Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance
2015; Elsevier BV; Volume: 213; Issue: 4 Linguagem: Inglês
10.1016/j.ajog.2015.08.040
ISSN1097-6868
AutoresChong Jai Kim, Roberto Romero, Piya Chaemsaithong, Noppadol Chaiyasit, Bo Hyun Yoon, Yeon Mee Kim,
Tópico(s)Neonatal and Maternal Infections
ResumoAcute inflammatory lesions of the placenta consist of diffuse infiltration of neutrophils at different sites in the organ. These lesions include acute chorioamnionitis, funisitis, and chorionic vasculitis and represent a host response (maternal or fetal) to a chemotactic gradient in the amniotic cavity. While acute chorioamnionitis is evidence of a maternal host response, funisitis and chorionic vasculitis represent fetal inflammatory responses. Intraamniotic infection generally has been considered to be the cause of acute chorioamnionitis and funisitis; however, recent evidence indicates that “sterile” intraamniotic inflammation, which occurs in the absence of demonstrable microorganisms induced by “danger signals,” is frequently associated with these lesions. In the context of intraamniotic infection, chemokines (such as interleukin-8 and granulocyte chemotactic protein) establish a gradient that favors the migration of neutrophils from the maternal or fetal circulation into the chorioamniotic membranes or umbilical cord, respectively. Danger signals that are released during the course of cellular stress or cell death can also induce the release of neutrophil chemokines. The prevalence of chorioamnionitis is a function of gestational age at birth, and present in 3–5% of term placentas and in 94% of pacentas delivered at 21-24 weeks of gestation. The frequency is higher in patients with spontaneous labor, preterm labor, clinical chorioamnionitis (preterm or term), or ruptured membranes. Funisitis and chorionic vasculitis are the hallmarks of the fetal inflammatory response syndrome, a condition characterized by an elevation in the fetal plasma concentration of interleukin-6, and associated with the impending onset of preterm labor, a higher rate of neonatal morbidity (after adjustment for gestational age), and multiorgan fetal involvement. This syndrome is the counterpart of the systemic inflammatory response syndrome in adults: a risk factor for short- and long-term complications (ie, sterile inflammation in fetuses, neonatal sepsis, bronchopulmonary dysplasia, periventricular leukomalacia, and cerebral palsy). This article reviews the definition, pathogenesis, grading and staging, and clinical significance of the most common lesions in placental disease. Illustrations of the lesions and diagrams of the mechanisms of disease are provided. Acute inflammatory lesions of the placenta consist of diffuse infiltration of neutrophils at different sites in the organ. These lesions include acute chorioamnionitis, funisitis, and chorionic vasculitis and represent a host response (maternal or fetal) to a chemotactic gradient in the amniotic cavity. While acute chorioamnionitis is evidence of a maternal host response, funisitis and chorionic vasculitis represent fetal inflammatory responses. Intraamniotic infection generally has been considered to be the cause of acute chorioamnionitis and funisitis; however, recent evidence indicates that “sterile” intraamniotic inflammation, which occurs in the absence of demonstrable microorganisms induced by “danger signals,” is frequently associated with these lesions. In the context of intraamniotic infection, chemokines (such as interleukin-8 and granulocyte chemotactic protein) establish a gradient that favors the migration of neutrophils from the maternal or fetal circulation into the chorioamniotic membranes or umbilical cord, respectively. Danger signals that are released during the course of cellular stress or cell death can also induce the release of neutrophil chemokines. The prevalence of chorioamnionitis is a function of gestational age at birth, and present in 3–5% of term placentas and in 94% of pacentas delivered at 21-24 weeks of gestation. The frequency is higher in patients with spontaneous labor, preterm