Hindawi Publishing Corporation

Infectious Diseases in Obstetrics and Gynecology

Volume 2012, Article ID 157159, 12 pages
doi:10.1155/2012/157159
Review Article
Antimicrobials for PretermBirth Prevention: An Overview
Akila Subramaniam,
1, 2
Adi Abramovici,
1
WilliamW. Andrews,
1
and Alan T. Tita
1
1
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Alabama at Birmingham,
1700 6th Avenue South, Birmingham, AL 35223, USA
2
Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Women and Infants Center,
1700 6th Avenue South, Birmingham, AL 35223, USA
Correspondence should be addressed to Akila Subramaniam, [Link]@[Link]
Received 2 June 2011; Accepted 21 November 2011
Academic Editor: Joseph Hwang
Copyright 2012 Akila Subramaniam et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Objective. Preterm birth (PTB) remains a major cause of neonatal morbidity and mortality. The association between PTB and
infection is clear. The purpose of this report is to present a focused review of information on the use of antibiotics to prevent PTB.
Methods. We performed a search of the PubMed database restricted to clinical trials or meta-analyses published in English from
1990 through May 2011 using keywords antibiotics or antimicrobials and preterm. Results. The search yielded 67 abstracts for
review. We selected 31 clinical trials (n = 26) or meta-analysis (n = 5) for further full-text review. Discussion of each eligible
clinical trial, its specic inclusion criteria, antibiotic regimen used, and study results are presented. Overall, trials evaluating
antibiotic treatment to prevent preterm birth have yielded mixed results regarding any benet. Conclusion. Routine antibiotic
prophylaxis is not recommended for prevention of preterm birth.
1. Introduction
Preterm birth (PTB) continues to be a leading cause of neo-
natal morbidity and mortality. Dened as birth prior to 37
weeks of gestation, PTB accounts for over 35% of health
care spending for infants and 10% of health care spending
for children in the United States [1]. The incidence of PTB
has been estimated to be 12-13% in the United States
or approximately 467,000 annual live birthssignicantly
higher compared to European and other developed countries
with incidence at 59% [24]. In fact, from 1996 to 2006,
there was a steady increase in PTBs in the US to a peak at
12.8%with the rst decline in 2007 with a PTB rate of
12.7% [5, 6]. Moreover, despite advances in management of
preterm labor and care of preterm infants, PTB still con-
stitutes 75% of neonatal mortality and 50% of long-term
neurologic impairment in children [7]. Spontaneous PTB
(SPTB) accounts for the large majority (6585%) of PTB and
is strongly associated with infection [8]. As a result, consider-
able eort has been dedicated to evaluate antimicrobial ther-
apy as an intervention to prevent PTB. The purpose of this
report is to review the role of infection in the epidemiology
of PTB specically focusing on the use antibiotics to prevent
PTB.
2. Methods
We implemented a descriptive and analytic literature review
of antimicrobial therapy to prevent PTB; our objective was
not to conduct a synthetic meta-analysis (with summary esti-
mates). Rather, it was to identify relevant contemporary
articles on infection and antimicrobial therapy for PTB pre-
vention. We searched the PubMed database restricted to clin-
ical trials or meta-analyses published in English since 1990.
Keywords for this search included antibiotics or antimicro-
bials and preterm yielding 67 abstracts for review by 2
authors. Of these 67 abstracts, only 31 eligible clinical trials
(n = 26) or meta-analysis (n = 5) evaluated the use of anti-
microbials to prevent PTB, and this was retrieved for further
full-text review. For each eligible study we present its specic
inclusion criteria, the antibiotic regimen used, and the study
results.
2 Infectious Diseases in Obstetrics and Gynecology
3. Background
3.1. Epidemiologic Overview, Subtypes, and Mechanisms of
Preterm Birth. Part of the diculty in preventing PTB is its
multifactorial etiology. The relative frequencies of the 3 ma-
jor subcategories of preterm birth are the following: spon-
taneous preterm labor (50%), delivery for maternal or fetal
indications (30%), and preterm premature rupture of mem-
branes or PPROM (20%) [8, 9]. Compared with other eth-
nicities, black women are at disproportionately increased risk
for PTB; risks are generally lower among Hispanic women
[8]. Black women have double the rates of PTB as white
women and women with a previous preterm delivery have a
1550% recurrence risk [8]. Increasing prevalence of assisted
reproductive technology and multiple gestations [10], as well
as maternal and fetal indications including hypertension,
diabetes, and intrauterine growth restriction contribute to
rates of PTB [11].
