{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:12:54Z","timestamp":1781104374569,"version":"3.54.1"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000124","name":"Office of Research on Women's Health","doi-asserted-by":"publisher","award":["BIRCWH K12 KD HDO57022"],"award-info":[{"award-number":["BIRCWH K12 KD HDO57022"]}],"id":[{"id":"10.13039\/100000124","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["10CRP3670014"],"award-info":[{"award-number":["10CRP3670014"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007305","name":"Maternal and Child Health Bureau","doi-asserted-by":"publisher","award":["340B program H30MC24049"],"award-info":[{"award-number":["340B program H30MC24049"]}],"id":[{"id":"10.13039\/100007305","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Preeclampsia is both a vascular and inflammatory disorder. Since the placenta is a conduit for fetal development, preeclampsia should be a presumed cause of adverse infant outcomes. Yet, the relationship of placental pathology, inflammation and neurological outcomes after preeclampsia are understudied. We prospectively examined a cohort of maternal-infant dyads with preeclampsia for maternal inflammatory cytokines at time of preeclampsia diagnosis and delivery, and fetal cord blood cytokines (IL-1\u03b2, IL-6, IL-8, and TNF-\u03b1). Placentas were analyzed for inflammatory and vascular pathologies. Neurodevelopmental assessment of infants utilizing the Pediatric Stroke Outcome Measure (PSOM) was conducted at 6-month corrected gestational age. Eighty-one maternal-newborn dyads were examined. Worse neurological outcomes were not associated with elevated maternal \/ fetal cytokines. Early preterm birth (gestational age \u2264 32 weeks) was associated with worse neurological outcomes at 6-months regardless of maternal\/ fetal cytokine levels, placental pathology, or cranial ultrasound findings (OR 1.70, [1.16\u20132.48], p = 0.006). When correcting for gestational age, elevated IL-6 approached significance as a predictor for worse developmental outcome (OR 1.025 [0.985\u20131.066], p = 0.221). Pathological evidence of maternal malperfusion and worse outcomes were noted in early preterm, although our sample size was small. Our study did not demonstrate an obvious association of inflammation and placental pathology in preeclampsia and adverse neurodevelopmental outcome at 6-month corrected age but does suggest maternal malperfusion at earlier gestational age may be a risk factor for worse outcome.<\/jats:p>","DOI":"10.1371\/journal.pone.0260094","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T18:39:15Z","timestamp":1637001555000},"page":"e0260094","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inflammatory cytokines, placental pathology, and neurological outcomes in infants born to preterm preeclamptic mothers"],"prefix":"10.1371","volume":"16","author":[{"given":"Alexandra","family":"Sotiros","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianne","family":"Thornhill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam D.","family":"Post","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia D.","family":"Winn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3797-3562","authenticated-orcid":true,"given":"Jennifer","family":"Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"pone.0260094.ref001","doi-asserted-by":"crossref","first-page":"j3448","DOI":"10.1136\/bmj.j3448","article-title":"Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks\u2019 gestation in France in 2011: EPIPAGE-2 cohort study","volume":"358","author":"V Pierrat","year":"2017","journal-title":"BMJ"},{"issue":"9615","key":"pone.0260094.ref002","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S0140-6736(08)60380-3","article-title":"Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study.","volume":"371","author":"B Larroque","year":"2008","journal-title":"Lancet"},{"issue":"12","key":"pone.0260094.ref003","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1080\/14767050600965882","article-title":"Epidemiology of preterm birth and its clinical subtypes.","volume":"19","author":"CV Ananth","year":"2006","journal-title":"J Matern Fetal Neonatal Med"},{"key":"pone.0260094.ref004","doi-asserted-by":"crossref","first-page":"214365","DOI":"10.1155\/2011\/214365","article-title":"Maternal preeclampsia and neonatal outcomes.","volume":"2011","author":"CH Backes","year":"2011","journal-title":"J Pregnancy."