ETM Experimental and Therapeutic Medicine 1792-0981 1792-1015 D.A. Spandidos 10.3892/etm.2020.9090 ETM-0-0-9090 Articles Treating vaginitis with probiotics in non-pregnant females: A systematic review and meta-analysis JengHuey-Sheng 1 2 YanTsong-Rong 1 ChenJing-Yi 3 Department of Chemical Engineering and Biotechnology, Institute of Chemical Engineering and Biotechnology, Tatung University, Taipei 10452, Taiwan, R.O.C. Department of Urology, Zhong-Xing Branch, Taipei City Hospital, Taipei 10341, Taiwan School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan, R.O.C. Correspondence to: Professor Tsong-Rong Yan, Department of Chemical Engineering and Biotechnology, Institute of Chemical Engineering and Biotechnology, Tatung University, Number 40, Section 3, Zhongshan North Road, Taipei 10452, Taiwan, R.O.C. tryan@gm.ttu.edu.tw

Abbreviations: BV, bacterial vaginosis; VVC, vulvovaginal candidiasis; UTI, urinary tract infection

 10 2020 03 08 2020 20 4 3749 3765 11 11 2019 24 03 2020 Copyright: © Jeng et al. 2020 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Vaginitis, also known as vulvovaginitis, is an inflammation of the vagina and vulva and a common disease in females. It is thought to be caused by vaginal dysbiosis and improved by probiotics. Bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) are the major types of vaginal infections. The present systematic review and meta-analysis aimed to clarify the efficacy of probiotics in the treatment of common vaginal infections in non-pregnant females. Literature on randomized controlled trials and two-armed prospective studies on any intervention with probiotics published until December 24th, 2018 was searched in the PubMed, Cochrane and EMBASE databases. The outcomes of interest were recurrence rate, cure rate, remission rate and normal vaginal flora restoration. Finally, a total of 30 studies on bacterial vaginosis (BV) and/or VVC were included and stratified into 3 study types based on treatment design as follows: Type I, antibiotic/probiotics vs. antibiotics/antifungals (22 studies); Type II, probiotics vs. placebo (5 studies); Type III, probiotics vs. antibiotics (3 studies). The type I studies comprised 1,788 non-pregnant females and had the highest inter-study comparability in post-treatment follow-up design and meta-analysis outcome data. Probiotics interventions were significantly associated with a lower recurrence rate of vaginitis [pooled odds ratio (OR)=0.27, 95% CI: 0.18-0.41, P<0.001] and higher cure/remission rate (pooled OR=2.28, 95% CI: 1.20-4.32, P=0.011). However, a significant increase in normal vaginal flora after probiotic treatment was observed only in BV (pooled OR=4.55, 95% CI: 1.44-14.35, P=0.01). In addition, supportive but heterogeneous results were obtained from the 6-month follow-up data of Type-I studies, different infection types and supplementary analysis of Type-II studies. In conclusion, probiotics have a significant short-term effect in the treatment of common vaginal infections in non-pregnant females. In order to evaluate the long-term effects of probiotics in common vaginal infections, it is worthwhile to perform higher-quality clinical trials in the future.

 probiotics Lactobacillus vaginitis bacterial vaginosis vulvovaginal candidiasis meta-analysis Introduction

Vaginal infections of bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) are common in females, accounting for almost 80% of all cases of vaginitis also known as vulvovaginitis, is an inflammation of the vagina and vulva. Symptoms may include itching, burning, pain, discharge and a bad odor (1,2). While BV is generally regarded as a mild disease, it has been indicated to be associated with the occurrence of endometritis and pelvic inflammatory disease in females without clinical symptoms of BV and may lead to spontaneous abortion, premature rupture of the membranes, and premature delivery during pregnancy (2,3). VVC results from overgrowth of one or more types of yeast organism (e.g., Candida albicans) that normally inhabit the vaginal mucosa in small numbers, and symptoms include external dysuria, pruritus, redness and flocculant vaginal discharge (2,4). In most cases, standard treatments with antibiotics or anti-fungals are effective for BV and VVC. However, the use of antibiotics may cause physiological and non-physiological changes in patients, and interfere with the balance of the normal vaginal microbiota. Thus, the common side-effects of antibiotic treatment are characterized by reduction or depletion of the Lactobacillus species and the excessive growth of Candida species. In addition, excessive use of antibiotics frequently causes the emergence of resistant strains.

Probiotics are defined as ‘live microorganisms when administered in adequate amounts confer a health benefit to the host’ (5). Over the past 2 decades, accumulating evidence has indicated that the intestinal and urogenital microflora has a central role in maintaining the health of human beings (5). In addition, the use of beneficial bacteria to improve dysbiosis by replacing pathogenic bacteria or augmenting normal microflora has been gradually accepted and proven useful in conditions including necrotizing enterocolitis and antibiotic-resistant infections (5). The intestinal, vaginal and urethral microflora have an important role in maintaining health and preventing gynecologic infections in females, and the use of probiotics has been extended to the treatment of refractory cases of female urogenital infections (5).

The use of probiotics has been examined in a number of studies over the past 2 decades as a method of treating and reducing the risk and recurrence rate of gynecologic infections in females, particularly in whom standard treatments are not effective. Probiotics may protect the vagina from pathogen colonization through a number of mechanisms, including blocking potential sites of attachment, production of microbiocidal substances, e.g. hydrogen peroxide, maintenance of a low pH and induction of anti-inflammatory cytokine responses in epithelial cells (3-5). The most common probiotics used in female patients are of the Lactobacillus species (3-5).

While numerous clinical trials have been performed to determine the effectiveness of probiotics for the treatment of vaginal infections, the results have generally been inconsistent, with certain studies suggesting an excellent response and other indicating no effect. Meta-analyses have also provided inconsistent results. A meta-analysis by Huang et al (3) from 2014 indicated that probiotic supplementation improves the cure rate for BV. Other previously published systematic reviews have suggested that the use of probiotics remains controversial in preventing BV and VVC in adult females due to evidence limitations (4,6,7). Potential bias on the benefits of probiotics cannot be ruled out, as the majority of evidence came from small-scale studies, heterogeneous populations, different lengths of follow-up and inhomogeneous treatment designs among the study. Similar views were also expressed by a recently published systemic review by Hanson et al (4) from 2016 with a focus on urogenital infections in non-pregnant females, highlighting the requirement of carefully-planned study stratification upon meta-analysis.

The purpose of the present study was to perform a meta-analysis of randomized controlled trials (RCTs) and two-armed prospective studies identified by a thorough systematic review and meta-analysis of adequately-selected literature to determine the effect of probiotics for the treatment of common vaginal infections in non-pregnant adult females.

