CLINICAL OBSTETRICS AND GYNECOLOGYVolume 47, Number 4, 796–807
Ó 2004, Lippincott Williams & Wilkins
Treatment of VaginalInfections to PreventPreterm Birth:A Meta-Analysis
MARGARET A. RIGGS, PhD andMARK A. KLEBANOFF, MD
Division of Epidemiology, Statistics and Prevention Research,National Institute of Child Health and Human Development,National Institutes of Health, Department of Health andHuman Services, Bethesda, Maryland
Approximately 10% of all pregnancies in the
United States end in preterm birth, but this
10% accounts for approximately 70% of the
perinatal deaths and half of the long-term
delivery with and without labor at various
neurologic morbidity.1,2 A majority of mor-
gestational ages, there was an inverse asso-
bidity and mortality is concentrated in those
ciation between positive cultures and gesta-
infants delivered at less than 32 weeks ges-
tional age, suggesting that microbial coloni-
tation and birth weight ,1500 g.2,3 Intra-
zation is more frequent among spontaneous
uterine infection has been found to play a
preterm births at lower gestational ages.8–11
major role in preterm birth and is thought
It is likely that maternal and fetal signals in
to be responsible for preterm birth in up to
response to infection are what initiate pre-
term labor after silent chorioamnionitis.7
of intrauterine infection and resultant amni-
An active inﬂammatory response occurs in
otic infection is thought to be the ascending
brane cultures as shown by high concentra-
Intrauterine infection may occur early in
interleukin-6 in amniotic ﬂuid.12,13 In vivo
studies in women have linked increasedexpression of proinﬂammatory cytokinesin vaginal secretions, amniotic ﬂuid, and
Correspondence: Mark A. Klebanoff, MD, DESPR,
maternal and fetal blood with adverse preg-
NICHD, NIH, 6100 Bldg, Room 7B05, Bethesda, MD20892. E-mail: firstname.lastname@example.org
In the normal vaginal environment, lacto-
bacilli protect against overgrowth of endog-
(TNF), interleukin (IL)-1a and IL-1b, IL-6,
Gardnerella vaginalis by producing hydro-
activating a local inﬂammatory reaction. In
gen peroxide, lactic acid, and bacteriocins.16
response, prostaglandin synthesis and re-
lease is stimulated. Prostaglandins are re-
characterized by reduction or elimination
in the normal lactobacilli and overgrowth
and are known to stimulate uterine contrac-
sponsible for the release of metalloproteases
though a substantial fraction of women with
that are responsible for deterioration of cho-
this condition are asymptomatic. In clinical
rioamniotic membranes, leading to rupture.4
settings, it is usually deﬁned as the presence
of 3 of the following: elevated vaginal pH
the association between other organisms and
and/or amniotic ﬂuid of pregnancies with
ﬂuid on a glass slide; and the presence of
spontaneous preterm labor with intact mem-
‘‘clue cells’’ (vaginal epithelial cells with in-
distinct borders due to attached bacteria) on
microscopic examination of vaginal ﬂuid.17
In research settings, a gram stain of vaginal
micro-organisms most often associated with
clinical chorioamnionitis and fetal infection
et al18 is the preferred diagnostic method.
cocci (GBS) and Escherichia coli, are only
occasionally found in the uterus.7 However,
asymptomatic college students to 60% among
the association between preterm birth and
women attending an STD clinic.19 Bacterial
lower genital tract colonization with these
vaginosis has been consistently associated
organisms is less clear. Up to 30% of preg-
with an increased risk of preterm birth, but
it is not known whether BV actually causes
Group B streptococci is a leading cause of
preterm birth, or is only a marker for intra-
neonatal sepsis, and a substantial fraction
preterm delivery have been examined in ani-
mal, in vitro, and human studies.7 Bacterial
during pregnancy has been associated with
vaginosis is associated with increased con-
preterm delivery.30 In the Vaginal Infections
centrations of elastase, mucinase, and siali-
dase in the vagina and cervix,21,22 and, most
colonized with T. vaginalis had a 30% higher
importantly, may be a marker for microbial
risk of delivering an infant with low birth
colonization of the upper genital tract.7 The
weight or delivering before term and a 40%
higher risk of giving birth to an infant who
was both preterm and of low birth weight.
