A C TA Obstetricia et Gynecologica

AOGS M A I N R E S E A R C H A R T I C L E

Intra-amniotic inflammation predicts microbial invasion of

the amniotic cavity but not spontaneous preterm delivery in
preterm prelabor membrane rupture
TERESA COBO1 , MARIAN KACEROVSKY2 , ROSE-MARIE HOLST3 , DAVID M. HOUGAARD4 , KRISTIN
SKOGSTRAND4 , ULLA-BRITT WENNERHOLM3 , HENRIK HAGBERG3 & BO JACOBSSON3,5
1

Maternal Fetal Medicine Department, Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS),
University of Barcelona, Barcelona, Spain, 2 Department of Obstetrics and Gynecology, University Hospital Hradec Kralove,
Hradec Kralove, Czech Republic, 3 Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg,
Sweden, 4 Department of Clinical Biochemistry and Immunology, State Serum Institute, Copenhagen, Denmark, and
5
Department of Genes and Environment, Institute of Public Health, Oslo, Norway

Key words
amniotic cavity, intra-amniotic inflammation,
microbial invasion, preterm prelabor
membrane rupture, spontaneous preterm
delivery
Correspondence
Teresa Cobo, Prematurity Unit, Department of
Maternal-Fetal Medicine, Hospital Clinic,
Sabino de Arana 1, Barcelona 08028, Spain.
E-mail: tcobo@clinic.ub.es

Conflict of interest
The authors have stated explicitly that there
are no conflicts of interest in connection with
this article.
Please cite this article as: Cobo T, Kacerovsky
M, Holst R-M, Hougaard DM, Skogstrand K,
Wennerholm U-B, Hagberg H, Jacobsson B.
Intra-amniotic inflammation predicts microbial
invasion of the amniotic cavity but not
spontaneous preterm delivery in preterm
prelabor membrane rupture. Acta Obstet
Gynecol Scand 2012;91:930935.
Received: 8 November 2011
Accepted: 6 April 2012
DOI: 10.1111/j.1600-0412.2012.01427.x

930

Abstract
Objective. To predict microbial invasion of the amniotic cavity (MIAC) and spontaneous preterm delivery within seven days using a panel of selected proteins from
amniotic fluid in a Swedish population of preterm prelabor membrane rupture
(PPROM). Design. Prospective cohort study. Setting. Evaluation of intra-amniotic
inflammation in preterm premature rupture of membranes. Population. Sixty-six
pregnant women with preterm prelabor membrane rupture at 22+0 33+6 weeks
gestational age. Methods. Twenty-seven amniotic fluid proteins were assayed by a
multiple immunoassay. Main outcome measures. The intra-amniotic inflammatory
response was evaluated according to the presence of MIAC and the risk of spontaneous preterm delivery within seven days. A prediction model was constructed using logistic regression. Results. The overall rates of MIAC and spontaneous preterm
delivery within seven days were 20 and 50%, respectively. There was a higher inflammatory response in women with MIAC than in those without. Earlier gestational
age at delivery and lower birthweight were observed in the presence of microbial
invasion of the amniotic cavity. Amniotic fluid interleukin (IL)-6 and IL-10 were
the best predictors of MIAC in terms of sensitivity (69%), specificity (81%), positive
predictive value (47%), negative predictive value (91%) and a positive likelihood
ratio of 3.6. There were no differences in intra-amniotic inflammatory response
according to the risk of spontaneous preterm delivery within seven days. Conclusion. Amniotic fluid IL-6 and IL-10 are the best inflammatory biomarkers to predict
MIAC in women with PPROM. Intra-amniotic inflammation does not predict the
occurrence of spontaneous preterm delivery within seven days of PPROM.
Abbreviations: BDNF, brain-derived neurotrophic factor; GM-CSF, granulocyte
macrophage colony-stimulating factor; IFN- , interferon- ; IL, interleukin;
MCP-1, monocyte chemotactic protein-1; MIAC, microbial invasion of amniotic cavity; MIP-1, macrophage inflammatory protein-1; MIF, migration inhibiting factor; MIP-1, macrophage inflammatory protein-1; MMP-9, matrix
metalloproteinase-9; NT3, neutropin-3; NT4, neutropin-4; PPROM, preterm
prelabor membrane rupture; RANTES, regulated on activation normal T-expressed
and secreted protein; sIL6r, soluble IL-6 receptor; sTNFR1, soluble TNF receptor
1; TGF-, transforming growth factor ; TNF-, tumor necrosis factor ; TNF-,
tumor necrosis factor ; TREM-1, triggering receptor expressed on myeloid cells-1.