 Materials and methods <sec> <title>Literature search strategy and inclusion criteria

The present systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (8). On December 24th, 2018, the Pubmed, Cochrane and EMBASE databases were searched for all studies published previously using the following key words: ‘Probiotics’, ‘Lactobacillus’, ‘urogenital infections’, ‘bacterial vaginosis’, ‘vulvovaginitis’, ‘vaginitis’ and ‘candidiasis’. The search strategy was (probiotics or Lactobacillus) and (vaginosis or vulvovaginal candidiasis or vaginitis or vulvovaginitis or urogenital infections). Articles of interest were also hand-searched for potentially relevant studies. Searches were performed by 2 independent reviewers (HSJ and JYC) and any disagreements were resolved by a third reviewer (TRY). Inclusion criteria for the analysis were as follows: i) RCTs and two-armed prospective studies; ii) studies including females with a current or history of gynecologic infections of BV and/or VCC; iii) studies that examined probiotic treatment vs. non-probiotics treatment (control) with or without antibiotics; iv) studies that provided quantitative data of the outcomes of interest; and v) full-text articles published in English or Chinese. Exclusion criteria were as follows: i) Retrospective studies, cohort studies, case series, letters, comments, editorials, case reports, proceedings, personal communications and one-arm studies; ii) studies on pediatric patients, pregnant females or males; iii) studies on healthy females with/without a history of recurrent urogenital infections. Studies designed to examine Lactobacillus treatment in combination with estriol, probiotic agents containing an unknown number of Lactobacilli or a mixture of multiple types of non-Lactobacillus bacteria were also excluded.

 Data extraction

The following information/data was extracted from studies that met the inclusion criteria: Name of the first author, year of publication, study design, number of participants in each group, participants' age, type of infection, type of interventions, probiotic agents, probiotic administration, length of follow-up period and major outcomes (recurrence rate, cure/remission rate and/or the rate of restoring normal vaginal flora).

 Quality assessment

The quality of the RCTs included was assessed using the Cochrane ‘assessing risk of bias’ table, which consists of 6 domains (random sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessment, incomplete outcome data and selective reporting risk) (9). The quality of non-RCTs was assessed using a Cochrane risk of bias assessment tool for non-randomized studies of interventions (ACROBAT-NRSI) (10). This tool assesses 7 sources of bias associated with confounding, selection of participants, measurement of interventions, departures from intended interventions (10), missing data, measurement of outcomes and selection of the reported result.

 Statistical analysis

Outcome measures for the meta-analysis were recurrence rate, cure and/or remission rate and restoration rate of normal flora. The odds ratios (ORs) with 95% CIs were calculated for each individual study and for all the studies combined. ORs of <1 for recurrence and ORs of >1 for cure and/or remission rate and normal flora restoration rate indicated that the probiotic group was favored. By contrast, ORs of >1 for recurrence and ORs of <1 for cure and/or remission rate and normal flora restoration rate indicated the control group was favored. OR=1 indicated that the probiotic and control groups had comparable outcomes. A χ2-based test of homogeneity was performed and the inconsistency index (I2) and Q-statistics were determined. A random effect model (DerSimonian-Laird method) was considered for the meta-analysis if either the Q statistic of P<0.10 or I2 value of >50% were derived; otherwise, a fixed effect model (Mantel-Haenszel method) was considered for the meta-analysis (11). Heterogeneity determined using the I2 statistic was defined as follows: 0-24%, no heterogeneity; 25-49%, moderate heterogeneity; 50-74%, high heterogeneity; and 75-100%, extreme heterogeneity. When the number of studies included in a meta-analysis is small, heterogeneity tests have low statistical power (12) and in this situation, a random-effects model of analysis is used (13). The National Research Council recommends the use of random-effects approaches for meta-analysis and the exploration of sources of variation in study results (14). Pooled effects were calculated and a 2-sided P<0.05 was considered to indicate statistical significance. Sensitivity analysis was performed using the leave-one-out approach to test the validity and robustness of the major results (12). All analyses were performed using Comprehensive Meta-Analysis statistical software, version 2.0 (Biostat).

 Results <sec> <title>Literature search

A flow diagram of the study selection process is provided in Fig. 1. A total of 771 articles were identified by database- and hand-searching with duplicates removed. After screening by title and abstract, 682 articles were excluded based on inclusion and exclusion criteria. The full text of the remaining 89 articles was reviewed and 59 were further excluded for reasons presented in Fig. 1. The remaining 30 articles were included in the qualitative synthesis, including 20 studies for BV alone or with other pathogens (15-34), 10 studies for VVC alone (31,35-43) and 1 study for BV/VVC (44).

 Characteristics of the reviewed studies

Studies were categorized into three types based on treatment design (Table I): Type I, antibiotics plus Lactobacillus (probiotic) vs. antibiotic with or without placebo (control; n=22) (15,17,18,20,22-26,29,31,32,35-41); type II, Lactobacillus (probiotic) vs. placebo (control; no antibiotics; n=5) (19,21,27,33,34); and type III, Lactobacillus (probiotic) vs. antibiotic (control; n=3) (16,28,30). A summary of the patients' characteristics and interventions for the treatment of BV and/or VVC is provided in Table I. The age range of the female patients included in the analysis was between 18 to 50 years. Table II presents a summary of the outcomes of the studies included. Table III provides a summary of the type of probiotic and the route and dose of administration for the treatment of vaginitis. Probiotic species included L. rhamnosus BMX54, L. fermentum, L. plantarum, L. gasseri, L. plantarum, L. acidophilus, L. brevis CD2, L. salivarius subsp. Salicinius, L. delbrueckii subsp. lactis, L. reuteri, P. acidilactici, L. casei rhamnosus, L. reuteris, B. bifidum, B. longum, L. crispatus and Lactobacillus GG either alone or in various combinations depending on the infection being treated. The route of administration included oral capsule, vaginal tablet and vaginal capsule (Table III).

 Meta-analysis

The detailed treatment outcomes of all studies reviewed are summarized in Table II. The majority of studies adopted a type I treatment design for BV and/or VVC infections and those with 1- and/or 6-months follow-up data were included in the meta-analysis. These comprised of a total of 21 articles (10 articles on BV, 9 studies on VVC and 2 on BV/VVC) (15,17,18,20,22-26,29,31,32,35-41). The total number of patients evaluated in the 21 type I studies was 1,788 (probiotic test group, n=910; control group, n=878). These type I studies were the major focus of the present meta-analysis, while type II and III studies were analyzed separately for supplementation.

With respect to recurrence at 1 month after treatment, 9 studies [2 on BV alone (15,26), 5 on VVC alone (37,38,40,42,43) and 2 on BV/VVC (31,44)] with complete quantitative data were included in the present meta-analysis. A total of 1,220 patients were evaluated (probiotic test group, n=631; control group, n=589). There was no heterogeneity present among all 9 studies or those on either BV or VVC (total: Q=11.82, I2=24%; BV: Q=2.14, I2=7%; VVC: Q=1.86, I2=0%; Fig. 2A). The analysis indicated that patients in the probiotic group had a significantly lower recurrence rate than those in the control group (pooled OR=0.27, 95% CI: 0.18-0.41; Fig. 2A). A favorable outcome associated with the probiotics group was also observed when analyzing BV and VVC individually (BV: Pooled OR=0.10, 95% CI: 0.04-0.26; VVC: Pooled OR=0.27, 95% CI: 0.16-0.45; all P<0.001; Fig. 2A). However, there was no significant difference in the recurrence rate between the probiotic and control groups at 6 months after treatment (Fig. 2A).

