Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2019 Jun 1.
Published in final edited form as: Nogyogyaszati Szuleszeti Tovabbkepzo Szemle. 2018 Jun;20(3):103–112.

Clinical Chorioamnionitis at Term: New Insights into the Etiology, Microbiology, and the Fetal, Maternal and Amniotic Cavity Inflammatory Responses

Roberto Romero 1,2,3,4, Nardhy Gomez-Lopez 1,5,6, Juan Pedro Kusanovic 1,7,8, Percy Pacora 1,5, Bogdan Panaitescu 1,5, Offer Erez 1,5, Bo Hyun Yoon 1,9
PMCID: PMC6177213  NIHMSID: NIHMS981736  PMID: 30320312

Abstract

Clinical chorioamnionitis is the most common infection related diagnosis made in labor and delivery units worldwide. It is traditionally believed to be due to microbial invasion of the amniotic cavity, which elicits a maternal inflammatory response characterized by maternal fever, uterine tenderness, maternal tachycardia and leukocytosis. The condition is often associated with fetal tachycardia and a foul smelling amniotic fluid. Recent studies in which amniocentesis has been used to characterize the microbiologic state of the amniotic cavity and the inflammatory response show that only 60% of patients with the diagnosis of clinical chorioamnionitis have proven infection using culture or molecular microbiologic techniques. The remainder of the patients have intra-amniotic inflammation without demonstrable microorganisms or a maternal systemic inflammatory response (fever) in the absence of intra-amniotic inflammation. The latter cases often represent a systemic inflammatory response after epidural anesthesia/analgesia has been administered. The most common microorganisms are Ureaplasma species and Gardnerella vaginalis. In the presence of ruptured membranes, the frequency of infection is 70%, which is substantially higher than patients who have intact membranes (25%). The amniotic fluid inflammatory response is characterized by an infiltration of neutrophils and monocytes. Both cell types are activated in the presence of infection and can produce inflammatory cytokines. The white blood cells in the amniotic fluid can be of fetal or maternal origin. The maternal inflammatory response is characterized by an elevation in the concentration of pyrogenic cytokines. The cytokine plasma concentrations in the fetal circulation are elevated even if there is no evidence of an intra-amniotic inflammatory response suggesting that maternal plasma cytokines may cross the placental barrier and induce a mild fetal inflammatory response. Placental pathology is of limited value in the diagnosis of proven intra-amniotic infection. The clinical criteria traditionally used in clinical medicine have accuracy around 50% and therefore, they cannot distinguish between patients with a proven intra-amniotic infection and those with intra-amniotic inflammation alone. Analysis of amniotic fluid with a bedside test for MMP-8 can allow the rapid identification of the patient at risk for infection and may decrease the need for antibiotic administration to neonates. An important consideration is whether antibiotics effective against Ureaplasma species should be administered to patients with clinical chorioamnionitis, given that these genital mycoplasmas are the most common organisms found in the amniotic fluid. The emergent picture is that clinical chorioamnionitis is a heterogeneous syndrome, which requires further study to optimize maternal and neonatal outcomes.

Keywords: Intra-amniotic infection, maternal fever, fetal tachycardia, amniotic fluid, cytokines, neutrophils, monocytes, MMP-8, biomarkers, rapid diagnosis, treatment, antibiotics, maternal morbidity, neonatal morbidity

Introduction

Clinical chorioamnionitis is the most common infection-related diagnosis made in labor and delivery units worldwide [1–4]. The standard clinical definition refers to the presence of maternal fever associated with clinical signs (i.e. foul smelling discharge, uterine tenderness, maternal and fetal tachycardia) as well as laboratory abnormalities (i.e. leukocytosis) [5, 6]. These signs are thought to be manifestations of both local and systemic maternal-fetal inflammatory processes initiated in response to microbial invasion of the amniotic cavity (MIAC) [7–13].

Clinical chorioamnionitis at term is associated with a 2- to 4-fold increase in endometritis [14], wound infection [14], septic pelvic thrombophlebitis [3, 14], pelvic abscess [3, 14], maternal admission to the intensive care unit [3, 15], and postpartum hemorrhage [3, 16]. Importantly, neonates born to mothers with clinical signs of chorioamnionitis have a high risk of neonatal mortality [1], short- and long-term complications such as neonatal sepsis [17–19], meconium aspiration syndrome [20, 21], stillbirth [22, 23], and neurodevelopmental disorders including cerebral palsy [24–35].

Although this condition is common, affecting thousands of women daily and has been known for centuries as a precursor of puerperal (or childbed) fever [36, 37], new information has emerged which has characterized, for the first time, the microbiology and inflammatory responses in the mother, fetus, and amniotic cavity. This article will review new insight gained from studies published in the last three years.

The syndrome of clinical chorioamnionitis: evidence for microbiologic and inflammatory heterogeneity

Among patients with clinical chorioamnionitis, we have identified three distinct groups [38]: 1) patients who have intra-amniotic infection, defined by the presence of an elevated concentration of interleukin (IL)-6 [a marker of inflammation [39]] and the presence of microorganisms; 2) patients who have sterile intra-amniotic inflammation, in which no organisms can be detected using standard cultivation techniques or 16S RNA broad assays, although they have an elevated amniotic fluid IL-6; and 3) patients who have neither intra-amniotic inflammation or microorganisms in the amniotic cavity. The frequency with which these conditions are present varies according to whether the membranes are ruptured at the time of amniocentesis to assess the microbial state of the amniotic cavity [38]. When the membranes are intact, the frequency of intra-amniotic infection is 25%, while it is 70% when the membranes are ruptured [38]. The relative contribution of the different entities presenting as clinical chorioamnionitis are illustrated in (Figure 1). A small group of patients has microbial invasion of the amniotic cavity without inflammation.

Figure 1.

Figure 1.

