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INTRAUTERINE INFECTION
AND
PREMATURITY
INTRODUCTION
reterm labor is a clinical syndrome characterized by uterine contractility, cervical ripening, and/or membrane rupture occurring before 37 weeks of gestation [Romero et
al., 1994]. Pathologic processes implicated in the etiology of the
preterm labor syndrome include infection, uteroplacental ischemia, uterine overdistension, abnormal allograft recognition,
allergic phenomena, and cervical disease [Romero et al., 1994].
Infection has emerged during the last twenty years as an
important and frequent mechanism of disease in premature
labor. Indeed, it is the only pathologic process for which a firm
causal link with prematurity has been established and for which
a defined molecular pathophysiology is known. Moreover, fetal
infection/inflammation has been implicated in the genesis of
fetal or neonatal injury leading to cerebral palsy and chronic lung
disease.
This article will review the pathogenesis of intrauterine
infection, its microbiology, the potential role for modern molecular microbiologic techniques in the identification of this
condition, the temporal relationship between infection and pre-
Fig. 1. The stages of ascending infection (from Romero R, Mazor M. 1988. Infection and preterm
labor: pathways for intrauterine infections. Clin Obstet Gynecol 31:558).
INTRAUTERINE INFECTION
AND
PREMATURITY
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ET AL.
Table 1. Microbial Invasion of the Amniotic Cavity in Women With Preterm Labor and Intact
Membranes as Determined by Amniotic Fluid Studies Obtained by Transabdominal Amniocentesis
Preterm Delivery
in Patients with
Positive Cultures
(%)
Relative Risk
[95% CI]
Author
Ref. Year
No.
Patients
Positive Cultures
No. (%)
Mycoplasma
Culture
Clinical
Chorioamnionitis
No. (%)
Miller et al.
Bobbitt et al.
Wallace and
Herrick
Hameed et al.
Wahbeh et al.
Wieble and Randall
Leight and Garite
Gravett et al.
Iams et al.
Duff and Kopelman
Romero et al.
Skoll et al.
Romero et al.
Romero et al.
Romero et al.
Gauthier et al.
Romero et al.
Coultrip et al.
Watts et al.
Romero et al.
Coultrip et al.
Yoon et al.
Markenson
Gomez
Hussey
Kara
Oyarzun
Rizzo
Greci
Yoon
Elimian
Gonzalez-Bosquet
Locksmith
Total
1980
1981
1981
23
31
25
11 (47.8)
8 (25.8)
3 (12.0)
No
No
No
8 (72, 7)
6 (75, 0)
1 (33, 3)
7 (87, 5)
1984
1984
1985
1986
1986
1987
1987
1988a
1989
1989a
1990b
1990c
1991
1991b
1992
1992
1993a
1994
1996
1997
1998
1998
1998
1998
1998
1998
1998
1998
1999
1999
37
33
35
59
54
5
24
41
127
264
109
168
113
195
107
105
120
89
102
54
103
127
74
50
144
103
181
104
113
44
2963
4 (10.8)
7 (21.2)
1 (2.9)
7 (11.9)
13 (24.1)
0 (0.0)
1 (4.2)
4 (9.8)
7 (5.5)
24 (9.1)
15 (13.8)
23 (13.7)
18 (15.9)
25 (12.8)
12 (11.2)
20 (19.0)
11 (9.2)
12 (13.5)
11 (10.8)
5 (9.3)
11 (10.7)
16 (12.6)
25 (33.8)
6 (12)
18 (12.5)
9 (8.7)
21 (11.6)
12 (11.5)
13 (11.5)
6 (13.6)
379 (12.8)
No
No
No
No
Yes
Yes
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
3 (75, 0)
2 (28, 5)
1 (100)
4 (57, 1)
5 (38, 5)
0 (0)
1 (14, 3)
3 (12, 5)
4 (17, 4)
4 (16, 0)
7 (63, 6)
2 (18,2)
7 (58,3)
2 (18, 2)
60 (37.5)
3 (75, 0)
5 (71, 4)
7 (100)
5 (38, 5)
0 (0)
7 (100)
24 (100)
15 (100)
25 (100)
17 (85, 0)
11 (100)
5 (100)
4 (66.7)
110 (85.3)
*: Clinical chorioamnionitis is expressed as percentage of patients with positive amniotic fluid culture.
INTRAUTERINE INFECTION
AND
PREMATURITY
ALVES
GONC
Table 2.
Microbial Invasion of the Amniotic Cavity in Women With Preterm PROM as Determined
by Amniotic Fluid Studies Obtained by Transabdominal Amniocentesis
Author
Garite et al.
