the feasible methods for the treatment of BV, different intervention methods lead to different treatment results. Therefore, up-to-date and comprehensive evidence in this regard is essential for the development of intervention strategies.

Objective

This meta-analysis aims to systematically evaluate the role of probiotics in the treatment of BV in adult women.

Methods

We searched the databases of Embase, Cochrane Library, PubMed, Web of Science and ClinicalTrials.gov for Randomized Controlled Trials published until November 7, 2021. Meta-analysis was performed by Revman5.3 software to systematically evaluate the clinical efficacy of probiotics adjunctive therapy in the treatment of BV. The literatures were screened and evaluated according to the inclusion and exclusion criteria. Chi-square test was used to test the heterogeneity between trials. Random or Fixed effect models were used to analyze the cure rate of BV.

Results

Fourteen randomized controlled trials compared the efficacy of probiotics with antibiotic therapy (probiotics + antibiotics group) versus antibiotics alone or plus placebo (antibiotics (+ placebo) group) for BV [Risk Ratios (RR) = 1.23, 95% CI (1.05, 1.43), P = 0.009]. Three compared the efficacy of probiotics regimen (probiotics group) and antibiotics (antibiotics group) in the treatment of BV [RR = 1.12, 95% CI (0.60, 2.07), P = 0.72]. Another Three compared the efficacy of probiotics regimen (probiotics group) with placebo (placebo group) [RR = 15.20, 95% CI (3.87, 59.64), P < 0.0001].

Conclusion

Our meta-analysis suggests probiotics may play a positive role in the treatment of BV, but more strong evidence is needed.

Plain Language Summary

Our meta-analysis found that probiotics may play an active role in adjuvant treatment of bacterial vaginosis by conventional antibiotic therapy. It was emphasized that oral administration of L. rhamnose was more effective than vaginal application of L. rhamnose in the treatment of bacterial vaginosis. The therapeutic effect of probiotics varies with the administration route and dosage of probiotics.

Peer Review reports

Introduction

As one of the most common vaginal infectious diseases in the child-bearing period of women [1], bacterial vaginosis is caused by the imbalance of microecology in the vagina and the mixed infection of Gardnerella Vaginalis (GV) and anaerobic bacteria owning to regular irrigation, multiple sexual partners, non-condom use, smoking and reduced estrogen levels [1,2,3,4]. BV patients often have symptoms including increased secretion of vaginal discharge, fishy smell in leucorrhea, and pruritus and burning in vulvas. In addition, some studies have shown that BV is likely to cause a range of health problems such as premature birth, pelvic inflammation, infection and transmission of sexually transmitted diseases including acquired immune deficiency syndrome [5,6,7,8,9,10,11]. And because of the obvious discomfort of vulva when BV onsets and the high recurrence rate of BV, women's life quality and even their mental health are significantly negatively affected by BV, although the prevalence of BV varies geographically [5].

Approximately 50% of BV patients have clinical symptoms, which can be diagnosed by Amsel standard or Nugent score. Among them, Amsel standard is a convenient and practical method, which is widely used as the gold standard in clinic [1, 12]. If possible, the vaginal flora could also be graded and evaluated by Nugent scoring system [13, 14]. Nugent scoring system diagnosis of BV shows a higher sensitivity and lesser dependence on clinicians.

Since the vaginal microbiota of BV patients has changed from Lactobacillus, the dominant microbiota of vagina, to a more diversified community mainly composed of facultative and obligate anaerobic bacteria. Nowadays, antibiotics such as metronidazole and clindamycin are used worldwide in clinical treatment to fight against BV related microbes in a short period to give space for normal vaginal microbiota to restore [15, 16]. However, an extremely high recurrence rate of 69% could be observed in patients after effective antibiotic treatment. And there may be some adverse effects like gastrointestinal discomfort such as nausea and vomiting from antibiotic use, as well as the risk of developing resistance to antibiotics [3, 9, 17]. Therefore, it is crucial to explore a safer and more long-lasting clinical treatment for BV. Fortunately, probiotics preparations have been proved to be a safe alternative for restoring the microecological balance of female reproductive tract and they are generally accepted by patients [18]. However, even though more and more Randomized Controlled Trials (RCTs) of using probiotics as an alternative or adjunctive treatment for BV have been reported, they result in a controversial efficacy. There are also obvious differences in dosage regimens of probiotics in previous studies [19,20,21,22,23].

This study aimed to clarify the efficacy and role of probiotics in BV treatment by adopting meta-analysis to integrate scattered literatures and systematic analysis to explore the source of heterogeneity and its impact on trial results.