Open in a new tab

Prevalence of microbial-associated intra-amniotic inflammation and intra-amniotic inflammation without detectable microorganisms in patients with clinical signs of chorioamnionitis at term according to the status of the membranes at the time of amniocentesis (intact vs. ruptured). Microbial-associated intra-amniotic inflammation was diagnosed in 70% (21/30) of the cases with rupture of membranes, and in 25% (4/16) of patients with intact membranes.

The mechanism responsible for sterile intra-amniotic inflammation have not been defined [38, 40–42] and could represent inflammation induced by danger signals (or alarmins) [43–47], or alternatively, infections which have escaped detection with current cultivation and molecular microbiologic techniques [48–54]. For example, it is possible that deep DNA and RNA sequencing may identify organisms which are present below the level of detection of culture and 16S PCR; however, this question remains to be addressed.

What are the microorganisms found in the amniotic cavity in clinical chorioamnionitis at term?

The original study describing the microbiology of clinical chorioamnionitis at term was performed using cultivation techniques of amniotic fluid obtained with transcervical catheters placed in the amniotic cavity [5]. This approach may not have provided an accurate description of the microbiology of clinical chorioamnionitis, since the placement of a transcervical catheter is frequently associated with contamination of the vaginal ecosystem. Conventional cultivation techniques cannot identify the entire microbial diversity of an ecological niche, because the conditions required for the growth of microorganisms in vitro are not known, and some organisms are, therefore, considered to be non-culturable [55]. By using both cultivation and molecular biology techniques (broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry or PCR/ESI-MS), it is possible to gain a more complete understanding of the microbiology of the amniotic cavity [56].

In a study of 46 women with clinical chorioamnionitis at term, amniotic fluid was obtained by transabdominal amniocentesis or at the time of Cesarean delivery under sterile conditions [38]. We found that conventional culture identified bacteria in the amniotic fluid from 46% (21/46) of the participants, while PCR/ESI-MS was positive for microorganisms in 59% (27/46) of the patients. The combination of these two approaches resulted in the detection of amniotic fluid microorganisms in 61% (28/46) of women with clinical chorioamnionitis at term [38]. Molecular microbiologic techniques identified more microorganisms than cultivation; yet, some bacterial taxa were preferentially identified by each technique [38].

Ureaplasma spp. and Gardnerella vaginalis are the most commonly identified microorganisms by cultivation and PCR/ESI-MS, respectively [38]. This has clinical implications, because the antibiotics used to treat patients with clinical chorioamnionitis or puerperal endometritis do not include agents that eradicate infections due to Ureaplasma spp.

The cellular intra-amniotic inflammatory response: neutrophils and monocytes in the amniotic fluid

An inflammatory response is characterized by cellular and soluble components. The typical changes in the soluble meditators are those that occur in the inflammatory cytokine network. However, cellular mediators are prominent, and mainly involve the innate immune response.

Using flow cytometry, we found that neutrophils are the most common leukocyte subset in the amniotic fluid, followed by monocytes; other white blood cells (such as lymphocytes and natural killer cells) are scarce in the amniotic fluid [57] (Figure 2). The absolute counts of neutrophils and monocytes are significantly higher in patients with microorganisms found in the amniotic fluid than in those without detectable microorganisms [57]. In addition, the profile of cytokine expression differs between monocytes and neutrophils; while neutrophils predominantly produce tumor necrosis factor (TNF)-α and macrophage inflammatory protein (MIP)-1β, monocytes express higher levels of IL-1β and IL-1α [57]. These cytokines are implicated in both the process of parturition and host response against intra-amniotic infection [58–75].

Figure 2.

Figure 2.

Open in a new tab

Histological examination of amniotic fluid neutrophils and monocytes in women with clinical chorioamnionitis. A) Hematoxylin & Eosin staining shows the typical morphology of neutrophils (N, green arrow) and monocytes (M, red arrow) in the amniotic fluid of women with clinical chorioamnionitis. Magnification 400X. Scale bars: 50μm. B) Immunofluorescence of neutrophils and monocytes in the amniotic fluid of women with clinical chorioamnionitis. Neutrophils (CD15+ cells) are green, monocytes (CD14+ cells) are red, and nuclei are blue (DAPI). Magnification 400X.

Amniotic fluid white blood cells can be of fetal or maternal origin

Although traditionally considered to be of fetal origin [76, 77], neutrophils in amniotic fluid in cases of infection can be of maternal, fetal, or mixed (both) origin, as demonstrated by studies using DNA fingerprinting [78]. In general, we found that patients with intra-amniotic infection and preterm gestations had neutrophils of fetal origin, while those with intra-amniotic infection/inflammation at term had predominantly maternal neutrophils or a cellular infiltrate of mixed origin (maternal and fetal) [78]. (Figure 3) shows the DNA fingerprinting of amniotic fluid neutrophils of fetal, maternal, or mixed (maternal and fetal) origin.

Figure 3. DNA fingerprinting of amniotic fluid neutrophils.

Figure 3.

Open in a new tab

DNA fingerprinting of purified amniotic fluid neutrophils of fetal (A), maternal (B) or mixed (C) origin, the fetus (umbilical cord), and the mother (buffy coat from peripheral blood) is shown in electropherograms. Each electropherogram contains 16 genetic sites: D3S1358, TH01, D21S11, D18S51, Penta_E, D5S818, D13S317, D7S820, D16S539, CSF1PO, Penta_D, X- and Y-specific amalogenin genes, vWA, D8S1179, TPOX, and FGA. Each electropherogram was separated into three sections: blue, green, and black. Each color indicates the dye used for the PCR multiplex: blue represents the genes amplified using fluorescein (FL dye), green represents the genes amplified using 6-carboxy-4′,5′-dichloro-2′,7′-dimethoxyfluorescein (JOE dye), and black represents the genes amplified using tetramethylrhodamine (TMR dye). Each genetic site has STR alleles, which is represented by peaks. The number next to/above each STR allele (peak) is the number of repeats for each STR allele.

