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This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 4
http://www.thecochranelibrary.com
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 2.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Probiotic + Metronidazole versus placebo + Metronidazole, Outcome 1 Microbiological cure.
Analysis 2.1. Comparison 2 Vaginal probiotic capsules versus metronidazole vaginal gel, Outcome 1 Microbiological
cure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.2. Comparison 2 Vaginal probiotic capsules versus metronidazole vaginal gel, Outcome 2 Resolution of
symptoms as reported by patient. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.3. Comparison 2 Vaginal probiotic capsules versus metronidazole vaginal gel, Outcome 3 Adverse effects. .
Analysis 3.1. Comparison 3 Probiotic versus placebo (after open treatment with clindamycin ovules), Outcome 1
Microbiological cure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Probiotic versus placebo (after open treatment with clindamycin ovules), Outcome 2 Resolution
of symptoms as reported by patient. . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.3. Comparison 3 Probiotic versus placebo (after open treatment with clindamycin ovules), Outcome 3 Clinical
cure as reported by physician. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.1. Comparison 4 Probiotics with estriol versus placebo, Outcome 1 Microbiological cure. . . . . . .
Analysis 4.2. Comparison 4 Probiotics with estriol versus placebo, Outcome 2 Clinical cure as reported by physician.
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1
2
2
3
3
5
7
8
9
10
10
10
13
20
21
21
22
22
23
23
24
24
25
25
27
27
27
27
28
28
[Intervention Review]
and Gynaecology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. 3 Dept of Medical and Morphological
Research, Section of Microbiology, School of Medicine, University of Udine, Udine, Italy
Contact address: Abiola C Senok, Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab
Emirates. bsenok@yahoo.co.uk.
Editorial group: Cochrane Sexually Transmitted Diseases Group.
Publication status and date: New, published in Issue 4, 2009.
Review content assessed as up-to-date: 31 December 2008.
Citation: Senok AC, Verstraelen H, Temmerman M, Botta GA. Probiotics for the treatment of bacterial vaginosis. Cochrane Database
of Systematic Reviews 2009, Issue 4. Art. No.: CD006289. DOI: 10.1002/14651858.CD006289.pub2.
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
The dominance of lactobacilli in healthy vaginal microbiota and its depletion in bacterial vaginosis (BV) has given rise to the concept
of oral or vaginal instillation of probiotic Lactobacillus strains for the management of this condition.
Objectives
To ascertain the efficacy of probiotics in the treatment of BV.
Search methods
We searched electronic databases irrespective of publication status or language. These included: Cochrane Central Register of Controlled
Trials (CENTRAL), the HIV/AIDS and STD Cochrane Review Groups specialized registers, the Cochrane Complementary Medicine
Fields Register of Controlled Trials, MEDLINE (1966 to 2008), EMBASE (1980 to 2007), ISI science citation index (1955 to 2007),
CINAHL (Cumulative Index to Nursing & Allied Health Literature (1982 to 2007).
We handsearched of specialty journals, conference proceedings and publications list on the website of the International Scientific
Association of Probiotics and Prebiotics (http://www.isapp.net/default.asp).
For unpublished studies or ongoing trials, we contacted authors from relevant publications, nutraceutical companies and probioticrelated scientific associations. We searched electronic databases on ongoing clinical trials.
Selection criteria
Randomized controlled trials using probiotics for the treatment of women of any age diagnosed with bacterial vaginosis, regardless
of diagnostic method used. The probiotic preparation could be single or cocktail of strains, any preparation type/dosage/route of
administration. Studies comparing probiotics with placebo, probiotics used in conjunction with conventional antibiotics compared
with placebo or probiotics alone compared with conventional antibiotics were eligible for inclusion.
Data collection and analysis
We screened titles and abstracts , obtained full reports of relevant trialsand independently appraised them for eligibility. A data extraction
form was used to extract data from the four included studies. For dichotomous outcomes, odds ratios (OR) and 95% confidence
intervals (CI) were derived for each study using RevMan (versions 4.2 and 5). We did not perform meta-analysis due to significant
differences in the probiotic preparations and trial methodologies.
Probiotics for the treatment of bacterial vaginosis (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
Analysis suggests beneficial outcome of microbiological cure with the oral metronidazole/probiotic regimen (OR 0.09 (95% CI 0.03
to 0.26)) and the probiotic/estriol preparation (OR 0.02, (95% CI 0.00 to 0.47)). For the probiotic/estriol preparation, the OR and
95% CI for physician-reported resolution of symptoms was OR 0.04 (95% CI 0.00 to 0.56).