Methods

Search strategy

Literature retrieval was conducted independently by two researchers. The Cochrane Library, PubMed, EMBASE, Web of Science databases and ClinicalTrials.gov website were searched for RCTs on probiotics in the treatment of bacterial vaginosis that were published prior to 7 November 2021. We searched the literature using subject terms and free words, including terms related to or included “Vaginosis, Bacterial”, including Bacterial Vaginitides; Vaginitides, Bacterial; Bacterial Vaginosis; Vaginitis, Nonspecific; Nonspecific Vaginitis; Bacterial Vaginoses; Vaginoses, Bacterial; Bacterial Vaginitis; Vaginitis, Bacterial. Words related to “Probiotics” or "Lactobacillales", including Lactic Acid Bacteria, Lactobacillus, Lactobacilli, Bifidobacterium, and LB were also searched. The study protocol was registered on PROSPERO (CRD42021289871).

Inclusion and exclusion criteria

The following were the inclusion criteria for considering full-text publications: (a) studies must be RCTs; (b) study population was women in childbearing age who were non-pregnant and were diagnosed only with BV by either Nugent score [13] or Amsel criteria [1]; (c)intervention for experimental group was probiotics only (regardless of dose, route of administration, single or mixed strain) or probiotics in combination of conventional antibiotics treatment matched with antibiotics or placebo as control; (d) the prioritized treatment outcomes was cure or recurrent rate of BV.

The exclusion criteria were articles that (a) studies which included pregnant women, women with sexually transmitted infections or other urinary tract infections other than BV; (b) had no full text available or was not written in English; (c) failed to report the required results; (d) had unextractable outcome indicators. For example, those studies which barely demonstrated the cure or recurrence rate without the detailed number of cured or recurrent participants.

Determination of main outcome indicators

The main outcome indicator was higher BV cure rate in the probiotics group against placebo group or the antibiotic group, which was evaluated by cure corresponds to the diagnostic criteria. In some articles, the outcome index was the percentage of the recurrence rate, which we had converted to the cure rate for evaluation. Cure refers to the normalization of diagnostic indicators, such as Amsel criteria ≤ 1 or Nugent score ≤ 3.

Secondary observation indicators included (a) disappeared clue cells, negative in sialidase test, and had no symptoms and signs of BV (such as no unpleasant secretion or odor); (b) normal vaginal flora; (c) prolonged time of recurrence after initial treatment when adjuvant therapy with lactic acid bacteria was used; (d) improved Nugent score to below 7 after treatment.

The most common local adverse events were abnormal vaginal discharge, abnormal vaginal odor, external genital irritation and genital pruritus. Safety was assessed by recording all side effects. Adverse events that occurred during the trial were evaluated in the treatment group and the placebo group to determine whether there was a significant difference between the two groups.

Data extraction and synthesis

Data were extracted in tables, including author, year of publication, type of study, age, sample size (intervention/control), intervention measures (type, dosage, drug-delivery way, intervention time), follow-up time, and diagnosis criteria.

Quality assessment of the studies

Cochrane Handbook for Systematic Reviews of Interventions for assessing risk of bias was recommended quality assessment method used in randomized controlled trials, which mainly includes 7 aspects. Two researchers (Chen and Li) conducted data extraction and risk assessment respectively. Any differences were discussed and a third investigator (Qing) was presented to decide whether to reach an agreement.

Statistical analysis

RevMan5.3 software was used for statistical analysis of the included data. The statistical method was expressed as Mantel–Haenszel (M-H), and the effect measure as RR and 95% Confidence Interval (CI). P < 0.05 indicated that the difference was statistically significant. Chi-square test was used for heterogeneity analysis. If P > 0.1 and I2 ≤ 50%, the heterogeneity between studies was low. If P ≤ 0.1 and I2 > 50%, it indicated that there was significant heterogeneity between studies. Due to the different clinical designs of these randomized controlled trials, fixed effect models were used for meta-analysis of trials with low heterogeneity. For trials with high heterogeneity, we used random effect models for meta-analysis, and subgroup analysis or impact analysis.

Subgroup analysis was to find out the causes of heterogeneity by grouping the route of administration, diagnostic criteria, recruitment area, follow-up time, species of probiotics, use of L. rhamnose and dosage of probiotics. Sensitivity analysis was to gradually exclude the included literature and recalculate the I2 and P values. If heterogeneity has changed greatly after the exclusion of an article, it may be the main source of heterogeneity.

