ArticleNeonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICUGrunau, Ruth E.a,b,e,*; Holsti, Liisaa,d,e; Haley, David W.a,b; Oberlander, Tima,b,e; Weinberg, Joannea,c; Solimano, Alfonsob,e; Whitfield, Michael F.b,e; Fitzgerald, Colleena; Yu, WaynecAuthor Information aCentre for Community Child Health Research, British Columbia Research Institute for Children's and Women's Health, Vancouver, BC, Canada bDepartment of Pediatrics, University of British Columbia, Canada cDepartment of Anatomy, Cell Biology and Physiology, University of British Columbia, Canada dSchool of Rehabilitation Sciences, University of British Columbia, Canada eChildren's and Women's Health Centre of British Columbia, Vancouver, Canada *Corresponding author. Address: Centre for Community Child Health Research, Room F6, 4480 Oak Street, Vancouver, BC, Canada V6H 3V4. Tel.: +1 604 875 2447; fax: +1 604 875 3569. E-mail address:email@example.com E-mail address:http://www.bcricwh.bc.ca/our_research/researchers/researcher_by_name/ruth_grunau.htm Received 12 August 2004; received in revised form 5 October 2004; accepted 25 October 2004. Pain: February 2005 - Volume 113 - Issue 3 - p 293-300 doi: 10.1016/j.pain.2004.10.020 Buy Metrics Abstract Data from animal models indicate that neonatal stress or pain can permanently alter subsequent behavioral and/or physiological reactivity to stressors. However, cumulative effects of pain related to acute procedures in the neonatal intensive care unit (NICU) on later stress and/or pain reactivity has received limited attention. The objective of this study is to examine relationships between prior neonatal pain exposure (number of skin breaking procedures), and subsequent stress and pain reactivity in preterm infants in the NICU. Eighty-seven preterm infants were studied at 32 (±1 weeks) postconceptional age (PCA). Infants who received analgesia or sedation in the 72 h prior to each study, or any postnatal dexamethasone, were excluded. Outcomes were infant responses to two different stressors studied on separate days in a repeated measures randomized crossover design: (1) plasma cortisol to stress of a fixed series of nursing procedures; (2) behavioral (Neonatal Facial Coding System; NFCS) and cardiac reactivity to pain of blood collection. Among infants born ≤28 weeks gestational age (GA), but not 29–32 weeks GA, higher cumulative neonatal procedural pain exposure was related to lower cortisol response to stress and to lower facial (but not autonomic) reactivity to pain, at 32 weeks PCA, independent of early illness severity and morphine exposure since birth. Repeated neonatal procedural pain exposure among neurodevelopmentally immature preterm infants was associated with down-regulation of the hypothalamic–pituitary–adrenal axis, which was not counteracted with morphine. Differential effects of early pain on development of behavioral, physiologic and hormonal systems warrant further investigation. © 2005 Lippincott Williams & Wilkins, Inc.