!
C 2012 The Authors
C 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 930935
Acta Obstetricia et Gynecologica Scandinavica !

Inflammation predicts infection

T. Cobo et al.

Key Message
Intra-amniotic inflammation predicts microbial invasion
of the amniotic cavity, but not spontaneous preterm delivery, in preterm prelabor membrane rupture.

Introduction
Preterm prelabor membrane rupture (PPROM) is responsible for approximately one-third of spontaneous preterm
deliveries and for a substantial proportion of neonatal morbidity and mortality in relation to gestational age and the risk
of infection (1). Predicting the risk of these adverse outcomes
constitutes the basis for improving pregnancy management
and parental counseling.
Intra-amniotic inflammation has been proposed as the
strongest predictor of microbial invasion of the amniotic cavity (MIAC) in either preterm labor or PPROM (210). Several
inflammatory biomarkers alone or in combination have been
previously reported as markers of MIAC (5,8,9,1113). However, most studies are limited to the identification of a few
R
inflammatory biomarkers. xMAP!
technology (Luminex,
Austin, TX, USA) provides a broader characterization of the
intra-amniotic inflammatory response, making it possible to
measure a broad panel of candidate proteins simultaneously
(14,15).
The importance of some pro-inflammatory cytokines as
predictors of spontaneous preterm delivery has previously
been suggested in women with preterm labor and in women
with PPROM (1113,15). However, the prediction of spontaneous preterm delivery in PPROM using this precise and
accurate technology has not been explored.
The aim of the study was to evaluate the intra-amniotic inflammatory response regarding the presence of MIAC and the
risk of spontaneous preterm delivery within seven days and
therefore to determine the best prediction model of MIAC
and spontaneous preterm delivery in a Swedish population of
PPROM pregnancies using different proteins in the amniotic
fluid.

Material and methods

A prospective cohort study was performed in pregnant
women with a diagnosis of PPROM who were admitted to
the Department of Obstetrics and Gynecology, Salgrenska
University Hospital, Gothenburg, Sweden, between 1996 and
2005. Samples from some of the women included (n = 47)
had been analyzed previously by ELISA (9,12,13). Gestational
age was established according to routine ultrasound in the
second trimester (16th to 19th week of gestation).
The women enrolled in this study were singleton pregnant
women with PPROM from 22+0 to 33+6 weeks. Women with

clinical chorioamnionitis, contractions before rupture of the

membranes, known uterine abnormalities, fetal malformations, significant vaginal bleeding, imminent delivery or fetal
distress were not considered eligible.
PPROM was defined as the leakage of amniotic fluid which
precedes the onset of uterine contraction by at least two
hours. This condition was diagnosed by a sterile speculum
examination confirming the pooling of amniotic fluid in the
vagina. Digital examination was not performed.
A complete course of antenatal steroids, betamethasone
12 mg intramuscular injection in two doses, was administered from 24+0 to 33+6 weeks. Tocolytic therapy was used
only if uterine contractions were identified according to a departmental protocol. Non-antenatal antibiotic treatment was
used except in women with clinical symptoms of chorioamnionitis. Ultrasound-guided transabdominal amniocentesis
was performed under antiseptic conditions within 24 hours
from admission, and 3050 mL of amniotic fluid aspirated.
After sampling, the amniotic fluid was immediately placed in
a refrigerator (4 C) and processed within five hours. It was
centrifuged at 855 g at 4 C for 10 minutes and stored at 80 C
until analysis. A sample of uncentrifuged amniotic fluid was
immediately transported to the microbiological laboratory
for PCR analysis of Ureaplasma urealyticum and Mycoplasma
hominis and for aerobic and anaerobic culture. The results
were available for clinical management.
MIAC was defined as a positive PCR for genital mycoplasmas and/or a positive amniotic fluid culture, with the exception of coagulase negative-Staphylococcus, which was considered to be a skin contamination except for women with high
levels of amniotic fluid IL-6.
Informed consent was obtained from all subjects. The regional ethical committee approved the collection of the material and use of these samples and information for research
50699/ Dnr 47605).
purposes (Dnr 34995/ O