With respect to cure or remission after treatments, a total of 12 studies were included. These comprised 12 studies with 1-month follow-up results [6 for BV alone (15,18,23,24,26,29), 4 for VVC alone (37,38,40,42) and 2 for BV/VVC (31,44)] and 2 studies (22,24) with 6-month follow-up for BV alone. In the 12 studies with 1-month follow-up outcomes, 1,643 patients in total were evaluated (probiotic test group, n=836; control group, n=807). There was moderate to high heterogeneity among the 12 studies with 1-month follow-up (total: Q=52.69, I2=77%; BV: Q=47.02, I2=87. %; VVC: Q=5.45, I2=27%), as well as between studies with 6-month follow-up (Q=1.70, I2=40%). The analysis indicated that probiotic treatment was favorable among all studies and those focusing on VVC alone 1 month after treatment (total: Pooled OR=2.28, 95% CI: 1.21-4.32, P=0.011; VVC: Pooled OR=1.72, 95% CI: 1.13-2.64, P=0.012), as well as 6 months after treatment of BV (pooled OR=2.58, 95% CI: 1.07-6.23, P=0.036; Fig. 2B). However, there was no significant difference in the cure rate at 1 month for BV (pooled OR=2.59; 95% CI: 0.76-8.85; P=0.129; Fig. 2B).

With respect to restoration of the normal flora, 4 studies (15,24,26,29) had complete quantitative data at 1 month and 4 studies (17,24,25,32) at 6 months after treatments for BV, and were included in the analysis. High heterogeneity existed among the studies on the restoration of normal flora at 1 month and 6 months after treatment (1 month: Q=17.28, I2=83%; 6 months: Q=47.86, I2=94%). The analysis indicated that patients in the probiotic group had a significantly higher rate of normal flora restoration at 1 month after treatment (pooled OR=4.55, 95% CI: 1.44-14.36, P=0.010). However, there were no differences in the normal flora restoration rate between the two groups at 6 months after treatment (Fig. 2C).

Additional analyses were performed for type II (19,21,27,33,34) or type III (16,28) studies that had at least one follow-up outcome. These studies all focused on BV and had varied heterogeneity (Recurrence: Q=7.98; I2=87%; Cure or remission: Q=1.94; I2=0%; Restored normal flora: Q=4.37; I2=54% for type II and Cure or remission: Q=2.58; I2=61%; for type III). Patients with BV given type II treatments in the probiotic group were indicated to have a higher cure or remission rate and normal flora restoration rate than those in the control group (cure/remission rate: Pooled OR=12.44, 95% CI: 4.86-31.89, P<0.001; normal flora restoration rate: Pooled OR=3.32, 95% CI: 1.11-9.97, P=0.033). In BV patients given type III treatments, the probiotic group had a higher cure/remission rate than the control group (cure/remission rate: Pooled OR=8.39, 95% CI: 1.32-53.23, P=0.024; Table IV).

 Quality assessment

The risk of bias assessment for individual studies is provided in Fig. 3, including the potential risk of individual studies (Fig. 3A and B) and the overall risk (Fig. 3C and D). Overall, the studies had a low risk of attrition bias and reporting bias, and low or unclear risk of selection bias and detection bias. Furthermore, 3 studies had a high risk of performance bias due to improper blinding of participants and researchers.

 Sensitivity analysis

Sensitivity analyses were performed on the major results using the leave-one-out approach, in which the meta-analysis was performed with each study removed in turn (Table V). The direction of combined estimates on recurrence rates and cure/remission rates at 1 month and normal flora restoration rates at 6 months did not vary markedly with the removal of the studies, indicating that the meta-analysis had good reliability and supported that there was no or little inter-study heterogeneity. However, for normal flora restoration rates at 1 month, the study of Marcone et al (24) from 2008 may have had a disproportionate effect on the pooled OR, as the difference became more significant and greater when this study was not included in the meta-analysis, while the three other studies had no such effect.

 Discussion

The overall summary of the qualitative analysis of the 30 studies suggests that probiotic treatments are useful for managing common vaginal infections, particularly BV and VVC. However, patient populations, treatment protocols, endpoints and follow-up time-points exhibited a marked variation. The results of the meta-analysis indicated that probiotics as a supplement of antibiotic/anti-fungal treatments (as observed in type I studies) reduced the recurrence rate and increased the cure/remission rate in non-pregnant adult females at 1 month after treatment. With less evident data, the normal bacterial flora restoration rate was also increased by probiotic-supplemented treatments in BV. The short-term benefits of probiotics were further supported by individual analysis of BV and VVC, although probiotics supplementary to standard treatments did not increase the cure/remission rate in BV and the post-treatment normal bacterial restoration rate in VVC was lacking. However, observations at 6 months post-treatment were less frequently reported. In line with the results demonstrated by probiotic-supplemented treatments, probiotics alone without antibiotics may have clinical benefits in promoting the cure/remission rate and normal flora restoration rates in BV.

To the best of our knowledge, the present meta-analysis was the first to review and analyze the effect of probiotics in common vaginal infections reported by RCTs or appropriately-controlled studies. Furthermore, only few studies have evaluated the benefits of probiotics in vaginal infection stratified by treatment regimen. The quantitative data of the present study are supported by conclusions from two published systemic reviews, which examined the overall effect of probiotics in females with urogenital infections qualitatively. In 2009, Abad and Safdar (6) identified 25 studies that used Lactobacillus-containing probiotics to either prevent or treat a urogenital infection [BV, VVC and urinary tract infections (UTI)]. Of the 25 studies, 18 used Lactobacillus preparations for the treatment or prevention of urogenital infections and 7 focused solely on vaginal colonization (6). Of the 18 studies, only 8 studies included patients with BV, 4 included patients with VVC, 5 included patients with UTI and 1 was on multiple infections (6). Overall, Lactobacilli were beneficial for the treatment of BV, while no clear benefit was observed for VVC or UTI (6). A more recent systematic review published in 2016 investigated probiotics for the treatment and prevention of urogenital infections in females (4). A total of 20 studies (published from 2008 to 2015) were identified, with 14 examining BV, 2 examining VCC, 3 examining UTI and 1 examining human papillomavirus (HPV) (4). While the studies reviewed by Hanson et al (4) in 2016 were heterogeneous with respect to study type, design, intervention and outcomes and varied in quality (4 of good quality, 9 of fair and 7 of poor quality), the authors still made to the conclusion that the use of probiotics may be effective for the treatment and prevention of BV, recurrent candidiasis or UTI, as well as HPV lesions. In the current review, an analysis of quantitative outcomes from a total of 1,788 patients with common vaginal infections was presented, with focus on BV and VVC that are most directly impacted by an imbalanced microflora/dysbiosis.

One prior meta-analysis examined the use of probiotics for treating BV. In a meta-analysis published in 2014, Huang et al (3) indicated that the use of probiotic supplementation significantly improved the cure rate in adult females with BV [risk ratio (RR)=1.53; 95% CI: 1.19-1.97]. When only 9 high-quality studies were included in the analysis, the RR increased slightly to 1.60 (95% CI: 1.16-2.22) (3). Of note, when a subgroup analysis was performed, a single treatment with probiotics may only be effective for short-term follow-up (≤1 month) but not for long-term follow-up (>1 month) (3), which was consistent with the present result that no difference between two groups in recurrence rate and cure/remission rates was determined at 6 months after the treatment. In a meta-analysis by Huang et al (3) from 2014, the eligible articles were searched up to May 2013 and the studies included in the meta-analysis were also heterogeneous. In the present meta-analysis, the literature search was further updated to December 24th, 2018, and studies all except one RCT analyzed in the previous study by Huang et al (3) from 2014 were included. This particular RCT was excluded from the present study due to its study design for healthy females with a history of BV (45); furthermore, it had different follow-up time-points from other studies analyzed in the present study and was deemed unsuitable for analysis of post-treatment outcomes.

