Abstract
Objective: Recent studies indicate that clinical chorioamnionitis is a heterogeneous condition and only approximately one-half of the patients have bacteria in the amniotic cavity, which is often associated with intra-amniotic inflammation. The objective of this study is to characterize the nature of the inflammatory response within the amniotic cavity in patients with clinical chorioamnionitis at term according to the presence or absence of 1) bacteria in the amniotic cavity and 2) intra-amniotic inflammation.
Materials and methods: A retrospective cross-sectional case-control study was conducted to examine cytokine and chemokine concentrations in the amniotic fluid (AF). Cases consisted of women with clinical chorioamnionitis at term (n=45). Controls were women with uncomplicated pregnancies at term who did not have intra-amniotic inflammation and were in labor (n=24). Women with clinical chorioamnionitis were classified according to the results of AF cultures, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry, and AF concentration of interleukin-6 (IL-6) into those: 1) without intra-amniotic inflammation, 2) with microbial-associated intra-amniotic inflammation, and 3) with intra-amniotic inflammation without detectable bacteria. The AF concentrations of 29 cytokines/chemokines were determined using sensitive and specific V-PLEX immunoassays.
Results: 1) The AF concentrations of pro- and anti-inflammatory cytokines/chemokines such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-4 (IL-4), macrophage inflammatory protein-1 beta (MIP-1β), and interleukin-8 (IL-8) (except Eotaxin-3) were significantly higher in women with clinical chorioamnionitis at term than in controls (term labor without intra-amniotic inflammation); 2) patients with microbial-associated intra-amniotic inflammation, and those with intra-amniotic inflammation without detectable bacteria, had a dramatic differential expression of cytokines and chemokines in AF compared to patients with spontaneous labor without intra-amniotic inflammation. However, no difference could be detected in the pattern of the intra-amniotic inflammatory response between patients with intra-amniotic inflammation with and without detectable bacteria; and 3) in patients with clinical chorioamnionitis at term but without intra-amniotic inflammation, the behavior of cytokines and chemokines in the AF was similar to those in spontaneous labor at term.
Conclusions: Patients with clinical chorioamnionitis who had microbial-associated intra-amniotic inflammation or intra-amniotic inflammation without detectable bacteria had a dramatic upregulation of the intra-amniotic inflammatory response assessed by amniotic fluid concentrations of cytokines. A subset of patients with term clinical chorioamnionitis does not have intra-amniotic infection/inflammation, as demonstrated by elevated AF concentrations of inflammation-related proteins, when compared to women in term labor with uncomplicated pregnancies, suggesting over-diagnosis. These observations constitute the first characterization of the cytokine/chemokine network in the amniotic cavity of patients with clinical chorioamnionitis at term.
Introduction
Clinical chorioamnionitis is defined by the presence of maternal fever and at least two or more of the following clinical criteria: maternal or fetal tachycardia; maternal leukocytosis; uterine tenderness; or foul-smelling amniotic fluid (AF) [1–12]. The standard clinical treatment of this condition is the administration of antibiotics because the diagnosis is considered to represent evidence of intra-amniotic bacterial infection [8, 13–19]. This intervention is expected to reduce the rate of complications in both mother and neonate [8, 13–16]. A role for bacterial infection in clinical chorioamnionitis is based on previous microbiologic studies [3], which have been largely based on cultivation techniques [3]. Recently, we have reported, using both cultivation and molecular microbiologic techniques, that 54% of patients with clinical chorioamnionitis had microbial-associated intra-amniotic inflammation [presence of bacteria in AF and AF interleukin (IL)-6 concentration ≥2.6 ng/mL], and 24% had intra-amniotic inflammation without demonstrable bacteria (absence of bacteria in AF and AF IL-6 concentration ≥2.6 ng/mL), whereas 22% had no intra-amniotic inflammation (AF IL-6 concentration <2.6 ng/mL) [11].
The objective of this study was to characterize the nature of the intra-amniotic inflammatory response in patients with a diagnosis of clinical chorioamnionitis at term by analyzing the behavior of the concentrations of cytokines and chemokines in the AF, according to the presence or absence of intra-amniotic inflammation and the presence of bacteria.
Material and methods
Study population
A retrospective cross-sectional case-control study was conducted by searching the clinical database and bank of biologic samples of Wayne State University, the Detroit Medical Center, and the Perinatology Research Branch (NICHD/NIH). The inclusion criteria were: 1) singleton gestations; 2) gestational age ≥37 weeks; 3) sufficient AF obtained by transabdominal amniocenteses for molecular microbiologic studies; and 4) absence of fetal malformations.
Cases were women with clinical chorioamnionitis at term. These women were included in a prior study which contains a detailed description of sample collection, microbiological studies, and determination of AF IL-6 concentrations using a sensitive and specific enzyme-linked immunosorbent assay [11].
In brief, controls were women presenting with an episode of suspected preterm labor and with an uncertain gestational age. Sonographic fetal biometry had not been performed during pregnancy, as it was largely unavailable as part of the routine prenatal care. Patients were offered an amniocentesis to evaluate the status of fetal lung maturity, to determine whether tocolysis and steroids were required, and to determine the microbial status of the amniotic cavity. The lung maturity tests included a “shake” test (or Clements’ test), or counting the number of orange cells [20–23]. Lecithin/sphingomyelin ratio and other fetal lung maturity tests were not available at the institutions where this study was conducted. These women did not have intra-amniotic inflammation (AF IL-6 <2.6 ng/mL) and were considered to be at term because they met the following criteria: 1) analysis of AF consistent with fetal lung maturity; 2) birthweight >2500 g; 3) absence of respiratory distress syndrome or other complications of prematurity; and 4) physical examination by a pediatrician consistent with a term neonate.
All patients provided written informed consent and the use of biological specimens as well as clinical and ultrasound data for research purposes were approved by the Institutional Review Boards of NICHD, Wayne State University, and the Sótero del Río Hospital, Santiago, Chile. All patients were enrolled at the Sótero del Río Hospital in Santiago, Chile.
Clinical definitions
Clinical chorioamnionitis was diagnosed by the presence of maternal fever (temperature >37.8oC) accompanied by two or more of the following criteria: 1) maternal tachycardia (heart rate >100 beats/min); 2) uterine tenderness; 3) foul-smelling odor of the AF; 4) fetal tachycardia (heart rate >160 beats/min); and 5) maternal leukocytosis (leukocyte count >15,000 cells/mm3) [3, 14].
Microbial invasion of the amniotic cavity (MIAC) was defined according to the results of AF culture and polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) (Ibis® Technology – Athogen, Carlsbad, CA) [24–27]. Intra-amniotic inflammation was diagnosed when the AF IL-6 concentration was ≥2.6 ng/mL [28–38]. Based on the results of AF cultures, PCR/ESI-MS and AF concentrations of IL-6, patients with clinical chorioamnionitis at term were classified as having: 1) no intra-amniotic inflammation, or 2) microbial-associated intra-amniotic inflammation (combination of MIAC and intra-amniotic inflammation), or 3) intra-amniotic inflammation without detectable bacteria (an elevated AF IL-6 concentration without evidence of bacteria using both cultivation and molecular methods). Acute histologic chorioamnionitis was diagnosed based on the presence of inflammatory cells in the chorionic plate and/or in the chorioamniotic membranes [28, 39–44], and acute funisitis was diagnosed by the presence of neutrophils in the wall of the umbilical vessels and/or in the Wharton’s jelly, using criteria previously described [37, 41–43, 45–49]. Fetal inflammatory response syndrome (FIRS) was defined as an umbilical cord IL-6 concentration >11 pg/mL [25, 45, 50–59]. Acute inflammatory lesions of the placenta, or placental lesions consistent with AF infection, were defined by the presence of acute histologic chorioamnionitis and/or acute funisitis.
Multiplex determination of cytokines and chemokines
The AF concentrations of the following 29 cytokines/chemokines were determined with a sensitive and specific V-PLEX immunoassays (Meso Scale Discovery, Gaithersburg, MD, USA) [Pro-inflammatory cytokines: interferon gamma (IFN-γ), IL-1α, IL-1β, IL-2, IL-6, IL-7, IL-12p70, IL-12/IL-23p40, IL-15, IL-16, IL-17a tumor necrosis factor alpha (TNF-α), TNF-β, vascular endothelial growth factor (VEGF), granulocyte macrophage colony-stimulating factor; anti-inflammatory cytokines: IL-4, IL-5, IL-10, IL-13; and chemokines: IL-8, thymus and activation-regulated chemokine (TARC), Eotaxin, Eotaxin-3, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1α, MIP-1β, monocyte chemoattractant protein (MCP)-1, MCP-4, C-X-C motif chemokine 10 (CXCL-10), or interferon gamma-induced protein 10 (IP-10)]. Briefly, 50 μL of AF or a calibrator was dispensed into separate wells of the plates and incubated for 2 h with vigorous shaking at room temperature. The samples and calibrators were discarded and the plates were washed three times with phosphate buffered saline and 0.05% Tween 20, (Meso Scale Discovery) followed by an addition of 25 μL of the 1× Detection Antibody Solution (Meso Scale Discovery) into each well. Plates were then incubated for 2 h with vigorous shaking at room temperature. The detection antibody was removed, and the plates were washed three times. One hundred and fifty microliters of 2X Read Buffer T (Meso Scale Discovery) were added to each well and the signals were read by the SECTOR® Imager 2400 (Meso Scale Discovery). Standard curves were generated and the assay values of the samples were interpolated from the curves. The assay characteristics are described in the Supplementary Table. The coefficient of variation was less than 15% for 17 of the 29 analytes. For samples with concentrations below the limit of detection, missing values were replaced with 99% of the lowest detectable concentration. VEGF was removed from the analysis as 90% (62/69) of participants had VEGF concentrations below the limit of detection of the assay.
Statistical analysis
Demographics data analysis:
The Kolmogorov-Smirnov test was used to test whether the distribution of continuous variables was normal. Chi-square and Fisher’s exact tests were used for comparisons of proportions. Kruskal-Wallis and the Mann-Whitney U-tests were used to compare median concentrations of analytes between and among groups. Statistical analysis of demographics data was performed using SPSS 19 (IBM Corp, Armonk, NY, USA). A P value <0.05 was considered statistically significant.
Comparison of analyte concentrations determined by multiplex assay was restricted to the analytes that were detected in a number of samples larger than half of the size of the smallest group. Statistical analysis was performed using Wilcoxon rank-sum test and R statistical environment [60]. Nominal P values were adjusted using the Benjamini and Hochberg method [61], controlling the false discovery rate at 5%.
Results
Characteristics of the study population
A total of 45 cases with clinical chorioamnionitis diagnosed at term (between 37 and 42 weeks of gestation) and 24 controls with uncomplicated pregnancies at term that were in labor were included in this study. Descriptive characteristics of the study population are displayed in Table 1. There were no significant differences in the median maternal age, frequency of nulliparity, median AF glucose, and median birthweight between term pregnancy in labor and clinical chorioamnionitis at term (all P-values >0.05).
Clinical characteristics of the study population.
| Term in labor (n=24) | Clinical chorioamnionitis at term (n=45) | P-value | |
|---|---|---|---|
| Maternal age (years) | 21 (18.5–23.8) | 21 (18–25) | 0.6 |
| Nulliparity | 50% (12/24) | 64.4% (29/45) | 0.25 |
| Body mass index (kg/m2) | NA | 23.7 (21.7–24.9) | NA |
| Amniotic fluid glucose (mg/dL) | 8.7 (7.1–10) | 9 (9–9) | 0.5 |
| Amniotic fluid white blood cell (cell/mm3) | 7 (2–24.8) | 58 (5–695) | 0.002 |
| Gestational age at amniocentesis and delivery (weeks) | 39 (38.1–39.9) | 39.6 (38.9–40.7) | 0.008 |
| Birthweight (grams) | 3380 (3032.5–3615) | 3550 (3220–3790) | 0.99 |
Data presented as median (interquartile range) or % (n); NA=not applicable.