Results

Study identification and selection

According to the established retrieval strategy, 926 relevant literatures were preliminarily retrieved. After removing the repeated 455 literatures, there were 471 literatures that can be screened. After excluding reviews, meeting minutes, and others non relevant article types, 382 papers remained. After reading the title and abstract, there were 57 articles left. An additional 37 articles were excluded based on inclusion and exclusion criteria. Finally, 20 relevant articles were included in this study, involving 2093 participants. The flowchart shows the process of literature selection (Fig. 1).

Fig. 1
figure 1

PRISMA flow diagram

Full size image

Risk of bias assessment

The assessment of risk of bias for the included 20 RCTs are shown in Fig. 2. Risk of bias were mainly derived from Random Sequence Generation, eight studies in this section had uncertain bias risk. Six of the included studies achieved a score of seven, indicating good quality. Overall, the quality of the included studies was moderate. Of the 20 studies, most had an uncertain risk of bias, and only five were considered high risk of bias.

Fig. 2
figure 2

Risk of bias assessment

Full size image

Characteristics of the studies

The main characteristics of the 20 randomized controlled trials included in this meta-analysis are shown in Table 1. The included trials were published between 1992 and 2021, and consist of 1067 patients in the experimental group and 1026 patients in the control group. These twenty articles can be divided into three cases according to different experimental schemes. Fourteen randomized controlled trials compared the efficacy of antibiotics in addition to probiotics in BV (antibiotics + probiotics group) and antibiotics alone (or with placebo) in BV (antibiotics (+ placebo) group). Three trials compared the efficacy of probiotics (probiotics group) with antibiotics (antibiotics group) for BV, and three randomized controlled trials compared the efficacy of probiotics (probiotics group) with placebo (placebo group) for BV.

Table 1 Characteristics of the included studies in the meta-analysis
Full size table

Meta-analysis of treatment efficacy

A total of 20 RCTs were included in this study which were divided into three groups (G1, G2, G3) for analysis according to the different intervention methods. Funnel plots suggested the heterogeneity between those studies (Fig. 3).

Fig. 3
figure 3

Funnel plot for risk of bias

Full size image

G1: Fourteen randomized controlled trials [19, 24,25,26,27,28,29,30,31,32,33,34,35,36] compared the efficacy of probiotic-assisted antibiotic therapy for BV with antibiotics alone (or plus placebo), including data from 1662 patients with BV. The cure rate was 72.98% (624/855) in the antibiotics + probiotics group and 62.70% (506/807) in the antibiotics (+placebo) group, with P = 0.009, reaching a statistically significant difference. The results showed that RR was 1.23 with 95% CI (1.05, 1.43). However, the results were heterogeneous (I2 = 83%, P < 0.00001), indicating the combined analysis could not be carried out directly, and the subgroup analysis was needed (Fig. 4A).

Fig. 4
figure 4

Forest plot of efficacy outcome. A Forest plot of Antibiotics + Probiotics/Antibiotics (+Placebo), used the random effect model. B Forest plot of Probiotics/Antibiotics, used the random effect model. C Forest plot of Probiotics/Placebo, used the fixed effect model

Full size image

G2: Three randomized controlled trials [21, 36, 37] were conducted to compare the effects of probiotics and antibiotics. Among them, 92 cases (64.79%) were cured in the probiotics group and 127 cases (77.44%) were cured in the antibiotics group. There was no significant difference in the cure rate of BV between the two treatments (P = 0.72), and there was evidence of obvious heterogeneity (I2 = 92%, P < 0.00001), therefore random effect analysis was used for further analysis. In conclusion (RR = 1.12, 95% CI (0.60, 2.07)), the result of G2 analysis cannot be considered that probiotics alone is more effective in treating BV than using antibiotics alone. The number of articles in G2 is so small that we cannot make further analysis. Therefore, more studies are needed to compare the efficacy of antibiotics alone versus probiotics alone in the treatment of BV (Fig. 4B).

G3: Three randomized controlled trials [38,39,40] compared the efficacy of probiotics with placebo, involving a total of 125 eligible patients with BV. In the probiotics group, 39 out of 70 patients were cured (55.71%), compared to 1 out of 55 patients (0.02%) in the placebo group (P < 0.0001, indicating a statistically significant difference in cure rate). The results of G3 analysis shown I2 = 0% and P = 0.68, indicating that there was a low heterogeneity in the included studies, so a fixed model was used to analyze G3, with a result of RR equaled to 15.20 with 95% CI (3.87, 59.64). We can extrapolate from these results that probiotics might has a therapeutic effect on BV compared to placebo (Fig. 4C).