A recent meta-analysis study suggested that, although probiotics appeared effective in treating VVC, relevant studies were not sufficient in number (5-7 studies included for each analysis) or of comparable quality (7). In the present study, which focused on common vaginal infections as a whole, only studies with comparable treatment designs and study follow-up schedules were included in the meta-analysis. Furthermore, the major results of the present study were based on >10 RCTs or prospective studies with control arms. In 2006, Falagas et al (46) reported on several clinical trials on VVC that support the effectiveness of Lactobacilli administered either orally or intravaginally in decreasing colonization of C. albicans or preventing vaginal candidiasis. However, most of the relevant clinical trials had methodological problems, including small sample size, no control group (single-arm) and included females without confirmed recurrent VVC. All of the studies on VVC reviewed in the present meta-analysis were designed to compare Lactobacillus capsule-supplemented anti-fungal treatments (probiotic group) with anti-fungal agents alone (control group). Despite the follow-up period ranging from <1 week to 6 months among the studies included, only those with comparable follow-up schedules were included in the present meta-analysis. The outcome supports the effectiveness of Lactobacilli in decreasing the recurrence rate and improving the cure rate.

The primary limitation of the present study has already been mentioned-the large heterogeneity between studies with respect to the patient population, type of treatment, probiotic strains and outcome follow-ups. However, it was sought to overcome this by carefully-planned stratification based on treatment design and follow-up schedules. The major results on short-term benefits of combined therapy of antibiotics/anti-fungals with probiotics was further confirmed by the sensitivity test. By contrast, the limited sample size and heterogeneous study design prevented us from a reliable subgroup analysis of long-term benefits and of probiotics treatment alone without antibiotic/anti-fungal agents.

In conclusion, the results of the present study confirm the results of other reports in a quantitative manner, namely that probiotics as a supplement to conventional pharmacological treatments are effective in the short term for the treatment of common vaginal infections in non-pregnant adult females. However, high-quality evidence for the effectiveness of probiotics alone in recurrent or curative vaginal infections is limited. Further high-quality clinical trials are necessary to identify the most effective probiotic strains, the most effective treatment regimens (with or without antibiotics) and the subpopulations of females (e.g. pre-menopausal vs. post-menopausal) that may benefit the most from probiotics.

 Acknowledgements

Not applicable.

 Funding

No funding was received.

 Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

 Authors' contributions

HSJ conceived and designed the current study, defined the content of the research, conducted literature research, performed statistical analysis and prepared and edited the manuscript. TRY is the guarantor of study integrity, designed the current study, defined the content of the research and reviewed the manuscript. JYC conducted literature research, acquired data and performed statistical analysis. All authors read and approved the final manuscript.

 Ethics approval and consent to participate

Not applicable.

 Patient consent for publication

Not applicable.

 Competing interests

The authors declare that there are no competing interests.

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AnukamKOsazuwaEAhonkhaiINgwuMOsemeneGBruceAWReidGAugmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: Randomized, double-blind, placebo controlled trialMicrobes Infect81450145420061669723110.1016/j.micinf.2006.01.003 AnukamKCOsazuwaEOsemeneGIEhigiagbeFBruceAWReidGClinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosisMicrobes Infect82772277620061704583210.1016/j.micinf.2006.08.008 BradshawCSPirottaMDe GuingandDHockingJSMortonANGarlandSMFehlerGMorrowAWalkerSVodstrcilLAFairleyCKEfficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: Randomised placebo-controlled double-blind trialPLoS One7e3454020122250931910.1371/journal.pone.0034540 ErikssonKCarlssonBForsumULarssonPGA double-blind treatment study of bacterial vaginosis with normal vaginal lactobacilli after an open treatment with vaginal clindamycin ovulesActa Derm Venereol85424620051584899010.1080/00015550410022249 HallenAJarstrandCPåhlsonCTreatment of bacterial vaginosis with lactobacilliSex Transm Dis191461481992152353010.1097/00007435-199205000-00007 HeczkoPBTomusiakAAdamskiPJakimiukAJStefanskiGMikołajczyk-CichońskaASuda-SzczurekMStrusMSupplementation of standard antibiotic therapy with oral probiotics for bacterial vaginosis and aerobic vaginitis: A randomised, double-blind, placebo-controlled trialBMC Womens Health1511520152663509010.1186/s12905-015-0246-6 HemalathaRMastromarinoPRamalaxmiBABalakrishnaNVSesikeranBEffectiveness of vaginal tablets containing lactobacilli versus pH tablets on vaginal health and inflammatory cytokines: A randomized, double-blind studyEur J Clin Microbiol Infect Dis313097310520122277759210.1007/s10096-012-1671-1 LarssonPGStray-PedersenBRyttigKRLarsenSHuman