752

Bacterial vaginosis (BV) is a common condition in

which the normal vaginal lactobacilli are replaced by a
mixture of anaerobic bacteria and mycoplasmas, includ-
ing Gardnerella vaginalis, Mobiluncus, Bacteroides spp, and
Mycoplasma hominis. Clinical diagnosis is based on its clas-
sic appearance as a white thin homogenous discharge
with a characteristic fishy odor, the presence of clue
cells, and a vaginal pH >4.5.
1
BV may affect a substantial
proportion of women during pregnancy, and many of
these cases will never develop into symptomatic disease.
2
The condition may also resolve spontaneously but is
more likely to be persistent throughout pregnancy.
A large body of literature indicates that intrauterine in-
fection plays a major role in the pathogenesis of preterm
birth, which itself is responsible for 70% of perinatal
death and almost one half of long-term neurologic mor-
bidity.
3
Although the role of BV itself in the pathogenesis
of preterm labor and delivery is not well understood, the
association between BV and preterm birth has been con-
firmed repeatedly and consistently.
4,5
Because the screening and treatment of BV in early
pregnancy would be a simple and straightforward strat-
egy to prevent preterm birth, several studies have already
tested this approach. Oral treatment regimens that use
metronidazole alone or metronidazole and erythromycin
combined have shown to be effective in lowering the rate
of preterm deliveries in high-risk patients with a history of
at least one spontaneous preterm birth.
6-8
In a systematic
review in the Cochrane Library,
9
the conclusion was that
there is some suggestion that the detection and treat-
ment of BV in high-risk women may decrease the rate of
preterm deliveries. It was also concluded that there is no
benefit in screening and treating all pregnant women for
BV to prevent preterm birth.
In a recent, large study of the National Institute of
Child Health and Human Development,
10
however, oral
metronidazole did not prevent preterm deliveries in a
From the Departments of Obstetrics and Gynecology
a
and Medical Com-
puter Sciences,
b
Section of Clinical Biometrics, University of Vienna.
Received for publication February 28, 2002; revised September 30,
2002; accepted November 5, 2002.
Reprint requests: Harald Leitich, MD, PhD, Department of Obstetrics
and Gynecology, University of Vienna, Whringer Grtel 18-20, 1090
Vienna, Austria. E-mail: harald.leitich@univie.ac.at
2003, Mosby, Inc. All rights reserved.
0002-9378/2003 $30.00 + 0
doi:10.1067/mob.2003.167
Antibiotic treatment of bacterial vaginosis in pregnancy:
A meta-analysis
Harald Leitich, MD, PhD,
a
Mathias Brunbauer, MD,
a
Barbara Bodner-Adler, MD,
a
Alexandra Kaider, MSc,
b
Christian Egarter, MD,
a
and Peter Husslein, MD
a
Vienna, Austria
OBJECTIVE: The purpose of this study was to evaluate the effectiveness of antibiotic treatment of bacterial
vaginosis in pregnancy to reduce preterm delivery.
STUDY DESIGN: We performed a meta-analysis of published, English-language, randomized, placebo-con-
trolled clinical trials of antibiotic treatment of bacterial vaginosis in pregnant women with intact amniotic
membranes at <37 weeks of gestation. Primary outcomes included preterm delivery, perinatal or neonatal
death, and neonatal morbidity.
RESULTS: Ten studies with results for 3969 patients were included. In patients without preterm labor, antibi-
otic treatment did not significantly decrease preterm delivery at <37 weeks of gestation, in all patients com-
bined (odds ratio, 0.83; 95% CI, 0.57-1.21) nor in high-risk patients with a previous preterm delivery (odds
ratio, 0.50; 95% CI, 0.22-1.12). In both groups, significant statistical heterogeneity was observed. A signifi-
cant reduction in preterm delivery and no statistical heterogeneity were observed in 338 high-risk patients
who received oral regimens with treatment durations of 7 days (odds ratio, 0.42; 95% CI, 0.27-0.67). Non-
significant effects and no statistical heterogeneity were observed in low-risk patients (odds ratio, 0.94; 95%
CI, 0.71-1.25) and with vaginal regimens (odds ratio, 1.25; 95% CI: 0.86-1.81). In one study antibiotic treat-
ment in patients with preterm labor led to a nonsignificant decrease in the rate of preterm deliveries (odds
ratio, 0.31; 95% CI, 0.03-3.24).
