Clinical significance of intra-amniotic inflammation in patients

with preterm labor and intact membranes

Bo Hyun Yoon, MD, PhD, Roberto Romero, MD, Jeong Bin Moon, MD, Soon-Sup Shim, MD,
Miha Kim, MD, Gilja Kim, MT, and Jong Kwan Jun, MD, PhD
Seoul, Korea

OBJECTIVE: The purpose of this study was to determine the frequency and clinical significance of intra-
amniotic inflammation in patients with preterm labor and intact membranes.
STUDY DESIGN: Amniocentesis was performed in 206 patients with preterm labor and intact membranes.
Amniotic fluid was cultured for aerobic and anaerobic bacteria and mycoplasmas. The diagnosis of intra-
amniotic inflammation was made in patients with a negative amniotic fluid culture on the basis of amniotic
fluid concentrations of interleukin-6 (>2.6 ng/mL, derived from receiver operating characteristic curve analy-
sis). Statistical analysis was conducted with contingency tables and survival techniques.
RESULTS: Intra-amniotic inflammation (negative amniotic fluid culture but elevated amniotic fluid interleukin-6)
was more common than intra-amniotic infection (positive amniotic fluid culture regardless of amniotic fluid
interleukin-6 concentration; 21% [44/206 women] vs 10% [21/206 women]; P < .001). The amniocentesis-
to-delivery interval was significantly shorter in patients with intra-amniotic inflammation than in patients with a
negative culture and without an inflammation (median, 20 hours [range, 0.1-2328 hours] vs median, 701
hours [range, 0.1-3252 hours], respectively; P < .0001). Spontaneous preterm delivery of <37 weeks was
more frequent in patients with intra-amniotic inflammation than in those with a negative culture and without
inflammation (98% vs 35%; P < .001). Patients with intra-amniotic inflammation had a significantly higher rate
of adverse outcome than patients with a negative culture and without intra-amniotic inflammation. Adverse
outcomes included clinical and histologic chorioamnionitis, funisitis, early preterm birth, and significant
neonatal morbidity. There were no significant differences in the rate of adverse outcomes between patients
with a negative culture but with intra-amniotic inflammation and patients with intra-amniotic infection (positive
culture regardless of amniotic fluid interleukin-6 concentration).
CONCLUSION: Intra-amniotic inflammation/infection complicates one third of the patients with preterm labor
(32%; 65/206 women), and its presence is a risk factor for adverse outcome. The outcome of patients with
microbiologically proven intra-amniotic infection is similar to that of patients with intra-amniotic inflammation
and a negative amniotic fluid culture. We propose that the treatment of patients in preterm labor be based on
the operational diagnosis of intra-amniotic inflammation rather than the diagnosis of intra-amniotic infection
because the latter diagnosis cannot be undertaken rapidly. (Am J Obstet Gynecol 2001;185:1130-6.)

Key words: Amniotic fluid, infection, inflammation, interleukin-6, preterm labor, prematurity,
chorioamnionitis

Microbial invasion of the amniotic cavity in patients
with preterm labor and intact membranes is a risk factor
for the progression of labor to preterm delivery despite
tocolysis, spontaneous rupture of membranes, clinical
From the Department of Obstetrics and Gynecology, Seoul National Uni-
versity College of Medicine; and the Laboratory of Fetal Medicine Re-
search, Clinical Research Institute, Seoul National University Hospital.
Supported by grant 2000-N-NL-01-C-078 from the Korea Institute of Sci-
ence and Technology Evaluation and Planning (KISTEP), Republic of
Korea.
Presented at the Twenty-first Annual Meeting of the Society for Maternal-
Fetal Medicine, Reno, Nev, February 5-10, 2001.
Reprint requests: Bo Hyun Yoon, MD, PhD, Department of Obstetrics
and Gynecology, College of Medicine, Seoul National University, Seoul
National University College of Medicine, Seoul, 110-744, Korea.
Copyright © 2001 by Mosby, Inc.
0002-9378/2001 $35.00 + 0 6/6/117680
doi:10.1067/mob.2001.117680
chorioamnionitis, and adverse neonatal outcome (ie, sep-
sis, non-infection-related complications).1-10 The gold
standard for the diagnosis of infection in clinical medi-
cine is the isolation and identification of the micro-or-
ganism from body fluids and tissues of patients with
suspected infection. However, results of microbial culture
may take days, and are often not available in time for
some clinical decisions.
In contrast to the diagnosis of infection, the identifica-
tion of intrauterine inflammation can be easily and
rapidly detected by laboratory tests (such as an amniotic
fluid white blood cell count and cytokine determina-
tions). A substantial number of patients with preterm
labor and intact membranes or preterm premature rup-
ture of membranes have demonstrable intra-amniotic in-
flammation with a negative amniotic fluid culture.11-15
The frequency and clinical significance of intra-amniotic

