Correlation of Syndecan-1 levels with adjunct hematological markers of sepsis in preterm newborns with and without exposure to maternal chorioamnionitis

Correlation of Syndecan-1 levels with adjunct hematological markers of sepsis in preterm newborns with and without exposure to maternal chorioamnionitis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Correlation of Syndecan-1 levels with adjunct hematological markers of sepsis in preterm newborns with and without exposure to maternal chorioamnionitis Sasha Demeulenaere, Jonathan Muraskas, Michaela O'Neil, Phillip DeChristopher, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8321567/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives To investigate the association between Syndecan-1 (S1) serum levels with admission complete blood count (CBC) and differential, in preterm newborns (PN) exposed to chorioamnionitis (CA), with and without funisitis. Methods A cohort of PN born (< 33 weeks gestational age) admitted to the Loyola University Medical Center NICU (2015–2020) was recruited. Within 48 hours of birth, placentas were sent for pathologic analysis, and blood was drawn and stored. Serum S1 levels were quantified by ELISA. The CBC with differential, including neutrophil indices (immature-to-total neutrophil ratio and left shift) and neutropenia (absolute neutrophil count < 1.5 × 10⁹/L), was obtained within 12 hours of admission. Placentas were classified as having (1) no CA, (2) CA without umbilical cord involvement, or (3) CA with extension to the umbilical cord, known as funisitis. S1 levels, left shift, and neutropenia were compared between PN with exposure to CA vs. PN exposure to CA with funisitis vs. without exposure to CA. Results Among 56 PN, 27 (48%) had exposure to CA. Mean S1 was significantly higher in CA-exposed vs. unexposed PN (255.9 ± 129.2 ng/mL vs. 164.8 ± 77.7; p = 0.003). S1 levels rose stepwise from CA only (221.0 ± 86.0) to CA + funisitis (288.3 ± 155.6 ng/mL). A left shift was present in 12/27 CA-exposed preterm neonates (44%) and in 0/29 unexposed neonates (Fisher’s exact p < 0.001; approximate OR for CA-exposed vs unexposed 48, 95% CI 2.6–859, using a continuity correction). Neutropenia occurred in 12/29 unexposed (41%) versus 5/27 CA-exposed (19%) neonates (OR 0.32, 95% CI 0.10–1.09, p = 0.084). Among CA-exposed infants, left shift was more frequent in those with funisitis (9/14, 64%) than in those with CA only (3/13, 23%; OR 6.0, 95% CI 1.11–32.6, Fisher’s exact p = 0.054), indicating a strong trend toward an augmented hematologic response in the presence of a fetal inflammatory component. Conclusions S1 is elevated in PN exposed to CA, especially when funisitis is present, and correlates with left shift on admission. Combined assessment of endothelial (S1) and hematologic immature-to-total neutrophil (I/T ratio) markers may enhance diagnostic precision for fetal inflammatory response syndrome (FIRS) and early-onset neonatal sepsis (EONS), supporting more targeted neonatal management. These findings indicate that endothelial glycocalyx degradation parallels hematopoietic activation during the fetal inflammatory response. Elevated S1 in CA-exposed PN, particularly those with funisitis, may reflect endothelial injury secondary to systemic inflammation. The strong association between left shift and increased S1 levels suggests that concurrent evaluation of admission CBC indices and S1 could improve early identification of intraamniotic infection and guide antibiotic stewardship. Accordingly, the presence of a left shift on admission in a PN could potentially guide both the maternal and neonatal diagnosis and management of intraamniotic infections and EONS. Health sciences/Diseases/Infectious diseases/Bacterial infection Health sciences/Biomarkers/Diagnostic markers Health sciences/Biomarkers/Predictive markers Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Chorioamnionitis (CA) is a perinatal condition characterized by inflammation of the fetal and placental membranes, complicating up to 70% of preterm births due to premature rupture of membranes and/or preterm labor. 1 Obstetrics terminology is shifting toward “intrapartum intraamniotic infection” to reflect the clinical reality that CA is often diagnosed based on maternal and fetal signs prior to delivery. 2 Premature newborn (PN) exposure to CA increases the risk of early-onset neonatal sepsis (EONS) by tenfold. 3 While there is overlap between clinical and histological CA, the latter—diagnosed by microscopic examination of the placenta—is more common and includes both clinical and subclinical cases. However, pathology reports often take several days to finalize, well after treatment decisions have been made. 4 The ability to identify reliable clinical or laboratory markers early is therefore crucial to guide obstetric and neonatal management, as well as antibiotic stewardship. One such histopathologic marker is funisitis, which reflects inflammation of the umbilical cord and represents the fetal extension of intraamniotic infection. 5 Funisitis is characterized by infiltration of the umbilical cord with neutrophils of fetal origin and is closely associated with the fetal inflammatory response syndrome (FIRS) and EONS. 6 FIRS describes the fetal immune response to infection or injury, mediated by the release of cytokines and chemokines, including interleukins, TNFα, CRP, and metalloproteinases. 7 Nationally, approximately 12% of PN with FIRS have positive blood cultures compared with 1% of PN without FIRS. 8 The overall incidence of EONS in late preterm and term newborns is 1/1000 livebirths; CA is 1/100, and CA with FIRS/funisitis is 12/1000 (diagnoses made with blood cultures and clinical factors). 8 However, blood culture, with the provision of adequate specimen volumes and other diagnostic results, takes time (upwards of 48 hours), which can complicate and delay timely treatment in this vulnerable population. PN are especially vulnerable to sepsis, and there is currently no single diagnostic test for detecting EONS, leading to a heavy reliance on empirical treatments. 9 EONS typically presents within the first 72 hours of life and is marked by non-specific symptoms and high mortality. 