The Journal of Pediatrics
Volume 153, Issue 1 , Pages 3-4, July 2008

The Pathogenesis of Chorioamnionitis

  • Armond S. Goldman, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Armond S. Goldman, MD, Emeritus Professor, Division of Infectious Diseases and Immunology, Section of Immunology/Allergy/Rheumatology, Department of Pediatrics, The Children's Hospital, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0369.
    • ,
  • Frank C. Schmalstieg, MD, PhD

The Department of Pediatrics, The University of Texas Medical Branch, Galveston, Texas

Article Outline

Abbreviations: IL, Interleukin, MCP, Monocyte chemoattractant protein

 

The pathogenesis of chorioamnionitis must be understood to discover how to diagnose the problem in its earliest stage and how to treat or prevent it. To do so, one must delve into the complexity of inflammation that encompasses not only the cellular aspects, but also the intertwined molecular processes that recruit, activate, modulate, and terminate cellular inflammatory responses.

See related articles, p 16 and p 19

Perhaps it is appropriate that 2 articles about the predisposition to chorioamnionitis appear in this issue of The Journal,1, 2 at the cusp of the celebration of the 100th anniversary of the award of the Nobel Prize in Physiology or Medicine shared by Ilya Metchnikoff3 and Paul Ehrlich4 for their fundamental discoveries in cellular and humoral immunology, respectively. It is more germane to this discussion that Metchnikoff discovered that highly mobile leukocytes (neutrophils) from the blood were induced to pass through the walls of small blood vessels (diapidesis), migrate in a directed fashion to the eliciting agent in the tissue (chemotaxis), engulf it (phagocytosis), and destroy it by intracellular digestion.5, 6 These observations still form the basis of our thoughts on inflammation and cellular immunology.

In the case of chorioamnionitis, a lesion characterized by an intense infiltration of maternal neutrophils in the chorioamniotic tissues,7 questions are being asked about the genetic and molecular controls over this pathology. The questions are very important because chorioamnionitis commonly causes premature labor and delivery and sepsis in premature infants.

A few decades ago, the emphasis about the prevention or amelioration of chorioamnionitis was limited to an identification of bacterial pathogens and a selection of the most appropriate antibiotics to eliminate the infections. Those measures are still appropriate, but not always sufficient. Indeed, the need to control the inflammation was recently evidenced in an experimentally induced group B streptococcal amnionitis in which therapeutic intervention with an antibiotic was compared with treatment with the same antibiotic and 2 anti-inflammatory agents.8 The combined therapy was superior to antibiotics per se in suppressing the production of pro-inflammatory cytokines and in prolonging the gestational period. In that respect, there is considerable evidence that pro-inflammatory cytokines are important in the pathogenesis of human chorioamnionitis. Intra-amniotic levels of interleukin (IL)-6, IL-8, IL-18, monocyte chemoattractant protein (MCP)-1, and MCP-3 are significantly higher in cases of premature labor in which there is histologic evidence of chorioamnionitis.9 There is also experimental evidence in macaques (rhesus monkeys) that preterm labor is induced by intra-amniotic infusions of IL-1β and tumor necrosis factor-α, but not by IL-6 or IL-8.10

Although exogenous IL-6 did not induce preterm labor in rhesus monkeys,10 the participation of IL-6 and other pro-inflammatory cytokines was not ruled out because these agents often provoke each other's production. As reported in this issue of The Journal,1 2 genotypes of the IL-6 gene promoter region,1 IL-6 174 GG and −572 GC, correlated closely with histologic evidence of chorioamnionitis.1 This is in keeping with the enhanced release of elastase by neutrophils exposed to IL-611 and associations of those same IL-6 gene promoter polymorphisms with severe systemic inflammation in children with sepsis12 and with other inflammatory disorders cited in their article.1

In the study by Aly et al in this issue of The Journal,2 the data suggested that chronic alcohol ingestion and anemia were dominant risk factors for the development of chorioamnionitis.2 In that respect, the effects of alcohol on the immune system and the inflammatory responses are complex. Some effects are immunosuppressive and anti-inflammatory; other effects are pro-inflammatory. One anti-inflammatory effect is that ethanol decreases the expression of the adherence molecule CD11b on neutrophils stimulated in vitro by lipopolysaccharide or IL-8.13 Consequently, the migration of such neutrophils into inflammatory sites would be impaired. However, serum levels of IL-6 are increased in heavy consumers of ethanol.14

