Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2015 Sep 2.
Published in final edited form as: J Matern Fetal Neonatal Med. 2014 Oct 20;28(13):1500–1509. doi: 10.3109/14767058.2014.961009

The relationship between the intensity of intra-amniotic inflammation and the presence and severity of acute histologic chorioamnionitis in preterm gestations

Sun Min KIM 1, Roberto ROMERO 2, Jeong Woo PARK 1, Kyung Joon OH 1, Jong Kwan JUN 1, Bo Hyun YOON 1
PMCID: PMC4404170  NIHMSID: NIHMS399363  PMID: 25184305

Abstract

OBJECTIVE

Acute histologic chorioamnionitis (HCA) is associated with increased risk of perinatal mortality and morbiditiy. The purpose of this study was to determine the relationship between the intensity of intra-amniotic inflammation (IAI) and the severity of acute HCA in preterm gestation.

METHODS

The relationship between the intensity of IAI and the presence and severity of acute HCA was examined in 412 singleton patients who delivered within 120 hours of transabdominal amniocentesis. The concentration of amniotic fluid (AF) metalloproteinase (MMP)-8 was assayed to determine the presence and intensity of IAI. Acute HCA was defined as the presence of inflammatory change in any tissue samples according to the criteria previously reported (AJOG 1995;172:960–70). The total grade of acute HCA was used to determine the severity of HCA.

RESULTS

1) Patients with IAI had a significantly higher rate of acute HCA than those without IAI [76.9% (133/173)] vs 20.9% (50/239), P<0.001]. The AF MMP-8 concentration was significantly higher in patients with acute HCA than in those without acute HCA (median[range]; 188.3ng/mL[0.3–6142.6] vs 1.8ng/mL[0.3–2845.5], P <0.001); 2) of 183 patients with acute HCA, AF MMP-8 concentration was positively correlated with severity of acute HCA(P<0.001).

CONCLUSIONS

AF MMP-8 concentration was not only a predictor of presence of acute HCA, but its concentration also correlated with the severity of acute HCA. The higher the intensity of IAI, the worse the degree of acute HCA in preterm gestation.

Keywords: Preterm birth, chorioamnionitis, prematurity, amniotic fluid, matrix metalloproteinase-8

Introduction

Acute histologic chorioamnionitis is an inflammatory lesion of placenta frequently observed after a preterm birth. The presence of acute histologic chorioamnionitis is associated with an increased risk of perinatal mortality and morbidity, including neonatal sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia and cerebral palsy. [1–22] However, not all newborns whose placentas had acute histologic chorioamnionitis have adverse outcomes. In a previous study, when placental inflammation was divided into anatomical segments (e.g. amnion, choriodecidua and chorionic plate), involvement of the amnion was the most advanced stage of the maternal inflammatory response and a good predictor of early-onset neonatal sepsis.[23]

Intra-amniotic inflammation and/or infection is present in about one-third of patients with preterm labor and intact membranes [24] and in about half of patients with preterm premature rupture of membranes, [25] and it is a risk factor for impending preterm delivery and adverse perinatal outcomes. [3, 7, 13, 24–89] Metalloproteinase-8 (MMP-8) is a matrix-degrading enzyme stored within specific granules of neutrophils and released during activation,[90] and an increased concentration of MMP-8 in the amniotic fluid has been extensively used to define intra-amniotic inflammation.[25, 56–58, 64, 71, 85, 87, 91–101] Thus, this study was performed to analyze the relationship between the concentration of amniotic fluid MMP-8 and the grading of histologic chorioamnionitis to examine the intensity of intra-amniotic inflammation and the severity of acute histologic chorioamnionitis.

Materials and Methods

Study population

The relationship between the intensity of intra-amniotic inflammation and the presence and severity of acute histologic chorioamnionitis was examined in 412 cases delivered at the Seoul National University Hospital, Seoul, Korea between January 1993 and February 2009. Patients included met the following criteria: (1) singleton gestation; (2) preterm birth at gestational age between 24 and 35 weeks; (3) transabdominal amniocentesis for microbiologic studies in amniotic fluid or assessment of fetal lung maturity; (4) delivery within 120 hours of amniocentesis (to preserve a meaningful temporal relationship between the results of amniotic fluid studies and the histologic findings of placenta); and (5) placental histological examination after preterm delivery.

Amniocentesis was performed with written informed consent, and the Institutional Review Board of our institution (Seoul National University Hospital, Seoul, Korea) approved the collection and utilization of the biological materials and clinical data for research purposes. The Seoul National University has a Federal Wide Assurance (FWA) with the Office for Human Research Protections (OHRP) of the Department of Health and Human Services (DHHS) of the United States.

Retrieval of amniotic fluid and amniotic fluid MMP-8 concentration measurements

Amniotic fluid was obtained by transabdominal amniocentesis with ultrasound guide and aseptic technique. Amniotic fluid was cultured for aerobic, anaerobic bacteria and genital mycoplasmas (ureaplasmas [Ureaplasma urealyticum & Ureaplasma parvum] and Mycoplasma hominis) or used for assessment of fetal lung maturity. The remaining amniotic fluid was centrifuged, and supernatant was stored at −70°C until assayed.

MMP-8 concentrations were measured with commercially available enzyme-linked immunosorbent assay (Amersham Pharmacia Biotech, Inc., Little Chalfont, Bucks, UK) with sensitivity of 0.3 ng/mL. Both inter-and intra- assay coefficients of variation were < 10%. Intra-amniotic inflammation was defined as an elevated amniotic fluid MMP-8 concentration (> 23 ng/mL) according to a previous study.[91]

Placental examination

Placental tissue samples were obtained from amnion, choriodecidua, umbilical cord and chorionic plate. These samples were fixed in 10% neutral-buffered formalin and embedded in paraffin. Sections of tissue blocks were stained with hematoxylin and eosin. The degree of acute inflammation was classified as grade 1 or 2 in each tissue (amnion, choriodecidua, umbilical cord and chorionic plate) according to previously published criteria.[4] Grade 1 inflammation of the choriodecidua or amnion was diagnosed as the presence of at least 1 focus of > 5 neutrophils, and grade 2 inflammation of the choriodecidua or amnion was diagnosed as the presence of diffuse neutrophilic inflammation; in the chorionic plate, grade 1 inflammation was diagnosed in the presence of more than 1 focus of at least 10 neutrophilic foci or diffuse inflammation in subchorionic fibrin, and grade 2 inflammation was diagnosed as diffuse and dense inflammation, neutrophilic infiltration into connective tissue of placental plate or placental vasculitis. Acute histologic chorioamnionitis was defined as the presence of inflammatory change in any part of the tissue samples (amnion, choriodecidua and chorionic plate) and the highest total grade of acute histologic chorioamnionitis could be 6 if each score was 2 in all three sections. Funisitis was diagnosed as the presence of neutrophil infiltration into the umbilical vessel walls or Wharton’s jelly. Funisitis was classified separately from acute histologic chorioamnionitis as it is a fetal (rather than maternal) inflammatory response.[102–104]

Statistical analysis

Comparison of the continuous variables that could not be assumed as normal distribution was performed by using the Mann-Whitney U test. Proportions were compared with the use of the Chi-square test or Fisher’s exact test. Among three or more groups, Kruskal-Wallis test and Jonckheere-Terpstra test were used for comparison of continuous variables and linear-by-linear association was used for comparison of the proportions. Logistic regression analysis was used to examine the relationship between the presence of histologic chorioamnionitis and outcome of interest after adjusting for potential confounding factors. A probability value of < 0.05 was considered statistically significant.

Results

Four hundred and twelve patients met the inclusion criteria. The prevalence of acute histologic chorioamnionitis was 44.4% (183/412). The overall rate of intra-amniotic inflammation was 42.0% (173/412); proven intra-amniotic infection was found in 18.5% (74/400). The most common micro-organism cultured from amniotic fluid was genital mycoplasmas (ureaplasmas [Ureaplasma urealyticum & Ureaplasma parvum] and Mycoplasma hominis) (47/74). Other micro-organisms, such as Candida spp., Streptococcus spp., Staphylococcus spp., Lactobacillus spp., Corynebacterium spp., Actinetobacter bauman, Klebsiella pneumonia, Burkholderia cepacia, Gardnerella vaginalis, Enterococcus faecalis and Escherichia coli were also isolated.

