non-invasive prediction of chorioamnionitis in...
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학 사 학 논
Non-invasive prediction of chorioamnionitis in
women with preterm premature rupture of
membranes
만삭 조 양막 열 산모에 침습
인자를 통한 모양막염
2014 2 월
울 학 학원
학과 산부인과 공
수아
↑
2cm
↓
만
삭
조
양
막
열
산
모
에
침
습
인
자
를
통
한
모
양
막
염
↑
2.5cm
↓
2
0
1
4
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4cm
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3cm
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수
아
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2cm
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학 사 학 논
Non-invasive prediction of chorioamnionitis in
women with preterm premature rupture of
membranes
만삭 조 양막 열 산모에 침습
인자를 통한 모양막염
2014 2 월
울 학 학원
학과 산부인과 공
수아
Non-invasive prediction of chorioamnionitis in
women with preterm premature rupture of
membranes
지도 수 박 훈
이 논 학 사 학 논 출함
2013 10 월
울 학 학원
학과 산부인과 공
수아
수아 학 사 학 논 인 함
2014 1 월
원 장 (인)
부 원장 (인)
원 (인)
학 논 원 공 스에 한 동
본인 학 논 에 하여 울 학 가 아래 같이 학 논 공하는 것에
동 합니다.
1. 동 사항
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본 문 저 타 에게 양도하거나 또는 판 허락하는 등 동 내 변경하고
할 는 학(원)에 공개 보 또는 해지 즉시 통보하겠습니다.
3. 울 학 무
① 울 학 는 본 문 에 제공할 경우 저 보 치(DRM) 사 하여야 합니다.
② 울 학 는 본 문에 한 공개 보나 해지 신청 시 즉시 처리해야 합니다.
논 목 : (Place thesis title here)
학 구분 : 사
학 과 : 학과 산부인과 공
학 번 : 2012-21679
연 락 처 :
작 자 : 수아 (인)
출 일 : 2014 2 월 5 일
울 학 장 귀하
i
Abstract
Non-invasive prediction of chorioamnionitis in
women with preterm premature rupture of
membranes
Su Ah Kim
Obstetrics & Gynecology
The Graduate School
Seoul National University
Introduction: The purpose of this study was to develop a model based on non-invasive clinical and
ultrasonographic parameters to predict the occurrence of subsequent chorioamnionitis in pregnant
women with preterm premature rupture of membranes (PPROM). Additionally, this investigation was
conducted to determine if additional invasive test results improve the prediction of occurrence of
subsequent chorioamnionitis from the non-invasive model.
Methods: Transvaginal ultrasonographic assessment of cervical length was performed. Maternal
serum C-reactive protein (CRP) and white blood cell (WBC) counts were also measured immediately
after amniocentesis in 146 consecutive women with PPROM at 20+0 and 33+6 weeks of gestation.
Amniotic fluid (AF) obtained by amniocentesis was cultured, and interleukin-6 (IL-6) levels and
WBC counts were determined. Outcome measures were histologic or clinical chorioamnionitis. The
ii
placentas were examined histologically for the presence of chorioamnionitis and the pregnant women
were evaluated for evidence of clinical chorioamnionitis.
Results: The prevalence of histological and clinical chorioamnionitis was 50.7% (74/146) and 8.9%
(13/146), respectively. A risk score based on a non-invasive model (model 1), including serum CRP
and gestational age, was calculated for each patient. The model was shown to have an adequate
goodness of fit, and the area under the receiver operating characteristic curve (AUC) was 0.742.
When including AF tests results (e.g., AF IL-6 levels) as invasive markers in the non-invasive model,
serum CRP was excluded from the final model (model 2) as insignificant, whereas AF IL-6 and
gestational age remained in model 2. No significant difference in AUC was found between models 1
and 2. For the outcome of clinical chorioamnionitis, none of the parameters studied could be used to
identify pregnant women at high risk for the development of clinical chorioamnionitis.
Conclusions: For pregnant women with PPROM, the non-invasive model based on serum CRP and
gestational age was shown to be moderately predictive of histologic chorioamnionitis development.
However, invasive test results did not add predictive information to the non-invasive model in this
setting.
