Seminars in Fetal & Neonatal Medicine
Volume 17, Issue 1 , Pages 20-25, February 2012

Inflammatory response in acute chorioamnionitis

  • Raymond W. Redline

      Affiliations

    • Pediatric and Perinatal Pathology, Case Western Reserve University School of Medicine, OH 44106, USA
    • University Hospitals Case Medical Center, Cleveland, OH 44106, USA
    • Corresponding Author InformationCorresponding author. Department of Pathology, University Hospitals, Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106 USA. Tel.: +1 216 844 1813; fax: +1 216 844 1810.

published online 25 August 2011.

Article Outline

Summary 

Acute chorioamnionitis is the principal antecedent of premature birth and an important contributor to specific neonatal and other complications that may extend throughout subsequent life. A large number of studies have addressed surrogate markers of in-utero inflammation including cytokines, chemokines, pathogen-associated molecular patterns, and elicited host proteins. However, chorioamnionitis means inflammation occurring within the chorioamnion and the only practical direct measure available to assess this finding in most placentas is histopathology. The maternal and fetal inflammatory response to the presence of organisms within the placental membranes, so-called histologic chorioamnionitis, is the focus of this review. The issues addressed are the nature and origin of the eliciting antigen, mode of spread to the placenta, general characteristics of placental immunity, and a specific characterization of the spectrum of pathologic lesions observed in placentas with membrane infection.

Keywords: Acute chorioamnionitis, Fetal inflammatory response, Histologic chorioamnionitis, Perinatal infections, Placenta

 

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1. Introduction 

Acute chorioamnionitis (ACA) is the pathologic term describing an inflammatory response to an acute infection of the placental membranes generally occurring in the second half of pregnancy. Its prevalence is inversely proportional to gestational age ranging from >50% at viability (23–24 weeks) to ∼5% at term (>37 weeks).1, 2, 3, 4 Although generally caused by antibiotic-susceptible organisms, it occurs within an anatomically closed space – the gestational sac – that in some respects has properties of an immunologically privileged site. This latter aspect may reflect the need to protect the allogeneic fetus from rejection by the mother. By way of analogy to other infections occurring in closed spaces (e.g. abscesses) and involving other privileged regions [e.g. eye, testis, central nervous system (CNS)], placental infections are generally not curable by modalities other than evacuation of the uterine cavity.

By far the most important consequence of ACA is preterm delivery.5 Prematurity is the leading cause of neonatal morbidity and mortality in both the developed and developing world and ACA is believed to be its leading cause.6 Although not considered in this chapter, numerous studies have also implicated the histologic fetal inflammatory response (FIR) associated with ACA in a variety of adverse outcomes affecting premature infants, including respiratory distress syndrome, chronic lung disease, retinopathy of prematurity, CNS hemorrhage, and cerebral palsy.7, 8, 9, 10 These associations are controversial and other studies suggest that ACA may actually reduce the incidence of respiratory distress syndrome and neonatal death when adjusted for gestational age.11, 12 The lack of a suitable control group not affected by alternative pathologies handicaps all such comparisons.

The focus of this chapter will be the pathology of infectious ACA in humans, and an outline of the patterns to be discussed is given in Box I. Human placental infections not affecting the membranes, inflammatory processes resulting from exposure to surrogate stimuli such as lipopolysaccharide rather than live organisms, and animal models of ACA will not be considered. The perspective of this chapter will be that microscopic identification of neutrophils in the placental membranes, so-called histologic chorioamnionitis (HCA), is the gold standard for true local infection. Other surrogate measures of inflammation such as increases in acute phase reactants, cytokine responses, bacterial cultures, or clinical symptomatology in the mother or fetus will be considered only in terms of their relationship to HCA.

Box 1. Pathologic patterns of injury associated with chorioamnionitis


A.Maternal inflammatory response
Stage 1:early acute subchorionitis/chorionitis.

Stage 2:acute chorioamnionitis.

Stage 3:necrotizing chorioamnionitis.

High grade/severe: subchorionic microabscesses.

Prolonged: subacute (chronic) chorioamnionitis.

Differential diagnosis: laminar necrosis, chronic (non-infectious) chorioamniontis.


B.Fetal inflammatory response
Stage 1:umbilical phlebitis/chorionic vasculitis.

Stage 2:umbilical arteritis.

Stage 3:concentric periphlebitis/necrotizing funisitis.

High grade/severe: intense chorionic vasculitis.

Prolonged: subnecrotizing funisitis.

Differential diagnosis: eosinophil–T-cell vasculitis, villitis of unknown etiology with obliterative fetal vasculopathy, umbilical ‘pseudo-vasculitis’.


C.Specific patterns
Peripheral funisitis: Candida spp.

Acute intervillositis/intervillous abscesses: L. monocytoenes, other rare bacteria.