Patients with intra-amniotic inflammation had a significantly higher rate of acute histologic chorioamnionitis than those without intra-amniotic inflammation (76.9% [133/173] vs 20.9% [50/239], P <0.001). Table 1 presents the characteristics of the study population according to the presence of acute histologic chorioamnionitis. The amniotic fluid MMP-8 concentration was significantly higher in patients with acute histologic chorioamnionitis than in those without histologic chorioamnionitis (median, 188.3 ng/ml [range, 0.3–6142.6] vs 1.8 ng/ml [range, 0.3–2845.5], P <0.001). Intra-amniotic inflammation and infection were also more common in patients with acute histologic chorioamnionitis than in those without histologic chorioamnionitis (72.7% [133/183] vs 17.5% [40/229] and 31.1% [56/180] vs 8.2% [18/220], P <0.001). This difference remained significant after adjusting the gestational age at amniocentesis by logistic regression analysis.

Table 1.

Clinical characteristics of patients according to the presence or absence of acute histologic chorioamnionitis

Characteristics Acute histologic chorioamnionitis P value
Present (n=183) Absent (n=229) Unadjusted Adjustedd
Maternal age (y) a 30.0 (21–43) 30.0 (21–41) 0.74 -
Nulliparity (n) 86 (47.0%) 109 (47.6%) 0.92 -
Gestational age at amniocentesis (wk)a 30.9 (23.7–34.9) 32.7 (24.0–34.9) <0.001 -
Gestational age at delivery (wk)a 31.3 (24.0–35.0) 32.9 (24.0–35.0) <0.001 0.002
Birth weight (g) a 1580 (500–3950) 1710 (450–3280) 0.025 <0.001
Amniocentesis to delivery interval (hr)a 18.0 (0.0–118.3) 4.2 (0.0–106.7) <0.001 0.001
Positive AF culture (n/N)b 56/180 (31.1%) 18/220 (8.2%) <0.001 <0.001
AF MMP-8 concentration(ng/mL)a 188.3 (0.3–6142.6) 1.8 (0.3–2845.5) <0.001 <0.001
IAI (n)c 133 (72.7%) 40 (17.5%) <0.001 <0.001
Open in a new tab

AF, amniotic fluid; MMP-8, matrix metalloproteinase-8; IAI, intra-amniotic inflammation

a

Median value and range

b

Total cases with AF culture results: 400

c

AF MMP-8 concentration > 23 ng/mL

d

Adjusted for gestational age at amniocentesis

Tables 2 and 3 present the relationship between amniotic fluid MMP-8 concentration and the amniotic fluid white blood cell (WBC) count and prevalence of funisitis, amnionitis, proven intra-amniotic infection and intra-amniotic inflammation according to an increase in the total grade of acute histologic chorioamnionitis. The amniotic fluid concentration of MMP-8 and the amniotic fluid WBC count, the prevalence of funisitis, amnionitis, positive amniotic culture and intra-amniotic inflammation increased significantly as a function of the severity of acute histologic chorioamnionitis (total grade of histologic chorioamnionitis).

Table 2.

The prevalence of funisitis, amnionitis and positive amniotic fluid culture according to the total grade of acute histologic chorioamnionitis

Total grade of HCA Prevalence of each grade (%) Funisitis (n) Pa Amnionitis (n) Pa AF culture (n) Pa
0 (n=229) 55.6 4 (1.7%) <0.001 0 <0.001 18 (8.2%) <0.001
1 (n=78) 18.9 15 (19.2%) 0 19 (24.7%)
2 (n=38) 9.2 21 (55.3%) 21 (55.3%) 16 (43.2%)
3 (n=32) 7.8 20 (62.5%) 27 (84.4%) 8 (25.0%)
4 (n=19) 4.6 17 (89.5%) 18 (94.7%) 6 (31.6%)
5 (n=5) 1.2 4 (80.0%) 5 (100.0%) 3 (60.0%)
6 (n=11) 2.7 10 (90.9%) 11 (100.0%) 4 (40.0%)
Open in a new tab

HCA, acute histologic chorioamnionitis; AF, amniotic fluid

a

Linear-by-Linear Association

Table 3.

The prevalence of intra-amniotic inflammation and amniotic fluid matrix metalloproteinase-8 concentration, amniotic fluid white blood cell count according to the total grade of acute histologic chorioamnionitis

Total grade of HCA IAIc (n) Pa AF MMP-8 (ng/ml)d Pb AF WBC d Pb
0 (n=229) 17.5% (40) <0.001 1.8 (0.3–2845.5) <0.001 2 (0–7200) <0.001
1 (n=78) 51.3% (40) 25.9 (0.3–4202.7) 5 (0–50000)
2 (n=38) 81.6% (31) 229.7 (0.3–3929.0) 405 (0–13248)
3 (n=32) 96.9% (31) 486.2 (0.4–3392.0) 478 (0–15000)
4 (n=19) 89.5% (17) 422.4 (0.6–6142.6) 892 (1–5800)
5 (n=5) 100.0% (5) 257.0 (35.1–1007.3) 198 (17–>1000)
6 (n=11) 81.8% (9) 1475.7 (0.5–3116.7) 1026 (1–8640)
Open in a new tab

HCA, acute histologic chorioamnionitis; IAI, intra-amniotic inflammation; AF, amniotic fluid; MMP-8, matrix metalloproteinase-8; WBC, white blood cell

a

Linear-by-Linear Association

b

Kruskal-Wallis analysis test and Jonckheere-Terpstra test

c

AF MMP-8 concentration > 23 ng/mL

d

Values are given as median (range)

There were noticeable differences between acute histologic chorioamnionitis with a total grade 1 and histologic chorioamnionitis with total grade 2 or more. First, patients with a total grade 1 histologic chorioamnionitis accounted for over 40% (78/183) of all cases of acute histologic chorioamnionitis. The prevalence of funisitis was only 19.2% in patients with histologic chorioamnionitis (grade 1), while it was over 50% in patients with acute histologic chorioamnionitis (grade 2 or more). There were no cases of amnionitis in patients with a total grade 1 histologic inflammation. Amnionitis was present in patients with total grade 2 or more histologic chorioamnionitis, and increased as the total grade of histologic chorioamnionitis became higher. The prevalence of intra-amniotic inflammation was only 51.3% in patients with total grade 1 histologic chorioamnionitis, while it was over 80% in patients with total grade 2 or higher acute histologic chorioamnionitis. The median value of amniotic fluid MMP-8 concentrations and amniotic fluid WBC count was also higher in patients with a total grade 2 or more acute histologic chorioamnionitis than in those with grade 1.

When the placenta was examined by region, inflammation was most common in choriodecidua (43.9%), while the frequency of inflammation of the amnion and chorionic plate was 19.9% and 14.6% for each.

Figure 1 shows the amniotic fluid MMP-8 concentration according to the total grade of histologic chorioamnionitis; amniotic fluid MMP-8 concentration was positively correlated with the total grade of acute histologic chorioamnionitis for each (r2=0.37, P<0.001 by Spearman’s rho).

Figure 1.

Figure 1

Open in a new tab

Amniotic fluid MMP-8 concentration was positively correlated with the total grade of HCA (r2=0.37, P<0.001 by Spearman’s rho)

Discussion

Principal finding and strength of this study

The higher the amniotic fluid MMP-8 concentration, the worse the intensity of the inflammatory response in the placenta.

