List of Abbreviations
PID – pelvic inflammatory disease
HIV – human immunodeficiency virus
DNA – deoxyribonucleic acid
ICD – International Classification of Diseases
TLR – Toll-like receptors
Terms and Definitions
Bacterial vaginosis (BV) is a non-inflammatory syndrome characterized by dysbiosis of the vaginal microbiota, manifested by a decrease in the number of lactobacilli (up to their complete disappearance) and an increase in the number of obligate and facultative anaerobic opportunistic microorganisms.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Bacterial vaginosis (BV) is a non-inflammatory syndrome characterized by dysbiosis of the vaginal microbiota, manifested by a decrease in the number of lactobacilli (up to their complete disappearance) and an increase in the number of obligate and facultative anaerobic opportunistic microorganisms.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Bacterial vaginosis is a polymicrobial dysbiotic disease characterized by a sharp decrease in the number of Lactobacillus spp. and an increase in the number of facultative and obligate anaerobes and microaerophiles (Gardnerella vaginalis, Peptostreptococcus, Clostridiales spp., Prevotella spp., Bacteroides, Fusobacterium, Veillonella, Eubacterium, Atopobium vaginaе, Mobiluncus spp., Megasphaera, Sneathia, Leptotrichia spp., Sneathia spp., Mycoplasma hominis, Ureaplasma urealyticum, Streptococcus viridans). At present, the leading role of Gardnerella vaginalis and Atopobium vaginae in the etiopathogenesis of bacterial vaginosis is recognized.
The biocenosis structure of the vagina in healthy women contains more than 40 species of microorganisms. Lactobacillus dominate (90–95%), while the remaining 5–10% are represented by obligate anaerobic and, to a lesser extent, facultatively anaerobic, aerobic, and microaerophilic bacteria. The concentration of aerobes in the vagina is 10 times lower than that of anaerobes.
In a healthy vaginal ecosystem, there are several defense mechanisms against infections: the vaginal epithelium, the vaginal microbiota (hydrogen peroxide-producing lactobacilli), and humoral and cellular immunity. Estrogens induce the accumulation of glycogen in the vaginal epithelium, which serves as a metabolic substrate for lactobacilli, and also stimulate the formation of receptors for lactobacilli on epithelial cells. Lactobacilli break down glycogen to form lactic acid, which ensures an acidic environment in the vagina (pH 4.0–4.5), and hydrogen peroxide, a natural antiseptic. In addition, lactobacilli compete with other microorganisms for adhesion sites on vaginal epithelial cells. The level of the immune response is regulated by the intensity of antigenic stimulation of the mucous membranes by the acidophilic microbiota. Lactobacilli activate epithelial cell TLR receptors, which recognize various microorganisms, leading to the production of pro-inflammatory cytokines in quantities sufficient to control the proliferation of undesirable microbiota.
When lactobacilli are deficient, the concentration of lactic acid decreases, and the vaginal pH shifts toward the alkaline side. The niche vacated by lactobacilli is occupied by G. vaginalis in synergy with anaerobes. G. vaginalis produces vaginolysin, which has a cytotoxic effect on the vaginal epithelium and increases the activity of gardnerellas by more than 250 times. In addition, G. vaginalis in association with Lactobacterium iners can produce a cytolysin that destroys vaginal epithelial cells and exhibit aggressive properties atypical of the normal microbiota.
Due to the intensive destruction of vaginal epithelial cells (cytolysis), excess carbohydrates become a substrate for the synthesis of short-chain fatty acids (C3-C6), which are marker metabolites of bacterial vaginosis. A vicious circle is formed: the free glucose pool is depleted, glycogen stores are not replenished, the destruction of vaginal epithelial cells increases, and the pH shifts toward the alkaline side. BV marker metabolites have an immunomodulatory effect, preventing the development of an inflammatory response.
Recent data have shown that bacterial vaginosis is associated with the development of a linked polymicrobial biofilm containing a large number of G. vaginalis and a smaller number of bacteria associated with bacterial vaginosis. Features of this type of bacterial vaginosis include: a protracted course of the process, a tendency toward chronicity, an increased likelihood of pathogen dissemination, and the ineffectiveness of traditional therapy.