Subgroup analysis

For studies with large heterogeneity (G1), we set up a subgroup analysis and used a random effects model to explore the causes of heterogeneity (Table 2).

Table 2 Summary of subgroup analysis results
Full size table

There were no significant differences in other subgroups, such as vaginal administration of probiotics, diagnostic criteria, recruitment areas and species of probiotics. Although the results of short-term follow-up were statistically significant, the removal of any study could not reduce its heterogeneity, and the high heterogeneity made the results unreliable.

Although studies of oral administration to probiotics had great heterogeneity (P = 0.003, I2 = 72%), but it was statistically significant (P = 0.0001). Sensitivity analysis would be carried out in the next step to further explore the cause of heterogeneity.

The results of L. rhamnose group and high dose group were statistically significant (P = 0.03, P = 0.006), but mainly affected by route of administration. High-dose probiotics (≥ 1 × 109 CFU) was more effective than low-dose probiotics (< 1 × 109 CFU). When L. rhamnose was taken orally, the results were statistically significant (P = 0.04), but the heterogeneity was high (I2 = 76% P = 0.0008). When L. rhamnose was used in the vagina, the results were not statistically significant. It may be because L. rhamnose is an intestinal isolate.

Sensitivity analysis

Following subgroup analysis of G1, the oral administration route showed higher heterogeneity (I2 = 71%, P = 0.008). When Zhang Y.2021 was excluded, the whole oral administration group showed no heterogeneity (I2 = 0%, P = 0.43). After being analyzed by fixed effects, the results were statistically significant (RR = 1.93, 95% CI (1.59, 2.35), P < 0.00001). This result indicated that when probiotics was added adjunctively in conventional antibiotic therapy for BV treatment, the cure rate was higher than antibiotic therapy alone (or plus placebo) in oral administration. The heterogeneity of Zhang Y.2021 may come from its research method: vaginal administration of metronidazole and oral probiotic, because the research methods of the other four articles were oral antibiotics and oral probiotics.

Discussion

The main purpose of this study was to systematically evaluate the clinical efficacy of probiotics in the treatment of bacterial vaginosis. The results showed that the cure rate of probiotics combined with antibiotics in the treatment of BV was better than that of antibiotics alone, there was no difference between probiotics and antibiotics alone, and the efficacy of probiotics alone in the treatment of BV was better than that of placebo. For the use of probiotics, oral probiotics was better than vaginal administration in the treatment of BV, oral administration of L. rhamnose was more effective than vaginal in the treatment of BV, high-dose probiotics was more effective than low-dose probiotics, and the effective rate was different in short-term follow-up but not in long-term follow-up. These results might provide a reference for future clinical treatment of BV.

According to this study, the cure rate of patients with bacterial vaginosis treated only with probiotics was significantly higher than that of patients treated with placebo, suggesting that probiotics may play a role in the treatment of BV. Compared with the efficacy of probiotics and antibiotics in the treatment of BV, there was no significant difference in the cure rate between the two groups. The clinical cohort study [37] showed 10-day intravaginal injection of probiotics maintained normal vaginal microbiota for longer, compared with 7-day intravaginal injection of metronidazole. Probiotics could effectively and stably restore vaginal microflora and maintain normal vaginal flora for a longer time, which provided a new idea for the treatment of BV. We also need more research on the comparison of the efficacy of probiotics and antibiotics. Our analysis showed that using probiotics as an adjuvant therapy to antibiotics in BV treatment is effective and promising. When probiotic was given orally, it could be considered that the efficacy of probiotics assisted antibiotics in treating BV was better than that of antibiotics alone. In a meta-analysis published in 2017 [41] there was limited evidence to support the fact that metronidazole combined with probiotic supplements was more effective in the treatment of BV than metronidazole alone. However, two other meta-analyses [42, 43] concluded that, despite limited and weak evidence, probiotics showed beneficial effects as a substitute or combination therapy for BV. A meta-analysis published in 2019 [44] showed that probiotics alone were more effective in treating BV in both short and long term, whereas probiotics after antibiotic treatment was only effective in the short term. In short, appropriate sample size and experimental design are needed to further confirm the effectiveness and safety of this treatment strategy.

