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The relationship among the progression of inflammation in umbilical cord, fetal inflammatory response, early-onset neonatal sepsis, and chorioamnionitis.

ABSTRACT: OBJECTIVES:No information exists about whether fetal inflammatory-response(FIR), early-onset neonatal sepsis(EONS) and chorioamnionitis(an advanced-stage of maternal inflammatory-response in extraplacental membranes) continuously increase according to the progression of inflammation in umbilical-cord(UC). The objective of current-study is to examine this-issue. METHODS:Study-population included 239singleton pregnant-women(gestational-age[GA] at delivery: 21.6~36weeks) who had inflammation in extraplacental membranes or chorionic plate (CP) and either preterm-labor or preterm-PROM. We examined FIR, and the frequency of fetal inflammatory-responses syndrome(FIRS), proven-EONS, suspected-EONS and chorioamnionitis according to the progression of inflammation in UC. The progression of inflammation in UC was divided with a slight-modification from previously reported-criteria as follows: stage0, inflammation-free UC; stage-1: umbilical phlebitis only; stage-2: involvement of at least one UA and either the other UA or UV without extension into WJ; stage-3: the extension of inflammation into WJ. FIR was gauged by umbilical-cord-plasma(UCP) CRP concentration(ng/ml) at birth, and FIRS was defined as an elevated UCP CRP concentration at birth(?200ng/ml). RESULTS:Stage-0, stage-1, stage-2 and stage-3 of inflammation in UC were present in 48.1%, 15.5%, 6.7%, and 29.7% of cases. FIR continuously increased according to the progression of inflammation in UC(Kruskal-Wallis test,P<0.001; Spearman-rank-correlation test,P<0.000001,r = 0.546). Moreover, there was a significant and stepwise increase in the frequency of FIRS, proven-EONS, suspected-EONS and chorioamnionitis according to the progression of inflammation in UC(each for P<0.000005 in both chi-square test and linear-by-linear-association). Multiple logistic-regression analysis demonstrated that the more advanced-stage in the progression of inflammation in UC(i.e., stage-1 vs. stage-2 vs. stage-3), the better predictor of suspected-EONS (Odds-ratio[OR]3.358, 95%confidence-interval[CI]:1.020-11.057 vs. OR5.147, 95%CI:1.189-22.275 vs. OR11.040, 95%CI:4.118-29.592) and chorioamnionitis(OR6.593, 95%CI:2.717-15.999 vs. OR16.508, 95%CI:3.916-69.596 vs. OR20.167, 95%CI:8.629-47.137). CONCLUSION:FIR, EONS and chorioamnionitis continuously increase according to the progression of inflammation in UC among preterm-gestations with inflammation in extraplacental membranes or CP. This finding may suggest that funisitis(inflammation in UC) is both qualitatively and quantitatively histologic-counterpart of FIRS, and a surrogate-marker for chorioamnionitis.

SUBMITTER: Oh JW

PROVIDER: S-EPMC6863554 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The relationship among the progression of inflammation in umbilical cord, fetal inflammatory response, early-onset neonatal sepsis, and chorioamnionitis.

Oh Jeong-Won JW Park Chan-Wook CW Moon Kyung Chul KC Park Joong Shin JS Jun Jong Kwan JK

PloS one 20191119 11

<h4>Objectives</h4>No information exists about whether fetal inflammatory-response(FIR), early-onset neonatal sepsis(EONS) and chorioamnionitis(an advanced-stage of maternal inflammatory-response in extraplacental membranes) continuously increase according to the progression of inflammation in umbilical-cord(UC). The objective of current-study is to examine this-issue.<h4>Methods</h4>Study-population included 239singleton pregnant-women(gestational-age[GA] at delivery: 21.6~36weeks) who had infl ...[more]

PMID: 31743377

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Project description:BackgroundChorioamnionitis is a risk factor for future asthma development. Animal models of chorioamnionitis demonstrate increased TH17-to-Treg ratios associated with proinflammatory cytokine elevations. The association of chorioamnionitis on human neonatal immune cells systemically and within tissues is not known.MethodsWe enrolled two cohorts to evaluate TH17 and regulatory T cell (Treg) phenotypic markers in chorioamnionitis. From a cohort of 19 live birth infants, we collected cord blood and placenta samples to evaluate for signs of acute and chronic histologic inflammation and cell phenotype characterization. We analyzed a second cohort of stillborn infants with and without chorioamnionitis to classify and enumerate cell infiltrate phenotypes in the spleen, thymus, and lung. We used linear regression analysis determine the association of retinoic acid-related orphan receptor gamma t positive (RORγt+) and Treg cell frequency with different types of inflammation seen in the live cohort subjects. Using linear mixed models, we evaluated for any associations between chorioamnionitis and T- and B-cell with a logarithmic scale for level of expression of cellular markers. We then performed Wilcoxon rank sum tests to assess the associations between cell count and chorioamnionitis.ResultsIn the live birth subjects with chronic placental inflammation we observed an increased proportion of RORγt+ cells in Foxp3+ cells, regardless of the presence of acute inflammation, compared to subjects with neither acute nor chronic inflammation. We also found an increased proportion of RORγt+ cells within Foxp3+ cells in subjects with acute high stage fetal and maternal inflammation compared to those without acute or chronic inflammation. In the stillborn subjects with chorioamnionitis, we observed a decrease in splenic Foxp3+ cells and an increase in lung CD3+ cells compared with subjects that did not have chorioamnionitis.ConclusionExposure to chorioamnionitis in utero may affect immune activation in neonates with an increased frequency of RORγt+ cells systemically as well as lymphocytic infiltrate in the lung. Our findings suggest an increase in RORγt+ cells during chorioamnionitis and thus may support the known associations between chorioamnionitis with asthma.