CONCLUSION: The screening of pregnant women who have bacterial vaginosis and who have had a previ-
ous preterm delivery and treatment with an oral regimen of longer duration can be justified on the basis of
current evidence. More studies are needed to confirm the effectiveness of this strategy, both in high-risk pa-
tients without preterm labor and in patients with preterm labor. (Am J Obstet Gynecol 2003;188:752-8.)
Key words: Bacterial vaginosis, preterm delivery, antibiotic treatment, meta-analysis
Volume 188, Number 3 Leitich et al 753
Am J Obstet Gynecol
mixed population of pregnant women, and, more impor-
tant, it increased rather than decreased the rate of pre-
term deliveries in the high-risk subgroup. After the
publication of this study, uncertainty about the role of BV
in preterm birth and the usefulness of screen-and-treat
strategies increased. A recent review of screening for BV
in pregnancy, which was carried out for the US Preventive
Services Task Force, could not explain the heterogeneous
results among the studies, including high-risk patients.
11
The authors suggested that high-risk patients themselves
constitute a heterogeneous population, which consists of
more general high-risk patients for whom antibiotic treat-
ment would not be effective and more selected high-risk
patients for whom treatment might still be effective.
Based on the results of this review, the US Preventive Ser-
vices Task Force concluded that the evidence is insuffi-
cient to recommend for or against routine screening of
high-risk pregnant women for BV.
12
The Task Force also
recommended against routinely screening average-risk
asymptomatic pregnant women for BV.
Similarly, in a recent clinical treatment guideline that
was published by the American College of Obstetricians
and Gynecologists,
13
the statement was made that there
are no current data to support the use of BV screening
strategies to prevent preterm birth.
We carried out the present meta-analysis to re-evaluate
the role of antibiotic treatment of BV in pregnancy. Our
specific goals were to include new evidence and to put
special emphasis on the identification of differences in
screen-and-treat strategies among the existing studies to
identify strategies that will produce more consistent re-
sults. This would allow us to draw more reliable conclu-
sions about these strategies and to separate them from
other strategies that provide inconsistent results and that
are in need of continued research activity.
Material and methods
In June 2001, we searched MEDLINE from 1966, EM-
BASE from 1988, and SCIENCE CITATION INDEX EX-
PANDED from 1997 to identify all literature that was
included under (vaginitis or vaginosis or vagina* infec-
tion or vagina* inflammation) and (pregnan* or gravid*
or birth? or labor?r?) and (antibiotic* or antimicrob*).
The following criteria were used to select studies for in-
clusion: article (original published English-language re-
port), study design (randomized placebo-controlled
clinical trial), population (women entered <37 weeks of
gestation with intact amniotic membranes and with BV,
diagnosed either by clinical criteria or by criteria based
on Gram stain findings [positive cultures for BV-associ-
ated microflora alone were not sufficient]), intervention
(antibiotic treatment), and 1 of the following out-
comes: preterm delivery by any available definition, peri-
natal or neonatal death, or any information regarding
neonatal morbidity. We scanned all of the abstracts from
the computer printouts, the retrieved full-text reports,
review articles, and the references from each retrieved
report to determine whether studies met our
inclusion criteria. The literature search and the applica-
tion of inclusion criteria were done by two independent
investigators. Results were then compared, and a con-
sensus was reached.
To determine the internal validity of the trials that are
included, we extracted information regarding the process
of randomization including concealment, the similarity of
baseline characteristics between study groups, the num-
bers of patients excluded after randomization and the
reasons for exclusion, completeness of outcome assess-
ment, and assessment of patient compliance.
To determine the clinical homogeneity of the studies
included, we extracted patient inclusion and exclusion
criteria, mean gestational ages at randomization, criteria
for a diagnosis of BV, treatment characteristics that in-
cluded the administration of antibiotic treatment and the
treatment of patients with concomitant genitourinary in-
fections, and the definitions of outcomes. If mean gesta-
tional ages at randomization were missing in individual
studies, we estimated them from patient inclusion criteria.
For all outcomes in each individual study, we extracted
total numbers of patients with results and the numbers of
true-positive, true-negative, false-positive, and false-nega-
tive results. Primary outcomes included preterm delivery
by any available definition, perinatal or neonatal death,
and any information regarding neonatal morbidity. As a
secondary outcome, we also extracted data regarding ma-
ternal infectious morbidity. When the numbers of true-
positive, true-negative, false-positive, and false-negative
results were not available, we attempted to recalculate
them from the reported results.
For all outcomes in each individual study, we calculated
odds ratios with 95% CIs to determine the efficacy of the
antibiotic treatment.