1130
Volume 185, Number 5
Am J Obstet Gynecol
inflammation without microbial invasion remains to be
determined. The purpose of this study was to determine
the frequency and maternal/neonatal outcome of pa-
tients with intra-amniotic inflammation but with a nega-
tive amniotic fluid culture.
Material and methods
Study population. The study population consisted of
consecutive patients admitted to Seoul National Univer-
sity Hospital between January 1993 and July 1998 with the
diagnosis of preterm labor and intact membranes (<36
weeks of gestation) and singleton gestation who under-
went amniocentesis. Amniocentesis is routinely offered to
all patients who are admitted with the diagnosis of pre-
term labor at our institution. Amniocentesis was per-
formed after written informed consent was obtained. The
institutional review board of our institution approved the
collection of biologic materials and data from these pa-
tients for research purposes.
Patients were divided into 3 groups according to the re-
sults of amniotic fluid culture and amniotic fluid concen-
trations of interleukin-6 (IL-6). Group 1 consisted of 141
women with a negative amniotic fluid culture and with-
out an elevated amniotic fluid IL-6 concentration; group
2 consisted of 44 women with a negative amniotic fluid
culture but with an elevated amniotic fluid IL-6 concen-
tration (intra-amniotic inflammation); group 3 consisted
of 21 women with a positive amniotic fluid culture, re-
gardless of amniotic fluid IL-6 concentration (intra-
amniotic infection).
Amniotic fluid. Amniotic fluid was retrieved by transab-
dominal amniocentesis and was cultured for aerobic and
anaerobic bacteria and for genital mycoplasmas (Urea-
plasma urealyticum and Mycoplasma hominis) according to
methods described in detail previously.14 Fluid that was
not used for diagnostic studies was centrifuged and
stored at –70°C until assayed. IL-6 concentrations were
measured with a commercially available enzyme-linked
immunosorbent assay (R&D Systems, Minneapolis,
Minn). The sensitivity of the test was <1.0 pg/mL. Intra-
and interassay coefficients of variation were <10%.
Diagnosis of chorioamnionitis, funisitis, and neonatal
morbidity. Clinical chorioamnionitis was diagnosed
when a temperature was elevated to 37.8°C and when ≥2
of the following criteria were present: uterine tender-
ness, malodorous vaginal discharge, maternal leukocyto-
sis (>15,000 cells/mm3), maternal tachycardia (>100
beats/min), and fetal tachycardia (>160 beats/min).
Histologic chorioamnionitis was defined in the presence
of acute inflammatory changes on examination of a
membrane roll and chorionic plate of the placenta; fu-
nisitis was diagnosed in the presence of neutrophil infil-
tration into the umbilical vessel walls or Wharton’s jelly
with the use of criteria published previously.14, 16 Neona-
tal sepsis, respiratory distress syndrome, pneumonia,
Yoon et al 1131
bronchopulmonary dysplasia, intraventricular hemor-
rhage, and necrotizing enterocolitis were diagnosed ac-
cording to the definitions that were previously described
in detail.14, 16
Statistical analysis. Proportions were compared with
the Fisher exact test. The Kruskal-Wallis analysis of vari-
ance (ANOVA) test was used for comparison of continu-
ous variables among the groups. Multiple comparisons
among groups were performed with Mann-Whitney
U tests. The McNemar test was used for comparison of
proportions of correlated samples. The generalized
Wilcoxon test for survival analysis was used to compare
