Expert review
Obstetrics
Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance

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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.

Section snippets

Definition

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.9 Specifically, when the inflammatory process affects the chorion and amnion, this is termed acute chorioamnionitis9; if it affects the villous tree, this represents acute villitis.9 If the inflammatory process involves the umbilical cord

Prevalence of acute chorioamnionitis

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.2 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).2 This is consistent with multiple studies subsequently reported by our group17 and others18, 19, 20 and emphasizes the role of acute inflammation

Pathology

The placenta is considered to be the apposition or fusion of the fetal membranes/placental disc to the uterine mucosa (decidua) for physiologic exchange.35 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

Histologic grading and staging of acute chorioamnionitis

Several grading and staging systems have been proposed to describe the severity of acute chorioamnionitis.9, 19, 42, 43, 44, 45, 46, 47 The most widely used system is that recommended by the Amniotic Fluid Infection Nosology Committee of the Perinatal Section of the Society for Pediatric Pathology and reported by Redline et al9 in 2003. Although that article refers to the term amniotic fluid infection syndrome, it is now clear that these lesions do not always represent intraamniotic infection.

Pathways of microbial invasion of the amniotic cavity

Under normal conditions, the amniotic cavity is sterile for microorganisms with the use of cultivation51 and molecular microbiologic techniques, based on the detection of the 16S ribosomal RNA (rRNA) gene (present in all bacteria, but not in mammalian cells). Four pathways have been proposed whereby microorganisms reach the amniotic cavity52, 53, 54, 55, 56: (1) ascending from the lower genital tract,1, 7, 57, 58 (2) hematogenous,59, 60, 61 (3) accidental introduction at the time of

Inflammatory response to microbial invasion of the amniotic cavity

Microbial invasion of the amniotic cavity induces a robust local inflammatory response, and this is accompanied by a dramatic increase in the concentrations of proinflammatory cytokines such as IL-1,31, 32, 34, 106, 186, 187, 188, 189, 190, 191, 192 tumor necrosis factor–α (TNF-α),188, 189, 190, 193, 194, 195, 196 IL-6,12, 34, 94, 129, 188, 197, 198, 199, 200, 201, 202, 203, 204, 205 IL-8 (CXCL8),26, 187, 188, 189, 196, 199, 200, 202, 206, 207, 208, 209, 210, 211 and CXCL6,212 as well as a

Pathogenesis: chemotactic signals in the amniotic cavity are responsible for acute chorioamnionitis and funisitis

Chemotactic stimuli are required for neutrophils to migrate into tissue (Figure 11).215, 216 Such stimuli are provided by neutrophil chemokines (eg, IL-8, also known as neutrophil-activating peptide, and CXCL6, a granulocyte chemotactic protein).215, 216, 296 Intraamniotic inflammation due to microorganisms or “danger signals” can result in the production of the following chemokines: IL-826, 187, 188, 189, 196, 199, 200, 202, 206, 207, 208, 209, 210, macrophage inhibitory cytokine,297, 298 MCP,

Acute chorioamnionitis should not be equated with intraamniotic infection

Acute inflammatory lesions of the placenta have been considered to reflect the presence of amniotic fluid infection.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 149, 320, 321, 322 In 1987, Dong et al323 reported that acute chorioamnionitis was present in 97% of patients (32/33) with intraamniotic infection, defined as the presence of microorganisms detected using cultivation techniques. However, the amniotic fluid samples in that study were obtained by transcervical collection.323 Interestingly, acute

The host response to microbial invasion of the amniotic cavity is stronger in preterm than in term gestations

The frequency of microbial invasion of the amniotic cavity is similar in patients with spontaneous labor at term and those with preterm labor and intact membranes who subsequently deliver a preterm neonate (17% vs 22%, respectively).24, 93 Yet, preterm neonates born to mothers with microbial invasion of the amniotic cavity have a higher frequency of neonatal sepsis, a systemic inflammatory response (defined as an elevated umbilical cord IL-6 concentration), and funisitis than those born to

The fetal inflammatory response syndrome

Microbial invasion of the amniotic cavity can progress to fetal invasion. The ports of entry for bacteria into the fetus include the respiratory tract, gastrointestinal tract, skin, and ear. (Amniotic fluid fills the external auditory canal, and bacteria can invade the tympanic membrane and middle ear). Similarly, depending on the gestational age, microorganisms may gain access to the conjunctiva.

Once microorganisms gain access to the fetal mucosa, they are recognized by pattern recognition

Conclusion

Acute chorioamnionitis and acute funisitis are acute inflammatory lesions with important short- and long-term clinical significance. Substantial progress has been made in the understanding of the mechanisms responsible for maternal and fetal inflammation in the context of infection. Determining the causes of sterile intraamniotic inflammation represents an important clinical and scientific challenge.

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    Supported, in part, by the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract no. HSN275201300006C.

    The authors report no conflict of interest.

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