{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T12:26:05Z","timestamp":1763727965746,"version":"3.41.2"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017051","name":"College of Medicine, Seoul National University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> The chorionic plate (CP) has been denigrated by the well-known route of the extraplacental membranes from the decidua parietalis through the chorion to the amnion in the progression of ascending intrauterine infection among preterm births (PTBs). However, considering previous studies reporting the relationship among intra-amniotic inflammatory response (IAIR), the progression of inflammation in extraplacental membranes and early-onset neonatal sepsis (EONS), and the anatomic connection between extraplacental membranes and CP, there is a good chance that IAIR would be more likely and severe according to the progression of inflammation in CP, and this progression of inflammation in CP would be associated with a significant increase in EONS in neonates delivered due to either PTL or preterm-PROM. Unfortunately, there is no information about the relationship among IAIR, the progression of inflammation in CP, and EONS among spontaneous PTBs. The objective of the current study is to examine this issue.<\/jats:p><jats:p><jats:bold>Method:<\/jats:bold> The study population included 309 singleton pregnant women-delivered preterm neonates with the following conditions: (1) gestational age (GA) at delivery: 20.0~36.9 weeks; (2) spontaneous PTBs: PTL (151 cases) or preterm-PROM (158 cases); (3) available results of placental histologic examination; (4) without congenital anomaly; and (5) delivery within 60 h of amniocentesis. We examined IAIR, and the frequency of intra-amniotic inflammation (IAI) and EONS according to the progression of inflammation in CP [i.e., stage-0, inflammation-free CP; stage-1, inflammation restricted to subchorionic fibrin (SCF); stage-2, inflammation in connective tissue (CT) of CP but without chorionic vasculitis; and stage-3, chorionic vasculitis]. IAIR was determined by amniotic fluid (AF) matrix metalloproteinase-8 (MMP-8) concentration (ng\/ml), and IAI was defined as an elevated AF MMP-8 concentration (\u226523 ng\/ml). EONS included either suspected or proven EONS.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> (1) Each stage (stage-0 to stage-3) was present in 69.3% (214\/309), 15.9% (49\/309), 11.0% (34\/309), and 3.9% (12\/309) of the study population. (2) AF MMP-8 concentrations continuously elevated according to the progression of inflammation in CP [stage-0 vs. stage-1 vs. stage-2 vs. stage-3; median (ng\/ml), range (ng\/ml); 6.0 (0.3\u20134202.7) vs. 153.9 (0.3\u20136142.6) vs. 464.9 (5.8\u20133929.0) vs. 1,780.4 (35.1\u20135019.5); Kruskal\u2013Wallis test, <jats:italic>P<\/jats:italic> &amp;lt; 0.001 and Spearman's rank-correlation test, <jats:italic>P<\/jats:italic> &amp;lt; 0.000001, <jats:italic>r<\/jats:italic> = 0.553]. (3) Moreover, the frequency of IAI and EONS gradually increased with the progression of inflammation in CP [stage-0 vs. stage-1 vs. stage-2 vs. stage-3; IAI, 30.5% (64\/210) vs. 70.2% (33\/47) vs. 96.7% (29\/30) vs. 100% (12\/12); EONS, 3.5% (7\/200) vs. 25.5% (12\/47) vs. 32.3% (10\/31) vs. 40.0% (4\/10); each for Pearson's chi-square test, <jats:italic>P<\/jats:italic> &amp;lt; 0.000001 and linear-by-linear association, <jats:italic>P<\/jats:italic> &amp;lt; 0.000001]. (4) Of note, multiple logistic regression analysis demonstrated that a more advanced stage in the progression of inflammation within CP was associated with a higher odds ratio (OR) for EONS [stage-1 vs. stage-2 vs. stage-3; OR, 7.215, 95% confidence-interval (CI) (2.177\u201323.908) vs. OR, 10.705, 95% CI (2.613\u201343.849) vs. OR, 27.189, 95% CI (2.557\u2013289.124)] compared with stage-0 even after the adjustment for potential confounding variables.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> IAIR is more likely and severe according to the progression of inflammation in CP, and this progression of inflammation in CP is an independent risk factor for EONS in spontaneous PTBs. This finding suggests that CP may be another playground for the progression of ascending intrauterine infection in addition to extraplacental membranes, and the progression of inflammation in CP may be used for the prediction of EONS in spontaneous PTBs.<\/jats:p>","DOI":"10.3389\/fped.2021.582472","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T05:01:55Z","timestamp":1619672515000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The Relationship Among Intra-Amniotic Inflammatory Response, The Progression of Inflammation in Chorionic Plate and Early-Onset Neonatal Sepsis"],"prefix":"10.3389","volume":"9","author":[{"given":"Kyung Chul","family":"Moon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeong-Won","family":"Oh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chan-Wook","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joong Shin","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong Kwan","family":"Jun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1126\/science.1251816","article-title":"Preterm labor: one syndrome, many causes","volume":"345","author":"Romero","year":"2014","journal-title":"Science."},{"key":"B2","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1111\/pin.12412","article-title":"Preterm labor and preterm premature rupture of membranes have a different pattern in the involved compartments of acute histologoic chorioamnionitis and\/or funisitis: patho-physiologic implication related to different clinical manifestations","volume":"66","author":"Park","year":"2016","journal-title":"Pathol Int."