The preferred route of administration of probiotics has been controversial. On the one hand, an animal experiment [45] had shown that oral administration was more effective than vaginal administration on GV-induced BV. The anti-BV effect of orally intake of a Lactobacillus rhamnosus HN001 (L1), Lactobacillus acidophilus GLA-14 (L2) and Lactoferrin RCXTM (PM; RECETA ®) may be due to the regulation of immune response through the gastrointestinal tract by these probiotics rather than the completion or killing of GV through the vagina. According to previous studies [46], the vaginal mucus barrier prevented the drug from approaching the folded vaginal epithelium, by which might affect the therapeutic effect of local drugs. On the other hand, a 16SrRNA gene sequencing-based study [25] concluded that oral probiotics were ineffective because probiotics were rarely detected in both vaginal and fecal microbiota. Our analysis showed that when probiotic was given orally, it could be considered that the efficacy of probiotics assisted antibiotics in treating BV was better than that of antibiotics alone. The effectiveness of probiotic products depends on the number of living cells per administration, while the probiotic dose is not clearly defined [47]. Our study showed that the effect of high-dose probiotics in the treatment of BV was better than that of low-dose probiotics in the treatment of BV. The results of this study showed that the effect of L. rhamnose was statistically significant only when it was administered orally. L. rhamnose is a common Lactobacillus isolated from gastrointestinal tract. It has been proved that L. rhamnose HN001 could survive under adverse gastrointestinal conditions and adhered to intestinal mucosa [48]. L. rhamnose HN001 showed the ability to regulate the composition of intestinal microbiota [49], but had no significant effect on the diversity and richness of intestinal microbiota [49, 50].

At present, the main focus of RCTs on probiotics in the treatment of BV is still effectiveness, so future research should pay more attention to the safety of probiotics and the comparison of the efficacy of antibiotics alone and probiotics alone in the treatment of BV. This study did not limit the types of antibiotics, the heterogeneity between studies was controlled, and the possible causes of heterogeneity in subgroups were found.

Conclusion

Our meta-analysis found that probiotics may play an active role as an adjuvant treatment to conventional antibiotic therapy for female bacterial vaginosis. However, we need more high-quality, standardized large-sample randomized controlled trials to verify the efficacy of probiotics. In addition, the side effects of probiotics and the selection of high-quality strains may need to be further studied.

Limitations

There were non-negligible limitations this study. Although we believed that Lactobacillus had an effect on the treatment of bacterial vaginosis, in order to include as many literatures as possible, we did not set restrictions on their usage. The RCT follow-up period included in this study was not long, and the long-term effective rate and recurrence rate cannot be observed, so these variables need to be included in the future to evaluate the effectiveness of probiotics in the treatment of BV.

Availability of data and materials

The datasets employed in the current study can be available from the corresponding author upon the reasonable request.

Abbreviations

BV:

Bacterial vaginosis

RR:

Risk ratio

GV:

Gardnerella vaginalis

RCTs:

Randomized controlled trials

PROSPERO:

Prospective Register of Systematic Reviews

M-H:

Mantel–Haenszel

CI:

Confidence Interval

NSFC:

National Natural Science Foundation of China

References

  1. Amsel R, Totten PA, Spiegel CA, Chen KC, Eschenbach D, Holmes KK. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med. 1983;74:14–22.

    Article  CAS  PubMed  Google Scholar 

  2. Koumans EH, Sternberg M, Bruce C, McQuillan G, Kendrick J, Sutton M, Markowitz LE. The prevalence of bacterial vaginosis in the United States, 2001–2004; associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis. 2007;34:864–9.

    Article  PubMed  Google Scholar 

  3. Bradshaw CS, Vodstrcil LA, Hocking JS, Law M, Pirotta M, Garland SM, De Guingand D, Morton AN, Fairley CK. Recurrence of bacterial vaginosis is significantly associated with posttreatment sexual activities and hormonal contraceptive use. Clin Infect Dis. 2013;56:777–86.

    Article  CAS  PubMed  Google Scholar 

  4. Schwebke JR, Muzny CA, Josey WE. Role of Gardnerella vaginalis in the pathogenesis of bacterial vaginosis: a conceptual model. J Infect Dis. 2014;210:338–43.

    Article  PubMed  Google Scholar 

  5. Kenyon C, Colebunders R, Crucitti T. The global epidemiology of bacterial vaginosis: a systematic review. Am J Obstet Gynecol. 2013;209:505–23.

    Article  PubMed  Google Scholar 

  6. Nasioudis D, Linhares IM, Ledger WJ, Witkin SS. Bacterial vaginosis: a critical analysis of current knowledge. BJOG. 2017;124:61–9.

    Article  CAS  PubMed  Google Scholar 

  7. Onderdonk AB, Delaney ML, Fichorova RN. The human microbiome during bacterial vaginosis. Clin Microbiol Rev. 2016;29:223–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Taylor BD, Darville T, Haggerty CL. Does bacterial vaginosis cause pelvic inflammatory disease? Sex Transm Dis. 2013;40:117–22.