Upon admission, 66.7% (30/45) of patients had ruptured membranes at the time of amniocentesis. Only 20% (9/45) of these women were admitted with fever; the remainder (80%, 36/45) developed fever after hospital admission. In addition to maternal fever, the most frequent criteria that configured the diagnosis of clinical chorioamnionitis were maternal [91.1% (41/45)] and fetal tachycardia [75.6% (34/45)], which were followed by maternal leukocytosis [73.3% (33/45)]. Most women had a vaginal delivery [75.6% (34/45)], and half had placental lesions consistent with acute AF infection (23/45) (Table 2). All patients had epidural anesthesia during labor. Amniocenteses were performed before the administration of epidural analgesia in 78% (35/45) of these patients. Among those who received antibiotics (n=42), 88% (37/42) received them after the amniocentesis. Five patients received antibiotics before the amniocentesis (in 3 and 2 patients the amniocentesis was performed 5 and 45 min after the administration of antibiotics, respectively).
Clinical characteristics of the patients with clinical chorioamnionitis at term.
| Median (IQR) or % (n/N) | |
|---|---|
| Rupture of the membranes at the time of amniocentesis | 66.7% (30/45) |
| Gestational age at amniocentesis (weeks) | 39 (37.9–40) |
| Fever before admission | 20% (9/45) |
| Maternal tachycardia (>100 beats/min) | 91.1% (41/45) |
| Fetal tachycardia (>160 beats/min) | 75.6% (34/45) |
| Uterine tenderness | 8.9% (4/45) |
| Foul-smelling amniotic fluid | 6.7% (3/45) |
| Maternal leukocytosis | 73.3% (33/45) |
| Labor | |
| Spontaneous | 82.2% (37/45) |
| Induced | 15.6% (7/45) |
| C-section | 24.4% (11/45) |
| Epidural analgesia | |
| Before amniocentesis | 77.8% (35/45) |
| AF white blood cells (cells/mm3) | 58 (5–695) |
| AF glucose (mg/dL) | 9 (9–9) |
| AF Gram stain positive | 13 (6/46) |
| AF interleukin-6 (ng/mL) | 6.4 (2.9–18.7) |
| Subgroups of clinical chorioamnionitis | |
| No intra-amniotic inflammation | 22% (10/45) |
| Intra-amniotic inflammation without demonstrable microorganisms in the amniotic cavity | 22% (10/45) |
| Microbial-associated intra-amniotic inflammation | 56% (25/45) |
| Polymicrobial intra-amniotic infection | 27% (12/45) |
| Placental lesions consistent with amniotic fluid infection | 51.1% (23/45) |
| Fetal inflammatory response syndrome | 22% (10/44)a |
| Suspected neonatal sepsis | 33.3% (15/45) |
Data presented as median (IQR) or % (n), IQR=interquartile range, AF=amniotic fluid, GA=gestational age, PCR=polymerase chain reaction, ESI-MS=electrospray ionization mass spectrometry. Placental lesions consistent with AF infection: acute histological chorioamnionitis or acute funisitis, no intra-amniotic inflammation/infection: negative AF culture or PCR/ESI-MS and AF IL-6 <2.6 ng/mL, MIAC: positive microorganisms by either AF cultures or PCR/ESI-MS without intra-amniotic inflammation); microbial-associated intra-amniotic inflammation (combination of MIAC and intra-amniotic inflammation); intra-amniotic inflammation without detectable microorganisms (an elevated AF IL-6 concentration without evidence of microorganisms using cultivation or molecular methods).
aUmbilical cord blood IL-6 concentration was not available for one case.
When classified according to the presence or absence of both intra-amniotic inflammation and bacteria (by AF cultures and PCR/ESI-MS), 56% (25/45) of the patients had microbial-associated intra-amniotic inflammation in the amniotic cavity, 22% (10/45) had intra-amniotic inflammation without demonstrable bacteria, and 22% (10/45) had no evidence of intra-amniotic inflammation (Table 2). A description of the identified bacteria in AF was reported previously [11]. Polymicrobial intra-amniotic infection was diagnosed in 27% (12/45) of patients with clinical chorioamnionitis at term.
Amniotic fluid cytokine and chemokine concentrations in cases and controls
Clinical chorioamnionitis vs. normal spontaneous labor at term
The median (interquartile range: IQR) cytokine and chemokine concentrations in AF between cases and controls are described in Table 3. Women with clinical chorioamnionitis had significantly higher AF concentrations for 8 of the 14 pro-inflammatory cytokines (after correcting for a false discovery rate of 5%) than controls. The fold-change difference in median concentrations of IL-1β, IFN-γ, TNF-α, TNF-β, IL-2, IL-12/IL-23p40, IL-6, and IL-12p70 ranged from 1.2 to 9 (Table 3). Cases also had significantly higher median AF concentrations of each of the four anti-inflammatory cytokines (IL-4, IL-10, IL-13, and IL-5), with a fold-change difference in median concentrations that ranged from 1.3 to 4.
Amniotic fluid cytokines and chemokines concentrations in term in labor vs. clinical chorioamnionitis at term.
| Analytes (pg/mL) | Term in labor median (IQR) (n=24) | Clinical chorioamnionitis at term median (IQR) (n=45) | Fold change | Adjusted P-value |
|---|---|---|---|---|
| Pro-inflammatory cytokines | ||||
| IL-1β | 2.61 (1.07–5.5) | 24.17 (4.93–119.8) | 9.26 | 0.0001 |
| IFN-γ | 1.23 (0.35–3.08) | 10.36 (3.46–26.08) | 8.42 | 0.0001 |
| TNF-α | 1.59 (0.79–3.61) | 10.38 (2.77–65.09) | 6.51 | 0.0001 |
| TNF-β | 0.01 (0.009–0.04) | 0.06 (0.009–0.09) | 6.00 | 0.002 |
| IL-2 | 0.17 (0.09–0.23) | 0.82 (0.09–2.68) | 4.82 | 0.004 |
| IL-12/IL-23p40 | 11.58 (8.87–17.42) | 30.09 (24.07–45.94) | 2.60 | 0.000005 |
| IL-6 | 672.39 (385.41–964.89) | 1668.03 (731.68–5589.26) | 2.48 | 0.001 |
| IL-12p70 | 0.049 (0.04–0.04) | 0.06 (0.04–1.95) | 1.21 | 0.005 |
| IL-1α | 121.21 (80.6–164.305) | 161.75 (98.93–243.84) | 1.33 | 0.06 |
| GM-CSF | 52.35 (30.11–72.83) | 59.02 (35.85–96.97) | 1.13 | 0.39 |
| IL-16a | 66.24 (40.45–117.83) | 103.86 (41.17–323.71) | 1.57 | 0.23 |
| IL-15 | 16.46 (12.64–21.89) | 18.43 (13.15–29.02) | 1.12 | 0.41 |
| IL-7 | 2.97 (2.41–3.53) | 2.73 (2.05–3.43) | 0.92 | 0.31 |
| IL-17α | 0.25 (0.21–0.38) | 0.19 (0.04–0.39) | 0.75 | 0.30 |
| Anti-inflammatory cytokines | ||||
| IL-4 | 0.12 (0.07–0.28) | 0.53 (0.16–3.36) | 4.42 | 0.004 |
| IL-10 | 0.64 (0.31–1.23) | 1.83 (0.45–9.71) | 2.86 | 0.031 |
| IL-13 | 5.83 (3.93–8.7) | 15.76 (9.27–29.03) | 2.70 | 0.0001 |
| IL-5 | 0.24 (0.16–0.29) | 0.32 (0.23–0.45) | 1.33 | 0.004 |
| Chemokines | ||||
| MIP-1β | 46.33 (37.21–123.08) | 276.07 (62.18–892.27) | 5.96 | 0.007 |
| IL-8 | 1828.6 (10690.05–2771.78) | 7873.58 (3985.27–32,99.2) | 4.31 | 0.000005 |
| MIP-1α | 29.48 (20.23–54.4) | 118.13 (30.18–551.1) | 4.01 | 0.002 |
| TARC | 6.31 (4.34–9.51) | 13.47 (6.48–25.3) | 2.13 | 0.037 |
| MDC | 74.37 (54.35–135.14) | 151.74 (85.55–275.31) | 2.04 | 0.021 |
| MCP-1 | 1205.21 (828.22–1618.69) | 1654.03 (1243.3–3887.23) | 1.37 | 0.03 |
| Eotaxin-3 | 5.49 (3.56–10.79) | 1.23 (1.24–4.15) | 0.23 | 0.001 |
| CXCL-10 or IP-10 | 366.3 (280.9–834.81) | 729.56 (61.93–2692.43) | 1.99 | 0.49 |
| MCP-4 | 59.66 (26.12–100.63) | 66.57 (28.39–170.1) | 1.12 | 0.28 |
| Eotaxin | 12.29 (9.23–16.35) | 10.22 (3.21–19.24) | 0.83 | 0.22 |
IQR=interquartile, IFN-γ=interferon gamma, IL=interleukin, TNF=tumor necrosis factor, GM-CSF=granulocyte macrophage colony-stimulating factor, TARC=thymus and activation-regulated chemokine, MDC=macrophage-derived chemokine, MIP=macrophage inflammatory protein, CXCL-10=C-X-C motif chemokine 10, IP-10=interferon gamma-induced protein 10, MCP-1=monocyte chemoattractant protein-1.
aIL-16 has pro- and anti-inflammatory properties. The units of all analytes are in pg/mL.
In this study, 6 of the 10 chemokines had significantly higher concentrations in cases than in controls (MIP-1β, IL-8, MIP-1α, TARC, MDC, and MCP-1), with fold changes ranging from 1.4 to 6 fold. Eotaxin-3 was the only chemokine with significant lower concentrations in clinical chorioamnionitis than in controls (Table 3).
Clinical chorioamnionitis without intra-amniotic inflammation, inflammation without detectable bacteria, or microbial-associated intra-amniotic inflammation vs. normal spontaneous labor at term
The median (IQR) concentration of the inflammation-related proteins in AF from women with clinical chorioamnionitis was classified by the presence or absence of both intra-amniotic inflammation and bacteria in the amniotic cavity (Table 4). There were no significant differences in the median AF concentration of any of the 14 pro-inflammatory cytokines between cases without intra-amniotic inflammation and controls (adjusted P values >0.2). In contrast, the median of six of these analytes differed significantly between cases with intra-amniotic inflammation without demonstrable bacteria and controls. The median AF concentration of IFN-γ, TNF-α, IL-1β, IL-12/IL-23p40, IL-2, and IL-12p70 was 3–15 times higher in cases with intra-amniotic inflammation without demonstrable microorganisms than in those who were in labor at term with uncomplicated pregnancies (Figure 1 and Table 4). The median concentration of these analytes, and IL-6, IL-16 as well as IL-1α, was also significantly higher in cases with microbial-associated intra-amniotic inflammation than in controls, with a median fold difference that ranged from 1.7 to nearly 15 (Figure 1 and Table 4).
The amniotic fluid (AF) concentrations of pro-inflammatory cytokine in patients with term in labor (control) (n=24), clinical chorioamnionitis without intra-amniotic inflammation (n=10), clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria (n=10), and clinical chorioamnionitis with microbial-associated intra-amniotic inflammation (n=25). (A) The median AF concentrations of interleukin (IL)-1β are 2.6 pg/mL (term in labor), 1.3 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 18.5 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 38.8 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation). (B) The median AF concentrations of tumor necrosis factor-alpha (TNF-α) are 1.6 pg/mL (term in labor), 1.2 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 15.4 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 22.6 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation). (C) The median AF concentrations of interferon-gamma (IFN-γ) are 1.2 pg/mL (term in labor), 3.6 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 11.4 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 14.7 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation). LOD=limit of detection. (D) The median AF concentrations of interleukin-2 (IL-2) are 0.2 pg/mL (term in labor), 0.09 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 0.8 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 2.1 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation). LOD=limit of detection. (E) The median AF concentrations of interleukin-12p70 (IL-12p70) are 0.05 pg/mL (term in labor), 0.05 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 0.7 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 0.3 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation). LOD=limit of detection.