Key words: amniotic fluid, chorioamnionitis, C-reactive protein, gestational age, non-invasive model,
preterm premature rupture of membranes,
Student number: 2012-21679
iii
List of Tables
Table 1. Demographic and clinical characteristics of the study population according to the presence or
absence of histologic chorioamnionitis ------------------------------------------------------------------------13
Table 2. The final non-invasive model and the final model that included the additional invasive test
results for determining risk scores to predict histologic chorioamnionitis --------------------------------15
Table 3. Sensitivity, specificity, positive (PPV) predictive values, and likelihood ratios (LRs) of the
different cut-off values for predicting histologic chorioamnionitis using the final model based on the
dichotomization of two non-invasive parameters-------------------------------------------------------------16
Table 4. Demographic and clinical characteristics of the study population according to the presence or
absence of clinical chorioamnionitis ----------------------------------------------------------------------------17
iv
List of Figures
Figure 1. Receiver operating characteristic curves for each of (A) non-invasive and (B) invasive
parameters in predicting subsequent histologic chorioamnionitis (gestational age: area under the curve
[AUC] 0.734, SE 0.042, P < 0.001; serum C-reactive protein: AUC 0.617, SE 0.048, P <0.015;
maternal blood white blood cell (WBC): AUC 0.640, SE 0.046, P=0.003; amniotic fluid (AF) WBC:
AUC 0.702, SE 0.044, P <0.001; AF interleukin-6: AUC 0.743, SE 0.041, P <0.001)---------------- 19
Figure 2. ROC curves comparing the power of the non-invasive model (model 1, solid line), and the
addition (model 2, dotted line) of amniotic fluid tests results as invasive markers to the non-invasive
model for predicting subsequent histologic chorioamnionitis development (model 1: area under the
curve [AUC], 0.742; 95% confidence interval [CI], 0.661-0.823 versus model 2: AUC, 0.757; 95% CI,
0.677-0.836; P = 0.623)-------------------------------------------------------------------------------------------21
v
Contents
Introduction------------------------------------------------------------------------------1
Material and Methods------------------------------------------------------------------3
Results-------------------------------------------------------------------------------------8
Discussion--------------------------------------------------------------------------------22
Reference--------------------------------------------------------------------------------28
국 ---------------------------------------------------------------------------------35
1
Introduction
Histologic chorioamnionitis is present in approximately 50-60% of pregnant women with
preterm premature rupture of membranes (PPROM).1-5 This condition is thought to represent
antenatal exposure to inflammation/infection, which contributes to occurrence of impending
preterm birth and neonatal sepsis, chronic lung disease and brain injury. 1, 3, 5-9 Early and
accurate diagnosis of chorioamnionitis is important, but is limited by the fact that placental
pathology cannot be evaluated before delivery. Several studies have attempted to identify
rapid, yet highly sensitive and specific diagnostic markers for diagnosing chorioamnionitis
via analysis of amniotic fluid (AF) obtained through amniocentesis, such as the AF
interleukin-6 (IL-6), this parameter has accordingly been reported as a significant predictor.1,
6, 7 However, amniocentesis is an invasive procedure with accompanying risks 10and
decreased AF volume in cases of PPROM often makes it difficult or impossible to obtain AF.
Consequently, alternative approaches for non-invasive and rapid identification of
chorioamnionitis are needed for pregnant women with PPROM.
Previous studies have shown that the measurement of C-reactive protein (CRP)
levels or white blood cell (WBC) counts in maternal blood may be useful, non-invasive
tools for diagnosing histologic chorioamnionitis before birth in pregnant women with
PPROM.11-13 It has also been reported that gestational age at the time of rupture and parity
are significant risk factors for histologic chorioamnionitis.1, 7 However, none of these factors
appear to be sufficiently sensitive or specific on an individual basis. This is perhaps because
2
the development of imminent chorioamnionitis before or after membrane rupture in a preterm
gestation may potentially be influenced by various pathogenetic factors including the hosts'
innate immune function and status, anatomical factors, mucosal immunity, and maternal
and/or fetal genotypes.14 It is likely that the only way to improve the predictability of
histologic chorioamnionitis is to use a combination of different markers, probably reflecting
the various pathogenetic factors underlying the disease. The purposes of the present study
were to develop a model based on non-invasive clinical and ultrasonographic parameters to
predict the probability of developing chorioamnionitis in pregnant women with PPROM, and
to determine if additional invasive test results improve the predictive value of the non-
invasive model.
3
Materials and Methods
A retrospective cohort study was conducted that included consecutive pregnant women
diagnosed with PPROM at Seoul National University Bundang Hospital (Seongnamsi, South
Korea) between June 2004 and August 2013. The inclusion criteria were: (1) singleton
gestation; (2) a live fetus with a gestational age between 20+0 and 33+6 weeks; (3)
transabdominal amniocentesis performed to assess the microbiologic and inflammatory status
of the amniotic cavity and/or fetal lung maturity; (4) maternal blood drawn to measure the
WBC count and CRP level at the time of amniocentesis; (5) cervical length measured at the
time of amniocentesis; (6) absence of active labor, defined by the presence of cervical
dilatation > 3 cm measured by sterile speculum examination; (7) no history of prior or
subsequent cervical cerclage; and (8) absence of a major congenital anomaly. Gestational age
was estimated based on ultrasound data obtained before 20 weeks of gestation. PPROM was
defined as spontaneous rupture of the fetal membranes before the onset of uterine
contractions, as diagnosed by a sterile speculum examination confirming both AF pooling in
the vagina, or leaking from the cervical os and a positive nitrazine test. Digital examinations
were not performed until the onset of labor (defined by the presence of regular and painful
uterine contractions). Non-invasive clinical parameters that were collected at the time of
enrollment included demographic variables (maternal age, parity, and previous preterm
delivery), gestational age at the time of assessment, CRP level, maternal WBC count, and
cervical length measured by transvaginal ultrasonography. Amniocentesis for AF retrieval
and measurement of cervical length was immediately offered to patients who diagnosed with
4
PPROM and admitted at our institution. Throughout the study period, maternal WBC counts
and serum CRP levels were routinely determined at the time of amniocentesis for all women
with PPROM. The primary outcome measures were histologic or clinical chorioamnionitis.