    Article  PubMed  Google Scholar 

  9. Sobel R, Sobel JD. Metronidazole for the treatment of vaginal infections. Expert Opin Pharmacother. 2015;16:1109–15.

    Article  CAS  PubMed  Google Scholar 

  10. Brotman RM, Klebanoff MA, Nansel TR, Yu KF, Andrews WW, Zhang J, Schwebke JR. Bacterial vaginosis assessed by gram stain and diminished colonization resistance to incident gonococcal, chlamydial, and trichomonal genital infection. J Infect Dis. 2010;202:1907–15.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cohen CR, Lingappa JR, Baeten JM, Ngayo MO, Spiegel CA, Hong T, Donnell D, Celum C, Kapiga S, Delany S, Bukusi EA. Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples. PLoS Med. 2012;9: e1001251.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mohammadzadeh F, Dolatian M, Jorjani M, Alavi Majd H. Diagnostic value of Amsel’s clinical criteria for diagnosis of bacterial vaginosis. Glob J Health Sci. 2014;7:8–14.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nugent R, Krohn M, Hillier S. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. 1991;29:297–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Muthusamy S, Varghese J, Raveendran V, Ezilarasan K, Easow JM. Evaluation of interobserver reliability of Nugent score for diagnosis of bacterial vaginosis. Indian J Sex Transm Dis AIDS. 2018;39:120–3.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Coudray MS, Madhivanan P. Bacterial vaginosis—a brief synopsis of the literature. Eur J Obstet Gynecol Reprod Biol. 2020;245:143–8.

    Article  CAS  PubMed  Google Scholar 

  16. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64:1–137.

    PubMed  Google Scholar 

  17. Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB, Moss LM, Horvath LB, Kuzevska I, Fairley CK. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis. 2006;193:1478–86.

    Article  PubMed  Google Scholar 

  18. Marrazzo JM, Cook RL, Wiesenfeld HC, Murray PJ, Busse B, Krohn M, Hillier SL. Women’s satisfaction with an intravaginal Lactobacillus capsule for the treatment of bacterial vaginosis. J Womens Health. 2006;15:1053–60.

    Article  Google Scholar 

  19. Anukam K, Osazuwa E, Ahonkhai I, Ngwu M, Osemene G, Bruce AW, Reid G. Augmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: randomized, double-blind, placebo controlled trial. Microbes Infect. 2006;8:1450–4.

    Article  CAS  PubMed  Google Scholar 

  20. Bradshaw C, Pirotta M, Hocking J, Garland S, De Guigand D, Fehler G, Morrow A, Walker S, Vodstrcil L, Fairley C. Double-blind randomised placebo controlled trial of oral metronidazole in combination with either vaginal clindamycin or an oestrogen-containing vaginal probiotic for the treatment of bacterial vaginosis. Sex Transm Infect. 2011;87:A80–1.

    Article  Google Scholar 

  21. Anukam KC, Osazuwa E, Osemene GI, Ehigiagbe F, Bruce AW, Reid G. Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis. Microbes Infect. 2006;8:2772–6.

    Article  CAS  PubMed  Google Scholar 

  22. Armstrong E, Hemmerling A, Miller S, Burke K, Newmann S, Morris S, Reno H, Huibner S, Cohen CR, Kaul R. Impact of LACTIN-V (Lactobacillus crispatus CTV-05) on genital immunology following standard bacterial vaginosis treatment: results from a randomized placebo-controlled trial. J Int AIDS Soc. 2021;24:46.

    Google Scholar 

  23. Zhang Y, Lyu J, Ge L, Huang L, Peng Z, Liang Y, Zhang X, Fan S. Probiotic Lacticaseibacillus rhamnosus GR-1 and Limosilactobacillus reuteri RC-14 as an adjunctive treatment for bacterial vaginosis do not increase the cure rate in a Chinese cohort: a prospective, parallel-group, randomized, controlled study. Front Cell Infect Microbiol. 2021;11: 669901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Happel AU, Singh R, Mitchev N, Mlisana K, Jaspan HB, Barnabas SL, Passmore JS. Testing the regulatory framework in South Africa—a single-blind randomized pilot trial of commercial probiotic supplementation to standard therapy in women with bacterial vaginosis. BMC Infect Dis. 2020;20:491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang Y, Lyu J, Ge L, Huang L, Peng Z, Liang Y, Zhang X, Fan S. Probiotic Lacticaseibacillus rhamnosus GR-1 and Limosilactobacillus reuteri RC-14 as an adjunctive treatment for bacterial vaginosis do not increase the cure rate in a Chinese cohort: a prospective, parallel-group, randomized, controlled study. Front Cell Infect Microbiol. 2021;11:543.