},{"key":"B3","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1056\/NEJM198810133191503","article-title":"A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity","volume":"319","author":"Hillier","year":"1988","journal-title":"N Engl J Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1016\/0002-9378(92)91609-E","article-title":"The relationship between acute inflammatory lesions of the preterm placenta and amniotic fluid microbiology","volume":"166","author":"Romero","year":"1992","journal-title":"Am J Obstet Gynecol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"731","DOI":"10.3109\/15513819609169300","article-title":"Clinical significance of increasing histologic severity of acute inflammation in the fetal membranes and umbilical cord","volume":"16","author":"van Hoeven","year":"1996","journal-title":"Pediatr Pathol Lab Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.placenta.2013.11.001","article-title":"Do placental histologic findings of chorion-decidual hemorrhage or inflammation in spontaneous preterm birth influence outcomes in the subsequent pregnancy?","volume":"35","author":"Hackney","year":"2014","journal-title":"Placenta."},{"key":"B7","doi-asserted-by":"publisher","first-page":"265","DOI":"10.2350\/09-02-0604-OA.1","article-title":"Fetal inflammatory response is often present at early stages of intra-amniotic infection, and its distribution along cord is variable","volume":"13","author":"Katzman","year":"2010","journal-title":"Pediatr Dev Pathol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.1016\/j.ajog.2006.06.072","article-title":"Preterm labor is induced by intraamniotic infusions of interleukin-1 beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model","volume":"195","author":"Sadowsky","year":"2007","journal-title":"Am J Obstet Gynecol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1515\/jpm-2012-0034","article-title":"Midtrimester amniotic fluid concentrations of interleukin-6 and interferon-gamma-inducible protein-10: evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early (<32 weeks) and late (>32 weeks) preterm delivery","volume":"40","author":"Gervasi","year":"2012","journal-title":"J Perinat Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.placenta.2008.09.017","article-title":"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","volume":"30","author":"Park","year":"2009","journal-title":"Placenta."},{"key":"B11","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3109\/14767058.2013.806898","article-title":"Fetal, amniotic and maternal inflammatory responses in early stage of ascending intrauterine infection, inflammation restricted to chorio-decidua, in preterm gestation","volume":"27","author":"Park","year":"2014","journal-title":"J Matern Fetal Neonatal Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.placenta.2017.07.324","article-title":"Inflammation in the connective-tissue of chorion, but not inflammation restricted to the trophoblast-layer of chorion and the decidua, is associated with the development of amnionitis and more intense acute-histologic chorioamnionitis in the context of choriodeciduitis","volume":"57","author":"Oh","year":"2017","journal-title":"Placenta."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1016\/0002-9378(93)90297-V","article-title":"Neutrophil attractant\/activating peptide-1\/interleukin-8: association with histologic chorioamnionitis, preterm delivery, and bioactive amniotic fluid leukoattractants","volume":"169","author":"Cherouny","year":"1993","journal-title":"Am J Obstet Gynecol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1016\/0002-9378(95)90028-4","article-title":"Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity","volume":"172","author":"Yoon","year":"1995","journal-title":"Am J Obstet Gynecol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1515\/jpme.1996.24.6.633","article-title":"Correlation between cytokine levels of amniotic fluid and histological chorioamnionitis in preterm delivery","volume":"24","author":"Negishi","year":"1996","journal-title":"J Perinat Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1034\/j.1600-0412.1998.770508.x","article-title":"The relationship between amniotic fluid interleukin-6 concentration and histologic evidence of chorioamnionitis","volume":"77","author":"Tsuda","year":"1998","journal-title":"Acta Obstet Gynecol Scand."},{"key":"B17","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1111\/j.1440-1827.2004.01659.x","article-title":"Chorionic plate vessels as an origin of amniotic fluid neutrophils","volume":"54","author":"Lee","year":"2004","journal-title":"Pathol Int."},{"key":"B18","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1080\/01443610600604432","article-title":"Amniotic fluid neutrophil elastase and lactate dehydrogenase: association with histologic chorioamnionitis","volume":"85","author":"Kidokoro","year":"2006","journal-title":"Acta Obstet Gynecol Scand."},{"key":"B19","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1097\/AOG.0b013e31816102aa","article-title":"Using proteomic analysis of the human amniotic fluid to identify histologic chorioamnionitis","volume":"111","author":"Buhimschi","year":"2008","journal-title":"Obstet Gynecol."},{"key":"B20","first-page":"733","article-title":"Value of amniotic fluid interleukin-8 for the prediction of histological chorioamnionitis in preterm premature rupture of membranes","volume":"30","author":"Kacerovsky","year":"2009","journal-title":"Neuro Endocrinol Lett."