Authors conclusions
The results do not provide sufficient evidence for or against recommending probiotics for the treatment of BV. The metronidazole/
probiotic regimen and probiotic/estriol perparation appear promising but well-designed randomized controlled trials with standardized
methodologies and larger patient size are needed.
BACKGROUND
Bacterial vaginosis (BV) is one of the most common causes of
genital discomfort in women of reproductive age. This condition
occurs as a result of an imbalance in the normal vaginal microbiota and is characterized by a decrease or depletion of the Lactobacilli spp and a concomitant overgrowth of other vaginal anaerobic bacteria. The micro-organisms commonly cultured in BV
include Gardnerella vaginalis, Mobiluncus spp, Mycoplasma hominis, Prevotella spp, Preptostreptococcuss spp and more recently, new
molecular methods have identified Atopobium vaginae as a BVassociated microbe (Fredricks 2005; Marrazzo 2004; Verstraelen
2004). Under normal conditions, the production of lactic acid
by vaginal lactobacilli, particularly by strong hydrogen peroxide
(H2 O2 ) producers such as Lactobacillus crispatus and Lactobacillus
jensenii, help to maintain the low vaginal pH which prevents the
overgrowth of other anaerobic bacteria (Antonio 1990).
The underlying cause of BV is still not fully understood, but factors such as vaginal douching, black ethnicity, low socioeconomic
status, use of an intra-uterine contraceptive device, and new/multiple sex partners appear to increase the risk of this perturbation
Lactobacilli, Gardnerella, and curved bacteria (Mobiluncus) morphotypes per high-power field. Various studies have used the Nugent scoring system as an alternative method to the Amsel criteria
and there is a close correlation between both methods due to the
high sensitivity and specificity of microbial quantification of Gram
stained vaginal smears (Honest 2004). New diagnostic methods
using molecular techniques are now being developed and applied
in various studies (Forsum 2005; Verhelst 2004; Verstraelen 2004).
It is now known that BV is associated with potentially severe gynaecological and obstetric complications and sequelae. Current
data suggest a causal association between BV, pelvic inflammatory disease, and tubal factor infertility (Wilson 2002). Pregnant
women with BV have a higher risk of adverse outcomes such as
late miscarriage, chorioamnionitis, premature rupture of membranes, preterm birth and postpartum endometritis (Marrazzo
2004). In women undergoing in vitro fertilization, BV may result
in lower implantation rates and increased rates of early pregnancy
loss (Eckert 2003; Verstraelen 2005).
There is growing evidence of an association between BV and sexually transmitted infections, making it of grave concern, particularly in light of the HIV/AIDS epidemic. There are data indicative
of a relationship between BV and increased risk of HIV transmission and acquisition (Cu-Uvin 2001; Sewankambo 1997). The
presence of BV was associated with up to a six-fold increment in
quantity of HIV shedding (Cu-Uvin 2001). Furthermore, there is
a correlation between the absence of vaginal lactobacilli and a positive result for the carriage of Neisseria gonorrhoeae and Chlamydia
trachomatis (Wiesenfeld 2003). BV has been identified as a risk
factor for herpes virus type 2 infection and increased viral shedding in infected women (Cherpes 2005). Recent reports also indicate that BV may increase the risk of acquisition or reactivation
of Human Papillomavirus infection, particularly high-risk HPVtypes (da Silva 2004). The displacement of the H2 O2 -producing
Lactobacilli, elevated vaginal pH with the presence of bacteria that
produce sialidase and mucin-degrading enzymes as seen in BV,
probably combine to create a milieu conducive to the survival of
these pathogens (Olmsted 2003).
In light of all these adverse BV-associated conditions, adequate
treatment of this condition is crucial. Current guidelines for treatment of BV stipulate the use of metronidazole or clindamycin administered orally or intravaginally (Anonymous 2002; Marrazzo
2004). Other treatment regimens that have been suggested include acidification of the vagina and the use of povidone-iodine
vaginal suppositories. Up to 10% to15% of patients fail to respond to initial antimicrobial therapy, and recurrence rates over
time among responders remain significant, reaching up to 80%
and necessitating repeated administration of antibiotics. Such repeated antibiotic exposure increases the risk of emergence of resistant strains, alteration of microbiota, and possible persistence
of BV-associated pathogens. The high recurrence rates associated
with antibiotic therapy have stimulated the search for alternative
OBJECTIVES
To ascertain the efficacy of probiotics in the treatment of bacterial
vaginosis
METHODS
Types of studies
Randomized controlled trials using probiotics (alone or as adjuncts
to conventional antibiotics). Studies using probiotic preparations
containing other substances e.g. estriol will be included although
a sub-analysis will be carried out for such preparations.