The soluble amniotic fluid inflammatory response: changes in the cytokine inflammatory network and lipidome

The amniotic fluid concentrations of inflammatory cytokines [such as interferon gamma (IFN-γ), TNFα, IL-4, MIP-1β, and IL-8] are higher in patients with clinical chorioamnionitis at term than in women with spontaneous labor at term without intra-amniotic inflammation [75]. Of interest is that once a patient had intra-amniotic inflammation, the changes in the amniotic fluid cytokine network are similar in those with proven infection vs. those with intra-amniotic inflammation without demonstrable microorganisms [75].

Given that lipids are important mediators of the inflammatory response, we have examined the behavior of bioactive lipids using discovery techniques (i.e. lipidomics) [79]. An elevated leukotriene B4 (LTB4) was associated with the presence of microorganisms in the amniotic cavity [80]. Therefore, lipid mediators can be assessed with mass spectrometry techniques could have value as biomarkers [80].

How well do clinical criteria perform in the identification of proven intra-amniotic infection?

Only 54% of patients with the diagnosis of clinical chorioamnionitis at term have intra-amniotic inflammation and detectable bacteria [38]. These findings indicate that only half of the women with clinical chorioamnionitis at term may benefit from antibiotic administration. Therefore, we evaluated the diagnostic performance and accuracy of clinical signs for the diagnosis of clinical chorioamnionitis using the “gold standard” [a combination of cultivation and molecular biology techniques [56]] for the identification of intra-amniotic infection [81].

We reported that clinical signs of chorioamnionitis do not accurately identify patients with intra-amniotic infection [81]. Maternal and fetal tachycardia, as well as maternal leukocytosis, have low specificity (5%-30%), whereas foul-smelling amniotic fluid and uterine tenderness have poor sensitivity (<15%) for the diagnosis of intra-amniotic infection [81]. These findings call for the development of novel approaches to facilitate the rapid identification of bacteria in the amniotic fluid and reevaluation of the management of clinical chorioamnionitis at term.

The maternal plasma cytokine profile

Most of the signs of clinical chorioamnionitis (except for fetal tachycardia and foul-smelling amniotic fluid) are thought to reflect a maternal inflammatory response to microbial invasion of the amniotic cavity [4, 82]. Maternal plasma concentrations of pyrogenic cytokines (IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) are higher in patients with clinical chorioamnionitis at term than in those with spontaneous labor at term without clinical chorioamnionitis [83]. However, the maternal plasma concentrations of cytokines are not significantly different among the 3 major subgroups of patients with clinical chorioamnionitis at term [83]. In addition, women with clinical chorioamnionitis at term without intra-amniotic inflammation have greater maternal plasma concentrations of pyrogenic cytokines than those with spontaneous labor at term without this clinical condition [83]. These findings indicate that the absolute concentration of cytokines in the maternal plasma cannot be used to identify women who have bacteria in the amniotic fluid and that the assessment of the amniotic fluid is required to identify intra-amniotic inflammation and/or infection.

Umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response

Neonates born to mothers with clinical chorioamnionitis are at risk for sepsis [3, 17–19, 32, 84–89], meconium aspiration syndrome [17, 90–94], neonatal encephalopathy [31, 34, 95–97], and long-term neurodevelopmental disabilities including cognitive impairment [98–101] and cerebral palsy [27, 28, 30, 34, 35, 86, 102–104], as well as neonatal death [1, 22, 24, 88, 105]. Such adverse neonatal outcomes may be attributed to the effects of a maternal systemic inflammatory response on the fetus [83] and/or the local inflammatory response in the amniotic cavity [38, 75].

Neonates born to mothers with clinical chorioamnionitis at term have higher umbilical cord plasma concentrations of several inflammatory cytokines (IL-6, IL-12p70, IL-16, IL-13, IL-4, IL-10 and IL-8) compared to those born to mothers with spontaneous labor at term without this clinical condition [106]. Interestingly, neonates born to mothers with clinical chorioamnionitis at term without intra-amniotic inflammation also have higher concentrations of inflammatory cytokines (IL-6, IL-12p70, IL-13, IL-4, IL-5, and IL-8) than neonates not exposed to clinical chorioamnionitis, suggesting that maternal fever in the absence of intra-amniotic inflammation leads to a change in the fetal cytokine network [106]. In addition, there are significant and positive correlations between maternal and umbilical cord plasma IL-6 and IL-8 concentrations consistent with placental transfer of cytokines [106]. All neonates born to mothers with proven intra-amniotic infection were diagnosed with fetal inflammatory response syndrome (FIRS) [106].

Can placental pathology identify the patient with intra-amniotic infection?

Examination of the placenta, the largest human biopsy, can provide information about fetal exposure to intra-amniotic inflammation or infection [10, 11, 13, 24, 26, 33, 107–124]. Indeed, inflammation of the umbilical cord or chorionic vessels represents a fetal response and is indicative that the fetus was exposed to inflammatory stimuli before birth [113]. Therefore, we examined the diagnostic performance of placental histologic features of acute inflammation in the identification of intra-amniotic infection and FIRS in patients with clinical chorioamnionitis at term [125]. Acute histologic chorioamnionitis and funisitis are indeed associated with the presence of intra-amniotic infection and FIRS [125]. However, current placental histopathologic methods have limitations in identifying whether the fetus was exposed to microorganisms in the amniotic cavity [125]. The available data suggest that placental examination is neither sensitive nor specific for the identification of intra-amniotic infection, because acute histologic chorioamnionitis and funisitis can be observed when there is intra-amniotic inflammation in the absence of demonstrable microorganisms.

A rapid MMP-8 test for the identification of intra-amniotic inflammation

A rapid test which utilizes neutrophil collagenase or MMP-8 has been made available for the diagnosis of intra-amniotic inflammation [126–133]. This test in patients with intra-amniotic inflammation and clinical chorioamnionitis has the following diagnostic indices, predictive values, and likelihood ratios: sensitivity of 82.4% (28/34), specificity of 90% (9/10), positive predictive value of 96.6% (28/29), negative predictive value of 60% (9/15), positive likelihood ratio 8.2 (95% CI 1.3–53.2), and negative likelihood ratio 0.2 (95% CI 0.1–0.4) [134].