The study was approved by the institutional review board of the Seoul National University
Bundang Hospital. Informed consent was obtained from all study subjects for the
amniocentesis procedure and use of AF samples for research purposes.
AF was retrieved by transabdominal amniocentesis using an aseptic technique with
ultrasound guidance. Aerobic and anaerobic bacteria as well as genital mycoplasma
(Ureaplasma urealyticum and Mycoplasma hominis) present in the AF samples were cultured
according to methods previously described in detail .15 An aliquot of AF was transferred to
the hematology laboratory and examined in a hemocytometer chamber for the presence of
WBCs. The absolute WBC count was calculated by multiplying the area examined by a factor
of 10 per area and expressed as the number of cells per cubic mL. The remaining AF was
centrifuged, and the supernatant was aliquoted and stored at -70°C until assayed. The samples
were not allowed to freeze-thaw cycles before being assayed. IL-6 concentrations were
measured with an enzyme-linked immunosorbent assay (ELISA) human IL-6 DuoSet Kit
(R&D System, Minneapolis, MN, USA). The range of the IL-6 standard curve was 7.8-600
pg/mL. The assay was carried out by strictly following the instructions provided by the
manufacturer and all samples were measured in duplicate. The calculated intra- and inter-
assay coefficients of variation were < 10%. Maternal blood WBC counts were determined
using an automated hemocytometer (XE-2100; Sysmex, Tokyo, Japan). The CRP
5
concentration was measured with a latex-enhanced turbidimetric immunoassay (Denka
Seiken, Tokyo, Japan) using an automated analyzer (Toshiba 200FR; Toshiba, Tokyo, Japan).
Transvaginal ultrasonographic assessment of cervical length was performed by
trained obstetrician immediately after amniocentesis using either an Envisor (Philips Medical
System, Eindhoven, The Netherlands) or an Accuvix XQ (Medison Co. Ltd., Seoul, Korea)
ultrasound machine with a 6.0 MHz transducer covered by a sterile condom. The method
used to measure the cervical length has been previously described.16 Three measurements
were performed and the shortest distance was taken as the cervical length.
Histologic chorioamnionitis was diagnosed in the presence of acute inflammatory
changes in any of the tissue samples (amnion, chorion-decidua, umbilical cord, and
chorionic plate) using previously published criteria.6 Funisitis was diagnosed by the
presence of neutrophil infiltration into the umbilical vessel walls or Wharton's jelly. Clinical
chorioamnionitis was defined as a body temperature ≥ 37.8°C on two occasions at least 4
hours apart, and two or more of the following criteria: uterine tenderness; malodorous
vaginal discharge; maternal leukocytosis (> 15,000/mm3); maternal tachycardia (> 100
beats/min) and fetal tachycardia (>160 beats/min).17 Tocolytic therapy and corticosteroids
were administered at the discretion of the attending obstetrician. Whenever possible,
prophylactic antibiotics were given, but the type of antibiotics was left to the discretion of
the attending obstetrician. Ampicillin was the main antibiotic used. However,
erythromycin or azithromycin was additionally administered in many cases. Tocolytic
therapy as well as treatment with corticosteroids and antibiotics was started after
6
amniocentesis.
Shapiro-Wilk and Kolmogorov-Smirnov tests were used to test for normal
distribution of the data. Univariate analysis was conducted with Student’s t-test, Mann-
Whitney U test, χ2 test, or Fisher’s exact test. A multivariable logistic regression analysis
was then performed, using the forward stepwise technique to develop models for
predicting the development of histologic chorioamnionitis. Two separate models were
constructed for each non-invasive variable along with the combination of non-invasive and
invasive parameters. Model 1 only included non-invasive variables. Model 2 included
several variables (AF WBC count, AF IL-6 level, and AF culture results) using invasive
amniocentesis in addition to non-invasive parameters. The linearity assumption was
assessed with a Wald χ2 test. For the logistic regression model, all factors were entered as
dichotomous variables because the assumption of linearity in the logit was not satisfied,
especially for gestational age, maternal blood WBC count, and AF WBC count and IL-6
concentration were concerned. Receiver operating characteristic (ROC) curves were used to
identify the best cut-off values for the dichotomization of variables. The optimal cut-off
values were obtained based on the Youden index, maximum [(sensitivity + specificity)-1].18
Risk scores based on each model were calculated according to the coefficients of variables
obtained from the forward stepwise modeling. P values < 0.2 from the univariate analysis
were required for entry into the stepwise modeling, and a P value < 0.05 was required for
final inclusion in the model. Goodness-of-fit of the logistic regression model was assessed
by the Hosmer-Lemeshow test. Tests for interaction were performed by entering cross-
7
product terms into the logistic models. The discriminatory ability of the model was assessed
by the ROC curve analysis.19 The model’s value that maximized the sum of the sensitivity
and specificity was considered the best cut-off point. To determine whether or not
additional invasive test results improved the prediction of histologic chorioamnionitis from
the non-invasive model, we estimated the statistical significance of the difference in the area
under the ROC curve (AUC) between models 1 and 2 using the method described by Hanley
and McNeil.20 All reported P values were two-sided, and P values <0.05 were considered
statistically significant. SPSS 18.0 for Windows (SPSS Inc., Chicago, IL, USA) was used
for statistical analyses.
