Obstet Gynecol Clin N Am

30 (2003) 685 694

Gynecologic consequences of
bacterial vaginosis
Jane R. Schwebke, MD
Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham,
703 19th Street South, Zeigler Research Building #239, Birmingham, AL 35294-0007, USA

Bacterial vaginosis (BV) is the most prevalent cause of symptomatic vaginitis in

sexually active women. At the same time, 50% of the total number of BV infections
are asymptomatic. The cause of BV remains unknown; however, epidemiologically
it behaves as a sexually transmitted disease (STD) and is clearly associated with
sexual activity. BV has been associated with multiple obstetric and gynecologic
complications. The latter topic is the subject of this article.

Overview of vaginal flora and bacterial vaginosis

The three main causes of infectious vaginitis are vulvovaginal candidiasis,
trichomoniasis, and BV. It is estimated that more than 10 million office visits per
year in the United States occur as a result of vaginal infections [1]. Because none of
these infections is a reportable disease, accurate numbers are unavailable. BV is the
most prevalent infection, however. Although only trichomoniasis has been proved
to be sexually transmitted, BV has an epidemiologic profile much more similar to
trichomoniasis than to candidiasis [2], and most authorities consider BV to be at
least sexually associated.
BV is characterized by a shift in the vaginal flora away from a lactobacilluspredominant milieu to one with markedly increased quantities of anaerobic and
facultative anaerobic bacteria [3]. The decrease in the number of lactobacilli,
particularly those that produce hydrogen peroxide, is hypothesized to be a major
factor in the development of complications associated with BV. The large numbers
of anaerobic bacteria present in the vagina in women with BV undoubtedly

E-mail address: Schwebke@uab.edu

0889-8545/03/$ see front matter D 2003 Elsevier Inc. All rights reserved.
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contribute to the overall risk of infectious complications after instrumentation of

the upper genital tract.
Lactobacilli become the predominant inhabitant of the vagina at the time of
puberty, presumably because of the effect of estrogens on the glycogen content of
vaginal epithelial cells [4]. When estrogen levels fall, such as in postpartum or
menopausal women, the prevalence of lactobacilli declines [5]. In vitro, lactobacilli
have been shown to produce various potential microbial toxins, including H2O2
and more poorly defined bacteriocins [4,6]. Lactobacilli, which produce H2O2,
have been shown in vitro to inhibit various microorganisms, including Gardnerella
vaginalis, anaerobes, Neisseria gonorrhoeae, and HIV [5,7 11]. Women with
lactobacilli that produce H2O2 in vitro have been shown to be less likely to have BV
and STD pathogens, such as N gonorrhoeae, Chlamydia trachomatis, and
Trichomonas vaginalis [7,12,13]. It is postulated that microbial H2O2 production
may play an important stabilizing role for vaginal ecology. Other means by which
lactobacilli may play a protective role within the vaginal ecosystem include
competition for epithelial cell attachment sites and stimulation of the local immune
system [4,14]. The acidic pH of the vagina is also a result of the metabolism of the
lactobacilli and is in and of itself inhospitable to many potential pathogens.
Half of all women with BV complain of symptoms, especially vaginal discharge
or odor [15]. Treatment of women with asymptomatic BV remains controversial,
except in certain circumstances related to surgery and prevention of preterm birth
[16]. Recommended treatment regimens include either metronidazole or clindamycin; however, cure rates are 70% to 80% at best [17]. Recurrence rates are high,
with up to 70% of women experiencing recurrence within 3 months of treatment
[17]. Suboptimal cure rates and the high rates of recurrent disease make prevention
of complications associated with abnormal flora more difficult.

Gynecologic complications associated with bacterial vaginosis

Postoperative infections
BV is associated with gynecologic complications, such as endometritis and
pelvic inflammatory disease (PID), after invasive procedures of the upper genital
tract and posthysterectomy vaginal cuff cellulitis [18]. Soper et al [19] showed that
patients with BV had a threefold increased risk for the development of endometritis
after abdominal hysterectomy. No prospective, randomized treatment studies of the
effect of treatment for BV preoperatively have been reported. BV also has been
associated with postabortal PID. Larsson et al [20] reported a threefold increase for
this complication among patients with BV compared with women with lactobacillus-predominant flora. A randomized, double-blind study of the treatment of
BV with metronidazole before first-trimester abortion showed a significant
reduction in PID in the treatment group [21]. Based on these studies, the Centers
for Disease Control and Prevention (CDC) recommends screening and treatment
for BV before performing invasive gynecologic procedures [16].

