Cord Blood Acute Phase Reactants Predict Early Onset Neonatal Sepsis in Preterm Infants

PLoS One. 2017 Jan 3;12(1):e0168677. doi: 10.1371/journal.pone.0168677. eCollection 2017.


Background: Early onset sepsis (EOS) is a major cause of morbidity and mortality in preterm infants, yet diagnosis remains inadequate resulting in missed cases or prolonged empiric antibiotics with adverse consequences. Evaluation of acute phase reactant (APR) biomarkers in umbilical cord blood at birth may improve EOS detection in preterm infants with intrauterine infection.

Methods: In this nested case-control study, infants (29.7 weeks gestation, IQR: 27.7-32.2) were identified from a longitudinal cohort with archived cord blood and placental histopathology. Patients were categorized using culture, laboratory, clinical, and antibiotic treatment data into sepsis groups: confirmed sepsis (cEOS, n = 12); presumed sepsis (PS, n = 30); and no sepsis (controls, n = 30). Nine APRs were measured in duplicate from cord blood using commercially available multiplex immunoassays (Bio-Plex Pro™). In addition, placental histopathologic data were linked to biomarker results.

Results: cEOS organisms were Escherichia coli, Streptococcus agalactiae, Proteus mirabilis, Haemophilus influenzae and Listeria monocytogenes. C-reactive protein (CRP), serum amyloid A (SAA), haptoglobin (Hp), serum amyloid P and ferritin were significantly elevated in cEOS compared to controls (p<0.01). SAA, CRP, and Hp were elevated in cEOS but not in PS (p<0.01) and had AUCs of 99%, 96%, and 95% respectively in predicting cEOS. Regression analysis revealed robust associations of SAA, CRP, and Hp with EOS after adjustment for covariates. Procalcitonin, fibrinogen, α-2-macroglobulin and tissue plasminogen activator were not significantly different across groups. Placental acute inflammation was associated with APR elevation and was present in all cEOS, 9 PS, and 17 control infants.

Conclusion: This study shows that certain APRs are elevated in cord blood of premature infants with EOS of intrauterine origin. SAA, CRP, and Hp at birth have potential diagnostic utility for risk stratification and identification of infants with EOS.

MeSH terms

  • Acute-Phase Proteins / metabolism*
  • Area Under Curve
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Fetal Blood / metabolism*
  • Humans
  • Infant, Newborn
  • Infant, Premature
  • Inflammation
  • Linear Models
  • Longitudinal Studies
  • Male
  • Neonatal Sepsis / blood*
  • Placenta / pathology
  • Pregnancy
  • ROC Curve
  • Sepsis / blood*


  • Acute-Phase Proteins
  • Biomarkers