Our study demonstrated that amniotic fluid MMP-8 concentration is an indication of the likelihood and severity of inflammatory changes of the placenta before birth, although the placenta can only be obtained after delivery. Previous studies have suggested that there is an association between intra-amniotic infection and/or inflammation and acute histologic chorioamnionitis, [2, 4, 25, 65, 98, 105–117] but the current study analyzed the quantitative correlation between the intensity of intra-amniotic inflammation (expressed as amniotic fluid MMP-8 concentration) and the severity of histologic chorioamnionitis reflected by histopathologic grading.

Severity of the histologic chorioamnionitis

In a previous report, when placental inflammation was classified as affecting amnion, choriodecidua and chorionic plate, the involvement of amnion reflected the most advanced stage of the maternal inflammatory response and was a good predictor of early-onset neonatal sepsis.[23] In our study, there were no cases of amnionitis in patients with total grade 1 acute histologic chorioamnionitis, but amnionitis began to appear in placentas with a total grade 2 or more histologic chorioamnionitis and its frequency increased significantly as the degree of acute histologic chorioamnionitis worsened. These findings were consistent with the findings of a previous study[23] indicating that amnionitis reflects the most advanced form of inflammation of the extra-placental membranes.

Almost half of cases with histologic chorioamnionitis had a total grade 1 acute histologic chorioamnionitis. Funisitis and intra-amniotic inflammation were more common in patients with total grade 2 or higher of acute histologic chorioamnionitis than those with total grade 1 acute histologic chorioamnionitis, and the median amniotic fluid MMP-8 concentrations or median amniotic fluid WBC counts were significantly elevated in patients with total grade 2 or higher histologic chorioamnionitis. Therefore, we can categorize histologic chorioamnionitis into two groups: mild placental inflammation with a total grade 1 and severe placental inflammation with a total grade 2 or higher.

When placentas were examined by region, inflammation was most common in choriodecidua (43.9% of all cases). Considering that the overall frequency of histologic chorioamnionitis was 44.4%, this means that inflammation in choriodecidua was present in most cases with acute histologic chorioamnionitis. All cases with total grade 1 histologic chorioamnionitis (except one with inflammation of chorionic plate) had the score for the inflammation because of choriodecidual involvement.

Development and progression of histologic chorioamnionitis

The pathway of intrauterine infection has not been fully elucidated. Two pathways have been proposed.[23] The first suggests that microorganisms from the lower genital tract traverse the cervix and gain access to the decidua. Bacteria can multiply at this site and cross the chorioamniotic membranes to invade the amniotic cavity. The second proposed pathway is that microorganisms traversing the cervix cross intact membranes or the rupture site in the case of preterm PROM to gain access to the amniotic cavity. In this pathway, there is no broad dissemination of the organisms in the decidua. The findings of this current study suggest that inflammation begins in the decidua. This may occur in either pathway. If the bacteria or microorganisms are located in the decidua, maternal inflammatory cells will concentrate there. On the other hand, if the organisms are in the amniotic cavity, a chemotactic gradient would be established that would bring neutrophils from the decidua to invade the chorion, and eventually, the amnion. Therefore, in either pathway, the presence of inflammatory cells in the amnion would represent the most advanced stage of inflammation. Examples of chemokines which may be responsible for this gradient include interleukin-8 [11, 50, 118–120] and others [4, 22–25, 38, 40, 41, 53, 58, 64, 65, 91, 94, 112, 121–125] which have been shown to be elevated in patients with preterm labor and intra-amniotic infection/inflammation with intact or ruptured membranes, or even during the course of spontaneous labor at term.[126]

Funisitis and amniotic fluid MMP-8 concentration

Funisitis was excluded in the analysis of this study, because it reflects fetal inflammation. While acute histologic chorioamnionitis reflects a maternal immune response, funisitis is a hallmark of the fetal inflammatory response syndrome and is correlated with the plasma concentration of inflammatory cytokines such as interleukin-6, interleukin-10, or C-reactive protein in umbilical cord blood.[102, 103, 127–131] Funisitis is also a risk factor for cerebral palsy or other neonatal morbidity, such as neonatal sepsis.[11, 52, 91, 102, 103, 132–134] A previous study[91] indicated that AF MMP-8 concentration is a better predictor of funisitis than AF WBC count or the presence of a positive culture for microorganisms. In this study, the frequency of funisitis increased as a function of the severity of histologic chorioamnionitis.

In conclusion, we have demonstrated that the higher the amniotic fluid MMP-8 concentration, the more severe the acute inflammatory process in the placenta. Since advanced stages of acute histologic chorioamnionitis are associated with worse perinatal outcome, we infer that the magnitude of the elevation of MMP-8 concentrations may have prognostic value.

Acknowledgments

This study was supported by grant #03-2009-0250 from the SNUH Research Fund.

This study was supported, in part, by the Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS.

Footnotes

Declaration of Interests

The authors report no conflicts of interest.