Late preterm births (dened as birth between 34 and 36
weeks) contribute over 70% of PTB [6]. While these births
carry less risk of neonatal morbidity and mortality than ear-
lier births, they still carry a greater risk of neonatal impair-
ment compared to term births.
Overall, key risk factors for preterm birth include age,
race, nutritional status, a history of a previous PTB, multiple
gestation, smoking, altered vaginal bacterial ora, and
presence of infection [12]. Obesity itself is associated with
hypertension and preeclampsia leading to indicated preterm
birth but has been noted to be protective of spontaneous
preterm birth [12].
How these risk factors contribute to the pathogenesis
of spontaneous preterm labor and preterm premature rup-
ture of membranes (PPROM) is largely unknown. Proposed
mechanisms of term labor include progesterone withdrawal,
oxytocin initiation, decidual activation, and activation of the
fetal immune response [8]. The rst two pathways have not
been clearly elicited in humans, but inammation-mediated
decidual activation seems plausible. In this theory, infection,
inammation, or hemorrhage stimulates the innate immune
system; chemokines and cytokines induce prostaglandins
and other matrix degrading enzymes causing uterine con-
tractility and degradation of extracellular matrix leading to
labor and rupture of membranes [12, 13]. Activation of the
fetal immune response could have a similar impact [12].
While this could similarly be implicated in preterm labor and
PROM, other mechanisms include infection, inammation,
uteroplacental ischemia of hemorrhage, uterine overdisten-
sion, or psychosocial stress [12].
3.2. Infection and Preterm Birth. Intrauterine infection is es-
timated based on studies of amniotic uid and cultures to be
associated with approximately 2540% of PTBthe associa-
tion stronger, the earlier the gestation at birth [12]. The dif-
ferent types of infection involving the maternal fetal interface
include deciduitis, chorioamnionitis, villitis, and funisitis
[12]. Although infection is noted to be extremely common in
preterm delivery, it is often chronic, subclinical, and asymp-
tomatic (apart from labor). In one study of 602 women
delivered by cesarean section prior to membrane rupture,
121 (20.1%) had positive membrane culture; 50% of these
women also had positive amniotic uid cultureoften with
the same organism [12]. In another study of the placentas of
446 mother-infant pairs, women with a SPTB were signif-
icantly more likely to have acute inammation of the mem-
branes, chorionic plate, and the umbilical cord than women
with indicated preterm births [13].
The pathogenesis of SPTB in the setting of subclinical
infection is not fully elucidatedthe current understanding
is presented in Figure 1 [12]. Bacterial invasion of maternal
and fetal tissues causes release of endo and exotoxins. These
substances activate both a maternal response stimulating the
release of cytokines such as tumor necrosis factor alpha
(TNF-alpha), interleukin-1alpha, interleukin-1, interleu-
kin-6, interleukin-8, granulocyte colony-stimulating factor
(G-CSF), and other factors [12, 1418]. These active substan-
ces stimulate the production and release of prostaglandins
causing uterine contractilityand neutrophil activity and
thereby synthesis and release of metalloproteinasescausing
rupture of membranes and remodeling of collagen in the cer-
vix [1921]. A fetal response also may occur, in which infec-
tion stimulates the production of corticotropin-releasing
hormone (from the fetal hypothalamus and placenta) caus-
ing an increase in fetal corticotropin and thereby fetal cortisol
also stimulating prostaglandins [22].
Multiple inammatory markers have been noted to be
elevated in amniotic uid, the serum, or vaginal and cervical
secretions. These include amniotic uid interleukin-6 con-
centration interleukin-1, interleukin-8, G-CSF, and TNF-
alpha, ferritin, and fetal bronectin; however, none of these
markers have been found useful in predicting preterm deliv-
ery in routine clinical practice [12, 23].
