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Home , Chorioamnionitis, Meconium, Placentitis

SEMMELWEIS 200 SEMMELWEIS 200

Roberto Romero1-4, Nardhy Gomez-Lopez1,5,6, Juan Pedro Kusanovic1,7, Percy Pacora1,5, Bogdan Panaitescu1,5, Offer Erez1,5, Bo H. Yoon1,8 Clinical at term: New insights into the etiology, microbiology, and the fetal, maternal and amniotic cavity inflammatory responses

Roberto Romero, M.D., D.Med.Sci.

1 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, Bethesda, Maryland, and Detroit, Michigan, USA 2 Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA 3 Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA 4 Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA 5 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA 6 Department of Immunology, Microbiology and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan, USA 7 Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile 8 Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea

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Abstract

Clinical chorioamnionitis is the most common 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 and . The condition is often -as sociated with fetal tachycardia and a foul smelling . Recent studies in which 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 without demonstrable microorganisms or a maternal systemic inflammatory response (fever) in the absence of in- tra-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 . 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 infiltra- tion of and monocytes. Both cell types are activated in the presence of infection and can produce inflammatory cytokines. The white 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 inflam- matory 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 are the most common organisms found in the amniotic fluid. The emer- gent 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

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Introduction is 25%, while it is 70% when the membranes are ruptured [38]. Clinical chorioamnionitis is the most common infection-re- The relative contribution of the different entities presenting as lated diagnosis made in labor and delivery units worldwide clinical chorioamnionitis are illustrated in Figure 1. A small [1-4]. The standard clinical definition refers to the presence of group of patients has microbial invasion of the amniotic cavity maternal fever associated with clinical signs (i.e. foul smelling without inflammation. discharge, uterine tenderness, maternal and fetal tachycardia) The mechanism responsible for sterile intra-amniotic inflam- as well as laboratory abnormalities (i.e. leukocytosis) [5, 6]. mation have not been defined [38, 40-42] and could represent These signs are thought to be manifestations of both local inflammation induced by danger signals (or alarmins) [43-47], and systemic maternal-fetal inflammatory processes initiat- or alternatively, which have escaped detection with ed in response to microbial invasion of the amniotic cavity current cultivation and molecular microbiologic techniques (MIAC) [7-13]. [48-54]. For example, it is possible that deep DNA and RNA Clinical chorioamnionitis at term is associated with a 2- to sequencing may identify organisms which are present below 4-fold increase in [14], wound infection [14], the level of detection of culture and 16S PCR; however, this septic pelvic thrombophlebitis [3, 14], pelvic [3, 14], question remains to be addressed. maternal admission to the intensive care unit [3, 15], and postpartum hemorrhage [3, 16]. Importantly, neonates born to What are the microorganisms found in the amniotic cavity mothers with clinical signs of chorioamnionitis have a high risk in clinical chorioamnionitis at term? of neonatal mortality [1], short- and long-term complications The original study describing the microbiology of clinical such as neonatal [17-19], aspiration syndrome chorioamnionitis at term was performed using cultivation [20, 21], [22, 23], and neurodevelopmental disorders techniques of amniotic fluid obtained with transcervical catheters including [24-35]. placed in the amniotic cavity [5]. This approach may not have Although this condition is common, affecting thousands of provided an accurate description of the microbiology of clinical women daily and has been known for centuries as a precursor chorioamnionitis, since the placement of a transcervical catheter of puerperal (or childbed) fever [36, 37], new information has is frequently associated with contamination of the vaginal emerged which has characterized, for the first time, the mi- ecosystem. Conventional cultivation techniques cannot identify crobiology and inflammatory responses in the mother, , the entire microbial diversity of an ecological niche, because the and amniotic cavity. This article will review new insight gained conditions required for the growth of microorganisms in vitro from studies published in the last three years. are not known, and some organisms are, therefore, considered to be non-culturable [55]. By using both cultivation and molecular The syndrome of clinical chorioamnionitis: evidence for biology techniques (broad-range polymerase chain reaction microbiologic and inflammatory heterogeneity coupled with electrospray ionization mass spectrometry or PCR/ Among patients with clinical chorioamnionitis, we have iden­ti­ ESI-MS), it is possible to gain a more complete understanding fied three distinct groups [38]: 1) patients who have intra-amni- of the microbiology of the amniotic cavity [56]. otic infection, defined by the presence of an elevated concentra- In a study of 46 women with clinical chorioamnionitis at tion of interleukin (IL)-6 [a marker of inflammation [39]] and term, amniotic fluid was obtained by transabdominal amniocen- the presence of microorganisms; 2) patients who have sterile tesis or at the time of Cesarean delivery under sterile conditions intra-amniotic inflammation, in which no organisms can be [38]. We found that conventional culture identified in detected using standard cultivation techniques or 16S RNA the amniotic fluid from 46% (21/46) of the participants, while broad assays, although they have an elevated amniotic fluid IL-6; PCR/ESI-MS was positive for microorganisms in 59% (27/46) and 3) patients who have neither intra-amniotic inflammation of the patients. The combination of these two approaches re- or microorganisms in the amniotic cavity. The frequency with sulted in the detection of amniotic fluid microorganisms in which these conditions are present varies according to whether 61% (28/46) of women with clinical chorioamnionitis at term the membranes are ruptured at the time of amniocentesis to [38]. Molecular microbiologic techniques identified more mi- assess the microbial state of the amniotic cavity [38]. When the croorganisms than cultivation; yet, some bacterial taxa were membranes are intact, the frequency of intra-amniotic infection preferentially identified by each technique [38].