},{"key":"B21","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.ejogrb.2011.05.009","article-title":"Neutrophil elastase and interleukin-6 in amniotic fluid as indicators of chorioamnionitis and funisitis","volume":"158","author":"Miura","year":"2011","journal-title":"Euro J Obstet Gynecol Reprod Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1111\/aji.12360","article-title":"Accurate prediction of the stage of histological chorioamnionitis before delivery by amniotic fluid IL-8 level","volume":"73","author":"Yoneda","year":"2015","journal-title":"Am J Reprod Immun."},{"key":"B23","first-page":"175","article-title":"A microbiologic and clinical study of placental inflammation at term","volume":"70","author":"Dong","year":"1987","journal-title":"Obstet Gynecol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/0029-7844(95)00380-0","article-title":"Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: a comparison with amniotic fluid white blood cell count","volume":"87","author":"Yoon","year":"1996","journal-title":"Obstet Gynecol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/S0029-7844(96)00339-0","article-title":"Serum C-reactive protein, white blood cell count, and amniotic fluid white blood cell count in women with preterm premature rupture of membranes","volume":"88","author":"Yoon","year":"1996","journal-title":"Obstet Gynecol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/0002-9378(85)90617-9","article-title":"The fetal biophysical profile in patients with premature rupture of membranes\u2014an early predictor of fetal infection","volume":"152","author":"Vintzileos","year":"1985","journal-title":"Am J Obstet Gynecol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/S0002-9378(98)70272-8","article-title":"The fetal inflammatory response syndrome","volume":"179","author":"Gomez","year":"1998","journal-title":"Am J Obstet Gynecol."},{"key":"B28","first-page":"383","article-title":"The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies","volume":"73","author":"Salafia","year":"1989","journal-title":"Obstet Gynecol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1067\/mob.2001.117679","article-title":"The relationship between amniotic fluid matrix metalloproteinase-8 and funisitis","volume":"185","author":"Park","year":"2001","journal-title":"Am J Obstet Gynecol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/j.ajog.2004.06.085","article-title":"Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes","volume":"191","author":"Shim","year":"2004","journal-title":"Am J Obstet Gynecol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"698","DOI":"10.5858\/arpa.2015-0225-CC","article-title":"Sampling and definitions of placental lesions: amsterdam placental workshop group consensus statement","volume":"140","author":"Khong","year":"2016","journal-title":"Arch Pathol Lab Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1097\/00003081-195909000-00010","article-title":"Amniotic infection syndrome; pathogenesis, morphology, and significance in circumnatal mortality","volume":"2","author":"Blanc","year":"1959","journal-title":"Clin Obstet Gynecol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"S29","DOI":"10.1016\/j.ajog.2015.08.040","article-title":"Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance","volume":"213","author":"Kim","year":"2015","journal-title":"Am J Obstet Gynecol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1016\/0002-9378(89)90405-5","article-title":"Amniotic fluid leukotaxis assay as an early indicator of chorioamnionitis","volume":"161","author":"Pankuch","year":"1989","journal-title":"Am J Obstet Gynecol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1155\/S1064744997000471","article-title":"Determining the maternal and fetal cellular immunologic contributions in preterm deliveries with clinical or subclinical chorioamnionitis","volume":"5","author":"McNamara","year":"1997","journal-title":"Infect Dis Obstet Gynecol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1067\/mob.2001.116689","article-title":"Umbilical arteritis and phlebitis mark different stages of the fetal inflammatory response","volume":"185","author":"Kim","year":"2001","journal-title":"Am J Obstet Gynecol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.ajog.2017.09.013","article-title":"Are amniotic fluid neutrophils in women with intraamniotic infection and\/or inflammation of fetal or maternal origin?","volume":"217","author":"Gomez-Lopez","year":"2017","journal-title":"Am J Obstet Gynecol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1067\/mob.2001.117678","article-title":"An elevated amniotic fluid matrix metalloproteinase-8 level at the time of mid-trimester genetic amniocentesis is a risk factor for spontaneous preterm delivery","volume":"185","author":"Yoon","year":"2001","journal-title":"Am J Obstet Gynecol."}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.582472\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T05:02:03Z","timestamp":1619672523000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.582472\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,29]]},"references-count":38,"alternative-id":["10.3389\/fped.2021.582472"],"URL":"https:\/\/doi.org\/10.3389\/fped.2021.582472","relation":{},"ISSN":["2296-2360"],"issn-type":[{"type":"electronic","value":"2296-2360"}],"subject":[],"published":{"date-parts":[[2021,4,29]]},"article-number":"582472"}}