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.

  • Original Article
  • Published:

Inflammatory markers in cord blood or maternal serum for early detection of neonatal sepsis—a systemic review and meta-analysis

Journal of Perinatology volume 34, pages 268–274 (2014)Cite this article

Subjects

Abstract

Objective:

To perform a quantitative review of the evidence on the diagnostic value of inflammatory markers in maternal serum or umbilical cord blood for the diagnosis of early-onset neonatal sepsis (EONS).

Study Design:

We searched multiple databases for studies published through March 2013 that evaluated the diagnostic performance of procalcitonin (PCT), C-reactive protein (CRP) and interleukin-6 (IL-6), and leukocyte count (white blood cell, WBC) in either umbilical cord blood or maternal serum for diagnosis of EONS. We summarized test performance characteristics with the use of forest plots, hierarchical summary receiver operating characteristic curves and bivariate random effects models.

Result:

Our search identified 3874 citations, of which 15 studies evaluating 2178 episodes of suspected neonatal infection were included for analysis. IL-6 in cord blood with a pooled-positive likelihood ratio (LR+) of 9.47 (95% confidence interval: 3.86 to 23.3), PCT in cord blood with a LR+ of 5.72 (1.56 to 21.0) and IL-6 in maternal serum with a LR+ of 5.47 (2.10 to 14.2) can be qualified as a valid rule-in test. IL-6 in cord blood with a LR− of 0.10 (0.05 to 0.21) and PCT in cord blood with a LR− of 0.20 (0.12–0.37) can be qualified as a useful rule-out test. Either CRP or WBC was inadequate for diagnosis of EONS.

Conclusion:

For cord blood sample, IL-6 or PCT can be used as reliable rule-in and rule-out tool. For maternal serum, only IL-6 appeared to be sufficient for rule-in diagnosis. An interventional study may be needed to answer whether the addition of these tests will improve the outcome of patients with EONS.

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Koenig JM, Keenan WJ . Group B streptococcus and early-onset sepsis in the era of maternal prophylaxis. Pediatr Clin North Am 2009; 56 (3): 689–708.

    Article  Google Scholar 

  2. Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Van Meurs KP et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics 2011; 127 (5): 817–826.

    Article  Google Scholar 

  3. Lukacs SL, Schrag SJ . Clinical sepsis in neonates and young infants, United States, 1988-2006. J Pediatr 2012; 160 (6): 960–965 e961.

    Article  Google Scholar 

  4. Mishra UK, Jacobs SE, Doyle LW, Garland SM . Newer approaches to the diagnosis of early onset neonatal sepsis. Arch Dis Child Fetal Neonatal Ed 2006; 91 (3): F208–F212.

    Article  CAS  Google Scholar 

  5. Christensen RD, Baer VL, Gordon PV, Henry E, Whitaker C, Andres RL et al. Reference ranges for lymphocyte counts of neonates: associations between abnormal counts and outcomes. Pediatrics 2012; 129 (5): e1165–e1172.

    Article  Google Scholar 

  6. Chiesa C, Natale F, Pascone R, Osborn JF, Pacifico L, Bonci E et al. C reactive protein and procalcitonin: reference intervals for preterm and term newborns during the early neonatal period. Clin Chim Acta 2011; 412 (11-12): 1053–1059.

    Article  CAS  Google Scholar 

  7. Buttery JP . Blood cultures in newborns and children: optimising an everyday test. Arch Dis Child Fetal Neonatal Ed 2002; 87 (1): F25–F28.

    Article  CAS  Google Scholar 

  8. Chiesa C, Pellegrini G, Panero A, Osborn JF, Signore F, Assumma M et al. C-reactive protein, interleukin-6, and procalcitonin in the immediate postnatal period: influence of illness severity, risk status, antenatal and perinatal complications, and infection. Clin Chem 2003; 49 (1): 60–68.

    Article  CAS  Google Scholar 

  9. Chiesa C, Osborn JF, Pacifico L, Natale F, De Curtis M . Gestational- and age-specific CRP reference intervals in the newborn. Clin Chim Acta 2011; 412 (19-20): 1889–1890.