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Figure 1 Figure 2

No inflammation/infection Sterile intra-amniotic inflammation

Microbial invasion of the amniotic cavity Intra-amniotic infection (without inflammation)

100%

90% 16.7%

80% 37.5%

70%

60%

50% 25,0% 70.0% 40%

6.2% 30%

20% 31.3% 10% 6.6% 6.7% 0% Intact membranes (n=16) (n=30)

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 diag- nosed in 70% (21/30) of the cases with rupture of membranes, and in 25% (4/16) of patients with intact membranes.

Ureaplasma spp. and Gardnerella vaginalis are the most commonly identified microorganisms by cultivation and PCR/ ESI-MS, respectively [38]. This has clinical implications, because Histological examination of amniotic fluid neutrophils and monocytes in women with clinical chorioamnionitis. A) Hematoxylin & Eosin staining the antibiotics used to treat patients with clinical chorioam- shows the typical morphology of neutrophils (N, green arrow) and mono- nionitis or puerperal endometritis do not include agents that cytes (M, red arrow) in the amniotic fluid of women with clinical chorio- eradicate infections due to Ureaplasma spp. amnionitis. Magnification 400X. Scale bars: 50μm. B) Immunofluores- cence of neutrophils and monocytes in the amniotic fluid of women with The cellular intra-amniotic inflammatory response: neu- clinical chorioamnionitis. Neutrophils (CD15+ cells) are green, monocytes­ (CD14+ cells) are red, and nuclei are blue (DAPI). Magnification 400X. trophils and monocytes in the amniotic fluid An inflammatory response is characterized by cellular and soluble components. The typical changes in the soluble me­ are significantly higher in patients with microorganisms found ditators are those that occur in the inflammatory cytokine in the amniotic fluid than in those without detectable micro- network. However, cellular mediators are prominent, and mainly organisms [57]. In addition, the profile of cytokine expression involve the innate immune response. differs between monocytes and neutrophils; while neutrophils Using flow cytometry, we found that neutrophils are the predominantly produce tumor necrosis factor (TNF)-α and most common leukocyte subset in the amniotic fluid, followed macrophage inflammatory protein (MIP)-1β, monocytes ex- by monocytes; other white blood cells (such as lymphocytes press higher levels of IL-1β and IL-1α [57]. These cytokines are and natural killer cells) are scarce in the amniotic fluid [57] implicated in both the process of parturition and host response (Figure 2). The absolute counts of neutrophils and monocytes against intra-amniotic infection [58-75].