Acute intervillositis/perivillous fibrin: maternal sepsis (usually streptococci).

Acute villitis/fetal capillaritis: fetal sepsis (usually Gram-negative bacilli).


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2. Eliciting organisms 

ACA is usually a bacterial infection, often polymicrobial, caused by aerobic and anaerobic organisms originating in the genitourinary tract, gastrointestinal system, oral cavity, or skin. Other causative agents include fungi (usually Candida spp.) and mycoplasma (usually U. urealyticum). Whether chlamydia, viruses, protazoans, or other parasites ever cause HCA is debatable. Several studies correlating histology with the detection of micro-organisms using appropriate culture methods have shown a high degree of concordance between HCA and the isolation of bacteria from the membranes.13, 14, 15 More recently PCR has been used to identify uncultivatable organisms in cases of HCA with negative cultures.16, 17 It is important to emphasize that neither PCR nor culture is infallible, as organisms have been identified by each without the other being positive. It is also important to consider that both viable organisms and bacterial DNA may be cleared by local bactericidal and phagocytic inflammatory responses leading to a false-negative culture result.

2.1. Routes of infection 

The majority of cases of ACA are caused by organisms residing in the cerviovaginal region.9, 18, 19 These include normal bacterial flora, organisms increased in numbers due to changes in the local microenvironment (bacterial vaginosis), and colonizing organisms from other sites (e.g. Candida spp. and group B streptococci). The precise route of entry from the cervicovaginal region to the membranes is not clearly defined and may vary from case to case. Possibilities include inoculation of the amniotic fluid, spread as a biofilm over exposed amnion after membrane rupture, and invasion along choriodecidual tissue planes. Evidence favoring the first possibility has been published by Romero et al.20 Factors increasing the risk of spread of micro-organisms to the membranes include premature cervical dilatation, premature rupture of the membranes, the presence of foreign bodies (e.g. intrauterine device or cerclage), scarring from previous uterine surgery, negative pressure created by uterine contractions, and immunologic defects in host responsiveness (immune deficiencies, either generalized or specific to a particular micro-organism21, 22). Gestational age-specific developmental milestones also play a role in susceptibility. True ACA cannot occur prior to fusion of the amnion and chorion at around 11 weeks and is relatively rare in the time period before the placental membranes fuse with the lower uterine segment and the opposite side of the uterine cavity (around 19 weeks).

Non-cervicovaginal routes of infection include contiguous spread from adjacent abdominal structures and hematogenous seeding from distant sites. Examples of the former include salpingitis, cystitis, peritonitis, appendicitis and other gastrointestinal tract infections. A less common pathway is direct inoculation of skin flora at the time of amniocentesis. Hematogenous seeding can occur during maternal sepsis or transient bacteremias such as those occurring with dental infections. This latter pathway could, at least partially, explain the association of chronic periodontitis with premature delivery.23

Finally, the obstetric literature often alludes to a potential intermediary pathway in which ACA is preceded during early pregnancy by a low grade subclinical infection of the lower uterine segment, referred to as chronic choriodeciduitis.24 A parallel pathology literature has described several histologic lesions including chronic deciduitis, lymphoplasmacytic deciduitis, and chronic chorioamnionitis.25, 26, 27, 28 It has been suggested that both the clinical and pathologic entities represent subclinical infections acting alone or in concert with ACA to cause premature delivery. However, recent work by Romero and colleagues suggests that chronic inflammation of the membranes may not be infectious at all, but rather a maternal immune response to fetal antigen akin to another placental lesion known as villitis of unknown etiology (VUE).29 This proposal is consistent with lack of efficacy in antibiotic trials designed to clear these putative subclinical infections.30

2.2. Character of the placental immune response 

Both the maternal and fetal inflammatory responses to micro-organisms in the placental membranes are dominated by neutrophils. Upon entry into the infected membranes, neutrophils become activated for enhanced phagocytosis and bactericidal function, secrete cytokines and defensins, and form neutrophil extracellular traps following cell death; all contributing to control of bacterial growth and prevention of spread to the fetus.31 Other components of the innate immune system may also be seen. Macrophages appear in small numbers days to weeks after the onset of infection, primarily to engulf degenerating neutrophils and other cell debris. Eosinophils occasionally accompany the fetal inflammatory response in chorionic plate vessels, especially in very premature infants. Adaptive immunity, on the other hand, is strongly downregulated. Delayed-type hypersensitivity responses (T-lymphocytes and activated macrophages) are essentially absent in ACA, possibly because of the need to prevent priming of graft-versus-host-type reactivity. Likewise, local B-cell responses including the formation of lymphoid follicles or germinal centers are rare in ACA. Mechanisms downregulating adaptive as opposed to innate immunity at this site include local immunosuppression, lack of antigen–dendritic cell migration to local lymph nodes, and the presence of uterine T-regulatory cells during pregnancy.32, 33, 34

