Physiological correlates of pain in preterm infants: evidence from a meta-analytic approach

Background Preterm infants are frequently exposed to painful procedures during neonatal intensive care, yet their physiological capacity to respond to pain and the reliability of related biomarkers remain incompletely understood. This meta-analysis aimed to synthesize evidence on physiological correlates of pain in preterm infants to identify consistent objective indicators of pain. Methods A systematic search of PubMed, Scopus, Web of Science, Embase, and CINAHL was conducted for studies published between January 2017 and December 2025. Randomized controlled trials, cohort, and observational studies assessing physiological responses to procedural pain in preterm infants were included. Data were analyzed using random-effects models, and heterogeneity was assessed with the I² statistic. Results Fifteen studies involving 1,273 preterm infants met the inclusion criteria. Painful procedures induced significant increases in heart rate (mean difference +12.6 bpm, p < 0.001) and cortisol levels (SMD = + 0.68, p < 0.01), alongside decreases in heart rate variability (SMD = −0.81, p < 0.001), oxygen saturation (–4.3%, p < 0.01), melatonin (SMD = –0.54, p < 0.05), and cerebral oxygenation (–8.5%, p < 0.001). Subgroup analyses showed the strongest effects in cardiorespiratory parameters (SMD = 0.91). No significant publication bias was detected. Conclusion Procedural pain in preterm infants elicits robust physiological responses across autonomic, endocrine, and neurophysiological domains. Integrating these objective indicators into neonatal pain assessment may enhance early recognition and improve pain management practices, ultimately supporting better neurodevelopmental outcomes.