Annu. Rev. Med. 2000. 51:349–356Copyright q 2000 by Annual Reviews. All rights reserved

0066–4227/00/0201–0349$12.00 349

BACTERIAL VAGINOSIS

Jack D. SobelDivision of Infectious Diseases, Wayne State University School of Medicine, DetroitMedical Center, Detroit, Michigan 48201; e-mail: jsobel@intmed.wayne.edu

Key Words epidemiology, pathogenesis, diagnosis, complications, treatment

Abstract Bacterial vaginosis represents a unique upheaval of the complex vag-inal bacterial flora with disappearance of lactobacilli and overgrowth of Gardnerellavaginalis and resident anaerobic vaginal bacteria. Little progress has occurred in iden-tifying causal factors, although the pathophysiology of this syndrome is better under-stood. Although symptoms are easily recognizable, obstetric and gynecologiccomplications continue to increase in number. Bacterial vaginosis is far more than anuisance infection. Problems with diagnosis continue to dominate clinical practice,although new tests have been introduced. Therapeutic options have increased,although recurrent disease remains common, and management of this common com-plication constitutes a major challenge.

INTRODUCTION

Bacterial vaginosis (BV) is the most common cause of vaginitis in women ofchildbearing age. Estimates of its prevalence depend on the population studied,but include 17–19% in family planning clinics and 4–10% in student health clinics(1), increasing to 24–40% in sexually transmitted disease (STD) clinics. BV hasbeen observed in 16–29% of pregnant women and is more frequently detected(30%) in women attending infertility clinics. It predominantly affects young, sex-ually active females but can occur in the absence of sexual intercourse.

PATHOGENESIS

BV represents a complex change in vaginal flora characterized by a reduction inthe prevalence and concentration of H2O2-producing lactobacilli (2, 3) and anincrease in the prevalence and concentration of G. vaginalis; Mycoplasma hom-inis; anaerobic gram-negative rods belonging to the genera Prevotella, Porphy-romonas, and Bacteroides; and anaerobic Peptostreptococcus species (4, 5).

The massive overgrowth of vaginal anaerobes is associated with increased pro-duction of proteolytic carboxylase enzymes, which act to break down vaginal pep-tides to a variety of amines which, in high pH, become volatile and malodorous,

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Figure 1 Pathophysiology of bacterial vaginosis.

especially trimethylamine (Figure 1). The amines are associated with increasedvaginal transudation and squamous epithelial cell exfoliation, creating the typicaldischarge. In conditions of elevated pH, G. vaginalis more efficiently adheres tothe exfoliating epithelial cells, creating clue cells. Amines further provide a suit-able substrate for M. hominis growth. What remains unknown is whether the lossof lactobacilli precedes or follows this massive upheaval in flora.

Although lactobacilli are essential for normal vaginal acidity, they are them-selves acidophilic and hence are attracted to an acid environment. The moreanaerobic vaginal milieu of BV is not conducive to lactobacillary growth anddominance. The reduction of H2O2-producing lactobacilli in BV remains unex-plained. Since the original transmissible nature of BV was demonstrated by Gard-ner & Dukes in 1955, several studies have confirmed that G. vaginalis and otherBV-associated organisms may be transferred sexually (6); however, transmissionalone is not sufficient to cause disease because most of the microorganisms arenormally found in low numbers in the healthy vagina. Risk factors for BV includeuse of intrauterine devices, douching, nonwhite ethnicity, and prior pregnancy.A higher incidence of BV is observed in lesbian women (33%), possibly becauseof exchange of vaginal secretions or orogenital contact. Supporting the latter isincreased frequency of BV in women who experience cunnilingus.

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Figure 2 High-powermicrograph of clue cell. Noteloss of cell borders causedby adherent coccobacillaryorganisms.

CLINICAL FEATURES AND DIAGNOSIS

Women present with an unpleasant, “fishy-smelling” discharge that is morenoticeable after intercourse. The discharge is off-white, thin, and homogeneous.Erythema and inflammation are absent. The cervix is usually normal, and cervi-citis, if present, is usually caused by other pathogens. Many women with BV areasymptomatic.