Amniotic fluid analyses

Amniotic fluid interleukin (IL)-1-, IL-2, IL-4, IL-5, IL6, IL-8, IL-10, IL-12, IL-17, IL-18, soluble IL-6 receptor (sIL6r), interferon- (IFN- ), tumor necrosis factor
(TNF)-, tumor necrosis factor (TNF)-, transforming
growth factor- (TGF-), monocyte chemotactic protein-1
(MCP-1), macrophage inflammatory protein-1 (MIP-1),
macrophage inflammatory protein-1 (MIP-1), matrix
metalloproteinase-9 (MMP-9), triggering receptor expressed
on myeloid cells-1 (TREM-1), brain-derived neurotrophic
factor (BDNF), granulocyte macrophage colony-stimulating
factor (GM-CSF), neutropin-4 (NT4), neutropin-3 (NT3),
soluble TNF receptor 1 (sTNFR1), migration inhibiting factor (MIF) and regulated on activation normal T-expressed
and secreted (RANTES) protein, were analyzed at the
State Serum Institute (Department of Clinical Biochemistry,

!
C 2012 The Authors
C 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 930935
Acta Obstetricia et Gynecologica Scandinavica !

931

Inflammation predicts infection

T. Cobo et al.

Copenhagen, Denmark) using a multiple sandwich imR

techmunoassay based on flowmetric Luminex xMAP!
nology in accord with the workflow previously published
(1417). The samples of amniotic fluid were measured undiluted and in duplicate. Calibration curves were prepared in
assay buffer (phosphate-buffered saline containing 5 mL/L
Tween 20 and 10 g/L bovine serum albumin). The means
of intra- and interassay coefficients of variation were 6 and
12%, respectively. The defined working range described by
Skogstrand et al. (17) was used, due to the impossibility
of obtaining cytokine-free amniotic fluid. In this case, this
approach was considered to be a more accurate way of defining sensitivity than the commonly used signal-to-noise ratio
(limit of detection). Therefore, the detection level was defined
as half the lowest levels in the working range in amniotic fluid
(IL-1 40 pg/mL; IL-2 4 pg/mL; IL-4 4 pg/mL; IL-5 4 pg/mL;
IL-6 40 pg/mL; IL-8 40 pg/mL; IL-10 10 pg/mL; IL-12
4 pg/mL; IL-17 4 pg/mL; IL-18 40 pg/mL; sIL-6r 2500 pg/mL;
IFN- 4 pg/mL; TNF- 4 pg/mL; TNF- 4 pg/mL; TGF 4 pg/mL; MCP-1 156 pg/mL; MIP-1 40 pg /mL; MIP1 40 pg/mL; MMP-9 5000 pg/mL; TREM-1 100 pg/mL;
BDNF 10 pg/mL; GM-CSF 4 pg/mL; NT4 4 pg/mL; NT3
40 pg/mL; sTNFR1 156 pg/mL; MIF 100 pg/mL; and RANTES
40 pg/mL). The analyses were performed by an investigator
who was blinded to the clinical status of the women. Three
proteins (IL-17, TNF- and TGF-) were present at undetectable amniotic fluid levels in more than 50% of the samples
and were subsequently excluded from further analyses.