Types of participants
Women of any age diagnosed with bacterial vaginosis, regardless
of diagnostic method used. No study will be excluded because of
co-infection with other sexually transmitted infections.
Types of interventions
Any probiotic (single or mixture cocktail of strains, any preparation type, any dosage regimen, any route of administration):
used alone and compared with placebo or no treatment;
used in conjunction with conventional antibiotics (before, during,
or after antibiotic treatment) and compared with placebo or no
treatment;
used alone and compared with conventional antibiotic regimen.
Types of outcome measures
Primary outcome: restoration of normal lactobacilli microbiota,
with eradication of BV microbiota (microbiological cure), using
the Nugent criteria assessment completed between days 21 and 30
days post-treatment.
Secondary outcomes:
resolution of symptoms as reported by the patient;
clinical cure as reported by the physician or investigator;
persistence or recurrence of BV at follow up (from 30 days posttreatment);
occurrence of adverse reactions or side effects;
effect on BV-associated conditions.
iv. Abstracts and publications listed on the website of the International Scientific Association of Probiotics and Prebiotics (http://
www.isapp.net/default.asp)
We contacted experts in the field (particularly probiotics) identified from relevant publications by email and formal letters. We
also contacted leading nutraceutical companies marketing probiotic products. We sent emails to scientific associations dedicated to probiotic research including the International Scientific
Association of Probiotics and Prebiotics, Polish Society of Probiotics and International Probiotics Association. We requested
that our communication be forwarded to their members. In all
of these communications, we inquired about knowledge of published and unpublished studies and ongoing trials relevant to the
review.We also searched electronic databases on ongoing clinical
trials (www.trialscentral.org ; www.controlled-trials.com).
The following key terms were used in our search: bacterial vaginosis
intersected with probiotics, lactobacilli/lactobacillus, antibiotics,
drug therapy, treatment, complementary, alternative
The search strategy was as follows:
Bacterial *4 Vaginosis or
Vaginitis *4 Bacterial or
Vaginitis *4 Nonspecific or
Bacterial *4 Vaginitides or
Bacterial *4 Vaginitis or
Bacterial *4 Vaginoses or
Vaginitides *4 Bacterial or
Vaginoses *4 Bacterial or
Vaginosis, Bacterial or
colpitis *4 Bacterial or
Vaginitis *4 Nonspecific or
(vaginitis/exp AND (Bacterial or bacteria or nonspecific or nonspecific or non specific))
AND
clinical trial/exp or randomized controlled trial/exp or randomization/ or single blind procedure/exp or double blind procedure/ or crossover procedure/ or placebo/ or randomi*ed
controlled trial* or rct or random allocation or randomly allocated or allocated *2 random or random *2 allocated OR single blind* or double blind* or placebo* or prospective study/
exp or meta analysis/exp or ((meta *2 analy*) or metaanalys*) or
(systematic *3 (review* OR overview*))
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
We identified about 350 studies from the comprehensive search
and reviewed the abstracts for all. In some cases we reviewed the
statistical analysis (per-protocol) was well described and used appropriately. The results of between-group statistical comparisons
as well as the measure of the size of the treatment effect were reported for the key outcome measure.
A detailed description can be found in the Risk of Bias Table.
See Figure 1 and Figure 2 for methodological quality graph and
summary respectively.
Figure 1. Methodological quality graph: review authors judgements about each methodological quality
item presented as percentages across all included studies.
Figure 2. Methodological quality summary: review authors judgements about each methodological quality
item for each included study.
Effects of interventions
Primary outcome:
All four included studies assessed microbiological cure as a key
outcome measure. Using the reported data for the primary outcome, we calculated the Odds Ratio (OR) and 95% Confidence
Interval (CI) for each study.
Anukam 2006a reported a statistically significant difference at the
day 30 follow up in the per-protocol analysis with 43 of the 49
(88%) women in the antibiotic/probiotic treatment arm having
normal Nugent scores compared to 23 of the 57 women (40%)
in the antibiotic/placebo arm: OR 0.09 (95% CI 0.03 to 0.26).
