Abstract
Neonatal sepsis is a systemic response to a bacterial infection within the first 28 days of life. Diagnosis remains a challenge due to the subtle and nonspecific signs, often resulting in the use of empirical antibiotics and their associated risks. This systematic review aims to compare the diagnostic accuracy and clinical utility of C-reactive protein (CRP) and procalcitonin (PCT) in the early diagnosis of neonatal sepsis. The review was conducted using our search strategy across PubMed/Medline, PubMed Central, Europe PMC, ScienceDirect, and Google Scholar. Eligible studies included free full-text systematic reviews, narrative reviews, diagnostic accuracy studies, and observational studies published in English between 2020 and 2025. Studies published in foreign languages, based on non-human studies, as well as grey literature that lacked free full-text articles, were excluded from the analysis. The risk of bias was assessed using appropriate quality assessment tools. Of the 16 initially eligible studies, 12 met the inclusion criteria after quality assessment; these consisted of eight narrative reviews, three diagnostic accuracy studies, and one observational study. Our systematic review found that although CRP is widely utilized due to its low cost and simplicity, its limited early sensitivity and susceptibility to non-infectious factors reduce its utility in diagnosing neonatal sepsis. In contrast, PCT demonstrated an earlier rise, correlates with the severity of the disease, has higher sensitivity (reported as 97.6 and 97.7% in two studies), and can differentiate between bacterial, viral, and fungal infections. However, PCT displays a physiological rise, can be influenced by non-infectious factors, and is costlier. In both cases, serial measurements and the use of adjusted nomograms enhance their use. In conclusion, PCT demonstrates superior diagnostic potential and utility in guiding antibiotic therapy compared to CRP for early diagnosis of neonatal sepsis, especially when used in combination with other biomarkers. As part of our review, we noted the absence of procalcitonin in current international neonatal sepsis guidelines, and we have proposed a flowchart to guide its potential integration into clinical practice. Future research should focus on large, low-bias studies, the identification of standardized cut-off values, the development of adjusted nomograms, and the validation of emerging diagnostic technologies. This systematic review is not registered, as PROSPERO currently does not support registration of diagnostic test accuracy studies.