Amniotic fluid cytokine and chemokine concentrations in the subgroups of patients with clinical chorioamnionitis at term.
| Analytes (pg/mL) | Term in labor (controls) (n=24) | Clinical chorioamnnionitis at term (n=45) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Median (IQR) | Without intra-amniotic inflammation (n=10) | With intra-amniotic inflammation without demonstrable microorganisms (n=10) | With microbial-associated intra-amniotic inflammation (n=25) | |||||||||
| Median (IQR) | Adjusted P value (compared to term in labor) | Median (IQR) | Fold change (compared to term in labor) | Adjusted P value (compared to term in labor) | Adjusted P value (compared to without intra-amniotic inflammation) | Median (IQR) | Fold change (compared to term in labor) | Adjusted P value (compared to term in labor) | Adjusted P value (compared to without intra-amniotic inflammation) | Adjusted P value (compared to intra-amniotic inflammation without demonstrable microorganisms) | ||
| Pro-inflammatory cytokines | ||||||||||||
| TNF-α | 1.6 (0.8–3.6) | 1.21 (0.8–2.6) | 0.85 | 15.4 (5.0–35.2) | 9.63 | 0.003 | 0.007 | 22.6 (8.1–178.0) | 14.14 | 0.0000002 | 0.00004 | 0.69 |
| IFN-γ | 1.2 (0.4–3.1) | 3.56 (0.18–9.28) | 0.59 | 11.4 (8.0–48) | 9.24 | 0.0005 | 0.06 | 14.7 (3.7–27.8) | 11.97 | 0.00008 | 0.03 | 0.95 |
| IL-1β | 2.6 (1.1–5.5) | 1.3 (0.8–4.1) | 0.59 | 18.5 (6.4–42.5) | 7.08 | 0.0005 | 0.02 | 38.8 (15–597.9) | 14.87 | 0.0000002 | 0.0005 | 0.61 |
| IL-2 | 0.2 (0.1–0.2) | 0.09 (0.1–0.4) | 0.64 | 0.8 (0.2–1.2) | 4.88 | 0.044 | 0.06 | 2.1 (0.7–4.0) | 12.59 | 0.0001 | 0.002 | 0.64 |
| TNF-β | 0.01 (0.01–0.04) | 0.05 (0.01–0.07) | 0.51 | 0.04 (0.01–0.05) | 3.5 | 0.25 | 0.94 | 0.08 (0.05–0.1) | 8.00 | 0.0002 | 0.05 | 0.95 |
| IL-12/IL-23p40 | 11.6 (8.9–17.4 | 18.7 (13.7–28.6) | 0.31 | 35.8 (20.04–52.05) | 3.09 | 0.001 | 0.08 | 37.1 (26.7–52.4) | 3.20 | 0.0000004 | 0.001 | 0.89 |
| IL-6 | 672.4 (385.4–964.9) | 304.3 (155.3–637.3) | 0.21 | 1425.5 (1224.7–5424.9) | 1.72 | 0.22 | 0.0003 | 152.75 (83.01–624.3) | 2.31 | 0.02 | 0.00004 | 0.61 |
| IL-16 | 66.24 (40.5–117.8) | 31.4 (20.2–67.6) | 0.21 | 113.7 (54.3–352.5) | 1.72 | 0.22 | 0.06 | 152.8 (83.0–624.3) | 2.31 | 0.02 | 0.005 | 0.61 |
| IL-1α | 121.21 (80.6–164.3) | 117.7 (95.1–126.0) | 0.93 | 192.2 (121.9–237.1) | 1.59 | 0.13 | 0.13 | 207.03 (112.1–560.7) | 1.71 | 0.02 | 0.08 | 0.61 |
| IL-12p70 | 0.05 (0.05–0.05) | 0.05 (0.1–0.2) | 0.53 | 0.7 (0.05–1.7) | 15.35 | 0.027 | 0.16 | 0.3 (0.05–3.02) | 6.67 | 0.004 | 0.13 | 0.77 |
| IL-15 | 16.5 (12.6–21.9) | 15.5 (11.9–21.4) | 0.88 | 19.6 (15.5–28.7) | 1.19 | 0.42 | 0.38 | 20.6 (14.8–29.02) | 1.25 | 0.33 | 0.26 | 0.61 |
| GM-CSF | 52.4 (30.1–72.8) | 38 (27.5–69.3) | 0.59 | 57.0 (32.0–82.7) | 1.09 | 0.95 | 0.64 | 74.78 (51.5–115.2) | 1.43 | 0.08 | 0.05 | 0.64 |
| IL-7 | 2.97 (2.4–3.5) | 2.53 (2.1–3.0) | 0.53 | 2.5 (2.1–2.8) | 0.84 | 0.15 | 1 | 3.1 (2.1–3.9) | 1.05 | 0.82 | 0.36 | 0.61 |
| IL-17α | 0.25 (0.21–0.38) | 0.08 (0.04–0.26) | 0.21 | 0.05 (0.04–0.2) | 0.2 | 0.08 | 0.94 | 0.3 (0.04–0.5) | 1.22 | 0.82 | 0.11 | 0.61 |
| Anti-inflammatory cytokines | ||||||||||||
| IL-10a | 0.6 (0.3–1.2) | 0.04 (0.04–0.04) | 0.003 | 2.1 (1.0–9.1) | 3.2 | 0.04 | 0.007 | 2.6 (1.5–6.9) | 4.08 | 0.00004 | 0.0001 | 0.61 |
| IL-4 | 0.1 (0.07–0.3) | 0.045 (0.01–0.17) | 0.51 | 0.4 (0.2–3.1) | 3.17 | 0.12 | 0.08 | 1.2 (0.5–4.1) | 10 | 0.000008 | 0.0005 | 0.64 |
| IL-13 | 5.8 (3.9–8.7) | 6.54 (3.51–9.88) | 1.0 | 14.2 (11.1–28.0) | 2.44 | 0.0005 | 0.01 | 23.8 (13.9–34.2) | 4.08 | 0.000008 | 0.001 | 0.61 |
| IL-5 | 0.2 (0.2–0.3) | 0.26 (0.22–0.35) | 0.59 | 0.3 (0.2–0.4) | 1.25 | 0.13 | 0.82 | 0.4 (0.2–0.5) | 1.63 | 0.0008 | 0.09 | 0.61 |
| Chemokines | ||||||||||||
| MIP-1β | 46.3 (37.2–123.1) | 31.3 (23.1–54.9) | 0.32 | 308.0 (76.4–705.1) | 6.65 | 0.04 | 0.04 | 586.9 (179.9–1451.3) | 12.67 | 0.00003 | 0.0005 | 0.61 |
| CXCL-10 or IP-10 | 366.3 (280.9–834.8) | 438.2 (106.5–1752.7) | 0.93 | 1827.8 (570.0–6297.5) | 4.99 | 0.04 | 0.16 | 533.01 (41.4–2335.8) | 1.46 | 0.82 | 0.84 | 0.95 |
| MIP-1α | 29.5 (20.2–54.4) | 22.4 (10.9–29.8) | 0.59 | 134.5 (39.3–53.8) | 4.56 | 0.06 | 0.06 | 315.3 (71.6–1112.9) | 10.69 | 0.000002 | 0.0002 | 0.61 |
| IL-8 | 1828.6 (1069.0–2771.8) | 2728.2 (1674.6–3943.2) | 0.59 | 6790.5 (4516.7–23,825.8) | 3.71 | 0.0005 | 0.02 | 15,641.8 (7873.6–73,123.1) | 8.55 | 0.0000002 | 0.0002 | 0.64 |
| TARC | 6.31 (4.3–9.5) | 9.5 (2.7–14.9) | 0.93 | 19.3 (13.2–25.2) | 3.06 | 0.04 | 0.08 | 13.03 (6.3–35.2) | 2.06 | 0.04 | 0.15 | 0.95 |
| MDC | 74.4 (54.4–135.1) | 85.7 (53.8–142.1) | 1.0 | 153.9 (80.7–211.7) | 2.07 | 0.13 | 0.4 | 168.5 (109.0–347.7) | 2.26 | 0.003 | 0.03 | 0.64 |
| MCP-4 | 59.7 (26.1–100.6) | 37.0 (13.5–119.0) | 0.72 | 112.1 (57.7–140.6) | 1.88 | 0.09 | 0.21 | 68.8 (31.2–254.5) | 1.15 | 0.27 | 0.1 | 0.61 |
| MCP-1 | 1205.2 (828.2–1618.7) | 1170.0 (379.4–1506.6) | 0.59 | 1817.31 (1314.73–2490.14) | 1.51 | 0.1 | 0.07 | 2392.8 (1539.5–6830.8) | 1.99 | 0.001 | 0.002 | 0.61 |
| Eotaxin | 12.3 (9.2–16.4) | 6.9 (3.2–12.7) | 0.21 | 6.1 (3.2–13.5) | 0.5 | 0.13 | 0.84 | 11.7 (3.2–22.6) | 0.95 | 0.82 | 0.12 | 0.79 |
| Eotaxin-3a | 5.49 (3.56–10.79) | 1.2 (1.2–1.2) | 0.003 | 1.2 (1.2–6.7) | 0.23 | 0.09 | 0.38 | 1.2 (1.2–6.2) | 0.23 | 0.01 | 0.12 | 0.64 |
IQR=interquartile, IFN-γ=interferon gamma, IL=interleukin, TNF=tumor necrosis factor, GM-CSF=granulocyte macrophage colony-stimulating factor, TARC=thymus and activation-regulated chemokine, MDC=macrophage-derived chemokine, MIP=macrophage inflammatory protein, CXCL-10=C-X-C motif chemokine 10, IP-10=interferon gamma-induced protein 10, MCP=monocyte chemoattractant protein-1. The units of all analytes are in pg/mL.
aEight out of ten patients in this group had the concentrations of these proteins below the limit of detection.
Of the four anti-inflammatory cytokines, only the median concentration of IL-10 was significantly lower in patients with clinical chorioamnionitis without intra-amniotic inflammation than in controls (adjusted P-value=0.003; Table 4). In contrast, two of these four analytes were significantly higher in women with intra-amniotic inflammation without demonstrable bacteria, and all of them were significantly higher in patients with microbial-associated intra-amniotic inflammation, when the median concentration of each one of them was compared to that of controls. Women with clinical chorioamnionitis with intra-amniotic inflammation without detectable bacteria had a median AF concentration of IL-10 and IL-13 2–3 fold higher than controls, whereas the median concentration of the four anti-inflammatory cytokines was 1.6–10 fold higher in patients with microbial-associated intra-amniotic inflammation than in controls (Table 4).
Of the 10 chemokines analyzed in this study, only the median AF concentration of Eotaxin-3 was significantly lower in cases without intra-amniotic inflammation than in those with uncomplicated pregnancies at term who were in labor (Table 4). Four of these chemokines were significantly higher in cases with intra-amniotic inflammation without detectable bacteria, whereas seven differed significantly between cases with microbial-associated intra-amniotic inflammation, when each one was compared to controls. Women with clinical chorioamnionitis who had intra-amniotic inflammation without demonstrable bacteria had median concentrations of MIP-1β, CXCL-10 (IP-10), IL-8, (Figure 2) and TARC that were 3–6 fold higher than in controls. Women with clinical chorioamnionitis and microbial associated intra-amniotic inflammation had median concentrations of MIP-1β, MIP-1α, IL-8, (Figure 2) TARC, MDC, and MCP-1 that were 2–12 fold higher than those of controls, whereas the median concentration of Eotaxin-3 was 4 fold higher in controls than in these cases. CXCL-10 (IP-10) was the only analyte that had a significantly higher median AF concentration in cases with intra-amniotic inflammation without demonstrable bacteria, but not in cases with microbial-associated intra-amniotic inflammation, compared to controls (Figure 2). IL-12p70 had the highest median fold change when comparing cases with intra-amniotic inflammation without demonstrable bacteria to controls (Figure 1). However, no difference could be detected in the pattern of the intra-amniotic inflammatory response between patients with microbial and without bacterial intra-amniotic inflammation (Figure 1).