6 , 8 Blood cultures are the gold standard for confirming sepsis in PN, but results can take days while the infection progresses. Hematological markers, such as interleukin-6 (IL-6) and C-reactive protein (CRP), are used in conjunction with clinical factors, including gestational age, maternal risk factors, and the clinical state of the PN, to aid in diagnosis. 10 Several adjunct laboratory markers—including hematologic markers, acute phase reactants, and cytokine levels—are being explored, though none have demonstrated great sensitivity or specificity in identifying EONS. 8 Hematological markers, such as left shift, CRP, IL-6, serum amyloid A (SAA), and procalcitonin (PCT), have all shown usefullness in identifying signs of systemic inflammation early and supporting antibiotic stewardship of PN. 11,12 Additionally, transplacental passage of proinflammatory cytokines like IL-6 has been documented in term deliveries. 13 Still, clinicians must be cautious, as factors such as maternal preeclampsia or hypertension can lead to transient neonatal neutropenia unrelated to infection. 14 , 15 A thorough maternal and newborn clinical history remains essential in interpreting these markers accurately. One emerging area in the field is the role of endothelial injury in neonatal sepsis. The cellular endothelium has been identified as essential in regulating vascular tone, inflammation, growth, and thrombogenicity. 16 The endothelial surface is embedded with abundant proteoglycans, including endothelial glycocalyx, comprised of transmembrane core proteins known as syndecans. Syndecan-1 (S1)is a transmembrane proteoglycan that contributes to the inflammatory response by modulating leukocyte recruitment, cytokine release, cell adhesion, and angiogenesis. 17 It also serves as a protective barrier, shielding the endothelium from inflammatory damage. 18 During endothelial cell damage secondary to processes such as inflammation or vascular permeability, S1 is sloughed off and released into circulation. Elevated serum S1 levels have been reported in adult inflammatory conditions, including but not limited to preeclampsia, inflammatory bowel disease (IBD), and celiac disease. 19 In our prior work, we identified S1 as a promising histopathologic marker of fetal exposure to CA. 20 These findings suggest that S1 may also serve as a potential biomarker of PN endothelial damage and inflammatory processes of fetal origin. S1 and adjunct hematological markers have an immense potential for the early diagnosis and treatment of EONS. 21 METHODS This prospective cohort study was performed in the NICU of Loyola University Medical Center between July 2015 and March 2020. This study was approved by the University IRB, and informed consent was obtained from parents of PN at < 33 weeks gestational age. PN with major congenital anomalies, chromosomal abnormalities, or significant congenital heart disease were excluded. Within 48 hours of birth, placentas were sent for routine pathologic examination, and blood was drawn for a clinically indicated complete blood count (CBC) with differential; surplus serum was stored for later S1 measurement via ELISA. Placental pathology is routinely performed on all preterm births by the Department of Pathology and was submitted prior to running S1 levels. All reports stated clearly if: (1) No CA was present (2) CA was present without umbilical cord involvement (3) CA with extension to the cord was detected under microscopic examination. We defined funisitis as any detection of neutrophil invasion in any of the 3 vessels in the umbilical cord. Left shift was coded as a binary variable (present/absent) based on the admission neutrophil differential as interpreted in routine clinical practice, reflecting an increased proportion of immature neutrophil forms. An immature-to-total neutrophil (I/T) ratio > 0.2, calculated as bands / (bands + segmented neutrophils), is suggestive of left shift. Neutropenia was defined as an absolute neutrophil count (ANC) < 1.5 × 10⁹/L within 24 hours of birth; neutropenia status was confirmed through chart review of CBC results. All of these results can be found in Supplemental Fig. 1. Statistical Analyses Continuous variables were summarized as means ± standard deviation. Between-group comparisons of continuous variables were performed using Student’s t -test; when inspection of the data suggested unequal variances, Welch’s correction was applied. Categorical variables were compared using Fisher’s exact test. For 2×2 contingency tables, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to quantify the strength of association between chorioamnionitis exposure, funisitis, and hematologic parameters (left shift and neutropenia). When a cell contained zero observations, a Haldane–Anscombe correction (addition of 0.5 to each cell) was applied before computing the OR, and 95% CIs were obtained from Wald intervals on the log(OR) scale. Spearman’s rank correlation was used to assess the relationship between S1 level and I/T ratio. Statistics and plots were done on GraphPad Prism. RESULTS Of the 56 PN enrolled, 27 out of 56 (48.2%) had placental-proven CA. Mean gestational age was 27.7 ± 2.5 weeks, and mean birthweight was 1.09 ± 0.38 kg. Shortly after birth, PN exposed to CA were found to have significantly elevated S1 levels compared to the unexposed PN (Welch’s t-test). As shown in Fig. 1, the mean S1 level (ng/mL) in CA-exposed PN was 255.9 ± 129.2, while unexposed PN averaged 164.8 ± 77.7 (p < 0.003). This marked elevation suggests early endothelial glycocalyx degradation in response to intraamniotic inflammation. Within the CA-exposure group, S1 rose stepwise from CA-only (221.0 ± 86.0 ng/mL) to CA + funisitis (288.3 ± 155.6 ng/mL), consistent with a gradient of endothelial injury paralleling the histopathologic severity of infection. A one-way ANOVA revealed statistical significance between the unexposed PN and CA-exposed PN + funisitis, but no statistical difference with the CA-exposure only group (Fig. 2). S1 levels were then measured in PN with left shift and neutropenia. As shown in Fig. 3, the mean S1 level (ng/mL) in PN with left shift averaged 303.0 ± 154.7, while 227.3 ± 122.2 in PN with neutropenia (no statistical significance). As seen in Table 1, a left shift was observed in 12/27 CA-exposed PN (44%) and in none of the