2.3. Maternal inflammatory response in ACA 

Bacterial chemotactic factors, chemokines, and activated complement components promote the margination, adhesion, and transmigration of circulating maternal neutrophils from the intervillous space into the subchorionic fibrin and from post-capillary decidual venules into the decidua capsularis.35 Correspondingly, the earliest reliable histologic indicator of a maternal inflammatory response (MIR) to infection (stage 1) is a diffuse band of neutrophils either below the chorionic plate (acute subchorionitis) or at the choriodecidual junction of the placental membranes (acute chorionitis). The diffuse nature of this histologic infiltrate is important for avoiding false-positive diagnoses. Later, neutrophils breach the maternal–fetal barrier at the chorion to enter the connective tissue of the chorioamnion resulting in acute chorioamnionitis (stage 2). The normal lifespan of a tissue neutrophil is ∼24–36h, although this time period can be modulated by recently characterized survival factors.36, 37 Neutrophil apoptosis and fragmentation are among the defining characteristics for stage 3 of the maternal response, known as necrotizing chorioamnionitis. The other components are thickening of amniotic basement membrane and the desquamation of amnionic epithelial cells involving ≥30% of the amniotic surface. Less commonly, prolonged retention of the fetoplacental unit after infection leads to a mixed infiltrate of degenerating neutrophils and vacuolated macrophages known as chronic (subacute) chorioamnionitis.38 This lesion is most frequently associated with organisms of low pathogenicity such as U. urealyticum. An indicator of increased severity is the formation of subchorionic microabscesses (grade 2 MIR), a process that has been associated with adverse neonatal outcome in some studies.39

The pathologic differential diagnosis of HCA with MIR includes two lesions: laminar necrosis, characterized by focal areas of neutrophilic infiltration in the membranes and associated with microvascular ischemia40 and chronic chorioamnionitis, characterized by infiltration of the chorioamnion by CD3-positive T-lymphocytes.29 As discussed above, the latter may represent a graft-versus-host-type reaction based on its chemokine/cytokine signature.

Whereas deleterious effects of the fetal inflammatory response (FIR) to infection have been emphasized in many studies, there is some evidence suggesting that the MIR alone may also directly affect the fetus. One study showed that maternal cytokines could cross the interhemal barrier in the placenta, although a second report contradicted this finding.41, 42 Another group found that amnionitis – a type of MIR – was a better predictor of elevated fetal cytokines than funisitis, a type of FIR (see below).43

2.4. Fetal inflammatory responses in ACA 

The FIR to ACA is defined histologically by the presence of neutrophils within the muscular walls of veins or arteries in the chorionic plate (chorionic vasculitis) and/or umbilical cord (sometimes referred to as ‘funisitis‘). FIR restricted to the chorionic plate vessels tends to be more common in premature placentas, whereas involvement of umbilical vessels alone, particularly the vein, is more common at term. The prevalence of FIR in HCA increases with both gestational age and the stage and severity of the MIR. In ∼7–8% of inflamed placentas, FIR is seen in the absence of a recognizable MIR. The circulating cytokine profile in these cases is similar to that observed in placentas with both MIR and FIR, suggesting a similar pathogenesis.44 The FIR begins as a multifocal process with earlier and more severe involvement at the placental end compared with the fetal end.45, 46 As might be expected, funisitis is accompanied by upregulation of leukocyte adhesion molecules, such as ICAM-1, E-selectin, and VCAM-1, on umbilical vascular endothelial cells.47, 48 Affected fetuses may also have elevations of circulating soluble ICAM-1, possibly of umbilical origin. The predicted origins of neutrophils in the membranes (maternal) and chorionic vessels (fetal) have been confirmed by fluorescence in-situ hybridization (FISH) analysis for Y chromosome in male gestations.49 Less obviously, FISH analysis has shown that most neutrophils in the amniotic fluid and fetal compartments in continuity with amniotic fluid are also fetal in origin.50, 51