Table 1. Maternal and neonatal characteristics according to the pres-

Statistical analysis

the amniocentesis was performed after the administration

of antibiotics (n = 1) or steroids (n = 7). They were not
significantly or unequally distributed between the MIAC and
non-MIAC groups. Gestational age at birth and birthweight
were significantly lower in women with MIAC than in those
without.
The overall rate of MIAC was 20% (13/66). The most common microorganism isolated from amniotic fluid was Ureaplasma urealyticum (n = 8). Other microorganisms isolated
were: Mycoplasma hominis (n = 1), Staphylococcus coagulasenegative (n = 2), anaerobic gram-negative rod (n = 1) and
Peptostreptococcus (n = 1) (9). Both women with a positive
culture for Staphylococcus coagulase-negative had levels of IL6 in amniotic fluid of 22 286 and 40 000 pg/mL, respectively.
The comparison of levels of amniotic fluid cytokines according to the presence of MIAC is summarized in Table 2.
The intra-amniotic inflammatory response was significantly
higher in women with MIAC than in women without.
Maternal and neonatal characteristics according to the risk
of spontaneous preterm delivery within seven days are summarized in Table 3. No significant association was observed
of spontaneous preterm delivery within seven days with any
cytokine, and therefore logistic regression analysis to predict
spontaneous preterm delivery was not performed (Table 4).

Statistical analyses were performed using SPSS 19.0 for Windows XP OS (IBM SPSS Statistics 19, IBM Inc., Armonk, NY).
Demographic and clinical characteristics were compared using the nonparametric MannWhitney U-test presented as
median (range). Categorical variables were compared using
Fishers exact test and presented as number (%). All continuous variables were entered into a logistic regression with
a forward selection. Differences were considered significant
at a confidence level of p < 0.05 with two-sided alternative
hypotheses.

Results
Between 1995 and 2005, 66 women diagnosed with PPROM
between 22+0 and 33+6 weeks, were admitted to the Department of Obstetrics and Gynecology of Sahlgrenska University
Hospital, Gothenburg, and who met the inclusion criteria,
were included. Gestational age (median) at admission of the
entire study population was 31.4 (range: 22.333.5) weeks,
gestational age at sampling was 31.4 (22.433.6) weeks, and
gestational age at delivery was 33.2 (range: 23.140.1) weeks.
The maternal and neonatal characteristics according to the
presence of MIAC are summarized in Table 1. In eight women

932

ence of microbial invasion of the amniotic cavity.

Presence microbial Absence microbial
invasion of the
invasion of the
amniotic cavity
amniotic cavity
n = 53
n = 13
Maternal age
Nulliparous
Smoking
Body mass
index
Gestational
age at
admission
(weeks)
Gestational
age at
sampling
(weeks)
Gestational
age at
delivery
(weeks)
Birthweight (g)
5-min Apgar
score <7

30 (2043)
8 (61)
3 (23)
20.0 (16.932.6)

30 (1942)
25 (47)
9 (17)
22.1 (16.734.7)

0.789
0.480
0.795
0.473

31.1 (22.333.3)

31.4 (23.333.5)

0.694

31.1 (22.433.3)

31.4 (23.333.6)

0.646

32.0 (23.133.6)

33.3 (28.140.1)

0.010

1680 (4702505) 2202 (11553940)

0
2 (4)

0.043
0.787

Continuous variables were compared using a non-parametric

MannWhitney U-test presented as median (range). Categorical variables were compared using Fishers exact test and presented as number
(%).

!
C 2012 The Authors
C 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 930935
Acta Obstetricia et Gynecologica Scandinavica !

Inflammation predicts infection

T. Cobo et al.

Table 2. Comparison of levels of amniotic fluid proteins according to the presence of microbial invasion of the amniotic cavity.