Given the strong association between SPTB and infec-
tion, prophylactic antibiotics seem a logical preventative
strategy for PTB. This review focuses on the specic infec-
tions associated with PTB and the eectiveness and safety of
antibiotic prophylaxis.
3.3. Organisms and Mechanisms of Infection. In order to eval-
uate the eectiveness of specic antibiotics used to prevent
PTB, it is important to consider the microbes implicated in
associated intrauterine infections. Organisms most com-
monly gain access to the uterus and pregnancy by ascending
from the vagina and cervix [12]. Less frequent pathways in-
clude iatrogenic inoculation during amniocentesis or chori-
onic villus sampling, hematogeneous spread through uterine
and placental blood ow or through descending infection
from the abdominal cavity and fallopian tubes to the chori-
oamnion. Ascending infection extends to the choriodecidual
space and may ultimately invade the membranes, amniotic
uid, and fetus [12]. The exact timing of infection in rela-
tion to pregnancy is not fully elucidated but has been hy-
pothesized to occur early in gestation or even in the precon-
ceptional period [24].
The most commonly isolated organisms include mi-
crobes with low virulence: Ureaplasma urealyticum, Myco-
plasma hominis, Gardnerella vaginalis, peptostreptococcus,
and bacteroides speciesall organisms of vaginal ora [25
28]. Ureaplasma and Mycoplasma species are the most
Infectious Diseases in Obstetrics and Gynecology 3
Decidua
Maternal
response
Increased cytokines
and chemokines
Neutrophil
inltration
Increased
metalloproteases
Cervical
ripening
Increased
prostaglandins
Increased adrenal
cortisol production
Preterm delivery
Chorioamnion weakening
and rupture
Myometrial
contractions
Decreased chorionic
prostaglandin
dehydrogenase
Increased
corticotropin-releasing
hormone
Fetus
Fetal tissue
response
Chorioamnion
and placenta
Choriodecidual bacterial colonization
(endotoxins and exotoxins)
Figure 1: Potential Pathways from choriodecidual bacterial colonization to preterm delivery [12].
common microbes cultured from placental tissue and uids
obtained from patients with histologic and clinical chori-
oamnionitis. In a study of umbilical cord blood in preterm
2332-week births, Goldenberg et al. showed that Urea-
plasma urealyticum and/or Mycoplasma hominis were present
in 23%of culturesespecially in women undergoing sponta-
neous compared to indicated preterm delivery (34.7% versus
3.2%, P < 0.001) [29].
Bacterial vaginosis (BV) is also commonly associated
with PTB. Due to an interruption in normal vaginal ora,
it is characterized by a reduction in lactobacillus and an
overgrowth of other anaerobic bacteria such as gardenerella,
bacteroides, and mobiluncus. Its diagnosis is based on either
Amsels criteria (taking into account vaginal pH, presence of
discharge, amine odor, or presence of clue cells) or Nugents
score (a gram stain scoring system). Bacterial vaginosis is
present in 1542% of pregnant women and confers a 2 to 4-
fold independent increase in the risk of spontaneous preterm
birth and PROM [3033]. In a meta-analysis including 18
studies, Leitich et al. shows that the associated risk is greater
when BV is diagnosed at earlier gestation [33]. The alter-
ations in vaginal ora by bacterial vaginosis may also increase
susceptibility to other ascending genital tract infections.
Sexually transmitted infections including Trichomonas
vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis and
syphilis have also been associated with preterm delivery and
intrauterine infection [3436]. Numerous small studies have
shown adverse outcomes associated with trichomoniasis
including PTB, PROM, and low birth weight [34]. In the
largest study of trichomoniasis during pregnancy, Cotch et al.
studied over 12,000 women and noted a modest 1.3 odds
ratio of preterm delivery (95% CI 1.11.4) [34]. Other geni-
tourinary microbes such as Group B streptococcus and Escher-
ichia coli have also been described in intrauterine infection
and consequent preterm delivery [12].