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Figure 3 DNA fingerprinting of amniotic fluid neutrophils

A

Amniotic 16 7 8 10 12 11 14 9 13 10 12 9 X 16 18 14 11 19 31 31.2 Fluid 17 18 8 7 10 24 16 DNA

16 7 8 31 31.2 10 12 11 14 9 13 10 12 9 X 16 18 14 11 19 24 Origin 8 Fetal 17 18 7 10 16 DNA Fetal

7 9 17 18 10 14 10 11 12 13 7 10 9 X 17 18 24 Maternal 15 16 11 14 27 31.2 13 16 6 11 DNA

B

9 12 11 18 19 15 Amniotic 7 8 Fluid 29 30 10 11 X 18.2 14 16 17 11 13 8 9 24 Neutrophil 17 8 12 8 11 DNA Origin

7 9 11 15 8 9 16 19 Fetal 9 10 X 16 17 28 10 13 8 DNA 29 12 11 8 20 24 16 17 11 8 10 Maternal

7 8 9 12 11 15 Maternal 29 30 18 19 DNA 14 11 13 10 11 X 17 16 17 8 12 8 9 18.2 24 8 11

C

Amniotic 16 13 2.2 X 14 8 7 11 11 21 Fluid 29 11 8 10 13 18 11 14 12 16 r igi n Neutrophil 16 10 19 10 6 8 28 31 15 8 12 9 12 10 7 8 10 Y 22 29

O DNA 13

a l

7 8 11 11 8 10 8 10 2.2 13 14 16 28 12 9 13 19 Fetal 13 29 11 DNA 16 18 8 14 X Y 8 21 29 Mater n

X a nd

6 7 16 11 11 8 13 16 10 14

eta l Maternal 7 10 X 12 12 11 21 F 2.2 DNA 29 31 14 10 22 15 18 11 8 10

DNA fingerprinting of purified amniotic fluid neutrophils of fetal (A), maternal (B) or mixed (C) origin, the fetus (), 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'-dimethoxyflu- orescein (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.

Amniotic fluid white blood cells can be of fetal or maternal origin The soluble amniotic fluid inflammatory response: changes Although traditionally considered to be of fetal origin [76, in the cytokine inflammatory network and lipidome 77], neut­rophils in amniotic fluid in cases of infection can be The amniotic fluid concentrations of inflammatory cytokines of maternal, fetal, or mixed (both) origin, as demonstrated by [such as interferon gamma (IFN-γ), TNFα, IL-4, MIP-1β, and studies using DNA fingerprinting [78]. In general, we found that IL-8] are higher in patients with clinical chorioamnionitis at patients with intra-amniotic infection and preterm gestations term than in women with spontaneous labor at term without had neutrophils of fetal origin, while those with intra-amniotic intra-amniotic inflammation [75]. Of interest is that once infection/inflammation at term had predominantly maternal a patient had intra-amniotic inflammation, the changes in neutrophils or a cellular infiltrate of mixed origin (maternal and the amniotic fluid cytokine network are similar in those with fetal) [78]. Figure 3 shows the DNA fingerprinting of amniotic fluid proven infection vs. those with intra-amniotic inflammation neutrophils of fetal, maternal, or mixed (maternal and fetal) origin. without demonstrable microorganisms [75].