It has also been found that alcohol decreases the transcription of the acute phase reactant hepcidin and promotes duodenal transport of iron.15 Excess tissue iron has the potential to cause oxidative damage by the formation of reactive oxygen species.16 Therefore, alcohol may lead to inflammation via oxidative mechanisms. Damage to the local innate immune system caused by these events cannot be ruled out.17 If this is the case, the local defenses against bacterial pathogens would be impaired. Clearly the association of excessive ethanol ingestion with chorioamnionitis2 needs to be verified before more elaborate investigations are conducted.

Anemia also was found to be a risk factor in patients with chorioamnionitis,2 but there is no evidence that anemia alone predisposes a patient to inflammation. However, the reverse is true.18 It is recognized that inflammation leads to anemia by the production of hepcidin that binds to and induces the destruction of the iron transporter ferroportin.19 Consequently, iron is sequestered in tissues such as the liver and spleen and in macrophages involved in the recycling of iron. Thus, an iron deficiency anemia develops, but, as previously indicated, the tissue overload of iron may have deleterious effects. Perhaps in future studies the relationships among hepcidin, inflammatory mediators, and iron traffic in the pathogenesis of chorioamnionitis will be explored. A further impetus for such studies is that IL-6 induces the expression of hepcidin.20 Thus it seems possible that increases in serum hepcidin occur during the development of chorioamnionitis. Therefore, the main points of these 2 articles—IL-6 promoter genotypes in 1 article1 and excessive ethanol ingestion and anemia in the other article2—which at first seem widely separated, may be closely connected.

In that respect, studies of the genetic aspects of inflammation, differences in the inflammation provoked by different bacterial pathogens, the effects of environmental agents, the distinctive inflammatory reactions at different organ sites,2 and the status of innate defenses in the inflamed tissues may further our understanding of the pathogenesis of chorioamnionitis and of ways of preventing and ameliorating this cause of premature delivery. Finally, it is possible that chorioamnionitis may have more than 1 cause. Molecular markers of the susceptibility to infection and inflammation of the chorion and amnion may be instrumental in ascertaining whether that is the case.21

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References 

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  2. Aly H, Alhabashi G, Hammad TA, Owusu-Ansah S, Bathgate S, Mohamed M. ABO phenotype and risk factors associated with chorioamnionitis. J Pediatr. 2008;153:16–18
  3. Metchnikov E. The Nobel Prize in Physiology or Medicine 1908 (On the present state of the question of immunity in infectious diseases. December 11, 1908. Nobel Prize Organization). http://nobelprize.org/nobel_prizes/medicine/laureates/1908/Mechnikov-lecture.htmlAccessed Sep 6, 2007
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  21. Schmalstieg FC, Goldman AS. The basis of susceptibility to lung infection. In:  Cagle P,  Fander DS,  Jagidr J,  Barrios R,  Haque A,  Popper H editor. Molecular pathology of lung disease. New York: Springer; 2008;p. 369–381

PII: S0022-3476(08)00222-9

doi:10.1016/j.jpeds.2008.03.029

Refers to article:

  • ABO Phenotype and Other Risk Factors Associated with Chorioamnionitis , 04 April 2008

    Hany Aly, Galeb Alhabashi, Tarek A. Hammad, Sylvia Owusu-Ansah, Susanne Bathgate, Mohamed Mohamed
    The Journal of Pediatrics July 2008 (Vol. 153, Issue 1, Pages 16-18)

  • Interleukin-6 Polymorphism is Associated with Chorioamnionitis and Neonatal Infections in Preterm Infants , 04 April 2008

    Milla Reiman, Harry Kujari, Eeva Ekholm, Helena Lapinleimu, Liisa Lehtonen, Leena Haataja, PIPARI Study Group
    The Journal of Pediatrics July 2008 (Vol. 153, Issue 1, Pages 19-24.e1)

The Journal of Pediatrics
Volume 153, Issue 1 , Pages 3-4, July 2008

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