14
We also calculated the odds ratios
and 95% CIs for all studies combined and for subgroups
of studies according to the following characteristics: pa-
tient inclusion criteria (patients admitted with symptoms
of preterm labor, patients without preterm labor at low or
high risk for preterm delivery, and inclusion of patients
with multifetal gestation), gestational age at randomiza-
tion, choice of antibiotic treatment, and route of admin-
istration.
15
A statistical test of homogeneity was carried out for
each analysis to address the statistical validity of the ag-
gregation of the trials.
15
This test assumes that differ-
ences in the results of the individual trials are due to
chance alone (ie, that all trial results are homogenous).
To calculate overall results for each outcome and all
subgroups,
15
we generally used a fixed-effects model. In
such models, the overall effect is obtained as a weighted
average of the individual trial effects. However, if signifi-
cant heterogeneity was observed (which we defined as a
754 Leitich et al March 2003
Am J Obstet Gynecol
probability value of the homogeneity test of .10 because
of the low power of the test), we used a random-effects
model instead. Trials with zero cells in both the study and
control groups were not included in the calculation of
combined results.
Results
Ten studies were included in this meta-analysis.
6-8,10,16-21
Study populations of two studies overlapped, so results
were available for 3969 individual patients.
17,18
Because
the study of Kurkinen-Rty et al
18
was the report of one
study center that was included in a larger multicenter
study reported by Kekki et al,
17
we generally extracted
information from the larger multicenter study only. Any
information that was not available in the multicenter,
but only in the single-center, study was extracted from
the latter.
Four studies were excluded.
22-25
In one study, results
for preterm delivery and other obstetric complications
were reported in text, but not in numeric form.
22
In the
other three studies of antibiotic treatment of pregnant
women
23
or patients with preterm labor,
24,25
subgroups
of patients with BV were identified, but the results were
not reported for these subgroups.
All studies that were included followed a randomized,
double-blind, placebo-controlled design. Baseline char-
acteristics between the treatment and control groups
were reported to be similar in all but one study, in which
the percentage of teenage pregnancies in the placebo
group was larger than in the antibiotics group.
7
In two
studies, patients were excluded after randomization.
8,19
Reasons for exclusion were fetal distress before receiving
study medication (one patient), patients who de-
clined treatment (two patients), clinical chorioamnioni-
tis (three patients), exclusions according to study
exclusion criteria (six patients), pharmacy error (one pa-
tient), and twins (one patient) in one study
19
and follow-
up losses (five patients), a lack of compliance (six
patients), or the need of additional antibiotic therapy for
renal or pulmonary disease (three patients) in the other
study.
8
Results were available for 98.3%,
10
98.7%,
6
91.4%,
16
100%,
17
97.5%,
7
88%,
19
90.8%,
20
85.1%,
8
and
100%
21
of patients in the individual studies. Assessment
of compliance was described in all except one study.
17
In
four studies, compliance in the treatment and control
groups was reported to be similar.
6,7,10,21
Patient inclusion criteria, mean gestational age at ran-
domization, criteria for a diagnosis of BV, and treatment
regimens of the studies that were included are shown in
Table I. In three studies, patients with a history of at least
one preterm delivery (high-risk patients) were included.
In two studies, only patients without a previous preterm
delivery (low-risk patients) were included; in four studies,
both low-risk and high-risk patients were included. Pa-
tients with symptoms of preterm labor were included in
only one study. Multiple pregnancies were excluded from
all studies.
Patient exclusion criteria in individual studies mostly
comprised the use of antibiotic therapy before study initia-
tion,
6-8,10,16,19,20
severe fetal anomalies,
8,10,16,19-21
significant
maternal conditions,
6-8,10,16,19-21
concomitant infections,
7,8,10
current or planned cervical cerclage,
7,10,19,20
symptoms of
Table I. Patients and methods of studies included
Patients with Mean gestational age
Study results (No.) Patient inclusion criteria at randomization (wk)
Carey et al, 2000
10
1919 Singleton pregnancy between 16-23 wk 19.7
Hauth et al, 1995
6
258 Singleton pregnancy between 22-24 wk and either 22.9
previous preterm delivery or prepregnancy weight <50 kg
Joesoef et al, 1995
16
681 Singleton pregnancy between 14-26 wk 20.3
Kekki et al, 2001
17
* 375 Singleton, low-risk pregnancy between 10-17 wk 13.5
Kurkinen et al, 2000
18
* 101 Singleton, low-risk pregnancy at 12 wk 12.4
McDonald et al, 1997
7
480 Singleton pregnancy between 16-26 wk 24.1
McGregor et al, 1991
19
25 Singleton pregnancies at 34 wk with preterm labor 30.7
McGregor et al, 1994
20
129 Singleton pregnancy between 16-27 wk 21.5
Morales et al, 1994
8
80 Singleton pregnancy between 13-20 wk and spontaneous 16.5
preterm delivery in the preceding pregnancy
Vermeulen and Bruinse, 1999
21
22 Singleton pregnancy <26 wk and preterm delivery in 20.0
the preceding pregnancy
*Study populations are overlapping.