This finding is suggestive of a beneficial effect of the antibiotic/
probiotic regimen in the treatment of BV.
In Anukam 2006b, according to the per-protocol analysis, 11 of
the 17 (64.7%) women in the probiotic arm had normal Nugent
scores on day 30 compared to 6 out of 18 (33.3%) in the metronidazole arm: OR 0.27 (95% CI 0.07 to 1.10).
In Eriksson 2005, the ITT analysis of the primary outcome published in the article was based on Amsels criteria. The assessment
of the primary outcome based on Nugent criteria was presented
only for those included in the per-protocol analysis. The study
authors kindly provided us with the ITT analysis data (for 217
women) based on Nugent criteria. Of the 108 women in the treatment arm, 75 (69.4%) had normal Nugent scores at follow up
after the second menstruation compared to 80 out of 109 (73.3%)
in the placebo arm: OR 1.21 (95% CI 0.67 to 2.19).
InParent 1996, microbiological cure on day 28 was documented in
7 of the 8 (87.5%) women in the probiotic/estriol arm compared
to 1 out of 7 (14.2%) in the placebo/estriol arm: OR 0.02 (95% CI
0.00 to 0.47). This statistical analysis suggests that the probiotic/
DISCUSSION
BV occurs as a result of imbalance in the normal vaginal microbiota
and is characterized by a decrease or depletion of the Lactobacilli
spp and a concomitant overgrowth of other vaginal anaerobic bacteria. It remains a common cause of genital discomfort in women
and it is associated with potentially severe gynaecological and obstetric sequelae. Unfortunately, currently available treatment of
BV with the use of metronidazole or clindamycin administered
orally or intravaginally has been shown to be associated with poor
initial cure rates in 10% to 15% of patients and recurrence rates
of up to 80% in those who show initial response. The dominance
of lactobacilli in healthy vaginal microbiota and its obliteration
in BV has given rise to the concept of oral or vaginal instillation
of probiotic Lactobacillus strains to restore the balance. Indeed,
available evidence now indicates that certain strains of lactobacilli
administered intravaginally are capable of colonizing the vagina.
This systematic review assesses the evidence for the use of probiotic regimen in the treatment of BV.
We identified four randomized controlled trials which investigated the use of probiotics in women with BV and met the inclusion criteria outlined in the protocol for this systematic review.
There were significant variations in the design of the trials identified. Anukam 2006a assessed the efficacy of augmentation of oral
metronidazole with oral probiotics in the treatment of BV. In contrast, Anukam 2006b compared intravaginal probiotic capsules
with metronidazole gel for the treatment of BV. Eriksson 2005
used clindamycin ovules for the open treatment followed by use of
probiotic impregnated tampons versus placebo tampons. Parent
1996 used combined probiotic/estriol vaginal tablets with both
pregnant and non-pregnant women included in the study population. As per our protocol, the results of included studies were
to be combined for each outcome where appropriate and a metaanalysis conducted. However, due to these significant differences
in the types of probiotics used and the trial methodologies, we did
not perform a meta-analysis. Variation in the methodologies and
probiotic preparations is thus identified as a major hindrance in
comparing the outcome of different trials, making it difficult to
conclude on the beneficial effect of probiotics in the treatment of
BV and we recommend that this should be addressed in the design
of future trials.
Methodological quality was inadequate in two studies (Eriksson
2005; Parent 1996). The randomization method was not adequately described and allocation concealment was not carried out
in either study. Although described as a randomized placebo-controlled clinical trial with parallel group design, there was no mention or description of blinding in Parent 1996. Although three
studies (Anukam 2006a; Anukam 2006b; Eriksson 2005) did
power calculations to determine sample size, in all the trials patients were lost to follow up leading to considerable possible attrition bias. It is therefore possible that the sample size of these
included studies were ultimately not large enough to detect statis-
be evaluated as an important outcome if probiotics are to be considered successful for the treatment of BV. However none of the
studies reported data on BV recurrence following probiotic use. In
addition, as BV is associated with a number of gynaecological and
obstetric complications, the effect of probiotics on such sequelae
is an important secondary outcome. Unfortunately, this was not
evaluated in any of the studies.
AUTHORS CONCLUSIONS
Implications for practice
The results do not provide sufficient evidence for or against recommending probiotics for the treatment of BV. In addition, there is
no conclusive evidence to recommend the use of probiotics either
before, during or after antibiotic treatment as a means of ensuring
successful treatment or reduce recurrence.