sulting in phospholipase and prostaglandin
Eleven percent of preterm deliveries among
ered potentially attributable to trichomonia-
the decidua and fetal membranes to produce
sis.30 Trichomoniasis during pregnancy is
or yeast) and (antibiotic or treatment) and
(preterm or premature) and (randomized or
randomised) and (clinical trial). Bibliogra-
phies of all relevant articles were reviewed
for further potential references. Studies with
fected.32 It has been associated with adverse
titles or abstracts discussing antibiotic treat-
pregnancy outcomes in several reports.32,33
ment of vaginal infections and prematurity
were retrieved. Any study with primary data
investigating a relevant exposure and out-
genitourinary tract of women and are con-
come was submitted for further review. The
sidered a potential cause of intrauterine in-
following criteria were used to select studies
fection.34 Patients with amniotic ﬂuid cul-
for inclusion: article (original published),
tures positive for only U. urealyticum had a
study design (randomized placebo-controlled
signiﬁcantly higher rate of adverse perinatal
clinical trial), population (women at less than
37 weeks gestation, not in labor with intact
amniotic membranes), intervention (antibiotic
treatment) and relevant outcome, gestational
weight, neonatal morbidity, and perinatal
age at birth, as well as any of the following
death. However, although isolation of M.
hominis from the lower genital tract is asso-
births when the mother had a prior preterm.
birth,36 isolation of U. urealyticum from the
lower tract does not appear to increase the
studies in languages other than English were
In response to the association between in-
stract or upon translation that indicated they
fectious micro-organisms and adverse preg-
were not clinical trials. When one report dif-
nancy outcome, many investigators have tried
to show that treatment of these infections can
patients into the same study, we included
prevent preterm birth. Several different or-
the ﬁnal report. We evaluated total preterm
ganisms have been targeted, using a variety
births as the outcome, unless only data on
of regimens with different antibiotics and
spontaneous preterm birth were presented,
routes of administration. Some studies have
in which case we evaluated spontaneous pre-
term birth. Some studies treated women re-
others enrolled women who have had a pre-
gardless of the presence of infection (eg,
mass community treatment trials; treatment
of women who had a prior preterm birth re-
to evaluate the role of antibiotic treatment of
gardless of the current presence of speciﬁc
a variety of vaginal infections in pregnancy
infections). If those studies presented results
speciﬁcally for a particular infection, we in-cluded those results; otherwise the studywas excluded. Two studies enrolled women
with either BV or intermediate ﬂora. One(McDonald et al40) presented most results
those speciﬁc results in this review. The
other (Ugwumadu et al41) presented nearly
using keywords (vaginitis or vaginosis or va-
all results only for the entire group, and there-
gina* infection) and (group B strep* or GBS
fore, we used the results for all randomized
Quality of the trials was assessed on a 6-
point scale using a modiﬁed Jadad Scale.42
evaluated ORs and conﬁdence intervals for
Studies were given 1 point each for descrip-
subgroups deﬁned by antibiotic used, route
tion of randomization, description of double
of administration, and obstetrical history.
dropouts, analyzed as intent to treat, and an
was assessed to determine the appropriate-
additional point each was given for both ap-
ness of combining trial results.43 To calcu-
late overall results for each outcome and all
blinding or a point was deducted for each if
subgroups, we generally used the ﬁxed ef-
they were inappropriately done. Studies with
fects model. If signiﬁcant heterogeneity was
a score less than 3 were considered of poor
used a random effects model instead. Trialswith zero cells in both the study and control
groups were not included in the calculation
The studies identiﬁed by the criteria de-
scribed above were reviewed independentlyby both authors. Disagreements were settledby discussion and consensus. The following
inclusion criteria were applied: 1) appropri-
A total of 155 articles were retrieved.