labor, clinical chorioamnionitis (preterm or term), or ruptured membranes. Funisitis and chorionic vasculitis are the hallmarks of the fetal inflammatory response syndrome, a condition characterized by an elevation in the fetal plasma concentration of interleukin-6, and associated with the impending onset of preterm labor, a higher rate of neonatal morbidity (after adjustment for gestational age), and multiorgan fetal involvement. This syndrome is the counterpart of the systemic inflammatory response syndrome in adults: a risk factor for short- and long-term complications (ie, sterile inflammation in fetuses, neonatal sepsis, bronchopulmonary dysplasia, periventricular leukomalacia, and cerebral palsy). This article reviews the definition, pathogenesis, grading and staging, and clinical significance of the most common lesions in placental disease. Illustrations of the lesions and diagrams of the mechanisms of disease are provided. Acute chorioamnionitis is the most frequent diagnosis in placental pathology reports and is generally considered to represent the presence of intraamniotic infection or “amniotic fluid infection syndrome.”1Blanc W.A. Amniotic infection syndrome; pathogenesis, morphology, and significance in circumnatal mortality.Clin Obstet Gynecol. 1959; 2: 705-734Crossref PubMed Google Scholar, 2Russell P. Inflammatory lesions of the human placenta: clinical significance of acute chorioamnionitis.Am J Diagn Gynecol Obstet. 1979; 2: 127-137Google Scholar, 3Blanc W.A. Pathology of the placenta and cord in ascending and in haematogenous infection.Ciba Found Symp. 1979; 77: 17-38PubMed Google Scholar, 4Hillier S.L. Martius J. Krohn M. Kiviat N. Holmes K.K. Eschenbach D.A. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity.N Engl J Med. 1988; 319: 972-978Crossref PubMed Google Scholar, 5Benirschke K, Burton GJ, Baergen RN, eds. Infectious diseases. In: Pathology of the human placenta, 6th ed. Berlin: Springer; 2012:557-656.Google Scholar, 6Fox H, Sebire NJ. Infections and inflammatory lesions of the placenta. In: Pathology of the placenta, 3d ed. China: Elsevier; 2007:303-54.Google Scholar, 7Romero R. Salafia C.M. 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Placental inflammation.Semin Neonatol. 2004; 9: 265-274Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Yet, acute chorioamnionitis can occur in the setting of “sterile intraamniotic inflammation” in the absence of demonstrable microorganisms and is induced by “danger signals” released under conditions of cellular stress, injury, or death.11Romero R. Miranda J. Chaiworapongsa T. et al.A novel molecular microbiologic technique for the rapid diagnosis of microbial invasion of the amniotic cavity and intra-amniotic infection in preterm labor with intact membranes.Am J Reprod Immunol. 2014; 71: 330-358Crossref PubMed Scopus (13) Google Scholar, 12Romero R. Miranda J. Chaiworapongsa T. et al.Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes.Am J Reprod Immunol. 2014; 72: 458-474Crossref PubMed Scopus (12) Google Scholar, 13Romero R. Miranda J. Chaemsaithong P. et al.Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes.J Matern Fetal Neonatal Med. 2014; Sept 29: 1-16Google Scholar, 14Romero R. Miranda J. Chaiworapongsa T. et al.Sterile intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix: prevalence and clinical significance.J Matern Fetal Neonatal Med. 2014; Sept 24: 1-17Google Scholar, 15Romero R. Miranda J. Kusanovic J.P. et al.Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques.J Perinat Med. 2015; 43: 19-36Crossref PubMed Google Scholar Therefore, acute chorioamnionitis is evidence of intraamniotic inflammation and not necessarily intraamniotic infection. The characteristic morphologic feature of acute chorioamnionitis is diffuse infiltration of neutrophils into the chorioamniotic membranes.9Redline R.W. Faye-Petersen O. Heller D. Qureshi F. Savell V. Vogler C. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.Pediatr Dev Pathol. 