ACKNOWLEDGEMENTS
We thank Dr Malaz Fadlallah who worked as a research assistant
on this project for her assistance in the identification of studies
and data collection. We acknowledge the assistance of Ms Nadia
Masood, Librarian, College of Medicine, University of Sharjah in
the development of the search strategy and carrying out the search.
REFERENCES
10
Additional references
Amsel 1983
Amsel R, Totten PA, Spiegel CA, et al.Nonspecific vaginitis.
Diagnostic criteria and microbial and epidemiologic
associations. American Journal of Medicine 1983;74:1422.
Anonymous 2002
Anonymous. Sexually transmitted disease treatment
guidelines: Center for Disease Control and Prevention.
Morbidity and Mortality Weekly Report 2002;51(RR-6):
180.
Antonio 1990
Antonio MA, Hawes SE, Hillier SL. The identification
of vaginal Lactobacillus species and the demographic and
microbiologic characteristics of women colonized by these
species. Journal of Infectious Diseases 1999;180:19506.
Behets 2001
Behets F, Andriamiadana J, Rasamilalao D, et al.Sexually
transmitted infections and associated socio-demographic
and behavioural factors in women seeking primary care
suggest Madagascars vulnerability to rapid HIV spread.
Tropical Medicine and International Health 2001;6:20211.
Calzolari 2000
Calzolari E, Masciangelo R, Milite V, et al.Bacterial
vaginosis and contraceptive methods. International Journal
of Gynaecology and Obstetrics 2000;70:3416.
Cherpes 2005
Cherpes TL, Melan MA, Kant JA, et al.Genital tract
shedding of herpes simplex virus type 2 in women: effects
of hormonal contraception, bacterial vaginosis, and vaginal
group B Streptococcus colonization. Clinical Infectious
Diseases 2005;40:14228.
Cu-Uvin 2001
Cu-Uvin S, Hogan JW, Caliendo AM, et al.Association
between bacterial vaginosis and expression of human
immunodeficiency virus type 1 RNA in the female genital
tract. Clinical Infectious Diseases 2001;33:8946.
da Silva 2004
da Silva CS, Adad SJ, Hazarabedian de Souza MA, et
al.Increased frequency of bacterial vaginosis and Chlamydia
trachomatis in pregnant women with human papillomavirus
infection. Gynecologic and Obstetric Investigation 2004;58:
18993.
Eckert 2003
Eckert LO, Moore DE, Patton DL, et al.Relationship
of vaginal bacteria and inflammation with conception
and early pregnancy loss following in-vitro fertilization.
11
Olmsted 2003
Olmsted SS, Meyn LA, Rohan LC, et al.Glycosidase and
proteinase activity of anaerobic gram-negative bacteria
isolated from women with bacterial vaginosis. Sexually
Transmitted Diseases 2003;30:25761.
Reid 2001
Reid G, Bruce AW, Fraser N, et al.Oral probiotics can
resolve urogenital infections. FEMS Immunology and
Medical Microbiology 2001;30:4952.
Royce 1999
Royce RA, Jackson TP, Thorp JM, Jr, et al.Race/ethnicity,
vaginal flora patterns, and pH during pregnancy. Sexually
Transmitted Diseases 1999;26:96102.
Senok 2005
Senok AC, Ismaeel AY, Botta GA. Probiotics: facts and
myths. Clinical Microbiology and Infection 2005;11:95866.
Sewankambo 1997
Sewankambo N, Gray RH, Wawer MJ, et al.HIV-1
infection associated with abnormal vaginal flora morphology
and bacterial vaginosis. Lancet 1997;350:54650.
Trutnovsky 2001
Trutnovsky G, Law C, Simpson JM, et al.Use of
complementary therapies in a sexual health clinic setting.
International Journal of STD & AIDS 2001;12:3079.
Verhelst 2004
Verhelst R, Verstraelen H, Claeys G, et al.Cloning of 16S
rRNA genes amplified from normal and disturbed vaginal
microflora suggests a strong association between Atopobium
vaginae, Gardnerella vaginalis and bacterial vaginosis. BMC
Microbiology 2004;4:16.
Verstraelen 2004
Verstraelen H, Verhelst R, Claeys G, et al.Cultureindependent analysis of vaginal microflora: the unrecognized
association of Atopobium vaginae with bacterial vaginosis.
American Journal of Obstetrics and Gynecology 2004;191:
11302.