Project description:BackgroundEarly onset sepsis (EOS) is a major cause of morbidity and mortality in preterm infants, yet diagnosis remains inadequate resulting in missed cases or prolonged empiric antibiotics with adverse consequences. Evaluation of acute phase reactant (APR) biomarkers in umbilical cord blood at birth may improve EOS detection in preterm infants with intrauterine infection.MethodsIn this nested case-control study, infants (29.7 weeks gestation, IQR: 27.7-32.2) were identified from a longitudinal cohort with archived cord blood and placental histopathology. Patients were categorized using culture, laboratory, clinical, and antibiotic treatment data into sepsis groups: confirmed sepsis (cEOS, n = 12); presumed sepsis (PS, n = 30); and no sepsis (controls, n = 30). Nine APRs were measured in duplicate from cord blood using commercially available multiplex immunoassays (Bio-Plex Pro™). In addition, placental histopathologic data were linked to biomarker results.ResultscEOS organisms were Escherichia coli, Streptococcus agalactiae, Proteus mirabilis, Haemophilus influenzae and Listeria monocytogenes. C-reactive protein (CRP), serum amyloid A (SAA), haptoglobin (Hp), serum amyloid P and ferritin were significantly elevated in cEOS compared to controls (p<0.01). SAA, CRP, and Hp were elevated in cEOS but not in PS (p<0.01) and had AUCs of 99%, 96%, and 95% respectively in predicting cEOS. Regression analysis revealed robust associations of SAA, CRP, and Hp with EOS after adjustment for covariates. Procalcitonin, fibrinogen, ?-2-macroglobulin and tissue plasminogen activator were not significantly different across groups. Placental acute inflammation was associated with APR elevation and was present in all cEOS, 9 PS, and 17 control infants.ConclusionThis study shows that certain APRs are elevated in cord blood of premature infants with EOS of intrauterine origin. SAA, CRP, and Hp at birth have potential diagnostic utility for risk stratification and identification of infants with EOS.

Project description:Background: Preterm infants exposed to chorioamnionitis and with a fetal inflammatory response are at risk for neonatal morbidity and adverse outcome. Alarmins S100A8, S100A9, and S100A12 are expressed by myeloid cells and have been associated with inflammatory activation and monocyte modulation. Aim: To study S100A alarmin expression in cord blood monocytes from term healthy and preterm infants and relate results to clinical findings, inflammatory biomarkers and alarmin protein levels, as well as pathways identified by differentially regulated monocyte genes. Methods: Cord blood CD14+ monocytes were isolated from healthy term (n = 10) and preterm infants (<30 weeks gestational age, n = 33) by MACS technology. Monocyte RNA was sequenced and gene expression was analyzed by Principal Component Analysis and hierarchical clustering. Pathways were identified by Ingenuity Pathway Analysis. Inflammatory proteins were measured by Multiplex ELISA, and plasma S100A proteins by mass spectrometry. Histological chorioamnionitis (HCA) and fetal inflammatory response syndrome (FIRS) were diagnosed by placenta histological examination. Results: S100A8, S100A9, and S100A12 gene expression was significantly increased and with a wider range in preterm vs. term infants. High S100A8 and S100A9 gene expression (n = 17) within the preterm group was strongly associated with spontaneous onset of delivery, HCA, FIRS and elevated inflammatory proteins in cord blood, while low expression (n = 16) was associated with impaired fetal growth and physician-initiated delivery. S100A8 and S100A9 protein levels were significantly lower in preterm vs. term infants, but within the preterm group high S100A gene expression, spontaneous onset of labor, HCA and FIRS were associated with elevated protein levels. One thousand nine hundred genes were differentially expressed in preterm infants with high vs. low S100A alarmin expression. Analysis of 124 genes differentially expressed in S100A high as well as FIRS and HCA groups identified 18 common pathways and S100A alarmins represented major hubs in network analyses. Conclusion: High expression of S100A alarmins in cord blood monocytes identifies a distinct clinical risk group of preterm infants exposed to chorioamnionitis and with a fetal inflammatory response. Gene and pathway analyses suggest that high S100A alarmin expression also affects monocyte function. The connection with monocyte phenotype and inflammation-stimulated S100A expression in other cell types (e.g., neutrophils) warrants further investigation.