References

  • 1.Hillier SL, Krohn MA, Kiviat NB, Watts DH, Eschenbach DA. Microbiologic causes and neonatal outcomes associated with chorioamnion infection. Am J Obstet Gynecol. 1991;165:955–961. doi: 10.1016/0002-9378(91)90447-y. [DOI] [PubMed] [Google Scholar]
  • 2.Romero R, Salafia CM, Athanassiadis AP, Hanaoka S, Mazor M, Sepulveda W, Bracken MB. The relationship between acute inflammatory lesions of the preterm placenta and amniotic fluid microbiology. Am J Obstet Gynecol. 1992;166:1382–1388. doi: 10.1016/0002-9378(92)91609-e. [DOI] [PubMed] [Google Scholar]
  • 3.Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL. A review of premature birth and subclinical infection. Am J Obstet Gynecol. 1992;166:1515–1528. doi: 10.1016/0002-9378(92)91628-n. [DOI] [PubMed] [Google Scholar]
  • 4.Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, Syn HC. 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;172:960–970. doi: 10.1016/0002-9378(95)90028-4. [DOI] [PubMed] [Google Scholar]
  • 5.Yoon BH, Romero R, Yang SH, Jun JK, Kim IO, Choi JH, Syn HC. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol. 1996;174:1433–1440. doi: 10.1016/s0002-9378(96)70585-9. [DOI] [PubMed] [Google Scholar]
  • 6.Arias F, Victoria A, Cho K, Kraus F. Placental histology and clinical characteristics of patients with preterm premature rupture of membranes. Obstet Gynecol. 1997;89:265–271. doi: 10.1016/S0029-7844(96)00451-6. [DOI] [PubMed] [Google Scholar]
  • 7.Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, Kim IO. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol. 1997;177:19–26. doi: 10.1016/s0002-9378(97)70432-0. [DOI] [PubMed] [Google Scholar]
  • 8.Redline RW, Wilson-Costello D, Borawski E, Fanaroff AA, Hack M. Placental lesions associated with neurologic impairment and cerebral palsy in very low-birth-weight infants. Arch Pathol Lab Med. 1998;122:1091–1098. [PubMed] [Google Scholar]
  • 9.Elimian A, Verma U, Beneck D, Cipriano R, Visintainer P, Tejani N. Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes. Obstet Gynecol. 2000;96:333–336. doi: 10.1016/s0029-7844(00)00928-5. [DOI] [PubMed] [Google Scholar]
  • 10.Dexter SC, Pinar H, Malee MP, Hogan J, Carpenter MW, Vohr BR. Outcome of very low birth weight infants with histopathologic chorioamnionitis. Obstet Gynecol. 2000;96:172–177. doi: 10.1016/s0029-7844(00)00886-3. [DOI] [PubMed] [Google Scholar]
  • 11.Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, Han TR. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol. 2000;182:675–681. doi: 10.1067/mob.2000.104207. [DOI] [PubMed] [Google Scholar]
  • 12.Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA. 2000;284:1417–1424. doi: 10.1001/jama.284.11.1417. [DOI] [PubMed] [Google Scholar]
  • 13.Redline RW, Wilson-Costello D, Borawski E, Fanaroff AA, Hack M. The relationship between placental and other perinatal risk factors for neurologic impairment in very low birth weight children. Pediatr Res. 2000;47:721–726. doi: 10.1203/00006450-200006000-00007. [DOI] [PubMed] [Google Scholar]
  • 14.Gibbs RS. The relationship between infections and adverse pregnancy outcomes: an overview. Ann Periodontol. 2001;6:153–163. doi: 10.1902/annals.2001.6.1.153. [DOI] [PubMed] [Google Scholar]
  • 15.Gaudet LM, Smith GN. Cerebral palsy and chorioamnionitis: the inflammatory cytokine link. Obstet Gynecol Surv. 2001;56:433–436. doi: 10.1097/00006254-200107000-00023. [DOI] [PubMed] [Google Scholar]
  • 16.Holcroft CJ, Askin FB, Patra A, Allen MC, Blakemore KJ, Graham EM. Are histopathologic chorioamnionitis and funisitis associated with metabolic acidosis in the preterm fetus? Am J Obstet Gynecol. 2004;191:2010–2015. doi: 10.1016/j.ajog.2004.05.005. [DOI] [PubMed] [Google Scholar]
  • 17.Choi C, Kim B, Park J, Koh Y, Choi J-H, Choi J. Risk factors for the different types of chronic lung diseases of prematurity according to the preceding respiratory distress syndrome. Pediatr Int. 2005;47:417–423. doi: 10.1111/j.1442-200x.2005.02081.x. [DOI] [PubMed] [Google Scholar]
  • 18.Dempsey E, Chen MF, Kokottis T, Vallerand D, Usher R. Outcome of neonates less than 30 weeks gestation with histologic chorioamnionitis. Am J Perinatol. 2005;22:155–159. doi: 10.1055/s-2005-865020. [DOI] [PubMed] [Google Scholar]
  • 19.Andrews W, Goldenberg R, Faye Petersen O, Cliver S, Goepfert A, Hauth J. The Alabama Preterm Birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am J Obstet Gynecol. 2006;195:803–808. doi: 10.1016/j.ajog.2006.06.083. [DOI] [PubMed] [Google Scholar]
  • 20.Gotsch F, Romero R, Kusanovic J, Mazaki Tovi S, Pineles B, Erez O, Espinoza J, Hassan S. The fetal inflammatory response syndrome. Clin Obstet Gynecol. 2007;50:652–683. doi: 10.1097/GRF.0b013e31811ebef6. [DOI] [PubMed] [Google Scholar]
  • 21.Rocha G, Proenca E, Quintas C, Rodrigues T, Guimaraes H. Chorioamnionitis and brain damage in the preterm newborn. J Matern Fetal Neonatal Med. 2007;20:745–749. doi: 10.1080/14767050701580515. [DOI] [PubMed] [Google Scholar]
  • 22.Hendson L, Russell L, Robertson CMT, Liang Y, Chen Y, Abdalla A, Lacaze Masmonteil T. Neonatal and neurodevelopmental outcomes of very low birth weight infants with histologic chorioamnionitis. J Pediatr. 2011;158:397–402. doi: 10.1016/j.jpeds.2010.09.010. [DOI] [PubMed] [Google Scholar]
  • 23.Park C-W, Moon K, Park J, Jun J, Romero R, Yoon B. The involvement of human amnion in histologic chorioamnionitis is an indicator that a fetal and an intra-amniotic inflammatory response is more likely and severe: clinical implications. Placenta. 2009;30:56–61. doi: 10.1016/j.placenta.2008.09.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Yoon BH, Romero R, Moon JB, Shim SS, Kim M, Kim G, Jun JK. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2001;185:1130–1136. doi: 10.1067/mob.2001.117680. [DOI] [PubMed] [Google Scholar]
  • 25.Shim S-S, Romero R, Hong J-S, Park C-W, Jun J, Kim B, Yoon B. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 2004;191:1339–1345. doi: 10.1016/j.ajog.2004.06.085. [DOI] [PubMed] [Google Scholar]
  • 26.Bobitt JR, Ledger WJ. Amniotic fluid analysis. Its role in maternal neonatal infection. Obstet Gynecol. 1978;51:56–62. [PubMed] [Google Scholar]
  • 27.Naeye RL, Ross SM. Amniotic fluid infection syndrome. Clin Obstet Gynaecol. 1982;9:593–607. [PubMed] [Google Scholar]
  • 28.Garite TJ, Freeman RK. Chorioamnionitis in the preterm gestation. Obstet Gynecol. 1982;59:539–545. [PubMed] [Google Scholar]
  • 29.Wahbeh CJ, Hill GB, Eden RD, Gall SA. Intra-amniotic bacterial colonization in premature labor. Am J Obstet Gynecol. 1984;148:739–743. doi: 10.1016/0002-9378(84)90558-1. [DOI] [PubMed] [Google Scholar]
  • 30.Gravett MG, Hummel D, Eschenbach DA, Holmes KK. Preterm labor associated with subclinical amniotic fluid infection and with bacterial vaginosis. Obstet Gynecol. 1986;67:229–237. doi: 10.1097/00006250-198602000-00013. [DOI] [PubMed] [Google Scholar]
  • 31.Leigh J, Garite TJ. Amniocentesis and the management of premature labor. Obstet Gynecol. 1986;67:500–506. [PubMed] [Google Scholar]
  • 32.Romero R, Quintero R, Oyarzun E, Wu YK, Sabo V, Mazor M, Hobbins JC. Intraamniotic infection and the onset of labor in preterm premature rupture of the membranes. Am J Obstet Gynecol. 1988;159:661–666. doi: 10.1016/s0002-9378(88)80030-9. [DOI] [PubMed] [Google Scholar]