Patients with abnormal Gram stain only.
Patients with BV only.
Volume 188, Number 3 Leitich et al 755
Am J Obstet Gynecol
threatened preterm delivery,
6,8,10,16,20
and incompetent
cervix or uterine anomalies.
8,16,19-21
Mean gestational ages at randomization ranged from
12.4 to 30.7 weeks. In all except one study,
10
mean gesta-
tional ages at randomization had to be estimated from pa-
tient inclusion criteria, either because they were not stated
for the whole study
8,16,17,20
or for the subgroup of patients
with BV.
6,7,19,21
Criteria for a diagnosis of BV were clinical
in 1 study, based on Gram stain findings in five studies and
based on combinations of clinical and Gram stain findings
in four studies. Therapies used in individual studies in-
cluded intravenous clindamycin followed by oral clin-
damycin, vaginal clindamycin, oral metronidazole, or oral
metronidazole and erythromycin combined.
In three studies, patients with symptomatic vaginosis or
vaginitis,
7,10
a positive culture of Chlamydia trachomatis,
10
Trichomonas vaginalis,
8,10
Treponema pallidum,
10
or Neisseria
gonorrhoeae
10
or patients with asymptomatic bacteriuria
8
were not admitted to the studies. In six other studies, ac-
tive screening and treatment of study patients for the fol-
lowing microorganisms or infections were reported: C
trachomatis,
16,20
T vaginalis,
6,16
group B streptoccocci,
8,19
T pallidum,
16
N gonorrhoeae,
16,20
yeast,
6,19
or urinary tract
infections.
19,20
The results of the quantitative analyses of individual
studies are displayed in Table II. Results for the outcome
of preterm delivery were reported in all studies. The re-
sults for maternal infectious morbidity were available in
only one study,
17
and the results for neonatal death or
morbidity were available in none. One study reported
that there was no significant difference in maternal in-
fections or neonatal outcome between both study
groups, but no numeric data were displayed.
10
In an-
other three studies, results regarding maternal infec-
tions
19
or neonatal outcome
7,19,21
were not reported for
the BV subgroup.
A significant treatment effect was observed in high-risk
patients that were included in two studies only.
6,8
In all
other studies, antibiotic treatment did not lead to a lower
rate of preterm delivery or maternal infections.
In eight studies, the rates of BV after antibiotic or
placebo treatment were presented. For one study,
21
the
elimination rates were published separately in a sec-
ondary analysis of the study.
26
With intravenous or oral
treatment regimens, antibiotic treatment eliminated
78%,
10
70%,
6
75%,
7
or 89%
8
of BV cases, and placebo
treatment was associated with spontaneous resolution of
BV in 38%,
10
18%,
6
or 14%
8
of cases, respectively. With
vaginal treatment regimens, the elimination rates in the
antibiotics groups were 86%,
16
66%,
17
96%,
20
or 67%,
26
and the corresponding rates of spontaneous resolution in
the placebo groups were 56%,
16
34%,
17
45%,
20
and
43%.
26
In Table III, the results for all studies are combined.
One study that used the outcome of delivery at <35 weeks
of gestation was pooled with other studies as the com-
bined outcome of delivery at <34 weeks of gestation.