unexposed PN (Fisher’s exact test p < 0.001). Because of the zero cell in the unexposed group, the odds ratio for CA-exposed versus unexposed is very large (approximate OR 47.6, 95% CI 2.6–858.6 using a continuity correction). In contrast, neutropenia occurred in 12/29 unexposed (41%) versus 5/27 CA-exposed (19%) PN (OR 0.32, 95% CI 0.10–1.09, p = 0.08), indicating a nonsignificant trend toward lower odds of neutropenia among CA-exposed infants. As seen in Table 2, among CA subgroups, left shift was present in 3/13 CA-only (23%) versus 9/14 CA + funisitis (64%). The odds of left shift were higher in the CA + funisitis subgroup (OR 6.0, 95% CI 1.11–32.6); using two-sided Fisher’s exact test, this difference showed a strong trend but did not reach conventional statistical significance (p = 0.054). Lastly, a Spearman correlation (Fig. 4) demonstrated a positive association between serum S1 and I/T ratio ( r = 0.32, p = 0.015), which persisted after adjusting for gestational age. This moderate but significant correlation supports the concept that endothelial glycocalyx shedding and hematologic activation occur concurrently during the fetal inflammatory response. DISCUSSION In this cohort of PN, CA exposure—particularly when accompanied by funisitis—was associated with marked endothelial glycocalyx shedding, reflected by elevated circulating S1 levels and concurrent hematologic evidence of fetal inflammatory response. Our findings revealed that elevated S1 levels are significantly associated with PN exposed to CA, with a left shift. A left shift was present in nearly half of CA-exposed PN but absent in unexposed PN, underscoring its diagnostic specificity. The absence of increased neutropenia in CA-exposed infants suggests that depletion of circulating neutrophils may characterize non-inflammatory or stress-related immaturity rather than infection-driven activation. S1 release in serum correlated with I/T ratio, suggesting that endothelial glycocalyx degradation parallels systemic inflammatory activation. S1 elevation in CA-exposed PN is consistent with prior studies, which link glycocalyx shedding to microvascular leak and cytokine-driven injury. 22 , 23 These data imply that S1 levels may serve as an early biochemical indicator of fetal endothelial activation, preceding clinical diagnosis of EONS. Routine CBC indices retain diagnostic value, but coupling them with biomarkers of endothelial injury, such as S1, could enhance early risk stratification for FIRS and EONS. The presence of a left shift on admission, when paired with elevated S1 levels, could serve as a rapid and accessible marker for intraamniotic infection and EONS. This combination may improve early risk stratification and guide both obstetric and neonatal clinical decision-making—potentially enhancing antibiotic stewardship by informing the initiation and duration of empiric therapy. Given that blood differentials are routinely performed and quickly available, these findings have immediate translational relevance. Clinical signs of infection, however, should always take priority over adjunct markers of sepsis. 22 Validation in larger cohorts is warranted to establish predictive thresholds and test sensitivity. With further characterization, incorporating S1 assessment at birth alongside the PN CBC with differential could support more targeted management strategies for EONS. The significant risks of infections in PN often lead neonatal providers to initiate powerful antibiotic empiric treatments that carry their own risks. 11 Prolonged antibiotic exposure without confirmed EONS is associated with morbidities, neurodevelopmental delays, and even death. 12 Therefore, improving diagnostic precision through early and sensitive biomarkers could greatly enhance clinical decision-making and antibiotic stewardship. 13 , 14 This emphasizes the great need for more research investigating the potential of S1 and other biomarkers of EONS. Notably, while left shift correlated with S1 elevation and CA exposure, neutropenia was observed across both exposed and unexposed groups and did not associate with S1 levels. Transient neonatal neutropenia is not uncommon in noninfected preterm neonates born to mothers with hypertensive diseases of pregnancy 24 , 25 . This divergence in the correlation of S1 may reflect distinct fetal bone marrow responses to systemic stress and warrants further investigation. While studies have shown that S1 levels are elevated during inflammation, its role in neonatal inflammation has not been thoroughly explored. Serum S1 plays both pro-inflammatory and anti-inflammatory roles, with dynamic expression patterns that evolve over the course of the inflammatory response. 26 It is worth further investigating how serum S1 levels may help re-establish homeostasis during inflammation and their potential use as biomarkers of inflammation, especially in the neonatal population, where there is a paucity of data regarding serum S1 levels 15 . Future research should further characterize the temporal kinetics and mechanistic role of S1 in the neonatal immune response. In conditions such as EONS, where timely and precise identification of inflammation is critical, early recognition of specific markers of inflammation, such as S1, could transform and expedite the management of care. Further characterizing a combination of biomarkers along with S1 would be ideal for helping the diagnosis of EONS. In conclusion, CA exposure and funisitis in PN were associated with a 1.6-fold increase in circulating S1 and a marked increase in left shift prevalence in CA-exposed preterm newborns, particularly in those with funisitis (64% vs 23%; OR 6.0, 95% CI 1.1–32.6). S1 correlated with I/T ratio, supporting its role as a quantitative biomarker of endothelial activation in the fetal inflammatory response. References Tita ATN, Andrews WW. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol. 2010;37(2):339–354. doi: 10.1016/j.clp.2010.02.003 Committee Opinion No. 712: Intrapartum Management of Intraamniotic Infection. Obstet Gynecol. 2017;130(2):e95-e101. doi: 10.1097/AOG.0000000000002236 Beck C, Gallagher K, Taylor LA, Goldstein JA, Mithal LB, Gernand AD. Chorioamnionitis and Risk for Maternal and Neonatal Sepsis: A Systematic Review and Meta-analysis. Obstet Gynecol. 