The AF concentrations of chemokine in patients with term in labor (control) (n=24), clinical chorioamnionitis without intra-amniotic inflammation (n=10), clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria (n=10), and clinical chorioamnionitis with microbial-associated intra-amniotic inflammation (n=25). (A) The median AF concentrations of macrophage inflammatory protein-1alpha (MIP-1α) are 29.5 pg/mL (term in labor), 22.4 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 134.5 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 315.3 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation). (B) The median AF concentrations of macrophage inflammatory protein-1 beta (MIP-1β) are 46.3 pg/mL (term in labor), 31.3 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 308 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 586.9 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation). (C) The median AF concentrations of interleukin-8 (IL-8) are 1828.6 pg/mL (term in labor), 2728.2 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 6790.5 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 15,641.8 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation). (D) The median AF concentrations of C-X-C motif chemokine 10 (CXCL-10) or interferon gamma (IFN-γ)-inducible protein 10 or IP-10 are 366.3 pg/mL (term in labor), 438.2 pg/mL (clinical chorioamnionitis without intra-amniotic inflammation), 1827.8 pg/mL (clinical chorioamnionitis with intra-amniotic inflammation without demonstrable bacteria), and 533 pg/mL (clinical chorioamnionitis with microbial-associated intra-amniotic inflammation).
The remaining cytokines/chemokines scatterplots are displayed in Supplementary Figure 1 (pro-inflammatory cytokines), Supplementary Figure 2 (anti-inflammatory cytokines), and Supplementary Figure 3 (chemokines).
Discussion
Principal findings of the study
The principal findings of the study are as follows: 1) AF concentrations of pro- and anti-inflammatory cytokines and chemokines (except Eotaxin-3) were significantly higher in women with clinical chorioamnionitis at term than in controls (women at term in labor without intra-amniotic inflammation); 2) Patients with microbial-associated intra-amniotic inflammation (also known as intra-amniotic infection) and those with intra-amniotic inflammation without detectable bacteria had dramatic differential expression of cytokines and chemokines in the AF compared to patients with spontaneous labor without intra-amniotic inflammation; 3) Among patients with clinical chorioamnionitis and intra-amniotic inflammation, no differences could be detected in the profile of the intra-amniotic inflammatory response between those with and without bacteria in the AF; and 4) Interestingly, in patients diagnosed with clinical chorioamnionitis at term who had no evidence of intra-amniotic inflammation, the profile of AF cytokines and chemokines was similar to that of patients in spontaneous labor at term without intra-amniotic inflammation.
Cytokine and chemokine profile in amniotic fluid of women with clinical chorioamnionitis at term
This is the first study to characterize the behavior of the chemokine and cytokine network in the amniotic cavity of women with clinical chorioamnionitis at term. A major finding is that an intra-amniotic inflammatory response is readily detectable in women with this diagnosis. Higher concentrations of pro-inflammatory cytokines and chemokines, as well as a select group of anti-inflammatory cytokines in the AF, were found in patients with clinical chorioamnionitis compared to those with spontaneous labor at term without intra-amniotic inflammation.
As clinical chorioamnionitis is a heterogeneous condition, we examined the profile of cytokines and chemokines in the AF in different subsets of patients with this diagnosis. Specifically, we have shown that women with clinical chorioamnionitis can be subdivided into three subgroups based on the results of AF analysis for microorganisms and IL-6 concentrations: 1) microbial-associated intra-amniotic inflammation (microorganisms detected by culture or molecular microbiologic techniques and an elevated AF IL-6 concentration); 2) intra-amniotic inflammation without detectable microorganisms (an elevated AF IL-6 concentration without microorganisms detectable by culture or PCR); and 3) absent intra-amniotic inflammation (neither bacteria detectable and an AF IL-6 <2.6 ng/mL). The key observations of this study are that patients with intra-amniotic inflammation (regardless of whether this was associated with microorganisms) had dramatic elevations in the concentrations of pro- and anti-inflammatory cytokines, as well as chemokines in the AF compared to women with clinical chorioamnionitis without intra-amniotic inflammation. In contrast, there was no difference in the cytokine and chemokine profiles between women with clinical chorioamnionitis without intra-amniotic inflammation and those with spontaneous term labor without clinical chorioamnionitis.
Chemokines and cytokines differentially expressed in cases of microbial-associated clinical chorioamnionitis
The major cytokines overexpressed in patients with microbial-associated clinical chorioamnionitis are IL-1β, TNF-α, IFN-γ, IL-2, and the chemokines IL-8, MIP-1α, and MIP-1β. In contrast, we found that Eotaxin-3 concentrations were significantly lower in the same patients. These observations are consistent with previous studies reporting the intra-amniotic inflammatory response in patients with preterm labor and preterm prelabor rupture of the membranes (PROM) with MIAC have overexpression of the same cytokines and chemokines (i.e., IL-1β [62–76], TNF-α [63, 66, 68, 71–74, 77–79], IFN-γ [63, 68, 74, 80, 81], IL-8 [68, 71, 72, 74, 82–89], MIP-1α [68, 72, 74, 89–91], MIP-1β [63, 68, 72, 74], and IL-6 [33, 39, 50, 66, 68, 70–72, 74, 75, 80, 86, 88, 89, 92–98]). An elevation of IL-2 concentrations in the AF [80] and maternal circulation [99, 100] has been reported in patients with preterm delivery accompanied by histologic or clinical chorioamnionitis, respectively. The nature and intensity of the inflammatory response may be a function of a microbial type [101], virulence [101], or genetic factor that controls inflammation [102].
IL-1β [103–105] and TNF-α [106–109] are potent pro-inflammatory cytokines upregulated by microbial and nonmicrobial danger signals. These cytokines are produced by a wide variety of host cells [104, 105, 110, 111], and can induce the production of prostaglandins (universal mediators of the onset of labor) [65, 112–129], and stimulate the production of matrix-degrading enzymes, which have been implicated in the mechanisms of membrane rupture [130–139] and cervical remodeling [138, 140–146]. These cytokines can also stimulate the production of anti-microbial peptides, which play an important role in host defense against microorganisms [147–164]. The observations reported herein, coupled with those described in studies of patients with preterm labor and preterm PROM, suggest that the elevation of these cytokines is a consistent feature of the intra-amniotic inflammatory response to microorganisms and their products.
Chemokines and cytokines differentially expressed in intra-amniotic inflammation without detectable bacteria
Cytokines and chemokines substantially over-expressed (defined as a fold change >10) in the AF of patients with intra-amniotic inflammation without detectable bacteria are very similar to those upregulated in women with microbial-associated intra-amniotic inflammation – namely, TNF-α, IFN-γ, IL-1β, and IL-2, MIP-1β, MIP-1α, and IL-8. Of interest, the concentrations of CXCL-10 (or IP-10) and IL-12p70 were much higher in patients with intra-amniotic inflammation without detectable bacteria than in the control group (spontaneous labor at term). It is noteworthy that the AF concentration of CXCL-10 was not significantly higher in patients with microbial-associated inflammation than in controls, suggesting that an elevation of CXCL-10 might be a feature of sterile inflammation. Further work is required to confirm these findings; however, we previously reported that the AF concentration of CXCL-10 is elevated in patients who have chronic chorioamnionitis [31, 165–167] (in which there is infiltration of lymphocytes of the chorioamniotic membranes) in the absence of microorganisms in the amniotic cavity. We have proposed that an isolated elevation of CXCL-10 may represent a novel form of intra-amniotic inflammation associated with maternal anti-fetal rejection [167]. Previous reports have addressed the changes in the alarmin high mobility group box-1 in clinical chorioamnionitis at term [10].
IL-12 is a pro-inflammatory cytokine which induces the production of IFN-γ [168–170]. A previous study has reported that patients with preterm labor and acute histologic chorioamnionitis have higher concentrations of maternal-circulating IL-12 than those without this placental lesion [100]. Herein is the first report that the IL-12p70 subunit is elevated in the amniotic cavity of patients with clinical chorioamnionitis at term.
Clinical chorioamnionitis in the absence of an intra-amniotic inflammatory response
One of the findings in the current study is that a subset of patients with clinical chorioamnionitis does not have evidence of changes in the majority of AF cytokine and chemokine concentrations. Such patients can be readily identified because they do not have microorganisms in the amniotic cavity and the AF IL-6 concentration is consistently low and similar to that of patients in spontaneous labor at term (IL-6 <2.6 ng/mL). AF IL-10 and Eotaxin-3 concentrations were significantly lower in patients with clinical chorioamnionitis without intra-amniotic inflammation than in those with uncomplicated pregnancy in labor at term. The coefficient of variation (CV) for the determination of Eotaxin-3 is high (>15%) and, therefore, this finding should be interpreted with caution, and is one for which replication is desired. Importantly, most of these patients do not have placental lesions associated with acute AF infection (i.e., acute histologic chorioamnionitis and/or funisitis). Why these patients have a fever is unclear; however, our results suggest that the inflammatory stimuli do not seem to arise from the amniotic cavity. Whether fever is the result of epidural analgesia or any other extra-amniotic inflammatory processes remains to be established [171–187]. Further studies are required to determine whether patients with or without intra-amniotic inflammation can be differentiated by assessing maternal plasma concentrations of cytokines and chemokines.
Strengths and limitations
The strengths of this study are that AF concentrations of multiple inflammation-related proteins were studied in women with clinical chorioamnionitis at term and in controls in labor at term. Advanced techniques were used to identify bacteria in the amniotic cavity of patients with clinical chorioamnionitis. We also leveraged AF specimens from women with uncertain gestational age who presented with suspected preterm labor without ultrasound dating, but subsequently were considered to have a term pregnancy based on the following characteristics: 1) spontaneous labor; 2) delivery within 48 h of amniocentesis; 3) analysis of AF consistent with fetal lung maturity; 4) birthweight >2500 g; 5) absence of respiratory distress syndrome or other complications of prematurity; and 6) physical examination by a pediatrician which was consistent with the diagnosis of a term neonate.
Potentially limiting circumstances include the use of banked rather than fresh specimen; the coefficient of variation was >15% for 12 analytes (Supplementary Table). Further studies with a larger number of observations are desirable because the lack of difference in the concentrations of cytokines and chemokines between patients with intra-amniotic infection and intra-amniotic inflammation with microorganisms may represent a type II error.
Conclusion
Microbial-associated intra-amniotic inflammation and intra-amniotic inflammation without detectable bacteria are associated with a dramatic upregulation of the intra-amniotic inflammatory response. A subset of patients with term clinical chorioamnionitis without intra-amniotic inflammation has an expression of cytokines/chemokines in the AF similar to that of patients with labor at term without intra-amniotic inflammation. The observations reported herein have implications, as they shed light on the biology of a common complication of pregnancy, clinical chorioamnionitis at term.
Acknowledgments
This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C.