ate exposure and outcome measures, as de-
ﬁned above; 2) randomized clinical trial; and
3) relative risk (RR) or odds ratio (OR) with
phy review. Sixty-seven publications were
95% conﬁdence interval (CI) provided or
submitted for review. The remaining articles
able to be calculated from the data presented
were discarded because of redundancy with
in the article. The following data were ab-
other articles, data reporting, lack of original
stracted onto standardized forms: publication
data, Jadad score of 0, or lack of infection-
year, gestational age when treatment began,
speciﬁc results. The remaining 16 studies
antibiotic therapy, micro-organisms identi-
are summarized in Table 1.44–54 Only one
ﬁed, birth weight, gestational age at birth,
study was included in the analysis with a
Jadad score of ,3 (Odendaal et al51). All
births when the mother had a prior preterm,
studies that were included followed a ran-
whether it was analyzed as intent to treat, ex-
tent of blinding, extent of controlling for po-
studies were stratiﬁed ﬁrst by type of bacte-
tential confounding, and relevant risk ratio
rial infection and then by type of antibiotic
therapy used for treatment of BV and by his-tory of a previous preterm birth.
STATISTICAL ANALYSISFor the outcomes in each individual study,
we determined treatment effectiveness by cal-
There has only been 1 randomized, placebo-
controlled double-blind study of treatment of
95% CIs. This produced a weighted average
GBS colonization to prevent preterm birth
(Klebanoff et al28). In that study, pregnant
version 4.2.5. There were few clinical trials
placebo continuously for up to 10 weeks in
the third trimester. No statistically signiﬁcant
ing subanalysis. However, there were many
beneﬁt was seen for birth weight ,2500 g
studies of treatment of bacterial vaginosis,
,37 weeks (OR 0.91, 95% CI 0.61–1.36), or
others. Therefore, in addition to an overall
preterm PROM (OR 1.0, 95% CI 0.46–2.11).
TABLE 1. Summary of Study Characteristics
birth, or low birth weight infant in the prior
Only 1 clinical trial of treatment of Chla-
pregnancy, no reduction in low birth weight
birth was noted by treatment in the current
done (Martin et al32). The design and treat-
pregnancy (1.19, 95% CI 0.50–2.85).
ment was identical to the GBS trial notedabove. There was no statistically signiﬁcantreduction in low birthweight (OR 0.74, 95%
TRICHOMONAS VAGINALISThere have been 2 randomized controlled
CI 0.38–1.45), preterm birth (OR 0.89, 95%
trials of treatment of trichomoniasis to pre-
CI 0.49–1.62), or preterm PROM (OR 0.70,
vent adverse pregnancy outcome. One trial
(Klebanoff et al54) screened asymptomaticwomen for trichomoniasis and treated them
with 2 doses of 2 g each of metronidazole or
placebo at 16 to 23 weeks and again at 24 to
Ureaplasma urealyticum using the same de-
29 weeks. The other (Kigozi et al53) was a
sign as the studies above.52 No statistically
treatment trial in which villages in Uganda
birth weight (1.36, 95% CI 0.85–2.17) or
in preterm birth (1.02, 95% CI 0.67–1.54).
treatment with metronidazole, azithromycin,
Among women who had a miscarriage, still-
Both studies found an elevated risk of low
Eleven studies evaluated the association be-
birth weight among the treated women; the
tween treatment of BV and gestational age
elevation was statistically signiﬁcant in one.
to 2.26 (Fig. 1). Eight of these 11 found
the 2 trials was 1.68 (95% CI 1.11–2.53),
no signiﬁcant association, and again the
and there was no signiﬁcant heterogeneity
between the studies (P ¼ 0.20). Results were
was not statistically signiﬁcant. However,
there was signiﬁcant heterogeneity between
found an elevated risk in the treated women,
studies (P ¼ 0.007). Five studies evaluated
which was signiﬁcant in one. The combined
OR for preterm birth in the 2 trials was 1.71
(95% CI 1.19–2.46); there was no signiﬁ-
(95% CI 0.33–1.81), but there was signiﬁ-
was not reduced in the one study reporting
this outcome (OR 1.1, 95% CI 0.5–2.3).