lactobacilli as supplementation of clindamycin to patients with bacterial vaginosis reduce the recurrence rate; a 6-month, double-blind, randomized, placebo-controlled studyBMC Womens Health8320081819797410.1186/1472-6874-8-3 LaueCPapazovaELiesegangAPannenbeckersAArendarskiPLinnerthBDomigKJKneifelWPetricevicLSchrezenmeirJEffect of a yoghurt drink containing Lactobacillus strains on bacterial vaginosis in women-a double-blind, randomised, controlled clinical pilot trialBenef Microbes9355020182906571010.3920/BM2017.0018 MarconeVCalzolariEBertiniMEffectiveness of vaginal administration of Lactobacillus rhamnosus following conventional metronidazole therapy: How to lower the rate of bacterial vaginosis recurrencesNew Microbiol31429433200818843900 MarconeVRoccaGLichtnerMCalzolariELong-term vaginal administration of Lactobacillus rhamnosus as a complementary approach to management of bacterial vaginosisInt J Gynaecol Obstet11022322620102057334810.1016/j.ijgo.2010.04.025 MartinezRCFranceschiniSAPattaMCQuintanaSMGomesBCDe MartinisECReidGImproved 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 trialCan J Microbiol5513313820091929564510.1139/w08-102 MastromarinoPMacchiaSMeggioriniLTrinchieriVMoscaLPerluigiMMidullaCEffectiveness of Lactobacillus-containing vaginal tablets in the treatment of symptomatic bacterial vaginosisClin Microbiol Infect15677420091904616910.1111/j.1469-0691.2008.02112.x ParentDBossensMBayotDKirkpatrickCGrafFWilkinsonFEKaiserRRTherapy of bacterial vaginosis using exogenously-applied Lactobacilli acidophili and a low dose of estriol: A placebo-controlled multicentric clinical trialArzneimittelforschung46687319968821521 PetricevicLWittAThe role of Lactobacillus casei rhamnosus Lcr35 in restoring the normal vaginal flora after antibiotic treatment of bacterial vaginosisBJOG1151369137420081882348710.1111/j.1471-0528.2008.01882.x LingZLiuXChenWLuoYYuanLXiaYNelsonKEHuangSZhangSWangYThe restoration of the vaginal microbiota after treatment for bacterial vaginosis with metronidazole or probioticsMicrob Ecol6577378020132325011610.1007/s00248-012-0154-3 LinHMengXBClinical application of Lactasin capsules in vaginitisJ Practical Medicine22192719282006 RecineNPalmaEDomeniciLGiorginiMImperialeLSassuCMusellaAMarchettiCMuziiLBenedetti PaniciPRestoring vaginal microbiota: Biological control of bacterial vaginosis. A prospective case-control study using Lactobacillus rhamnosus BMX 54 as adjuvant treatment against bacterial vaginosisArch Gynecol Obstet29310110720162614289210.1007/s00404-015-3810-2 VicariottoFMognaLDel PianoMEffectiveness 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 studyJ Clin Gastroenterol48 (Suppl 1)S106S11220142529111610.1097/MCG.0000000000000226 VujicGJajac KnezADespot StefanovicVKuzmic VrbanovicVEfficacy of orally applied probiotic capsules for bacterial vaginosis and other vaginal infections: A double-blind, randomized, placebo-controlled studyEur J Obstet Gynecol Reprod Biol168757920132339555910.1016/j.ejogrb.2012.12.031 AnukamKCDuruMUEzeCCEgharevbaJAiyebelehinABruceAReidGOral use of probiotics as an adjunctive therapy to fluconazole in the treatment of yeast vaginitis: A study of Nigerian women in an outdoor clinicMicrobial Ecol Health Dis2172772009 DavarRNokhostinFEftekharMSekhavatLBashiri ZadehMShamsiFComparing the recurrence of vulvovaginal candidiasis in patients undergoing prophylactic treatment with probiotic and placebo during the 6 monthsProbiotics Antimicrob Proteins813013320162720651410.1007/s12602-016-9218-x HanYXZhaoSWClinical observation of Ding JunSheng and clotrimazole vaginal tablet in the treatment ofvulvovaginal candidiasisAnh Med J275285292006 HuaYLinMWangLXiaLObservation of curative effect of miconazole and Lactobacillus on vulvovaginal candidiasis treatedChin J Microecol203863872008 MaLLiLMiconazole plus Lactasin capsules to treat vulvovaginal candidiasis (54 cases)Herald Med26104110422007 MaiXYAnalysis of probiotic Lactobacillus's effect on vulvovaginal candidiasisChin J Microecol193623632007 NouraeiSAmir Ali AkbariSJorjaniMAlavi MajdHAfrakhtehMGhafoorianATafazzoli HarandiHComparison between fluconazole with oral protexin combination and fluconazole in the treatment of vulvovaginal candidiasisISRN Obstet Gynecol201237580620122311917510.5402/2012/375806 YangQZhaoWFZhengJPClinical observat ion of mycobacterium lacticola preparation in treatment of vaginal vini candidiasis using clotrimazole effervescent tabletsChin Hosp Pharm J29137713792009 MartinezRCFranceschiniSAPattaMCQuintanaSMCandidoRCFerreiraJCDe MartinisECReidGImproved treatment of vulvovaginal candidiasis with fluconazole plus probiotic Lactobacillus rhamnosus GR‐1 and Lactobacillus reuteri RC‐14Lett Appl Microbiol4826927420091918750710.1111/j.1472-765X.2008.02477.x EhrstromSDaroczyKRylanderESamuelssonCJohannessonUAnzènBPåhlsonCLactic acid bacteria colonization and clinical outcome after probiotic supplementation in conventionally treated bacterial vaginosis and vulvovaginal candidiasisMicrobes Infect1269169920102047209110.1016/j.micinf.2010.04.010 YaWReiferCMillerLEEfficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: A double-blind, randomized, placebo-controlled studyAm J Obstet Gynecol203120.e1e620102065960210.1016/j.ajog.2010.05.023 FalagasMEBetsiGIAthanasiouSProbiotics for prevention of recurrent vulvovaginal candidiasis: A reviewJ Antimicrob Chemother5826627220061679046110.1093/jac/dkl246

