Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Chorioamnionitis-exposure alters serum cytokine trends in premature neonates

Journal of Perinatology volume 43, pages 758–765 (2023)Cite this article

Subjects

Abstract

Objectives

Determine if chronologic age and/or chorioamnionitis exposure alter normal serum cytokine and chemokine levels in uninfected preterm neonates during their initial NICU stay.

Study design

A 7-plex immunoassay measured levels of serum IL-1β, IL-6, IL-8, IL-10, TNF-α, CCL2, and CCL3 longitudinally from chorioamnionitis-exposed and unexposed preterm neonates under 33 weeks’ gestation.

Results

Chorioamnionitis-exposed and unexposed preterm neonates demonstrated differences in the trends of IL-1β, IL-6, IL-8, IL-10, TNF-α, and CCL2 over the first month of life. The unexposed neonates demonstrated elevated levels of these inflammatory markers in the first two weeks of life with a decrease by the third week of life, while the chorioamnionitis-exposed neonates demonstrated differences over time without a predictable pattern. Chorioamnionitis-exposed and unexposed neonates demonstrated altered IL-10 and TNF-α trajectories over the first twelve weeks of life.

Conclusion

Chorioamnionitis induces a state of immune dysregulation in preterm neonates that persists beyond the immediate neonatal period.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Comparison of cytokines and chemokines obtained in the first and second weeks of life in preterm neonates.
Fig. 2: Longitudinal cytokine and chemokine trends over time in chorioamnionitis-exposed and unexposed preterm neonates.
Fig. 3: Longitudinal cytokine and chemokine trajectories over time in chorioamnionitis-exposed and unexposed preterm neonates.

Similar content being viewed by others

References

  1. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379:2162–72.

    Article  PubMed  Google Scholar 

  2. Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014;27:21–47.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Matoba N, Yu Y, Mestan K, Pearson C, Ortiz K, Porta N, et al. Differential patterns of 27 cord blood immune biomarkers across gestational age. Pediatrics. 2009;123:1320–8.

    Article  PubMed  Google Scholar 

  4. Lusyati S, Hulzebos CV, Zandvoort J, Sauer PJ. Levels of 25 cytokines in the first seven days of life in newborn infants. BMC Res Notes. 2013;6:547.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Salio M, Speak AO, Shepherd D, Polzella P, Illarionov PA, Veerapen N, et al. Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation. Proc Natl Acad Sci USA. 2007;104:20490–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Peng CC, Chang JH, Lin HY, Cheng PJ, Su BH. Intrauterine inflammation, infection, or both (Triple I): A new concept for chorioamnionitis. Pediatr Neonatol. 2018;59:231–7.

    Article  PubMed  Google Scholar 

  7. Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Tarca AL, Bhatti G, et al. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response. J Perinat Med. 2016;44:53–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. de Jong E, Hancock DG, Wells C, Richmond P, Simmer K, Burgner D, et al. Exposure to chorioamnionitis alters the monocyte transcriptional response to the neonatal pathogen Staphylococcus epidermidis. Immunol Cell Biol. 2018;96:792–804.

    Article  PubMed  Google Scholar 

  9. Bermick J, Gallagher K, denDekker A, Kunkel S, Lukacs N, Schaller M. Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes. FEBS J. 2019;286:82–109.

    Article  CAS  PubMed  Google Scholar 

  10. Schrag SJ, Hadler JL, Arnold KE, Martell-Cleary P, Reingold A, Schuchat A. Risk factors for invasive, early-onset Escherichia coli infections in the era of widespread intrapartum antibiotic use. Pediatrics. 2006;118:570–6.

    Article  PubMed  Google Scholar 

  11. Garcia-Munoz Rodrigo F, Galan Henriquez G, Figueras Aloy J, Garcia-Alix, Perez A. Outcomes of very-low-birth-weight infants exposed to maternal clinical chorioamnionitis: a multicentre study. Neonatology. 2014;106:229–34.

    Article  PubMed  Google Scholar 

  12. Redline RW, Faye-Petersen O, Heller D, Qureshi F, Savell V, Vogler C, et al. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol. 2003;6:435–48.

    Article  PubMed  Google Scholar 

  13. Khong TY, Mooney EE, Ariel I, Balmus NC, Boyd TK, Brundler MA, et al. Sampling and definitions of placental lesions: amsterdam placental workshop group consensus statement. Arch Pathol Lab Med. 2016;140:698–713.

    Article  PubMed  Google Scholar 

  14. Khaertynov KS, Boichuk SV, Khaiboullina SF, Anokhin VA, Andreeva AA, Lombardi VC, et al. Comparative assessment of cytokine pattern in early and late onset of neonatal sepsis. J Immunol Res. 2017;2017:8601063.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Leviton A, O’Shea TM, Bednarek FJ, Allred EN, Fichorova RN, Dammann O. Systemic responses of preterm newborns with presumed or documented bacteraemia. Acta Paediatr. 2012;101:355–9.