2003; 6: 435-448Crossref PubMed Scopus (229) Google Scholar Since obstetricians use the term chorioamnionitis to refer to a clinical syndrome (the combination of fever, maternal or fetal tachycardia, uterine tenderness, foul-smelling amniotic fluid) frequently associated with “acute chorioamnionitis” on microscopic examination of the placenta, the word histologic has been introduced into the medical lexicon to specify the differences between the clinical syndrome, clinical chorioamnionitis, and the pathologic diagnosis of acute chorioamnionitis. These terms are not synonymous, and confusion occurs when they are used interchangeably. Herein, the term acute chorioamnionitis will refer to “acute histologic chorioamnionitis” given the focus of this article is the pathologic condition rather than the clinical syndrome. We will review the acute inflammatory responses deployed by the mother and fetus in response to inflammatory stimuli within the amniotic cavity. The placenta is composed of three major structures: the placental disc, the chorioamniotic membranes, and the umbilical cord (Figure 1). Acute inflammatory lesions of the placenta are characterized by the infiltration of neutrophils in any of these structures.9Redline R.W. Faye-Petersen O. Heller D. Qureshi F. Savell V. Vogler C. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.Pediatr Dev Pathol. 2003; 6: 435-448Crossref PubMed Scopus (229) Google Scholar Specifically, when the inflammatory process affects the chorion and amnion, this is termed acute chorioamnionitis9Redline R.W. Faye-Petersen O. Heller D. Qureshi F. Savell V. Vogler C. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.Pediatr Dev Pathol. 2003; 6: 435-448Crossref PubMed Scopus (229) Google Scholar; if it affects the villous tree, this represents acute villitis.9Redline R.W. Faye-Petersen O. Heller D. Qureshi F. Savell V. Vogler C. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.Pediatr Dev Pathol. 2003; 6: 435-448Crossref PubMed Scopus (229) Google Scholar If the inflammatory process involves the umbilical cord (umbilical vein, umbilical artery, and the Wharton’s jelly), this is referred to as acute funisitis, the histologic counterpart of the fetal inflammatory response syndrome (FIRS; Figure 1).16Pacora P. Chaiworapongsa T. Maymon E. et al.Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome.J Matern Fetal Neonatal Med. 2002; 11: 18-25Crossref PubMed Google Scholar Table 1 shows the frequency of acute chorioamnionitis as a function of gestational age at delivery in a study of 7505 placentas from singleton pregnancies that were delivered after 20 weeks of gestation.2Russell P. Inflammatory lesions of the human placenta: clinical significance of acute chorioamnionitis.Am J Diagn Gynecol Obstet. 1979; 2: 127-137Google Scholar It is noteworthy that the frequency of acute chorioamnionitis in patients who delivered between 21-24 weeks of gestation was 94.4% (17/18 patients).2Russell P. Inflammatory lesions of the human placenta: clinical significance of acute chorioamnionitis.Am J Diagn Gynecol Obstet. 1979; 2: 127-137Google Scholar This is consistent with multiple studies subsequently reported by our group17Lee S.M. Park J.W. Kim B.J. 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: e79941Crossref PubMed Scopus (3) Google Scholar and others18Srinivas S.K. Ma Y. Sammel M.D. et al.Placental inflammation and viral infection are implicated in second trimester loss.Am J Obstet Gynecol. 2006; 195: 797-802Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 19Van Hoeven K.H. Anyaegbunam A. Hochster H. et al.Clinical significance of increasing histologic severity of acute inflammation in the fetal membranes and umbilical cord.Pediatr Pathol Lab Med. 1996; 16: 731-744Crossref PubMed Scopus (69) Google Scholar, 20Srinivas S.K. Ernst L.M. Edlow A.G. 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Acute chorioamnionitis is observed more frequently in the placentas of women who delivered after spontaneous labor at term than in the absence of labor21Seong H.S. Lee S.E. Kang J.H. Romero R. Yoon B.H. 