Flow diagram of study selection in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Forest plots for antibiotic plus Lactobacillus vs. antibiotic plus placebo (type I study) in the treatment of bacterial vaginosis and vulvovaginal candidiasis: (A) 1-month and 6-month recurrence rate; (B) 1-month and 6-month cure or remission rate; (C) restoration of normal flora after 1 month of follow-up. BV, bacterial vaginosis; VVC, vulvovaginal candidiasis; df, degrees of freedom.

Quality assessment of included studies. Risk of bias summary of (A) randomized controlled trials and (B) non-randomized controlled trials. Risk of bias graph of (C) randomized controlled trials and (D) non-randomized controlled trials.

Summary of patient characteristics and interventions for the treatment of bacterial vaginosis.

A, Type I, antibiotics plus Lactobacillus (probiotic) vs. antibiotic with or without placebo (control)
          Disease      
First author (publication year) Study design Grouping Number of patients Age (years) Diagnosis Diagnostic standard Intervention Follow-up time (Refs.)
Laue (2018) RCT Probiotic 18 32.6 BV Amsel criteria Metronidazole plus Lactobacillus 4 weeks (23)
    Control 18 39     Metronidazole plus placebo    
Davar (2016) RCT Probiotic 28 32.3 VVC Symptoms and positive culture Fluconazole plus probiotic tablet 6 months (36)
    Control 31 31.1     Fluconazole plus placebo    
Recine (2016) Prospective Probiotic 125 29.3 BV ≥3 of Amsel criteriaa MTZ plus Lactobacillus 9 months (32)
    Control 125 29.5     MTZ plus placebo    
Heczko (2015) RCT Probiotic 73 18-50 BV/AV Clinical signs, NSb MTZ plus Lactobacillus NA (20)
    Control 81       MTZ plus placebo    
Bradshaw (2012) RCT Probiotic 140 27c BV NS 7-10 MTZ plus clindamycin cream 6 months (17)
    Control 133 27c   or ≥3 of Amsel criteria and NS 4-10 MTZ plus vaginal pessary containing Lactobacillus    
    Clindamycin 135 27c     MTZ plus placebo vaginal pessary    
Nouraei (2012) RCT Probiotic 45 18-40 VVC Symptoms and culture Fluconazole plus probiotic 5-7 days (41)
    Control 45       Fluconazole plus placebo    
Ehrström (2010) RCT Probiotic 60 18-45 BV/VVC ≥3 Amsel criteria Antibiotics plus vaginal capsule containing Lactobacillus 1 menstruation (44)
    Control 35       Antibiotics plus placebo vaginal capsule    
Marcone (2010) RCT Probiotic 24 N/A BV Fulfilled all MTZ plus Lactobacillus tablet 12 months (25)
    Control 25     Amsel criteria MTZ plus placebo tablet    
Anukam (2009) RCT Probiotic 19 18-50 VVC Positive culture Fluconazole plus L. rhamnosus GR-1 3 months (35)
    Control 7       Fluconazole plus placebo capsule    
Martinez (2009a) RCT Probiotic 32 N/A BV ≥3 Amsel criteria Tinidazole plus Lactobacillus 28 days (26)
    Control 32     or NS 7-10 Tinidazole plus placebo capsule    
Martinez (2009b) RCT Probiotic 29 29.1±7.5 VVC Symptoms and positive culture Fluconazole plus L. rhamnosus GR-1 and L. reuteri RC-14 4 wks (43)
    Control 26 26.9±7.8     Fluconazole plus placebo    
Yang (2009) RCT Probiotic 44 36 (range: 25-48) VVC Symptoms and microscopy Clotrimazole plus Lactobacillus 30 days (42)
    Control 42       Clotrimazole    
Hua (2008) RCT Probiotic 118 28.45 VVC Symptoms and microscopy Miconazole plus Lactobacillus 33-37 days (38)
    Control 117       Miconazole    
Larsson (2008) RCT Probiotic 50 34.3 BV Amsel criteria Clindamycin plus Lactobacillus 6 months (22)
    Control 50       Clindamycin plus placebo    
Marcone (2008) RCT Probiotics 42 18-40 BV Fulfilled all MTZ plus Lactobacillus tablet 1 month (24)
    Control 42     Amsel criteria MTZ plus placebo tablet    
Petricevic (2008) RCT Probiotics 83 32.6 BV NS 7-10 Clindamycin plus Lactobacillus 1 month (29)
    Control 88       Clindamycin plus placebo    
Ma (2007) RCT Probiotics 54 26 VVC Symptoms and microscopy Miconazole plus Lactobacillus NA (39)
    Control 54       Miconazole    
Mai (2007) RCT Probiotics 85 30.1 (range: 20-47) VVC Symptoms and microscopy Clotrimazole plus Lactobacillus 30 days (40)
    Control 84       Clotrimazole    
Anukam (2006a) RCT Probiotic 65 18-44 BV NS 7-10 and positive BV Blue test MTZ plus Lactobacillus tablet 30 days (15)
    Control 60       MTZ plus placebo tablet    
Han (2006) RCT Probiotic 86 37 (range: 19-48) VVC Symptoms and microscopy Clotrimazole plus lactobacillus capsule 30 days (37)
    Control 90       Clotrimazole    
Lin (2006) RCT Probiotic 32 30 (range: 20-44) Trichomonial Microscopy MNZ plus lactobacillus capsule 30 days (31)
    Control 30   Vaginitis        
    Probiotic 53   VVC Microscopy Cretrozole plus lactobacillus capsule    
    Control 52            
    Probiotic 59   BV Amsel criteria MNZ plus Lactobacillus capsule    
    Control 51            
Eriksson (2005) RCT Probiotics 91 32c BV ≥3 Amsel criteria Clindamycin plus tampons containing Lactobacillus NA (18)
    Control 96 32c     Clindamycin plus placebo tampons    
B, Type II studies: Lactobacillus (probiotic) vs. placebo (control)
          Disease      
First author (publication year) Study design Grouping Number of patients Age (years) Diagnosis Diagnostic standard Intervention Follow-up time (Refs.)
Vicariotto (2014) RCT Probiotic 24 34.7 BV ≥3 of Amsel criteria Lactobacillus 56 days (33)
    Control 10     or NS 7-10 Placebo tablet    
Vujic (2013) RCT Probiotic 395 N/A BV and ≥3 Amsel criteria Lactobacillus capsule 44.16 days (34)
    Control 149   Other vaginal infections or NS 7-10 Placebo capsule    
Hemalatha (2012) RCT Probiotic 34 N/A BV NS 7-10 Lactobacillus 9 days (21)
    Control 27       Placebo tablet    
Mastromarino (2009) RCT Probiotics 18 33 BV NS 7-10 Vaginal tablets containing Lactobacillus 2 weeks (27)
    Control 16 35     Placebo vaginal tablets    
Hallen (1992) RCT Probiotics 28 24 BV ≥3 Amsel criteria Vaginal tablets containing Lactobacillus 7-10 days; 20-40 days (19)
    Control 29       Placebo vaginal tablets    
C, Type III studies: Lactobacillus (probiotic) vs. antibiotics (control)
          Disease      
First author (publication year) Study design Grouping Number of patients Age (years) Diagnosis Diagnostic standard Intervention Follow-up time (Refs.)
Ling (2013) RCT Probiotic 25 N/A BV Amsel criteria and NS Intravaginal Lactobacillus 30 days (30)
    Control 30       MTZ    
Anukam (2006b) RCT Probiotic 20 N/A BV NS7-10 and positive BV Blue test Lactobacillus capsule 30 days (16)
    Control 20   (Symptomatic)   MTZ    
Parent (1996) RCT Probiotics 16 31.1 BV ≥3 Amsel criteria Lactobacillus tablet 28 days (28)
    Control 16 34.4     MTZ plus placebo tablet    

aAmsel criteria: i) presence of a characteristic homogeneous grey discharge; ii) vaginal fluid pH of >4.5; iii) positive amine odor test; iv) the identification of ‘clue cells’ by microscopic examination of vaginal fluid mixed with saline. bNugent score: 10-point scale based on the presence or absence of Lactobacillus morphotypes under oil immersion (x1,000 magnification). A score of 0-3 was interpreted as consistent with a normal Gram-positive rod-dominated microbiota; a score of 4-6 as intermediate; a score of 7-10 was considered consistent with BV-like conditions in which the samples were dominated by small Gram-negative and Gram-variable straight and curved rods. cMedian of age. AV, aerobic vaginitis; BV, bacterial vaginosis; MTZ, metronidazole; NS, Nugent score; RCT, randomized controlled trial; TMP-SMX, trimethoprim-sulfamethoxazole; VVC, vulvovaginal candidiasis.

Summary of the outcomes in the meta-analysis.