10
In patients without preterm labor, no significant reduc-
tion of the rate of preterm deliveries was observed if all
studies were pooled together. Large, yet insignificant,
beneficial treatment effects were observed for high-risk
patients and with oral antibiotic treatment. However, the
Diagnosis of BV Administration of antibiotics
Abnormal Gram stain (Nugent score 7)
32
and 2 Doses of oral metronidazole (2 g) or placebo 48 hours apart,
vaginal pH >4.5 treatment or placebo repeated at follow-up visit at 24-29 wk in all
patients
Clinical BV (Amsel criteria 3)
1
and/or abnormal Oral metronidazole (250 mg), 3 times daily for 7 days and 333 mg
Gram stain (Spiegel definition)
33
of oral erythromycin, 3 times daily for 14 days or placebo;
treatment or placebo repeated after 2-4 wk in persistent BV
Abnormal Gram stain (Nugent score 7)
32
and Vaginal clindamycin (5 g) or placebo, once daily for 7 days
vaginal pH > 4.5
Abnormal Gram stain (Spiegel definition)
33
Vaginal clindamycin (5 g) or placebo, once daily for 7 days
Abnormal Gram stain (Spiegel definition)
33
Vaginal clindamycin (5 g) or placebo, once daily for 7 days
Abnormal Gram stain (Spiegel definition)
33
Oral metronidazole (400 mg) or placebo twice daily for 2 days,
treatment or placebo repeated after 4 wk in persistent BV
Abnormal Gram stain (Nugent score 7)
32
Intravenous clindamycin (900 mg) or placebo every 8 hours for
3 days, followed by oral clindamycin (300 mg) or placebo 4 times
daily for 4 days
Clinical BV and abnormal Gram stain (Nugent score 7)
32
Vaginal clindamycin (5 g) or placebo once daily for 7 days
Clinical BV Oral metronidazole (250 mg) or placebo, 3 times daily for 7 days
Abnormal Gram stain (Nugent score 7)
32
Vaginal clindamycin (5 g) or placebo once daily for 7 days at
26 and 32 wk
756 Leitich et al March 2003
Am J Obstet Gynecol
degrees of heterogeneity within those two subgroups of
studies were also high. Thus, a random effects model was
used in these cases that resulted in wide 95% CIs of the ef-
fects odds ratios.
Within the group of studies that used oral antibiotic
treatment, heterogeneity was strongly reduced, if studies
were grouped according to treatment duration. A large
and significant effect was seen with longer treatment,
and a nonsignificant effect was seen with shorter treat-
ment.
Heterogeneity was not reduced if studies were grouped
according to gestational age of treatment initialization.
Both with earlier and later treatment, heterogeneity re-
mained significant, and the treatment effects were non-
significant. Heterogeneity was much smaller among
studies that included low-risk patients or studies that used
vaginal antibiotic regimens, and the results in these sub-
groups consistently showed no treatment effect. Hetero-
geneity was also small if preterm delivery was defined
more restrictively as delivery at <34 or <32 weeks of gesta-
tion. With either of these outcomes, no significant reduc-
tion of preterm births could be observed.
Comment
The results of this meta-analysis show that strategies of
screening and treating pregnant women for BV remain
controversial. Such a strategy was suggested generally for
high-risk patients with a previous preterm delivery. How-
ever, there is now a large degree of heterogeneity among
the studies that include high-risk patients and thus a large
degree of uncertainty about the true effect that the an-
tibiotic treatment of BV would have in this patient popu-
lation.
The situation is much clearer for low-risk patients with-
out a previous preterm delivery. The consistent result in
the respective subgroup analysis shows that antibiotic
treatment of BV does not decrease the rate of preterm de-
liveries in this population.
The subgroups of studies as defined in our meta-analy-
sis are not mutually independent, butto a smaller or
larger degreeoverlap each other. High-risk patients, for
example, were treated almost exclusively with oral regi-
mens. The subgroup of studies that used oral regimens of
longer duration (the only subgroup with both a signifi-
cant treatment effect and absent heterogeneity) con-
tained only high-risk patients. Nothing, practically, can be
said about the effect of vaginal clindamycin therapy in
high-risk patients because the only study that used this
strategy included 22 high-risk patients with BV.
21
Low-risk patients, on the other hand, have been
treated both with oral and vaginal regimens, and no ap-
parent effect was seen in either route of administration.
In the respective subgroup, no statistical heterogeneity
was observed that allows us to draw this conclusion with
a larger degree of certainty. Because vaginal clindamycin
therapy was used almost exclusively in low-risk patients,
the consistent results in the subgroup of studies that
used vaginal regimens are, in fact, the consistent results
of studies that used vaginal clindamycin in low-risk pa-
tients. For this patient population, it can be concluded
reliably that vaginal clindamycin does not have a treat-
ment effect.