IL-1
IL-2
IL-4
IL-5
IL-6
IL-8
IL-10
IL-12
IL-18
sIL6r
IFN-
TNF-
MCP-1
MIP-1
MIP-1
MMP-9
TREM-1
BDNF
GM-CSF
NT4
NT3
sTNFR1
MIF
RANTES

Presence of microbial invasion of amniotic cavity n = 13

Absence of microbial invasion of amniotic cavity n = 53

276(405822)
172(613692)
10(454)
42(16137)
22285(2614.789 212.5)
11841(1341.7685 217.1)
765(255.616 363.1)
23(3.7179.9)
165(64.91165.1)
5045(250024 953)
235(4751.3)
154(27.94694.8)
9319(1864.398 625.5)
2604(189.348 982.0)
2602(19432 193)
72916(40 243.21 415 088.8)
4161(491.631947.7)
2499(327.36024.8)
463(76.51487.6)
46(20372)
6914(2115.522 352.9)
24617(12 83383 098)
81167(9248.1141 074.8)
4205(664.447 983)

40(409732)
147(42250)
6.5(4275)
20(4712)
3351(232.240 000)
2835(221.440 000)
148(108875.5)
12(3.3473.4)
96(35.91022.2)
4164(50235340)
4(49926.3)
65(41095.5)
3193(31370 534.5)
140(32.59554.2)
330(3915 124)
45826(3455.8907 994.3)
2007(5057 003.3)
667(106719.8)
164(10.61683.9)
30(3420)
3599(40214 140.2)
20300(127583 352)
53952(3007.5136 205.2)
692(4050 023.6)

0.000
0.385
0.134
0.022
0.001
0.018
0.000
0.156
0.028
0.051
0.036
0.012
0.027
0.027
0.000
0.003
0.168
0.006
0.067
0.027
0.079
0.036
0.033
0.003

Continuous variables were compared using a non-parametric MannWhitney U-test presented as median (range). IL, interleukin; sIL6r, soluble IL-6
receptor; IFN- , interferon- ; TNF-, tumor necrosis factor ; MCP-1, monocyte chemotactic protein-1; MIP-1, macrophage inflammatory protein-1;
MIP-1, macrophage inflammatory protein-1; MMP-9, matrix metalloproteinase-9; TREM-1, triggering receptor expressed on myeloid cells-1; BDNF,
brain-derived neurotrophic factor; GM-CSF, granulocyte macrophage colony-stimulating factor; NT4, neutropin-4; NT3, neutropin-3; sTNFR1, soluble
TNF receptor 1; MIF, migration inhibiting factor; RANTES, regulated on activation normal T-expressed and secreted protein.

All amniotic fluid cytokines were entered into a logistic

regression with a forward selection to predict microbial invasion of the amniotic cavity. Amniotic fluid IL-6 and IL-10
were the best predictors of MIAC (area under curve of 0.83

with a 95% confident interval of 0.740.90) in terms of accuracy (78%), sensitivity (69%), specificity (81%), positive
predictive value (47%), negative predictive value (91%) and
positive likelihood ratio of 3.6.

Table 3. Maternal and neonatal characteristics according to the risk of spontaneous preterm delivery within seven days.

Maternal age
Nulliparous
Smoking
Body mass index
Gestational age at admission (weeks)
Gestational age at sampling (weeks)
Gestational age at delivery (weeks)
Birthweight (grams)
Microbial invasion of the amniotic
cavity
5-min Apgar score < 7

Spontaneous preterm delivery within

seven days, n = 33

No spontaneous preterm delivery

within seven days, n = 33

32(2043)
22(66)
6(18)
24.0(16.932.6)
32.5(22.333.5)
32.5(22.433.6)
32.5(23.134.3)
2130(4702885)
10(30)

27(1942)
13(39)
6(18)
21.9(16.734.7)
29.3(23.333.3)
29.3(23.333.3)
33.6(28.140.1)
2155(11553940)
3(9)

1(3)

1(3)

p
0.074
0.048
1.000
0.398
0.000
0.000
0.011
0.130
0.073
0.368

Continuous variables were compared using a non-parametric MannWhitney U-test presented as median (range). Categorical variables were compared
using Fishers exact test and presented as number (%).

