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Updated: Aug 23, 2026
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Neonatal procedural pain and preterm infant cortisol response to novelty at 8 months
Ruth E Grunau1, Joanne Weinberg, Michael F Whitfield
1Centre for Community Child Health Research, British Columbia Research Institute for Children's & Women's Health, Vancouver, British Columbia, Canada. rgrunau@cw.bc.ca
Insights
Extremely low gestational age preterm infants show altered cortisol stress responses at 8 months corrected age. Neonatal procedural pain and skin-breaking procedures may contribute to these long-term changes in stress regulation.
Area of Science:
- Neonatal physiology
- Developmental psychology
- Pediatric endocrinology
Background:
- Neonatal intensive care can expose preterm infants to significant stress, including procedural pain.
- Long-term effects of early stress on stress system development in preterm infants are not well understood.
- Cortisol levels are a key indicator of the body's stress response.
Purpose of the Study:
- To compare cortisol stress responses to visual novelty at 8 months corrected age in extremely low gestational age (ELGA), very low gestational age (VLGA), and term-born infants.
- To investigate the relationship between neonatal procedural pain, morphine exposure, and cortisol levels at 8 months corrected age in preterm infants.
Main Methods:
- Salivary cortisol was measured in 76 infants (54 preterm, 22 term) at 8 months corrected age.
- Cortisol levels were assessed at baseline, after novel toy exposure, and after developmental assessment.
- Infants with major sensory, motor, or cognitive impairments were excluded.
Main Results:
- ELGA infants exhibited significantly higher basal and sustained salivary cortisol levels compared to VLGA and term infants.
- Higher basal cortisol levels in preterm infants were associated with a greater number of neonatal skin-breaking procedures.
- Neonatal pain and gestational age at birth predicted cortisol responses to novelty, but morphine dosing did not.
Conclusions:
- Extremely low gestational age preterm infants display distinct cortisol patterns in response to visual novelty compared to more mature infants.
- Extensive neonatal skin-breaking procedures may alter basal arousal systems in preterm infants.
- Early life stress in the NICU may have lasting impacts on stress system development in vulnerable preterm populations.
Objectives:
Stress systems may be altered in the long term in preterm infants for multiple reasons, including early exposure to procedural pain in neonatal intensive care. This question has received little attention beyond hospital discharge. Stress responses (cortisol) to visual novelty in preterm infants who were born at extremely low gestational age (ELGA; < or =28 weeks), very low gestational age (VLGA; 29-32 weeks), and term were compared at 8 months of age corrected for prematurity (corrected chronological age [CCA]). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit.
Methods:
Seventy-six infants, 54 preterm (< or =32 weeks' GA at birth) and 22 term-born infants who were seen at 8 months CCA composed the study sample, after excluding those with major sensory, motor, or cognitive impairment. Salivary cortisol was measured before (basal) and 20 minutes after introduction of novel toys (post 1) and after developmental assessment (post 2).
Results:
Salivary cortisol was significantly higher in ELGA infants at 8 months, compared with the VLGA and term groups before and after introduction of visual novelty. Term-born and VLGA infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher basal cortisol levels in preterm infants at 8 months' CCA were associated with higher number of neonatal skin-breaking procedures. In contrast, cortisol responses to novelty were predicted equally well by neonatal pain or GA at birth. No relationship between morphine dosing and cortisol response was demonstrated in these infants.
Conclusions:
ELGA preterm infants show a different pattern of cortisol levels before and after positive stimulation of visual novelty than more maturely born, VLGA preterm and term-born infants. Exposure to high numbers of skin-breaking procedures may contribute to "resetting" basal arousal systems in preterm infants.