Table II. Results of individual studies
Outcome Antibiotics Control Odds ratio
Study Patients (wk) group group (95% CI)
Carey et al, 2000
10
All Delivery <37 116/953 121/966 0.97 (0.74-1.27)
All Delivery <35 48/953 49/966 0.99 (0.66-1.49)
All Delivery <32 22/953 26/966 0.85 (0.48-1.52)
Low risk Delivery <37 86/852 95/857 0.90 (0.66-1.23)
High risk Delivery <37 30/101 26/109 1.35 (0.73-2.49)
Hauth et al, 1995
6
High risk Delivery <37 54/172 42/86 0.48 (0.28-0.82)
Joesoef et al, 1995
16
All Delivery <37 51/340 46/341 1.13 (0.74-1.74)
All Delivery <32 16/340 9/341 1.82 (0.79-4.18)
Kekki et al, 2001
17
* Low risk Delivery <37 9/187 7/188 1.31 (0.48-3.59)
Low risk Peripartum infections 21/187 33/188 0.59 (0.33-1.07)
Kurkinen et al, 2000
18
* Low risk Delivery <34 1/51 0/50 NC
Low risk Delivery <32 1/51 0/50 NC
McDonald et al, 1997
7
All Delivery <37 11/242 15/238 0.71 (0.32-1.57)
Low risk Delivery <37 10/225 9/221 1.10 (0.44-2.75)
High risk Delivery <37 1/17 6/17 0.11 (0.01-1.09)
McGregor et al, 1991
19
Preterm labor Delivery <37 11/15 9/10 0.31 (0.03-3.24)
McGregor et al, 1994
20
All Delivery <37 9/60 5/69 2.26 (0.71-7.16)
Morales et al, 1994
8
High risk Delivery <37 8/44 16/36 0.28 (0.10-0.76)
High risk Delivery <34 2/44 4/36 0.38 (0.07-2.21)
Vermeulen and Bruinse, 1999
21
High risk Delivery <34 1/11 1/11 1.00 (0.05-18.30)
NC, Not calculable.
*Study populations are overlapping.
Volume 188, Number 3 Leitich et al 757
Am J Obstet Gynecol
BV early in pregnancy has been identified to be a
strong risk factor for preterm delivery.
27,28
However,
within the subgroups of studies with earlier or later treat-
ment (defined as treatment before or after week 20 of
gestation), statistical heterogeneity was not diminished,
and no significant treatment effect was observed in either
subgroup. Thus, the results of these subgroup analyses
were not helpful to make a more reliable statement about
when treatment should be commenced.
Rates of BV elimination after treatment are used often
to measure the effectiveness of antibiotic regimens in pa-
tients with BV. We did not see obvious differences in the
rates of BV elimination between different antibiotic regi-
mens and especially not between oral and vaginal regi-
mens. Rates of BV elimination that were determined by
clinical or Gram-based assessment of vaginal discharge
may only reflect changes in vaginal bacterial colonization
but do not predict necessarily the elimination of bacteria
that have already ascended to the uterine cavity. Systemic
treatment of longer duration may be necessary to treat in-
trauterine infection, which has been described as a
chronic infection starting early in pregnancy.
3
It may be
for this reason that oral regimens of longer duration ap-
peared to be effective in our meta-analysis, but regimens
of shorter duration were not.
Regarding choice of antibiotic agents, oral treatment
aimed at the BV set of microbes, including genital my-
coplasmas and anaerobes, with oral clindamycin or a
combination of oral enteric-coated erythromycin and
metronidazole has been recommended specifically to
treat BV in pregnancy.
5
Unfortunately, the data pre-
sented in this review do not allow us to make recommen-
dations for specific (combinations of) antibiotic agents.
Because multiple pregnancies were excluded from all
the studies that were included in this review, there are no
data to support strategies of screening and treating BV in
this population. Also, BV was not found to be associated
significantly with preterm delivery in two studies,
29,30
in-
cluding patients with twin gestations.
Strategies to screen and treat BV in patients who were
admitted for preterm labor are studied only poorly. Only
one study with 25 patients with preterm labor and BV was
included in our meta-analysis; although the results for
those patients were promising, the effect, because of
small sample size, did not reach statistical significance.
19
The paucity of evidence for this strategy is surprising be-
cause it is used often as part of the infection workup of
patients who were admitted for preterm labor. Surely,
more clinical evidence is needed to confirm the effective-
ness of this approach.
More controlled studies are also needed to make more
reliable conclusions about the effectiveness of antibiotic
treatment of BV in high-risk patients. A specific goal
would be to determine whether the rate of preterm deliv-
eries (with the use of a more restrictive definition, such as
delivery at <34 or <32 weeks of gestation) would be dimin-
ished in this population. With current knowledge, such a
study should treat high-risk patients early in pregnancy
with an oral regimen of longer duration. Also, the promis-
ing results of a subgroup analysis
31
of the largest study in-
cluded in this review,
10
which showed a nonsignificant
reduction in preterm birth in women with both BV
and/or T vaginalis and a positive fetal fibronectin test,
must be confirmed. No more resources, on the other
hand, should be allocated to study or implement screen-
and-treat strategies in a general low-risk population.
In the meantime, before more evidence is available,
screen-and-treat strategies for high-risk patients (as used
in those studies) that show clear treatment effects can be
justified, even on the basis of current knowledge.