A, Type I
First author (year) Disease type Patients (n) Intervention Recurrence Cure/remission Restored normal flora (Refs.)
Laue (2018) BV 18 Probiotic   16(100)   (23)
    18 Control   13 (76.5)    
Davar (2016) VVC 28 Probiotic 2 (7.2)     (36)
    31 Control 11 (35.5)      
Recine (2016) BV 125 Probiotic     2 mo: 113 (90.4) 6 mo: 106 (74.6) 9 mo: 118 (79.7) (32)
    125 Control     2 mo: 99 (79.2) 6 mo: 36 (25.4) 9 mo: 30 (20.3)  
Heczko (2015) BV/AV 73 Probiotic 33 (45.2)     (20)
    81 Control 38 (47.0)      
Bradshaw (2012) BV 140 Clindamycin 42(30)   92 (65.7) (17)
    133 Probiotic 37 (27.8)   63 (47.4)  
    135 Control 36 (26.7)   63 (46.7)  
Nouraei (2012) VVC 45 Probiotic   42 (93.3)   (41)
    45 Control   37 (82.2)    
Ehrström (2010) BV/VVC 60 Probiotic 1 mo: 13 (22.4) 1 mo: 47(78) 2 mo: 23 (38.1) 6 mo: 35 (58.4)   (44)
    35 Control 1 mo: 10 (29.4) 2 mo: 13 (38.1) 6 mo: 20 (56.6) 1 mo: 25(71)    
Marcone (2010) BV 24 Probiotic     6 mo: 18(74) (25)
            12 mo: 16(69)  
    25 Control     6 mo: 24(96) 12 mo: 23(91)
Anukam (2009) VVC 19 Probiotic   15(79)   (35)
    7 Control   3(43)    
Martinez (2009a) BV 32 Probiotic 4 (12.5) 28 (87.5) 24(75) (26)
    32 Control 15 (46.9) 16(50) 11 (34.4)  
Martinez (2009b) VVC 29 Probiotic 3 (10.3)     (43)
    26 Control 10 (38.5)      
Yang (2009) VVC 44 Probiotic 3 (7.1) 42 (92.86)   (42)
    42 Control 7 (16.7) 38 (83.33)    
Hua (2008) VVC 118 Probiotic 4 (4.8) 83 (70.34)   (38)
    117 Control 11 (13.9) 79 (67.52)    
Larsson (2008) BV 50 Probiotics   24 (64.9)   (22)
    50 Control   18 (46.2)    
Marcone (2008) BV 42 Probiotics   1 mon: 22(96) 6 mon: 23(98) 30 d: 37(88) 90 d: 37(88) 180 d: 35(83) (24)
    42 Control   1 mon: 21(91) 6 mo: 17(74) 30 d: 34(81) 90 d: 30(71) 180 d: 28(67)  
Petricevic (2008) BV 83 Probiotics   1 mon: 83(100) 69 (83.1) (29)
    88 Control   1 mon: 35 (39.8) 31(35.2)  
Ma (2007) VVC 54 Probiotics   46 (85.2)   (39)
    54 Control   38 (70.4)    
Mai (2007) VVC 85 Probiotics 5 (5.9) 80 (94.1)   (40)
    84 Control 13 (15.5) 70 (83.3)    
Anukam (2006a) BV 65 Probiotic 0 (0) 8(12) 57(88) (15)
    60 Control 17(28) 19(32) 24(40)  
Han (2006) VVC 86 Probiotic 3 (3.9) 74 (96.10)   (37)
    90 Control 9 (13.0) 60 (86.96)    
Lin (2006) VVC 53 Probiotic 2 (3.8) 52 (98.1)   (31)
    52 Control 13 (25.0) 49 (94.2)    
Lin (2006) BV 59 Probiotic 1 (1.7) 58 (98.3)   (31)
    51 Control 12 (23.5) 47 (92.2)    
Eriksson (2005) BV 91 Probiotics   52 (56.8)   (18)
    96 Control   58 (60.2)    
B, Type II
First author (year) Disease type Patients (n) Intervention Recurrence Cure/remission Restored normal flora (Refs.)
Vicariotto (2014) BV 24 Probiotic Day 28: 2 (8.3) Day 56: 4 (16.7) Day 28: 22 (91.7) Day 56: 20 (83.3)   (33)
    10 Control Day 28: 8(80) Day 56: 9(90) Day 28: 2(20) Day 56: 1(10)    
Vujic (2013) BV and other infection 395 Probiotic     1.5 mo: 243 (61.5) 3 mo: 202 (51.1) (34)
    149 Control     1.5 mo: 40 (26.8) 3 mo: 31 (20.8)
Hemalatha (2012) BV 34 Probiotic 7(21)   11(32) (21)
    27 Control 7(26)   7(26)  
Mastromarino (2009) BV 18 Probiotics   11(61) 9(50) (27)
    16 Control   3 (18.75) 1 (6.25)  
Hallen (1992) BV 28 Probiotics   7-10 d: 16 (57.1) 20-40 d: 0 (0)   (19)
    29 Control   7-10 d: 3 (10.3) 20-40 d: 0 (0)    
C, Type III
First author (year) Disease type Patients (n) Intervention Recurrence Cure/remission Restored normal flora (Refs.)
Ling (2013) BV 25 Probiotic       (30)
    30 Control        
Anukam (2006b) BV 20 Probiotic 2(10) 15(75) 11(55) (16)
    20 Control 9(45) 9(45) 6(30)  
Parent (1996) BV 16 Probiotics   14 (87.5)   (28)
    16 Control   4 (22.2)    

Values are expressed as n for patients' number, n (%) for recurrence, cure/remission, and restored normal flora. mo, months; d, days; BV, bacterial vaginosis; VVC, vulvovaginal candidiasis; AV, aerobic vaginitis; Ref., reference.

Types of probiotics and route and dose of administration of probiotics for treatment.

A, Disease type, BV
First author (year) Probiotic regimen Brand Dosage and duration Route of administration Length of follow-up period (Refs.)
Laue (2018) Lactobacillus Verum 125 g yoghurt containing (besides L. delbrueckii ssp. bulgaricus and S. thermophilus) living strains L. crispatus LbV 88, L. gasseri LbV 150N, L. jensenii LbV 116 and L. rhamnosus LbV96, each 1x107 cfu/ml; placebo was 125 g chemically acidified milk. Twice daily for 4wks Oral 4 wks (23)
Recine (2016) L. rhamnosus BMX54 NORMOGIN Once a day for 10 d, twice a week for 15 d and once every 5 d for 7 mo as maintenance therapy Vaginal tablet 9 mo (32)
Heczko (2015) L. fermentum, L. plantarum, and L. gasseri prOVag One capsule daily for 10 d perimenstrually Oral Approximately 4 menstrual periods (20)
Vicariotto (2014) L. fermentum plus L. plantarum N/A Once a day for 7 nights, followed by 1 tablet every 3 nights for 3 wks and 1 tablet per wk Vaginal tablet 56 d (33)
Bradshaw (2012) L. acidophilus N/A 12 nights Vaginal tablet 6 mo (17)
Hemalatha (2012) L. brevis CD2, L. salivarius subsp. Salicinius, L. plantarum Florisia 8 nights Vaginal tablet 9 d (21)
Ling (2013) L. delbrueckii subsp. lactis N/A 10 d Vaginal capsule 30 d (30)
Vujic (2013) L. rhamnosus and L. reuteri Lactogyn Twice daily Oral 6 mo (34)
Ehrström (2010) L gasseri, L. fermentum, L. casei subsp. rhamnosus and P. acidilactici N/A 2 capsules daily for 5 d Vaginal capsule 6 mo (44)
Marcone (2010) L. rhamnosus Normogin Once a week for 6 mo of a capsule containing 40 mg of L. rhamnosus (N40000 CFU; Normogin), beginning 8 d after MTZ discontinued Oral 12 mo (25)
Martinez (2009a) GR-1, RC-14   2 Capsule daily for the following 4 wks Vaginal capsule 28 d (26)
Mastromarino (2009) L. brevis, L. salivarius subsp. salicinius, and L. plantarum N/A Daily for 7 d Vaginal tablet 2 wks (27)
Larsson (2008) L. gasseri and L. rhamnosus EcoVag® 10 d during 3 menstrual cycles Vaginal capsule 6 mo (22)
Marcone (2008) L. rhamnosus N/A Once a week at bedtime for 2 mo starting 1 wk after the last antibiotic administration Vaginal tablet   (24)
Petricevic (2008) L. caseirhamnosus N/A 7 d Vaginal capsule 1 mo (29)
Anukam (2006a) L. rhamnosus and L. reuteri N/A 1-30 d Vaginal tablet 30 d (15)
Anukam (2006b) L. rhamnosus and L. reuteri N/A 2 capsules for 5 d Vaginal tablet 30 d (16)
Eriksson (2005) L. gasseri, L. caseivarrhamnosus and L. fermentum Medipharm AB During the following menstruation Tampon containing lactobacilli After the second menstrual period (~1 mo) (18)
Parent (1996) L. acidophilus Gynoflor 1-2 tablets daily for 6 d Vaginal tablet 28 d (28)
Hallen (1992) L. acidophilus (Vivag) Vigag Twice daily for 6 d Vaginal capsule 7-10 d, 20-40 d (19)
Lin (2006) Lactobacillus capsule   Once daily for 7 d Vaginal capsule 30 d (31)
B, Disease type, VVC
First author (year) Probiotic regimen Brand Dosage and duration Route of administration Length of follow-up period (Refs.)
Davar (2016) L. acidophilus, B. bifidum and B. longum Pro-Digest Twice daily for 10 d Oral 6 mo (36)
Anukam (2009) L. rhamnosus and L. reuteri N/A Once daily for 3 mo Oral 3 mo (35)
Martinez (2009b) L. rhamnosus and L. reuteri N/A Once daily for 28 d Oral 4 wks (43)
Nouraei (2012)   protexin 20 capsules within an interval of 72 h (3 d) Oral 5-7 d (41)
Yang (2009) Lactobacillus capsule Ding-jun-sheng Once daily for 10 d Vaginal capsule 30 d (42)
Hua (2008) Lactobacillus capsule Ding-jun-sheng Once daily for 10 d Vaginal capsule 33-37 d (38)
Ma (2007) Lactobacillus capsule N/A 0.5 g once daily for 7 d Vaginal capsule N/A (39)
Mai (2007) Lactobacillus capsule Ding-jun-sheng 0.25 g capsule, once daily for 10 d Vaginal capsule 30 d (40)
Han (2006) Lactobacillus capsule Ding-jun-sheng Once daily for 10 d Vaginal capsule 30 d (37)
Lin (2006) Lactobacillus capsule N/A Once daily for 7 d Vaginal capsule 30 d (31)