There is general consensus regarding successive histologic stages of the FIR. In the system proposed by the Society for Pediatric Pathology working group,35 stage 1 is defined by neutrophils in the chorionic vessels (chorionic vasculitis) and/or umbilical vein (umbilical phlebitis). Stage 2 is reached when neutrophils enter the wall of the umbilical artery (umbilical arteritis), with or without minor degrees of extravasation into Wharton’s jelly. Stage 3 is heralded by organization of neutrophils in the Wharton’s jelly into arc-like bands surrounding one or more umbilical vessels (concentric umbilical perivasculitis or necrotizing funisitis). The stage 2 FIR has been correlated with significantly increased levels of circulating fetal interleukin (IL)-6.52, 53 The stage 3 FIR develops when neutrophils are attracted to immune complexes that precipitate at the ‘zone of equivalence’ where microbial antigens from amniotic fluid meet maternal IgG diffusing out from the fetal circulation.54 In cases with prolonged retention of the fetoplacental unit after infection, neutrophils within these arc-like bands degenerate and become replaced by fibrin, calcification, and, on occasion, fetal capillaries (neovascularization), a lesion known as subacute necrotizing funisitis.55 An indicator of increased severity, intense chorionic vasculitis (grade 2 FIR), defined by confluent neutrophilic infiltration of the amniotic aspect of chorionic plate vessels in the presence of histologic signs of endothelial activation and vessel wall damage, has been associated with adverse neurologic outcomes in several studies.56, 57 Finally, endothelial activation associated with the FIR may promote the formation of chorionic vessel thrombi, which may occasionally embolize to the fetus.

The pathologic differential diagnosis of FIR includes non-infectious inflammatory responses in chorionic plate vessels, such as idiopathic eosinophil–T-cell vasculitis or VUE with obliterative fetal vasculopathy, and isolated umbilical phlebitis, occasionally observed with prolonged meconium exposure in term infants.58, 59, 60 Degeneration of vascular smooth muscle cells in stillborn placentas can mimic a neutrophilic infiltrate, a process that has been called umbilical pseudo-vasculitis.61

2.5. Variant patterns 

The patterns mentioned above describe the typical pathologic features of most amniotic fluid infections. Variations from these patterns are important because they can suggest specific organisms or clinical situations. HCA with microabscesses on the outer surface of the umbilical cord (peripheral funisitis) is virtually pathognomonic for fungal infection by Candida spp.62 Candidal infections may also involve the neonatal skin or become disseminated leading to neonatal sepsis or parenchymal organ involvement. HCA with large aggregates of neutrophils in the intervillous space (acute intervillositis with intervillous abscesses) is highly suggestive of infection by Listeria monocytogenes, an organism associated with foodborn epidemics and a very high propensity for spread to the fetus.63 Other rare organisms associated with this pattern are Campylobacter fetus, Francisella tularensis, and Brucella abortus. More localized aggregates of fibrin and neutrophils (patchy acute intervillositis with perivillous fibrin) may be seen with maternal sepsis notably that associated with group A streptococci.64 Finally, acute villitis with fetal capillaritis and focal spillover into the intervillous space can accompany fetal sepsis, often caused by Gram-negative bacilli.19 Bacterial colonies in these latter cases are occasionally seen within the villous capillaries.

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3. Other issues 

Although the primary focus of this chapter has been the histologic diagnosis of membrane infections, it would be remiss not to briefly consider some related issues that sometimes cause confusion and controversy. The first issues involve the placenta. It has been reported that bacteria may occasionally be identified in the membranes without an accompanying inflammatory response.65 Some have suggested this indicates that the uterus possesses an endogenous flora which does not usually promote an inflammatory response.66 Although possible, it seems equally likely that factors such as low numbers of organisms, recent entry into the uterine environment, and the absence of co-stimulatory signals such as host Toll-like receptor (TLR) signaling or opsonizing maternal antibodies might explain the lack of an inflammatory response in these cases. The converse situation, acute inflammation without detectable organisms, has prompted some to speculate that HCA in certain situations such as term pregnancy may not always be infectious.67 Before adopting such a viewpoint, however, other alternatives such as rapid and efficient clearance by a vigorous host response need to be excluded. In both scenarios, the strong overall correlation between HCA and recovery of local micro-organisms in numerous previous studies should be emphasized. The final issue relating to the placenta is the relationship between histologic and clinical chorioamnionitis. The latter is usually defined by a combination of symptoms including maternal fever, abdominal tenderness, maternal and fetal tachycardia, increased maternal leukocyte count, and foul smelling vaginal discharge. Our data in very low birth weight infants demonstrated low overall sensitivity with only about 30% of HCA diagnosed clinically.68 This was especially true for HCA lacking FIR where the percentage with a positive clinical diagnosis (7%) was actually lower than for placentas with no histologic inflammation (9%). Other investigators have reported similar numbers.69 Several clinical modalities including amniotic fluid Gram stain, IL-6 levels, and the presence of inflammatory proteins such as S100A, defensins, and calgranulins have shown promise for increasing the sensitivity of clinical diagnosis.70, 71, 72 Specificity is also poor, particularly in term gestations where factors such as epidural anesthesia, maternal dehydration, atelectasis, and urinary tract infections can lead to a false-positive clinical diagnosis of chorioamnionitis.73