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Given that lipids are important mediators of the inflamma- at term without this clinical condition [83]. These findings tory response, we have examined the behavior of bioactive lipids indicate that the absolute concentration of cytokines in the using discovery techniques (i.e. lipidomics) [79]. An elevated maternal plasma cannot be used to identify women who leukotriene B4 (LTB4) was associated with the presence of have bacteria in the amniotic fluid and that the assessment microorganisms in the amniotic cavity [80]. Therefore, lipid of the amniotic fluid is required to identify intra-amniotic mediators can be assessed with mass spectrometry techniques inflammation and/or infection. could have value as biomarkers [80]. Umbilical cord plasma cytokine profile in the context of How well do clinical criteria perform in the identification a systemic maternal inflammatory response of proven intra-amniotic infection? Neonates born to mothers with clinical chorioamnionitis are Only 54% of patients with the diagnosis of clinical chorio­ at risk for sepsis [3, 17-19, 32, 84-89], meconium aspiration amnionitis at term have intra-amniotic inflammation and syndrome [17, 90-94], neonatal encephalopathy [31, 34, 95- detectable bacteria [38]. These findings indicate that only 97], and long-term neurodevelopmental disabilities including half of the women with clinical chorioamnionitis at term cognitive impairment [98-101] and cerebral palsy [27, 28, 30, may benefit from antibiotic administration. Therefore, 34, 35, 86, 102-104], as well as neonatal death [1, 22, 24, 88, we evaluated the diagnostic performance and accuracy of 105]. Such adverse neonatal outcomes may be attributed to clinical signs for the diagnosis of clinical chorioamnionitis the effects of a maternal systemic inflammatory response on using the “gold standard” [a combination of cultivation and the fetus [83] and/or the local inflammatory response in the molecular biology techniques [56]] for the identification of amniotic cavity [38, 75]. intra-amniotic infection [81]. Neonates born to mothers with clinical chorioamnionitis We reported that clinical signs of chorioamnionitis do not at term have higher umbilical cord plasma concentrations of accurately identify patients with intra-amniotic infection [81]. several inflammatory cytokines (IL-6, IL-12p70, IL-16, IL- Maternal and fetal tachycardia, as well as maternal leukocytosis, 13, IL-4, IL-10 and IL-8) compared to those born to mothers have low specificity (5%–30%), whereas foul-smelling amniotic with spontaneous labor at term without this clinical condition fluid and uterine tenderness have poor sensitivity (<15%) for the [106]. Interestingly, neonates born to mothers with clinical diagnosis of intra-amniotic infection [81]. These findings call chorioamnionitis at term without intra-amniotic inflam- for the development of novel approaches to facilitate the rapid mation also have higher concentrations of inflammatory identification of bacteria in the amniotic fluid and reevaluation cytokines (IL-6, IL-12p70, IL-13, IL-4, IL-5, and IL-8) than of the management of clinical chorioamnionitis at term. neonates not exposed to clinical chorioamnionitis, suggesting that maternal fever in the absence of intra-amniotic inflam- The maternal plasma cytokine profile mation leads to a change in the fetal cytokine network [106]. Most of the signs of clinical chorioamnionitis (except for fetal In addition, there are significant and positive correlations tachycardia and foul-smelling amniotic fluid) are thought to between maternal and umbilical cord plasma IL-6 and IL-8 reflect a maternal inflammatory response to microbial invasion concentrations consistent with placental transfer of cytokines of the amniotic cavity [4, 82]. Maternal plasma concentrations [106]. All neonates born to mothers with proven intra-am- of pyrogenic cytokines (IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) niotic infection were diagnosed with fetal inflammatory are higher in patients with clinical chorioamnionitis at response syndrome (FIRS) [106]. term than in those with spontaneous labor at term without clinical chorioamnionitis [83]. However, the maternal plasma Can placental pathology identify the patient with concentrations of cytokines are not significantly different intra-amniotic infection? among the 3 major subgroups of patients with clinical Examination of the , the largest human biopsy, can chorioamnionitis at term [83]. In addition, women with provide information about fetal exposure to intra-amniotic clinical chorioamnionitis at term without intra-amniotic inflammation or infection [10, 11, 13, 24, 26, 33, 107-124]. inflammation have greater maternal plasma concentrations Indeed, inflammation of the umbilical cord or chorionic of pyrogenic cytokines than those with spontaneous labor vessels represents a fetal response and is indicative that