References
[1] Gibbs RS. Diagnosis of intra-amniotic infection. Semin Perinatol. 1977;1:71–7.Search in Google Scholar
[2] MacVicar J. Chorioamnionitis. Clin Obstet Gynecol. 1970;13:272–90.10.1097/00003081-197006000-00005Search in Google Scholar
[3] Gibbs RS, Blanco JD, St Clair PJ, Castaneda YS. Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis. 1982;145:1–8.10.1093/infdis/145.1.1Search in Google Scholar
[4] Hollander D. Diagnosis of chorioamnionitis. Clin Obstet Gynecol. 1986;29:816–25.10.1097/00003081-198612000-00008Search in Google Scholar
[5] Gilstrap LC, 3rd, Cox SM. Acute chorioamnionitis. Obstet Gynecol Clin N Am. 1989;16:373–9.10.1016/S0889-8545(21)00165-0Search in Google Scholar
[6] Newton ER. Chorioamnionitis and intraamniotic infection. Clin Obstet Gynecol. 1993;36:795–808.10.1097/00003081-199312000-00004Search in Google Scholar PubMed
[7] Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006;11:317–26.10.1016/j.siny.2006.05.001Search in Google Scholar PubMed PubMed Central
[8] Tita AT, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol. 2010;37:339–54.10.1016/j.clp.2010.02.003Search in Google Scholar PubMed PubMed Central
[9] Fishman SG, Gelber SE. Evidence for the clinical management of chorioamnionitis. Semin Fetal Neonatal Med. 2012;17:46–50.10.1016/j.siny.2011.09.002Search in Google Scholar PubMed
[10] Romero R, Chaiworapongsa T, Savasan ZA, Hussein Y, Dong Z, Kusanovic JP, et al. Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE. J Matern Fetal Neonatal Med. 2012;25:558–67.10.3109/14767058.2011.599083Search in Google Scholar PubMed PubMed Central
[11] Romero R, Miranda J, Kusanovic JP, Chaiworapongsa T, Chaemsaithong P, Martinez A, et al. Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques. J Perinatal Med. 2015;43:19–36.10.1515/jpm-2014-0249Search in Google Scholar PubMed PubMed Central
[12] Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345:760–5.10.1126/science.1251816Search in Google Scholar
[13] Sperling RS, Ramamurthy RS, Gibbs RS. A comparison of intrapartum versus immediate postpartum treatment of intra-amniotic infection. Obstet Gynecol. 1987;70:861–5.Search in Google Scholar
[14] Gibbs RS, Dinsmoor MJ, Newton ER, Ramamurthy RS. A randomized trial of intrapartum versus immediate postpartum treatment of women with intra-amniotic infection. Obstet Gynecol. 1988;72:823–8.10.1097/00006250-198812000-00001Search in Google Scholar
[15] Gilstrap LC, 3rd, Leveno KJ, Cox SM, Burris JS, Mashburn M, Rosenfeld CR. Intrapartum treatment of acute chorioamnionitis: impact on neonatal sepsis. Am J Obstet Gynecol. 1988;159:579–83.10.1016/S0002-9378(88)80012-7Search in Google Scholar
[16] Maberry MC, Gilstrap LC, 3rd. Intrapartum antibiotic therapy for suspected intraamniotic infection: impact on the fetus and neonate. Clin Obstet Gynecol. 1991;34:345–51.10.1097/00003081-199106000-00016Search in Google Scholar PubMed
[17] Westover T, Knuppel RA. Modern management of clinical chorioamnionitis. Infect Dis Obstet Gynecol. 1995;3:123–32.10.1155/S1064744995000457Search in Google Scholar PubMed PubMed Central
[18] Fahey JO. Clinical management of intra-amniotic infection and chorioamnionitis: a review of the literature. J Midwifery Women’s Health. 2008;53:227–35.10.1016/j.jmwh.2008.01.001Search in Google Scholar PubMed
[19] Chapman E, Reveiz L, Illanes E, Bonfill Cosp X. Antibiotic regimens for management of intra-amniotic infection. Cochrane Database Syst Rev. 2014;12:CD010976.10.1002/14651858.CD010976Search in Google Scholar
[20] Gordon H, Brosens I. Cytology of amniotic fluid: a new test for fetal maturity. Obstet Gynecol. 1967;30:652–6.Search in Google Scholar
[21] Morrison JC, Morrison DL, Lovett FA, Whybrew WD, Bucovaz ET, Wiser WL, et al. Nile blue staining of cells in amniotic fluid for fetal maturity. I. A reappraisal. Obstet Gynecol. 1974;44:355–61.Search in Google Scholar
[22] Morrison JC, Morrison DL, Lovett FA, Whybrew WD, Bucovaz ET, Wiser WL, et al. Nile blue staining of cells in amniotic fluid for fetal maturity. II. In complicated obstetric cases. Obstet Gynecol. 1974;44:362–7.Search in Google Scholar
[23] Woods JR, Jr., Maibach H. Cell surface lipid in the amniotic fluid. Obstet Gynecol. 1979;53:602–7.Search in Google Scholar
[24] DiGiulio DB, Romero R, Amogan HP, Kusanovic JP, Bik EM, Gotsch F, et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PloS One. 2008;3:e3056.10.1371/journal.pone.0003056Search in Google Scholar PubMed PubMed Central
[25] DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol. 2010;64:38–57.10.1111/j.1600-0897.2010.00830.xSearch in Google Scholar PubMed PubMed Central
[26] DiGiulio DB, Gervasi M, Romero R, Mazaki-Tovi S, Vaisbuch E, Kusanovic JP, et al. Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods. J Perinatal Med. 2010;38:503–13.10.1515/jpm.2010.078Search in Google Scholar PubMed PubMed Central
[27] DiGiulio DB, Gervasi MT, Romero R, Vaisbuch E, Mazaki-Tovi S, Kusanovic JP, et al. Microbial invasion of the amniotic cavity in pregnancies with small-for-gestational-age fetuses. J Perinatal Med. 2010;38:495–502.10.1515/jpm.2010.076Search in Google Scholar PubMed PubMed Central
[28] 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;185:1130–6.10.1067/mob.2001.117680Search in Google Scholar PubMed
[29] Kim KW, Romero R, Park HS, Park CW, Shim SS, Jun JK, et al. A rapid matrix metalloproteinase-8 bedside test for the detection of intraamniotic inflammation in women with preterm premature rupture of membranes. Am J Obstet Gynecol. 2007;197:292 e1–5.10.1016/j.ajog.2007.06.040Search in Google Scholar PubMed
[30] Romero R, Chaiworapongsa T, Alpay Savasan Z, Xu Y, Hussein Y, Dong Z, et al. Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1. J Matern Fetal Neonatal Med. 2011;24:1444–55.10.3109/14767058.2011.591460Search in Google Scholar PubMed PubMed Central
[31] Gervasi MT, Romero R, Bracalente G, Erez O, Dong Z, Hassan SS, et al. Midtrimester amniotic fluid concentrations of interleukin-6 and interferon-gamma-inducible protein-10: evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early (<32 weeks) and late (>32 weeks) preterm delivery. J Perinatal Med. 2012;40: 329–43.10.1515/jpm-2012-0034Search in Google Scholar PubMed PubMed Central
[32] Romero R, Kadar N, Miranda J, Korzeniewski SJ, Schwartz AG, Chaemsaithong P, et al. The diagnostic performance of the Mass Restricted (MR) score in the identification of microbial invasion of the amniotic cavity or intra-amniotic inflammation is not superior to amniotic fluid interleukin-6. J Matern Fetal Neonatal Med. 2014;27:757–69.10.3109/14767058.2013.844123Search in Google Scholar PubMed PubMed Central
[33] Combs CA, Gravett M, Garite TJ, Hickok DE, Lapidus J, Porreco R, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210:125.e1–e15.10.1016/j.ajog.2013.11.032Search in Google Scholar PubMed
[34] Romero R, Miranda J, Chaiworapongsa T, Chaemsaithong P, Gotsch F, Dong Z, et al. A novel molecular microbiologic technique for the rapid diagnosis of microbial invasion of the amniotic cavity and intra-amniotic infection in preterm labor with intact membranes. Am J Reprod Immunol. 2014;71:330–58.10.1111/aji.12189Search in Google Scholar PubMed PubMed Central
[35] Romero R, Miranda J, Chaiworapongsa T, Korzeniewski SJ, Chaemsaithong P, Gotsch F, et al. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol. 2014;72:458–74.10.1111/aji.12296Search in Google Scholar PubMed PubMed Central
[36] Romero R, Miranda J, Chaiworapongsa T, Chaemsaithong P, Gotsch F, Dong Z, et al. Sterile intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix: prevalence and clinical significance. J Matern Fetal Neonatal Med. 2014:1–17. [Epub ahead of print].10.3109/14767058.2014.954243Search in Google Scholar PubMed PubMed Central
[37] Romero R, Miranda J, Chaemsaithong P, Chaiworapongsa T, Kusanovic JP, Dong Z, et al. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2014:1–16. [Epub ahead of print].10.3109/14767058.2014.958463Search in Google Scholar
[38] Chaemsaithong P, Romero R, Korzeniewski SJ, Dong Z, Yeo L, Hassan SS, et al. A point of care test for the determination of amniotic fluid interleukin-6 and the chemokine CXCL-10/IP-10. J Matern Fetal Neonatal Med. 2014:1–10. [Epub ahead of print].10.3109/14767058.2014.961417Search in Google Scholar
[39] Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, et al. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol. 1995;172:960–70.10.1016/0002-9378(95)90028-4Search in Google Scholar
[40] Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol. 2000;182:675–81.10.1067/mob.2000.104207Search in Google Scholar PubMed
[41] Redline RW, Heller D, Keating S, Kingdom J. Placental diagnostic criteria and clinical correlation--a workshop report. Placenta. 2005;26:S114–17.10.1016/j.placenta.2005.02.009Search in Google Scholar PubMed
[42] Redline RW. Inflammatory responses in the placenta and umbilical cord. Semin Fetal Neonatal Med. 2006;11:296–301.10.1016/j.siny.2006.02.011Search in Google Scholar PubMed
[43] Mi Lee S, Romero R, Lee KA, Jin Yang H, Joon Oh K, Park CW, et al. The frequency and risk factors of funisitis and histologic chorioamnionitis in pregnant women at term who delivered after the spontaneous onset of labor. J Matern Fetal Neonatal Med. 2011;24:37–42.10.3109/14767058.2010.482622Search in Google Scholar PubMed PubMed Central
[44] Lee Y, Kim HJ, Choi SJ, Oh SY, Kim JS, Roh CR, et al. Is there a stepwise increase in neonatal morbidities according to histological stage (or grade) of acute chorioamnionitis and funisitis?: effect of gestational age at delivery. J Perinatal Med. 2015;43:259–67.10.1515/jpm-2014-0035Search in Google Scholar PubMed
[45] Pacora P, Chaiworapongsa T, Maymon E, Kim YM, Gomez R, Yoon BH, et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med. 2002;11:18–25.10.1080/jmf.11.1.18.25Search in Google Scholar PubMed
[46] Park CW, Lee SM, Park JS, Jun JK, Romero R, Yoon BH. The antenatal identification of funisitis with a rapid MMP-8 bedside test. J Perinatal Med. 2008;36:497–502.10.1515/JPM.2008.079Search in Google Scholar PubMed PubMed Central
[47] Park HS, Romero R, Lee SM, Park CW, Jun JK, Yoon BH. Histologic chorioamnionitis is more common after spontaneous labor than after induced labor at term. Placenta. 2010;31:792–5.10.1016/j.placenta.2010.06.013Search in Google Scholar
[48] Korzeniewski SJ, Romero R, Cortez J, Pappas A, Schwartz AG, Kim CJ, et al. A “multi-hit” model of neonatal white matter injury: cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events. J Perinatal Med. 2014;42:731–43.10.1515/jpm-2014-0250Search in Google Scholar
[49] Kim SM, Romero R, Park JW, Oh KJ, Jun JK, Yoon BH. The relationship between the intensity of intra-amniotic inflammation and the presence and severity of acute histologic chorioamnionitis in preterm gestation. J Matern Fetal Neonatal Med. 2014:1–10. [Epub ahead of print].10.3109/14767058.2014.961009Search in Google Scholar
[50] Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998;179:194–202.10.1016/S0002-9378(98)70272-8Search in Google Scholar
