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

Tiziana Boggini, Sara Pozzoli, Paola Schiavolin, Raffaele Erario, Fabio Mosca, Paolo Brambilla, Monica Fumagalli

Research output: Contribution to journalReview articlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)320-336
Number of pages17
JournalNeuroscience and Biobehavioral Reviews
Volume123
DOIs
Publication statusPublished - Apr 2021

Keywords

  • Animal models
  • Brain development
  • DNA methylation
  • Epigenetics
  • Histology
  • MRI
  • NICU
  • Procedural pain
  • Repetitive insults
  • Skin-breaking procedures
  • SLC6A4
  • Very preterm infants

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

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