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Urinary tract infections

Various studies have shown an association between urinary tract infections
(UTIs) and abnormal vaginal flora. Harmanli et al studied women who presented
for routine gynecologic examinations and found that 22.4% with UTI also had BV
compared with 9.7% without BV (OR 2.79, 95% CI 1.05, 8.33), which suggests
that BV is a risk factor for UTI [22]. In a study of women with recurrent UTIs,
Gupta et al [23] demonstrated an inverse relationship between vaginal lactobacilli
and vaginal Escherichia coli that suggested that lactobacilli are integral in keeping
E coli levels under control and that women without sufficient numbers of
lactobacilli are at increased risk of recurrent UTI [13]. Prospective studies of the
treatment of BV as a means of reducing the risk of recurrent UTIs are needed.
Lower genital tract infection with bacterial vaginosis and sexually transmitted
diseases
BV is frequently present as a coinfection with cervical and vaginal STDs. For
example, women with trichomoniasis are highly likely to be coinfected with BV. In
a study of 88 women who attended a family planning clinic with complaints of
vaginal discharge, 37 (42%) were found to have trichomoniasis. Among the
women with trichomoniasis, 86% also met the diagnostic criteria for BV compared
with only 31% of the women without Trichomonas (P < 0.001) [13]. Among
women who attended an STD clinic in Seattle, 75% of women with trichomoniasis
also had BV compared with 47% of women without Trichomonas (P < 0.001) [12].
In a prospective study, acquisition of trichomoniasis was associated with abnormal
vaginal flora on Grams stain (HR, 1.8; 95% CI, 1.3 2.4) [24].
Infections with N gonorrhoeae and C trachomatis also have been significantly
associated with abnormal vaginal flora. In a cross-sectional study of women who
attended an STD clinic, screening cultures for N gonorrhoeae and inhibition
assays of the vaginal flora were performed. The investigators found that inhibitory
lactobacilli were present in significantly fewer women infected with gonorrhea
than uninfected women. Among women who reported a recent sexual contact to
men with gonorrhea, 28% of the women with gonorrhea had inhibitory lactobacilli
present versus 73% of the women who did not acquire the infection (P < 0.05) [7].
In a more recent cross-sectional analysis, female sexual contacts of men with
either gonorrhea or chlamydia were three to four times more likely to be infected
with the STD if they had BV than if they had normal vaginal flora. Vaginal
colonization with hydrogen peroxide producing lactobacilli was negatively
associated with infection with either gonorrhea or chlamydia [25]. Finally, a
prospective, longitudinal study of female sex workers in Kenya found that absence
of vaginal lactobacilli was significantly associated with acquisition of gonorrhea
in a multivariate model that controlled for other risk factors (HR, 1.7; 95%
CI, 1.3 2.4) [26].
Numerous studies have documented the association of BV with cervicitis
[27 29]. The etiology of cervicitis, which can include gonorrhea, chlamydia,

