Clinical Signs Associated With Mortality and Sepsis in Young Infants: A Systematic Review and Meta-Analysis
In infants aged 0 to 59 days, poor feeding and reduced alertness were strongly linked to death and sepsis.
*Systematic review and meta-analysis; Level 1a (OCEBM).
*Systematic review and meta-analysis; Level 1a (OCEBM).
Citation
Driker S, Mathias S, Fung A, et al. Clinical Signs Associated With Mortality and Sepsis in Young Infants: A Systematic Review and Meta-Analysis. JAMA Pediatrics. 2026;180(4):384-393. doi:10.1001/jamapediatrics.2025.5967. Published online February 2, 2026.
Background
Early identification of severe illness in young infants is difficult in settings without reliable laboratory testing. This review assessed which bedside signs are most associated with sepsis or death.
Patients
Infants aged 0 to 59 days (or mean/median age <60 days) in community, outpatient, or hospital settings. Excluded: specialized populations (for example, all infants undergoing surgery) and studies relying on clinician judgment alone without supportive tests for sepsis.
Intervention
Presence of 24 predefined clinical signs (history or exam).
Control
Absence of the clinical sign.
Outcome
All-cause mortality; culture-confirmed sepsis; clinically diagnosed sepsis supported by testing or imaging.
Follow-up Period
Up to 60 days of life or hospital discharge (mortality); at evaluation (sepsis).
Results
Fifty-two studies (140,885 infants) were included. All signs in the World Health Organization’s current young-infant checklist were significantly associated with either death or culture-confirmed sepsis.
| Outcome | Clinical sign | Pooled odds ratio (95% confidence interval) |
|---|---|---|
| Mortality (primary) | Weak, abnormal, or absent cry | 20.48 (6.59-63.67) |
| Mortality (primary) | Not able to feed at all | 18.32 (6.00-55.97) |
| Mortality (primary) | Not feeding well | 13.39 (6.97-25.72) |
| Mortality (primary) | Drowsiness or unconsciousness | 12.46 (6.06-25.62) |
| Mortality (primary) | Prolonged capillary refill | 12.06 (2.77-52.53) |
| Culture-confirmed sepsis (primary) | Not feeding well | 4.52 (1.10-18.59) |
| Culture-confirmed sepsis (primary) | Prolonged capillary refill | 3.59 (2.05-6.28) |
| Culture-confirmed sepsis (primary) | Lethargy | 3.44 (1.89-6.26) |
| Culture-confirmed sepsis (primary) | Drowsiness or unconsciousness | 3.07 (2.01-4.68) |
| Culture-confirmed sepsis (primary) | Feeding intolerance | 2.95 (1.67-5.21) |
| Clinical sepsis (primary) | Movement only when stimulated | 11.00 (3.40-35.58) |
Limitations
Sign definitions and sepsis reference standards varied across studies, limiting direct comparability. Most data were observational, so unmeasured factors could affect results. Associations do not prove that adding new signs improves outcomes.
Funding
World Health Organization; US National Institutes of Health grants to investigators.
Clinical Application
For infants under 60 days, treat poor feeding or low alertness as urgent warning signs; consider adding capillary refill and central cyanosis checks where training allows.
Discussion
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In this systematic review and meta-analysis of clinical signs in infants aged 0–59 days, weak/abnormal/absent cry was associated with mortality (OR 20.48; 95% CI, 6.59–63.67). Given observational input data, how should validity and applicability affect IMCI practice change? The meta-analysis reported that prolonged capillary refill was associated with culture-confirmed sepsis in young infants (OR 3.59; 95% CI, 2.05–6.28). Which interpretation is most appropriate?