The next issues involve the significance a diagnosis of HCA for the fetus. Although seemingly obvious, it should be emphasized that ACA is a localized infection involving an organ that is removed from the infant at the time of delivery. As with other local infections, the purpose of the regional inflammatory response is to prevent systemic spread and the placenta is quite efficient in this role. Although the rate of ‘presumed sepsis’ is quite high in NICU patients with HCA, the actual rate of documented in-utero transmission of micro-organisms is quite low and usually limited to highly virulent bacteria such as the aerobic streptococci, Gram-negative bacilli, and listeria. A corollary to this point is that HCA without sepsis is not an acceptable cause of intrauterine or neonatal death. A second question is whether culture-negative ‘presumed sepsis’ is more frequent in neonates whose placentas have HCA. Although this has not been systematically studied, it seems likely that bacterial products (e.g. lipopolysaccharide, other pathogen-associated molecular patterns, toxins) released during placental infection, cytokines entering the fetal circulation before birth, and the neonatal acute phase response all contribute to an increased rate of clinical diagnoses.74

The final question is the significance of a diagnosis of HCA for classification and predicting risk of recurrence in subsequent pregnancies. As discussed above, the primary adverse outcome to be considered is premature delivery. Virtually all gestations developing HCA will deliver within days of onset and most studies suggest that ACA is the leading cause of premature delivery worldwide. Premature deliveries not associated with HCA are highly likely to have a second placental disorder, maternal vascular malperfusion.75 This process can be secondary to maternal hypertension, diabetes, obesity, advanced age, coagulation disorders, renal disease, and autoimmunity, but is often idiopathic. There is only modest overlap between HCA and maternal malperfusion and some evidence suggests that they have distinct neonatal phenotypes and long term complications.76, 77, 78 Recurrence of HCA can occur in three scenarios: mothers with uterine abnormalities leading to recurrent premature cervical dilatation and/or labor, mothers with persistent and/or recurrent pelvic bacterial colonization, and mothers with underlying genetic susceptibilities leading to familial aggregation of preterm deliveries with HCA. Population studies have implicated specific polymorphisms in IL-6, TLR-4, and tumor necrosis factor-alpha with an increased prevalence or severity of HCA and preterm birth.79, 80, 81 These polymorphisms could act in one of two ways, either by compromising host defenses allowing organisms to inappropriately enter the uterus, or by decreasing the threshold for inflammatory responses to even very small numbers of organisms.82 A recent study specifically addressed placental pathology in women with premature infants and a family history of preterm birth.83 Whereas the prevalence of HCA was high, there were no features distinguishing familial from sporadic cases. Additional studies using this cohort are planned and may provide new insight into genetic pathways leading to HCA.

Practice points

 


•The minimum criterion for defining histologic chorioamnionitis is a diffuse band of neutrophils in the subchorionic fibrin overlying the intervillous space of the placenta.

•Umbilical arteritis, not funisistis not otherwise specified, reflects a critical threshold correlated with elevated levels of circulating fetal cytokines.

•Whereas organisms may occasionally be found in the membranes without inflammation and inflammation may occasionally be present without detectable organisms, a large body of literature supports the specific association of histologic chorioamnionitis with membrane infection at all gestational ages.

Research directions

 


•Continued exploration of the links between specific patterns of placental injury, fetal responses to injury, and adverse pregnancy outcomes.

•Identification of better techniques for detecting clinically silent chorioamnionitis.

•Genetic studies to clarify underlying host factors that increase the incidence of membrane infection and promote inflammatory responses resulting in preterm delivery.