8
Results
During the study period, 181 consecutive pregnant women diagnosed with PPROM who
fulfilled the inclusion criteria were recruited for this study. Out of the 181 pregnant women,
AF samples from seven women were not available for IL-6 measurement (four patients with a
negative AF culture and three patients with a positive culture), 17 had an incomplete data set
(lack of placental pathology [n = 6], lack of AF WBC counts [n = 2], lack of cervical length
measurement [n = 7], or lack of maternal serum CRP levels at the time of amniocentesis
[n=4]), three had a history of cervical cerclage placement during the index pregnancy, and
eight patients were transferred to another hospital. These women were subsequently excluded
from the study, leaving a total of 146 women suitable for evaluating the relationship between
histologic chorioamnionitis and the covariates. The mean gestational age (± standard
deviation) at the time of amniocentesis was 30.1 ± 3.3 weeks, with a range from 21 + 1 to 33
+ 6 weeks. The prevalence of histological and clinical chorioamnionitis was 50.7% (74/146)
and 8.9% (13/146), respectively. The overall rate of microbial invasion of the amniotic cavity
was 34.9% (51/146). Microorganisms isolated from the amniotic cavity included Ureaplasma
urealyticum (n = 41), Mycoplasma hominis (n = 28), Escherichia coli (n = 3),
Peptostreptococcus species (n = 2), Streptococcus agalactiae (n = 2), Streptococcus viridans
(n = 2), Lactobacillus species (n = 1), Staphylococcus aureus (n = 1), and unidentified Gram-
positive cocci (n = 1). Polymicrobial invasion was present in 30 cases (59 %; 30/51).
Table 1 shows the demographic and clinical characteristics of the women according
to the presence or absence of histologic chorioamnionitis. There were no statistically
9
significant differences in the mean maternal age or cervical length, the distribution of parous
and non-parous women, or the prevalence of previous spontaneous preterm delivery between
the two groups. However, women with histologic chorioamnionitis had a significantly lower
mean gestational age at the time of amniocentesis and delivery, higher mean maternal serum
CRP levels and WBC counts, and a higher rate of clinical chorioamnionitis than individuals
without histologic chorioamnionitis. Moreover, the mean AF WBC counts and AF IL-6 levels,
and the proportion of positive AF cultures were significantly higher in women with histologic
chorioamnionitis than in those without histologic chorioamnionitis.
The ROC curves of non-invasive and invasive parameters for predicting histologic
chorioamnionitis are presented in Figure 1. All the curves were above the 45o line, indicating
a significant relationship between these factors and histologic chorioamnionitis (for
gestational age: AUC = 0.734, SE = 0.042, P < 0.001; for maternal blood WBC: AUC =
0.640, SE = 0.046, P = 0.003; for serum CRP: AUC = 0.617, SE = 0.048, P < 0.015; for AF
WBC: AUC = 0.702, SE = 0.044, P < 0.001; for AF IL-6: AUC = 0.743, SE = 0.041, P <
0.001). The best cut-off values for predicting histologic chorioamnionitis were 32.0 weeks for
gestational age (sensitivity of 61% and specificity of 78%), 10,600 cells/mm³ for maternal
blood WBC (sensitivity of 62% and specificity of 61%), 5.1 mg/L for serum CRP
(sensitivity of 53% and specificity of 75%), 10 cells/mm³ for AF WBC (sensitivity of 69%
and specificity of 61%), and 2.4 ng/mL for AF IL-6 (sensitivity of 62% and specificity of
78%).
In an attempt to better predict which women with PPROM would have histologic
10
evidence of acute chorioamnionitis using a non-invasive technique, a multivariable analysis
was conducted with a forward stepwise logistic regression model. All continuous variables
were dichotomized using the cut-off values derived from the ROC curves because the
assumption of linearity in the logit was not verified. After the exclusion of variables (i.e., AF
IL-6 level, AF WBC count, and AF culture results) from invasive amniocentesis, four
variables (parity, gestational age at assessment, serum CRP level and maternal blood WBC
count) were found to have a significant correlation or association with histologic
chorioamnionitis based on the univariate analysis (P < 0.2) and entered into the multivariate
model. The final variables retained in the non-invasive model were gestational age at the time
of assessment and serum CRP levels (Table 2). There was no statistically significant
interaction between these two variables. The formula that was generated to predict histologic
chorioamnionitis was as follows: Y = logₑ (Z) = -1.289 + 1.589 (if gestational age at
assessment ≤ 32.0 weeks) + 0.960 (if serum CRP ≥ 5.1 mg/L). Z = eʸ and risk (%) = [Z/(1 +
Z)] × 100. The discriminatory ability of this model was 0.742 (95% confidence interval
[CI], 0.661-0.823), demonstrating a reasonably good capacity to discriminate between
women with and without histologic chorioamnionitis. The Hosmer-Lemeshow test showed an
adequate fit of the model studied (P = 0.389). A cut-off value ≥ 0.3 was identified as the
optimal threshold for the risk score with a sensitivity of 89% (95% CI, 80%-95%) and
specificity of 51% (95% CI, 39%-63%) to predict the occurrence of histologic
chorioamnionitis. Positive and negative LRs were 1.83 (95% CI, 1.40-2.40) and 0.21 (95%
CI, 0.10-0.40), respectively (Table 3).