the amniocentesis-to-delivery interval. Patients delivered
for maternal or fetal indications were treated as censored
observations, with a censoring time equal to the amnio-
centesis-to-delivery interval. Logistic regression analysis
was used to examine the relationship between the pres-
ence of intra-amniotic inflammation or positive amniotic
fluid culture and outcome of interest (ie, preterm deliv-
ery, neonatal complications) after adjusting for the ef-
fects of confounding variables (gestational age and the
degree of cervical dilatation). A probability value of <.05
was considered significant.
Results
Characteristics of study population. Table I compares
characteristics of the study population. Patients with a
negative amniotic fluid culture but with intra-amniotic in-
flammation (group 2) had a significantly lower mean ges-
tational age at amniocentesis and more advanced cervical
dilatation at presentation than patients with a negative
culture and without intra-amniotic inflammation (group
1). In contrast, there were no differences in the clinical
characteristics between patients in groups 2 and 3.
Result of amniotic fluid culture. Amniocentesis was per-
formed in 209 patients with preterm labor and intact
membranes during the study period. The prevalence of
positive amniotic fluid culture was 10% (21/209 pa-
tients). U urealyticum was the most common micro-organ-
ism isolated from the amniotic cavity (n = 14 patients).
Other isolates included Staphylococcus aureus (n = 2 pa-
tients), Enterococcus spp (n = 2 patients), Acinetobacter spp
(n = 2 patients), Lactobacillus spp (n = 2 patients), and 1
isolate each of Candida albicans, Porphyromonas asaccha-
rolytica, and coagulase-negative Staphylococcus. Three pa-
tients with a negative amniotic fluid culture but without
remaining amniotic fluid for IL-6 determinations were
excluded from the further analysis because they could
not be evaluated with respect to the presence or absence
of intra-amniotic inflammation.
Diagnosis of intra-amniotic inflammation. The diagno-
sis of intra-amniotic inflammation was based on amniotic
fluid concentration of IL-6. Fig 1 displays a receiver oper-
ating characteristic curve that describes the performance
of amniotic fluid IL-6 concentration in the identification
1132 Yoon et al
Table I. Characteristics of study population according to the results of amniotic fluid culture and IL-6 concentrations
Negative amniotic fluid culture
Low IL-6
Characteristic (group 1; n = 141) P* (group 2; n = 44)
Maternal age§ (y) 29.5 ± 4.3 NS
Nulliparity (n) 74 (52%) < .05
Gestational age at 31.3 ± 3.2 < .001
amniocentesis (wk)
Cervical dilation at 0.8 ± 1.1 < .001
presentation (cm)
Values given as mean ± SD. Low IL-6, interleukin-6 <2.6 ng/mL; High IL-6, interleukin-6 >2.6 ng/mL; NS, not significant.
*Comparison between groups 1 and 2.
†Comparison between groups 2 and 3.
‡Comparison between groups 3 and 1.
§P > .1, by Kruskal-Wallis ANOVA test.
P < .001, by Kruskal-Wallis ANOVA test.
Fig 1. Receiver operating characteristic curve that describes the
performance of amniotic fluid IL-6 concentration in the identi-
fication of a positive amniotic fluid culture (area under the
curve, 0.84: SE, 0.04; z, 9.26; P < .0001).
of positive amniotic fluid culture (area under the curve,
0.84; SE, 0.04; z, 9.26; P < .0001). A value of 2.6 ng/mL
was at the knee of the curve and was used to diagnose the
presence of intra-amniotic inflammation.
Prevalence of intra-amniotic inflammation. Amniotic
fluid concentrations of IL-6 were higher than 2.6