  • 33.Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med. 1988;319:972–978. doi: 10.1056/NEJM198810133191503. [DOI] [PubMed] [Google Scholar]
  • 34.McGregor JA, French JI, Lawellin D, Todd JK. Preterm birth and infection: pathogenic possibilities. Am J Reprod Immunol Microbiol. 1988;16:123–132. doi: 10.1111/j.1600-0897.1988.tb00181.x. [DOI] [PubMed] [Google Scholar]
  • 35.Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, Sabo V, Athanassiadis AP, Hobbins JC. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol. 1989;161:817–824. doi: 10.1016/0002-9378(89)90409-2. [DOI] [PubMed] [Google Scholar]
  • 36.Skoll MA, Moretti ML, Sibai BM. The incidence of positive amniotic fluid cultures in patients preterm labor with intact membranes. Am J Obstet Gynecol. 1989;161:813–816. doi: 10.1016/0002-9378(89)90407-9. [DOI] [PubMed] [Google Scholar]
  • 37.Ledger WJ. Infection and premature labor. Am J Perinatol. 1989;6:234–236. doi: 10.1055/s-2007-999583. [DOI] [PubMed] [Google Scholar]
  • 38.Romero R, Avila C, Santhanam U, Sehgal PB. Amniotic fluid interleukin 6 in preterm labor. Association with infection. J Clin Invest. 1990;85:1392–1400. doi: 10.1172/JCI114583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Gray DJ, Robinson HB, Malone J, Thomson RB., Jr Adverse outcome in pregnancy following amniotic fluid isolation of Ureaplasma urealyticum. Prenat Diagn. 1992;12:111–117. doi: 10.1002/pd.1970120206. [DOI] [PubMed] [Google Scholar]
  • 40.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;30:167–183. doi: 10.1111/j.1600-0897.1993.tb00618.x. [DOI] [PubMed] [Google Scholar]
  • 41.Romero R, Yoon BH, Mazor M, Gomez R, Diamond MP, Kenney JS, Ramirez M, Fidel PL, Sorokin Y, Cotton D, et al. The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 1993;169:805–816. doi: 10.1016/0002-9378(93)90009-8. [DOI] [PubMed] [Google Scholar]
  • 42.Romero R, Gomez R, Galasso M, Mazor M, Berry SM, Quintero RA, Cotton DB. The natural interleukin-1 receptor antagonist in the fetal, maternal, and amniotic fluid compartments: the effect of gestational age, fetal gender, and intrauterine infection. Am J Obstet Gynecol. 1994;171:912–921. doi: 10.1016/s0002-9378(94)70058-3. [DOI] [PubMed] [Google Scholar]
  • 43.Horowitz S, Mazor M, Horowitz J, Porath A, Glezerman M. Antibodies to Ureaplasma urealyticum in women with intraamniotic infection and adverse pregnancy outcome. Acta Obstet Gynecol Scand. 1995;74:132–136. doi: 10.3109/00016349509008922. [DOI] [PubMed] [Google Scholar]
  • 44.Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res. 1997;42:1–8. doi: 10.1203/00006450-199707000-00001. [DOI] [PubMed] [Google Scholar]
  • 45.Gomez R, Romero R, Edwin SS, David C. Pathogenesis of preterm labor and preterm premature rupture of membranes associated with intraamniotic infection. Infect Dis Clin North Am. 1997;11:135–176. doi: 10.1016/s0891-5520(05)70347-0. [DOI] [PubMed] [Google Scholar]
  • 46.Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA. 1997;278:207–211. [PubMed] [Google Scholar]
  • 47.Wenstrom KD, Andrews WW, Hauth JC, Goldenberg RL, DuBard MB, Cliver SP. Elevated second-trimester amniotic fluid interleukin-6 levels predict preterm delivery. Am J Obstet Gynecol. 1998;178:546–550. doi: 10.1016/s0002-9378(98)70436-3. [DOI] [PubMed] [Google Scholar]
  • 48.Greci LS, Gilson GJ, Nevils B, Izquierdo LA, Qualls CR, Curet LB. Is amniotic fluid analysis the key to preterm labor? A model using interleukin-6 for predicting rapid delivery. Am J Obstet Gynecol. 1998;179:172–178. doi: 10.1016/s0002-9378(98)70269-8. [DOI] [PubMed] [Google Scholar]
  • 49.Yoon BH, Chang JW, Romero R. Isolation of Ureaplasma urealyticum from the amniotic cavity and adverse outcome in preterm labor. Obstet Gynecol. 1998;92:77–82. doi: 10.1016/s0029-7844(98)00122-7. [DOI] [PubMed] [Google Scholar]
  • 50.Ghezzi F, Gomez R, Romero R, Yoon BH, Edwin SS, David C, Janisse J, Mazor M. 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. doi: 10.1016/s0301-2115(97)00236-4. [DOI] [PubMed] [Google Scholar]
  • 51.Alexander JM, Gilstrap LC, Cox SM, McIntire DM, Leveno KJ. Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol. 1998;91:725–729. doi: 10.1016/s0029-7844(98)00056-8. [DOI] [PubMed] [Google Scholar]
  • 52.Smulian JC, Vintzileos AM, Lai YL, Santiago J, Shen-Schwarz S, Campbell WA. Maternal chorioamnionitis and umbilical vein interleukin-6 levels for identifying early neonatal sepsis. J Matern Fetal Med. 1999;8:88–94. doi: 10.1002/(SICI)1520-6661(199905/06)8:3<88::AID-MFM4>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  • 53.Yoon BH, Romero R, Kim KS, Park JS, Ki SH, Kim BI, Jun JK. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol. 1999;181:773–779. doi: 10.1016/s0002-9378(99)70299-1. [DOI] [PubMed] [Google Scholar]
  • 54.Vigneswaran R. Infection and preterm birth: evidence of a common causal relationship with bronchopulmonary dysplasia and cerebral palsy. J Paediatr Child Health. 2000;36:293–296. doi: 10.1046/j.1440-1754.2000.00536.x. [DOI] [PubMed] [Google Scholar]
  • 55.Athayde N, Romero R, Maymon E, Gomez R, Pacora P, Yoon BH, Edwin SS. Interleukin 16 in pregnancy, parturition, rupture of fetal membranes, and microbial invasion of the amniotic cavity. Am J Obstet Gynecol. 2000;182:135–141. doi: 10.1016/s0002-9378(00)70502-3. [DOI] [PubMed] [Google Scholar]
  • 56.Yoon BH, Oh SY, Romero R, Shim SS, Han SY, Park JS, Jun JK. An elevated amniotic fluid matrix metalloproteinase-8 level at the time of mid-trimester genetic amniocentesis is a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol. 2001;185:1162–1167. doi: 10.1067/mob.2001.117678. [DOI] [PubMed] [Google Scholar]
  • 57.Angus SR, Segel SY, Hsu CD, Locksmith GJ, Clark P, Sammel MD, Macones GA, Strauss JF, Parry S. Amniotic fluid matrix metalloproteinase-8 indicates intra-amniotic infection. Am J Obstet Gynecol. 2001;185:1232–1238. doi: 10.1067/mob.2001.118654. [DOI] [PubMed] [Google Scholar]
  • 58.Maymon E, Romero R, Chaiworapongsa T, Berman S, Conoscenti G, Gomez R, Edwin S. Amniotic fluid matrix metalloproteinase-8 in preterm labor with intact membranes. Am J Obstet Gynecol. 2001;185:1149–1155. doi: 10.1067/mob.2001.118165. [DOI] [PubMed] [Google Scholar]
  • 59.Moon J, Kim J, Yoon B, Romero R, Kim G, Oh S-Y, Kim M, Shim S-S. Amniotic fluid matrix metalloproteinase-8 and the development of cerebral palsy. J Perinat Med. 2002;30:301–306. doi: 10.1515/JPM.2002.044. [DOI] [PubMed] [Google Scholar]
  • 60.Moss TJ, Newnham JP, Willett KE, Kramer BW, Jobe AH, Ikegami M. Early gestational intra-amniotic endotoxin: lung function, surfactant, and morphometry. Am J Respir Crit Care Med. 2002;165:805–811. doi: 10.1164/ajrccm.165.6.2108053. [DOI] [PubMed] [Google Scholar]
  • 61.Espinoza J, Chaiworapongsa T, Romero R, Edwin S, Rathnasabapathy C, Gomez R, Bujold E, Camacho N, Kim YM, Hassan S, Blackwell S, Whitty J, Berman S, Redman M, Yoon BH, Sorokin Y. 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. doi: 10.1080/jmf.13.1.2.21. [DOI] [PubMed] [Google Scholar]
  • 62.Berger A, Witt A, Haiden N, Kretzer V, Heinze G, Kohlhauser C. Microbial invasion of the amniotic cavity at birth is associated with adverse short-term outcome of preterm infants. J Perinat Med. 2003;31:115–121. doi: 10.1515/JPM.2003.016. [DOI] [PubMed] [Google Scholar]
  • 63.Ramsey P, Lieman J, Brumfield C, Carlo W. Chorioamnionitis increases neonatal morbidity in pregnancies complicated by preterm premature rupture of membranes. Am J Obstet Gynecol. 2005;192:1162–1166. doi: 10.1016/j.ajog.2004.11.035. [DOI] [PubMed] [Google Scholar]