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: 375.e1-375.e5Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 22Park H.S. Romero R. Lee S.M. Park C.W. Jun J.K. Yoon B.H. Histologic chorioamnionitis is more common after spontaneous labor than after induced labor at term.Placenta. 2010; 31: 792-795Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar (early labor with cervical dilation of <4 cm, 11.6% [10/86] vs no labor, 4.4% [34/775]; P < .01).22Park H.S. Romero R. Lee S.M. Park C.W. Jun J.K. Yoon B.H. Histologic chorioamnionitis is more common after spontaneous labor than after induced labor at term.Placenta. 2010; 31: 792-795Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Moreover, the longer the duration of labor and cervical dilation of >4 cm, the higher the frequency of acute chorioamnionitis (active labor, 30.4% [7/23] vs early labor, 11.6% [10/86]; P < .05).23Lee S.M. Lee K.A. Kim S.M. Park C.W. Yoon B.H. The risk of intra-amniotic infection, inflammation and histologic chorioamnionitis in term pregnant women with intact membranes and labor.Placenta. 2011; 32: 516-521Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar This observation has two possible explanations: first, the frequency of microbial invasion of the amniotic cavity is higher in women in spontaneous labor at term with intact membranes than in those without labor (17% vs 1.5%).24Romero R. Nores J. Mazor M. et al.Microbial invasion of the amniotic cavity during term labor: prevalence and clinical significance.J Reprod Med. 1993; 38: 543-548PubMed Google Scholar Alternatively, labor per se is an inflammatory state, as demonstrated by the study of the gene expression profile of the chorioamniotic membranes.25Haddad R. Tromp G. Kuivaniemi H. et al.Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature.Am J Obstet Gynecol. 2006; 195: 394.e1-394.e24Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The chorioamniotic membranes obtained from women who experienced labor (even in the absence of any detectable acute chorioamnionitis) overexpressed neutrophil-specific chemokines (chemokine [C-X-C motif] ligand 1 [CXCL1], CXCL2, and interleukin [IL]-8) and monocyte-specific chemokines (C-C motif ligand 3 [CCL3], macrophage inflammatory protein [MIP]-1α, CCL4 [MIP-1β], and CCL20 [MIP-3α]; Figure 2).25Haddad R. Tromp G. Kuivaniemi H. et al.Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature.Am J Obstet Gynecol. 2006; 195: 394.e1-394.e24Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This is consistent with reports that the amniotic fluid concentrations of chemokines such as IL-8,26Romero 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: 813-820Abstract Full Text PDF PubMed Scopus (207) Google Scholar monocyte chemotactic protein (MCP)-1,27Esplin M.S. Romero R. Chaiworapongsa T. et al.Amniotic fluid levels of immunoreactive monocyte chemotactic protein-1 increase during term parturition.J Matern Fetal Neonatal Med. 2003; 14: 51-56Crossref PubMed Google Scholar growth-regulated oncogene (GRO)-α,28Cohen J. Ghezzi F. 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Classics revisited: comparative morphogenesis of the fetal membranes and accessory uterine structures.Placenta. 1991; 12: 1-5Abstract Full Text PDF PubMed Google Scholar The decidua is of maternal origin; the chorioamniotic membranes and villous tree are of fetal origin. Thus, the precise origin of the inflammatory process (maternal vs fetal) can be determined by whether infiltrating neutrophils are of maternal or fetal origin. Neutrophils are not normally present in the chorioamniotic membranes and migrate from the decidua into the membranes in cases of acute chorioamnionitis (Figure 3).36Mcnamara M.F. Wallis T. Qureshi F. Jacques S.M. Gonik B. Determining the maternal and fetal cellular immunologic contributions in preterm deliveries with clinical or subclinical chorioamnionitis.Infect Dis Obstet Gynecol. 1997; 5: 273-279Crossref PubMed Google Scholar, 37Steel J.H. O’Donoghue K. Kennea N.L. Sullivan M.H. Edwards A.D. Maternal origin of inflammatory leukocytes in preterm fetal membranes, shown by fluorescence in situ hybridisation.Placenta. 