[51] Chaiworapongsa T, Romero R, Kim JC, Kim YM, Blackwell SC, Yoon BH, et al. Evidence for fetal involvement in the pathologic process of clinical chorioamnionitis. Am J Obstet Gynecol. 2002;186:1178–82.10.1067/mob.2002.124042Search in Google Scholar PubMed
[52] Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, et al. The fetal inflammatory response syndrome. Clinical Obstet Gynecol. 2007;50:652–83.10.1097/GRF.0b013e31811ebef6Search in Google Scholar PubMed
[53] Kim SK, Romero R, Chaiworapongsa T, Kusanovic JP, Mazaki-Tovi S, Mittal P, et al. Evidence of changes in the immunophenotype and metabolic characteristics (intracellular reactive oxygen radicals) of fetal, but not maternal, monocytes and granulocytes in the fetal inflammatory response syndrome. J Perinatal Med. 2009;37:543–52.10.1515/JPM.2009.106Search in Google Scholar PubMed PubMed Central
[54] Madsen-Bouterse SA, Romero R, Tarca AL, Kusanovic JP, Espinoza J, Kim CJ, et al. The transcriptome of the fetal inflammatory response syndrome. Am J Reprod Immunol. 2010;63:73–92.10.1111/j.1600-0897.2009.00791.xSearch in Google Scholar PubMed PubMed Central
[55] Chaiworapongsa T, Romero R, Berry SM, Hassan SS, Yoon BH, Edwin S, et al. The role of granulocyte colony-stimulating factor in the neutrophilia observed in the fetal inflammatory response syndrome. J Perinatal Med. 2011;39:653–66.10.1515/jpm.2011.072Search in Google Scholar PubMed PubMed Central
[56] Vaisbuch E, Romero R, Gomez R, Kusanovic JP, Mazaki-Tovi S, Chaiworapongsa T, et al. An elevated fetal interleukin-6 concentration can be observed in fetuses with anemia due to Rh alloimmunization: implications for the understanding of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med. 2011;24:391–6.10.3109/14767058.2010.507294Search in Google Scholar PubMed PubMed Central
[57] Romero R, Savasan ZA, Chaiworapongsa T, Berry SM, Kusanovic JP, Hassan SS, et al. Hematologic profile of the fetus with systemic inflammatory response syndrome. J Perinatal Med. 2011;40:19–32.Search in Google Scholar
[58] Romero R, Soto E, Berry SM, Hassan SS, Kusanovic JP, Yoon BH, et al. Blood pH and gases in fetuses in preterm labor with and without systemic inflammatory response syndrome. J Matern Fetal Neonatal Med. 2012;25:1160–70.10.3109/14767058.2011.629247Search in Google Scholar
[59] Stampalija T, Romero R, Korzeniewski SJ, Chaemsaithong P, Miranda J, Yeo L, et al. Soluble ST2 in the fetal inflammatory response syndrome: in vivo evidence of activation of the anti-inflammatory limb of the immune response. J Matern Fetal Neonatal Med. 2013;26:1384–93.10.3109/14767058.2013.784258Search in Google Scholar
[60] R Core Team. A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available at: http://www.R-project.org/. 2013 [cited 2014].Search in Google Scholar
[61] Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289–300.10.1111/j.2517-6161.1995.tb02031.xSearch in Google Scholar
[62] Romero R, Brody DT, Oyarzun E, Mazor M, Wu YK, Hobbins JC, et al. Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol. 1989;160:1117–23.10.1016/0002-9378(89)90172-5Search in Google Scholar
[63] Casey ML, Cox SM, Word RA, MacDonald PC. Cytokines and infection-induced preterm labour. Reproduction, fertility, and development. Reprod Fertil Dev. 1990;2:499–509.10.1071/RD9900499Search in Google Scholar
[64] Romero R, Mazor M, Brandt F, Sepulveda W, Avila C, Cotton DB, et al. Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition. Am J Reprod Immunol. 1992;27:117–23.10.1111/j.1600-0897.1992.tb00737.xSearch in Google Scholar
[65] Romero R, Tartakovsky B. The natural interleukin-1 receptor antagonist prevents interleukin-1-induced preterm delivery in mice. Am J Obstet Gynecol. 1992;167:1041–5.10.1016/S0002-9378(12)80035-4Search in Google Scholar
[66] Hillier SL, Witkin SS, Krohn MA, Watts DH, Kiviat NB, Eschenbach DA. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection. Obstet Gynecol. 1993;81:941–8.Search in Google Scholar
[67] Gravett MG, Witkin SS, Haluska GJ, Edwards JL, Cook MJ, Novy MJ. An experimental model for intraamniotic infection and preterm labor in rhesus monkeys. Am J Obstet Gynecol. 1994;171:1660–7.10.1016/0002-9378(94)90418-9Search in Google Scholar
[68] Gomez R, Ghezzi F, Romero R, Munoz H, Tolosa JE, Rojas I. Premature labor and intra-amniotic infection. Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol. 1995;22:281–342.10.1016/S0095-5108(18)30286-0Search in Google Scholar
[69] Cox SM, Casey ML, MacDonald PC. Accumulation of interleukin-1beta and interleukin-6 in amniotic fluid: a sequela of labour at term and preterm. Hum Reprod Update. 1997;3:517–27.10.1093/humupd/3.5.517Search in Google Scholar PubMed
[70] Gonzalez-Bosquet E, Cerqueira MJ, Dominguez C, Gasser I, Bermejo B, Cabero L. Amniotic fluid glucose and cytokines values in the early diagnosis of amniotic infection in patients with preterm labor and intact membranes. J Matern Fetal Med. 1999;8:155–8.10.3109/14767059909020480Search in Google Scholar
[71] Asrat T. Intra-amniotic infection in patients with preterm prelabor rupture of membranes. Pathophysiology, detection, and management. Clin Perinatol. 2001;28:735–51.10.1016/S0095-5108(03)00074-5Search in Google Scholar
[72] Figueroa R, Garry D, Elimian A, Patel K, Sehgal PB, Tejani N. Evaluation of amniotic fluid cytokines in preterm labor and intact membranes. J Matern Fetal Neonatal Med. 2005;18: 241–7.10.1080/13506120500223241Search in Google Scholar
[73] Sadowsky DW, Adams KM, Gravett MG, Witkin SS, Novy MJ. Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am J Obstet Gynecol. 2006;195:1578–89.10.1016/j.ajog.2006.06.072Search in Google Scholar
[74] Blank V, Hirsch E, Challis JR, Romero R, Lye SJ. Cytokine signaling, inflammation, innate immunity and preterm labour – a workshop report. Placenta. 2008;29:S102–4.10.1016/j.placenta.2007.10.011Search in Google Scholar
[75] Marconi C, de Andrade Ramos BR, Peracoli JC, Donders GG, da Silva MG. Amniotic fluid interleukin-1 beta and interleukin-6, but not interleukin-8 correlate with microbial invasion of the amniotic cavity in preterm labor. Am J Reprod Immunol. 2011;65:549–56.10.1111/j.1600-0897.2010.00940.xSearch in Google Scholar
[76] Puchner K, Iavazzo C, Gourgiotis D, Boutsikou M, Baka S, Hassiakos D, et al. Mid-trimester amniotic fluid interleukins (IL-1beta, IL-10 and IL-18) as possible predictors of preterm delivery. In Vivo. 2011;25:141–8.Search in Google Scholar
[77] Romero R, Manogue KR, Mitchell MD, Wu YK, Oyarzun E, Hobbins JC, et al. Infection and labor. IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor. Am J Obstet Gynecol. 1989;161:336–41.10.1016/0002-9378(89)90515-2Search in Google Scholar
[78] Romero R, Mazor M, Sepulveda W, Avila C, Copeland D, Williams J. Tumor necrosis factor in preterm and term labor. Am J Obstet Gynecol. 1992;166:1576–87.10.1016/0002-9378(92)91636-OSearch in Google Scholar
[79] Leslie KK, Lee SL, Woodcock SM, Davies JK, McDuffie RS, Jr., Hirsch E, et al. Acute intrauterine infection results in an imbalance between pro- and anti-inflammatory cytokines in the pregnant rabbit. Am J Reprod Immunol. 2000;43:305–11.10.1111/j.8755-8920.2000.430510.xSearch in Google Scholar PubMed
[80] Negishi H, Yamada H, Mikuni M, Kishida T, Okuyama K, Sagawa T, et al. Correlation between cytokine levels of amniotic fluid and histological chorioamnionitis in preterm delivery. J Perinatal Med. 1996;24:633–9.10.1515/jpme.1996.24.6.633Search in Google Scholar PubMed
[81] Shobokshi A, Shaarawy M. Maternal serum and amniotic fluid cytokines in patients with preterm premature rupture of membranes with and without intrauterine infection. Int J Gynaecol Obstet. 2002;79:209–15.10.1016/S0020-7292(02)00238-2Search in Google Scholar
[82] Romero R, Ceska M, Avila C, Mazor M, Behnke E, Lindley I. Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition. Am J Obstet Gynecol. 1991;165:813–20.10.1016/0002-9378(91)90422-NSearch in Google Scholar
[83] Cherouny PH, Pankuch GA, Romero R, Botti JJ, Kuhn DC, Demers LM, et al. Neutrophil attractant/activating peptide-1/interleukin-8: association with histologic chorioamnionitis, preterm delivery, and bioactive amniotic fluid leukoattractants. Am J Obstet Gynecol. 1993;169:1299–303.10.1016/0002-9378(93)90297-VSearch in Google Scholar
[84] Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F, et al. Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol. 1997;177:825–30.10.1016/S0002-9378(97)70276-XSearch in Google Scholar
[85] Ghezzi F, Gomez R, Romero R, Yoon BH, Edwin SS, David C, et al. Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia. Eur J Obstet Gynecol Reprod Biol. 1998;78:5–10.10.1016/S0301-2115(97)00236-4Search in Google Scholar
[86] Hsu CD, Meaddough E, Aversa K, Hong SF, Lu LC, Jones DC, et al. Elevated amniotic fluid levels of leukemia inhibitory factor, interleukin 6, and interleukin 8 in intra-amniotic infection. Am J Obstet Gynecol. 1998;179:1267–70.10.1016/S0002-9378(98)70144-9Search in Google Scholar
[87] Hsu CD, Meaddough E, Aversa K, Copel JA. The role of amniotic fluid L-selectin, GRO-alpha, and interleukin-8 in the pathogenesis of intraamniotic infection. Am J Obstet Gynecol. 1998;178:428–32.10.1016/S0002-9378(98)70414-4Search in Google Scholar
[88] 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;82:120–8.10.1034/j.1600-0412.2003.00047.xSearch in Google Scholar PubMed
[89] Cobo T, Kacerovsky M, Palacio M, Hornychova H, Hougaard DM, Skogstrand K, et al. Intra-amniotic inflammatory response in subgroups of women with preterm prelabor rupture of the membranes. PloS One. 2012;7:e43677.10.1371/journal.pone.0043677Search in Google Scholar PubMed PubMed Central
[90] Romero R, Gomez R, Galasso M, Munoz H, Acosta L, Yoon BH, et al. Macrophage inflammatory protein-1 alpha in term and preterm parturition: effect of microbial invasion of the amniotic cavity. Am J Reprod Immunol. 1994;32:108–13.10.1111/j.1600-0897.1994.tb01101.xSearch in Google Scholar PubMed
[91] Esplin MS, Romero R, Chaiworapongsa T, Kim YM, Edwin S, Gomez R, et al. Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection. J Matern Fetal Neonatal Med. 2005;17:365–73.10.1080/14767050500141329Search in Google Scholar
[92] Romero R, Avila C, Santhanam U, Sehgal PB. Amniotic fluid interleukin 6 in preterm labor. Association with infection. J Clin Invest. 1990;85:1392–400.10.1172/JCI114583Search in Google Scholar
[93] Romero R, Sepulveda W, Kenney JS, Archer LE, Allison AC, Sehgal PB. Interleukin 6 determination in the detection of microbial invasion of the amniotic cavity. Ciba Foundation Symp. 1992;167:205–20; discussion 20–3.10.1002/9780470514269.ch13Search in Google Scholar
[94] Romero R, Yoon BH, Kenney JS, Gomez R, Allison AC, Sehgal PB. Amniotic fluid interleukin-6 determinations are of diagnostic and prognostic value in preterm labor. Am J Reprod Immunol. 1993;30:167–83.10.1111/j.1600-0897.1993.tb00618.xSearch in Google Scholar
