Cumulative procedural pain and brain development in very preterm infants: A systematic review of clinical and preclinical studies

•Cumulative pain has been proven to influence brain development in preterm infants.•Translational animal studies show some harmful effects of pain on brain histology.•Evidence supporting epigenetics as potential underlying mechanism is still scarce.•The interplay among pain, epigenetics and brain development needs to be assessed.•Despite knowledge gaps, it is crucial to minimize pain exposure in neonatal units. Very preterm infants may manifest neurodevelopmental impairments, even in the absence of brain lesions. Pathogenesis is complex and multifactorial. Evidence suggests a role of early adversities on neurodevelopmental outcomes, via epigenetic regulation and changes in brain architecture. In this context, we focused on cumulative pain exposure which preterm neonates experience in neonatal intensive care unit (NICU). We systematically searched for: i) evidence linking pain with brain development and exploring the potential pathogenetic role of epigenetics; ii) preclinical research supporting clinical observational studies. Nine clinical neuroimaging studies, during neonatal or school age, mostly from the same research group, revealed volume reduction of white and gray matter structures in association with postnatal pain exposure. Three controlled animal studies mimicking NICU settings found increased cell death or apoptosis; nevertheless, eligible groups were limited in size. Epigenetic modulation (SLC6A4 promoter methylation) was identified in only two clinical trials. We call for additional research and, although knowledge gaps, we also point out the urgent need of minimizing painful procedures in NICUs.