A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol
ABSTRACT OBJECTIVE: There is no evidence for the participation of the human fetus in the mechanisms responsible for the onset of preterm labor. We propose that preterm labor in the setting of infection results from the actions of proinflammatory cytokines secreted as part of the fetal and/or maternal host response to microbial invasion. The objective of this study was to determine whether a systemic fetal inflammatory response, defined as an elevation of fetal plasma interleukin-6 concentrations, has a temporal relationship with the commencement of labor.
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- "Microorganisms and their products can initiate an inflammatory response by the engagement of pattern recognition receptors [163, 172, 186–200] and the production of cytokines [112, 122, 151, 201–224], chemokines [213, 215, 216, 219, 223, 225–244], prostaglandins                 , and proteases [142, 145, 262–277]. If microorganisms in the amniotic cavity reach the fetus, this can result in a fetal systemic inflammatory response  , which is associated with multi-organ involvement [141, 278, 280–289] and preterm delivery . We report herein, for the first time, a systematic study of the maternal cytokine profile using multiplex immunoassays in patients with clinical chorioamnionitis at term stratified according to the status of the amniotic cavity (presence/absence of inflammation and bacteria). "
ABSTRACT: Introduction: Fever is a major criterion for clinical chorioamnionitis; yet, many patients with intrapartum fever do not have demonstrable intra-amniotic infection. Some cytokines, such as interleukin (IL)-1, IL-6, interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), can induce a fever. The objective of this study was to determine whether maternal plasma concentrations of cytokines could be of value in the identification of patients with the diagnosis of clinical chorioamnionitis at term who have microbial-associated intra-amniotic inflammation. Methods: A retrospective cross-sectional study was conducted, including patients with clinical chorioamnionitis at term (n=41; cases) and women in spontaneous labor at term without clinical chorioamnionitis (n=77; controls). Women with clinical chorioamnionitis were classified into three groups according to the results of amniotic fluid culture, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS), and amniotic fluid IL-6 concentration: 1) no intra-amniotic inflammation; 2) intra-amniotic inflammation without detectable microorganisms; or 3) microbial-associated intra-amniotic inflammation. The maternal plasma concentrations of 29 cytokines were determined with sensitive and specific V-PLEX immunoassays. Nonparametric statistical methods were used for analysis, adjusting for a false discovery rate of 5%. Results: 1) The maternal plasma concentrations of pyrogenic cytokines (IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) were significantly higher in patients with clinical chorioamnionitis at term than in those with spontaneous term labor without clinical chorioamnionitis; 2) the maternal plasma concentrations of cytokines were not significantly different among the three subgroups of patients with clinical chorioamnionitis (intra-amniotic inflammation with and without detectable bacteria and those without intra-amniotic inflammation); and 3) among women with the diagnosis of clinical chorioamnionitis, but without evidence of intra-amniotic inflammation, the maternal plasma concentrations of pyrogenic cytokines were significantly higher than in patients with spontaneous labor at term. These observations suggest that a fever can be mediated by increased circulating concentrations of these cytokines, despite the absence of a local intra-amniotic inflammatory response. Conclusions: 1) The maternal plasma concentrations of pyrogenic cytokines (e.g. IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) are higher in patients with intra-partum fever and the diagnosis of clinical chorioamnionitis at term than in those in spontaneous labor at term without a fever; and 2) maternal plasma cytokine concentrations have limited value in the identification of patients with bacteria in the amniotic cavity. Accurate assessment of the presence of intra-amniotic infection requires amniotic fluid analysis.Journal of Perinatal Medicine 09/2015; DOI:10.1515/jpm-2015-0103 · 1.36 Impact Factor
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- "In PPROM, a lower genital tract infection may cause an ascending infection that leads to sequential inflammation of membranes and the umbilical cord  . Inflammation of the chorioamniotic membranes propagates from the chorion to the amnion, after which necrosis develops  . "
ABSTRACT: To test if there is a stepwise difference in neonatal outcomes according to the stage (or grade) of histological inflammatory response in the chorioamniotic membranes and umbilical cords of preterm premature rupture of membranes (PPROM). This retrospective study included singleton pregnancies diagnosed as PPROM and delivered prior to 34 weeks of gestation (n=339). Acute histological chorioamnionitis and funisitis were subdivided into stages (or grade) as defined by Redline et al. Neonatal composite morbidities and mortality were also monitored. Univariate and multivariate analyses were conducted. Increasing stage (or grade) of acute histological chorioamnionitis and funisitis was significantly associated with an earlier gestational age at membrane rupture and delivery. Among neonatal outcomes, respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage, retinopathy of prematurity, and composite morbidity showed incremental incidence according to increased stage (or grade) of acute chorioamnionitis, while periventricular leukomalacia and necrotizing enterocolitis did not. Only RDS, BPD, and composite morbidity showed similar incremental incidences associated with severity of funisitis stage. However, the incremental trends of each neonatal outcome were found to be nonsignificant by multivariate analysis adjusting confounding variables including gestational age at delivery. Higher incidences of neonatal morbidity according to increased stage (or grade) of either acute histological chorioamnionitis or funisitis were due to an earlier gestational age at delivery.Journal of Perinatal Medicine 08/2014; 43(2). DOI:10.1515/jpm-2014-0035 · 1.36 Impact Factor
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- "This study also documented that while F. nucleatum infection did not result in preterm birth in mice, it resulted in stillbirth (Han et al., 2004). This is akin to the " failed escape hypothesis " of stillbirth, which postulates that stillbirth occurs if a fetus fails to initiate a fetal inflammatory response with subsequent preterm birth (Blackwell et al., 2003; Romero et al., 1998). An independent study isolated bacteria from the oral cavity of a variety of individuals and subsequently used this mixture to infect gravid mice. "
ABSTRACT: The causes of preterm birth are multifactorial, but its association with infection has been well-established. The predominant paradigm describes an ascending infection from the lower genital tract through the cervix and into the presumably sterile fetal membranes and placenta. Thus, an evaluation of the role of the vaginal microbiome in preterm birth is implicated. However, emerging fields of data described in this review suggest that the placenta might not be sterile, even in the absence of clinical infection. We thus propose an additional mechanism for placental colonization and infection: hematogenous spread. When considered in the context of decades of evidence demonstrating a strong risk of recurrence for preterm birth, studies on parturition are ideal for applying the rapidly expanding field of metagenomics and analytic pipelines. The translational implications toward identification of innovative treatments for the prevention of preterm birth are further discussed. In sum, exciting advances in understanding the role of both host and microbiota in parturition and preterm birth are on the horizon.Journal of Reproductive Immunology 04/2014; 104(1). DOI:10.1016/j.jri.2014.03.006 · 2.82 Impact Factor