Nongynecologic infections have also been studied in PTB
including pneumonia, pyelonephritis, periodontitis, and gas-
trointestinal infections [37, 38]. The mechanism of action of
these infections is thought to be an acute inammatory
response, but for periodontal disease it is hypothesized to
be transient bacteremia and hematogenous spread to the
placenta, chorioamnion, and fetus [8]. Viral infections such
as varicella and inuenza have been associated with PTB;
however, the role of viral infection in PTB but has been
inadequately studied [8, 39, 40].
4. Results and Comments
4.1. Antibiotic Therapy to Prevent PTB. Given the abounding
data associating various infections with PTB, it is natural
to consider the use of antibiotic and other antimicrobial
therapy to prevent PTB. Studies have investigated the use of
dierent antimicrobials both as empiric therapy providing
broad coverage to prevent or treat infection and as targeted
therapy against specic infections. In addition, the timing of
4 Infectious Diseases in Obstetrics and Gynecology
antibiotic therapy in relation to pregnancy varies. Charac-
teristics and ndings from individual studies are presented
below and summarized in Tables 1 and 2.
4.1.1. Empiric Antibiotic Therapy. Macrolides (commonly
erythromycin, azithromycin), beta-lactams, clindamycin,
and metronidazole have been used in isolation or in com-
bination as empiric therapy to prevent PTB. Macrolides and
other bacteriostatic agents have been advocated since they
suppress bacterial virulence as opposed to bactericidal agents
such as penicillins, which theoretically may worsen out-
comes for preterm infants by releasing bacterial endotoxins
[60]. Combination antimicrobials provide empiric coverage
against the common microbes including ureaplasmas, gram-
negative rods, and anaerobes.
Beta-Lactams. Three randomized controlled studies have
focused solely on the penicillin family of antimicrobials and
PTB. Newton et al. failed to show any benet in terms of
days gained, neonatal outcome, or gestational age in a
double-blind trial of the combination of ampicillin/sulbac-
tam with indomethacina nonsteroidal anti-inammatory
tocolyticin the setting of magnesium tocolysis [41]. Simi-
larly, Cox et al. randomized 78 women in preterm labor with
intact membranes at 24 to 34 weeks of gestation to either par-
enteral ampicillin (2 grams) + sulbactam(1 grams) for 2 days
followed by oral amoxicillin-clavulanic acid (250 mg) for 5
days (n = 39), or to similar placebo (n = 39). Steroids or
tocolysis were not administered. There was no dierence in
the mean gestational age at delivery (34.2 0.7 versus 34.1
0.9, not signicant); other perinatal outcomes were similar
[42]. Finally, Gordon described similar ndings among 117
women in preterm labor randomized to receive 2 grams of
parenteral ceftizoxime or placebo for 5 days [43]. The pri-
mary outcome of interest, mean interval to delivery, was not
signicantly dierent between the two groups (34.5 21.1
days versus 34.624.5 days, P = 0.99). In these three studies,
regardless of the use of tocolysis or steroid administration, no
signicant benet was associated with the use of penicillins.
Clindamycin. While studies of beta-lactams have not been
promising, a small-randomized trial by McGregor et al.
showed some benet of clindamycin. Women on tocolysis
for preterm labor at gestational age less than 34 weeks
were randomized to receive either placebo versus parenteral
followed by oral clindamycin for 7 days. Patients treated with
clindamycin at gestational ages less than 32 weeks were more
likely to have increased duration of pregnancies (35 versus
25 days, P = 0.02). Moreover, in a subgroup analysis, those
women diagnosed with bacterial vaginosis and then treated
with clindamycin were more likely to have longer pregnancy
latency, increased birth weights, and increased gestational
age at delivery [44]. Lamont et al. described up to a 60%
reduction of PTB with the use of 2% clindamycin cream in
patients with abnormal genetic ora (4% versus 10%; P <
0.03) [45]. However, other studies of vaginal clindamycin
specically for bacterial vaginosisdiscussed belowhave
been contradictory [46]. Some studies have even suggested
increased risk of bacterial resistance and neonatal morbidity
[61, 62]. Given the disparity of ndings, the role of clinda-
mycin in PTB prevention remains inconclusive.