  • 64.Nien J, Yoon B, Espinoza J, Kusanovic J, Erez O, Soto E, Richani K, Gomez R, Hassan S, Mazor M, Edwin S, Bahado Singh R, Romero R. A rapid MMP-8 bedside test for the detection of intra-amniotic inflammation identifies patients at risk for imminent preterm delivery. Am J Obstet Gynecol. 2006;195:1025–1030. doi: 10.1016/j.ajog.2006.06.054. [DOI] [PubMed] [Google Scholar]
  • 65.Kim K, Romero R, Park H, Park C-W, Shim S-S, Jun J, Yoon B. 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.e291–292.e295. doi: 10.1016/j.ajog.2007.06.040. [DOI] [PubMed] [Google Scholar]
  • 66.Kusanovic JP, Espinoza J, Romero R, Goncalves LF, Nien JK, Soto E, Khalek N, Camacho N, Hendler I, Mittal P, Friel LA, Gotsch F, Erez O, Than NG, Mazaki-Tovi S, Schoen ML, Hassan SS. Clinical significance of the presence of amniotic fluid ‘sludge’ in asymptomatic patients at high risk for spontaneous preterm delivery. Ultrasound Obstet Gynecol. 2007;30:706–714. doi: 10.1002/uog.4081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Soto E, Espinoza J, Nien JK, Kusanovic JP, Erez O, Richani K, Santolaya-Forgas J, Romero R. Human beta-defensin-2: a natural antimicrobial peptide present in amniotic fluid participates in the host response to microbial invasion of the amniotic cavity. J Matern Fetal Neonatal Med. 2007;20:15–22. doi: 10.1080/14767050601036212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Gotsch F, Mittal P, Than NG, Nhan-Chang CL, Hamill N, Vaisbuch E, Chaiworapongsa T, Edwin SS, Nien JK, Gomez R, Espinoza J, Kendal-Wright C, Hassan SS, Bryant-Greenwood G. Visfatin/Pre-B cell colony-enhancing factor in amniotic fluid in normal pregnancy, spontaneous labor at term, preterm labor and prelabor rupture of membranes: an association with subclinical intrauterine infection in preterm parturition. J Perinat Med. 2008;36:485–496. doi: 10.1515/JPM.2008.084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Gotsch F, Romero R, Kusanovic JP, Erez O, Espinoza J, Kim CJ, Vaisbuch E, Than NG, Mazaki-Tovi S, Chaiworapongsa T, Mazor M, Yoon BH, Edwin S, Gomez R, Mittal P, Hassan SS, Sharma S. The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: a role for interleukin-10. J Matern Fetal Neonatal Med. 2008;21:529–547. doi: 10.1080/14767050802127349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Chaiworapongsa T, Hong JS, Hull WM, Romero R, Whitsett JA. Amniotic fluid concentration of surfactant proteins in intra-amniotic infection. J Matern Fetal Neonatal Med. 2008;21:663–670. doi: 10.1080/14767050802215664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Park C-W, Lee S, Park J, Jun J, Romero R, Yoon B. The antenatal identification of funisitis with a rapid MMP-8 bedside test. J Perinat Med. 2008;36:497–502. doi: 10.1515/JPM.2008.079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Gotsch F, Romero R, Chaiworapongsa T, Erez O, Vaisbuch E, Espinoza J, Kusanovic JP, Mittal P, Mazaki-Tovi S, Kim CJ, Kim JS, Edwin S, Nhan-Chang CL, Hamill N, Friel L, Than NG, Mazor M, Yoon BH, Hassan SS. Evidence of the involvement of caspase-1 under physiologic and pathologic cellular stress during human pregnancy: a link between the inflammasome and parturition. J Matern Fetal Neonatal Med. 2008;21:605–616. doi: 10.1080/14767050802212109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Kusanovic JP, Romero R, Mazaki-Tovi S, Chaiworapongsa T, Mittal P, Gotsch F, Erez O, Vaisbuch E, Edwin SS, Than NG, Camacho N, Pacora P, Rogers W, Hassan SS. Resistin in amniotic fluid and its association with intra-amniotic infection and inflammation. J Matern Fetal Neonatal Med. 2008;21:902–916. doi: 10.1080/14767050802320357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Nhan-Chang CL, Romero R, Kusanovic JP, Gotsch F, Edwin SS, Erez O, Mittal P, Kim CJ, Kim MJ, Espinoza J, Friel LA, Vaisbuch E, Than NG, Mazaki-Tovi S, Hassan SS. A role for CXCL13 (BCA-1) in pregnancy and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2008;21:763–775. doi: 10.1080/14767050802244946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Romero R, Espinoza J, Rogers WT, Moser A, Nien JK, Kusanovic JP, Gotsch F, Erez O, Gomez R, Edwin S, Hassan SS. Proteomic analysis of amniotic fluid to identify women with preterm labor and intra-amniotic inflammation/infection: the use of a novel computational method to analyze mass spectrometric profiling. J Matern Fetal Neonatal Med. 2008;21:367–388. doi: 10.1080/14767050802045848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Vaisbuch E, Romero R, Erez O, Kusanovic JP, Gotsch F, Than NG, Mazaki-Tovi S, Mittal P, Edwin S, Hassan SS. Total hemoglobin concentration in amniotic fluid is increased in intraamniotic infection/inflammation. Am J Obstet Gynecol. 2008;199:426 e421–427. doi: 10.1016/j.ajog.2008.06.075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Lee J, Oh K, Yang H, Park J, Romero R, Yoon B. The importance of intra-amniotic inflammation in the subsequent development of atypical chronic lung disease. J Matern Fetal Neonatal Med. 2009;22:917–923. doi: 10.1080/14767050902994705. [DOI] [PubMed] [Google Scholar]
  • 78.Snegovskikh VV, Schatz F, Arcuri F, Toti P, Kayisli UA, Murk W, Guoyang L, Lockwood CJ, Norwitz ER. Intra-amniotic infection upregulates decidual cell vascular endothelial growth factor (VEGF) and neuropilin-1 and -2 expression: implications for infection-related preterm birth. Reprod Sci. 2009;16:767–780. doi: 10.1177/1933719109336623. [DOI] [PubMed] [Google Scholar]
  • 79.Kusanovic JP, Romero R, Jodicke C, Mazaki-Tovi S, Vaisbuch E, Erez O, Mittal P, Gotsch F, Chaiworapongsa T, Edwin SS, Pacora P, Hassan SS. Amniotic fluid soluble human leukocyte antigen-G in term and preterm parturition, and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2009;22:1151–1166. doi: 10.3109/14767050903019684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Massaro G, Scaravilli G, Simeone S, Capuano S, Pastore E, Forte A, Parisi P, Ferraiolo A, Costanzo A, Balbi C. Interleukin-6 and Mycoplasma hominis as markers of preterm birth and related brain damage: our experience. J Matern Fetal Neonatal Med. 2009;22:1063–1067. doi: 10.3109/14767050903026473. [DOI] [PubMed] [Google Scholar]