ng/mL in 63 of 206 patients (31%) in the study, in 44 of
185 patients (24%) with a negative amniotic fluid cul-
ture (group 2, intra-amniotic inflammation), and in 19
of 21 patients (90%) with a positive amniotic fluid cul-
ture (group 3, intra-amniotic infection). Intra-amniotic
inflammation (group 2) was more common than intra-
amniotic infection (group 3; 21% [44/206] vs 10%
[21/206]; P < .001, McNemar test).
November 2001
Am J Obstet Gynecol
Positive amniotic fluid culture
High IL-6 Group 3
P† (n = 21) P‡
29.7 ± 3.6 NS 30.2 ± 5.3 NS
15 (34%) NS 9 (43%) NS
28.5 ± 4.1 NS 29.1 ± 3.9 <.01
3.3 ± 2.7 NS 2.6 ± 2.2 <.001
Fig 2. Frequency of a positive amniotic fluid (AF ) culture and
intra-amniotic inflammation (negative AF culture but with an AF
IL-6 of higher than 2.6 ng/mL) as a function of gestational age.
The lower the gestational age, the higher the frequency of a pos-
itive amniotic fluid culture and intra-amniotic inflammation (P <
.01 for culture and P < .001 for inflammation, respectively).
Hash-marked columns represent intra-amniotic inflammation.
Black columns represent positive amniotic fluid culture.
Fig 2 displays the frequency of a positive amniotic fluid
culture and intra-amniotic inflammation as a function of
gestational age. The lower the gestational age, the higher
the frequency of a positive amniotic fluid culture and intra-
amniotic inflammation (P < .01 and P < .001, respectively).
Amniocentesis-to-delivery interval. Fig 3 shows the in-
terval from amniocentesis to delivery. In patients who
were delivered because of maternal or fetal indications (n
= 34 women), this interval was treated as a censored ob-
servation. Patients with a negative amniotic fluid culture
but with intra-amniotic inflammation (group 2) had a sig-
nificantly shorter median amniocentesis-to-delivery inter-
val than women with a negative culture and without
intra-amniotic inflammation (group 1; P < .0001). How-
ever, there was no difference in the median amniocente-
sis-to-delivery interval between patients with a negative
Volume 185, Number 5
Am J Obstet Gynecol
Fig 3. Survival analysis of amniocentesis-to-delivery interval (group
1: median, 701 hours [range, 0.1-3252 hours]; group 2, median,
20 hours [range, 0.1-2328 hours]; group 3, median, 11 hours
[range, 0.1-983 hours]) according to the results of amniotic fluid
(AF) culture and IL-6 concentrations. NS, Not significant.
amniotic fluid culture but with intra-amniotic inflamma-
tion (group 2) and patients with a positive culture re-
gardless of amniotic fluid IL-6 concentration (group 3).
Multivariate survival analysis demonstrated that the am-
niocentesis-to-delivery interval in patients with a negative
amniotic fluid culture but with intra-amniotic inflamma-
tion (group 2) was significantly shorter than that of the
group with a negative culture and without intra-amniotic
inflammation (group 1) after the adjustment of gesta-
tional age and the degree of cervical dilatation at amnio-
centesis (hazards ratio, 3.1; 95% CI, 2.3-4.1; P < .0001,
Cox proportional hazards model analysis).
Outcomes of study population. Tables II and III com-
pare pregnancy and neonatal outcomes of study popula-
tion. Patients with a negative amniotic fluid culture but
with intra-amniotic inflammation (group 2) had a signifi-
cantly higher rate of adverse outcomes than patients with
a negative culture and without intra-amniotic inflamma-
tion (group 1). Adverse outcomes included higher rates
of clinical chorioamnionitis, preterm delivery, histologic
chorioamnionitis, funisitis, low Apgar scores, admission