d, day; mo, month; wk, week; N/A, not available; Ref., reference.

Extra meta-analysis for recurrence, cure or remission, and restored normal flora for patients with BV given type II and type III treatment.

Outcome/study [Author name (year) (Refs.)] Treatment type Time-point Odds ratio Lower limit Upper limit Z-value P-value Heterogeneity test
Recurrence               Q=7.977, df=1, P=0.005, I2=87.46%
     Vicariotto (2014) (33) BV-Type II 1 mon 0.023 0.003 0.189 -3.498 <0.001  
     Hemalatha (2012) (21) BV-Type II 9 d 0.757 0.230 2.492 -0.459 0.646  
     Combined     0.147 0.005 4.529 -1.096 0.273  
Cure or remission               Q=1.939, df=2, P=0.379, I2=0%
     Vicariotto (2014) (33) BV-Type II 1 mon 44.019 5.280 366.956 3.498 <0.001  
     Mastromarino (2009) (27) BV-Type II 14 d 6.806 1.412 32.809 2.390 0.017  
     Hallen (1992) (19) BV-Type II 40 d 11.560 2.821 47.366 3.401 0.001  
     Combined     12.444 4.856 31.888 5.251 <0.001  
Restored normal flora               Q=4.366, df=2, P=0.113, I2=54.19%
     Vujic (2013) (34) BV-Type II 3 mon 3.983 1.603 9.895 2.977 0.003  
     Hemalatha (2012) (21) BV-Type II 9 d 1.339 0.436 4.113 0.510 0.610  
     Mastromarino (2009) (27) BV-Type II 14 d 15.000 1.621 138.821 2.385 0.017  
     Combined     3.319 1.105 9.974 2.137 0.033  
Restored normal flora                
     Anukam (2006b) (16) BV-Type III 1 mon 2.852 0.777 10.467 1.580 0.114 Not assessed
Recurrence                
     Anukam (2006b) (16) BV-Type III 1 mon 0.136 0.025 0.748 -2.294 0.022 Not assessed
Cure or remission               Q=2.577, df=1, P=0.108, I2=61.19%
     Anukam (2006b) (16) BV-Type III 1 mon 3.667 0.958 14.028 1.898 0.058  
     Parent (1996) (28) BV-Type III 28d 24.532 3.693 162.947 3.312 0.001  
     Combined     8.393 1.323 53.227 2.257 0.024  

df, degrees of freedom; mon, months; d, days; BV, bacterial vaginosis.

Sensitivity analysis.

A, Recurrence at 1 month
  Statistics with study removed  
Author name (year) Odds ratio Lower limit Upper limit Z-value P-value (Refs.)
Ehrström (2010) 0.214 0.135 0.342 -6.478 <0.001 (44)
Martinez (2009a) 0.287 0.184 0.447 -5.516 <0.001 (26)
Martinez (2009b) 0.279 0.180 0.432 -5.720 <0.001 (43)
Yang (2009) 0.260 0.168 0.403 -6.023 <0.001 (42)
Hua (2008) 0.264 0.169 0.412 -5.848 <0.001 (38)
Mai (2007) 0.258 0.164 0.407 -5.848 <0.001 (40)
Anukam (2006a) 0.286 0.187 0.436 -5.809 <0.001 (15)
Han (2006) 0.269 0.173 0.420 -5.797 <0.001 (37)
Lin (2006) 0.288 0.188 0.441 -5.718 <0.001 (31)
Lin (2006) 0.288 0.186 0.444 -5.622 <0.001 (31)
B, Cure or remission at 1 month
  Statistics with study removed  
Author name (year) Odds ratio Lower limit Upper limit Z-value P-value (Refs.)
Laue (2018) 2.165 1.131 4.146 2.330 0.020 (23)
Ehrström (2010) 2.416 1.197 4.879 2.461 0.014 (44)
Martinez (2009a) 2.062 1.069 3.979 2.158 0.031 (26)
Yang (2009) 2.271 1.150 4.486 2.361 0.018 (42)
Hua (2008) 2.521 1.209 5.256 2.467 0.014 (38)
Marcone (2008) 2.286 1.179 4.431 2.447 0.014 (24)
Petricevic (2008) 1.818 1.047 3.155 2.123 0.034 (29)
Mai (2007) 2.224 1.117 4.427 2.275 0.023 (40)
Han (2006) 2.764 1.523 5.015 3.345 0.001 (37)
Lin (2006) 2.197 1.114 4.333 2.271 0.023 (31)
Lin (2006) 2.199 1.136 4.259 2.337 0.019 (31)
Eriksson (2005) 2.252 1.160 4.372 2.398 0.016 (18)
Anukam (2006a) 2.578 1.280 5.193 2.651 0.008 (15)
C, Restoration of normal flora at 1 month
  Statistics with study removed  
Author name (year) Odds ratio Lower limit Upper limit Z-value P-value (Refs.)
Martinez (2009a) 4.121 0.853 19.905 1.762 0.078 (26)
Marcone (2008) 8.705 5.274 14.368 8.464 <0.001 (24)
Petricevic (2008) 3.442 0.646 18.335 1.448 0.148 (29)
Anukam (2006a) 3.284 0.692 15.591 1.496 0.135 (15)
D, Restoration of normal flora at 6 months
  Statistics with study removed  
Author name (year) Odds ratio Lower limit Upper limit Z-value P-value (Refs.)
Recine (2016) 0.536 0.195 1.477 -1.205 0.228 (32)
Bradshaw (2012) 0.861 0.062 11.885 -0.112 0.911 (17)
Marcone (2010) 1.599 0.293 8.737 0.542 0.588 (25)
Marcone (2008) 1.312 0.197 8.715 0.281 0.779 (24)

BV, bacterial vaginosis.