},{"issue":"4","key":"pone.0260094.ref005","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.tins.2020.02.003","article-title":"Neurodevelopmental Outcomes of Prenatal Preeclampsia Exposure","volume":"43","author":"SB Gumusoglu","year":"2020","journal-title":"Trends Neurosci"},{"issue":"10","key":"pone.0260094.ref006","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1111\/j.1651-2227.2010.01861.x","article-title":"Impact of chorioamnionitis and preeclampsia on neurodevelopmental outcome in preterm infants below 32 weeks gestational age","volume":"99","author":"LJ Schlapbach","year":"2010","journal-title":"Acta Paediatr"},{"issue":"4 Suppl","key":"pone.0260094.ref007","doi-asserted-by":"crossref","first-page":"S115","DOI":"10.1016\/j.ajog.2015.08.042","article-title":"Why is placentation abnormal in preeclampsia?","volume":"213","author":"SJ Fisher","year":"2015","journal-title":"Am J Obstet Gynecol."},{"issue":"8","key":"pone.0260094.ref008","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nrneph.2014.102","article-title":"Pre-eclampsia part 1: current understanding of its pathophysiology.","volume":"10","author":"T Chaiworapongsa","year":"2014","journal-title":"Nat Rev Nephrol"},{"issue":"1","key":"pone.0260094.ref009","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1684\/ecn.2020.0443","article-title":"Increase of circulating inflammatory molecules in preeclampsia, an update","volume":"31","author":"G Guney","year":"2020","journal-title":"Eur Cytokine Netw"},{"issue":"2","key":"pone.0260094.ref010","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00281-007-0071-6","article-title":"Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia.","volume":"29","author":"C Rusterholz","year":"2007","journal-title":"Semin Immunopathol."},{"issue":"5","key":"pone.0260094.ref011","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0306-9877(94)90109-0","article-title":"The role of cytokines in early detection of preeclampsia.","volume":"43","author":"R Orvieto","year":"1994","journal-title":"Med Hypotheses."},{"key":"pone.0260094.ref012","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1159\/000087912","article-title":"Immunology of preeclampsia","volume":"89","author":"L Matthiesen","year":"2005","journal-title":"Chem Immunol Allergy"},{"issue":"6","key":"pone.0260094.ref013","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1042\/CS20150702","article-title":"The role of inflammation in the pathology of preeclampsia","volume":"130","author":"AC Harmon","year":"2016","journal-title":"Clin Sci (Lond)."},{"key":"pone.0260094.ref014","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/bs.pmbts.2017.04.001","article-title":"Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia.","volume":"148","author":"J Chen","year":"2017","journal-title":"Prog Mol Biol Transl Sci"},{"issue":"1","key":"pone.0260094.ref015","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s12016-016-8596-x","article-title":"Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review.","volume":"53","author":"J Alijotas-Reig","year":"2017","journal-title":"Clin Rev Allergy Immunol"},{"issue":"1\u20132","key":"pone.0260094.ref016","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jri.2005.10.007","article-title":"Cytokine mapping of sera from women with preeclampsia and normal pregnancies","volume":"70","author":"Y Jonsson","year":"2006","journal-title":"J Reprod Immunol"},{"issue":"4","key":"pone.0260094.ref017","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s11906-018-0833-7","article-title":"The Role of Interleukin-10 in the Pathophysiology of Preeclampsia.","volume":"20","author":"H Cubro","year":"2018","journal-title":"Curr Hypertens Rep."},{"issue":"6","key":"pone.0260094.ref018","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1007\/s10517-018-4066-1","article-title":"Complex Analysis of Total and Fetal DNA and Cytokines in Blood Plasma of Pregnant Women with Preeclampsia","volume":"164","author":"AM Krasnyi","year":"2018","journal-title":"Bull Exp Biol Med"},{"issue":"Suppl 1","key":"pone.0260094.ref019","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000354200","article-title":"Cytokines as key players in the pathophysiology of preeclampsia.","volume":"22","author":"R. Raghupathy","year":"2013","journal-title":"Med Princ Pract."},{"issue":"2 Pt 1","key":"pone.0260094.ref020","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0002-9378(99)70239-5","article-title":"Preeclampsia: an excessive maternal inflammatory response to pregnancy.","volume":"180","author":"CW Redman","year":"1999","journal-title":"Am J Obstet Gynecol."