Six studies evaluated the association be-
Most studies of antibiotic treatment of lower
tween treatment of BV with any antibiotic
genital tract infection to prevent preterm
prior preterm birth, with ORs ranging from
bacterial vaginosis; there have been 12 such
0.11 to 2.44 (Fig. 2). Three of these studies
studies, one of which was a subset of a sec-
found a signiﬁcant beneﬁt of treatment, 1
ond,55 for a total of 11 included in this re-
found signiﬁcant harm, and 2 found no sig-
view. Six studies evaluated the association
niﬁcant difference with treatment. The com-
but the results were extremely variable (het-
3.45. Five of these 6 studies found no signif-
icant association, and the combined OR of
for the 4 of these studies that used metroni-
0.92 (95% CI 0.60–1.40) was not statistically
dazole alone was 0.75 (95% CI 0.25–2.24),
signiﬁcant. However, there was a suggestion
but these studies were heterogeneous in their
of heterogeneity between studies (P ¼ 0.07).
results (P ¼ 0.002). The ﬁfth study (Hauth
FIGURE 1. Treatment of bacterial vaginosis to prevent preterm birth.
FIGURE 2. Treatment of bacterial vaginosis to prevent preterm birth inwomen with a previous preterm birth.
et al47) used metronidazole and erythromy-
birth, but several studies have evaluated oral
between treatment of BV with vaginal clin-
and there was no signiﬁcant heterogeneity
0.89, which was not statistically signiﬁcant
between studies (P ¼ 0.11). Four studies
evaluated the association between treatment
some possible evidence of statistical hetero-
of BV with vaginal clindamycin and gesta-
geneity between these studies (P ¼ 0.06).
Four studies evaluated the association be-
from 0.75 to 2.26. None of the studies found
tween metronidazole treatment and preterm
a signiﬁcant association. The combined OR
birth; one study found a signiﬁcant improve-
was 1.18 (95% CI 0.83–1.69), and there was
no signiﬁcant heterogeneity between studies
(P ¼ 0.59). Results for preterm PROM were
not statistically signiﬁcant (OR 0.92, 95%
reported by 2 studies, with ORs of 1.14 and
CI 0.52–1.62). Nevertheless, there was sig-
niﬁcant heterogeneity between studies (P ¼
0.66–5.38), and there was no signiﬁcant het-
0.009). Three studies evaluated the associa-
tion between treatment with metronidazole
FIGURE 3. Metronidazole treatment of bacterial vaginosis to prevent pre-term birth.
those who have a history of a previous pre-
0.10 to 1.13. One study found a signiﬁcant
term delivery). Current evidence does not
support routine testing for BV.’’56 Similarly,
signiﬁcant, although the conﬁdence limits
the U.S. Preventive Services Task Force57
notes that current evidence does not support
and there was signiﬁcant heterogeneity be-
screening for and treating BV in a general
obstetrical population, and the heterogeneity
between studies precludes making a deﬁni-
tive recommendation on screening and treat-
ing women with a prior preterm birth.
signiﬁcant improvement in low birth weight
with treatment of BV (OR 0.81; 95% CI 0.43–
most study results, not just in the studies that
1.51); there was an improvement in sponta-
treated women with a prior preterm birth.
neous preterm birth (OR 0.26; 95% CI 0.12–
Although several studies reported a beneﬁt
0.58), although total preterm birth was not
of treating BV, other studies reported an
overall adverse effect, and several more re-
0.31–1.04). Two studies used a combination
ported signiﬁcant increases in preterm birth
in various subgroups of women. Therefore,
et al47 and Andrews et al44) administered at
it is possible that differences in the popula-
an average gestation of 23 weeks. There was
tions enrolled in the various studies and/or
an overall signiﬁcant reduction in preterm
count for the highly variable results. Until
no heterogeneity between studies (P ¼ 0.29).
there is more understanding of the sourceof these different results, caution is advisedin treating BV to prevent preterm birth.