Simple diagnostic criteria established by Amsel et al have proved useful inclinical practice (7). Amsel criteria include (a) an adherent grayish-white dis-charge, (b) a positive sniff/whiff test on addition of 10% potassium hydroxide,(c) an elevated vaginal pH of .4.5, and (d) the presence of clue cells (Figure 2)on microscopy. Unfortunately, few clinicians are adequately trained to reliablyuse microscopy; hence, overdiagnosis is common, and therapy is frequentlyempirical.

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The presence of clue cells is the single most reliable predictor of BV (8). Gramstain of vaginal secretions is even more reliable than wet mount, with a sensitivityof 93% and specificity of 70%, but it is rarely used by practitioners (9). Althoughcultures for G. vaginalis are positive in almost all cases of BV, G. vaginalis maybe detected in 50–60% of women who do not meet the diagnostic criteria for BV.Accordingly, vaginal culture has no part in the diagnosis of BV. DNA probes forG. vaginalis are expensive and currently offer little additional diagnostic benefit,but may be useful to the practitioner unable to perform microscopy (10). Anotherdevice recently approved by the US Food and Drug Administration for the eval-uation of vaginal discharge is FemExamt pH and Amine Test Card, which is easyto read and has a high level of reproducibility (SL Hillier, JR Schwebke, JDSobel, et al, personal communcation).

COMPLICATIONS

To date, 7 published studies (2 case-control and 5 cohort studies) have reportedan increased risk of preterm birth in women with BV (12, 13). These studies,conducted in women of diverse ethnic groups and economic strata and in whomother infections were excluded, detected relative increased risks of preterm birthranging from 2.0 to 6.9 directly attributable to BV or an ;40% elevated risk ofpreterm low birth weight. Organisms found in the lower genital tract in womenwith BV are found in about half of the patients with positive cultures from amni-otic fluid or placenta (14). It is estimated that 15–20% of pregnant women haveBV (15). Thus, enormous numbers of otherwise healthy women are at risk. It ispossible that, in the future, screening and treatment will become routine. Theoptimal time for screening and treatment has not been defined. Although at leasttwo studies suggest that screening in the first or second trimester may be morepredictive of preterm delivery than later screening (16), additional studies areneeded. Hay et al concluded that BV is uncommon in pregnant women after 16weeks of gestation, and may remit spontaneously in those women who reach term(17). In randomized, placebo-controlled treatment trials, patients at high risk forpreterm delivery who were treated with oral metronidazole all showed consid-erable reduction in the incidence of preterm labor associated with BV (18–20).Unfortunately, similar results have not been forthcoming in low-risk pregnantwomen with asymptomatic BV; accordingly, the issue of routine screening isunresolved.

Since the 1970s, evidence has incriminated vaginal anaerobic flora in pelvicinflammatory disease (PID), especially in the absence of Chlamydia trachomatisand Neisseria gonorrhoeae (1). In a STD clinic, women with BV were more thaneight times as likely as controls to have adnexal tenderness on exam (8). Severalinvestigations confirmed a causal association (21), with demonstration of vaginalBV-associated anaerobes such as Prevotella bivia, other Prevotella species, andPeptostreptococcus species in fallopian tube tissue or on endometrial biopsy of

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patients with acute PID (22). Many women with tubal disease, however, lack ahistory of symptomatic PID, emphasizing missing links in the pathogenic process.It has been postulated that silent endometrial inflammation may be the missingpiece in the puzzle. In a study of women without signs or symptoms of uppergenital tract inflammation but with asymptomatic BV, Korn et al documented thefrequent presence (10/22 subjects) of plasma cell endometritis on endometrialbiopsy versus 1/19 controls (23). Moreover, BV-associated microorganisms wereusually present in endometrial cultures [9/11 versus 8/30 without plasma cellendometritis (odds ratio, 12.4; 95% confidence interval, 2–132; p 4 0.002)]. Themajority of women with laparoscopically proven salpingitis have evidence of anabnormal vaginal ecosystem (22).