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and primary herpes simplex virus infection, is unknown in up to half of the cases
[30]. Up to 50% of women with cervicitis have concomitant BV [27], a finding that
previously led to the hypothesis that the physiologic changes associated with
cervicitis might be responsible for creating conditions favorable for the development of BV [27]. This high coinfection rate created a therapeutic dilemma because
before the development of topical agents for treatment of BV, simultaneous
treatment of both processes required administration of two oral agents, each of
which had gastrointestinal side effects. This problem, combined with the belief that
BV might spontaneously resolve with cervicitis treatment, led to recommendations
to treat the cervical infection while postponing treatment for BV [27]. Such an
approach does not lead to the disappearance of BV, however, and leads to an
unnecessary and potentially undesirable delay in the re-establishment of normal
vaginal flora [31]. An alternative explanation for the frequent finding of cervicitis
in women with BV is that BV precedes and facilitates acquisition of cervicitis.
In a pilot study that examined the appropriate management of women with
cervicitis and BV, researchers made the observation that women who received
doxycycline and metronidazole were more likely to have resolution of cervical
inflammation than if they received doxycycline alone [32]. In a follow-up
randomized, double-blind treatment study, women with clinically defined BV
and cervicitis (mucopurulent endocervical discharge) were randomized to placebo
versus metronidazole gel and doxycycline and ofloxacin for the cervicitis. At
3 weeks after completion of therapy, 70% of women in the metronidazole group
had resolution of BV versus 21% in the placebo group (P = 0.001). Resolution of
cervical inflammation was significantly associated with use of metronidazole gel
and cure of BV. In a multivariate analysis, women who received metronidazole gel
were three times more likely to be cured of cervicitis [31].
The findings of this study, which relied on macroscopic findings of cervical
inflammation, recently were complemented by a study of molecular markers of
inflammation. Yudin et al [33] measured cervical cytokine levels in pregnant
women who were enrolled in a study that compared oral versus intravaginal
metronidazole for the treatment of BV. Levels of interleukin-6B were measured in
cervical secretions before and after therapy. Among the women who were cured of
BV, there was a significant decrease in the cytokine levels after treatment, which
was present in the oral and the intravaginal treatment arms. Among women who
failed therapy, no similar decrease was noted [33]. At both the macroscopic and
molecular levels, BV seems to cause inflammatory changes in cervical tissue.
Nongonococcal urethritis (NGU) in men provides an interesting parallel to
cervicitis. NGU is caused by chlamydia, Trichomonas, and herpes simplex virus;
however, just as with cervicitis, at least half of all cases are of unknown origina[34].
Keane et al [35] found a significant association between NGU and BV, particularly
in men without evidence of chlamydia as a cause of NGU. Among men with NGU,
31% of their female sexual contacts had BV. Among men without NGU, only 8% of
female contacts had BV. In a second study design, 71% of male partners of women
with BV had NGU compared with 33% of men with NGU who were partners to
women without BV [35]. Taken in aggregate, the cervicitis and the urethritis data

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suggest an interesting hypothesis about BV itself or a transmissible agent, which is

associated with BV causing these sexually transmitted infections.
Bacterial vaginosis and upper genital tract infection
Numerous studies have demonstrated a strong association between BV and
endometritis and PID. In a study conducted among women who attended an STD
clinic in San Francisco, Korn et al [36] performed endometrial biopsies for culture
and histology in a group of women who had BV but no clinical signs of upper tract
infection and no evidence of gonorrhea or chlamydia. They compared these
women to a control group with normal vaginal flora. The women with BV were
significantly more likely to have histologic evidence of endometritis than the
control group. Of 22 women with BV, 10 (45%) had plasma cell endometritis
compared with 1 woman in the control group (OR 15, 95% CI 2 686; P < 0.01).
Endometrial cultures yielded BV-associated organisms from 9 of 11 women (82%)
with endometritis versus 8 of 30 women (27%) without endometritis (OR 12.4,
95% CI 2 132; P = 0.002) [36]. Wiesenfeld et al [37] conducted a cross-sectional
study of women with BV, gonorrhea, or chlamydia or those at risk for gonorrhea or
chlamydia to determine the prevalence of subclinical PID as defined by endometritis. Subclinical PID was present in 27% of women with chlamydia, 26% of
women with gonorrhea, and 15% of women with BV (OR for BV 2.7, 95%
CI 1.1, 5.1) [37]. BV-associated organisms can ascend into the upper genital tract
and cause subclinical infection.
The relationship between BV and clinically apparent PID is clearly established
by many studies, although the cause-and-effect relationship is less clear [38 41].
Women with PID rarely have normal vaginal flora, as first indicated by Jacobsen
and Westrom [42] in 1969. In a more recent study of women with acute salpingitis,
82% of women with PID had vaginal Grams stains consistent with either BV or
intermediate flora (as opposed to a lactobacillus-predominant flora) [43]. In 1975,
Eschenbach et al [44] reported on the polymicrobial origin of PID, pointing out
that anaerobic organisms associated with BV were frequently recovered from
culdocentesis specimens. Studies of women with PID in which laparoscopy and
tubal cultures were performed also have shown that women with proven PID
frequently have organisms associated with BV isolated from the fallopian tubes,
often in the absence of traditional pathogens, such as N gonorrhoeae and
C trachomatis [45]. These findings have led to controversy in the treatment of
PID regarding inclusion of metronidazole in treatment regimens. Currently the
CDC STD treatment guidelines state that many experts recommend the addition of
oral metronidazole to the standard outpatient regimen of ceftriaxone and doxycycline [16].
Bacterial vaginosis and cervical dysplasia
BV has been linked to abnormalities on Pap smear. In a retrospective study in
Sweden, more than 6000 Pap smears were reviewed for the presence of clue cells