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References 

  1. Chellam VG, Rushton DI. Chorioamnionitis and funiculitis in the placentas of 200 births weighing less than 2.5 kg. Br J Obstet Gynaecol. 1985;92:808–814
  2. Mueller-Heubach E, Rubinstein DN, Schwarz SS. Histologic chorioamnionitis and preterm delivery in different patient populations. Obstet Gynecol. 1990;75:622–626
  3. Salafia CM, Weigl C, Silberman L. The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies. Obstet Gynecol. 1989;73(3 Pt 1):383–389
  4. Becroft DM, Thompson JM, Mitchell EA. Placental chorioamnionitis at term: epidemiology and follow-up in childhood. Pediatr Dev Pathol. 2010;13:282–290
  5. Guzick DS, Winn K. The association of chorioamnionitis with preterm delivery. Obstet Gynecol. 1985;65:11–16
  6. Goldenberg R, Hauth J, Andrews W. Intrauterine infection and preterm delivery. N Engl J Med. 2000;342:1500–1507
  7. Woldesenbet M, Rosenfeld CR, Ramilo O, Johnson-Welch S, Perlman JM. Severe neonatal hypoxic respiratory failure correlates with histological chorioamnionitis and raised concentrations of interleukin 6 (IL6), IL8 and C-reactive protein. Arch Dis Child Fetal Neonatal Ed. 2008;93:F413–F417
  8. Polam S, Koons A, Anwar M, Shen-Schwarz S, Hegyi T. Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants. Arch Pediatr Adolesc Med. 2005;159:1032–1035
  9. Leviton A, Allred EN, Kuban KC, et al. Microbiologic and histologic characteristics of the extremely preterm infant’s placenta predict white matter damage and later cerebral palsy. The ELGAN study. Pediatr Res. 2009;67:95–101
  10. Zanardo V, Vedovato S, Cosmi E, et al. Preterm premature rupture of membranes, chorioamnion inflammatory scores and neonatal respiratory outcome. BJOG. 2009;117:94–98
  11. Lee J, Oh KJ, Park CW, Park JS, Jun JK, Yoon BH. The presence of funisitis is associated with a decreased risk for the development of neonatal respiratory distress syndrome. Placenta. 2011;32:235–240
  12. Lahra MM, Jeffery HE. A fetal response to chorioamnionitis is associated with early survival after preterm birth. Am J Obstet Gynecol. 2004;190:147–151
  13. Pankuch GA, Appelbaum PC, Lorenz RP, Botti JJ, Schachter J, Naeye RL. Placental microbiology and histology and the pathogenesis of chorioamnionitis. Obstet Gynecol. 1984;64:802–806
  14. Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case–control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N. Engl J Med. 1988;319:972–980
  15. Zhang JM, Kraus FT, Aquino TI. Chorioamnionitis: a comparative histologic, bacteriologic, and clinical study. Int J Gynecol Pathol. 1985;4:1–10
  16. DiGiulio DB, Romero R, Kusanovic JP, 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;64:38–57
  17. DiGiulio DB, Romero R, Amogan HP, et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS One. 2008;3:e3056
  18. Blanc W. Pathology of the placenta and cord in ascending and hematogenous infections. In:  Marshall W editors. Perinatal infections, CIBA Foundation Symposium 77. London: Excerpta Medica; 1980;p. 17–38
  19. Kraus FT, Redline R, Gersell DJ, Nelson DM, Dicke JM. Placental pathology. Washington, DC: American Registry of Pathology; 2004;
  20. Kim MJ, Romero R, Gervasi MT, et al. Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection. Lab Invest. 2009;89:924–936
  21. Baker C, Kasper D. Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection. N Engl J Med. 1976;294:753–756
  22. Chi BH, Mudenda V, Levy J, Sinkala M, Goldenberg RL, Stringer JS. Acute and chronic chorioamnionitis and the risk of perinatal human immunodeficiency virus-1 transmission. Am J Obstet Gynecol. 2006;194:174–181
  23. Han YW, Fardinin Y, Chen C, et al. Term stillbirth caused by oral fusobacterium nucleatum. Obstet Gynecol. 2010;115(Pt 2):1–4
  24. Goldenberg RL, Andrews WW, Hauth JC. Choriodecidual infection and preterm birth. Nutr Rev. 2002;60(5 Pt 2):S19–S25
  25. Khong TY, Bendon RW, Qureshi F, et al. Chronic deciduitis in the placental basal plate: definition and inter-observer reliability. Hum Pathol. 2000;31:292–295
  26. Edmondson N, Bocking A, Machin G, Rizek R, Watson C, Keating S. The prevalence of chronic deciduitis in cases of preterm labor without clinical chorioamnionitis. Pediatr Dev Pathol. 2009;12:16–21
  27. Gersell DJ, Phillips NJ, Beckerman K. Chronic chorioamnionitis: a clinicopathologic study of 17 cases. Int J Gynecol Pathol. 1991;10:217–229
  28. Jacques S, Qureshi F. Chronic chorioamnionitis: a clinicopathologic and immunohistochemical study. Hum Pathol. 1998;29:1457–1461
  29. Kim CJ, Romero R, Kusanovic JP, et al. The frequency, clinical significance, and pathological features of chronic chorioamnionitis: a lesion associated with spontaneous preterm birth. Mod Pathol. 2010;23:1000–1011