!
C 2012 The Authors
C 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 930935
Acta Obstetricia et Gynecologica Scandinavica !

933

Inflammation predicts infection

T. Cobo et al.

Table 4. Comparison of levels of amniotic fluid proteins according to the risk of spontaneous preterm delivery within seven days.

IL-1
IL-2
IL-4
IL-5
IL-6
IL-8
IL-10
IL-12
IL-18
sIL6r
IFN-
TNF-
MCP-1
MIP-1
MIP-1
MMP-9
TREM-1
BDNF
GM-CSF
NT4
NT3
sTNFR1
MIF
RANTES

Spontaneous preterm delivery within 7 days n = 33

Spontaneous preterm delivery > 7 days n = 33

40(409732)
135(42250)
6(473)
22(4168)
5361(232.389 212.6)
3681(355.1685217.2)
185(1016 363.1)
15(3.4473.4)
123(35.91165.1)
4134(145518 932)
4(41179.2)
68(44694.8)
3069(31370 534.5)
168(32.540 000)
582(3932 193)
50646(3455.8335418)
1898(5057003.3)
597(106719.9)
164(36.81672.01)
32(3406)
3559(4065847.9)
20012(127557895)
60038(4381.4141074.9)
1170(4047983)

40(404043)
162(113692)
9(4275)
30.5(4712)
4473(343.640000)
3248(221.540 000)
297(109511.6)
12(3.7183.3)
124(401022.2)
5913(50235 340)
117(49926.3)
88(41418.7)
4696(31398625.5)
238(4048982.03)
436(3914280)
46121(13230.11415088.8)
2429(149.931947.7)
1486(105998.1)
179(10.61683.9)
42(5420)
4415(40214140.3)
22578(241083352)
58721(3007.6134804.1)
1168(4050023.6)

0.246
0.397
0.065
0.150
0.245
0.220
0.256
0.696
0.650
0.051
0.109
0.555
0.372
0.702
0.458
0.753
0.572
0.051
0.927
0.133
0.408
0.122
0.520
0.855

Continuous variables were compared using a nonparametric Mann-Whitney U test presented as median (range). Abbreviations: IL, interleukin; sIL6r,
soluble IL-6 receptor; IFN- , interferon- ; TNF-, tumor necrosis factor ; MCP-1, monocyte chemotactic protein-1; MIP-1, macrophage inflammatory
protein-1; MIP-1, macrophage inflammatory protein-1; MMP-9, matrix metalloproteinase-9; TREM-1, triggering receptor expressed on myeloid
cells-1; BDNF, brain-derived neurotrophic factor; GM-CSF, granulocyte macrophage colony-stimulating factor; NT4, neutropin-4; NT3, neutropin-3;
sTNFR1, soluble TNF receptor 1; MIF, migration inhibiting factor; RANTES, regulated on activation normal T-expressed and secreted protein.

Discussion
A higher intra-amniotic inflammatory response, as measured
by 24 cytokines, was observed in women with microbial invasion of the amniotic cavity. Amniotic fluid IL-6 and IL-10
were the most accurate cytokines to predict the status of
microbial invasion of the amniotic cavity. However, intraamniotic inflammation did not predict the risk of spontaneous delivery within seven days in women with preterm
prelabor membrane rupture.
In agreement with previous results (4,8), intra-amniotic
inflammation was significantly associated with MIAC. The
R
availability of the xMAP!
technology to measure a panel of
candidate proteins simultaneously, allowed a broader characterization of the relevant inflammatory biomarkers identified
in amniotic fluid (14,15,17). According to our data, from all
biomarkers analyzed, the two best predictors of MIAC cavity were IL-6 and IL-10. We have previously reported, in a
different cohort of women with PPROM, the role of these
cytokines as predictors of histological chorioamnionitis and
funisitis (18), which suggests that the presence of a high level
of IL-6 and IL-10 was associated with a severe stage of infection involving placental inflammation. This new finding
934