Azithromycin. Few studies have been performed solely on
macrolides. In the large 2200 patient APPLe study conducted
in Southern Malawi, van den Broek et al. conducted a place-
bocontrolled trial of oral azithromycin (1 gram) given at 16
24 and again at 2832-weeks, gestation to unselected women.
Findings showed no signicant dierences in outcomes
between the two groups regarding PTB (16.8% versus 17.4%,
odds ratio 0.96 (0.761.21)) or other perinatal outcomes
including perinatal mortality. Further inclusion of this study
in a meta-analysis with seven other studies also failed to show
any salutary eect on PTB [47].
Combination Antibiotic Regimens. It seems that, regardless
of the antibiotic of choice, gestational age at administration,
route of administration, days of therapy, or repeat dosages of
antibiotics, no single agent has been noted to be ecacious
in the prevention of PTB. Thus, trials involving empiric
combination antibiotic regimens are more prevalent in the
obstetric literature.
Beta-lactams Plus Metronidazole. Norman et al. randomized
81 women in preterm labor to receive parenteral ampicillin
or oral amoxicillin and metronidazole for 5 days (n = 43)
versus no antibiotic treatment (n = 38). All women were
treated with indomethacin and hexoprenaline for tocolysis
and betamethasone for fetal lung maturity. Women receiving
antibiotics had signicantly prolonged pregnancies (median
15 versus 2.5 days, P = 0.04). In addition, patients in the
control group had signicantly increased risks of necrotizing
enterocolitis (5 versus 0, P = 0.02) [48].
Similar benet of ampicillin plus metronidazole was
noted by Svare et al. in a randomized study of 112 women in
preterm labor with intact membranes between 26- and
34-weeks gestation. Women receiving parenteral ampicillin
for 24-hour followed by penicillin agent pivampicin 500
milligrams orally for 7 days) and metronidazole for 7 days
were compared to controls receiving placebo. Those receiving
antibiotics had prolonged pregnancy (47.5 days versus 27
days, P < 0.05), higher mean gestational age at delivery (37
versus 34 weeks, P < 0.05), decreased incidence of preterm
birth <37 weeks (42% versus 65%, P < 0.05), and lower rates
of admission to neonatal intensive care unit (40% versus
63%, P < 0.05) [49]. Although both studies noted some
benet with the beta-lactam plus metronidazole antibiotic
regimens, no larger studies have been performed. Moreover,
improved outcomes could have been secondary to tocolysis
and/or antenatal steroid therapy.
Beta-Lactams and Macrolides. Trials of beta-lactams com-
bined with macrolides have yielded mixed results. In a blind-
ed study by Newton et al., 103 women between 2435
weeks gestation in preterm labor undergoing tocolysis were
randomized to receive either parenteral ampicillin and oral
erythromycin for 7 days or placebo. No statistical dierences
Infectious Diseases in Obstetrics and Gynecology 5
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Infectious Diseases in Obstetrics and Gynecology 7
T
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N
o
8 Infectious Diseases in Obstetrics and Gynecology
were noted between groups in terms of time to delivery, fre-
quency of preterm birth, or birth weight [50].
Similarly no dierences were noted by Romero et al. in
a multicenter, randomized trial from the Maternal Fetal
Medicine Units Network [51]. In this study of 277 women
at six centers, 133 received intravenous ampicillin and eryth-
romycin for 48 hours followed by oral amoxicillin and eryth-
romycin for 5 days; the control group received placebo. No
statistically signicant dierences were noted in time to
delivery, frequency of preterm delivery <37 weeks, frequency
of premature rupture of membranes, or neonatal outcomes
including Neonatal Intensive Care Unit (NICU) admission,
respiratory distress, and sepsis. Further trials by Watts et al.
and Oyarz un et al. have also failed to demonstrate benet to
penicillins combined with macrolides [63, 64]. Furthermore,
in the Oracle II trial with over 6000 women in preterm labor,
erythromycin, amoxicillin-clavulanic acid as compared with
placebo was not associated with any maternal or fetal
benet [52]. Results of the longterm followup on women
in the Oracle II trial suggest an increase in cerebral palsy
indicating that routine beta-lactamand macrolide antibiotics
solely for PTB prevention may be ill-advised.