    Article  CAS  Google Scholar 

  10. Joram N, Boscher C, Denizot S, Loubersac V, Winer N, Roze JC et al. Umbilical cord blood procalcitonin and C reactive protein concentrations as markers for early diagnosis of very early onset neonatal infection. Arch Dis Child Fetal Neonatal Ed 2006; 91 (1): F65–F66.

    Article  CAS  Google Scholar 

  11. Howman RA, Charles AK, Jacques A, Doherty DA, Simmer K, Strunk T et al. Inflammatory and haematological markers in the maternal, umbilical cord and infant circulation in histological chorioamnionitis. PloS ONE 2012; 7 (12): e51836.

    Article  CAS  Google Scholar 

  12. Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM . Systematic reviews of diagnostic test accuracy. Ann Int Med 2008; 149 (12): 889–897.

    Article  Google Scholar 

  13. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J . The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003; 3: 25.

    Article  Google Scholar 

  14. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH . Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol 2005; 58 (10): 982–990.

    Article  Google Scholar 

  15. DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7 (3): 177–188.

    Article  CAS  Google Scholar 

  16. Lijmer JG, Bossuyt PM, Heisterkamp SH . Exploring sources of heterogeneity in systematic reviews of diagnostic tests. Stat Med 2002; 21 (11): 1525–1537.

    Article  Google Scholar 

  17. Cancelier AC, Petronilho F, Reinke A, Constantino L, Machado R, Ritter C et al. Inflammatory and oxidative parameters in cord blood as diagnostic of early-onset neonatal sepsis: a case-control study. Pediatr Crit Care Med 2009; 10 (4): 467–471.

    Article  Google Scholar 

  18. Cernada M, Badia N, Modesto V, Alonso R, Mejías A, Golombek S et al. Cord blood interleukin-6 as a predictor of early-onset neonatal sepsis. Acta Paediatr 2012; 101 (5): e203–e207.

    Article  CAS  Google Scholar 

  19. Gulati S, Bhatnagar S, Raghunandan C, Bhattacharjee J . Interleukin-6 as a predictor of subclinical chorioamnionitis in preterm premature rupture of membranes. Am J Reprod Immunol 2012; 67 (3): 235–240.

    Article  CAS  Google Scholar 

  20. Hatzidaki E, Gourgiotis D, Manoura A, Korakaki E, Bossios A, Galanakis E et al. Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome. Acta Obstet Gynecol Scand 2005; 84 (7): 632–638.

    Article  Google Scholar 

  21. Janota J, Stranak Z, Belohlavkova S, Mudra K, Simak J . Postnatal increase of procalcitonin in premature newborns is enhanced by chorioamnionitis and neonatal sepsis. Eur J Clin Invest 2001; 31 (11): 978–983.

    Article  CAS  Google Scholar 

  22. Kayem G, Goffinet F, Batteux F, Jarreau PH, Weill B, Cabrol D . Detection of interleukin-6 in vaginal secretions of women with preterm premature rupture of membranes and its association with neonatal infection: a rapid immunochromatographic test. Am J Obstet Gynecol 2005; 192 (1): 140–145.

    Article  CAS  Google Scholar 

  23. Kordek A, Giedrys-Kalemba S, Pawlus B, Podraza W, Czajka R . Umbilical cord blood serum procalcitonin concentration in the diagnosis of early neonatal infection. J Perinatol 2003; 23 (2): 148–153.

    Article  CAS  Google Scholar 

  24. Kordek A, Halasa M, Podraza W . Early detection of an early onset infection in the neonate based on measurements of procalcitonin and C-reactive protein concentrations in cord blood. Clin Chem 2008; 46 (8): 1143–1148.

    CAS  Google Scholar 

  25. Lewis DF, Barrilleaux PS, Wang Y, Adair CD, Baier J, Kruger T . Detection of interleukin-6 in maternal plasma predicts neonatal and infectious complications in preterm premature rupture of membranes. Am J Perinatol 2001; 18 (7): 387–391.