Bacterial vaginosis is diagnosed predominantly in women of reproductive age. The disease does not pose an immediate threat to a woman's life, but it is a risk factor for pregnancy complications: spontaneous abortions, intra-amniotic infection, premature rupture of membranes, premature birth, and the birth of low birth weight infants. Women with bacterial vaginosis may develop endometritis and sepsis after cesarean section. Currently, bacterial vaginosis is considered one of the causes of infectious complications after gynecological surgeries and abortions, pelvic inflammatory disease (PID), peritonitis, and pelvic abscesses following the insertion of intrauterine devices. A prolonged course of bacterial vaginosis is a risk factor for the development of cervical neoplasias and increased susceptibility to sexually transmitted infections, especially HIV infection and genital herpes.
1.3 Epidemiology of the Disease or Condition
According to global statistics, bacterial vaginosis ranks among the top vaginal diseases. Its prevalence in the population ranges from 12% to 80% and depends on the cohort of examined women. Bacterial vaginosis develops predominantly in women of reproductive age: in 80–87% of women with pathological vaginal discharge and 37–40% of pregnant women.
1.4 Features of Coding the Disease or Condition
N89 – Other noninflammatory disorders of vagina.
1.5 Classification of the disease or condition
None.
1.6 Clinical presentation of the disease or condition
Subjective symptoms:
- homogeneous whitish-gray discharge from the genital tract, often with an unpleasant "fishy" odor, which intensifies after unprotected sexual intercourse, hygiene procedures using soap, or menstruation;
- discomfort in the area of the external genitalia;
- pain during sexual intercourse (dyspareunia);
- rarely - itching and/or burning in the genital area;
- rarely - itching, burning, and pain during urination (dysuria).
Objective symptoms:
- homogeneous whitish-gray vaginal discharge of thick consistency, evenly distributed over the mucous membrane of the vulva and vagina.
Patients show no symptoms of an inflammatory reaction in the genital area.
2. Diagnostics, medical indications and contraindications for diagnostic methods
The diagnosis of bacterial vaginosis is established based on a combination of clinical manifestations and laboratory test results (microscopic examination of Gram-stained female genital discharge) – the detection of "clue cells".
2.1 Complaints and Anamnesis
Patients complain of pathological genital discharge with an unpleasant odor that intensifies after unprotected sexual intercourse, hygiene procedures using soap, and/or after menstruation; discomfort in the area of the external genitalia is possible.
2.2 Physical Examination
Objective symptoms:
- examination of the external genitalia may reveal free homogeneous discharge;
- examination using a Cusco speculum visualizes homogeneous whitish-gray vaginal discharge of thick consistency, evenly distributed over the mucous membrane of the vulva and vagina;
- there is no inflammatory reaction in the genital area.
2.3 Laboratory Diagnostics
It is recommended to verify the diagnosis of bacterial vaginosis based on laboratory microscopy results aimed at detecting "clue" cells: microscopic examination of female genital discharge for aerobic and facultatively anaerobic microorganisms [50,51].
GRL ALEL 2Grade of Recommendation A (Level of Evidence – 2)
It is recommended to perform microbiological studies and/or determine the DNA of Gardnerella vaginalis, Atopobium vaginae, Lactobacillus spp. and the total bacterial load in vaginal discharge using PCR (quantitative assay) to determine the species and quantitative composition of the vaginal microbiota, particularly for fastidious microorganisms, using test systems approved for medical use in the Russian Federation [52,53,62,63].
GRL ALEL 2Grade of Recommendation A (Level of Evidence – 2)
Comments: in microscopic examination, in addition to identifying "clue" cells, it is necessary to note a decrease in the number or disappearance of lactobacilli; an increase in the number of mixed microbial (non-lactobacillar) microbiota; and the absence of a local leukocytic reaction. Culture examination can be used to determine the species and quantitative composition of the vaginal microbiota (microbiological (culture) examination of female genital discharge for aerobic and facultatively anaerobic microorganisms). To evaluate the results of microscopic and culture examination, a comprehensive system for detecting vaginal microbiota disorders is used: "Integral Assessment of Vaginal Microbiota Status. Diagnosis of Opportunistic Infections".
2.4 Instrumental Diagnostics
Not applicable.
2.5 Other Procedures
It is recommended to determine the concentration of hydrogen ions (pH) of the vaginal mucosa discharge (performing vaginal discharge pH-metry using litmus paper). In bacterial vaginosis, pH is above 4.5 [54,64].
LEL 3Grade of Recommendation A (Level of Evidence – 3)
It is recommended to perform an amine test: applying vaginal discharge to a glass slide and adding a 10% KOH solution. The amine test in bacterial vaginosis is positive: an unpleasant "fishy" odor appears or intensifies [59,62].
Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)
Comments: the diagnosis of bacterial vaginosis is established based on the presence of three of the four Amsel criteria:
- homogeneous whitish-gray discharge from the genital tract, with an unpleasant "fishy" odor;
- pH of vaginal discharge above 4.5;
- positive amine test;
- detection of "clue" cells upon microscopy of vaginal discharge
It is recommended to schedule an obstetrician-gynecologist consultation for the management of pregnant women with bacterial vaginosis and concurrent pelvic inflammatory disease [55,56].
GRL CLEL 4Grade of Recommendation – C (Level of Evidence – 4).
It is recommended to consult an endocrinologist in cases of frequent recurrences of bacterial vaginosis to rule out comorbidities (conditions) that may contribute to the disruption of the normal vaginal microbiota [57,58].
GPP CLOE 5Level of recommendation evidence – C (level of data reliability – 5)
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Conservative Treatment
Treatment of bacterial vaginosis is carried out with drugs of the nitroimidazole group derivatives and clindamycin in order to eliminate or reduce the number of "clue" cells upon microscopic examination of vaginal discharge during follow-up and to achieve clinical recovery.
It is recommended to prescribe drugs of the nitroimidazole group derivatives and clindamycin for intravaginal use for the treatment of bacterial vaginosis in adults:
clindamycin, cream 2% 5.0 g intravaginally once daily (at bedtime) for 7 days [10, 13, 17-20]
LoE AGoE 2Level of Evidence A (Grade of Recommendation 2)
or
metronidazole, vaginal gel 5.0 g intravaginally twice daily for 5 days [10, 13, 17, 12-23]
LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)
or
clindamycin, vaginal suppositories 100 mg intravaginally once daily (at bedtime) for 3 days [31]
GPR BLEL 2Grade of Recommendation B (Level of Evidence 2)
It is recommended to prescribe drugs of the nitroimidazole group derivatives and clindamycin** orally for the treatment of bacterial vaginosis in adults:
#metronidazole** 500 mg orally twice daily for 7 days [10, 13, 20, 21, 24-27]
GCR ALEL 1Grade of Recommendation A (Level of Evidence 1)
or
#tinidazole 2.0 g orally once daily for 3 days [10,28-30,65].
LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)
or
#clindamycin** 300 mg orally twice daily for 7 days [10, 14]
LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)
or
#tinidazole 1.0 g orally once daily for 5 days [32]
GPR BLEL 2Grade of Recommendation B (Level of Evidence 2)
It is recommended for the treatment of bacterial vaginosis in pregnant women:
#metronidazole** 500 mg orally twice daily for 7 days, prescribed starting from the second trimester of pregnancy [10-36].
LoE AGoE 2Level of Evidence A (Grade of Recommendation 2)
or
#metronidazole** 250 mg orally 3 times daily for 7 days, prescribed starting from the second trimester of pregnancy [33-36].
LoE AGoE 2Level of Evidence A (Grade of Recommendation 2)
or
#clindamycin** 300 mg orally twice daily for 7 days [37, 38].
GCR ALEL 1Grade of Recommendation A (Level of Evidence 1)
It is recommended for the treatment of bacterial vaginosis in children:
#metronidazole** 10 mg per kg of body weight orally 3 times daily for 5 days [39, 66, 67].
LoR CLE 3Level of Recommendation C (Level of Evidence 3)
3.2 Surgical Treatment
Not applicable.
3.3 Other Treatment
Diet therapy is not used.
Pain management is not used.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Not applicable.
5. Prevention and Dispensary Observation
Determination of cure for bacterial vaginosis using a microscopic method is performed 14 days after the end of treatment. If test results are negative, patients do not require further follow-up.
The physician should advise the patient to abstain from sexual intercourse or use barrier methods of contraception during treatment and follow-up until cure is established.
Prevention:
- adherence to personal and sexual hygiene rules;
- exclusion of casual sexual contacts and frequent change of sexual partners;
- use of barrier contraception methods;
- exclusion of uncontrolled and frequent use of systemic antibacterial, antifungal drugs, and systemic hormonal drugs;
- exclusion of vaginal douches and irrigation;
- exclusion of prolonged use of intrauterine devices and vaginal diaphragms;
- avoidance of tight synthetic underwear and regular use of hygienic pads.
If there is no therapeutic effect, it is recommended to prescribe other drugs or treatment methods.