11
A further risk score was then designed using the four variables of the initial non-
invasive model and using the three variables (i.e., AF IL-6 level, AF WBC count and AF
culture results) for the application of invasive amniocentesis; thus, seven variables were
included in this model (model 2). When including AF IL-6 concentration, AF WBC count,
and AF culture results as invasive markers in the non-invasive model (model 1), serum CRP
level, parity, and maternal WBC count were excluded from the final model (model 2) as
insignificant, whereas AF IL-6 and gestational age remained in model 2. No interaction
between these two predictors was demonstrated. The Hosmer-Lemeshow test showed an
adequate fit of the model studied (P = 0.927). The formula that was generated to predict
histologic chorioamnionitis is as follows: Y = loge (Z) = -1.241 + 1.249 (if gestational age at
assessment ≤ 32.0 weeks) + 1.269 (if AF IL-6 ≥ 2.4 ng/mL). Z = ey, risk (%) = (Z/1+Z)×100.
AUCs for predicting histologic chorioamnionitis were 0.742 for model 1 and 0.757
for model 2 (Figure 2), and not significantly different between two models (P = 0.623). We
then analyzed our data to evaluate the difference in AUCs between the non-invasive model
(model 1) and each of the two parameters retained in the non-invasive model. The AUC for
the non-invasive model was significantly greater than that for the serum CRP level (P =
0.006), but not gestational age at the time of assessment (P = 0.79). Lastly, AUCs for the IL-6
level and gestational age at assessment were significantly greater than that for serum CRP
level (P = 0.017), although the AUC difference between gestational age and serum CRP did
not reach statistical significance (P = 0.051). The AUCs for the IL-6 level and gestational age
were not significantly different (P = 0.832).
12
To assess the relationship between clinical chorioamnionitis and the covariates, we
repeated the same analyses described above for 146 women with PPROM. As shown in Table
3, no parameters studied, including both non-invasive and invasive parameters, were found to
identify women at high risk for developing clinical chorioamnionitis.
13
Table 1. Demographic and clinical characteristics of the study population according to the
presence or absence of histologic chorioamnionitis
Histologic chorioamnionitis
P value Presence
(n=74)
Absence
(n=72)
Maternal age (years) 32.2 ± 3.6 31.4 ± 4.6 0.221
Nulliparity 37% (27/74) 49% (35/72) 0.138
Previous spontaneous preterm birth
(< 37 weeks) 5% (4/74) 10% (7/72) 0.323
Gestational age at assessment
(weeks) 29.1 ± 3.3 31.2 ± 2.9 <0.001
Gestational age at delivery (weeks) 30.3 ± 3.3 32.6 ± 2.4 <0.001
Cervical length by ultrasound
(mm) 22.2 ± 12.4 23.9 ± 11.1 0.372
Amniocentesis-to-delivery interval
(hours, median (% 95 Cl)) 123 (70-176) 253 (105-401) 0.315*
Maternal blood WBC count
(cells/mm3) 12,037 ± 3,623 10,434 ± 3,516 <0.01
Serum C-reactive protein (mg/L) 12.7 ± 1.68 4.8 ± 5.2 <0.001
Amniotic fluid IL-6 (ng/ml) 15.0 ± 23.2 2.8 ± 6.7 <0.001
Amniotic fluid WBC count
(cells/mm3) 1790 ± 8426 311± 1429 0.146
Positive amniotic fluid cultures 46% (34/74) 24% (17/72) <0.01
Funisitis 47% (35/74) 0% (0/72) <0.001
Clinical chorioamnionitis 14% (10/74) 4% (3/72) 0.047
Use of tocolytics 66% (49/74) 61% (44/72) 0.521
Use of antibiotics 96% (71/74) 94% (68/72) 0.671
Use of antenatal corticosteroids 81% (60/74) 86% (62/72) 0.412
14
Composite neonatal morbidity† 49% (33/68) 28% (20/71) <0.05
Congenital sepsis 7% (5/68) 10% (7/71) 0.599
Respiratory distress syndrome 31% (21/68) 18% (13/71) 0.085
Bronchopulmonary dysplasia 25% (17/68) 7% (5/71) <0.005
Necrotizing enterocolitis 4% (3/68) 0% (0/71) 0.114
Periventricular leukomalacia 9% (6/68) 11% (8/71) 0.632
Neonatal mortality† 1% (1/68) 1% (1/71) 1.000
Birth weight (g) 1584 ± 518 1991 ± 510 <0.001
Values are presented as the mean ± standard deviation or % (n), unless otherwise indicated.
*Log-rank test.
† Seven infants who were not actively resuscitated at birth due to extremely low gestational
age (less than 23.4 weeks of gestation) were excluded.
CI, confidence interval; WBC, white blood cell; IL-6, interleukin-6.