    Article  CAS  Google Scholar 

  26. Pfeiffer KA, Reinsberg J, Rahmun A, Schmolling J, Krebs D . Clinical application of maternal serum cytokine determination in premature rupture of membranes—interleukin-6, an early predictor of neonatal infection? Acta Obstet Gynecol Scand 1999; 78 (9): 774–778.

    Article  CAS  Google Scholar 

  27. Popowski T, Goffinet F, Maillard F, Schmitz T, Leroy S, Kayem G . Maternal markers for detecting early-onset neonatal infection and chorioamnionitis in cases of premature rupture of membranes at or after 34 weeks of gestation: a two-center prospective study. BMC Preg Childbirth 2011; 11: 26.

    Article  Google Scholar 

  28. Torbe A . Maternal plasma procalcitonin concentrations in pregnancy complicated by preterm premature rupture of membranes. Mediators Inflamm 2007; 2007: 35782.

    Article  Google Scholar 

  29. Torbe A, Czajka R . Are vaginal fluid procalcitonin levels useful for the prediction of subclinial infection in patients with preterm premature rupture of membranes? J Obstet Gynaecol Res 2005; 31 (5): 464–470.

    Article  CAS  Google Scholar 

  30. Torbe A, Czajka R, Kordek A, Rzepka R, Kwiatkowski S, Rudnicki J . Value of vaginal fluid proinflammatory cytokines for the prediction of early-onset neonatal infection in preterm premature rupture of the membranes. J Interferon Cytokine Res 2007; 27 (5): 393–398.

    Article  CAS  Google Scholar 

  31. van der Heyden JL, van Teeffelen SS, Coolen AC, Halbertsma FJ, Aardenburg R, Mertens HJ et al. Is it useful to measure C-reactive protein and leukocytes in patients with prelabor rupture of membranes? Am J Perinatol 2010; 27 (7): 543–547.

    Article  Google Scholar 

  32. Shahkar L, Keshtkar A, Mirfazeli A, Ahani A, Roshandel G . The role of IL-6 for predicting neonatal sepsis: a systematic review and meta-analysis. Iran J Pediatr 2011; 21 (4): 411–417.

    PubMed  PubMed Central  Google Scholar 

  33. Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI, Sánchez PJ et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 2009; 123 (1): 58–66.

    Article  Google Scholar 

  34. Halkin A, Reichman J, Schwaber M, Paltiel O, Brezis M . Likelihood ratios: getting diagnostic testing into perspective. QJM 1998; 91 (4): 247–258.

    Article  CAS  Google Scholar 

  35. Cordero L, Ayers LW . Duration of empiric antibiotics for suspected early-onset sepsis in extremely low birth weight infants. Infect Control Hosp Epidemiol 2003; 24 (9): 662–666.

    Article  Google Scholar 

  36. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR . Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr 2011; 159 (5): 720–725.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan

    H Su, C-M Han, K-Y Wu, C-Y Huang & C-L Lee

  2. Department of Family Medicine, Chang Gung Memorial Hospital, Taoyuan, and Chang Gung University College of Medicine, Taoyuan, Taiwan

    S-S Chang

  3. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    S-S Chang

  4. Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan

    M-C Li

  5. Department of Emergency Medicine, Chang Gung Memorial Hospital, Keelung, and Chang Gung University College of Medicine, Taoyuan, Taiwan

    J-Y Wu

  6. Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan

    J-Y Wu & C-C Lee

  7. Department of Emergency Medicine, National Taiwan University Hospital Yunlin Branch, Douliou, Taiwan

    C-C Lee

Authors
  1. H Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S-S Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C-M Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K-Y Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M-C Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C-Y Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C-L Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J-Y Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C-C Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to J-Y Wu or C-C Lee.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Su, H., Chang, SS., Han, CM. et al. Inflammatory markers in cord blood or maternal serum for early detection of neonatal sepsis—a systemic review and meta-analysis. J Perinatol 34, 268–274 (2014). https://doi.org/10.1038/jp.2013.186

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2013.186

Keywords

This article is cited by

Search

Advanced search

Quick links