Verstraelen 2005
Verstraelen H, Senok AC. Vaginal Lactobacilli, probiotics
and IVF. Reproductive Biomedicine Online 2005;11:6745.
Wiesenfeld 2003
Wiesenfeld HC, Hillier SL, Krohn MA, et al.Bacterial
vaginosis is a strong predictor of Neisseria gonorrhoeae
and Chlamydia trachomatis infection. Clinical Infectious
Diseases 2003;36:6638.
Wilson 2002
Wilson JD, Ralph SG, Rutherford AJ. Rates of bacterial
vaginosis in women undergoing in vitro fertilisation for
different types of infertility. BJOG: An International Journal
of Obstetrics and Gynaecology 2002;109:7147.
12
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Anukam 2006a
Methods
Participants
125 premenopausal women aged 18-44 with BV as diagnosed with Nugent criteria, BV
blue test and clinical features. Participants were from Benin city, Nigeria.
Exclusion criteria included pregnancy, lactation, sexually transmitted disease, use of systemic/per vagina antibiotic agent within 14 days; use of investigational drugs within the
preceding 30 days. Hypersensitivity to some drugs including metronidazole; menstruation at time of diagnosis
Interventions
Outcomes
Microbiological cure as assessed by Nugent score absence of clue cells and negative
salidase test at day 30
Resolution of symptoms and signs as reported by patient and clinician at day 30
Adverse effects
Notes
Risk of bias
Item
Authors judgement
Description
Yes
Allocation concealment?
Yes
Adequate, Allocation schedule was conducted off-site by the pharmacy and the
patients were allotted numbers. Identical looking probiotic and placebo capsules
were prepared and distributed in numbered containers by the pharmacy. The two
groups were similar at baseline regarding
the presence of BV
Blinding?
All outcomes
Yes
Study was described as double blind. Probiotic and metronidazole capsules looked
13
Anukam 2006a
(Continued)
Yes
Yes
Unclear
Anukam 2006b
Methods
Randomized controlled trial. Patients were not blinded but the outcome assessors were
blinded
Exclusion criteria: Presence of STI; age < 18 and > 50 years; pregnancy; ongoing menstruation or due to menstruate in the following 5 days. 5/40 lost to follow up on day 30
Participants
Interventions
Outcomes
Notes
Risk of bias
Item
Authors judgement
Description
14
Anukam 2006b
(Continued)
Yes
Allocation concealment?
Yes
Adequate, although allocation concealment was not indicated in the article, contact with the authors confirmed that this
was carried out and the allocation schedule
was conducted off-site by the pharmacy
and the patients were allotted numbers
Blinding?
All outcomes
No
Yes
Yes
Unclear
Eriksson 2005
Methods
Participants
255 women with BV aged 20-53 enrolled. BV diagnosed by Nugent criteria. Participants
from 13 clinics in Finland, Norway and Sweden
Exclusion criteria: Pregnancy, planning pregnancy, breastfeeding, antibiotic treatment
15
Eriksson 2005
(Continued)
Outcomes
Notes
All outcomes analysed. Only 187 women were included in per protocol analysis. Thirty
women were lost to follow up (15 in treatment group and 15 in placebo group). Thirtyeight women were excluded for violating protocol (21 in treatment group and 17 in
placebo group). Intention-to-treat analysis was carried out. Adverse reactions reported
Risk of bias
Item
Authors judgement
Description
Yes
Allocation concealment?
No
Not used
Blinding?
All outcomes
No
Yes
16
Eriksson 2005
(Continued)
Yes
Yes
Parent 1996
Methods
Randomized placebo controlled trial with parallel group design. Blinding of patients and
clinicians is unclear as it is not mentioned in the article
Drop outs: 17 out of 32 patients dropped out (53%)
Participants
Interventions
The treatment group (n = 17; 11 non-pregnant and 6 pregnant) received vaginal tablets
containing L acidophilus (106 CFU) and oestriol 0.03 mg
Placebo group (n = 15; 13 non-pregnant and 2 pregnant) received vaginal tablets which
did not contain either probiotic or oestrol.
Vaginal tabs inserted at night: once daily or twice daily for 6 days. Twice daily dosing was
for pregnant women with abundant leukorrhea or those whose therapy was interrupted
during menstruation and continued post-menstruation
Outcomes
Microbiological cure (Nugent criteria) and clinical cure were determined on days 15 and
28 post intervention
Notes
Adverse effects and tolerability reported. No response from the authors to our enquiries
Risk of bias
Item
Authors judgement
Description
17
Parent 1996
(Continued)
Yes
Allocation concealment?