15
Table 2. The final non-invasive model and the final model that included the additional
invasive test results for determining risk scores to predict histologic chorioamnionitis
Predictor Beta-
coefficient
S.E Odds
ratio
95% CI P value
Non-invasive model
Gestational age at assessment, ≤32.0 weeks
1.589 0.381 4.900 2.322-10.340 <0.001
Serum CRP, ≥5.1 mg/L 0.960 0.384 2.612 1.231-5.541 0.012
Constant -1.289 0.323 0.276 <0.001
Model including the
additional invasive test
results
Gestational age at
assessment, ≤32.0 weeks 1.249 0.406 3.485 1.574-7.719 0.002
AF IL-6, ≥2.4 ng/mL 1.269 0.405 3.557 1.609-7.861 0.002
Constant -1.241 0.311 0.289 <0.001
CRP, C-reactive protein; AF, amniotic fluid; IL-6, interleukin-6.
16
Table 3. Sensitivity, specificity, positive (PPV) predictive values, and likelihood ratios (LRs)
of the different cut-off values for predicting histologic chorioamnionitis using the final model
based on the dichotomization of two non-invasive parameters
Predicted
probability
(%)
Risk
factors
(n)
Screened
positive
(n (%))
Sensitivity
(%)
Specificity
(%)
PPV
(%)
NPV
(%)
LR+ LR-
21.6 0 146(100) 100 0 50.7 1.00
41.9 1 101(69.2) 89.2 51.4 65.3 82.2 1.83 0.21
57.5 1 86(58.9) 78.4 61.1 67.4 73.3 2.02 0.35
77.9 2 42(28.8) 41.9 84.7 73.8 58.7 2.74 0.69
17
Table 4. Demographic and clinical characteristics of the study population according to the
presence or absence of clinical chorioamnionitis
Subsequent development of clinical
chorioamnionitis
P value
Presence
(n=13)
Absence
(n=133)
Maternal age (years) 30.9 ± 4.1 31.9 ± 4.2 0.450
Nulliparity 46% (6/13) 42% (56/133) 0.778
Previous spontaneous preterm birth
(< 37 weeks) 8% (1/13) 8% (10/133) 1.000
Gestational age at assessment
(weeks) 30.2 ± 1.5 30.1 ± 3.4 0.326
Gestational age at delivery
(weeks) 31.5 ± 1.4 31.4 ± 3.2 0.254
Cervical length by ultrasound (mm) 23.4 ± 14.0 23.0 ± 11.7 0.904
Amniocentesis-to-delivery interval
(hours, median (% 95 Cl)) 153 (60-246) 270 (0-934) 0.932*
Maternal blood WBC count
(cells/mm3) 10,765 ± 3,813 11,293 ± 3,643 0.427
Serum C-reactive protein (mg/L) 9.0 ± 13.6 8.8 ± 13.1 0.680
Amniotic fluid IL-6 (ng/ml) 13.1 ± 25.1 8.9 ± 17.3 0.948
Amniotic fluid WBC count
(cells/mm3) 915 ± 2340 1063 ± 6303 0.704
Positive amniotic fluid cultures 54% (7/13) 33% (44/133) 0.134
Histologic chorioamnionitis 77% (10/13) 48% (64/133) 0.078
Funisitis 62% (8/13) 20% (27/133) 0.001
Use of tocolytics 69% (9/13) 63% (84/133) 0.664
Use of antibiotics 100% (13/13) 95% (126/133) 1.000
18
Use of antenatal corticosteroids 100% (13/13) 82% (109/133) 0.127
Composite neonatal morbidity† 54% (7/13) 37% (46/126) 0.220
Congenital sepsis 23% (3/13) 7% (9/126) 0.086
Respiratory distress syndrome 31% (4/13) 24% (30/126) 0.520
Bronchopulmonary dysplasia 15% (2/13) 16% (20/126) 1.000
Necrotizing enterocolitis 0% (0/13) 2% (3/126) 1.000
Periventricular leukomalacia 15% (2/13) 10% (12/126) 0.621
Neonatal mortality† 8% (1/13) 1% (1/126) 0.179
Birth weight (g) 1798 ± 337 1784 ± 568 0.706
Values are presented as the mean ± standard deviation or % (n), unless otherwise indicated.
*Log-rank test.
†Seven infants who were not actively resuscitated at birth due to extremely low gestational
age (less than 23.4 weeks of gestation) were excluded.
CI, confidence interval; WBC, white blood cell; IL-6, interleukin-6.
19
Figure 1. Receiver operating characteristic curves for each of (A) non-invasive and (B)
invasive parameters in predicting subsequent histologic chorioamnionitis (gestational age:
area under the curve [AUC] 0.734, SE 0.042, P < 0.001; serum C-reactive protein: AUC
0.617, SE 0.048, P <0.015; maternal blood white blood cell (WBC): AUC 0.640, SE 0.046,
P=0.003; amniotic fluid (AF) WBC: AUC 0.702, SE 0.044, P <0.001; AF interleukin-6: AUC
0.743, SE 0.041, P <0.001)
20
21
Figure 2. ROC curves comparing the power of the non-invasive model (model 1, solid line),
and the addition (model 2, dotted line) of amniotic fluid tests results as invasive markers to
the non-invasive model for predicting subsequent histologic chorioamnionitis development
(model 1: area under the curve [AUC], 0.742; 95% confidence interval [CI], 0.661-0.823
versus model 2: AUC, 0.757; 95% CI, 0.677-0.836; P = 0.623).