Garite and Freeman
Cotton et al.
Broekhuizen et al.
Vintzileos et al.
Felnstein et al.
Romero et al.
Gauthier et al.
Coultrip et al.
Gauthier and
Meyer
Romero et al.
Font et al.
Averbuch et al.
Carroll et al.
Gomez et al.
Hussey et al.
Rizzo et al.
Yoon et al.
Total
Ref.
Year
No. of
Patients
Positive Culture
No. (%)
Mycoplasma
Culture
Success Rate
(%)
Clinical Chorioamnionitis
No. (%)
1979
1982
1984
1985
1986
1986
1988b
1991
1992
1992
59
207
61
79
54
73
230
91
29
117
9/30 (30, 0)
20/86 (23, 3)
6/41 (14, 6)
15/53 (28, 3)
12/54 (22, 2)
12/50 (20, 0)
65/221 (29, 4)
49/91 (53, 8)
12/29 (41, 4)
56/117 (47, 9)
No
No
No
No
No
No
Yes
Yes
Yes
Yes
51
42
67
67
68
96
6 (66, 6)
11 (55, 0)
6 (100, 0)
3 (20, 0)
2 (16, 7)
6 (50)
3 (25, 0)
2 (22, 2)
5 (25, 0)
1 (16, 6)
8 (53, 3)
4 (33, 3)
5 (41, 6)
5 (12, 8)
1993b
1995
1995
1996
1998
1998
1998
2000
110
74
90
97
52
26
124
154
1727
42/110 (38, 2)
21/37 (56, 8)
32/90 (35, 6)
30/97 (30, 9)
30/52 (57, 7)
4/26 (15.4)
21/124 (16.9)
37/154 (24)
473/1462 (32.4)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
5 (11, 9)
7 (18.9)
49/165 (29.7)
20 (47, 6)
7 (21, 9)
10/32 (31.2)
67/277 (24.2)
The role of modern molecular microbiologic techniques in clinical obstetrics is under active investigation. PCRbased methods are at first difficult to
establish and require scrupulous handling
of specimens, not only in the laboratory
but also in the clinical area, to avoid
contamination and false-positive results.
The technique is more sensitive, more
rapid, and less expensive than standard
microbial cultures. Molecular microbiology techniques may be particularly useful
in the diagnosis of infections caused by
fastidious microorganisms or agents that
have not been discovered. Preliminary
results of amniotic fluid analysis will be
discussed below.
Frequency of Intra-Amniotic
Infection in Preterm and
Term Gestation
Microbial invasion of the amniotic cavity
and preterm delivery
Studies examining the clinical circumstances surrounding preterm delivery
indicate that one-third of all patients
present with preterm labor and intact
membranes, one-third with preterm premature rupture of membranes (PROM),
and the remaining third are the result of
indicated delivery because of maternal or
fetal indications (i.e., pre-eclampsia,
growth retardation, etc.) [Arias and
Tomich, 1982]. To examine the relationship between microbial invasion of
the amniotic cavity and preterm delivery,
we will review the evidence supporting
6
INTRAUTERINE INFECTION
AND
PREMATURITY
ALVES
GONC
ET AL.
Intrauterine infection is
closely related to preterm
labor. Treatment remains
a major clinical
challenge.
labor. However, no differences in the
rates of chorioamnionitis, cervical dilatation, and neonatal outcome are generally
observed between culture-positive and
culture-negative patients in patients at
term. Therefore, we believe that microbial invasion of the amniotic cavity can
occur during labor at term even with
intact membranes. However, the frequency of fetal invasion is extremely low
as is the intensity of the cytokine response to microorganisms and their
products in the amniotic cavity [interleukin (IL)-8] [Romero et al., 1991a;
1992b;d; Saito et al., 1993].
CHORIOAMNIOTIC
INFECTION, HISTOLOGIC
CHORIOAMNIONITIS AND
PRETERM BIRTH
Inflammation of the placenta and
membranes is a nonspecific host-response
to a variety of stimuli including infection.
Traditionally, acute inflammation of the
chorioamniotic membranes has been
considered an indicator of amniotic fluid
INTRAUTERINE INFECTION
AND
PREMATURITY
ALVES
GONC
INTRAUTERINE INFECTION
AND
PREMATURITY
ALVES
GONC
ET AL.
cum. Patients with Mycoplasma hominis delivered at 34 and 40 weeks without neonatal complications while those with
Ureaplasma urealyticum had premature delivery, neonatal sepsis, and neonatal death
at 24 and 29 weeks. Subsequently, Gray
et al. [1992] reported a 0.37% prevalence
(9/2,461) of positive cultures for Ureaplasma urealyticum in amniotic fluid samples obtained during second trimester genetic amniocentesis. After exclusion of
one case who had a therapeutic abortion,
all patients (8/8) with positive amniotic
fluid cultures had either a fetal loss within
four weeks of amniocentesis (n 6) or
preterm delivery (n 2). All had histologic evidence of chorioamnionitis.