Macrolides and Metronidazole. One large-scale study has
directly evaluated metronidazole with macrolides. Hauth et
al. in a double blind, randomized controlled study evaluated
the ecacy of treating patients with bacterial vaginosis in the
2nd trimester of pregnancy (2224 weeks). 624 women with
a history of a prior spontaneous preterm birth were allocated
in a 2 : 1 ratio in an antibiotic group (n = 433) or placebo
(191). The antibiotic regimen consisted of metronidazole 250
milligrams three times a day for 7 days and erythromycin 333
milligrams three times a day for 14 days. Patient receiving
antibiotics had a lower rate of preterm delivery (26% versus
36%, P = 0.01). Among the women with bacterial vaginosis
included in the Hauth trial, antibiotics signicantly reduced
the incidence of PTB (31% versus 49%, P = 0.006)
leading to the conclusion that antibiotic therapy may reduce
preterm delivery in patients at risk for premature delivery
with bacterial vaginosis [53]. These patients, however, were
treated earlier in pregnancy than any of the earlier discussed
trials and were all known to have documented infection with
bacterial vaginosis.
Meta-Analyses. In a Cochrane Review, King et al. included
11 studies (the largest of which was the Oracle II trial) and
a total of 7428 women. There was a reduction in maternal
infection (relative risk 0.74, 95% CI 0.640.87), but no sta-
tistically signicant dierences in mean gestational age at de-
livery, frequency of preterm birth, and neonatal outcomes
including mortality. In addition, no dierences were noted
in a subgroup analysis between the types of antibiotics [65].
Furthermore, no subgroup analysis was presented for pa-
tients receiving metronidazole in the rst half of pregnancy.
Similarly, a more recent meta-analysis performed by Sim-
cox et al. in 2007 identied 17 randomized controlled trials
comparing antibiotics to placebo in asymptomatic nonlabor-
ing women with a risk of PTB (previous PTB, positive fetal
bronectin, or abnormal vaginal ora). No signicant asso-
ciation was noted in the reduction of PTB, the antimicrobial
administered, or gestational age at treatment [66]. In sum-
mary, while small-scale studies have shown some benet to
antibiotic prophylaxisespecially in the case of beta-lactams
and metronidazoleno advantages, ecacy, or prevention
of PTB has been consistently presented to support routine
antibiotic therapy. The question then arises if there is any
ecacy to treating specic infections with targeted therapy.
4.1.2. Specic Antibiotic Therapy
Bacterial Vaginosis. Several studies have specically evalu-
ated the role of antibiotics prophylaxis for preterm delivery
in the setting of bacterial vaginosis. Hauth et al. in a double
blind, randomized controlled study described above con-
cluded that antibiotic therapy may reduce preterm delivery
in patients at risk for premature delivery with bacterial
vaginosis [53].
McDonald et al. revisited the possibility of a reduction
in the risk of SPTB with metronidazole treatment of women
with heavy growth of Gardnerella during mid-pregnancy.
Patients identied with heavy growth of Gardnerella or a
gram stain indicative of bacterial vaginosis were randomized
to receives oral metronidazole 400 milligrams or placebo
twice daily for two days at 24-week gestation and then again
at 29 weeks [54]. No dierences were noted in overall PTB
or SPTB; however, in a subgroup analysis of women with a
previous PTB, a signicant reduction in SPTB (9.1% versus
41.7%, OR 0.14 CI 0.010.84) was noted [54].