  • 81.Vaisbuch E, Romero R, Erez O, Mazaki-Tovi S, Kusanovic JP, Soto E, Gotsch F, Dong Z, Chaiworapongsa T, Kim SK, Mittal P, Pacora P, Yeo L, Hassan SS. Fragment Bb in amniotic fluid: evidence for complement activation by the alternative pathway in women with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2009;22:905–916. doi: 10.1080/14767050902994663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Pacora P, Romero R, Chaiworapongsa T, Kusanovic JP, Erez O, Vaisbuch E, Mazaki-Tovi S, Gotsch F, Jai Kim C, Than NG, Yeo L, Mittal P, Hassan SS. Amniotic fluid angiopoietin-2 in term and preterm parturition, and intra-amniotic infection/inflammation. J Perinat Med. 2009;37:503–511. doi: 10.1515/JPM.2009.093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Soto E, Romero R, Richani K, Yoon BH, Chaiworapongsa T, Vaisbuch E, Mittal P, Erez O, Gotsch F, Mazor M, Kusanovic JP. Evidence for complement activation in the amniotic fluid of women with spontaneous preterm labor and intra-amniotic infection. J Matern Fetal Neonatal Med. 2009;22:983–992. doi: 10.3109/14767050902994747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Sanders K, Bik EM, Chaiworapongsa T, Oyarzun E, Relman DA. 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. doi: 10.1111/j.1600-0897.2010.00830.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Romero R, Mazaki-Tovi S, Vaisbuch E, Kusanovic JP, Chaiworapongsa T, Gomez R, Nien JK, Yoon BH, Mazor M, Luo J, Banks D, Ryals J, Beecher C. Metabolomics in premature labor: a novel approach to identify patients at risk for preterm delivery. J Matern Fetal Neonatal Med. 2010;23:1344–1359. doi: 10.3109/14767058.2010.482618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Vaisbuch E, Mazaki-Tovi S, Kusanovic JP, Erez O, Than NG, Kim SK, Dong Z, Gotsch F, Mittal P, Chaiworapongsa T, Pacora P, Yeo L, Hassan SS, Romero R. Retinol binding protein 4: an adipokine associated with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2010;23:111–119. doi: 10.3109/14767050902994739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Mazaki-Tovi S, Romero R, Vaisbuch E, Kusanovic JP, Erez O, Mittal P, Gotsch F, Chaiworapongsa T, Than NG, Kim SK, Pacora P, Yeo L, Dong Z, Hassan SS. Adiponectin in amniotic fluid in normal pregnancy, spontaneous labor at term, and preterm labor: a novel association with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2010;23:120–130. doi: 10.3109/14767050903026481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Kusanovic JP, Romero R, Chaiworapongsa T, Mittal P, Mazaki-Tovi S, Vaisbuch E, Erez O, Gotsch F, Than NG, Edwin SS, Pacora P, Jodicke C, Yeo L, Hassan SS. Amniotic fluid sTREM-1 in normal pregnancy, spontaneous parturition at term and preterm, and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2010;23:34–47. doi: 10.3109/14767050903009248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Cruciani L, Romero R, Vaisbuch E, Kusanovic JP, Chaiworapongsa T, Mazaki-Tovi S, Mittal P, Ogge G, Gotsch F, Erez O, Kim SK, Dong Z, Pacora P, Lamont RF, Yeo L, Hassan SS, Di Renzo GC. Pentraxin 3 in amniotic fluid: a novel association with intra-amniotic infection and inflammation. J Perinat Med. 2010;38:161–171. doi: 10.1515/JPM.2009.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Balbin M, Fueyo A, Knauper V, Pendas AM, Lopez JM, Jimenez MG, Murphy G, Lopez-Otin C. Collagenase 2 (MMP-8) expression in murine tissue-remodeling processes. Analysis of its potential role in postpartum involution of the uterus. J Biol Chem. 1998;273:23959–23968. doi: 10.1074/jbc.273.37.23959. [DOI] [PubMed] [Google Scholar]
  • 91.Park JS, Romero R, Yoon BH, Moon JB, Oh SY, Han SY, Ko EM. The relationship between amniotic fluid matrix metalloproteinase-8 and funisitis. Am J Obstet Gynecol. 2001;185:1156–1161. doi: 10.1067/mob.2001.117679. [DOI] [PubMed] [Google Scholar]
  • 92.Shim SS, Romero R, Jun JK, Moon KC, Kim G, Yoon BH. C-reactive protein concentration in vaginal fluid as a marker for intra-amniotic inflammation/infection in preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2005;18:417–422. doi: 10.1080/14786430500362231. [DOI] [PubMed] [Google Scholar]
  • 93.Biggio JR, Jr, Ramsey PS, Cliver SP, Lyon MD, Goldenberg RL, Wenstrom KD. Midtrimester amniotic fluid matrix metalloproteinase-8 (MMP-8) levels above the 90th percentile are a marker for subsequent preterm premature rupture of membranes. Am J Obstet Gynecol. 2005;192:109–113. doi: 10.1016/j.ajog.2004.06.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Lee SE, Romero R, Park CW, Jun JK, Yoon BH. The frequency and significance of intraamniotic inflammation in patients with cervical insufficiency. Am J Obstet Gynecol. 2008;198:633 e631–638. doi: 10.1016/j.ajog.2007.11.047. [DOI] [PubMed] [Google Scholar]
  • 95.Lee SE, Park IS, Romero R, Yoon BH. Amniotic fluid prostaglandin F2 increases even in sterile amniotic fluid and is an independent predictor of impending delivery in preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2009;22:880–886. doi: 10.1080/14767050902994648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Lee J, Oh KJ, Yang HJ, Park JS, Romero R, Yoon BH. The importance of intra-amniotic inflammation in the subsequent development of atypical chronic lung disease. J Matern Fetal Neonatal Med. 2009;22:917–923. doi: 10.1080/14767050902994705. [DOI] [PubMed] [Google Scholar]
  • 97.Vaisbuch E, Hassan SS, Mazaki-Tovi S, Nhan-Chang CL, Kusanovic JP, Chaiworapongsa T, Dong Z, Yeo L, Mittal P, Yoon BH, Romero R. Patients with an asymptomatic short cervix (<or=15 mm) have a high rate of subclinical intraamniotic inflammation: implications for patient counseling. Am J Obstet Gynecol. 2010;202:433 e431–438. doi: 10.1016/j.ajog.2010.02.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Lee S, Romero R, Lee S, Yoon B. Amniotic fluid volume in intra-amniotic inflammation with and without culture-proven amniotic fluid infection in preterm premature rupture of membranes. J Perinat Med. 2010;38:39–44. doi: 10.1515/JPM.2009.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Oh KJ, Lee SE, Jung H, Kim G, Romero R, Yoon BH. Detection of ureaplasmas by the polymerase chain reaction in the amniotic fluid of patients with cervical insufficiency. J Perinat Med. 2010;38:261–268. doi: 10.1515/JPM.2010.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Kim BJ, Romero R, Mi Lee S, Park CW, Shin Park J, Jun JK, Yoon BH. Clinical significance of oligohydramnios in patients with preterm labor and intact membranes. J Perinat Med. 2011;39:131–136. doi: 10.1515/JPM.2010.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Lee J, Lee SM, Oh KJ, Park CW, Jun JK, Yoon BH. Fragmented forms of insulin-like growth factor binding protein-1 in amniotic fluid of patients with preterm labor and intact membranes. Reprod Sci. 2011;18:842–849. doi: 10.1177/1933719111399927. [DOI] [PubMed] [Google Scholar]
  • 102.Yoon BH, Romero R, Park JS, Kim M, Oh SY, Kim CJ, Jun JK. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol. 2000;183:1124–1129. doi: 10.1067/mob.2000.109035. [DOI] [PubMed] [Google Scholar]
  • 103.Pacora P, Chaiworapongsa T, Maymon E, Kim YM, Gomez R, Yoon BH, Ghezzi F, Berry SM, Qureshi F, Jacques SM, Kim JC, Kadar N, Romero R. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med. 2002;11:18–25. doi: 10.1080/jmf.11.1.18.25. [DOI] [PubMed] [Google Scholar]
  • 104.Yoon BH, Romero R, Shim JY, Shim SS, Kim CJ, Jun JK. C-reactive protein in umbilical cord blood: a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis. J Matern Fetal Neonatal Med. 2003;14:85–90. doi: 10.1080/jmf.14.2.85.90. [DOI] [PubMed] [Google Scholar]
  • 105.Blanc WA. Pathways of fetal and early neonatal infection. Viral placentitis, bacterial and fungal chorioamnionitis. J Pediatr. 1961;59:473–496. doi: 10.1016/s0022-3476(61)80232-1. [DOI] [PubMed] [Google Scholar]
  • 106.Maudsley RF, Brix GA, Hinton NA, Robertson EM, Bryans AM, Haust MD. Placental inflammation and infection. A prospective bacteriologic and histologic study. Am J Obstet Gynecol. 1966;95:648–659. doi: 10.1016/s0002-9378(16)34740-8. [DOI] [PubMed] [Google Scholar]
  • 107.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;81:941–948. [PubMed] [Google Scholar]
  • 108.Yoon BH, Jun JK, Park KH, Syn HC, Gomez R, Romero R. Serum C-reactive protein, white blood cell count, and amniotic fluid white blood cell count in women with preterm premature rupture of membranes. Obstet Gynecol. 1996;88:1034–1040. doi: 10.1016/s0029-7844(96)00339-0. [DOI] [PubMed] [Google Scholar]