Numerous studies have shown an association of BV with mucopurulent endo-cervicitis (24, 25). Up to 50% of women attending STD clinics and diagnosedwith mucopurulent endocervicitis have coexistent BV (25). Schwebke et al sug-gest the need to treat coexistent BV in women with mucopurulent endocervicitisregardless of the presence of other pathogens, since failure to do so resulted inan excess rate of persistent cervicitis (26). Studies also indicate that BV is asso-ciated with inflammatory changes noted on cervical cytology (27). There is pre-liminary evidence indicating an association between BV and nongonococcalurethritis in male partners of women with BV.

Postoperative infections, including post-abortion PID, post-hysterectomy cuffcellulitis, and post-Caesarian endomyometritis, have been shown to be associatedwith asymptomatic BV (28). Moreover, preoperative antibiotic prophylaxis thatcovers BV-associated flora can reduce these complications (29).

Platz-Christensen et al (30), in reviewing cervical Papanicolaou (PAP) smears,detected a strong association between clue cells detected on PAP smear andinflammatory atypia, as well as cervical intraepithelial neoplasia. The possibilitywas raised that BV was associated with the development of cervical intraepithelialneoplasis, i.e. as a cofactor to human papilloma virus. However, Peters et al failedto confirm this relationship in dyskaryotic cervical smears (31).

TREATMENT

Poor efficacy has been observed with triple-sulfa creams, erythromycin, tetracy-cline, acetic acid gel, and providone-iodine vaginal douches (32). Moderate curerates have been obtained only with ampicillin (mean cure rate 66%) and amoxi-cillin. The most successful oral therapy remains metronidazole. Most studiesusing multiple divided-dose regimens of 800–1200 mg/day for 1 week achievedclinical cure rates of .90% immediately, and cure rates of ;80% at 4 weeks.Although single-dose therapy with 2 g of metronidazole achieves comparableimmediate clinical-response rates, higher recurrence rates have been reported(32). The beneficial effect of metronidazole results predominantly from its anti-anaerobic activity and the susceptibility of G. vaginalis to the hydroxymetabol-

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ites of metronidazole. Even though Mycoplasma hominis and Mobiluncus curtissiare resistant to metronidazole, the organisms are usually not detected at follow-up visits of successfully treated patients.

Topical therapy with 2% clindamycin once daily for 7 days or 0.75% metro-nidazole gel once daily for 5 days has been shown to be as effective as oralmetronidazole (33). More recently, abbreviated 3-day courses of topical clinda-mycin and metronidazole have achieved comparable early cure rates, but long-term follow-up suggests higher rates of early recurrence (34).

In the past, asymptomatic BV was not treated, especially because patients oftenimprove spontaneously over several months. However, evidence linking asymp-tomatic BV with obstetric and gynecologic complications has caused reassess-ment of this policy, especially with the availability of convenient topical therapies.Asymptomatic BV should be treated before pregnancy, in women with unex-plained cervical abnormalities, and before elective gynecologic surgery.

After therapy with oral metronidazole, ;30% of patients who initiallyresponded experience recurrence of symptoms within 3 months (1). Reasons forrecurrence are unclear and include the possibility of reinfection, but recurrencemore likely reflects vaginal relapse with failure to eradicate the offending organ-isms at the same time that the normal protective Lactobacillus-dominant vaginalflora fails to reestablish itself. Management of acute BV symptoms during relapseincludes oral or vaginal metronidazole or clindamycin, usually prescribed for alonger treatment period (10–14 days). Maintenance antibiotic regimens have hadlargely disappointing results, and new approaches include exogenous Lactoba-cillus recolonization using suppositories that contain selected bacteria. Despiteindirect evidence of sexual transmission, no study has documented reduced recur-rence rates of BV in women whose partners have been treated with a variety ofregimens, including oral metronidazole and clindamycin (35). Accordingly, mostclinicians do not treat male partners.

HUMAN IMMUNODEFICIENCY VIRUS ANDBACTERIAL VAGINOSIS

Some evidence suggests that BV may increase the risk of human immunodefi-ciency virus (HIV) transmission. In a study of 144 sex workers in Thailand,women with BV had an increased risk of HIV (36). A large population-basedstudy in Uganda produced similar findings (37). It is feasible that absence ofH2O2-producing lactobacilli increases susceptibility to HIV as well as BV. Alter-natively, BV per se may facilitate HIV transmission. Additional studies areneeded.

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