    Google Scholar 

  26. Bradshaw CS, Pirotta M, de Guingand D, Hocking JS, Morton AN, Garland SM, Fehler G, Morrow A, Walker S, Vodstrcil LA, Fairley CK. Efficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: randomised placebo-controlled double-blind trial. PLoS ONE. 2012;7:e34540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cohen CR, Wierzbicki MR, French AL, Morris S, Newmann S, Reno H, Green L, Miller S, Powell J, Parks T, Hemmerling A. Randomized trial of lactin-V to prevent recurrence of bacterial vaginosis. N Engl J Med. 2020;382:1906–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Eriksson K, Carlsson B, Forsum U, Larsson PG. A double-blind treatment study of bacterial vaginosis with normal vaginal lactobacilli after an open treatment with vaginal clindamycin ovules. Acta Derm Venereol. 2005;85:42–6.

    Article  PubMed  Google Scholar 

  29. Larsson PG, Stray-Pedersen B, Ryttig KR, Larsen S. Human lactobacilli as supplementation of clindamycin to patients with bacterial vaginosis reduce the recurrence rate; a 6-month, double-blind, randomized, placebo-controlled study. BMC Womens Health. 2008;8:3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Laue C, Papazova E, Liesegang A, Pannenbeckers A, Arendarski P, Linnerth B, Domig KJ, Kneifel W, Petricevic L, Schrezenmeir J. Effect of a yoghurt drink containing Lactobacillus strains on bacterial vaginosis in women—a double-blind, randomised, controlled clinical pilot trial. Benef Microbes. 2018;9:35–50.

    Article  CAS  PubMed  Google Scholar 

  31. Marcone V, Calzolari E, Bertini M. Effectiveness of vaginal administration of Lactobacillus rhamnosus following conventional metronidazole therapy: how to lower the rate of bacterial vaginosis recurrences. New Microbiol. 2008;31:429–33.

    CAS  PubMed  Google Scholar 

  32. Marcone V, Rocca G, Lichtner M, Calzolari E. Long-term vaginal administration of Lactobacillus rhamnosus as a complementary approach to management of bacterial vaginosis. Int J Gynecol Obstet. 2010;110:223–6.

    Article  Google Scholar 

  33. Martinez RCR, Franceschini SA, Patta MC, Quintana SM, Gomes BC, De Martinis ECP, Reid G. Improved cure of bacterial vaginosis with single dose of tinidazole (2 g), Lactobacillus rhamnosus GR-1, and Lactobacillus reuteri RC-14: A randomized, double-blind, placebo-controlled trial. Can J Microbiol. 2009;55:133–8.

    Article  CAS  PubMed  Google Scholar 

  34. Petricevic L, Witt A. The role of Lactobacillus casei rhamnosus Lcr35 in restoring the normal vaginal flora after antibiotic treatment of bacterial vaginosis. BJOG. 2008;115:1369–74.

    Article  CAS  PubMed  Google Scholar 

  35. Russo R, Karadja E, De Seta F. Evidence-based mixture containing Lactobacillus strains and lactoferrin to prevent recurrent bacterial vaginosis: a double blind, placebo controlled, randomised clinical trial. Benef Microbes. 2019;10:19–26.

    Article  CAS  PubMed  Google Scholar 

  36. Ozmen S, Turhan NO, Seckin NC. Gardnerella-associated vaginitis: Comparison of three treatment modalities. Turk J Med Sci. 1998;2:171–4.

    Google Scholar 

  37. Ling Z, Liu X, Chen W, Luo Y, Yuan L, Xia Y, Nelson KE, Huang S, Zhang S, Wang Y, et al. The restoration of the vaginal microbiota after treatment for bacterial vaginosis with metronidazole or probiotics. Microb Ecol. 2013;65:773–80.

    Article  CAS  PubMed  Google Scholar 

  38. Hallén AJC, Pahlson C. Treatment of bacterial vaginosis with lactobacilli. Sex Transm Dis. 1992;19(3):146–8.

    Article  PubMed  Google Scholar 

  39. Mastromarino P, Macchia S, Meggiorini L, Trinchieri V, Mosca L, Perluigi M, Midulla C. Effectiveness of Lactobacillus-containing vaginal tablets in the treatment of symptomatic bacterial vaginosis. Clin Microbiol Infect. 2009;15:67–74.