ratifies the importance of both inflammatory biomarkers in

the inflammatory pathway as two of the main biomarkers
responsible for worse outcomes in women complicated with
PPROM. Due to the conservative management of PPROM in
our population, placental pathology at birth does not provide
the same information as at amniocentesis sampling. Therefore, the implications of placental markers in these women
with MIAC remain unknown.
Contrary to preterm labor with intact membranes (15),
the intra-amniotic inflammatory response does not predict
the risk of spontaneous preterm delivery within seven days
in women with PPROM. This is clinically relevant and suggests that a non-inflammatory mechanism may be primarily
responsible for this adverse outcome in PPROM or that the
inflammatory process is less intense and lasts for a longer
time. In preterm labor, a longer exposure or a different pattern of inflammation that reflects the contractility process
may explain the influence of intra-amniotic inflammation
on the origin of spontaneous preterm delivery.
One of the strengths of this study was that the conservative
management of PPROM did not interfere with the occurrence
of spontaneous preterm delivery and preterm delivery within
seven days. The main limitation was that it was performed

!
C 2012 The Authors
C 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 930935
Acta Obstetricia et Gynecologica Scandinavica !

Inflammation predicts infection

T. Cobo et al.

in a single institution, which prevented the use of a larger

sample size.
In summary, the identification of intra-amniotic inflammation in women with a membrane rupture confirms the
importance of microbial invasion of the amniotic cavity.
The identification of more severe inflammation in pregnant
women complicated with PPROM could probably improve
parenteral prognosis by enhancing the clinicians knowledge
of subclinical infection, but does not predict the risk of
preterm delivery within seven days.

9.

10.

Funding
Teresa Cobo thanks Instituto de Salud Carlos III, Spain, for
her Rio Hortega grant (CM09/00213). This work was supported by grants from the Swedish Medical Research Council
(VR 20063396), Swedish Medical Society (SLS 200821198),
Swedish government grants to researchers in the public health
service (ALFGBG-2863, ALFGBG-11522) and The Goteborg
Medical Society.
References
1. ACOG Practice Bulletin No. 80: premature rupture of
membranes. Clinical management guidelines for
obstetrician-gynecologists. Obstet Gynecol.
2007;109:100719.
2. Cobo T, Palacio M, Martinez-Terron M, Navarro-Sastre A,
Bosch J, Filella X, et al. Clinical and inflammatory markers in
amniotic fluid as predictors of adverse outcomes in preterm
premature rupture of membranes. Am J Obstet Gynecol.
2011;205:126.e18 (Epub Apr 8, 2011).
3. Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L,
Hassan S. The role of inflammation and infection in preterm
birth. Semin Reprod Med. 2007;25:2139.
4. Shim SS, Romero R, Hong JS, Park CW, Jun JK, Kim BI, et al.
Clinical significance of intra-amniotic inflammation in
patients with preterm premature rupture of membranes. Am
J Obstet Gynecol. 2004;191:133945.
5. Yoon BH, Romero R, Moon JB, Shim SS, Kim M, Kim G,
et al. Clinical significance of intra-amniotic inflammation in
patients with preterm labor and intact membranes. Am J
Obstet Gynecol. 2001;185:11306.
6. Buhimschi CS, Bhandari V, Hamar BD, Bahtiyar MO, Zhao
G, Sfakianaki AK, et al. Proteomic profiling of the amniotic
fluid to detect inflammation, infection, and neonatal sepsis.
PLoS Med. 2007;4:e18.
7. Cobo T, Palacio M, Navarro-Sastre A, Ribes A, Bosch J,
Filella X, et al. Predictive value of combined amniotic fluid
proteomic biomarkers and interleukin-6 in preterm labor
with intact membranes. Am J Obstet Gynecol. 2009;200:499
e16.
8. Buhimschi IA, Christner R, Buhimschi CS. Proteomic

11.