2021;137(6):1007–1022. doi: 10.1097/AOG.0000000000004377 Kuzniewicz MW, Puopolo KM. 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Semin Fetal Neonatal Med. 2020;25(4):101142. doi: 10.1016/j.siny.2020.101142 Meem M, Modak JK, Mortuza R, Morshed M, Islam MS, Saha SK. Biomarkers for diagnosis of neonatal infections: A systematic analysis of their potential as a point-of-care diagnostics. J Glob Health. 2011;1(2):201–209. Eichberger J, Resch E, Resch B. Diagnosis of Neonatal Sepsis: The Role of Inflammatory Markers. Front Pediatr. 2022;10:840288. doi: 10.3389/fped.2022.840288 Arnon S, Litmanovitz I, Regev RH, Bauer S, Shainkin-Kestenbaum R, Dolfin T. Serum amyloid A: an early and accurate marker of neonatal early-onset sepsis. J Perinatol Off J Calif Perinat Assoc. 2007;27(5):297–302. doi: 10.1038/sj.jp.7211682 Hincu MA, Zonda GI, Stanciu GD, Nemescu D, Paduraru L. Relevance of Biomarkers Currently in Use or Research for Practical Diagnosis Approach of Neonatal Early-Onset Sepsis. Child Basel Switz. 2020;7(12):309. doi: 10.3390/children7120309 Aaltonen R, Heikkinen T, Hakala K, Laine K, Alanen A. 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Front Immunol. 2020;11:227. doi: 10.3389/fimmu.2020.00227 Çekiç C, Kırcı A, Vatansever S, et al. Serum Syndecan-1 Levels and Its Relationship to Disease Activity in Patients with Crohn’s Disease. Gastroenterol Res Pract. 2015;2015:850351. doi: 10.1155/2015/850351 O’Neil M, Demeulenaere SK, DeChristopher PJ, et al. Syndecan-1 Level, a Marker of Endothelial Glycocalyx Degradation, Is Associated With Fetal Exposure to Chorioamnionitis and Is a Potential Biomarker for Early-Onset Neonatal Sepsis. Pediatr Dev Pathol Off J Soc Pediatr Pathol Paediatr Pathol Soc. 2024;27(4):318–326. doi: 10.1177/10935266241235504 Tzialla C, Manzoni P, Achille C, Bollani L, Stronati M, Borghesi A. New Diagnostic Possibilities for Neonatal Sepsis. Am J Perinatol. 2018;35(6):575–577. doi: 10.1055/s-0038-1639361 Puskarich MA, Cornelius DC, Tharp J, Nandi U, Jones AE. Plasma syndecan-1 levels identify a cohort of patients with severe sepsis at a high risk of intubation following large volume intravenous fluid resuscitation. J Crit Care. 2016;36:125–129. doi: 10.1016/j.jcrc.2016.06.027 Pudjiadi AH, Saidah F, Alatas FS. Correlation between syndecan-1 level and PELOD-2 score and mortality in pediatric sepsis. Rev Bras Ter Intensiva. 2021;33(4):549–556. doi: 10.5935/0103-507X.20210083 Maheshwari A. Neutropenia in the Newborn. Curr Opin Hematol. 2014;21(1):43–49. doi: 10.1097/MOH.0000000000000010 Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Effect of maternal hypertension on neonatal neutropenia and risk of nosocomial infection. Pediatrics. 1992;90(3):430–435. Gopal S. Syndecans in Inflammation at a Glance. Front Immunol. 2020;11:227. doi: 10.3389/fimmu.2020.00227 Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations There is NO conflict of interest to disclose. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8321567","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":571040870,"identity":"89979f33-2891-4dc9-a9ea-82f32e03fe63","order_by":0,"name":"Sasha 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09:06:46","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":451238,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/016864d6252ea81e90da7113.pdf"},{"id":100122832,"identity":"5ac2e29e-9baf-49c9-a5c4-013823af8386","added_by":"auto","created_at":"2026-01-13 09:06:46","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60149,"visible":true,"origin":"","legend":"","description":"","filename":"2514530structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/06bb51f953e11fd8fc8b03cd.xml"},{"id":100122837,"identity":"26debfbc-c2d3-4976-87e6-7ec841025e37","added_by":"auto","created_at":"2026-01-13 09:06:46","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":70862,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/399f4a0becef6e46de1f48d9.html"},{"id":100122827,"identity":"302ac431-0e33-44fd-ab32-88d8fb6d2450","added_by":"auto","created_at":"2026-01-13 09:06:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73705,"visible":true,"origin":"","legend":"\u003cp\u003eTable exhibiting comparison of mean S1 levels in PN unexposed vs. exposed to CA (left). Boxplots displaying these values (right).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/03f0f65989bb21e5725974d3.png"},{"id":100366313,"identity":"745e022c-6586-445a-9478-94eecc8fceb5","added_by":"auto","created_at":"2026-01-16 07:56:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":92909,"visible":true,"origin":"","legend":"\u003cp\u003eTable exhibiting comparison of mean S1 levels in PN unexposed vs. exposed to CA only vs. exposed to CA and funisitis (left). Boxplots displaying these values (right).\u003c/p\u003e\n\u003cp\u003eFigure\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/908d06f7d28a2617da4a9a69.png"},{"id":100366884,"identity":"6f9c7f7c-ca8b-4380-9e6d-a566dd87884d","added_by":"auto","created_at":"2026-01-16 07:56:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":67860,"visible":true,"origin":"","legend":"\u003cp\u003eTable exhibiting comparison of mean S1 levels in PN with left shift vs. with neutropenia (left). Boxplots displaying these values (right)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/8c20611b3e78c7a896d387b8.png"},{"id":100122828,"identity":"2a17cbf0-6730-49bc-b1cd-b27b5261e19b","added_by":"auto","created_at":"2026-01-13 09:06:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":83635,"visible":true,"origin":"","legend":"\u003cp\u003eSpearman correlation characterizing the association between S1 and the immature-to-total neutrophil (I/T) ratio in PN. Left shift was coded as a binary variable based on the admission neutrophil differential as interpreted in routine clinical practice. The I/T ratio was analyzed as a continuous variable; values \u0026gt; 0.2 are classically suggestive of left shift. In this cohort, all chart-coded left shifts occurred in CA-exposed PN.