No
No mention or description suggestive of allocation concealment and although the authors were contacted to clarify these issues,
no response was received
Blinding?
All outcomes
Unclear
No
In the treatment arm, 11/17 women returned on day 15 for evaluation and 8 /
17 returned for evaluation on day 28 and
hence the study was particularly prone to
attrition bias. In the control group 10 out
of 15 women were assessed on day 15 and
only 7 were evaluated on day 28. The data
for those lost to follow up were not addressed
Yes
Unclear
Study
Della 2006
This study described the comparison of one type of probiotic (L. acidophilus given per vagina) vs. the same probiotic
given in combination with an oral probiotic. This is not in keeping with our systematic review protocol. There
was no placebo control in this study
Hallen 1992
The primary outcome (microbiological cure) in this study was not assessed by Nugent criteria
Larsson 2008
The microbiological cure was assessed outside of the 21-30 day post-treatment window outlined in the protocol
for this review. In the first menstrual cycle, women received a 7-day course of clindamycin followed immediately
by 10-day course of probiotic capsules and vaginal smears were taken after cessation of bleeding. This time frame
was outside the 21-30 day post-treatment. The main outcome was reduction of recurrence and women who were
18
(Continued)
BV positive after the first menstruation were excluded from the study. Treatment efficacy was based on cure after
one month and length of time to relapse. Definition of cure was based on Hay/Ison criteria
Marrazzo 2006
The research question of the paper is not consistent with the research question of the systematic review: the paper
specifically addresses the acceptability of probiotic; thus the primary outcome in the paper was acceptability and
patient satisfaction
Neri 1993
The control group consisted of women who refused any kind of intervention and there is no mention of any per
vagina placebo given to these women. Methodology for assessment of primary outcome was not Nugent scoring
Ozkinay 2005
Micrological assessment of vaginal smears for number of lactobacilli, leucocytes and pathogenic micro-organisms
was carried out, but not according to Nugent, and hence not in accordance with our protocol
Reid 2001a
Reid 2001b
Study population consisted of healthy women without bacterial vaginosis. There was no control population in the
study
Reid 2003
64 healthy women who were not allocated for intervention on the basis of vaginal microflora at the beginning of
the trial
Reid 2004
The participants were healthy women who were not allocated for intervention on the basis of diagnosis of BV at
the beginning of the trial. Primary outcome was evaluated on day 56 (outside of the 21-30 day window specified
in our review protocol)
Ronnqvist 2006
Shalev 1996
The definition of the study population is unclear. It is a cross-over trial and there was no control group for
comparison; no indication of whether the time-out period was sufficient. There was a huge attrition rate
Wewalka 2002
Not a randomized study (authors described the study as a prospective controlled blind clinical study);
The intervention was comparison of probiotic with an antiseptic (betadine povidone) which is not in keeping
with the systematic review protocol. Primary outcome was assessed on days 8 and 15, well before the 21-30 day
window specified in the review protocol
19
No. of
studies
No. of
participants
106
Statistical method
Odds Ratio (M-H, Fixed, 95% CI)
Effect size
0.09 [0.03, 0.26]
No. of
studies
No. of
participants
1
1
35
35
35
Statistical method
Effect size
Comparison 3. Probiotic versus placebo (after open treatment with clindamycin ovules)
No. of
studies
No. of
participants
1
1
217
216
224
Statistical method
Effect size
No. of
studies
No. of
participants
1
1
15
17
Statistical method
Odds Ratio (M-H, Fixed, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
Effect size
0.02 [0.00, 0.47]
0.04 [0.00, 0.56]
20
Study or subgroup
Treatment
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
Anukam 2006a
6/49
34/57
100.0 %
49
57
100.0 %
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
Analysis 2.1. Comparison 2 Vaginal probiotic capsules versus metronidazole vaginal gel, Outcome 1
Microbiological cure.
Review:
Study or subgroup
Probiotics
Metronidazole gel
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
Anukam 2006b
6/17
12/18
100.0 %
17
18
100.0 %
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
21
Analysis 2.2. Comparison 2 Vaginal probiotic capsules versus metronidazole vaginal gel, Outcome 2
Resolution of symptoms as reported by patient.