22
Discussion
The principal findings of this study were: (1) a model based on non-invasive clinical and
laboratory parameters (gestational age and maternal CRP) was effective for predicting the
subsequent development of histologic chorioamnionitis in women with PPROM; and (2)
invasive test results requiring amniocentesis, such as AF IL-6 levels, did not add predictive
information to the non-invasive model in this setting. Similar observations have been
reported for pregnant women diagnosed with PPROM as well as intra-amniotic inflammation
and imminent preterm delivery by our groups and others.3, 21-23 Collectively, these findings
are relevant given that a costly and invasive amniocentesis may be avoided, and underscore
the importance of considering multiple clinical and laboratory factors when assessing the
likelihood of early intrauterine infection.
Up to now, the analysis of AF samples obtained via amniocentesis could help to
predict the subsequent development of histologic chorioamnionitis in women with PPROM.
Among AF tests for the rapid identification of women at risk for histologic chorioamnionitis,
AF IL-6 concentration is probably the strongest predictor.1, 6 However, clinical use of AF IL-6
levels may be limited because this requires an invasive procedure which poses technical
difficulties following PPROM; its assay is not yet commercially available for clinical use.
Results of the present study demonstrated that our model based on non-invasive clinical and
laboratory parameters has reasonably good discriminatory power for predicting histologic
chorioamnionitis, which was equivalent to the AF IL-6 measurement. We identified two non-
invasive parameters, gestational age at assessment, ≤ 32.0 weeks and serum CRP, ≥ 5.1 mg/L,
23
which could independently predict histologic chorioamnionitis development. Women with
both risk factors had a probability of 77.9%; women with one risk factor had a probability of
41.8% to 57.4%; and women with none of the risk factors had a probability of 21.6%. This
model for predicting histologic chorioamnionitis in women with PPROM seems appealing
since it is a simple, rapid, easily repetitive and non-invasive method.
At a lower gestational age, the most important characteristics of an ideal diagnostic
test for infection in case of PPROM would be very high specificity because the risk of
intervention in response to a false positive test, which could lead to an unnecessary elective
preterm birth, should be decreased. Therefore, from a clinical perspective, this non-invasive
model can be recommended as a screening tool for predicting intrauterine development of
infection at early stage rather than a diagnostic test. The results of our non-invasive model
may not provide a definitive diagnosis, but would help identify high risk women who require
more intensive observation and treatment (e.g., antibiotics and corticosteroid) as well as risk-
specific intervention (i.e., amniocentesis) during the antenatal periods following PPROM.
Our finding that the prevalence of histological chorioamnionitis was 50.7% (74/146)
is in agreement with findings from previous studies.11 In accordance with the previous
investigations,11, 12 we found that elevated CRP levels were associated with subsequent
histologic chorioamnionitis in women with PPROM. Our data also demonstrated the
superiority of measuring AF IL-6 concentrations compared to CRP determination, in terms of
predicting chorioamnionits occurrence. However, the performance of CRP in this study for
24
the prediction of histologic choriomanionitis was worse compared with that observed in
previous work from our institution (AUC, 0.617 versus 0.760, P = 0.039).7 The apparent
discrepancy between the current finding and those from the previous study is most likely
related to one of the enrolment criteria of the previous study, that is, delivery within 72 hours
after sampling. Based on the data reported by Fisk et al. showing that CRP elevation often
precedes clinical infection or delivery by several days,24 we believe that CRP accurately
serves as histologic evidence of chorioamnionitis within a few days before delivery. This
might also be a contributing factor for better performance of CRP in the previous study. This
view is further supported by a recent investigation that used daily blood samples from women
with PPROM to show that there is a significant elevation in serum IL-6 levels obtained 24 to
48 hours before delivery in women with PPROM who subsequently had histologic evidence
of infection.25
Contrary to preterm labor with intact membranes,26, 27 neither cervical length nor
latency period (time from PPROM to delivery) was associated with the risk of subsequent
histologic chorioamnionitis in women with PPROM. These observations are consistent with
data from previous reports.28 29 30 Significant differences between PPROM and preterm labor
with intact membranes in terms of cervical length and latency are probably related to the fact
that systemic antibiotic therapy is routinely given to women with PPROM, while systemic
antibiotic prophylaxis is not routinely administered in case of preterm labor. For women with
PPROM, administration of antibiotics, which has shown to significantly reduce the incidence
of histologic chorioamnionitis, prolong pregnancy, and improve neonatal outcomes,31, 32 may
25
potentially prevent a possible ascending infection or, alternatively, ameliorate local damage to
the placenta already undergoing acute inflammation.
Variation in the reported incidence of clinical chorioamnionitis has a wide range from
7% to 29%.33 In the present study, the finding that 8.9% of women in our cohort showed
clinical evidence of chorioamnionitis is similar to data from a recent report evaluating a
retrospective cohort of 430 patients with PPROM that had a clinical chorioamninitis
prevalence of 13%.34 In contrast to histologic chorioamnionitis, no parameters studied in our
cohort could be used to predict which women were at a high-risk for developing clinical
chorioamnionitis. This finding is inconsistent with ones from previous reports published in
the 1990s by different authors.13, 33 The discrepancy between our findings and those of other
groups may be related to the recent change in PPROM management regarding the
recommended timing of delivery and antibiotic treatment and different gestational ages at the
time of inclusion. The routine policy of management for women with PPROM in our hospital,
including the use of prophylactic broad-spectrum antibiotics and induction of labor at around
34.0 weeks, may reduce the risk of developing clinical chorioamnionitis that may occur late
in the course of intrauterine infection, and thus influence the identification of patients
destined to develop an obvious symptomatic infection.