  30. Tita AT, Cliver SP, Goepfert AR, et al. Clinical trial of interconceptional antibiotics to prevent preterm birth: subgroup analyses and possible adverse antibiotic–microbial interaction. Am J Obstet Gynecol. 2007;197:e361–e366
  31. Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33:657–670
  32. Lu CY, Redline R, Dustin L, McKay DB, Shea CM. Inhibition of macrophage and T-lymphocyte functions in the placenta and decidua during listeriosis: implications for tolerance of the fetoplacental allograft. In:  Wegmann TG,  Gill TJ,  Nisbet-Brown E editor. Immunobiology of the maternal fetal interface. New York: Oxford University Press; 1991;
  33. Collins MK, Tay CS, Erlebacher A. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J Clin Invest. 2009;119:2062–2073
  34. Kahn DA, Baltimore D. Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance. Proc Natl Acad Sci USA. 2010;107:9299–9304
  35. Redline RW, 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;6:435–448
  36. Molloy EJ, O’Neill AJ, Grantham JJ, et al. Labor promotes neonatal neutrophil survival and lipopolysaccharide responsiveness. Pediatr Res. 2004;56:99–103
  37. Witko-Sarsat V, Pederzoli-Ribeil M, Hirsh E, Sozzani S, Cassatella MA. Regulating neutrophil apoptosis: new players enter the game. Trends Immunol. 2011;32:117–124
  38. Ohyama M, Itani Y, Yamanaka M, et al. Re-evaluation of chorioamnionitis and funisitis with a special reference to subacute chorioamnionitis. Hum Pathol. 2002;33:183–190
  39. Keenan WJ, Steichen JJ, Mahmood K, Altshuler G. Placental pathology compared with clinical outcome. Am J Dis Child. 1977;131:1224–1227
  40. Stanek J, Al-Ahmadie HA. Laminar necrosis of placental membranes: a histologic sign of uteroplacental hypoxia. Pediatr Dev Pathol. 2005;8:34–42
  41. Zaretsky MV, Alexander JM, Byrd W, Bawdon RE. Transfer of inflammatory cytokines across the placenta. Obstet Gynecol. 2004;103:546–550
  42. Aaltonen R, Heikkinen T, Hakala K, Laine K, Alanen A. Transfer of proinflammatory cytokines across term placenta. Obstet Gynecol. 2005;106:802–807
  43. 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;30:56–61
  44. Hecht JL, Onderdonk A, Delaney M, et al. Characterization of chorioamnionitis in 2nd-trimester C-section placentas and correlation with microorganism recovery from subamniotic tissues. Pediatr Dev Pathol. 2008;11:15–22
  45. Kim CJ, Yoon BH, Kim M, Park JO, Cho SY, Chi JG. Histo-topographic distribution of acute inflammation of the human umbilical cord. Pathol Int. 2001;51:861–865
  46. Katzman PJ, Metlay LA. Fetal inflammatory response is often present at early stages of intra-amniotic infection, and its distribution along cord is variable. Pediatr Dev Pathol. 2009;13:265–272
  47. Craven CM, Ward K. Fetal endothelial cells express vascular cell adhesion molecule in the setting of chorioamnionitis. Am J Reprod Immunol. 2000;43:259–263
  48. D’Alquen D, Kramer BW, Seidenspinner S, et al. Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis. Pediatr Res. 2005;57:263–269
  49. Steel JH, O’Donoghue K, Kennea NL, Sullivan MH, Edwards AD. Maternal origin of inflammatory leukocytes in preterm fetal membranes, shown by fluorescence in situ hybridisation. Placenta. 2005;26:672–677
  50. Scott RJ, Peat D, Rhodes CA. Investigation of the fetal pulmonary inflammatory reaction in chorioamnionitis, using an in situ Y chromosome marker. Pediatr Pathol. 1994;14:997–1003
  51. Lee SD, Kim MR, Hwang PG, Shim SS, Yoon BH, Kim CJ. Chorionic plate vessels as an origin of amniotic fluid neutrophils. Pathol Int. 2004;54:516–522
  52. Kim CJ, Yoon BH, Romero R, et al. Umbilical arteritis and phlebitis mark different stages of the fetal inflammatory response. Am J Obstet Gynecol. 2001;185:496–500
  53. Rogers BB, Alexander JM, Head J, McIntire D, Leveno KJ. Umbilical vein interleukin-6 levels correlate with the severity of placental inflammation and gestational age. Hum Pathol. 2002;33:335–340
  54. Hood IC, DeSa DJ, Whyte RK. The inflammatory response in candidal chorioamnionitis. Hum Pathol. 1983;14:984–990
  55. Navarro C, Blanc WA. Subacute necrotizing funisitis. A variant of cord inflammation with a high rate of perinatal infection. J Pediatr. 1974;85:689–697
  56. Redline RW, Wilson-Costello D, Borawski E, Fanaroff AA, Hack M. Placental lesions associated with neurologic impairment and cerebral palsy in very low birth weight infants. Arch Pathol Lab Med. 1998;122:1091–1098
  57. Redline RW, O’Riordan MA. Placental lesions associated with cerebral palsy and neurologic impairment following term birth. Arch Pathol Lab Med. 2000;124:1785–1791