In patients with intra-amniotic infection and clinical chorioamnionitis, the rapid MMP-8 test has a sensitivity of 91.7% (22/24), specificity of 65% (13/20), positive predictive value of 75.9% (22/29), negative predictive value of 86.7% (13/15), positive likelihood ratio of 2.6 (95% CI 1.4–4.8), and negative likelihood ratio of 0.1 (95% CI 0.03–0.5) [134].

In addition, the rapid MMP-8 test has a significantly higher specificity than the ELISA IL-6 test in the identification of intra-amniotic inflammation [66.7% (14/21) vs. 42.9% (9/21); p=0.03] [134]. Importantly, the rapid MMP-8 test has 100% sensitivity and 100% negative predictive value in the identification of neonates affected with FIRS [134].

This study showed that a rapid MMP-8 point-of-care test can be used for the diagnosis of intra-amniotic inflammation and to identify the mother at risk of delivering a neonate with systemic inflammation among patients with clinical chorioamnionitis at term [134].

Conclusions

A series of systematic studies in patients with clinical chorioamnionitis at term have revealed the following:

  • Clinical chorioamnionitis at term is a heterogeneous condition, and only a fraction of these patients have proven intra-amniotic infection

  • The frequency of infection is higher when the chorioamniotic membranes are ruptured, rather than intact (70% vs 25%)

  • The most common organisms are Ureaplasma spp. and Gardnerella vaginalis – this is important because most treatment approaches in clinical obstetrics and neonatology do not provide appropriate coverage for genital mycoplasmas

  • The cellular intra-amniotic inflammatory response is characterized by an influx of neutrophils and monocytes

  • The soluble intra-amniotic inflammatory response is characterized by elevated concentrations of the major inflammatory cytokines

  • The maternal plasma cytokines are elevated in patients with clinical chorioamnionitis at term; however, the concentrations of these proteins cannot distinguish between patients who have proven intra-amniotic infection and those with intra-amniotic inflammation without demonstrable microorganisms

  • The fetal concentrations of inflammatory cytokines are elevated in neonates born to mothers with clinical chorioamnionitis compared to those without clinical chorioamnionitis at term. There is indirect evidence that elevations in neonatal inflammatory concentrations may reflect a systemic inflammatory response in the mother, even in the absence of intra-amniotic inflammation (this may occur in cases of epidural-induced fever)

  • Placental pathologic examination to detect acute histologic chorioamnionitis, funisitis, or chorionic vasculitis is neither specific nor sensitive for the identification of patients with proven intra-amniotic infection

  • Analysis of amniotic fluid is the only definitive way to make a diagnosis of intra-amniotic infection in patients with clinical chorioamnionitis at term

  • Potential biomarkers for intra-amniotic inflammation, which can be implemented at the bedside, is an MMP-8 rapid test which detects neutrophil collagenase

  • Future studies are required to determine if noninvasive collection of amniotic fluid with a special device in patients who have ruptured membranes can be of clinical value to diagnose intra-amniotic infection/inflammation

Acknowledgments

Funding: This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C. Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.

Footnotes

Disclosure: The authors report no conflict of interest.