Given these positive results, a larger Maternal Fetal
Medicine Units Network trial (n = 1953) was performed
using metronidazole to prevent PTB by treating asymp-
tomatic bacterial vaginosis between 16 and 24 weeks of
gestation [67]. Asymptomatic bacterial vaginosis (absence of
itching, odor or discharge) was diagnosed by Nugents crite-
ria and treated with two doses of metronidazole (2 grams)
or placebo. There were no dierences in the rates of preterm
delivery (12.2% versus 12.5%, relative risk 1.0, 95% CI
0.81.2), spontaneous rupture of membranes (4.2% versus
3.7%), delivery before 32 weeks (2.3% versus 2.7%), or neo-
natal outcomes [67]. A meta-analysis of 15 trials with over
5800 women with bacterial vaginosis that examined the eect
of metronidazole to treat bacterial vaginosis on pretermbirth
<37 weeks showed no risk reduction (odds ratio 0.91, 95%
CI: 0.781.06) [68]. In this meta-analysis, however, there
were no results presented regarding comparison between
patients with symptomatic versus asymptomatic infection.
Trials have also yielded mixed results regarding intrav-
aginal clindamycin for bacterial vaginosis. While Lamont
showed some benet regarding PTB in patients with abnor-
mal vaginal ora, in a study of over 5000 women by Kekki et
al., vaginal clindamycin did not decrease the rate of preterm
deliveries (OR 1.3, 95% CI 0.5,3.5) [45, 46]. Trials have
similarly yielded mixed results on the role of oral clin-
damycin for antibiotic prophylaxis in the setting of bacterial
vaginosis. Ugwumadu et al. studied patients at high risk for
late miscarriage or SPTB-randomized women between 12
Infectious Diseases in Obstetrics and Gynecology 9
and 22 weeks of gestation with bacterial vaginosis receiving
oral clindamycin 300 mg twice daily for ve days or placebo.
Women receiving clindamycin had signicantly fewer late
miscarriages or preterm deliveries (10.4% percentage dif-
ference, P < 0.001) [56]. No subgroup analysis of solely
preterm birth was reported.
It is evident that there is no convincing data to support
the routine use of metronidazole or clindamycin in the 2nd
trimester of pregnancy in patients with bacterial vaginosis.
While few small studies have shown some possible ecacy,
larger trials have refuted any benet. In fact, other trials have
even noted deleterious eects of clindamycin on neonatal
morbidityespecially noted to be infectious morbidity [61,
62].
Trichomonas Vaginalis. No benet for PTB prevention has
been shown for treatment of asymptomatic or symptomatic
trichomoniasis. Klebano et al. randomly assigned 617 pa-
tients with asymptomatic trichomoniasis (dened as tri-
chomonas on culture of vaginal secretions) to metronidazole
(two doses of 2 grams 48 hours apart) versus placebo be-
tween 16 to 23 weeks of gestation and then again at 24
29-week gestation. Delivery prior to 37 weeks occurred in
19% of women treated with antibiotics and 10.7% of patients
receiving placebo (relative risk 1.8, 95% CI: 1.22.7, P =
0.004) [55]. Thus, not only did they observe no benet for
treatment of asymptomatic trichomoniasis, intervention was
found to be harmful.
Kigozi et al. similarly noted no benet to treatment of tri-
chomonas during pregnancy. In their randomized controlled
trial women presumptively diagnosed with trichomonas
were randomized to receive oral 1 gram azithromycin, 400
milligrams cexime, and 2 grams metronidazole. Increased
rates of low birth weight, preterm birth, and 2-year mortality
were noted in patients treated for infection [57]. Again,
intervention was noted to be harmful. However, it should be
emphasized that these patients were treated at any gestational
age at pregnancy and were not a high-risk population for
PTB.
Timing of Antibiotic Administration. In addition to type and
specicity of antibiotic regimens, the timing of antibiotic
administration is an important consideration. Uterine infec-
tion may occur prior to conception, early in pregnancy or at
later gestational age. Therefore, it has been postulated that
the lack of benet in some trials, may in part be due to late
treatment when the mechanisms leading to PTB may already
be established. Based on this hypothesis, Andrews et al.
performed an interconceptional antibiotic randomized trial.
Women with a SPTB prior to 34 weeks were randomized
four months postpartum to receive oral azithromycin 1
gram twice (4 days apart) plus metronidazole 750 milligrams
daily for 7 days (n = 59) or placebo (n = 65). The reg-
imen was repeated every 4 months until next pregnancy.