  58. Fraser RB, Wright JR. Eosinophilic/T-cell chorionic vasculitis. Pediatr Dev Pathol. 2002;5:350–355
  59. Redline RW, Ariel I, Baergen RN, et al. Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol. 2004;7:443–452
  60. Burgess AM, Hutchins GM. Inflammation of the lungs, umbilical cord and placenta associated with meconium passage in utero. Review of 123 autopsied cases. Pathol Res Pract. 1996;192:1121–1128
  61. Genest DR, Granter S, Pinkus GS. Umbilical cord ‘pseudo-vasculitis’ following second trimester fetal death: a clinicopathological and immunohistochemical study of 13 cases. Histopathology. 1997;30:563–569
  62. Qureshi F, Jacques SM, Benson RW, et al. Candida funisitis: a clinicopathologic study of 32 cases. Pediatr Dev Pathol. 1998;1:118–124
  63. Driscoll SG, Gorbach A, Feldman D. Congenital listeriosis: diagnosis from placental studies. Obstet Gynecol. 1962;20:216–220
  64. Bendon R, Bornstein S, Faye-Petersen O. Two fetal deaths associated with maternal sepsis and with thrombosis of the intervillous space of the placenta. Placenta. 1998;19:385–389
  65. Steel JH, Malatos S, Kennea N, et al. Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor. Pediatr Res. 2005;57:404–411
  66. Espinoza J, Erez O, Romero R. Preconceptional antibiotic treatment to prevent preterm birth in women with a previous preterm delivery. Am J Obstet Gynecol. 2006;194:630–637
  67. Riley LE, Celi AC, Onderdonk AB, et al. Association of epidural-related fever and noninfectious inflammation in term labor. Obstet Gynecol. 2011;117:588–595
  68. Redline R, Wilson-Costello D, Borawski E, Fanaroff A, Hack M. The relationship between placental and other perinatal risk factors for neurologic impairment in very low birth weith children. Pediatr Res. 2000;47:721–726
  69. Van Hoeven KH, 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;16:731–744
  70. Yoon BH, Romero R, Kim CJ, et al. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol. 1995;172:960–970
  71. Buhimschi IA, Zhao G, Pettker CM, et al. The receptor for advanced glycation end products (RAGE) system in women with intraamniotic infection and inflammation. Am J Obstet Gynecol. 2007;196:181.e1–181.e13
  72. Buhimschi IA, Zambrano E, Pettker CM, et al. Using proteomic analysis of the human amniotic fluid to identify histologic chorioamnionitis. Obstet Gynecol. 2008;111(2 Pt 1):403–412
  73. Smulian JC, Shen-Schwarz S, Vintzileos AM, Lake MF, Ananth CV. Clinical chorioamnionitis and histologic placental inflammation. Obstet Gynecol. 1999;94:1000–1005
  74. Kallapur SG, Nitsos I, Moss TJ, et al. IL-1 mediates pulmonary and systemic inflammatory responses to chorioamnionitis induced by lipopolysaccharide. Am J Respir Crit Care Med. 2009;179:955–961
  75. McElrath TF, Hecht JL, Dammann O, et al. Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification. Am J Epidemiol. 2008;168:980–989
  76. Cetinkaya M, Ozkan H, Koksal N, Karali Z, Ozgur T. Neonatal outcomes of premature infants born to preeclamptic mothers. J Matern Fetal Neonatal Med. 2009;23:425–430
  77. Jarvis S, Glinianaia SV, Torrioli MG, et al. Cerebral palsy and intrauterine growth in single births: European collaborative study. Lancet. 2003;362(9390):1106–1111
  78. Byrne CD, Phillips DI. Fetal origins of adult disease: epidemiology and mechanisms. J Clin Pathol. 2000;53:822–828
  79. Kazzi SN, Jacques SM, Qureshi F, Quasney MW, Kim UO, Buhimschi IA. Tumor necrosis factor-alpha allele lymphotoxin-alpha+250 is associated with the presence and severity of placental inflammation among preterm births. Pediatr Res. 2004;56:94–98
  80. Simhan HN, MacPherson T, Caritis SN, Krohn MA. Maternal and fetal Toll-like receptor 4 genotype and chorionic plate inflammatory lesions. Am J Obstet Gynecol. 2008;199:e401–e404
  81. Reiman M, Kujari H, Ekholm E, Lapinleimu H, Lehtonen L, Haataja L. Interleukin-6 polymorphism is associated with chorioamnionitis and neonatal infections in preterm infants. J Pediatr. 2008;153:19–24
  82. Simhan HN, Caritis SN, Krohn MA, Martinez de Tejada B, Landers DV, Hillier SL. Decreased cervical proinflammatory cytokines permit subsequent upper genital tract infection during pregnancy. Am J Obstet Gynecol. 2003;189:560–567
  83. Defranco EA, Jacobs TS, Plunkett J, Chaudhari BP, Huettner PC, Muglia LJ. Placental pathologic aberrations in cases of familial idiopathic spontaneous preterm birth. Placenta. 2011;32:386–390

PII: S1744-165X(11)00091-6

doi:10.1016/j.siny.2011.08.003

Seminars in Fetal & Neonatal Medicine
Volume 17, Issue 1 , Pages 20-25, February 2012

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