References

  • 1.Malloy MH. Chorioamnionitis: epidemiology of newborn management and outcome United States 2008. J Perinatol. 2014;34(8):611–5. [DOI] [PubMed] [Google Scholar]
  • 2.Tita AT, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol. 2010;37(2):339–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Rouse DJ, Landon M, Leveno KJ, Leindecker S, Varner MW, Caritis SN, et al. The Maternal-Fetal Medicine Units cesarean registry: chorioamnionitis at term and its duration-relationship to outcomes. Am J Obstet Gynecol. 2004;191(1):211–6. [DOI] [PubMed] [Google Scholar]
  • 4.Newton ER. Chorioamnionitis and intraamniotic infection. Clin Obstet Gynecol. 1993;36(4):795–808. [DOI] [PubMed] [Google Scholar]
  • 5.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):1–8. [DOI] [PubMed] [Google Scholar]
  • 6.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(6):823–8. [DOI] [PubMed] [Google Scholar]
  • 7.Gilstrap LC 3rd, Cox SM. Acute chorioamnionitis. Obstet Gynecol Clin North Am. 1989;16(2):373–9. [PubMed] [Google Scholar]
  • 8.Gibbs RS, Duff P. Progress in pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol. 1991;164(5 Pt 1):1317–26. [DOI] [PubMed] [Google Scholar]
  • 9.Willi MJ, Winkler M, Fischer DC, Reineke T, Maul H, Rath W. Chorioamnionitis: elevated interleukin-6 and interleukin-8 concentrations in the lower uterine segment. J Perinat Med. 2002;30(4):292–6. [DOI] [PubMed] [Google Scholar]
  • 10.Lee SE, Romero R, Kim CJ, Shim SS, Yoon BH. Funisitis in term pregnancy is associated with microbial invasion of the amniotic cavity and intra-amniotic inflammation. J Matern Fetal Neonatal Med. 2006;19(11):693–7. [DOI] [PubMed] [Google Scholar]
  • 11.Lee SE, Romero R, Jung H, Park CW, Park JS, Yoon BH. 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(3):294 e1–6. [DOI] [PubMed] [Google Scholar]
  • 12.Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, et al. The fetal inflammatory response syndrome. Clin Obstet Gynecol. 2007;50(3):652–83. [DOI] [PubMed] [Google Scholar]
  • 13.Redline RW. Inflammatory response in acute chorioamnionitis. Semin Fetal Neonatal Med. 2012;17(1):20–5. [DOI] [PubMed] [Google Scholar]
  • 14.Hauth JC, Gilstrap LC 3rd, Hankins GD, Connor KD. Term maternal and neonatal complications of acute chorioamnionitis. Obstet Gynecol. 1985;66(1):59–62. [PubMed] [Google Scholar]
  • 15.Rojas-Suarez J, Paternina-Caicedo AJ, Miranda J, Mendoza R, Duenas-Castel C, Bourjeily G. Comparison of severity-of-illness scores in critically ill obstetric patients: a 6-year retrospective cohort. Crit Care Med. 2014;42(5):1047–54. [DOI] [PubMed] [Google Scholar]
  • 16.Mark SP, Croughan-Minihane MS, Kilpatrick SJ. Chorioamnionitis and uterine function. Obstet Gynecol. 2000;95(6 Pt 1):909–12. [PubMed] [Google Scholar]
  • 17.Yoder PR, Gibbs RS, Blanco JD, Castaneda YS, St Clair PJ. A prospective, controlled study of maternal and perinatal outcome after intra-amniotic infection at term. Am J Obstet Gynecol. 1983;145(6):695–701. [DOI] [PubMed] [Google Scholar]
  • 18.Yancey MK, Duff P, Kubilis P, Clark P, Frentzen BH. Risk factors for neonatal sepsis. Obstet Gynecol. 1996;87(2):188–94. [DOI] [PubMed] [Google Scholar]
  • 19.Ladfors L, Tessin I, Mattsson LA, Eriksson M, Seeberg S, Fall O. Risk factors for neonatal sepsis in offspring of women with prelabor rupture of the membranes at 34–42 weeks. J Perinat Med. 1998;26(2):94–101. [DOI] [PubMed] [Google Scholar]
  • 20.Rao S, Pavlova Z, Incerpi MH, Ramanathan R. Meconium-stained amniotic fluid and neonatal morbidity in near-term and term deliveries with acute histologic chorioamnionitis and/or funisitis. J Perinatol. 2001;21(8):537–40. [DOI] [PubMed] [Google Scholar]
  • 21.Greenwell EA, Wyshak G, Ringer SA, Johnson LC, Rivkin MJ, Lieberman E. Intrapartum temperature elevation, epidural use, and adverse outcome in term infants. Pediatrics. 2012;129(2):e447–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Moyo SR, Hagerstrand I, Nystrom L, Tswana SA, Blomberg J, Bergstrom S, et al. Stillbirths and intrauterine infection, histologic chorioamnionitis and microbiological findings. Int J Gynaecol Obstet. 1996;54(2):115–23. [DOI] [PubMed] [Google Scholar]
  • 23.Han YW, Fardini Y, Chen C, Iacampo KG, Peraino VA, Shamonki JM, et al. Term stillbirth caused by oral Fusobacterium nucleatum. Obstet Gynecol. 2010;115(2 Pt 2):442–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.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(4 Pt 1):955–61. [DOI] [PubMed] [Google Scholar]
  • 25.McGregor JA. Maternal and fetal infection. Curr Opin Obstet Gynecol. 1991;3(1):15–23. [PubMed] [Google Scholar]
  • 26.van Hoeven KH, Anyaegbunam A, Hochster H, Whitty JE, Distant J, Crawford C, et al. Clinical significance of increasing histologic severity of acute inflammation in the fetal membranes and umbilical cord. Pediatr Pathol Lab Med. 1996;16(5):731–44. [PubMed] [Google Scholar]
  • 27.Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA. 1997;278(3):207–11. [PubMed] [Google Scholar]
  • 28.Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA. 2000;284(11):1417–24. [DOI] [PubMed] [Google Scholar]
  • 29.Impey L, Greenwood C, MacQuillan K, Reynolds M, Sheil O. Fever in labour and neonatal encephalopathy: a prospective cohort study. BJOG. 2001;108(6):594–7. [DOI] [PubMed] [Google Scholar]
  • 30.Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA. 2003;290(20):2677–84. [DOI] [PubMed] [Google Scholar]
  • 31.Blume HK, Li CI, Loch CM, Koepsell TD. Intrapartum fever and chorioamnionitis as risks for encephalopathy in term newborns: a case-control study. Dev Med Child Neurol. 2008;50(1):19–24. [DOI] [PubMed] [Google Scholar]
  • 32.Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK, Canadian Neonatal N. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol. 2009;200(4):372 e1–6. [DOI] [PubMed] [Google Scholar]
  • 33.Lee SM, Park JW, Kim BJ, Park CW, Park JS, Jun JK, et al. Acute histologic chorioamnionitis is a risk factor for adverse neonatal outcome in late preterm birth after preterm premature rupture of membranes. PLoS One. 2013;8(12):e79941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Hagberg H, Wennerholm UB, Savman K. Sequelae of chorioamnionitis. Curr Opin Infect Dis. 2002;15(3):301–6. [DOI] [PubMed] [Google Scholar]