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/492d096991208c708a94ff4f.png"},{"id":104401316,"identity":"1345c58a-53e0-49c2-81d4-84993a9d516f","added_by":"auto","created_at":"2026-03-11 12:12:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":627710,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/6d5176cd-8dfd-430b-b771-161d639cb165.pdf"},{"id":100122826,"identity":"84f14c3b-b42e-42b9-b603-b029e4781ef1","added_by":"auto","created_at":"2026-01-13 09:06:45","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":57324,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"ManuscriptTables.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/d9f8f3eefef541187ae2218e.pdf"},{"id":100122830,"identity":"11721a49-7899-4a54-91fa-7b8eb7bc5baa","added_by":"auto","created_at":"2026-01-13 09:06:45","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13212,"visible":true,"origin":"","legend":"Data Set 1","description":"","filename":"Manuscriptrawdata.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8321567/v1/8c5f983c72519620764f8e25.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Correlation of Syndecan-1 levels with adjunct hematological markers of sepsis in preterm newborns with and without exposure to maternal chorioamnionitis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eChorioamnionitis (CA) is a perinatal condition characterized by inflammation of the fetal and placental membranes, complicating up to 70% of preterm births due to premature rupture of membranes and/or preterm labor.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Obstetrics terminology is shifting toward \u0026ldquo;intrapartum intraamniotic infection\u0026rdquo; to reflect the clinical reality that CA is often diagnosed based on maternal and fetal signs prior to delivery.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Premature newborn (PN) exposure to CA increases the risk of early-onset neonatal sepsis (EONS) by tenfold.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e While there is overlap between clinical and histological CA, the latter\u0026mdash;diagnosed by microscopic examination of the placenta\u0026mdash;is more common and includes both clinical and subclinical cases. However, pathology reports often take several days to finalize, well after treatment decisions have been made.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The ability to identify reliable clinical or laboratory markers early is therefore crucial to guide obstetric and neonatal management, as well as antibiotic stewardship.\u003c/p\u003e \u003cp\u003eOne such histopathologic marker is funisitis, which reflects inflammation of the umbilical cord and represents the fetal extension of intraamniotic infection.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Funisitis is characterized by infiltration of the umbilical cord with neutrophils of fetal origin and is closely associated with the fetal inflammatory response syndrome (FIRS) and EONS.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e FIRS describes the fetal immune response to infection or injury, mediated by the release of cytokines and chemokines, including interleukins, TNFα, CRP, and metalloproteinases.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Nationally, approximately 12% of PN with FIRS have positive blood cultures compared with 1% of PN without FIRS.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e The overall incidence of EONS in late preterm and term newborns is 1/1000 livebirths; CA is 1/100, and CA with FIRS/funisitis is 12/1000 (diagnoses made with blood cultures and clinical factors).\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e However, blood culture, with the provision of adequate specimen volumes and other diagnostic results, takes time (upwards of 48 hours), which can complicate and delay timely treatment in this vulnerable population.\u003c/p\u003e \u003cp\u003ePN are especially vulnerable to sepsis, and there is currently no single diagnostic test for detecting EONS, leading to a heavy reliance on empirical treatments.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e EONS typically presents within the first 72 hours of life and is marked by non-specific symptoms and high mortality.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Blood cultures are the gold standard for confirming sepsis in PN, but results can take days while the infection progresses. Hematological markers, such as interleukin-6 (IL-6) and C-reactive protein (CRP), are used in conjunction with clinical factors, including gestational age, maternal risk factors, and the clinical state of the PN, to aid in diagnosis.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSeveral adjunct laboratory markers\u0026mdash;including hematologic markers, acute phase reactants, and cytokine levels\u0026mdash;are being explored, though none have demonstrated great sensitivity or specificity in identifying EONS.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Hematological markers, such as left shift, CRP, IL-6, serum amyloid A (SAA), and procalcitonin (PCT), have all shown usefullness in identifying signs of systemic inflammation early and supporting antibiotic stewardship of PN.\u003csup\u003e11,12\u003c/sup\u003e Additionally, transplacental passage of proinflammatory cytokines like IL-6 has been documented in term deliveries.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Still, clinicians must be cautious, as factors such as maternal preeclampsia or hypertension can lead to transient neonatal neutropenia unrelated to infection.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e A thorough maternal and newborn clinical history remains essential in interpreting these markers accurately.\u003c/p\u003e \u003cp\u003eOne emerging area in the field is the role of endothelial injury in neonatal sepsis. The cellular endothelium has been identified as essential in regulating vascular tone, inflammation, growth, and thrombogenicity.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e The endothelial surface is embedded with abundant proteoglycans, including endothelial glycocalyx, comprised of transmembrane core proteins known as syndecans. Syndecan-1 (S1)is a transmembrane proteoglycan that contributes to the inflammatory response by modulating leukocyte recruitment, cytokine release, cell adhesion, and angiogenesis.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e It also serves as a protective barrier, shielding the endothelium from inflammatory damage.