    Article  PubMed  Google Scholar 

  16. Harris MC, Costarino AT Jr., Sullivan JS, Dulkerian S, McCawley L, Corcoran L, et al. Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J Pediatr. 1994;124:105–11.

    Article  CAS  PubMed  Google Scholar 

  17. Edelson MB, Bagwell CE, Rozycki HJ. Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics 1999;103:766–71.

    Article  CAS  PubMed  Google Scholar 

  18. Robison HM, Bailey RC. A guide to quantitative biomarker assay development using whispering gallery mode biosensors. Curr Protoc Chem Biol. 2017;9:158–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Robison HM, Escalante P, Valera E, Erskine CL, Auvil L, Sasieta HC, et al. Precision immunoprofiling to reveal diagnostic signatures for latent tuberculosis infection and reactivation risk stratification. Integr Biol (Camb). 2019;11:16–25.

    Article  PubMed  Google Scholar 

  20. Mudumba S, de Alba S, Romero R, Cherwien C, Wu A, Wang J, et al. Photonic ring resonance is a versatile platform for performing multiplex immunoassays in real time. J Immunol Methods. 2017;448:34–43.

    Article  CAS  PubMed  Google Scholar 

  21. Ofman G, Vasco N, Cantey JB. Risk of early-onset sepsis following preterm, prolonged rupture of membranes with or without chorioamnionitis. Am J Perinatol. 2016;33:339–42.

    PubMed  Google Scholar 

  22. Strunk T, Doherty D, Jacques A, Simmer K, Richmond P, Kohan R, et al. Histologic chorioamnionitis is associated with reduced risk of late-onset sepsis in preterm infants. Pediatrics 2012;129:e134–41.

    Article  PubMed  Google Scholar 

  23. Puri K, Taft DH, Ambalavanan N, Schibler KR, Morrow AL, Kallapur SG. Association of chorioamnionitis with aberrant neonatal gut colonization and adverse clinical outcomes. PLoS One. 2016;11:e0162734.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Villamor-Martinez E, Lubach GA, Rahim OM, Degraeuwe P, Zimmermann LJ, Kramer BW, et al. Association of histological and clinical chorioamnionitis with neonatal sepsis among preterm infants: a systematic review, meta-analysis, and meta-regression. Front Immunol. 2020;11:972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Canto E, Rodriguez-Sanchez JL, Vidal S. Distinctive response of naive lymphocytes from cord blood to primary activation via TCR. J Leukoc Biol. 2003;74:998–1007.

    Article  CAS  PubMed  Google Scholar 

  26. Marodi L. Down-regulation of Th1 responses in human neonates. Clin Exp Immunol. 2002;128:1–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Iroh Tam PY, Bendel CM. Diagnostics for neonatal sepsis: current approaches and future directions. Pediatr Res. 2017;82:574–83.

    Article  PubMed  Google Scholar 

  28. Kinjo T, Ohga S, Ochiai M, Honjo S, Tanaka T, Takahata Y, et al. Serum chemokine levels and developmental outcome in preterm infants. Early Hum Dev. 2011;87:439–43.

    Article  CAS  PubMed  Google Scholar 

  29. Franz AR, Steinbach G, Kron M, Pohlandt F. Interleukin-8: a valuable tool to restrict antibiotic therapy in newborn infants. Acta Paediatr. 2001;90:1025–32.

    Article  CAS  PubMed  Google Scholar 

  30. de Bont ES, Martens A, van Raan J, Samson G, Fetter WP, Okken A, et al. Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 plasma levels in neonatal sepsis. Pediatr Res. 1993;33:380–3.

    PubMed  Google Scholar 

  31. Dulay AT, Buhimschi IA, Zhao G, Bahtiyar MO, Thung SF, Cackovic M, et al. Compartmentalization of acute phase reactants interleukin-6, C-reactive protein and procalcitonin as biomarkers of intra-amniotic infection and chorioamnionitis. Cytokine 2015;76:236–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ye Q, Du LZ, Shao WX, Shang SQ. Utility of cytokines to predict neonatal sepsis. Pediatr Res. 2017;81:616–21.

    Article  CAS  PubMed  Google Scholar 

  33. Sarandakou A, Giannaki G, Malamitsi-Puchner A, Rizos D, Hourdaki E, Protonotariou E, et al. Inflammatory cytokines in newborn infants. Mediators Inflamm. 1998;7:309–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Protonotariou E, Malamitsi-Puchner A, Giannaki G, Rizos D, Phocas I, Sarandakou A. Patterns of inflammatory cytokine serum concentrations during the perinatal period. Early Hum Dev. 1999;56:31–8.