Table III. Results of all studies combined in patients without and with preterm labor
Studies Patients Test of Test of
included included heterogeneity Model Odds ratio treatment
Patients (No.) (No.) (P value) used* (95% CI) effect (P value)
Patients without preterm labor
Delivery at <37 wk
All patients 7 3922 <.02 Random 0.83 (0.57-1.21) .33
Low-risk patients 3 2530 .74 Fixed 0.94 (0.71-1.25) .69
High-risk patients 4 582 <.01 Random 0.50 (0.22-1.12) .09
Oral treatment 4 2737 <.02 Random 0.61 (0.36-1.03) .06
Oral treatment at 2 days 2 2399 .47 Fixed 0.94 (0.72-1.21) .62
Oral treatment 7 d 2 338 .38 Fixed 0.42 (0.27-0.67) <.0003
Vaginal treatment 3 1185 .54 Fixed 1.25 (0.86-1.81) .25
Treatment starting at <20 wk 3 2374 <.05 Random 0.75 (0.36-1.58) .46
Treatment starting at >20 wk 4 1548 <.03 Random 0.88 (0.49-1.57) .66
Delivery at <34 wk: all patients 4 2122 .54 Fixed 0.96 (0.65-1.42) .85
Delivery at <32 wk: all patients 3 2701 .22 Fixed 1.13 (0.71-1.79) .61
Maternal infection: all patients 1 375 0.59 (0.33-1.07)
Patients with preterm labor
Delivery at <37 wk: all patients 1 25 0.31 (0.03-3.24)
*Random denotes random effects model; fixed denotes fixed effects model.
758 Leitich et al March 2003
Am J Obstet Gynecol
REFERENCES
1. Amsel R, Totten PA, Spiegel CA, Chen KSC, Eschenbach D,
Holmes KK. Nonspecific vaginitis: diagnostic criteria and microbi-
ologic and epidemiologic associations. Am J Med 1983;74:14-22.
2. Eschenbach DA. History and review of bacterial vaginosis. Am J
Obstet Gynecol 1993;169:441-5.
3. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection
and preterm delivery. N Engl J Med 2000;342:1500-7.
4. Flynn CA, Helwig AL, Meurer LN. Bacterial vaginosis in preg-
nancy and the risk of prematurity: a meta-analysis. J Fam Pract
1999;48:885-92.
5. McGregor JA. Bacterial vaginosis in pregnancy. Obstet Gynecol
Surv 2000;55(Suppl):S1-19.
6. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB, Copper
RL. Reduced incidence of preterm delivery with metronidazole
and erythromycin in women with bacterial vaginosis. N Engl J
Med 1995;333:1732-6.
7. McDonald HM, OLoughlin JA, Vigneswaran R, Jolley PT, Har-
vey JA, Bof A, et al. Impact of metronidazole therapy on preterm
birth in women with bacterial vaginosis flora (Gardnerella vagi-
nalis): a randomised, placebo controlled trial. Br J Obstet Gy-
naecol 1997;104:1391-7.
8. Morales WJ, Schorr S, Albritton J. Effect of metronidazole in pa-
tients with preterm birth in preceding pregnancy and bacterial
vaginosis: a placebo-controlled, double-blind study. Am J Obstet
Gynecol 1994;171:345-9.
9. Brocklehurst P, Hannah M, McDonald H. Interventions for
treating bacterial vaginosis in pregnancy (Cochrane Review).
Cochrane Library, Issue 1, Oxford: Update Software; 2002.
10. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest
JM, et al. Metronidazole to prevent preterm delivery in pregnant
women with asymptomatic bacterial vaginosis. N Engl J Med
2000;342:534-40.
11. Guise JM, Mahon SM, Aickin M, Helfand M, Peipert JF, Westhoff
C. Screening for bacterial vaginosis in pregnancy. Am J Prev Med
2001;20:62-72.
12. The U.S. Preventive Services Task Force. Screening for bacterial
vaginosis in pregnancy: recommendations and rationale. Am J
Prev Med 2001;20:59-61.
13. American College of Obstetricians and Gynecologists. Assessment of
risk factors for preterm birth. Washington (DC): American College
of Obstetricians and Gynecologists; 2001. Practice bulletin No.: 31.
14. Demets DL. Methods for combining randomized clinical trials:
strengths and limitations. Stat Med 1987;6:341-8.
15. Whitehead A, Whitehead J. A general parametric approach to
the meta-analysis of randomized clinical trials. Stat Med
1991;10:1665-77.