to neonatal intensive care unit, neonatal respiratory dis-
tress syndrome, pneumonia, sepsis, intraventricular hem-
orrhage (≥grade II), and bronchopulmonary dysplasia
and lower gestational age at birth and birth weight. How-
ever, no differences were found between patients with a
negative amniotic fluid culture but with intra-amniotic in-
flammation (group 2) and patients with a positive culture
regardless of amniotic fluid IL-6 concentration (group 3;
P > .1).
One hundred thirty-two patients delivered preterm new-
borns (<37 weeks); 33% of the women (43/132) had intra-
Yoon et al 1133
amniotic inflammation (group 2) and 16% of the women
(21/132) had a positive amniotic fluid culture (group 3).
Thirty-four patients had maternal and/or fetal indica-
tion for preterm delivery. Of the remaining 172 women,
57% of the women (98/172 women) had a spontaneous
preterm delivery. Forty percent of these patients with a
spontaneous preterm delivery (39/98 women) had intra-
amniotic inflammation (group 2) and only 19% of these
women (19/98 women) had a positive amniotic fluid cul-
ture (group 3).
Comment
Our results indicate that intra-amniotic inflammation is
more common than microbiologically proven intra-amni-
otic infection in patients with preterm labor and intact
membranes (21% vs 10%; P < .001) and that intra-amniotic
inflammation per se is associated with adverse maternal
and neonatal outcome. A major finding of this study is that
the maternal and neonatal outcome of patients with intra-
amniotic infection did not differ from that of patients with
intra-amniotic inflammation without demonstrable intra-
amniotic infection.
In regard to microbial invasion of the amniotic cavity,
the prevalence, the type of microorganism, the inverse re-
lationship with gestational age, and the association with
adverse outcome are consistent with our previously re-
ported observations and with reports of other investiga-
tors.1-10 Moreover, we observed that the frequency of
intra-amniotic inflammation is double that of demonstra-
ble intra-amniotic infection, also in keeping with observa-
tions previously reported by us15 and other authors.17
In this study, 40% of all patients with preterm labor
who delivered a preterm neonate spontaneously had an
elevated amniotic fluid IL-6 but negative amniotic fluid
culture. What is the cause of the inflammatory process in
cases of negative culture? We have previously reported18
that, with the use of the polymerase chain reaction with
specific primers to U urealyticum, many patients with
intra-amniotic inflammation but with a negative culture
for U urealyticum had microbial footprints for this micro-
organism in the amniotic fluid. Moreover, these patients
had cytologic, pathologic, biochemical, and clinical evi-
dence of inflammation. Therefore, we suspect that some
patients with intra-amniotic inflammation of unknown
cause will eventually be proved to have infection that can-
not be demonstrated today with the use of standard mi-
crobiologic techniques. These laboratory procedures
demand knowledge on the culture conditions of all po-
tential pathogens, information that clearly is not avail-
able. Yet, a subgroup of patients with inflammation in the
amniotic cavity may have an extra-amniotic infection,
with micro-organisms located primarily in the decidua or
the space between chorion and amnion. Previous studies
have demonstrated that amniotic fluid IL-6 may be ele-
vated in these patients.15 Of course, we do not dismiss
1134 Yoon et al November 2001
Am J Obstet Gynecol