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and results were correlated with the original interpretation of the presence or
absence of cervical dysplasia. Cervical intraepithelial neoplasia was significantly
more common among women with BVas diagnosed by the presence of clue
cellsthan among women without BV (P < 0.001). The authors raised the hypothesis that BV could be a cofactor with human papillomavirus in the development of cervical intraepithelial neoplasia [46]. In a second study, Eltabbakh et al
[47] performed wet mounts of the vaginal fluid at the same time as the collection
of the Pap smear in asymptomatic women. They found that BV was significantly
correlated with inflammation on Pap smears and atypical cells of undetermined
significance. Although the links between BV and abnormal cervical cytology are
intriguing, prospective studies are lacking. It is possible that the absence of
lactobacilli in women with BV allows for enhanced pathogenicity of human
papillomavirus in this setting. It is also plausible that the presence of high numbers
of bacteria associated with BV interfere with the interpretation of the Pap smear.
Bacterial vaginosis and HIV
Information continues to accumulate on the role of BV as a risk factor for HIV
infection. Among female commercial sex workers in Thailand, HIV seropositivity
was significantly correlated with BV [48]. Similar findings were documented from
a study of women in Uganda [49]. The highest HIV seropositivity rates were
found among women with the most severe changes in their vaginal flora, as
documented by Grams stain. Royce et al [50] performed a similar but smaller
study among pregnant women in North Carolina. Women with normal flora by
Grams stain had an HIV seroprevalence of 0.82% compared with the group of
women with BV, who had a 3.3% prevalence of HIV (RR 4.0, 95% CI 1.1,14.9). A
recent prospective study of pregnant women conducted in Malawi confirmed the
findings of the previous cross-sectional studies. Among a cohort of pregnant
women, HIV seroconversion was significantly associated with alterations in
vaginal flora [51]. In yet another prospective study, Martin et al [24] showed that
HIV seroconversion was associated with BV and loss of lactobacilli, especially
those that did not produce hydrogen peroxide.
Although the cross-sectional studies do not prove cause and effect, the two
prospective studies cited are compelling. In a case-control study of the prevalence
of lower genital tract infections among HIV-positive and -negative women, rates
of BV were similar, which speaks against immunosuppression secondary to HIV
causing changes in vaginal flora [52].
The primary mechanism believed to be responsible for BV as a risk factor for
HIV acquisition is the absence of H2O2-producing lactobacilli. Other possible
mechanisms that have been discussed include elevated vaginal pH associated
with BV, stimulation of HIV replication by Gardnerella and other bacteria
associated with BV, and the elevated cytokine levels (tumor necrosis factor-a
and interleukin-1) found in the genital secretions of women with BV [53 55].
As is the case with STDs, BV seems to be a risk factor for acquisition and
transmission of HIV. In a study of genital tract shedding of HIV, Cu-Uvin et al [56]

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showed that among women with well-controlled HIV infection, women with BV
were nearly six times more likely to shed virus than women with vaginal
candidiasis. Of note, vaginal candidiasis is associated with a normal vaginal pH
and a lactobacillus-predominant flora.
Based on these studies, widespread control of BV has been suggested as a
possible means for decreasing the incidence of HIV in the developing world;
however, current achievable cure rates combined with high recurrence rates make
this solution impractical. The best example of this concept to date lies in a study of
STD control as a means of preventing HIV infection in the Rakai district in Africa.
As part of this study, women in the intervention arm were treated for BV with a
single 2-g dose of oral metronidazole at two 10-month intervals. Follow-up
evaluations did not show a significant difference in the rates of BV between the
intervention and control groups. Rates of HIV acquisition also did not differ
between the two groups [57].

Summary
BV is a prevalent sexually associated infection linked to several gynecologic
complications and acquisition of STDs and acquisition and transmission of HIV.
It seems that normalization of the vaginal flora may be effective for preventing
short-term complications. The implications of screening and treating BV to
prevent long-term complications are less clear and may depend on the availability
of more effective treatment regimens.

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