Review:
Study or subgroup
Probiotics
Metronidazole gel
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
Anukam 2006b
2/17
6/18
100.0 %
17
18
100.0 %
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
Analysis 2.3. Comparison 2 Vaginal probiotic capsules versus metronidazole vaginal gel, Outcome 3
Adverse effects.
Review:
Study or subgroup
Probiotics
Metronidazole gel
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
Anukam 2006b
2/17
11/18
100.0 %
17
18
100.0 %
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
22
Analysis 3.1. Comparison 3 Probiotic versus placebo (after open treatment with clindamycin ovules),
Outcome 1 Microbiological cure.
Review:
Comparison: 3 Probiotic versus placebo (after open treatment with clindamycin ovules)
Outcome: 1 Microbiological cure
Study or subgroup
Eriksson 2005
Treatment
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
33/108
29/109
100.0 %
108
109
100.0 %
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
Analysis 3.2. Comparison 3 Probiotic versus placebo (after open treatment with clindamycin ovules),
Outcome 2 Resolution of symptoms as reported by patient.
Review:
Comparison: 3 Probiotic versus placebo (after open treatment with clindamycin ovules)
Outcome: 2 Resolution of symptoms as reported by patient
Study or subgroup
Eriksson 2005
Treatment
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
34/108
41/108
100.0 %
108
108
100.0 %
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
23
Analysis 3.3. Comparison 3 Probiotic versus placebo (after open treatment with clindamycin ovules),
Outcome 3 Clinical cure as reported by physician.
Review:
Comparison: 3 Probiotic versus placebo (after open treatment with clindamycin ovules)
Outcome: 3 Clinical cure as reported by physician
Study or subgroup
Treatment
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
47/111
45/113
100.0 %
111
113
100.0 %
Eriksson 2005
Weight
Odds Ratio
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
Analysis 4.1. Comparison 4 Probiotics with estriol versus placebo, Outcome 1 Microbiological cure.
Review:
Study or subgroup
Parent 1996
Treatment
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
1/8
6/7
100.0 %
100.0 %
Weight
Odds Ratio
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
24
Analysis 4.2. Comparison 4 Probiotics with estriol versus placebo, Outcome 2 Clinical cure as reported by
physician.
Review:
Study or subgroup
Treatment
Control
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
1/8
7/9
100.0 %
100.0 %
Parent 1996
Weight
Odds Ratio
M-H,Fixed,95% CI
0.01
0.1
Favours experimental
10
100
Favours control
APPENDICES
Appendix 1. Cochrane
Bacterial *4 Vaginosis or
Vaginitis *4 Bacterial or
Vaginitis *4 Nonspecific or
Bacterial *4 Vaginitides or
Bacterial *4 Vaginitis or
Bacterial *4 Vaginoses or
Vaginitides *4 Bacterial or
Vaginoses *4 Bacterial or
Vaginosis, Bacterial or
colpitis *4 Bacterial or
Vaginitis *4 Nonspecific or
(vaginitis/exp AND (Bacterial or bacteria or nonspecific or non-specific or non specific))
AND
clinical trial/exp or randomized controlled trial/exp or randomization/ or single blind procedure/exp or double blind procedure/
or crossover procedure/ or placebo/ or randomi*ed controlled trial* or rct or random allocation or randomly allocated or
allocated *2 random or random *2 allocated OR single blind* or double blind* or placebo* or prospective study/exp or meta
analysis/exp or ((meta *2 analy*) or metaanalys*) or (systematic *3 (review* OR overview*))
25
26
26.
27.
28.
29.
30.
prospective study.mp.
meta analysis.mp.
systematic review.mp.
or / #16-28
#12 AND #15 AND #29
HISTORY
Protocol first published: Issue 4, 2006
Review first published: Issue 4, 2009
CONTRIBUTIONS OF AUTHORS
ACS formulated the idea for the review. ACS and HV developed the protocol, carried out data collection and analysis and wrote the
review. MT and GAB contributed in the development of the protocol and writing the review.
DECLARATIONS OF INTEREST
The authors declare that they do not have any conflict of interest.
SOURCES OF SUPPORT
Internal sources
University of Sharjah, United Arab Emirates.
Financial funding from University Research Board (URB Grant #060907)
27
External sources
No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)
Lactobacillus;
Anti-Bacterial Agents [administration & dosage]; Clindamycin [administration & dosage]; Estriol [administration &
dosage]; Probiotics [ administration & dosage]; Randomized Controlled Trials as Topic; Vagina [microbiology]; Vaginosis, Bacterial
[microbiology; therapy]
28