Table II. Pregnancy outcome of study population according to the results of amniotic fluid culture and interleukin-6
concentrations

Negative amniotic fluid culture Positive amniotic fluid culture

P* High IL-6 P† P‡
(group 1; (group 2; Group 3
Pregnancy outcome n = 141) Unadjusted Adjusted§ n = 44) (Un)adjusted§# (n = 21) Unadjusted Adjusted§

Gestational age 36.2 ± 3.8 <.001 — 29.0 ± 4.4 NS 29.5 ± 4.1 <.001 —
at delivery
(wk; mean ± SD)
Amniocentesis to
delivery interval (n)
≤48 hr 24 (17%) <.001 <.001 32 (73%) NS 16 (76%) <.001 <.01
≤72 hr 29 (21%) <.001 <.001 33 (75%) NS 16 (76%) <.001 <.01
≤ 7 days 36 (26%) <.001 <.001 40 (91%) NS 20 (95%) <.001 <.01
Preterm delivery 68 (48%) <.001 <.01 43 (98%) NS 21 (100%) <.001 NS
(< 37 wk)
Spontaneous 40/113 (35%) <.001 <.001 39/40 (98%) NS 19/19 (100%) <.001 NS
preterm delivery¶
(<37 wk)
Clinical 3 (2%) <.05 <.05 5 (11%) NS 5 (24%) <.001 <.05
chorioamnionitis
Histologic 18/67 (27%) <.001 < .001 30/35 (86%) NS 15/18 (83%) <.001 <.01
chorioamnionitis
Funisitis 2/67 (3%) <.001 <.001 17/35 (49%) NS 11/18 (61%) <.001 <.001

Low IL-6, interleukin-6 lower than 2.6 ng/mL; High IL-6, interleukin-6 higher than 2.6 ng/mL; NS, not significant.
*Comparison between groups 1 and 2.
†Comparison between groups 2 and 3.
‡Comparison between groups 3 and 1.
§Adjusted for gestational age and the degree of cervical dilatation at amniocentesis (logistic regression analysis).
#The differences between groups 2 and 3 were not significant before and after the adjustment for the gestational age and the degree
of cervical dilation at amniocentesis.
P < .001, by Kruskal-Wallis ANOVA test.
¶Thirty-four cases that were delivered for maternal or fetal indications were excluded from this analysis.

Table III. Neonatal outcome of study population according to the results of amniotic fluid culture and interleukin-6
concentrations
Negative amniotic fluid culture Positive amniotic fluid culture

Low IL-6 P* High IL-6 P† P‡

(group 1; (group 2; Group 3
Neonatal outcome n = 141) Unadjusted Adjusted§ n = 44) (Un)adjusted§# (n = 21) Unadjusted Adjusted§

Birth weight 2683 ± 785 <.001 — 1449 ± 691 NS 1497 ± 719 <.001 —
(g; mean ± SD)
1-min Apgar score <7 (n) 32 (23%) <.001 <.001 32 (73%) NS 12 (57%) <.01 <.05
5-min Apgar score <7 (n) 18 (13%) <.001 <.01 27 (61%) NS 10 (48%) <.001 NS
Admission to neonatal 39/135 (29%) <.001 <.001 31/36 (86%) NS 18/18 (100%) <.001 <.01
intensive care unit¶ (n)
Neonatal complications (n)
Congenital sepsis¶ 0/135 (0%) <.01 <.01 4/36 (11%) NS 1/18 (6%) NS NS
Respiratory distress¶ 8/135 (6%) <.001 <.05 11/36 (31%) NS 6/18 (33%) <.01 <.05
Pneumonia¶ 2/135 (1%) <.01 <.05 5/36 (14%) NS 2/18 (11%) .07 NS
Intraventricular hemorrhage 13/135 (10%) <.001 <.05 13/36 (36%) NS 8/18 (44%) <.001 <.05
(≥ grade II)¶
Bronchopulmonary 4/135 (3%) <.001 <.01 9/36 (25%) NS 4/18 (22%) <.01 NS
dysplasia¶
Necrotizing enterocolitis¶ 1/135 (1%) <.01 NS 4/36 (11%) NS 0/18 (0%) NS NS