},{"issue":"1","key":"pone.0260094.ref021","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/S0002-9378(98)70272-8","article-title":"The fetal inflammatory response syndrome.","volume":"179","author":"R Gomez","year":"1998","journal-title":"Am J Obstet Gynecol"},{"issue":"7","key":"pone.0260094.ref022","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ijdevneu.2007.08.017","article-title":"The effects of maternal inflammation on neuronal development: possible mechanisms","volume":"25","author":"GM Jonakait","year":"2007","journal-title":"Int J Dev Neurosci"},{"key":"pone.0260094.ref023","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jri.2018.01.004","article-title":"Microglia, the missing link in maternal immune activation and fetal neurodevelopment; and a possible link in preeclampsia and disturbed neurodevelopment?","volume":"126","author":"JR Prins","year":"2018","journal-title":"J Reprod Immunol"},{"key":"pone.0260094.ref024","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.brainres.2014.07.050","article-title":"Interactions of innate and adaptive immunity in brain development and function","volume":"1617","author":"AJ Filiano","year":"2015","journal-title":"Brain Res"},{"key":"pone.0260094.ref025","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.3389\/fimmu.2018.02186","article-title":"Prenatal Immune and Endocrine Modulators of Offspring\u2019s Brain Development and Cognitive Functions Later in Life.","volume":"9","author":"S Schepanski","year":"2018","journal-title":"Front Immunol"},{"issue":"5","key":"pone.0260094.ref026","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s41593-018-0128-y","article-title":"Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring","volume":"21","author":"MD Rudolph","year":"2018","journal-title":"Nat Neurosci"},{"issue":"7","key":"pone.0260094.ref027","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.4049\/jimmunol.0903349","article-title":"IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation","volume":"184","author":"S Girard","year":"2010","journal-title":"J Immunol"},{"issue":"6301","key":"pone.0260094.ref028","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1126\/science.aag3194","article-title":"Maternal immune activation: Implications for neuropsychiatric disorders","volume":"353","author":"ML Estes","year":"2016","journal-title":"Science"},{"issue":"8","key":"pone.0260094.ref029","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1001\/jamapsychiatry.2020.0306","article-title":"Association of Preeclampsia in Term Births With Neurodevelopmental Disorders in Offspring","volume":"77","author":"BZ Sun","year":"2020","journal-title":"JAMA Psychiatry"},{"key":"pone.0260094.ref030","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ijdevneu.2018.10.004","article-title":"A perspective on pre-eclampsia and neurodevelopmental outcomes in the offspring: Does maternal inflammation play a role?","volume":"77","author":"GM Maher","year":"2019","journal-title":"Int J Dev Neurosci"},{"issue":"7","key":"pone.0260094.ref031","doi-asserted-by":"crossref","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":"TY Khong","year":"2016","journal-title":"Arch Pathol Lab Med"},{"issue":"2","key":"pone.0260094.ref032","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ajog.2014.09.016","article-title":"Inflammatory predictors of neurologic disability after preterm premature rupture of membranes.","volume":"212","author":"J Armstrong-Wells","year":"2015","journal-title":"Am J Obstet Gynecol"},{"issue":"6","key":"pone.0260094.ref033","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1161\/STROKEAHA.111.639583","article-title":"The pediatric stroke outcome measure: a validation and reliability study","volume":"43","author":"L Kitchen","year":"2012","journal-title":"Stroke"},{"issue":"7","key":"pone.0260094.ref034","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1053\/j.semperi.2017.07.009","article-title":"Epidemiology of preterm birth.","volume":"41","author":"SE Purisch","year":"2017","journal-title":"Semin Perinatol."},{"issue":"1","key":"pone.0260094.ref035","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1053\/j.semperi.2006.01.007","article-title":"A recommendation for the definition of \"late preterm\" (near-term) and the birth weight-gestational age classification system.","volume":"30","author":"WA Engle","year":"2006","journal-title":"Semin Perinatol"},{"issue":"6","key":"pone.0260094.ref036","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1067\/mob.2002.127379","article-title":"Male predominance in fetal distress during labor.","volume":"187","author":"DJ Bekedam","year":"2002","journal-title":"Am J Obstet Gynecol"},{"issue":"1","key":"pone.0260094.ref037","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1017\/S0012162207000199.x","article-title":"Sex and the pathogenesis of cerebral palsy.","volume":"49","author":"MV Johnston","year":"2007","journal-title":"Dev Med Child Neurol"},{"key":"pone.0260094.ref038","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/dmcn.13021","article-title":"Biological sex and the risk of cerebral palsy in Victoria, Australia.","volume":"58","author":"Australian Cerebral Palsy Register G","year":"2016","journal-title":"Dev Med Child Neurol."