    Article  CAS  PubMed  Google Scholar 

  35. Reinhart K, Bauer M, Riedemann NC, Hartog CS. New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev. 2012;25:609–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kocabas E, Sarikcioglu A, Aksaray N, Seydaoglu G, Seyhun Y, Yaman A. Role of procalcitonin, C-reactive protein, interleukin-6, interleukin-8 and tumor necrosis factor-alpha in the diagnosis of neonatal sepsis. Turk J Pediatr. 2007;49:7–20.

    PubMed  Google Scholar 

  37. Leviton A, O’Shea TM, Bednarek FJ, Allred EN, Fichorova RN, Dammann O, et al. Systemic responses of preterm newborns with presumed or documented bacteraemia. Acta Paediatr. 2012;101:355–9.

    Article  PubMed  Google Scholar 

  38. Maheshwari A, Schelonka RL, Dimmitt RA, Carlo WA, Munoz-Hernandez B, Das A, et al. Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants. Pediatr Res. 2014;76:100–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sahni M, Yeboah B, Das P, Shah D, Ponnalagu D, Singh H, et al. Novel biomarkers of bronchopulmonary dysplasia and bronchopulmonary dysplasia-associated pulmonary hypertension. J Perinatol. 2020;40:1634–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kumar R, Yu Y, Story RE, Pongracic JA, Gupta R, Pearson C, et al. Prematurity, chorioamnionitis, and the development of recurrent wheezing: a prospective birth cohort study. J Allergy Clin Immunol. 2008;121:878–84 e6.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Schmatz M, Srinivasan L, Grundmeier RW, Elci OU, Weiss SL, Masino AJ, et al. Surviving sepsis in a referral neonatal intensive care unit: association between time to antibiotic administration and in-hospital outcomes. J Pediatr. 2020;217:59–65 e1.

    Article  PubMed  Google Scholar 

  42. Venkatesh M, Flores A, Luna RA, Versalovic J. Molecular microbiological methods in the diagnosis of neonatal sepsis. Expert Rev Anti Infect Ther. 2010;8:1037–48.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Sharma D, Farahbakhsh N, Shastri S, Sharma P. Biomarkers for diagnosis of neonatal sepsis: a literature review. J Matern Fetal Neonatal Med. 2018;31:1646–59.

    Article  PubMed  Google Scholar 

  44. Sharma AA, Jen R, Kan B, Sharma A, Marchant E, Tang A, et al. Impaired NLRP3 inflammasome activity during fetal development regulates IL-1beta production in human monocytes. Eur J Immunol. 2015;45:238–49.

    Article  CAS  PubMed  Google Scholar 

  45. Strunk T, Prosser A, Levy O, Philbin V, Simmer K, Doherty D, et al. Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation. Pediatr Res. 2012;72:10–8.

    Article  CAS  PubMed  Google Scholar 

  46. Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C, Jernberg C, et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut. 2014;63:559–66.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This project was funded through philanthropic funds from the Korneffel family and by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health AI141673.

Author information

Author notes

  1. These authors contributed equally: Gretchen E. Stepanovich, Cole A. Chapman, Ryan C. Bailey, Jennifer R. Bermick.

Authors and Affiliations

  1. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

    Gretchen E. Stepanovich, Lindsay A. Ellsworth & Jennifer R. Bermick

  2. Department of Chemistry, University of Michigan, Ann Arbor, MI, USA

    Cole A. Chapman, Krista L. Meserve & Ryan C. Bailey

  3. Biostatistics and Data Management Unit, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

    Julie M. Sturza

  4. Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, IA, USA

    Jennifer R. Bermick

Authors
  1. Gretchen E. Stepanovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cole A. Chapman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Krista L. Meserve
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julie M. Sturza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lindsay A. Ellsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ryan C. Bailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jennifer R. Bermick
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GES made substantial contributions to the acquisition, analysis and interpretation of the data and wrote the initial draft of the manuscript. CAC and KLM made substantial contributions to the acquisition, analysis and interpretation of the data and critically revised the manuscript. JMS made substantial contributions to the analysis and interpretation of the data and critically revised the manuscript. LAE made substantial contributions to the design of the work, analysis and interpretation of the data and critically revised the manuscript. RCB and JRB made substantial contributions to the conceptualization and design of the work, acquisition, analysis and interpretation of the data and critically revised the manuscript.

Corresponding author

Correspondence to Jennifer R. Bermick.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stepanovich, G.E., Chapman, C.A., Meserve, K.L. et al. Chorioamnionitis-exposure alters serum cytokine trends in premature neonates. J Perinatol 43, 758–765 (2023). https://doi.org/10.1038/s41372-022-01584-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-022-01584-2

This article is cited by

Search

Advanced search

Quick links