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e During endothelial cell damage secondary to processes such as inflammation or vascular permeability, S1 is sloughed off and released into circulation. Elevated serum S1 levels have been reported in adult inflammatory conditions, including but not limited to preeclampsia, inflammatory bowel disease (IBD), and celiac disease.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e In our prior work, we identified S1 as a promising histopathologic marker of fetal exposure to CA.\u003csup\u003e20\u003c/sup\u003e These findings suggest that S1 may also serve as a potential biomarker of PN endothelial damage and inflammatory processes of fetal origin. S1 and adjunct hematological markers have an immense potential for the early diagnosis and treatment of EONS.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis prospective cohort study was performed in the NICU of Loyola University Medical Center between July 2015 and March 2020. This study was approved by the University IRB, and informed consent was obtained from parents of PN at \u0026lt;\u0026thinsp;33 weeks gestational age. PN with major congenital anomalies, chromosomal abnormalities, or significant congenital heart disease were excluded. Within 48 hours of birth, placentas were sent for routine pathologic examination, and blood was drawn for a clinically indicated complete blood count (CBC) with differential; surplus serum was stored for later S1 measurement via ELISA. Placental pathology is routinely performed on all preterm births by the Department of Pathology and was submitted prior to running S1 levels. All reports stated clearly if:\u003c/p\u003e \u003cp\u003e(1) No CA was present\u003c/p\u003e \u003cp\u003e(2) CA was present without umbilical cord involvement\u003c/p\u003e \u003cp\u003e(3) CA with extension to the cord was detected under microscopic examination.\u003c/p\u003e \u003cp\u003eWe defined funisitis as any detection of neutrophil invasion in any of the 3 vessels in the umbilical cord. Left shift was coded as a binary variable (present/absent) based on the admission neutrophil differential as interpreted in routine clinical practice, reflecting an increased proportion of immature neutrophil forms. An immature-to-total neutrophil (I/T) ratio\u0026thinsp;\u0026gt;\u0026thinsp;0.2, calculated as bands / (bands\u0026thinsp;+\u0026thinsp;segmented neutrophils), is suggestive of left shift. Neutropenia was defined as an absolute neutrophil count (ANC)\u0026thinsp;\u0026lt;\u0026thinsp;1.5 \u0026times; 10⁹/L within 24 hours of birth; neutropenia status was confirmed through chart review of CBC results. All of these results can be found in Supplemental Fig.\u0026nbsp;1.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eContinuous variables were summarized as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Between-group comparisons of continuous variables were performed using Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test; when inspection of the data suggested unequal variances, Welch\u0026rsquo;s correction was applied. Categorical variables were compared using Fisher\u0026rsquo;s exact test. For 2\u0026times;2 contingency tables, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to quantify the strength of association between chorioamnionitis exposure, funisitis, and hematologic parameters (left shift and neutropenia). When a cell contained zero observations, a Haldane\u0026ndash;Anscombe correction (addition of 0.5 to each cell) was applied before computing the OR, and 95% CIs were obtained from Wald intervals on the log(OR) scale. Spearman\u0026rsquo;s rank correlation was used to assess the relationship between S1 level and I/T ratio. Statistics and plots were done on GraphPad Prism.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eOf the 56 PN enrolled, 27 out of 56 (48.2%) had placental-proven CA. Mean gestational age was 27.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5 weeks, and mean birthweight was 1.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38 kg. Shortly after birth, PN exposed to CA were found to have significantly elevated S1 levels compared to the unexposed PN (Welch\u0026rsquo;s t-test). As shown in Fig.\u0026nbsp;1, the mean S1 level (ng/mL) in CA-exposed PN was 255.9\u0026thinsp;\u0026plusmn;\u0026thinsp;129.2, while unexposed PN averaged 164.8\u0026thinsp;\u0026plusmn;\u0026thinsp;77.7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.003). This marked elevation suggests early endothelial glycocalyx degradation in response to intraamniotic inflammation. Within the CA-exposure group, S1 rose stepwise from CA-only (221.0\u0026thinsp;\u0026plusmn;\u0026thinsp;86.0 ng/mL) to CA\u0026thinsp;+\u0026thinsp;funisitis (288.3\u0026thinsp;\u0026plusmn;\u0026thinsp;155.6 ng/mL), consistent with a gradient of endothelial injury paralleling the histopathologic severity of infection. A one-way ANOVA revealed statistical significance between the unexposed PN and CA-exposed PN\u0026thinsp;+\u0026thinsp;funisitis, but no statistical difference with the CA-exposure only group (Fig.\u0026nbsp;2). S1 levels were then measured in PN with left shift and neutropenia. As shown in Fig.\u0026nbsp;3, the mean S1 level (ng/mL) in PN with left shift averaged 303.0\u0026thinsp;\u0026plusmn;\u0026thinsp;154.7, while 227.3\u0026thinsp;\u0026plusmn;\u0026thinsp;122.2 in PN with neutropenia (no statistical significance).\u003c/p\u003e \u003cp\u003eAs seen in Table\u0026nbsp;1, a left shift was observed in 12/27 CA-exposed PN (44%) and in none of the unexposed PN (Fisher\u0026rsquo;s exact test \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Because of the zero cell in the unexposed group, the odds ratio for CA-exposed versus unexposed is very large (approximate OR 47.6, 95% CI 2.6\u0026ndash;858.6 using a continuity correction). In contrast, neutropenia occurred in 12/29 unexposed (41%) versus 5/27 CA-exposed (19%) PN (OR 0.32, 95% CI 0.10\u0026ndash;1.09, p\u0026thinsp;=\u0026thinsp;0.08), indicating a nonsignificant trend toward lower odds of neutropenia among CA-exposed infants. As seen in Table\u0026nbsp;2, among CA subgroups, left shift was present in 3/13 CA-only (23%) versus 9/14 CA\u0026thinsp;+\u0026thinsp;funisitis (64%). The odds of left shift were higher in the CA\u0026thinsp;+\u0026thinsp;funisitis subgroup (OR 6.0, 95% CI 1.11\u0026ndash;32.6); using two-sided Fisher\u0026rsquo;s exact test, this difference showed a strong trend but did not reach conventional statistical significance (p\u0026thinsp;=\u0026thinsp;0.054). Lastly, a Spearman correlation (Fig.