},{"issue":"5","key":"pone.0260094.ref039","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.ajog.2003.10.703","article-title":"Fetal sex and indicated very preterm birth: results of the EPIPAGE study.","volume":"190","author":"J Zeitlin","year":"2004","journal-title":"Am J Obstet Gynecol"},{"issue":"1","key":"pone.0260094.ref040","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.earlhumdev.2003.10.004","article-title":"Delivery before 32 weeks of gestation for maternal pre-eclampsia: neonatal outcome and 2-year developmental outcome.","volume":"76","author":"SW Cheng","year":"2004","journal-title":"Early Hum Dev"},{"key":"pone.0260094.ref041","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.3389\/fimmu.2018.01661","article-title":"Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia.","volume":"9","author":"NG Than","year":"2018","journal-title":"Front Immunol"},{"key":"pone.0260094.ref042","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.preghy.2018.02.001","article-title":"Placental histopathological lesions in correlation with neonatal outcome in preeclampsia with and without severe features.","volume":"12","author":"E Weiner","year":"2018","journal-title":"Pregnancy Hypertens"},{"issue":"9","key":"pone.0260094.ref043","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.placenta.2013.05.008","article-title":"Decidual vasculopathy in preeclampsia: lesion characteristics relate to disease severity and perinatal outcome","volume":"34","author":"DU Stevens","year":"2013","journal-title":"Placenta"},{"issue":"2","key":"pone.0260094.ref044","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3109\/10641955.2013.842584","article-title":"Association between placental pathology and neonatal outcome in preeclampsia: a large cohort study.","volume":"33","author":"MT Vinnars","year":"2014","journal-title":"Hypertens Pregnancy"},{"issue":"3","key":"pone.0260094.ref045","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1017\/S2040174413000056","article-title":"Patterns of placental pathology in preterm premature rupture of membranes.","volume":"4","author":"J Armstrong-Wells","year":"2013","journal-title":"J Dev Orig Health Dis"},{"issue":"2","key":"pone.0260094.ref046","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ajog.2014.09.016","article-title":"Inflammatory predictors of neurologic disability after preterm premature rupture of membranes.","volume":"212","author":"J Armstrong-Wells","year":"2015","journal-title":"Am J Obstet Gynecol"},{"key":"pone.0260094.ref047","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.bbi.2012.12.012","article-title":"Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants.","volume":"29","author":"TM O\u2019Shea","year":"2013","journal-title":"Brain Behav Immun."},{"key":"pone.0260094.ref048","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.preghy.2018.02.009","article-title":"The impact of female fetal sex on preeclampsia and the maternal immune milieu.","volume":"12","author":"BD Taylor","year":"2018","journal-title":"Pregnancy Hypertens."},{"issue":"Suppl 2","key":"pone.0260094.ref049","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00234-013-1233-y","article-title":"Imaging the premature brain: ultrasound or MRI?","volume":"55","author":"LS de Vries","year":"2013","journal-title":"Neuroradiology"},{"issue":"6","key":"pone.0260094.ref050","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/s41390-018-0194-6","article-title":"Brain imaging in preterm infants <32 weeks gestation: a clinical review and algorithm for the use of cranial ultrasound and qualitative brain MRI","volume":"84","author":"J Ibrahim","year":"2018","journal-title":"Pediatr Res"},{"issue":"7","key":"pone.0260094.ref051","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/dmcn.13030","article-title":"Prediction of neuromotor outcome in infants born preterm at 11 years of age using volumetric neonatal magnetic resonance imaging and neurological examinations.","volume":"58","author":"S Setanen","year":"2016","journal-title":"Dev Med Child Neurol"},{"issue":"5","key":"pone.0260094.ref052","article-title":"Clinic Follow up and Neurological Disability in Children Following Pregnancies Complicated by Preterm Premature Rupture of Membranes and Preeclampsia","volume":"7","author":"TD Paulson L","year":"2021","journal-title":"Journal of Childhood & Developmental Disorders"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260094","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,12]],"date-time":"2023-11-12T17:26:08Z","timestamp":1699809968000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260094"}},"subtitle":[],"editor":[{"given":"Khursheed","family":"Iqbal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0260094","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]}}}