Annu. Rev. Med. 2000. 51:349356 Copyright 2000 by Annual Reviews.

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BACTERIAL VAGINOSIS
Jack D. Sobel
Division of Infectious Diseases, Wayne State University School of Medicine, Detroit Medical 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 vaginal bacterial ora with disappearance of lactobacilli and overgrowth of Gardnerella vaginalis and resident anaerobic vaginal bacteria. Little progress has occurred in identifying causal factors, although the pathophysiology of this syndrome is better understood. Although symptoms are easily recognizable, obstetric and gynecologic complications continue to increase in number. Bacterial vaginosis is far more than a nuisance 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 complication constitutes a major challenge.

INTRODUCTION
Bacterial vaginosis (BV) is the most common cause of vaginitis in women of childbearing age. Estimates of its prevalence depend on the population studied, but include 1719% in family planning clinics and 410% in student health clinics (1), increasing to 2440% in sexually transmitted disease (STD) clinics. BV has been observed in 1629% of pregnant women and is more frequently detected (30%) in women attending infertility clinics. It predominantly affects young, sexually active females but can occur in the absence of sexual intercourse.

PATHOGENESIS
BV represents a complex change in vaginal ora characterized by a reduction in the prevalence and concentration of H2O2-producing lactobacilli (2, 3) and an increase in the prevalence and concentration of G. vaginalis; Mycoplasma hominis; anaerobic gram-negative rods belonging to the genera Prevotella, Porphyromonas, and Bacteroides; and anaerobic Peptostreptococcus species (4, 5). The massive overgrowth of vaginal anaerobes is associated with increased production of proteolytic carboxylase enzymes, which act to break down vaginal peptides to a variety of amines which, in high pH, become volatile and malodorous,
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especially trimethylamine (Figure 1). The amines are associated with increased vaginal transudation and squamous epithelial cell exfoliation, creating the typical discharge. In conditions of elevated pH, G. vaginalis more efciently adheres to the exfoliating epithelial cells, creating clue cells. Amines further provide a suitable substrate for M. hominis growth. What remains unknown is whether the loss of lactobacilli precedes or follows this massive upheaval in ora. Although lactobacilli are essential for normal vaginal acidity, they are themselves acidophilic and hence are attracted to an acid environment. The more anaerobic vaginal milieu of BV is not conducive to lactobacillary growth and dominance. The reduction of H2O2-producing lactobacilli in BV remains unexplained. Since the original transmissible nature of BV was demonstrated by Gardner & Dukes in 1955, several studies have conrmed that G. vaginalis and other BV-associated organisms may be transferred sexually (6); however, transmission alone is not sufcient to cause disease because most of the microorganisms are normally found in low numbers in the healthy vagina. Risk factors for BV include use of intrauterine devices, douching, nonwhite ethnicity, and prior pregnancy. A higher incidence of BV is observed in lesbian women (33%), possibly because of exchange of vaginal secretions or orogenital contact. Supporting the latter is increased frequency of BV in women who experience cunnilingus.

Figure 1

Pathophysiology of bacterial vaginosis.

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CLINICAL FEATURES AND DIAGNOSIS

Women present with an unpleasant, shy-smelling discharge that is more noticeable after intercourse. The discharge is off-white, thin, and homogeneous. Erythema and inammation are absent. The cervix is usually normal, and cervicitis, if present, is usually caused by other pathogens. Many women with BV are asymptomatic. Simple diagnostic criteria established by Amsel et al have proved useful in clinical practice (7). Amsel criteria include (a) an adherent grayish-white discharge, (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 reliably use microscopy; hence, overdiagnosis is common, and therapy is frequently empirical.

Figure 2 High-power micrograph of clue cell. Note loss of cell borders caused by adherent coccobacillary organisms.

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The presence of clue cells is the single most reliable predictor of BV (8). Gram stain of vaginal secretions is even more reliable than wet mount, with a sensitivity of 93% and specicity of 70%, but it is rarely used by practitioners (9). Although cultures for G. vaginalis are positive in almost all cases of BV, G. vaginalis may be detected in 5060% of women who do not meet the diagnostic criteria for BV. Accordingly, vaginal culture has no part in the diagnosis of BV. DNA probes for G. vaginalis are expensive and currently offer little additional diagnostic benet, but may be useful to the practitioner unable to perform microscopy (10). Another device recently approved by the US Food and Drug Administration for the evaluation of vaginal discharge is FemExam pH and Amine Test Card, which is easy to read and has a high level of reproducibility (SL Hillier, JR Schwebke, JD Sobel, et al, personal communcation).