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the fetus was exposed to inflammatory stimuli before birth Conclusions [113]. Therefore, we examined the diagnostic performance A series of systematic studies in patients with clinical chorio­ of placental histologic features of acute inflammation in the amnionitis at term have revealed the following: identification of intra-amniotic infection and FIRS in patients • Clinical chorioamnionitis at term is a heterogeneous with clinical chorioamnionitis at term [125]. Acute histologic condition, and only a fraction of these patients have proven chorioamnionitis and funisitis are indeed associated with the intra-amniotic infection presence of intra-amniotic infection and FIRS [125]. However, • The frequency of infection is higher when the chorioamni- current placental histopathologic methods have limitations in otic membranes are ruptured, rather than intact (70% vs 25%) identifying whether the fetus was exposed to microorganisms • The most common organisms are Ureaplasma spp. and in the amniotic cavity [125]. The available data suggest that Gardnerella vaginalis – this is important because most treat- placental examination is neither sensitive nor specific for ment approaches in clinical obstetrics and neonatology do not the identification of intra-amniotic infection, because acute provide appropriate coverage for genital mycoplasmas histologic chorioamnionitis and funisitis can be observed • The cellular intra-amniotic inflammatory response is when there is intra-amniotic inflammation in the absence of characterized by an influx of neutrophils and monocytes demonstrable microorganisms. • The soluble intra-amniotic inflammatory response is char- acterized by elevated concentrations of the major inflammatory A rapid MMP-8 test for the identification of intra-amniotic cytokines inflammation • The maternal plasma cytokines are elevated in patients A rapid test which utilizes neutrophil collagenase or MMP-8 with clinical chorioamnionitis at term; however, the con- has been made available for the diagnosis of intra-amniotic centrations of these proteins cannot distinguish between inflammation [126-133]. This test in patients with intra- patients who have proven intra-amniotic infection and those amniotic inflammation and clinical chorioamnionitis has with intra-amniotic inflammation without demonstrable the following diagnostic indices, predictive values, and microorganisms likelihood ratios: sensitivity of 82.4% (28/34), specificity • The fetal concentrations of inflammatory cytokines are of 90% (9/10), positive predictive value of 96.6% (28/29), elevated in neonates born to mothers with clinical chorio- negative predictive value of 60% (9/15), positive likelihood amnionitis compared to those without clinical chorioamni- ratio 8.2 (95% CI 1.3–53.2), and negative likelihood ratio onitis at term. There is indirect evidence that elevations in 0.2 (95% CI 0.1–0.4) [134]. neonatal inflammatory concentrations may reflect a systemic In patients with intra-amniotic infection and clinical cho- inflammatory response in the mother, even in the absence rioamnionitis, the rapid MMP-8 test has a sensitivity of 91.7% of intra-amniotic inflammation (this may occur in cases of (22/24), specificity of 65% (13/20), positive predictive value epidural-induced fever) of 75.9% (22/29), negative predictive value of 86.7% (13/15), • Placental pathologic examination to detect acute histologic positive likelihood ratio of 2.6 (95% CI 1.4–4.8), and negative chorioamnionitis, funisitis, or chorionic is neither likelihood ratio of 0.1 (95% CI 0.03–0.5) [134]. specific nor sensitive for the identification of patients with In addition, the rapid MMP-8 test has a significantly higher proven intra-amniotic infection specificity than the ELISA IL-6 test in the identification of • Analysis of amniotic fluid is the only definitive way to intra-amniotic inflammation [66.7% (14/21) vs. 42.9% (9/21); make a diagnosis of intra-amniotic infection in patients with p=0.03] [134]. Importantly, the rapid MMP-8 test has 100% clinical chorioamnionitis at term sensitivity and 100% negative predictive value in the identifi- • Potential biomarkers for intra-amniotic inflammation, cation of neonates affected with FIRS [134]. which can be implemented at the bedside, is an MMP-8 rapid This study showed that a rapid MMP-8 point-of-care test test which detects neutrophil collagenase can be used for the diagnosis of intra-amniotic inflammation • Future studies are required to determine if noninvasive and to identify the mother at risk of delivering a neonate with collection of amniotic fluid with a special device in patients who systemic inflammation among patients with clinical chorio- have ruptured membranes can be of clinical value to diagnose amnionitis at term [134]. intra-amniotic infection/inflammation

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