The finding that infants in the chorioamnionitis group had significantly higher rate of
BPD is consistent with previous reports. 36, 37 Watterberg et al. reported that intubated infants
weighing less than 2,000 g at birth in whose BPD developed had increased exposure to
inflammation prenatally (chorioamnionitis) and evidence of increased lung inflammation
26
from the first postnatal day. In terms of fetal inflammatory response syndrome (FIRS),
Matsuda et al. reported that funisitis, which is histologic hallmark of fetal inflammatory
response, is associated with BPD.
Our study had a number of limitations. First, is the investigation was limited by its
retrospective nature. Our finding should therefore be confirmed by prospective studies,
although most data were prospectively collected using a standardized electronic Excel-based
(Microsoft Corporation, Redmond, WA, USA) data collection tool. Second, we lacked data
for some previously reported important biomarkers in non-invasive samples of women
presenting with PPROM, such as cervicovaginal fluid,22, 23 that help clinicians discriminate
between women at high risk or low risk for subsequent histologic chorioamnionitis. Third, we
did not perform a full characterization of inflammatory cytokines in the AF samples, as
previously reported for women with PPROM, but only measured IL-6 levels although AF IL-
6 concentration is consistently reported to be the best predictor of histologic
chorioamnionitis.1, 6 Fourth, our results were not validated in a different hospital or with a
different patient population. Therefore, the generalizability of our non-invasive model is
limited. Fifth, the design our study is likely to reduce the statistical power available to test our
hypothesis by dichotomizing continuous independent parameters,35 although the final results
are almost the same whether the variables added to the multivariate model were continuous
variable or dichotomized. C-index values for model 1 and 2 with all continuous variables
retained as continuous were 0.768 and 0.786, respectively. The strength of this study is that
the influence of histologic chorioamnionitis on neonatal outcomes was evaluated, and the
27
importance of predicting histologic chorioamnionitis was therefore evaluated in terms of
improving the outcomes of pregnancy management for cases of PPROM.
In conclusion, a model based on non-invasive clinical and laboratory parameters
(gestational age and maternal CRP) was effective for predicting the subsequent development
of histologic chorioamnionitis in women with PPROM; however, invasive test results
requiring amniocentesis, such as AF IL-6 levels, did not add predictive information to the
non-invasive model in this setting. None of the parameters studied, both non-invasive and
invasive parameters, could be used to identify women at high-risk for the development of
clinical chorioamnionitis. Additional large, prospective studies, especially those focused on
serial estimations of clinical and laboratory variables, are required to confirm our findings.
Ultimately, our simple non-invasive model may be used to provide an early diagnosis of
intrauterine infection in women with PPROM, thus avoiding the need for invasive
amniocentesis.
28
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34. Ramsey PS, Lieman JM, Brumfield CG, Carlo W. Chorioamnionitis increases
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34
36. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung
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35
국
만삭 조 양막 열 산모에 침습
인자를 통한 모양막염
: 만삭 조 양막 열 산모에 임상 , 인자 같 침습 인 인자를
통해 향후에 모양막염이 생 하는 모델 만들고자 한다. 또한 이
침습 모델 침습 모델과 하여 효용 알아보고자 한다.
재료 및 방법: 20 주 0 일부 33 주 6 일 사이에 조 양막 열 내원한 산모 양수
검사를 시행하고, 질 를 통해 자궁경부 이를 하고, 모체 액 C 반
단백질과 백 구 수 를 한, 146 명 산모가 이 연구에 포함 었다. 복식 양수
천자 얻어진 양수를 통해 인 루킨 6 과 양수내 백 구 수 를 하 다. 결과는
조직학 모양막염과 임상 모양막염 발 보았다.
결과: 만삭 조 양막 열 산모에 조직학 모양막염 50.7%(74/146), 임상
모양막염 8.9%(13/146)에 발견 었다. 모델 1 모체 액 C 반 단백질,
검사 재태주수 이루어진 침습 모델이며 수신 작동 특 곡 에 면 0.742
36
며, 모델 2 는 양수 내 인 루킨 6 검사 재태주수 이루어진 침습 인자를
통한 모델이다. 이 모델간 수신 작동 특 곡 면 통계학
한 차이를 보이지 않았다. 한편 임상 모양막염 할 수 있는 인자는
발견 지 않았다.
결 : 만삭 조 양막 열 산모에 모체 청 C 반 단백질과 검사 재태주수를
통해 향후 조직학 모 양막염 발 할 수 있었다. 본 연구에 침습 인
검사를 통한 인자가 침습 모델에 추가 인 보를 주지는 못했다.
주요어: 양수, 모양막염, C 반 단백질, 침습 모델, 만삭 조 양막 열
학번: 2012-21679