Low IL-6, interleukin-6 lower than 2.6 ng/mL; High IL-6, interleukin-6 higher than 2.6 ng/mL; NS, not significant.
*Comparison between groups 1 and 2.
†Comparison between groups 2 and 3.
‡Comparison between groups 3 and 1.
§Adjusted for gestational age and the degree of cervical dilatation at amniocentesis (logistic regression analysis).
#The differences between groups 2 and 3 were not significant before and after the adjustment for the gestational age and the degree
of cervical dilation at amniocentesis.
P < .001, by Kruskal-Wallis ANOVA test.
¶Seventeen infants were excluded from the analysis because they died in utero (n = 6 infants), were not actively resuscitated at birth,
or died in the delivery room despite intensive resuscitative efforts as a result of extreme prematurity (n = 10 infants) or congenital anom-
aly (n = 1 infant) and thus could not be evaluated with respect to the presence or absence of complications.
Volume 185, Number 5
Am J Obstet Gynecol
the possibility that inflammation may have a noninfec-
tious cause.
Two patients with microbial invasion of the amniotic cav-
ity did not have an elevated IL-6 above the cutoff selected
in our study. This may represent earlier stages of the infec-
tion process in which the host did not have time to elicit a
full cytokine response or, alternatively, these cases may rep-
resent microbial invasion of the amniotic cavity in patients
who are hyporesponders. Functional polymorphism in sev-
eral cytokines (including IL-6) have been reported.19-22
Hyporesponder mothers may not mount enough of a
proinflammatory cytokine response in the decidua for
labor to be initiated. Consequently, micro-organisms
would proliferate in the decidua, cross intact membranes,
and stimulate fetal cells to produce cytokines into the am-
niotic cavity. If the fetal genotype determines hyporespon-
siveness, microbial invasion of the amniotic cavity would be
associated with low concentrations of cytokines in amniotic
fluid. Another explanation for our findings is that micro-
organisms differ in their capacity to stimulate cytokine pro-
duction by the host. Indeed, not all endotoxins are equally
potent in stimulating cytokine production.23, 24
The major finding of our study was that the outcome of
patients with intra-amniotic inflammation but with a nega-
tive amniotic fluid culture (group 2) was similar to that of
patients with demonstrable infection (group 3) and much
worse than that of patients without inflammation and with a
negative amniotic fluid culture (group 1). This was the case
for both maternal and fetal complications. Therefore, we
propose that patients with evidence of intra-amniotic in-
flammation, regardless of whether there is demonstrable in-
fection, be considered a separate group from patients
without inflammation in clinical studies and randomized
trials in preterm labor. The identification of patients be-
longing to this inflammatory cluster and who are at risk for
adverse outcomes would have substantial clinical implica-
tions. For example, it would be ideal if tocolytic trials could
identify patients with inflammation and either exclude or
stratify these patients, given the substantial likelihood of pre-
term delivery within 24, 48, and 72 hours (Table II). Other-
wise, there is a risk of considering therapies to be ineffective,
which may benefit the subset of patients without inflamma-
tion. This is critical, given the high frequency of intra-amni-
otic inflammation observed in this study. The diagnosis of
intra-amniotic inflammation can be readily made by either a
cytokine assay or an amniotic fluid white blood cell count.
Moreover, we have recently proposed that screening can be
conducted by assaying cytokines in cervical fluid in preterm
premature rupture of membranes.25 Therefore, we propose
that the operational definition of preterm labor with intra-
amniotic inflammation be used to classify patients with pre-
term labor in studies of therapeutic interventions and to
evaluate short- and long-term neonatal outcome.
The pathophysiologic and clinical implications of the
presence of intra-amniotic inflammation in so many pa-
Yoon et al 1135
tients with preterm labor appear not to have been fully un-
derstood in clinical obstetric practice. Antimicrobial treat-
ment of patients with infection often leads to the release of
microbial products (eg, endotoxin), which may exacerbate
the cytokine response and lead to clinical worsening.26
This issue is a major concern in the treatment of septic
shock and often considered a cause of death.27 A similar
scenario may occur in patients with microbial invasion of
the decidua and/or the amniotic cavity. Antimicrobial
agents may lead to an initial worsening of the inflamma-
tory response, which may accelerate the process of parturi-
tion and/or fetal damage. Basic and clinical research is
urgently required to understand the value of agents that
modulate the inflammatory response in obstetrics. It is pos-
sible that transient down-regulation of the effects of the in-
flammatory response would permit the time that is
required to eradicate the infectious process, without injury
to the fetus. Under these circumstances, prolongation of
pregnancy may be safe and desirable.
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