[95] Yoon BH, Romero R, Moon J, Chaiworapongsa T, Espinoza J, Kim YM, et al. Differences in the fetal interleukin-6 response to microbial invasion of the amniotic cavity between term and preterm gestation. J Matern Fetal Neonatal Med. 2003;13:32–8.10.1080/jmf.13.1.32.38Search in Google Scholar
[96] Cobo T, Jacobsson B, Kacerovsky M, Hougaard DM, Skogstrand K, Gratacos E, et al. Systemic and local inflammatory response in women with preterm prelabor rupture of membranes. PloS One. 2014;9:e85277.10.1371/journal.pone.0085277Search in Google Scholar
[97] Kacerovsky M, Musilova I, Hornychova H, Kutova R, Pliskova L, Kostal M, et al. Bedside assessment of amniotic fluid interleukin-6 in preterm prelabor rupture of membranes. Am J Obstet Gynecol. 2014;211:385 e1–9.10.1016/j.ajog.2014.03.069Search in Google Scholar
[98] Kacerovsky M, Musilova I, Andrys C, Hornychova H, Pliskova L, Kostal M, et al. Prelabor rupture of membranes between 34 and 37 weeks: the intraamniotic inflammatory response and neonatal outcomes. Am J Obstet Gynecol. 2014;210:325.e1–e10.10.1016/j.ajog.2013.10.882Search in Google Scholar
[99] Lencki SG, Maciulla MB, Eglinton GS. Maternal and umbilical cord serum interleukin levels in preterm labor with clinical chorioamnionitis. Am J Obstet Gynecol. 1994;170:1345–51.10.1016/S0002-9378(13)90462-2Search in Google Scholar
[100] Gargano JW, Holzman C, Senagore P, Thorsen P, Skogstrand K, Hougaard DM, et al. Mid-pregnancy circulating cytokine levels, histologic chorioamnionitis and spontaneous preterm birth. J Reprod Immunol. 2008;79:100–10.10.1016/j.jri.2008.08.006Search in Google Scholar PubMed PubMed Central
[101] Allen-Daniels MJ, Serrano MG, Pflugner LP, Fettweis JM, Prestosa MA, Koparde VN, et al. Identification of a gene in Mycoplasma hominis associated with preterm birth and microbial burden in intraamniotic infection. Am J Obstet Gynecol 2015:[Epub ahead of print].10.1016/j.ajog.2015.01.032Search in Google Scholar
[102] Romero R, Chaiworapongsa T, Kuivaniemi H, Tromp G. Bacterial vaginosis, the inflammatory response and the risk of preterm birth: a role for genetic epidemiology in the prevention of preterm birth. Am J Obstet Gynecol. 2004;190:1509–19.10.1016/j.ajog.2004.01.002Search in Google Scholar
[103] Loppnow H, Werdan K, Reuter G, Flad HD. The interleukin-1 and interleukin-1 converting enzyme families in the cardiovascular system. Eur Cytokine Network. 1998;9:675–80.Search in Google Scholar
[104] Tato CM, Cua DJ. SnapShot: cytokines I. Cell. 2008;132:324, e1.Search in Google Scholar
[105] Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014;1843:2563–82.10.1016/j.bbamcr.2014.05.014Search in Google Scholar
[106] Tartaglia LA, Goeddel DV. Two TNF receptors. Immunol Today. 1992;13:151–3.10.1016/0167-5699(92)90116-OSearch in Google Scholar
[107] Rothe J, Gehr G, Loetscher H, Lesslauer W. Tumor necrosis factor receptors--structure and function. Immunol Res. 1992;11:81–90.10.1007/BF02918612Search in Google Scholar
[108] Smith CA, Farrah T, Goodwin RG. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994;76:959–62.10.1016/0092-8674(94)90372-7Search in Google Scholar
[109] Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104:487–501.10.1016/S0092-8674(01)00237-9Search in Google Scholar
[110] Arend WP, Palmer G, Gabay C. IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev. 2008;223:20–38.10.1111/j.1600-065X.2008.00624.xSearch in Google Scholar
[111] Tato CM, Cua DJ. SnapShot: cytokines III. Cell. 2008;132:900.Search in Google Scholar
[112] Topley N, Floege J, Wessel K, Hass R, Radeke HH, Kaever V, et al. Prostaglandin E2 production is synergistically increased in cultured human glomerular mesangial cells by combinations of IL-1 and tumor necrosis factor-alpha 1. J Immunol. 1989;143:1989–95.10.4049/jimmunol.143.6.1989Search in Google Scholar
[113] Romero R, Durum S, Dinarello CA, Oyarzun E, Hobbins JC, Mitchell MD. Interleukin-1 stimulates prostaglandin biosynthesis by human amnion. Prostaglandins. 1989;37:13–22.10.1016/0090-6980(89)90028-2Search in Google Scholar
[114] Romero R, Mazor M, Wu YK, Avila C, Oyarzun E, Mitchell MD. Bacterial endotoxin and tumor necrosis factor stimulate prostaglandin production by human decidua. Prostaglandins, leukotrienes, and essential fatty acids. 1989;37:183–6.10.1016/0952-3278(89)90083-5Search in Google Scholar
[115] Mitchell MD, Edwin S, Romero RJ. Prostaglandin biosynthesis by human decidual cells: effects of inflammatory mediators. Prostaglandins Leukot Essen Fatty Acids. 1990;41:35–8.10.1016/0952-3278(90)90128-8Search in Google Scholar
[116] Romero R, Parvizi ST, Oyarzun E, Mazor M, Wu YK, Avila C, et al. Amniotic fluid interleukin-1 in spontaneous labor at term. J Reprod Med. 1990;35:235–8.Search in Google Scholar
[117] Romero R, Mazor M, Tartakovsky B. Systemic administration of interleukin-1 induces preterm parturition in mice. Am J Obstet Gynecol. 1991;165:969–71.10.1016/0002-9378(91)90450-6Search in Google Scholar
[118] Mitchell MD, Romero RJ, Avila C, Foster JT, Edwin SS. Prostaglandin production by amnion and decidual cells in response to bacterial products. Prostaglandins Leukot Essen Fatty Acids. 1991;42:167–9.10.1016/0952-3278(91)90152-USearch in Google Scholar
[119] Lundin-Schiller S, Mitchell MD. Prostaglandin production by human chorion laeve cells in response to inflammatory mediators. Placenta. 1991;12:353–63.10.1016/0143-4004(91)90343-ESearch in Google Scholar
[120] Ishihara O, Khan H, Sullivan MH, Elder MG. Interleukin-1 beta stimulates decidual stromal cell cyclo-oxygenase enzyme and prostaglandin production. Prostaglandins. 1992;44:43–52.10.1016/0090-6980(92)90106-4Search in Google Scholar
[121] Romero R, Sepulveda W, Mazor M, Brandt F, Cotton DB, Dinarello CA, et al. The natural interleukin-1 receptor antagonist in term and preterm parturition. Am J Obstet Gynecol. 1992;167:863–72.10.1016/S0002-9378(12)80003-2Search in Google Scholar
[122] Mitchell MD, Edwin SS, Silver RM, Romero RJ. Potential agonist action of the interleukin-1 receptor antagonist protein: implications for treatment of women. J Clin Endocrinol Metab. 1993;76:1386–8.Search in Google Scholar
[123] Alleva DG, Burger CJ, Elgert KD. Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-alpha production. Role of tumor-derived IL-10, TGF-beta, and prostaglandin E2. J Immunol. 1994;153:1674–86.10.4049/jimmunol.153.4.1674Search in Google Scholar
[124] Mitchell MD, Romero RJ, Edwin SS, Trautman MS. Prostaglandins and parturition. Reprod Fertil Dev. 1995;7:623–32.10.1071/RD9950623Search in Google Scholar PubMed
[125] Brown NL, Alvi SA, Elder MG, Bennett PR, Sullivan MH. Regulation of prostaglandin production in intact fetal membranes by interleukin-1 and its receptor antagonist. J Endocrinol. 1998;159:519–26.10.1677/joe.0.1590519Search in Google Scholar PubMed
[126] Hertelendy F, Rastogi P, Molnar M, Romero R. Interleukin-1beta-induced prostaglandin E2 production in human myometrial cells: role of a pertussis toxin-sensitive component. Am J Reprod Immunol. 2001;45:142–7.10.1111/j.8755-8920.2001.450304.xSearch in Google Scholar PubMed
[127] Hertelendy F, Molnar M, Romero R. Interferon gamma antagonizes interleukin-1beta-induced cyclooxygenase-2 expression and prostaglandin E(2) production in human myometrial cells. J Soc Gynecol Invest. 2002;9:215–19.Search in Google Scholar
[128] Mitchell MD, Chang MC, Chaiworapongsa T, Lan HY, Helliwell RJ, Romero R, et al. Identification of 9alpha,11beta-prostaglandin F2 in human amniotic fluid and characterization of its production by human gestational tissues. J Clin Endocrinol Metab. 2005;90:4244–8.10.1210/jc.2004-2496Search in Google Scholar PubMed
[129] Romero R, Gotsch F, Pineles B, Kusanovic JP. Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev. 2007;65:S194–202.10.1111/j.1753-4887.2007.tb00362.xSearch in Google Scholar
[130] So T, Ito A, Sato T, Mori Y, Hirakawa S. Tumor necrosis factor-alpha stimulates the biosynthesis of matrix metalloproteinases and plasminogen activator in cultured human chorionic cells. Biol Reprod. 1992;46:772–8.10.1095/biolreprod46.5.772Search in Google Scholar
[131] Fortunato SJ, Menon R, Lombardi SJ. Collagenolytic enzymes (gelatinases) and their inhibitors in human amniochorionic membrane. Am J Obstet Gynecol. 1997;177:731–41.10.1016/S0002-9378(97)70260-6Search in Google Scholar
[132] Fortunato SJ, Menon R, Lombardi SJ. MMP/TIMP imbalance in amniotic fluid during PROM: an indirect support for endogenous pathway to membrane rupture. J Perinatal Med. 1999;27:362–8.10.1515/JPM.1999.049Search in Google Scholar PubMed
[133] Arechavaleta-Velasco F, Ogando D, Parry S, Vadillo-Ortega F. Production of matrix metalloproteinase-9 in lipopolysaccharide-stimulated human amnion occurs through an autocrine and paracrine proinflammatory cytokine-dependent system. Biol Reprod. 2002;67:1952–8.10.1095/biolreprod.102.004721Search in Google Scholar PubMed
[134] Park KH, Chaiworapongsa T, Kim YM, Espinoza J, Yoshimatsu J, Edwin S, et al. Matrix metalloproteinase 3 in parturition, premature rupture of the membranes, and microbial invasion of the amniotic cavity. J Perinatal Med. 2003;31:12–22.10.1515/JPM.2003.002Search in Google Scholar PubMed
[135] Zaga V, Estrada-Gutierrez G, Beltran-Montoya J, Maida-Claros R, Lopez-Vancell R, Vadillo-Ortega F. Secretions of interleukin-1beta and tumor necrosis factor alpha by whole fetal membranes depend on initial interactions of amnion or choriodecidua with lipopolysaccharides or group B streptococci. Biol Reprod. 2004;71:1296–302.10.1095/biolreprod.104.028621Search in Google Scholar PubMed
[136] Vadillo-Ortega F, Estrada-Gutierrez G. Role of matrix metalloproteinases in preterm labour. Br J Obstet Gynaecol. 2005;112:19–22.10.1111/j.1471-0528.2005.00579.xSearch in Google Scholar PubMed
[137] Kumar D, Fung W, Moore RM, Pandey V, Fox J, Stetzer B, et al. Proinflammatory cytokines found in amniotic fluid induce collagen remodeling, apoptosis, and biophysical weakening of cultured human fetal membranes. Biol Reprod. 2006;74:29–34.10.1095/biolreprod.105.045328Search in Google Scholar PubMed
[138] Oner C, Schatz F, Kizilay G, Murk W, Buchwalder LF, Kayisli UA, et al. Progestin-inflammatory cytokine interactions affect matrix metalloproteinase-1 and -3 expression in term decidual cells: implications for treatment of chorioamnionitis-induced preterm delivery. J Clin Endocrinol Metab. 2008;93:252–9.10.1210/jc.2007-1538Search in Google Scholar PubMed PubMed Central
[139] Moore RM, Mansour JM, Redline RW, Mercer BM, Moore JJ. The physiology of fetal membrane rupture: insight gained from the determination of physical properties. Placenta. 2006;27:1037–51.10.1016/j.placenta.2006.01.002Search in Google Scholar
[140] Chwalisz K, Benson M, Scholz P, Daum J, Beier HM, Hegele-Hartung C. Cervical ripening with the cytokines interleukin 8, interleukin 1 beta and tumour necrosis factor alpha in guinea-pigs. Hum Reprod. 1994;9:2173–81.10.1093/oxfordjournals.humrep.a138413Search in Google Scholar
[141] El Maradny E, Kanayama N, Kobayashi H, Hossain B, Khatun S, Liping S, et al. The role of hyaluronic acid as a mediator and regulator of cervical ripening. Hum Reprod. 1997;12:1080–8.10.1093/humrep/12.5.1080Search in Google Scholar