    Article  CAS  PubMed  Google Scholar 

  40. Vicariotto F, Mogna L, Del Piano M. Effectiveness of the two microorganisms Lactobacillus fermentum LF15 and Lactobacillus plantarum LP01, formulated in slow-release vaginal tablets, in women affected by bacterial vaginosis: a pilot study. J Clin Gastroenterol. 2014;48:S106–12.

    Article  PubMed  Google Scholar 

  41. Tan H, Fu Y, Yang C, Ma C. Effects of metronidazole combined probiotics over metronidazole alone for the treatment of bacterial vaginosis: a meta-analysis of randomized clinical trials. Arch Gynecol Obstet. 2017;295:1331–9.

    Article  CAS  PubMed  Google Scholar 

  42. Huang H, Song L, Zhao WJ. Effects of probiotics for the treatment of bacterial vaginosis in adult women: a meta-analysis of randomized clinical trials. Arch Gynecol Obstet. 2014;289:1225–34.

    Article  PubMed  Google Scholar 

  43. Hanson L, VandeVusse L, Jermé M, Abad C, Safdar N. Probiotics for treatment and prevention of urogenital infections in women: a systematic review. J Midwifery Women’s Health. 2016;61:339–55.

    Article  Google Scholar 

  44. Wang Z, He Y, Zheng Y. Probiotics for the treatment of bacterial vaginosis: a meta-analysis. Int J Environ Res Public Health. 2019;16:3859.

    Article  CAS  PubMed Central  Google Scholar 

  45. Jang SE, Jeong JJ, Choi SY, Kim H, Han MJ, Kim DH. Lactobacillus rhamnosus HN001 and Lactobacillus acidophilus La-14 attenuate Gardnerella vaginalis-infected bacterial vaginosis in mice. Nutrients. 2017;9:531.

    Article  PubMed Central  CAS  Google Scholar 

  46. Ensign L, Tang B, Wang Y, Tse T, Hoen T, Cone R, Hanes J. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci Transl Med. 2012;4:138ra179.

    Article  Google Scholar 

  47. Tomás M, Palmeira-de-Oliveira A, Simões S, Martinez-de-Oliveira J, Palmeira-de-Oliveira R. Bacterial vaginosis: standard treatments and alternative strategies. Int J Pharm. 2020;587:119659.

    Article  PubMed  CAS  Google Scholar 

  48. Inturri R, Stivala A, Blandino G. Microbiological characteristics of the probiotic strains B. longum BB536 and L. rhamnosus HN001 used in combination. Minerva Gastroenterol Dietol. 2015;61:191–7.

    CAS  PubMed  Google Scholar 

  49. Toscano M, De Grandi R, Stronati L, De Vecchi E, Drago L. Effect of Lactobacillus rhamnosus HN001 and Bifidobacterium longum BB536 on the healthy gut microbiota composition at phyla and species level: a preliminary study. World J Gastroenterol. 2017;23:2696–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kristensen N, Bryrup T, Allin K, Nielsen T, Hansen T, Pedersen O. Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials. Genome Med. 2016;8:52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We would like to express our deepest gratitude to NSFC for its grant support. All the authors contributed to this study.

Funding

This work was funded by National Natural Science Foundation of China (NSFC82002201 (CMX), NSFC81925026 (ZHW)).

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Rongdan Chen, Rong Li, Wei Qing, Yingxuan Zhang, Zuyi Zhou, Yi Hou, Yiya Shi, Hongwei Zhou & Muxuan Chen

  2. Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Rongdan Chen, Rong Li, Wei Qing, Yingxuan Zhang, Zuyi Zhou, Yi Hou, Yiya Shi, Hongwei Zhou & Muxuan Chen

Authors
  1. Rongdan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Qing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingxuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zuyi Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yiya Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hongwei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Muxuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RC and RL: have contributed to the conception and design, acquisition of the data, analysis and interpretation of data, drafting the manuscript, critical revision of the manuscript. WQ, YXZ, ZZ, YH and YS: have contributed to analysis and interpretation of data, critical revision of the manuscript, revised the subsequent of drafts of manuscript. MC and HZ: have contributed to critical revision of the manuscript, revised the subsequent of drafts of manuscript, final approval of the version to be published. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Muxuan Chen.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

All authors have no conflict of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rongdan Chen and Rong Li are joint first author

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, R., Li, R., Qing, W. et al. Probiotics are a good choice for the treatment of bacterial vaginosis: a meta-analysis of randomized controlled trial. Reprod Health 19, 137 (2022). https://doi.org/10.1186/s12978-022-01449-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12978-022-01449-z

Keywords

Reproductive Health

ISSN: 1742-4755