2005; 26: 672-677Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar On the other hand, maternal neutrophils normally circulate in the intervillous space (Figure 1). When there is a chemotactic gradient, neutrophils migrate toward the amniotic cavity, neutrophils in the intervillous space mobilize into the chorionic plate of the placenta, which is normally devoid of these cells. Thus, inflammation of the chorionic plate, except chorionic vasculitis, is also a maternal inflammatory response. Neutrophils in acute chorioamnionitis are of maternal origin. Fluorescence in situ hybridization (FISH) with probes for X and Y chromosomes performed in cytospin slides of placentas from male fetuses showed that approximately 90% of neutrophils derived from the membranes were of maternal origin.36Mcnamara M.F. Wallis T. Qureshi F. Jacques S.M. Gonik B. Determining the maternal and fetal cellular immunologic contributions in preterm deliveries with clinical or subclinical chorioamnionitis.Infect Dis Obstet Gynecol. 1997; 5: 273-279Crossref PubMed Google Scholar Subsequently, FISH combined with immunohistochemistry for CD45 (to identify leukocytes) demonstrated that CD45 positive cells in the chorionic membranes were of maternal origin.37Steel J.H. O’Donoghue K. Kennea N.L. Sullivan M.H. Edwards A.D. Maternal origin of inflammatory leukocytes in preterm fetal membranes, shown by fluorescence in situ hybridisation.Placenta. 2005; 26: 672-677Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar In contrast, inflammation of the umbilical cord and the chorionic vessels on the chorionic plate of the placenta is of fetal origin.38Lee S.D. Kim M.R. Hwang P.G. Shim S.S. Yoon B.H. Kim C.J. Chorionic plate vessels as an origin of amniotic fluid neutrophils.Pathol Int. 2004; 54: 516-522Crossref PubMed Scopus (16) Google Scholar This conclusion is largely based on the understanding of the anatomy of these tissues, because neutrophils invading the walls of the umbilical vein and arteries must migrate from the fetal circulation to enter the walls of these vessels (Figure 4). Insofar as the origin of white blood cells in the amniotic fluid in cases of intraamniotic inflammation, the only study reported to date for cases of intrauterine infection with intact membranes suggested that 99% of neutrophils are of fetal origin.39Sampson J.E. Theve R.P. Blatman R.N. et al.Fetal origin of amniotic fluid polymorphonuclear leukocytes.Am J Obstet Gynecol. 1997; 176: 77-81Abstract Full Text Full Text PDF PubMed Google Scholar Inflammation of the umbilical vessels begins in the vein (phlebitis) and is followed by involvement of the arteries (arteritis). Infiltration of neutrophilis into the Wharton's jelly is common in acute funisitis.40Kim C.J. Yoon B.H. Kim M. Park J.O. Cho S.Y. Chi J.G. Histo-topographic distribution of acute inflammation of the human umbilical cord.Pathol Int. 2001; 51: 861-865Crossref PubMed Scopus (11) Google Scholar The molecular pathogenesis of funisitis has been studied with the use of microarray analysis followed by quantitative real-time polymerase chain reaction (PCR) obtained from micro-dissected umbilical arteries and veins. The expression of IL-8 messenger RNA (mRNA; the prototypic neutrophil chemokine) is higher in the umbilical vein than in the umbilical artery.40Kim C.J. Yoon B.H. Kim M. Park J.O. Cho S.Y. Chi J.G. Histo-topographic distribution of acute inflammation of the human umbilical cord.Pathol Int. 2001; 51: 861-865Crossref PubMed Scopus (11) Google Scholar Moreover, there are substantial differences in the genes expressed by the walls of the umbilical artery and vein. 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Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.Pediatr Dev Pathol. 2003; 6: 435-448Crossref PubMed Scopus (229) Google Scholar classified acute inflammatory lesions of the placenta into two categories: maternal inflammatory response and fetal inflammatory response. The term stage refers to the progression of the process based on the anatomical regions infiltrated by neutrophils; the term grade refers to the intensity of the acute inflammatory process at a particul
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