It is recommended for the prevention of bacterial vaginosis recurrences, after completion of therapy, to use other antiseptics and antimicrobial drugs for the treatment of gynecological diseases (vaginal probiotic preparations containing lactobacilli, for example, Lactobacillus Casei Rhamnosus) [60,61].
LoE AGoE 2Level of Evidence A (Grade of Recommendation 2)
6. Organization of Medical Care
Treatment of bacterial vaginosis is carried out on an outpatient basis.
7. Additional Information
Exogenous and endogenous risk factors for the development of bacterial vaginosis should be considered:
Endogenous risk factors for the development of bacterial vaginosis include: hormonal changes (age-related – during puberty and menopause; in pregnancy pathology; in the postpartum and post-abortive periods), hypotrophy and atrophy of the vaginal mucosa, presence of cysts and polyps of the vaginal walls, hymenal area, impaired receptor function of the vaginal epithelium, antagonism between vaginal microorganisms, decreased concentration of hydrogen peroxide in the vaginal environment due to a decrease in the concentration of lactobacilli, etc.
Exogenous risk factors for the development of bacterial vaginosis include: infection with pathogens of sexually transmitted infections and colonization of the genital tract by genital mycoplasmas, drug therapy (systemic antibacterial drugs, cytotoxic antitumor drugs, glucocorticosteroids, systemic antimicrobial drugs), radiation therapy; presence of foreign bodies in the vagina and uterus; malformations of the genital organs or their deformations after childbirth and surgical interventions; impaired genital hygiene, including frequent use of douches and vaginal irrigation; use of intravaginal contraceptives, including spermicides.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Level of evidence | Level of evidence |
|---|---|---|---|
1 | Diagnosis confirmed by three of the 4 Amsel criteria (homogeneous, whitish-gray vaginal discharge with an unpleasant odor; vaginal discharge pH > 4.5; positive amine test result; presence of "clue" cells) | 1 | A |
2 | Therapy with clindamycin, metronidazole, or tinidazole was administered | 4 | C |
3 | Disappearance or reduction in the number of "clue" cells upon microscopic examination of vaginal discharge during follow-up was achieved | 4 | C |
4 | Disappearance of clinical symptoms of the disease (clinical recovery) was achieved | 4 | C |
References
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Appendix A1. Working Group Composition
1. Kubanov Alexey Alekseevich – Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, President of the Russian Society of Dermatovenerologists and Cosmetologists.
2. Vladimir N. Serov, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, President of the Russian Society of Obstetricians and Gynecologists.
3. Irina O. Malova – Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists.
4. Margarita R. Rakhmatulina – Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists.
5. Ksenia I. Plakhova – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.
6. Inna A. Apolikhina – Doctor of Medical Sciences, Professor, Member of the Russian Society of Obstetricians and Gynecologists.
7. Tatyana V. Priputnevich, Doctor of Medical Sciences, Head of the Department of Microbiology and Clinical Pharmacology at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.
Conflict of interest:
The authors declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
1. Medical specialists: dermatovenereologists, obstetricians-gynecologists.
2. Residents and trainees of continuing professional education courses in the specified specialty.
Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Level of evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definitions |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
These clinical guidelines were developed taking into account the following regulatory legal documents:
1) Procedure for the provision of medical care in the profile "dermatovenereology", approved by Order of the Ministry of Health of the Russian Federation No. 924n dated November 15, 2012.
2) Procedure for the provision of medical care in the profile "obstetrics and gynecology", approved by Order of the Ministry of Health of the Russian Federation No. 572n dated November 1, 2012.
Appendix B. Physician Action Algorithms
Flowchart 1. Patient Management Algorithm
Appendix C. Patient Information
1. During the period of treatment and follow-up observation, it is necessary to abstain from sexual intercourse or use barrier methods of contraception until cure is confirmed.
2. To confirm cure, a repeat medical visit for examination is required 14 days after the end of treatment.
3. It is necessary to observe personal and sexual hygiene rules, avoid excessive use of soap, avoid frequent changes of sexual partners and casual sexual liaisons.
4. To prevent recurrent episodes of bacterial vaginosis, it is necessary to avoid uncontrolled use of antibacterial and hormonal drugs, timely treat endocrine pathology, background gynecological diseases, gastrointestinal tract diseases, do not abuse frequent douches; abandon tight synthetic underwear and regular use of hygienic pads.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
None.