These observations suggest that microbial
invasion could be clinically silent in the
mid-trimester of pregnancy and that
pregnancy loss/preterm delivery could
take weeks to occur. A similar finding
was reported by Horowitz et al. [1995]
who detected Ureaplasma urealyticum in
2.8% (6/214) of amniotic fluid samples
obtained between 16 and 20 weeks of
gestation. The rate of adverse pregnancy
outcome (fetal loss, preterm delivery, and
low birth weight) was significantly
higher in patients with a positive amniotic fluid culture than in those with a
negative culture [3/6 (50%) vs. 15/123
(12%), P 0.035]. Of interest is that
patients with a positive amniotic fluid
culture were more likely to have an obstetrical history that included more than
three previous abortions than those with
a negative culture [33% (2/6) vs. 4% (5/
123); P 0.034].
Chronic Intra-Amniotic
Inflammation and Preterm Birth
Interleukin-6 concentrations in
amniotic fluid are considered a marker of
intra-amniotic inflammation frequently
associated with microbiological infection
in the amniotic fluid or the chorioamniotic space [Romero et al., 1990b; 1992f;
1993e; Yoon et al., 1995]. Romero et al.
[1995] reported the results of a case control study in which IL-6 determinations
were conducted in stored fluid of patients
who had a pregnancy loss after a midtrimester amniocentesis and a control
group who delivered at term. Patients
who had a pregnancy loss had a significantly higher median amniotic fluid IL-6
than those with a normal outcome. Similar findings were reported by Wenstrom
et al. [1996]. Of note is that maternal
plasma concentrations of IL-6 were not
associated with adverse pregnancy outcome.
The same approach was subsequently used to test the association beMRDD RESEARCH REVIEWS
INTRAUTERINE INFECTION
AND
PREMATURITY
ALVES
GONC
that a major issue is the diagnosis of bacterial vaginosis, as this condition has been
identified in up to 23% of pregnant
women. Recent observations indicate
that some patients with bacterial vaginosis have elevated pro-inflammatory cytokines in vaginal fluid and others do not
[Imseis et al., 1997]. It is possible that
only the sub-group with evidence of inflammation would benefit from treatment and that the potential beneficial
effects of such therapy are diluted in clinical trials which included all patients with
the laboratory diagnosis of bacterial vaginosis. Similarly, antibiotic therapy of patients with asymptomatic Trichomonas
vaginalis [Carey and Klebanoff, 2000],
Streptococcus agalactia [Klebanoff et al.,
1995], and Ureaplasma urealyticum [Eschenbach et al., 1991] did not reduce the
rate of preterm birth.
Anti-microbial therapy has been
used to treat patients with preterm labor
and intact membranes and also preterm
PROM. Meta-analysis of randomized
clinical trials of antibiotic therapy in patients with intact membranes have not
demonstrated a beneficial effect [Egarter
et al., 1996a; Mercer et al., 1997; Mercer,
1998]. The largest trial conducted to date
(ORACLE II) [Kenyon et al., 2001a],
including 6,295 patients, confirmed these
results. However, it remains to be determined if patients with proven microbial
invasion of the amniotic cavity may
benefit from antibiotic treatment. Metaanalysis of randomized clinical trials of
antibiotic administration to patients
with preterm PROM indicates that antibiotic treatment can prolong the duration of the latency period and reduce
the rate of clinical chorioamnionitis,
intracranial hemorrhage and proven
neonatal sepsis [Egarter et al., 1996b].
Sub-group analysis of the randomized
clinical trial known as ORACLE I
indicated that treatment with erythromycin was associated with a reduction
in the rate of neurosonographically detected brain lesions in neonates [Kenyon et al., 2001b].
An important but unanswered
question is why some patients develop an
ascending intrauterine infection and others do not. Adequate mucosal immunity,
innate and specific immunity, and maternal and/or fetal genotypes may play a
central role in determining susceptibility
to intrauterine infection, the host response, and likelihood of fetal damage. A
deeper understanding of these factors appears essential to design rational approaches to therapy.
10
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AND
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ALVES
GONC
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AND
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ET AL.
INTRAUTERINE INFECTION
AND
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GONC
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