No statistical dierences were observed between subsequent
SPTB at less than 37, 35, or 32 weeks. Interestingly, patients
in the antibiotic group were noted to have decreased mean
birth weight and earlier mean delivery gestational age, albeit
not statistically signicant [69]. Therefore, additional well-
tailored trials are needed to further clarify this issue.
Antibiotics for Other Indications Associated with PTB. PTB
may occur not only as a result of intrauterine subclinical
infection, but also from systemic infection and PROM. In a
Cochrane review of PROM, Kenyon analyzed 6800 subjects
in 22 randomized controlled clinical trials. Antibiotics were
associated with decreased rates of chorioamnionitis, delivery
within 48 hours, and delivery within 7 days. Neonatal short-
term outcomes were also improved [70]. A similar benet
was noted with the utilization of antibiotics for asymp-
tomatic bacteriuria in a 14 study meta-analysis conducted by
Smail et al. While there was no clear reduction in preterm
delivery, asymptomatic bacteriuria, pyelonephritis, and low
birthweight were reduced [71]. As a result of this evidence
supporting antibiotic treatment for these two conditions
as least for short-termoutcomesantibiotic prophylaxis and
treatment is now routinely employed.
In addition, positive fetal bronectin (FFN) is strongly
associated with both infection and PTB. FFN leaks into the
genital tract with disruption of the maternal-fetal interface
through mechanisms such as infection, inammation, and
hemorrhage. Therefore randomized trials have evaluated the
potential benet of antibiotic therapy among those with a
positive fetal bronectin test. Andrews et al. randomized
women to metronidazole or placebo. No dierences were
noted in SPTB <37 weeks (OR 1.17, 95% CI: 0.81.70) or
at earlier gestational age cutos [58].
In another trial by Shennan et al., asymptomatic women
with positive fetal bronectin were randomized to a one-
week course of metronidazole or placebo. Previous studies
regarding metronidazole showed mixed results with regard
to benet in terms of preterm labor especially in patients
with bacterial vaginosis. However, Shennan chose to study
the eect of this antimicrobial in patients between 2427
weeks of gestational age and with positive vaginal FFN.
Patients randomized to metronidazole had an increased risk
of pretermdelivery less than 30 weeks (21%versus 11%, odds
ratio 1.9, 95% CI: 0.725.09, P = 0.18) as well as prior to 37
weeks (62% versus 39%, odds ratio 1.6, 95% CI: 1.052.4,
P = 0.02). The trial was prematurely stopped. Thus, similar
to the ndings for BV, treatment may increase the risk of
preterm delivery [59].
5. Conclusions
There is no doubt that preterm birth continues to be an
obstetrical and neonatal priority in the 21st centurywith
infection as a major cause. Trials evaluating antibiotic treat-
ment to prevent PTB have yielded mixed results regard-
ing benet. No identiable patterns regarding timing of
antibiotic administration, gestational age at administration,
antibiotic of choice, repeat dosages of antibiotics, the pres-
ence of documented underlying infection, or positive fetal
bronectin have emerged to suggest a role for these prophy-
lactic antibiotics at this time. Moreover, a number of studies
have suggested harm, and antibiotics should be avoided
10 Infectious Diseases in Obstetrics and Gynecology
for prophylaxis for asymptomatic bacterial vaginosis and
trichomoniasis. As such, routine antibiotic prophylaxis is not
recommended for prevention of PTB. Based on the review,
there may be promise of further studying the timing of
antibiotic administrationeven before conceptionas well
as more directed antimicrobial therapy. Studies targeted at
timing of antibiotic therapy could be undertaken by treating
patients not only during early pregnancy, but between preg-
nancies or shortly in the postpartum period with specic
evaluation of the microbial = human ora interacrtion.
Further studies aimed at elucidating the exact mechanism
of decidual activation and the most-implicated microbes
may be helpful to delineate specic antimicrobial agents and
their optimal mode of delivery (oral versus vaginal versus
parenteral). Furthermore, molecular receptor analysis, ge-
netics, and proteomics may be the other steps needed to
elucidate the black box that occurs between infection and
preterm delivery.
Conict of Interests
No nancial conict of interests are noted by the authors.
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