  • 35.Nelson KB. The epidemiology of cerebral palsy in term infants. Ment Retard Dev Disabil Res Rev. 2002;8(3):146–50. [DOI] [PubMed] [Google Scholar]
  • 36.Kirkland T A Treatise on Child-bed Fevers: And on the Methods of Preventing Them Being a Supplement to the Books Lately Written on the Subject. To which are Prefixed Two Dissertations, The One on the Brain and Nerves; the Other on the Sympathy of the Nerves, and on Different Kinds of Irritability. By Kirkland Thomas: Baldwin R, No. 47, and Dawson W, No. 7, Pater-Noster-Row; 1774. [Google Scholar]
  • 37.DeLacy M Puerperal fever in eighteenth-century Britain. Bulletin of the History of Medicine. 1989;63(4):521. [PubMed] [Google Scholar]
  • 38.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 Perinat Med. 2015;43(1):19–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.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(5):1130–6. [DOI] [PubMed] [Google Scholar]
  • 40.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(5):458–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.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. 2015;28(12):1394–409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Chaiworapongsa T, Erez O, Kusanovic JP, Vaisbuch E, Mazaki-Tovi S, Gotsch F, et al. Amniotic fluid heat shock protein 70 concentration in histologic chorioamnionitis, term and preterm parturition. J Matern Fetal Neonatal Med. 2008;21(7):449–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.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(12):1444–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.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(6):558–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Gomez-Lopez N, Romero R, Plazyo O, Panaitescu B, Furcron AE, Miller D, et al. Intra-Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth. Am J Reprod Immunol. 2016;75(1):3–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Plazyo O, Romero R, Unkel R, Balancio A, Mial TN, Xu Y, et al. HMGB1 Induces an Inflammatory Response in the Chorioamniotic Membranes That Is Partially Mediated by the Inflammasome. Biol Reprod. 2016;95(6):130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Baschat AA, Towbin J, Bowles NE, Harman CR, Weiner CP. Prevalence of viral DNA in amniotic fluid of low-risk pregnancies in the second trimester. J Matern Fetal Neonatal Med. 2003;13(6):381–4. [DOI] [PubMed] [Google Scholar]
  • 49.Baschat AA, Towbin J, Bowles NE, Harman CR, Weiner CP. Is adenovirus a fetal pathogen? Am J Obstet Gynecol. 2003;189(3):758–63. [DOI] [PubMed] [Google Scholar]
  • 50.Srinivas SK, Ma Y, Sammel MD, Chou D, McGrath C, Parry S, et al. Placental inflammation and viral infection are implicated in second trimester pregnancy loss. Am J Obstet Gynecol. 2006;195(3):797–802. [DOI] [PubMed] [Google Scholar]
  • 51.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(8):e3056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Miller JL, Harman C, Weiner C, Baschat AA. Perinatal outcomes after second trimester detection of amniotic fluid viral genome in asymptomatic patients. J Perinat Med. 2009;37(2):140–3. [DOI] [PubMed] [Google Scholar]
  • 53.Tsekoura EA, Konstantinidou A, Papadopoulou S, Athanasiou S, Spanakis N, Kafetzis D, et al. Adenovirus genome in the placenta: association with histological chorioamnionitis and preterm birth. J Med Virol. 2010;82(8):1379–83. [DOI] [PubMed] [Google Scholar]
  • 54.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(1):38–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Stewart EJ. Growing unculturable bacteria. J Bacteriol. 2012;194(16):4151–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.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(4):330–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Martinez-Varea A, Romero R, Xu Y, Miller D, Ahmed AI, Chaemsaithong P, et al. Clinical chorioamnionitis at term VII: the amniotic fluid cellular immune response. J Perinat Med. 2017;45(5):523–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.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(2):336–41. [DOI] [PubMed] [Google Scholar]
  • 59.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(5):1576–87. [DOI] [PubMed] [Google Scholar]
  • 60.Fortunato SJ, Menon R. Distinct molecular events suggest different pathways for preterm labor and premature rupture of membranes. Am J Obstet Gynecol. 2001;184(7):1399–405; discussion 405–6. [DOI] [PubMed] [Google Scholar]
  • 61.Fortunato SJ, Menon R, Lombardi SJ. Role of tumor necrosis factor-alpha in the premature rupture of membranes and preterm labor pathways. Am J Obstet Gynecol. 2002;187(5):1159–62. [DOI] [PubMed] [Google Scholar]
  • 62.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(11–12):1037–51. [DOI] [PubMed] [Google Scholar]
  • 63.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(1):29–34. [DOI] [PubMed] [Google Scholar]
  • 64.Menon R, Fortunato SJ. Infection and the role of inflammation in preterm premature rupture of the membranes. Best Pract Res Clin Obstet Gynaecol. 2007;21(3):467–78. [DOI] [PubMed] [Google Scholar]
  • 65.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(5 Pt 1):1117–23. [DOI] [PubMed] [Google Scholar]
  • 66.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(3):235–8. [PubMed] [Google Scholar]
  • 67.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(3–4):117–23. [DOI] [PubMed] [Google Scholar]
  • 68.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(6):941–8. [PubMed] [Google Scholar]
  • 69.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(2):281–342. [PubMed] [Google Scholar]
  • 70.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(4):825–30. [DOI] [PubMed] [Google Scholar]
  • 71.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(4):155–8. [DOI] [PubMed] [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(4):241–7. [DOI] [PubMed] [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(6):1578–89. [DOI] [PubMed] [Google Scholar]
  • 74.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(6):549–56. [DOI] [PubMed] [Google Scholar]
  • 75.Romero R, Chaemsaithong P, Korzeniewski SJ, Tarca AL, Bhatti G, Xu Z, et al. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. J Perinat Med. 2016;44(1):5–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Sampson JE, Theve RP, Blatman RN, Shipp TD, Bianchi DW, Ward BE, et al. Fetal origin of amniotic fluid polymorphonuclear leukocytes. Am J Obstet Gynecol. 1997;176(1 Pt 1):77–81. [DOI] [PubMed] [Google Scholar]