Project description:BackgroundThe relationship between histological chorioamnionitis and haematological and biochemical markers in mothers and infants at delivery, and in infants postnatally, is incompletely characterised. These markers are widely used in the diagnosis of maternal and neonatal infection. Our objective was to investigate the effects of histological chorioamnionitis (HCA) on haematological and biochemical inflammatory markers in mothers and infants at delivery, and in infants post-delivery.MethodsTwo hundred and forty seven mothers, delivering 325 infants, were recruited at the only tertiary perinatal centre in Western Australia. Placentae were assessed for evidence of HCA using a semi-quantitative scoring system. Maternal high sensitivity C-reactive protein (hsCRP), procalcitonin, and umbilical cord hsCRP, procalcitonin, white cell count and absolute neutrophil count were measured at delivery. In infants where sepsis was clinically suspected, postnatal CRP, white cell count and absolute neutrophil count were measured up to 48 hours of age. The effect of HCA on maternal, cord and neonatal markers was evaluated by multivariable regression analysis.ResultsThe median gestational age was 34 weeks and HCA was present in 26 of 247 (10.5%) placentae. Mothers whose pregnancies were complicated by HCA had higher hsCRP (median 26 (range 2-107) versus 5.6 (0-108) mg/L; P<0.001). Histological chorioamnionitis was associated with higher umbilical cord hsCRP (75(th) percentile 2.91 mg/L (range 0-63.9) versus 75(th) percentile 0 mg/L (0-45.6); P<0.001) and procalcitonin (median 0.293 (range 0.05-27.37) versus median 0.064 (range 0.01-5.24) ug/L; P<0.001), with a sustained increase in neonatal absolute neutrophil count (median 4.5 (0.1-26.4)×10(9)/L versus 3.0 (0.1-17.8)×10(9)/L), and CRP up to 48 hours post-partum (median 10 versus 6.5 mg/L) (P<0.05 for each).ConclusionHistological chorioamnionitis is associated with modest systemic inflammation in maternal and cord blood. These systemic changes may increase postnatally, potentially undermining their utility in the diagnosis of early-onset neonatal infection.

Project description:ImportanceUmbilical cord pH (UC-pH) level is an important objective indicator of intrapartum fetal hypoxia and is used to predict neonatal morbidity and mortality. A UC-pH value of less than 7.00 is often defined as a threshold for severe acidosis, but existing evidence is divergent and largely based on UC-pH measurements from selected populations; consequently, the results are challenging to interpret.ObjectiveTo investigate the association between UC-pH levels and the risk of adverse neonatal outcomes in a national setting with universal UC-pH measurement.Design, setting, and participantsThis national, population-based cohort study included all liveborn, singleton, full-term infants without malformations born in Denmark from January 1, 2012, to December 31, 2018. Data were analyzed from January 1, 2023, to March 1, 2024.ExposureUmbilical cord pH level categorized as less than 7.00, 7.00 to 7.09, 7.10 to 7.19 and 7.20 to 7.50 (reference group).Main outcomes and measuresThe primary outcome was a composite of severe adverse neonatal outcomes: neonatal death, therapeutic hypothermia, mechanical ventilation, treatment with inhaled nitric oxide, or seizures. Secondary outcomes were individual components of the primary outcome, Apgar score, respiratory outcomes, and hypoglycemia. Data are presented as adjusted risk ratios (ARRs) with 95% CIs.ResultsAmong the 340 431 infants included, mean (SD) gestational age was 39.9 (1.6) weeks; mean (SD) birth weight was 3561 (480) g; and 51.3% were male. Umbilical cord pH of less than 7.20 was observed more often among infants with a gestational age of 40 or 41 weeks (31.6%-33.6% compared with 18.2%-20.2% at a gestational age of 39 weeks) and among male infants (53.9%-55.4% vs 44.6%-46.1% among female infants). Compared with the pH reference group (576 of 253 540 [0.2%]), the risk for the primary outcome was increased for the groups with UC-pH levels of less than 7.00 (171 of 1743 [9.8%]), 7.00 to 7.09 (101 of 11 904 [0.8%]), and 7.10 to 7.19 (259 of 73 244 [0.4%]). Comparable patterns were observed for the individual outcomes, except for neonatal death, which was only increased in the group with UC-pH levels of less than 7.10. The risk of treatment with continuous positive airway pressure was increased when UC-pH levels were less than 7.20, and the risk of hypoglycemia was 21.5% if UC-pH levels were less than 7.10.Conclusions and relevanceIn this cohort study of 340 431 newborn infants, results support and extend previous studies indicating a higher risk of adverse outcomes even at UC-pH levels above 7.00. The threshold for more intensive observation and treatment may be reconsidered.

Dataset Information

The relationship among the progression of inflammation in umbilical cord, fetal inflammatory response, early-onset neonatal sepsis, and chorioamnionitis.

Publications

The relationship among the progression of inflammation in umbilical cord, fetal inflammatory response, early-onset neonatal sepsis, and chorioamnionitis.

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