Pediatric investigation study examines the diagnostic utility of C-reactive protein for newborn early-onset sepsis

Neonatal EOS, a severe bloodstream infection that strikes within the first three days of life, is a major cause of infant illness and death worldwide. Because clinical features such as poor feeding, breathing problems, or lethargy are non-specific, doctors often rely on laboratory markers like C-reactive protein (CRP) to help decide which newborns might need urgent antibiotics. However, although CRP measurements have a high negative predictive value for sepsis, its optimal cut-off values have not been fully established for the first three days of life.

To evaluate the diagnostic utility of CRP for EOS and to determine the cut-off values, a team of researchers led by Professor Hugh Simon Lam from the Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China, conducted a multicenter retrospective study using large-scale, population-based data. The study was published in the journal of Pediatric Investigation on October 24, 2025.

“Ours is the first population-based study to evaluate how well CRP testing can identify EOS in newborns, highlighting the fluctuations of CRP levels in a real-world setting,” says Prof. Hugh Simon Lam.

Using electronic health records from all public hospitals in Hong Kong between 2006 and 2017, the team reviewed 100,327 newborns who had CRP levels measured within 72 hours of birth and before receiving antibiotics. Of these, 448 infants developed culture-confirmed EOS, and 34 had meningitis.

The researchers found that in healthy, uninfected babies, CRP levels increased naturally about eight hours after birth, peaking between 24 and 32 hours. This rise was especially pronounced in term babies, whose CRP levels were significantly higher than those of preterm babies. Because of this physiological increase, a high CRP reading soon after birth may not indicate infection.

Notably, the CRP test performed much better in preterm babies than in those born at term. Among infants born before 34 weeks, a CRP level above 8.0 mg/L after four hours of life was a strong indicator of infection, showing an area under the receiver operating characteristic curve of 0.88, indicating good diagnostic performance. But in term babies, the same test had low sensitivity and specificity across all time points, indicating many infections could be missed while others were wrongly suspected.

The team also explored whether CRP could help estimate the risk of early-onset meningitis, a rare but devastating infection of the brain. They found that a CRP level above 12.0 mg/L best predicted meningitis risk, with strong specificity and a high negative predictive value, suggesting that low CRP levels could help rule out infection.

The study highlights the need to interpret CRP results in the context of gestational and postnatal age, rather than using a single fixed cut-off for all newborns. It also underscores the risk of misdiagnosis and unnecessary antibiotic exposure when CRP is used indiscriminately, particularly in term babies whose levels may rise for non-infectious reasons such as the birth process or maternal complications. Despite these limitations, CRP still has value in neonatal care when interpreted correctly.

“Although CRP isn’t a perfect biomarker for EOS detection, it can still help assess infection risk in preterm babies and guide clinicians on whether further testing for meningitis is needed,” says Prof. Hugh Simon Lam.

The findings suggest that CRP should be used selectively in preterm infants and always interpreted alongside other clinical signs, risk factors, and timing of birth. Until faster and more precise biomarkers become available, CRP remains a useful but limited tool in neonatal sepsis screening.

“The results of our population-based analysis will aid in effective utilization of this simple, cost-effective, and widely available CRP test for screening of neonatal sepsis in a select portion of the newborn population,” concludes Prof. Hugh Simon Lam.

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Reference
DOI: 10.1002/ped4.70025

About Professor Hugh Simon Lam
Dr. Hugh Simon Lam is a Professor at the Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China. He also serves as Assistant Dean (Clinical Education and Internship) at the Faculty of Medicine and Warden of the Madam SH Ho Hostel for Medical Students. His research interests include neonatology, pediatric respiratory medicine, neonatal intensive care, and neonatal sepsis.