COMPLICATIONS
To date, 7 published studies (2 case-control and 5 cohort studies) have reported an 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 whom other infections were excluded, detected relative increased risks of preterm birth ranging from 2.0 to 6.9 directly attributable to BV or an 40% elevated risk of preterm low birth weight. Organisms found in the lower genital tract in women with BV are found in about half of the patients with positive cultures from amniotic uid or placenta (14). It is estimated that 1520% of pregnant women have BV (15). Thus, enormous numbers of otherwise healthy women are at risk. It is possible that, in the future, screening and treatment will become routine. The optimal time for screening and treatment has not been dened. Although at least two studies suggest that screening in the rst or second trimester may be more predictive of preterm delivery than later screening (16), additional studies are needed. Hay et al concluded that BV is uncommon in pregnant women after 16 weeks of gestation, and may remit spontaneously in those women who reach term (17). In randomized, placebo-controlled treatment trials, patients at high risk for preterm delivery who were treated with oral metronidazole all showed considerable reduction in the incidence of preterm labor associated with BV (1820). Unfortunately, similar results have not been forthcoming in low-risk pregnant women with asymptomatic BV; accordingly, the issue of routine screening is unresolved. Since the 1970s, evidence has incriminated vaginal anaerobic ora in pelvic inammatory disease (PID), especially in the absence of Chlamydia trachomatis and Neisseria gonorrhoeae (1). In a STD clinic, women with BV were more than eight times as likely as controls to have adnexal tenderness on exam (8). Several investigations conrmed a causal association (21), with demonstration of vaginal BV-associated anaerobes such as Prevotella bivia, other Prevotella species, and Peptostreptococcus 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 a history of symptomatic PID, emphasizing missing links in the pathogenic process. It has been postulated that silent endometrial inammation may be the missing piece in the puzzle. In a study of women without signs or symptoms of upper genital tract inammation but with asymptomatic BV, Korn et al documented the frequent presence (10/22 subjects) of plasma cell endometritis on endometrial biopsy versus 1/19 controls (23). Moreover, BV-associated microorganisms were usually present in endometrial cultures [9/11 versus 8/30 without plasma cell endometritis (odds ratio, 12.4; 95% condence interval, 2132; p 0.002)]. The majority of women with laparoscopically proven salpingitis have evidence of an abnormal vaginal ecosystem (22). Numerous studies have shown an association of BV with mucopurulent endocervicitis (24, 25). Up to 50% of women attending STD clinics and diagnosed with mucopurulent endocervicitis have coexistent BV (25). Schwebke et al suggest the need to treat coexistent BV in women with mucopurulent endocervicitis regardless of the presence of other pathogens, since failure to do so resulted in an excess rate of persistent cervicitis (26). Studies also indicate that BV is associated with inammatory changes noted on cervical cytology (27). There is preliminary evidence indicating an association between BV and nongonococcal urethritis in male partners of women with BV. Postoperative infections, including post-abortion PID, post-hysterectomy cuff cellulitis, and post-Caesarian endomyometritis, have been shown to be associated with asymptomatic BV (28). Moreover, preoperative antibiotic prophylaxis that covers BV-associated ora 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 and inammatory atypia, as well as cervical intraepithelial neoplasia. The possibility was raised that BV was associated with the development of cervical intraepithelial neoplasis, i.e. as a cofactor to human papilloma virus. However, Peters et al failed to conrm this relationship in dyskaryotic cervical smears (31).

TREATMENT
Poor efcacy has been observed with triple-sulfa creams, erythromycin, tetracycline, acetic acid gel, and providone-iodine vaginal douches (32). Moderate cure rates have been obtained only with ampicillin (mean cure rate 66%) and amoxicillin. The most successful oral therapy remains metronidazole. Most studies using multiple divided-dose regimens of 8001200 mg/day for 1 week achieved clinical cure rates of 90% immediately, and cure rates of 80% at 4 weeks. Although single-dose therapy with 2 g of metronidazole achieves comparable immediate clinical-response rates, higher recurrence rates have been reported (32). The benecial effect of metronidazole results predominantly from its antianaerobic activity and the susceptibility of G. vaginalis to the hydroxymetabol-

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ites of metronidazole. Even though Mycoplasma hominis and Mobiluncus curtissi are resistant to metronidazole, the organisms are usually not detected at followup visits of successfully treated patients. Topical therapy with 2% clindamycin once daily for 7 days or 0.75% metronidazole gel once daily for 5 days has been shown to be as effective as oral metronidazole (33). More recently, abbreviated 3-day courses of topical clindamycin and metronidazole have achieved comparable early cure rates, but longterm follow-up suggests higher rates of early recurrence (34). In the past, asymptomatic BV was not treated, especially because patients often improve spontaneously over several months. However, evidence linking asymptomatic BV with obstetric and gynecologic complications has caused reassessment of this policy, especially with the availability of convenient topical therapies. Asymptomatic BV should be treated before pregnancy, in women with unexplained cervical abnormalities, and before elective gynecologic surgery. After therapy with oral metronidazole, 30% of patients who initially responded experience recurrence of symptoms within 3 months (1). Reasons for recurrence are unclear and include the possibility of reinfection, but recurrence more likely reects vaginal relapse with failure to eradicate the offending organisms at the same time that the normal protective Lactobacillus-dominant vaginal ora fails to reestablish itself. Management of acute BV symptoms during relapse includes oral or vaginal metronidazole or clindamycin, usually prescribed for a longer treatment period (1014 days). Maintenance antibiotic regimens have had largely disappointing results, and new approaches include exogenous Lactobacillus recolonization using suppositories that contain selected bacteria. Despite indirect evidence of sexual transmission, no study has documented reduced recurrence rates of BV in women whose partners have been treated with a variety of regimens, including oral metronidazole and clindamycin (35). Accordingly, most clinicians do not treat male partners.

HUMAN IMMUNODEFICIENCY VIRUS AND BACTERIAL VAGINOSIS

Some evidence suggests that BV may increase the risk of human immunodeciency 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-based study in Uganda produced similar ndings (37). It is feasible that absence of H2O2-producing lactobacilli increases susceptibility to HIV as well as BV. Alternatively, BV per se may facilitate HIV transmission. Additional studies are needed.

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LITERATURE CITED
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