12.

13.

14.

15.

16.

17.

18.

biomarker analysis of amniotic fluid for identification of

intra-amniotic inflammation. Br J Obstet Gynaecol.
2005;112:17381.
Jacobsson B, Mattsby-Baltzer I, Andersch B, Bokstrom H,
Holst RM, Nikolaitchouk N, et al. Microbial invasion and
cytokine response in amniotic fluid in a Swedish population
of women with preterm prelabor rupture of membranes.
Acta Obstet Gynecol Scand. 2003;82:42331.
Jacobsson B, Mattsby-Baltzer I, Andersch B, Bokstrom H,
Holst RM, Wennerholm UB, et al. Microbial invasion and
cytokine response in amniotic fluid in a Swedish population
of women in preterm labor. Acta Obstet Gynecol Scand.
2003;82:1208.
Jacobsson B, Holst RM, Andersson B, Hagberg H. Monocyte
chemotactic protein-2 and -3 in amniotic fluid: relationship
to microbial invasion of the amniotic cavity, intra-amniotic
inflammation and preterm delivery. Acta Obstet Gynecol
Scand. 2005;84:56671.
Jacobsson B, Holst RM, Mattsby-Baltzer I, Nikolaitchouk N,
Wennerholm UB, Hagberg H. Interleukin-18 in cervical
mucus and amniotic fluid: relationship to microbial invasion
of the amniotic fluid, intra-amniotic inflammation and
preterm delivery. Br J Obstet Gynaecol. 2003;110:598603.
Jacobsson B, Holst RM, Wennerholm UB, Andersson B, Lilja
H, Hagberg H. Monocyte chemotactic protein-1 in cervical
and amniotic fluid: relationship to microbial invasion of the
amniotic cavity, intra-amniotic inflammation, and preterm
delivery. Am J Obstet Gynecol. 2003;189:11617.
Holst RM, Hagberg H, Wennerholm UB, Skogstrand K,
Thorsen P, Jacobsson B. Prediction of microbial invasion of
the amniotic cavity in women with preterm labour: analysis
of multiple proteins in amniotic and cervical fluids. Br J
Obstet Gynaecol. 118:2409.
Holst RM, Hagberg H, Wennerholm UB, Skogstrand K,
Thorsen P, Jacobsson B. Prediction of spontaneous preterm
delivery in women with preterm labor: analysis of multiple
proteins in amniotic and cervical fluids. Obstet Gynecol.
2009;114:26877.
Vogel I, Goepfert AR, Thorsen P, Skogstrand K, Hougaard
DM, Curry AH, et al. Early second-trimester inflammatory
markers and short cervical length and the risk of recurrent
preterm birth. J Reprod Immunol. 2007;75:13340.
Skogstrand K, Thorsen P, Norgaard-Pedersen B, Schendel
DE, Sorensen LC, Hougaard DM. Simultaneous
measurement of 25 inflammatory markers and
neurotrophins in neonatal dried blood spots by
immunoassay with xMAP technology. Clin Chem.
2005;51:185466.
Cobo T, Kacerovsky M, Palacio M, Hornychova H, Hougaard
DM, Skogstrand K, et al. A prediction model of histological
chorioamnionitis and funisitis in preterm prelabor rupture
of membranes: analyses of multiple proteins in the amniotic
fluid. J Matern Fetal Neonatal Med. 2012 (Epub Mar23,
2012).

!
C 2012 The Authors
C 2012 Nordic Federation of Societies of Obstetrics and Gynecology 91 (2012) 930935
Acta Obstetricia et Gynecologica Scandinavica !

935

Copyright of Acta Obstetricia et Gynecologica Scandinavica is the property of Wiley-Blackwell and its content
may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express
written permission. However, users may print, download, or email articles for individual use.