In spite of a consistent association between
duced interesting results, with one study
a variety of lower genital tract infections and
(Ugwumadu et al41) reporting a beneﬁt of
adverse pregnancy outcome, results of this
treatment of prevention of preterm delivery.
meta-analysis show that screening for and
However, this is the only trial to date exam-
treating vaginal infections in a general pop-
ining treatment with this antibiotic. Data on
the occurrence of PROM were not reported,
does not appear to reduce the rate of preterm
and randomization did not balance the base-
delivery or low birth weight. This is in con-
line history of previous miscarriage between
treatment groups. In addition, the lack of an
no reduction in preterm birth by screening
effect of treatment on birth weight, which is
for bacterial vaginosis. The only exception
gestational age, seems inconsistent with the
may be for those with a prior history of pre-
dramatic reduction in preterm birth that was
term birth, but the heterogeneity between
observed. These inconsistencies need to be re-
studies precludes a deﬁnitive conclusion.
solved before recommendations can be made.
vention has recognized this in their 2002
surprising ﬁnding that preterm birth and
by treatment. There is no obvious explana-
‘‘Evaluation for bacterial vaginosis (BV)
tion for this surprising ﬁnding, although it
ﬁrst prenatal visit for asymptomatic patients
T. vaginalis are infected with M. hominis,
who are at high risk for preterm labor (eg,
which might be released when the parasite
is killed.58 Trichomonads are often noted in
though no speciﬁc infections were reported,
Pap smears obtained during pregnancy from
neither study found a statistically signiﬁcant
asymptomatic women, and these trial results
beneﬁt of treatment on preterm birth. (OR
raise the difﬁcult question of whether to treat
the infection in this circumstance. Perhaps
57% preterm in treated and placebo groups,
a reasonable course would be for the physi-
P ¼ 0.515.61 The Andrews et al study found
cian to explain the evidence to the woman
a substantial reduction in mean gestational
and offer the option of treating, or of delay-
age and birth weight among treated women;
ing treatment until after pregnancy unless
the birth weight difference was statistically
symptoms develop before then. If the latter
signiﬁcant. The latter study in particular
course is taken, it seems reasonable to ad-
should give pause to a general recommenda-
tion in favor of early pregnancy treatment
not prevent preterm birth, there are other
reasons to screen and treat this organism.
have shown an association between a variety
First, there is the public health beneﬁt of de-
of vaginal infections and preterm birth, there
tection and treatment of this STD. Second,
is little evidence that treatment of these
infections lowers the risk. The statistical het-
prevents maternal postpartum morbidity, as
erogeneity of the bacterial vaginosis studies,
well as transmission to the infant at delivery,
with the attendant morbidity. The Centers
groups of women who beneﬁt, and possibly
for Disease Control (CDC) currently recom-
mend screening at the ﬁrst prenatal visit,
during pregnancy. Therefore, future research
during the third trimester.56 The recommen-
also have upper tract infection and might
screening and treatment allows for reinfec-
therefore beneﬁt from treatment; on inﬂam-
tion later and also acknowledges that evi-
matory response modiﬁers such as cytokine
dence is lacking that treatment early in preg-
nancy can prevent preterm birth. Similarly,
anti-inﬂammatory therapy in addition to
the CDC’s recommendations for screening
antibiotics in the presence of infection.63
and treatment of group B streptococci areintended to prevent neonatal sepsis, not toprevent preterm birth.59
birth weight to infant mortality and child-
but were not included in this review because
they did not report results for women with
any speciﬁc infection. One study treated women
who had either U. urealyticum or M. hominis
tremely immature infants—a perinatal di-
with either erythromycin or clindamycin.60
Unfortunately, the results of erythromycin
treatment were not presented separately for
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Thomas Carr College Medication Policy Date of approval: Date of review: To be reviewed by: College Nurse, Director of Student Services To be ratified by: Medication Policy Policy Statement Thomas Carr College is committed to the provision of medication needs to promote the wellbeing of all students. No student is to be in possession of any med
Von Deflagrationen und Detonationen1 Viktor Obendrauf 1. Von Stickstofftriiodid, Nitroglycerin, Schießbaumwolle und Lachgas-Wuffis Seit dem Erscheinen des ersten Teils dieses Beitrags , in dem das unterrichtswissenschaftliche Modewort „Edutainment“ aus der Sicht eines Chemielehrers mit der traditionsreichen Geschichte der „Abendvorlesungen“ und Christmas-Lectures in Verbindu