  • 109.Yoon BH, Yang SH, Jun JK, Park KH, Kim CJ, Romero R. Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: a comparison with amniotic fluid white blood cell count. Obstet Gynecol. 1996;87:231–237. doi: 10.1016/0029-7844(95)00380-0. [DOI] [PubMed] [Google Scholar]
  • 110.Yoon BH, Romero R, Park JS, Chang JW, Kim YA, Kim JC, Kim KS. Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol. 1998;179:1254–1260. doi: 10.1016/s0002-9378(98)70142-5. [DOI] [PubMed] [Google Scholar]
  • 111.Yoon BH, Romero R, Moon JB, Oh SY, Han SY, Kim JC, Shim SS. The frequency and clinical significance of intra-amniotic inflammation in patients with a positive cervical fetal fibronectin. Am J Obstet Gynecol. 2001;185:1137–1142. doi: 10.1067/mob.2001.118162. [DOI] [PubMed] [Google Scholar]
  • 112.Lee S, Romero R, Jung H, Park C-W, Park J, Yoon B. The intensity of the fetal inflammatory response in intraamniotic inflammation with and without microbial invasion of the amniotic cavity. Am J Obstet Gynecol. 2007;197:294.e291–294.e296. doi: 10.1016/j.ajog.2007.07.006. [DOI] [PubMed] [Google Scholar]
  • 113.DiGiulio D, Romero R, Amogan H, Kusanovic J, Bik E, Gotsch F, Kim C, Erez O, Edwin S, Relman D. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS ONE. 2008;3:e3056–e3056. doi: 10.1371/journal.pone.0003056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Chaiworapongsa T, Erez O, Kusanovic JP, Vaisbuch E, Mazaki-Tovi S, Gotsch F, Than NG, Mittal P, Kim YM, Camacho N, Edwin S, Gomez R, Hassan SS, Romero R. Amniotic fluid heat shock protein 70 concentration in histologic chorioamnionitis, term and preterm parturition. J Matern Fetal Neonatal Med. 2008;21:449–461. doi: 10.1080/14767050802054550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Erez O, Romero R, Tarca AL, Chaiworapongsa T, Kim YM, Than NG, Vaisbuch E, Draghici S, Tromp G. Differential expression pattern of genes encoding for anti-microbial peptides in the fetal membranes of patients with spontaneous preterm labor and intact membranes and those with preterm prelabor rupture of the membranes. J Matern Fetal Neonatal Med. 2009;22:1103–1115. doi: 10.3109/14767050902994796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Park CW, Moon KC, Park JS, Jun JK, Yoon BH. The frequency and clinical significance of intra-uterine infection and inflammation in patients with placenta previa and preterm labor and intact membranes. Placenta. 2009;30:613–618. doi: 10.1016/j.placenta.2009.04.005. [DOI] [PubMed] [Google Scholar]
  • 117.Luciano AA, Yu H, Jackson LW, Wolfe LA, Bernstein HB. Preterm labor and chorioamnionitis are associated with neonatal T cell activation. PLoS ONE. 2011;6:e16698. doi: 10.1371/journal.pone.0016698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Cherouny PH, Pankuch GA, Romero R, Botti JJ, Kuhn DC, Demers LM, Appelbaum PC. Neutrophil attractant/activating peptide-1/interleukin-8: association with histologic chorioamnionitis, preterm delivery, and bioactive amniotic fluid leukoattractants. Am J Obstet Gynecol. 1993;169:1299–1303. doi: 10.1016/0002-9378(93)90297-v. [DOI] [PubMed] [Google Scholar]
  • 119.Romero R, Gomez R, Galasso M, Munoz H, Acosta L, Yoon BH, Svinarich D, Cotton DB. Macrophage inflammatory protein-1 alpha in term and preterm parturition: effect of microbial invasion of the amniotic cavity. Am J Reprod Immunol. 1994;32:108–113. doi: 10.1111/j.1600-0897.1994.tb01101.x. [DOI] [PubMed] [Google Scholar]
  • 120.Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F, Kim BI. 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;177:825–830. doi: 10.1016/s0002-9378(97)70276-x. [DOI] [PubMed] [Google Scholar]
  • 121.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 symposium. 1992;167:205–220. doi: 10.1002/9780470514269.ch13. discussion 220–203. [DOI] [PubMed] [Google Scholar]
  • 122.Romero R, Yoon BH, Mazor M, Gomez R, Gonzalez R, Diamond MP, Baumann P, Araneda H, Kenney JS, Cotton DB, et al. A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 1993;169:839–851. doi: 10.1016/0002-9378(93)90014-a. [DOI] [PubMed] [Google Scholar]
  • 123.Maymon E, Romero R, Chaiworapongsa T, Kim JC, Berman S, Gomez R, Edwin S. Value of amniotic fluid neutrophil collagenase concentrations in preterm premature rupture of membranes. Am J Obstet Gynecol. 2001;185:1143–1148. doi: 10.1067/mob.2001.118166. [DOI] [PubMed] [Google Scholar]
  • 124.Kim SM, Romero R, Lee J, Lee SM, Park C, Park JS, Yoon BH. The frequency and clinical significance of intra-amniotic inflammation in women with preterm uterine contractility but without cervical change: do the diagnostic criteria for preterm labor need to be changed? J Matern Fetal Neonatal Med. 2011 doi: 10.3109/14767058.2011.629256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125.Mi Lee S, Romero R, Park JW, Kim SM, Park CW, Korzeniewski S, Chaiworapongsa T, Yoon BH. The clinical significance of a positive Amnisure test() in women with preterm labor. J Matern Fetal Neonatal Med. 2012 doi: 10.3109/14767058.2012.657279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.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;165:813–820. doi: 10.1016/0002-9378(91)90422-n. [DOI] [PubMed] [Google Scholar]
  • 127.Kashlan F, Smulian J, Shen Schwarz S, Anwar M, Hiatt M, Hegyi T. Umbilical vein interleukin 6 and tumor necrosis factor alpha plasma concentrations in the very preterm infant. Pediatr Infect Dis J. 2000;19:238–243. doi: 10.1097/00006454-200003000-00013. [DOI] [PubMed] [Google Scholar]
  • 128.Naccasha N, Hinson R, Montag A, Ismail M, Bentz L, Mittendorf R. Association between funisitis and elevated interleukin-6 in cord blood. Obstet Gynecol. 2001;97:220–224. doi: 10.1016/s0029-7844(00)01149-2. [DOI] [PubMed] [Google Scholar]
  • 129.Kim CJ, Yoon BH, Park SS, Kim MH, Chi JG. Acute funisitis of preterm but not term placentas is associated with severe fetal inflammatory response. Hum Pathol. 2001;32:623–629. doi: 10.1053/hupa.2001.24992. [DOI] [PubMed] [Google Scholar]
  • 130.Rogers B, Alexander J, Head J, McIntire D, Leveno K. Umbilical vein interleukin-6 levels correlate with the severity of placental inflammation and gestational age. Hum Pathol. 2002;33:335–340. doi: 10.1053/hupa.2002.32214. [DOI] [PubMed] [Google Scholar]
  • 131.Wirbelauer J, Seidenspinner S, Thomas W, Kunzmann S, Speer C. Funisitis is associated with increased interleukin-10 gene expression in cord blood mononuclear cells in preterm infants ≤32 weeks of gestation. Eur J Obstet Gynecol Reprod Biol. 2011;155:31–35. doi: 10.1016/j.ejogrb.2010.11.013. [DOI] [PubMed] [Google Scholar]
  • 132.Overbach AM, Daniel SJ, Cassady G. The value of umbilical cord histology in the management of potential perinatal infection. J Pediatr. 1970;76:22–31. doi: 10.1016/s0022-3476(70)80125-1. [DOI] [PubMed] [Google Scholar]
  • 133.Kim CJ, Yoon BH, Romero R, Moon JB, Kim M, Park SS, Chi JG. Umbilical arteritis and phlebitis mark different stages of the fetal inflammatory response. Am J Obstet Gynecol. 2001;185:496–500. doi: 10.1067/mob.2001.116689. [DOI] [PubMed] [Google Scholar]
  • 134.Goepfert A, Andrews W, Carlo W, Ramsey P, Cliver S, Goldenberg R, Hauth J. Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity. Am J Obstet Gynecol. 2004;191:1375–1381. doi: 10.1016/j.ajog.2004.06.086. [DOI] [PubMed] [Google Scholar]

RESOURCES