[142] Watari M, Watari H, DiSanto ME, Chacko S, Shi GP, Strauss JF, 3rd. Pro-inflammatory cytokines induce expression of matrix-metabolizing enzymes in human cervical smooth muscle cells. Am J Pathol. 1999;154:1755–62.10.1016/S0002-9440(10)65431-4Search in Google Scholar
[143] Winkler M, Rath W. Changes in the cervical extracellular matrix during pregnancy and parturition. J Perinatal Med. 1999;27:45–60.10.1515/JPM.1999.006Search in Google Scholar
[144] Watari M, Watari H, Nachamkin I, Strauss JF. Lipopolysaccharide induces expression of genes encoding pro-inflammatory cytokines and the elastin-degrading enzyme, cathepsin S, in human cervical smooth-muscle cells. J Soc Gynecol Invest. 2000;7:190–8.10.1177/107155760000700309Search in Google Scholar
[145] Fujimoto T, Savani RC, Watari M, Day AJ, Strauss JF, 3rd. Induction of the hyaluronic acid-binding protein, tumor necrosis factor-stimulated gene-6, in cervical smooth muscle cells by tumor necrosis factor-alpha and prostaglandin E(2). Am J Pathol. 2002;160:1495–502.10.1016/S0002-9440(10)62575-8Search in Google Scholar
[146] Timmons B, Akins M, Mahendroo M. Cervical remodeling during pregnancy and parturition. Trends Endocrinol Metab. 2010;21:353–61.10.1016/j.tem.2010.01.011Search in Google Scholar PubMed PubMed Central
[147] Harder J, Bartels J, Christophers E, Schroder JM. A peptide antibiotic from human skin. Nature. 1997;387:861.10.1038/43088Search in Google Scholar PubMed
[148] Singh PK, Jia HP, Wiles K, Hesselberth J, Liu L, Conway BA, et al. Production of beta-defensins by human airway epithelia. Proc Natl Acad Sci USA. 1998;95:14961–6.10.1073/pnas.95.25.14961Search in Google Scholar PubMed PubMed Central
[149] Weinberg A, Krisanaprakornkit S, Dale BA. Epithelial antimicrobial peptides: review and significance for oral applications. Crit Rev Oral Biol Med. 1998;9:399–414.10.1177/10454411980090040201Search in Google Scholar
[150] Schroder JM, Harder J. Human beta-defensin-2. Int J Biochem Cell Biol. 1999;31:645–51.10.1016/S1357-2725(99)00013-8Search in Google Scholar
[151] Abiko Y, Mitamura J, Nishimura M, Muramatsu T, Inoue T, Shimono M, et al. Pattern of expression of beta-defensins in oral squamous cell carcinoma. Cancer Lett. 1999;143:37–43.10.1016/S0304-3835(99)00171-8Search in Google Scholar
[152] Mathews M, Jia HP, Guthmiller JM, Losh G, Graham S, Johnson GK, et al. Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands. Infect Immunity. 1999;67:2740–5.10.1128/IAI.67.6.2740-2745.1999Search in Google Scholar PubMed PubMed Central
[153] Harder J, Meyer-Hoffert U, Teran LM, Schwichtenberg L, Bartels J, Maune S, et al. Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. Am J Resp Cell Mol Biol. 2000;22:714–21.10.1165/ajrcmb.22.6.4023Search in Google Scholar PubMed
[154] Dale BA, Krisanaprakornkit S. Defensin antimicrobial peptides in the oral cavity. J Oral Pathol Med. 2001;30:321–7.10.1034/j.1600-0714.2001.300601.xSearch in Google Scholar PubMed
[155] Bajaj-Elliott M, Fedeli P, Smith GV, Domizio P, Maher L, Ali RS, et al. Modulation of host antimicrobial peptide (beta-defensins 1 and 2) expression during gastritis. Gut. 2002;51:356–61.10.1136/gut.51.3.356Search in Google Scholar PubMed PubMed Central
[156] Espinoza J, Chaiworapongsa T, Romero R, Edwin S, Rathnasabapathy C, Gomez R, et al. Antimicrobial peptides in amniotic fluid: defensins, calprotectin and bacterial/ permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes. J Matern Fetal Neonatal Med. 2003;13:2–21.10.1080/jmf.13.1.2.21Search in Google Scholar PubMed
[157] McDermott AM, Redfern RL, Zhang B, Pei Y, Huang L, Proske RJ. Defensin expression by the cornea: multiple signalling pathways mediate IL-1beta stimulation of hBD-2 expression by human corneal epithelial cells. Invest Ophthalmol Visual Sci. 2003;44:1859–65.10.1167/iovs.02-0787Search in Google Scholar PubMed PubMed Central
[158] Liu L, Roberts AA, Ganz T. By IL-1 signaling, monocyte-derived cells dramatically enhance the epidermal antimicrobial response to lipopolysaccharide. J Immunol. 2003;170:575–80.10.4049/jimmunol.170.1.575Search in Google Scholar PubMed
[159] Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171:3262–9.10.4049/jimmunol.171.6.3262Search in Google Scholar
[160] Harder J, Meyer-Hoffert U, Wehkamp K, Schwichtenberg L, Schroder JM. Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid. J Invest Dermatol. 2004;123:522–9.10.1111/j.0022-202X.2004.23234.xSearch in Google Scholar
[161] Jang BC, Lim KJ, Paik JH, Kwon YK, Shin SW, Kim SC, et al. Up-regulation of human beta-defensin 2 by interleukin-1beta in A549 cells: involvement of PI3K, PKC, p38 MAPK, JNK, and NF-kappaB. Biochem Biophys Res Commun. 2004;320:1026–33.10.1016/j.bbrc.2004.06.049Search in Google Scholar
[162] Jang BC, Lim KJ, Suh MH, Park JG, Suh SI. Dexamethasone suppresses interleukin-1beta-induced human beta-defensin 2 mRNA expression: involvement of p38 MAPK, JNK, MKP-1, and NF-kappaB transcriptional factor in A549 cells. FEMS Immunol Med Microbiol. 2007;51:171–84.10.1111/j.1574-695X.2007.00293.xSearch in Google Scholar
[163] Jang BC, Lim KJ, Choi IH, Suh MH, Park JG, Mun KC, et al. Triptolide suppresses interleukin-1beta-induced human beta-defensin-2 mRNA expression through inhibition of transcriptional activation of NF-kappaB in A549 cells. Int J Mol Med. 2007;19:757–63.Search in Google Scholar
[164] Brandenburg LO, Varoga D, Nicolaeva N, Leib SL, Wilms H, Podschun R, et al. Role of glial cells in the functional expression of LL-37/rat cathelin-related antimicrobial peptide in meningitis. J Neuropathol Exp Neurol. 2008;67:1041–54.10.1097/NEN.0b013e31818b4801Search in Google Scholar
[165] Kim CJ, Romero R, Kusanovic JP, Yoo W, Dong Z, Topping V, et al. The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth. Modern Pathol. 2010;23:1000–11.10.1038/modpathol.2010.73Search in Google Scholar
[166] Ogge G, Romero R, Lee DC, Gotsch F, Than NG, Lee J, et al. Chronic chorioamnionitis displays distinct alterations of the amniotic fluid proteome. J Pathol. 2011;223:553–65.10.1002/path.2825Search in Google Scholar
[167] Romero R, Chaemsaithong P, Korzeniewski SJ, Kim CJ, Kim SJ, Gotsch F, et al. Elevated amniotic fluid concentrations of CXCL-10 without IL-6 is a biomarker for chronic placental inflammatory lesions and preterm delivery. Am J Obstet Gynecol (in preparation). 2015.Search in Google Scholar
[168] Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospisil M, Young HA, et al. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991;173:869–79.10.1084/jem.173.4.869Search in Google Scholar
[169] D’Andrea A, Rengaraju M, Valiante NM, Chehimi J, Kubin M, Aste M, et al. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992;176:1387–98.10.1084/jem.176.5.1387Search in Google Scholar
[170] Morris SC, Madden KB, Adamovicz JJ, Gause WC, Hubbard BR, Gately MK, et al. Effects of IL-12 on in vivo cytokine gene expression and Ig isotype selection. J Immunol. 1994;152:1047–56.10.4049/jimmunol.152.3.1047Search in Google Scholar
[171] Vinson DC, Thomas R, Kiser T. Association between epidural analgesia during labor and fever. J Fam Pract. 1993;36:617–22.Search in Google Scholar
[172] Ramin SM, Gambling DR, Lucas MJ, Sharma SK, Sidawi JE, Leveno KJ. Randomized trial of epidural versus intravenous analgesia during labor. Obstet Gynecol. 1995;86:783–9.10.1016/0029-7844(95)00269-WSearch in Google Scholar
[173] Herbst A, Wolner-Hanssen P, Ingemarsson I. Risk factors for fever in labor. Obstet Gynecol. 1995;86:790–4.10.1016/0029-7844(95)00254-OSearch in Google Scholar
[174] Ploeckinger B, Ulm MR, Chalubinski K, Gruber W. Epidural anaesthesia in labour: influence on surgical delivery rates, intrapartum fever and blood loss. Gynecol Obstet Invest. 1995;39:24–7.10.1159/000292370Search in Google Scholar PubMed
[175] Mayer DC, Chescheir NC, Spielman FJ. Increased intrapartum antibiotic administration associated with epidural analgesia in labor. Am J Perinatol. 1997;14:83–6.10.1055/s-2007-994103Search in Google Scholar PubMed
[176] Sharma SK, Sidawi JE, Ramin SM, Lucas MJ, Leveno KJ, Cunningham FG. Cesarean delivery: a randomized trial of epidural versus patient-controlled meperidine analgesia during labor. Anesthesiology. 1997;87:487–94.10.1097/00000542-199709000-00006Search in Google Scholar PubMed
[177] Lieberman E, Lang JM, Frigoletto F, Jr., Richardson DK, Ringer SA, Cohen A. Epidural analgesia, intrapartum fever, and neonatal sepsis evaluation. Pediatrics. 1997;99:415–19.10.1542/peds.99.3.415Search in Google Scholar PubMed
[178] Dashe JS, Rogers BB, McIntire DD, Leveno KJ. Epidural analgesia and intrapartum fever: placental findings. Obstet Gynecol. 1999;93:341–4.10.1097/00006250-199903000-00005Search in Google Scholar
[179] Yancey MK, Zhang J, Schwarz J, Dietrich CS, 3rd, Klebanoff M. Labor epidural analgesia and intrapartum maternal hyperthermia. Obstet Gynecol. 2001;98:763–70.10.1097/00006250-200111000-00010Search in Google Scholar
[180] Kaul B, Vallejo M, Ramanathan S, Mandell G. Epidural labor analgesia and neonatal sepsis evaluation rate: a quality improvement study. Anesth Analg. 2001;93:986–90.10.1097/00000539-200110000-00038Search in Google Scholar PubMed
[181] Lucas MJ, Sharma SK, McIntire DD, Wiley J, Sidawi JE, Ramin SM, et al. A randomized trial of labor analgesia in women with pregnancy-induced hypertension. Am J Obstet Gynecol. 2001;185:970–5.10.1067/mob.2001.117970Search in Google Scholar PubMed
[182] Sharma SK, Alexander JM, Messick G, Bloom SL, McIntire DD, Wiley J, et al. Cesarean delivery: a randomized trial of epidural analgesia versus intravenous meperidine analgesia during labor in nulliparous women. Anesthesiology. 2002;96:546–51.10.1097/00000542-200203000-00007Search in Google Scholar PubMed
[183] Goetzl L, Zighelboim I, Badell M, Rivers J, Mastrangelo MA, Tweardy D, et al. Maternal corticosteroids to prevent intrauterine exposure to hyperthermia and inflammation: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 2006;195:1031–7.10.1016/j.ajog.2006.06.012Search in Google Scholar PubMed
[184] Segal S. Labor epidural analgesia and maternal fever. Anesth Analg. 2010;111:1467–75.10.1213/ANE.0b013e3181f713d4Search in Google Scholar PubMed
[185] Goetzl L, Manevich Y, Roedner C, Praktish A, Hebbar L, Townsend DM. Maternal and fetal oxidative stress and intrapartum term fever. Am J Obstet Gynecol. 2010;202: 363.e1–5.10.1016/j.ajog.2010.01.034Search in Google Scholar PubMed PubMed Central
[186] Goetzl L. Epidural analgesia and maternal fever: a clinical and research update. Curr Opin Anaesthesiol. 2012;25:292–9.10.1097/ACO.0b013e3283530d7cSearch in Google Scholar PubMed
[187] Goetzl L. Epidural fever in obstetric patients: it’s a hot topic. Anesth Analg. 2014;118:494–5.10.1213/ANE.0000000000000112Search in Google Scholar PubMed
The authors stated that there are no conflicts of interest regarding the publication of this article.
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