  • 77.Macias AE, Wong SW, Sadowsky DW, Luetjens CM, Axthelm MK, Gravett MG, et al. Maternal or fetal origin of rhesus monkey (Macaca mulatta) amniotic fluid leukocytes can be identified by polymerase chain reaction using the zinc finger Y gene. Am J Primatol. 2001;55(3):159–70. [DOI] [PubMed] [Google Scholar]
  • 78.Gomez-Lopez N, Romero R, Xu Y, Leng Y, Garcia-Flores V, Miller D, et al. Are amniotic fluid neutrophils in women with intraamniotic infection and/or inflammation of fetal or maternal origin? Am J Obstet Gynecol. 2017;217(6):693 e1–e16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Maddipati KR, Romero R, Chaiworapongsa T, Chaemsaithong P, Zhou SL, Xu Z, et al. Clinical chorioamnionitis at term: the amniotic fluid fatty acyl lipidome. J Lipid Res. 2016;57(10):1906–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Maddipati KR, Romero R, Chaiworapongsa T, Chaemsaithong P, Zhou SL, Xu Z, et al. Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals up-regulation of leukotriene B4. FASEB J. 2016;30(10):3296–307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Romero R, Chaemsaithong P, Korzeniewski SJ, Kusanovic JP, Docheva N, Martinez-Varea A, et al. Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection? J Perinat Med. 2016;44(1):23–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Gibbs RS. Diagnosis of intra-amniotic infection. Semin Perinatol. 1977;1(1):71–7. [PubMed] [Google Scholar]
  • 83.Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Tarca AL, Bhatti G, et al. Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile. J Perinat Med. 2016;44(1):77–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Benitz WE, Gould JB, Druzin ML. Risk factors for early-onset group B streptococcal sepsis: estimation of odds ratios by critical literature review. Pediatrics. 1999;103(6):e77. [DOI] [PubMed] [Google Scholar]
  • 85.Volante E, Moretti S, Pisani F, Bevilacqua G. Early diagnosis of bacterial infection in the neonate. J Matern Fetal Neonatal Med. 2004;16 Suppl 2:13–6. [DOI] [PubMed] [Google Scholar]
  • 86.Martinelli P, Sarno L, Maruotti GM, Paludetto R. Chorioamnionitis and prematurity: a critical review. J Matern Fetal Neonatal Med. 2012;25 Suppl 4:29–31. [DOI] [PubMed] [Google Scholar]
  • 87.de Sam Lazaro S, Cheng Y, Snowden J, Pereira L, Aziz N, Caughey A. 746. Does the neonatal impact of chorioamnionitis in the setting of PPROM vary depending on degree of prematurity? Am J Obstet Gynecol. 2013;208(1):S314. [Google Scholar]
  • 88.Uyemura A, Ameel B, Caughey A. 425. Outcomes of chorioamnionitis in term pregnancies. Am J Obstet Gynecol. 2014;210(1):S215. [Google Scholar]
  • 89.Garcia-Munoz Rodrigo F, Galan Henriquez GM, Ospina CG. Morbidity and mortality among very-low-birth-weight infants born to mothers with clinical chorioamnionitis. Pediatr Neonatol. 2014;55(5):381–6. [DOI] [PubMed] [Google Scholar]
  • 90.Romero R, Hanaoka S, Mazor M, Athanassiadis AP, Callahan R, Hsu YC, et al. Meconium-stained amniotic fluid: a risk factor for microbial invasion of the amniotic cavity. Am J Obstet Gynecol. 1991;164(3):859–62. [DOI] [PubMed] [Google Scholar]
  • 91.Wen TS, Eriksen NL, Blanco JD, Graham JM, Oshiro BT, Prieto JA. Association of clinical intra-amniotic infection and meconium. Am J Perinatol. 1993;10(6):438–40. [DOI] [PubMed] [Google Scholar]
  • 92.Cleary GM, Wiswell TE. Meconium-stained amniotic fluid and the meconium aspiration syndrome. An update. Pediatr Clin North Am. 1998;45(3):511–29. [DOI] [PubMed] [Google Scholar]
  • 93.Romero R, Yoon BH, Chaemsaithong P, Cortez J, Park CW, Gonzalez R, et al. Bacteria and endotoxin in meconium-stained amniotic fluid at term: could intra-amniotic infection cause meconium passage? J Matern Fetal Neonatal Med. 2014;27(8):775–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Romero R, Yoon BH, Chaemsaithong P, Cortez J, Park CW, Gonzalez R, et al. Secreted phospholipase A2 is increased in meconium-stained amniotic fluid of term gestations: potential implications for the genesis of meconium aspiration syndrome. J Matern Fetal Neonatal Med. 2014;27(10):975–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Adamson SJ, Alessandri LM, Badawi N, Burton PR, Pemberton PJ, Stanley F. Predictors of neonatal encephalopathy in full-term infants. BMJ. 1995;311(7005):598–602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Willoughby RE Jr., Nelson KB. Chorioamnionitis and brain injury. Clin Perinatol. 2002;29(4):603–21. [DOI] [PubMed] [Google Scholar]
  • 97.Chorioamnionitis Cooke R., maternal fever, and neonatal encephalopathy. Dev Med Child Neurol. 2008;50(1):9. [DOI] [PubMed] [Google Scholar]
  • 98.Versland LB, Sommerfelt K, Elgen I. Maternal signs of chorioamnionitis: persistent cognitive impairment in low-birthweight children. Acta Paediatr. 2006;95(2):231–5. [DOI] [PubMed] [Google Scholar]
  • 99.Burd I, Brown A, Gonzalez JM, Chai J, Elovitz MA. A mouse model of term chorioamnionitis: unraveling causes of adverse neurological outcomes. Reprod Sci 2011;18(9):900–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.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 Perinat Med. 2014;42(6):731–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Pappas A, Kendrick DE, Shankaran S, Stoll BJ, Bell EF, Laptook AR, et al. Chorioamnionitis and early childhood outcomes among extremely low-gestational-age neonates. JAMA Pediatr. 2014;168(2):137–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Eastman NJ, Deleon M. The etiology of cerebral palsy. Am J Obstet Gynecol. 1955;69(5):950–61. [DOI] [PubMed] [Google Scholar]
  • 103.Nelson KB, Willoughby RE. Infection, inflammation and the risk of cerebral palsy. Curr Opin Neurol. 2000;13(2):133–9. [DOI] [PubMed] [Google Scholar]
  • 104.Shatrov JG, Birch SC, Lam LT, Quinlivan JA, McIntyre S, Mendz GL. Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol. 2010;116(2 Pt 1):387–92. [DOI] [PubMed] [Google Scholar]
  • 105.Mendez-Figueroa H, Abramovici A, O’Neil AE, Dahlke J, Pedroza C, Chauhan S. 647. Chorioamnionitis without and with neonatal sepsis: newborn and infant outcomes. Am J Obstet Gynecol. 2015;212(1):S318–19. [Google Scholar]