\u0026nbsp;4) demonstrated a positive association between serum S1 and I/T ratio (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.32, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015), which persisted after adjusting for gestational age. This moderate but significant correlation supports the concept that endothelial glycocalyx shedding and hematologic activation occur concurrently during the fetal inflammatory response.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this cohort of PN, CA exposure\u0026mdash;particularly when accompanied by funisitis\u0026mdash;was associated with marked endothelial glycocalyx shedding, reflected by elevated circulating S1 levels and concurrent hematologic evidence of fetal inflammatory response. Our findings revealed that elevated S1 levels are significantly associated with PN exposed to CA, with a left shift. A left shift was present in nearly half of CA-exposed PN but absent in unexposed PN, underscoring its diagnostic specificity. The absence of increased neutropenia in CA-exposed infants suggests that depletion of circulating neutrophils may characterize non-inflammatory or stress-related immaturity rather than infection-driven activation.\u003c/p\u003e \u003cp\u003eS1 release in serum correlated with I/T ratio, suggesting that endothelial glycocalyx degradation parallels systemic inflammatory activation. S1 elevation in CA-exposed PN is consistent with prior studies, which link glycocalyx shedding to microvascular leak and cytokine-driven injury.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e These data imply that S1 levels may serve as an early biochemical indicator of fetal endothelial activation, preceding clinical diagnosis of EONS. Routine CBC indices retain diagnostic value, but coupling them with biomarkers of endothelial injury, such as S1, could enhance early risk stratification for FIRS and EONS. The presence of a left shift on admission, when paired with elevated S1 levels, could serve as a rapid and accessible marker for intraamniotic infection and EONS. This combination may improve early risk stratification and guide both obstetric and neonatal clinical decision-making\u0026mdash;potentially enhancing antibiotic stewardship by informing the initiation and duration of empiric therapy. Given that blood differentials are routinely performed and quickly available, these findings have immediate translational relevance. Clinical signs of infection, however, should always take priority over adjunct markers of sepsis.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Validation in larger cohorts is warranted to establish predictive thresholds and test sensitivity. With further characterization, incorporating S1 assessment at birth alongside the PN CBC with differential could support more targeted management strategies for EONS.\u003c/p\u003e \u003cp\u003eThe significant risks of infections in PN often lead neonatal providers to initiate powerful antibiotic empiric treatments that carry their own risks.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Prolonged antibiotic exposure without confirmed EONS is associated with morbidities, neurodevelopmental delays, and even death.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Therefore, improving diagnostic precision through early and sensitive biomarkers could greatly enhance clinical decision-making and antibiotic stewardship.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e This emphasizes the great need for more research investigating the potential of S1 and other biomarkers of EONS.\u003c/p\u003e \u003cp\u003eNotably, while left shift correlated with S1 elevation and CA exposure, neutropenia was observed across both exposed and unexposed groups and did not associate with S1 levels. Transient neonatal neutropenia is not uncommon in noninfected preterm neonates born to mothers with hypertensive diseases of pregnancy\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. This divergence in the correlation of S1 may reflect distinct fetal bone marrow responses to systemic stress and warrants further investigation.\u003c/p\u003e \u003cp\u003eWhile studies have shown that S1 levels are elevated during inflammation, its role in neonatal inflammation has not been thoroughly explored. Serum S1 plays both pro-inflammatory and anti-inflammatory roles, with dynamic expression patterns that evolve over the course of the inflammatory response.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e It is worth further investigating how serum S1 levels may help re-establish homeostasis during inflammation and their potential use as biomarkers of inflammation, especially in the neonatal population, where there is a paucity of data regarding serum S1 levels\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Future research should further characterize the temporal kinetics and mechanistic role of S1 in the neonatal immune response. In conditions such as EONS, where timely and precise identification of inflammation is critical, early recognition of specific markers of inflammation, such as S1, could transform and expedite the management of care. Further characterizing a combination of biomarkers along with S1 would be ideal for helping the diagnosis of EONS.\u003c/p\u003e \u003cp\u003eIn conclusion, CA exposure and funisitis in PN were associated with a 1.6-fold increase in circulating S1 and a marked increase in left shift prevalence in CA-exposed preterm newborns, particularly in those with funisitis (64% vs 23%; OR 6.0, 95% CI 1.1\u0026ndash;32.6). S1 correlated with I/T ratio, supporting its role as a quantitative biomarker of endothelial activation in the fetal inflammatory response.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTita ATN, Andrews WW. Diagnosis and management of clinical chorioamnionitis. 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Am J Perinatol. 2018;35(6):575\u0026ndash;577. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1055/s-0038-1639361\u003c/span\u003e\u003cspan address=\"10.1055/s-0038-1639361\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePuskarich MA, Cornelius DC, Tharp J, Nandi U, Jones AE. Plasma syndecan-1 levels identify a cohort of patients with severe sepsis at a high risk of intubation following large volume intravenous fluid resuscitation. J Crit Care. 2016;36:125\u0026ndash;129. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jcrc.2016.06.027\u003c/span\u003e\u003cspan address=\"10.1016/j.jcrc.2016.06.027\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePudjiadi AH, Saidah F, Alatas FS. Correlation between syndecan-1 level and PELOD-2 score and mortality in pediatric sepsis. Rev Bras Ter Intensiva. 2021;33(4):549\u0026ndash;556. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5935/0103-507X.20210083\u003c/span\u003e\u003cspan address=\"10.5935/0103-507X.20210083\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaheshwari A. Neutropenia in the Newborn. Curr Opin Hematol. 2014;21(1):43\u0026ndash;49. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MOH.0000000000000010\u003c/span\u003e\u003cspan address=\"10.1097/MOH.0000000000000010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Effect of maternal hypertension on neonatal neutropenia and risk of nosocomial infection. Pediatrics. 1992;90(3):430\u0026ndash;435.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGopal S. Syndecans in Inflammation at a Glance. Front Immunol. 2020;11:227. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fimmu.2020.00227\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2020.00227\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8321567/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8321567/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eTo investigate the association between Syndecan-1 (S1) serum levels with admission complete blood count (CBC) and differential, in preterm newborns (PN) exposed to chorioamnionitis (CA), with and without funisitis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA cohort of PN born (\u0026lt;\u0026thinsp;33 weeks gestational age) admitted to the Loyola University Medical Center NICU (2015\u0026ndash;2020) was recruited. Within 48 hours of birth, placentas were sent for pathologic analysis, and blood was drawn and stored. Serum S1 levels were quantified by ELISA. The CBC with differential, including neutrophil indices (immature-to-total neutrophil ratio and left shift) and neutropenia (absolute neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;1.5 \u0026times; 10⁹/L), was obtained within 12 hours of admission. Placentas were classified as having (1) no CA, (2) CA without umbilical cord involvement, or (3) CA with extension to the umbilical cord, known as funisitis. S1 levels, left shift, and neutropenia were compared between PN with exposure to CA vs. PN exposure to CA with funisitis vs. without exposure to CA.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 56 PN, 27 (48%) had exposure to CA. Mean S1 was significantly higher in CA-exposed vs. unexposed PN (255.9\u0026thinsp;\u0026plusmn;\u0026thinsp;129.2 ng/mL vs. 164.8\u0026thinsp;\u0026plusmn;\u0026thinsp;77.7; p\u0026thinsp;=\u0026thinsp;0.003). S1 levels rose stepwise from CA only (221.0\u0026thinsp;\u0026plusmn;\u0026thinsp;86.0) to CA\u0026thinsp;+\u0026thinsp;funisitis (288.3\u0026thinsp;\u0026plusmn;\u0026thinsp;155.6 ng/mL). A left shift was present in 12/27 CA-exposed preterm neonates (44%) and in 0/29 unexposed neonates (Fisher\u0026rsquo;s exact \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; approximate OR for CA-exposed vs unexposed 48, 95% CI 2.6\u0026ndash;859, using a continuity correction). Neutropenia occurred in 12/29 unexposed (41%) versus 5/27 CA-exposed (19%) neonates (OR 0.32, 95% CI 0.10\u0026ndash;1.09, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.084). Among CA-exposed infants, left shift was more frequent in those with funisitis (9/14, 64%) than in those with CA only (3/13, 23%; OR 6.0, 95% CI 1.11\u0026ndash;32.6, Fisher\u0026rsquo;s exact \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.054), indicating a strong trend toward an augmented hematologic response in the presence of a fetal inflammatory component.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eS1 is elevated in PN exposed to CA, especially when funisitis is present, and correlates with left shift on admission. Combined assessment of endothelial (S1) and hematologic immature-to-total neutrophil (I/T ratio) markers may enhance diagnostic precision for fetal inflammatory response syndrome (FIRS) and early-onset neonatal sepsis (EONS), supporting more targeted neonatal management. These findings indicate that endothelial glycocalyx degradation parallels hematopoietic activation during the fetal inflammatory response. Elevated S1 in CA-exposed PN, particularly those with funisitis, may reflect endothelial injury secondary to systemic inflammation. The strong association between left shift and increased S1 levels suggests that concurrent evaluation of admission CBC indices and S1 could improve early identification of intraamniotic infection and guide antibiotic stewardship. Accordingly, the presence of a left shift on admission in a PN could potentially guide both the maternal and neonatal diagnosis and management of intraamniotic infections and EONS.\u003c/p\u003e","manuscriptTitle":"Correlation of Syndecan-1 levels with adjunct hematological markers of sepsis in preterm newborns with and without exposure to maternal chorioamnionitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 09:06:41","doi":"10.21203/rs.3.rs-8321567/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"64003f96-c2bf-4534-9392-b422cc4db9b3","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60768233,"name":"Health sciences/Diseases/Infectious diseases/Bacterial infection"},{"id":60768234,"name":"Health sciences/Biomarkers/Diagnostic markers"},{"id":60768235,"name":"Health sciences/Biomarkers/Predictive markers"}],"tags":[],"updatedAt":"2026-03-03T16:01:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-13 09:06:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8321567","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8321567","identity":"rs-8321567","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}