16. Joesoef MR, Hiller SL, Wiknjosastro G, Sumampouw H, Linnan
M, Norojono W, et al. Intravaginal clindamycin treatment for
bacterial vaginosis: effects on preterm delivery and low birth
weight. Am J Obstet Gynecol 1995;173:1527-31.
17. Kekki M, Kurki T, Pelkonen J, Kurkinen-Rty M, Cacciatore B,
Paavonen J. Vaginal clindamycin in preventing preterm birth
and peripartal infections in asymptomatic women with bacterial
vaginosis: a randomized, controlled trial. Obstet Gynecol
2001;97:643-8.
18. Kurkinen-Rty M, Vuopala S, Koskela M, Kekki M, Kurki T,
Paavonen J, et al. A randomized controlled trial of vaginal clin-
damycin for early pregnancy bacterial vaginosis. Br J Obstet Gy-
naecol 2000;107:1427-32.
19. McGregor JA, French JI, Seo K. Adjunctive clindamycin therapy
for preterm labor: results of a double-blind, placebo-controlled
trial. Am J Obstet Gynecol 1991;165:867-75.
20. McGregor JA, French JI, Jones W, Milligan K, McKinney PJ, Pat-
terson E, et al. Bacterial vaginosis is associated with prematurity
and vaginal fluid mucinase and sialidase: results of a controlled
trial of topical clindamycin cream. Am J Obstet Gynecol 1994;
170:1048-60.
21. Vermeulen GM, Bruinse HW. Prophylactic administration of
clindamycin 2% vaginal cream to reduce the incidence of spon-
taneous preterm birth in women with an increased recurrence
risk: a randomized placebo-controlled double-blind trial. Br J
Obstet Gynaecol 1999;106:652-7.
22. Duff P, Lee ML, Hillier SL, Herd LM, Krohn MA, Eschenbach
DA. Amoxicillin treatment of bacterial vaginosis during preg-
nancy. Obstet Gynecol 1991;77:431-5.
23. McGregor JA, French JI, Richter R, Vuchetich M, Bachus V, Seo
K, et al. Cervicovaginal microflora and pregnancy outcome: re-
sults of a double-blind, placebo-controlled trial of erythromycin
treatment. Am J Obstet Gynecol 1990;163:1580-91.
24. Newton ER, Dinsmoor MJ, Gibbs RS. A randomized, blinded,
placebo-controlled trial of antibiotics in idiopathic preterm
labor. Obstet Gynecol 1989;74:562-6.
25. Newton ER, Shields L, Ridgway LE III, Berkus MD, Elliott BD.
Combination antibiotics and indomethacin in idiopathic pre-
term labor: a randomized double-blind clinical trial. Am J Obstet
Gynecol 1991;165:1753-9.
26. Vermeulen GM, van Zwet AA, Bruinse HW. Changes in the vagi-
nal flora after two percent clindamycin vaginal cream in women
at high risk of spontaneous preterm birth. Br J Obstet Gynaecol
2001;108:697-700.
27. Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ, Ison C,
Pearson J. Abnormal bacterial colonisation of the genital tract
and subsequent preterm delivery and late miscarriage. BMJ
1994;308:295-8.
28. Kurki T, Sivonen A, Renkonen O-V, Savia E, Ylikorkala O. Bacte-
rial vaginosis in early pregnancy and pregnancy outcome. Obstet
Gynecol 1992;80:173-7.
29. Goldenberg RL, Iams JD, Miodovnik M, Van Dorsten JP, Thur-
nau G, Bottoms S, et al. The preterm prediction study: risk fac-
tors in twin gestations. Am J Obstet Gynecol 1996;175:1047-53.
30. Wennerholm U-B, Holm B, Mattsby-Baltzer I, Nielsen T, Platz-
Christensen JJ, Sundell G, et al. Interleukin-1, interleukin-6
and interleukin-8 in cervico/vaginal secretion for screening of
preterm birth in twin gestation. Acta Obstet Gynecol Scand
1998;77:508-14.
31. Goldenberg RL, Klebanoff M, Carey JC, MacPherson C, Na-
tional Institute of Child Health and Human Development Ma-
ternal-Fetal Medicine Units Network. Metronidazole treatment
of women with a positive fetal fibronectin test result. Am J Obstet
Gynecol 2001;185:485-6.
32. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bac-
terial vaginosis is improved by a standardized method of Gram
stain interpretation. J Clin Microbiol 1991;29:297-301.
33. Spiegel CA, Amsel R, Holmes KK. Diagnosis of bacterial vagi-
nosis by direct Gram stain of vaginal fluid. J Clin Microbiol
1983;18:170-7.