  • 106.Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Tarca AL, Bhatti G, et al. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response. J Perinat Med. 2016;44(1):53–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Benirschke K, Clifford SH. Intrauterine bacterial infection of the newborn infant: frozen sections of the cord as an aid to early detection. J Pediatr. 1959;54(1):11–8. [DOI] [PubMed] [Google Scholar]
  • 108.Olding L Value of placentitis as a sign of intrauterine infection in human subjects. Acta Pathol Microbiol Scand A. 1970;78(3):256–64. [DOI] [PubMed] [Google Scholar]
  • 109.Zhang JM, Kraus FT, Aquino TI. Chorioamnionitis: a comparative histologic, bacteriologic, and clinical study. Int J Gynecol Pathol. 1985;4(1):1–10. [PubMed] [Google Scholar]
  • 110.Svensson L, Ingemarsson I, Mardh PA. Chorioamnionitis and the isolation of microorganisms from the placenta. Obstet Gynecol. 1986;67(3):403–9. [PubMed] [Google Scholar]
  • 111.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(15):972–8. [DOI] [PubMed] [Google Scholar]
  • 112.Smulian JC, Shen-Schwarz S, Vintzileos AM, Lake MF, Ananth CV. Clinical chorioamnionitis and histologic placental inflammation. Obstet Gynecol. 1999;94(6):1000–5. [DOI] [PubMed] [Google Scholar]
  • 113.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(1):18–25. [DOI] [PubMed] [Google Scholar]
  • 114.Rhone SA, Magee F, Remple V, Money D. The association of placental abnormalities with maternal and neonatal clinical findings: a retrospective cohort study. J Obstet Gynaecol Can. 2003;25(2):123–8. [DOI] [PubMed] [Google Scholar]
  • 115.Redline RW, Heller D, Keating S, Kingdom J. Placental diagnostic criteria and clinical correlation--a workshop report. Placenta. 2005;26 Suppl A:S114–7. [DOI] [PubMed] [Google Scholar]
  • 116.Redline RW. Inflammatory responses in the placenta and umbilical cord. Semin Fetal Neonatal Med. 2006;11(5):296–301. [DOI] [PubMed] [Google Scholar]
  • 117.Seong HS, Lee SE, Kang JH, Romero R, Yoon BH. The frequency of microbial invasion of the amniotic cavity and histologic chorioamnionitis in women at term with intact membranes in the presence or absence of labor. Am J Obstet Gynecol. 2008;199(4):375 e1–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Kim MJ, Romero R, Gervasi MT, Kim JS, Yoo W, Lee DC, et al. Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection. Lab Invest. 2009;89(8):924–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.Park CW, Moon KC, Park JS, Jun JK, Romero R, Yoon BH. 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(1):56–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120.Roberts DJ, Celi AC, Riley LE, Onderdonk AB, Boyd TK, Johnson LC, et al. Acute histologic chorioamnionitis at term: nearly always noninfectious. PLoS One. 2012;7(3):e31819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Park CW, Yoon BH, Kim SM, Park JS, Jun JK. Which is more important for the intensity of intra-amniotic inflammation between total grade or involved anatomical region in preterm gestations with acute histologic chorioamnionitis? Obstet Gynecol Sci 2013;56(4):227–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122.Park CW, Yoon BH, Park JS, Jun JK. A fetal and an intra-amniotic inflammatory response is more severe in preterm labor than in preterm PROM in the context of funisitis: unexpected observation in human gestations. PLoS One. 2013;8(5):e62521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123.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. 2015;28(13):1500–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124.Park CW, Kim SM, Park JS, Jun JK, Yoon BH. Fetal, amniotic and maternal inflammatory responses in early stage of ascending intrauterine infection, inflammation restricted to chorio-decidua, in preterm gestation. J Matern Fetal Neonatal Med. 2014;27(1):98–105. [DOI] [PubMed] [Google Scholar]
  • 125.Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Kusanovic JP, Yoon BH, et al. Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity. J Perinat Med. 2016;44(1):33–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Nien JK, Yoon BH, Espinoza J, Kusanovic JP, Erez O, Soto E, et al. 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(4):1025–30. [DOI] [PubMed] [Google Scholar]
  • 127.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(3):292 e1–5. [DOI] [PubMed] [Google Scholar]
  • 128.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 Perinat Med. 2008;36(6):497–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 129.Park HS, Kim SA. Abstract No. 322: The value of the genedia MMP-8 rapid test for diagnosing intraamniotic infection/inflammation and predicting adverse pregnancy outcomes in women with preterm prematue rupture of membranes. Am J Obstet Gynecol. 2015;212(1):S174. [Google Scholar]
  • 130.Chaemsaithong P, Romero R, Docheva N, Chaiyasit N, Kim YM, Dong Z, et al. A rapid point-of-care test (MMP-8) for the identification of intra-amniotic inflammation and impending preterm delivery Abstract presented at 12th World Congress of Perinatal Medicine, 3rd-6th November, 2015, Madrid, Spain: 2015. [Google Scholar]
  • 131.Chaemsaithong P, Romero R, Chaiyasit N, Docheva N, Korzeniewski SJ, Kim YM, et al. Rapid MMP-8 as a point-of-care test in the identification of intra-amniotic inflammation in patients with preterm PROM Abstract presented at 12th World Congress of Perinatal Medicine, 3rd-6th November, 2015, Madrid, Spain: 2015. [Google Scholar]
  • 132.Chaiyasit N, Chaemsaithong P, Romero R, Docheva N, Dong Z, Kim CJ, et al. A rapid MMP-8 test for the identification of intra-amniotic inflammation/infection in patients with clinical chorioamnionitis at term : a solution at last! Abstract presented at 12th World Congress of Perinatal Medicine, 3rd-6th November, 2015, Madrid, Spain: 2015. [Google Scholar]
  • 133.Kim SM, Romero R, Lee J, Chaemsaithong P, Lee MW, Chaiyasit N, et al. About one-half of early spontaneous preterm deliveries can be identified by a rapid matrix metalloproteinase-8 (MMP-8) bedside test at the time of mid-trimester genetic amniocentesis. J Matern Fetal Neonatal Med. 2016;29(15):2414–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 134.Chaiyasit N, Romero R, Chaemsaithong P, Docheva N, Bhatti G, Kusanovic JP, et al. Clinical chorioamnionitis at term VIII: a rapid MMP-8 test for the identification of intra-amniotic inflammation. J Perinat Med. 2017;45(5):539–50. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES