Early stress in immature infants, both animal and human, has the potential for long-term effects. Medical care of infants born prematurely at extremely low gestational ages (ELGA; < 29 weeks gestation) involves systematic repeated exposure to noxious procedures that frequently induce stress and pain. Pain in biologically immature neonates induces numerous physiologic, endocrine and behavioral changes that may contribute to changes in neuro-development - affecting pain systems, the ability to self-regulate behaviorally and physiologically, as well as affecting multiple aspects of attention, learning, and memory. These difficulties impact on the infant's adjustment to the environment, parent-infant interaction and later educational achievement, but their etiology is largely unknown. Using a biobehavioural interdisciplinary approach we have gained new knowledge about pain reactivity, and about relationships between response systems in vulnerable preterm, compared to healthy term born, babies.
The focus of my interdisciplinary research program is biobehavioural reactivity and infant neurodevelopment, broadly encompassing multiple aspects of infant arousal, self-regulation, attention and cognition in preterm and term born infants, including pain responses. This research program is currently funded by the Canadian Institutes of Health Research (CIHR), the National Institutes of Health (NIH, USA), with additional support from the Human Early Learning Partnership (HELP).
Clinical practice of pain management in the Neonatal Intensive Care Unit (NICU) has changed in recent years from no concern with pain to widespread use of analgesia and sedation, but there are major gaps in knowledge of pain assessment in immature infants, and in long term effects inherent to both pain itself, and varying exposure to pain medications. With the goal to improve pain assessment, we recently confirmed that, along with recognized facial and heart rate changes, there are motor stress behaviors unique to premature infants (e.g. backward splaying of fingers). Conversely, other behaviors such as twitches and startles appear to reflect sleep/waking state, and are not stress cues. Currently we are exploring whether stress and pain responses can be differentiated in preterm infants, or whether they are on a continuum. We have shown that greater exposure to early pain in the NICU is associated subsequently with generally dampened pain responses, and that altered pain reactivity persists after discharge from hospital. Further, we have some preliminary evidence that morphine given to babies during the acute care phase in the NICU may ameliorate altered pain reactivity, but very little is known about the effects (negative or positive) of early opioid exposure on other aspects of neurodevelopment.
Pain in infants born at extremely low gestational age is developmentally "unexpected" and occurs at the time of most rapid brain development. In a series of longitudinal studies, we are evaluating changes in behavior, physiologic, and cortisol response (the primary human stress hormone), to varying physical stress and pain during hospitalization as a function of prior experience in the NICU, including early illness severity, pain and morphine exposure.
After NICU discharge we have a series of studies that grew from our earlier findings at ages 3, 4.5 and 9 years, that children born extremely low birthweight, compared to term born peers, displayed stress behaviors to cognitive challenges involving processing novelty. To explore the etiology, we are examining biobehavioral reactivity (behavior, physiologic, cortisol) to visual novelty in preterm compared to term born infants in home visits at 3 and 6 months, and in our lab in the Biobehavioural Research Unit at 8 months (ages corrected for prematurity). In addition to comparing responses of preterm and term born groups, among the preterm infants we are examining reactivity to visual novelty in relation to prior experience in the NICU. Furthermore, we are studying to what extent caregiver interaction style and parenting stress may modify infant behavior, as well as ameliorate or exacerbate effects of early stress/pain experience in preterm infants.
Recently we began a new study of behavioral, cardiac and hormonal (cortisol) reactivity to pain of immunization at 6 months CA comparing responses in preterm and term born infants. Mother-infant interaction and stress reactivity as moderators of pain responses are also being examined.
Haley DW, Grunau RE, Oberlander TF, Weinberg J.: Contingency Learning and Reactivity in Preterm and Full-Term Infants at 3 Months. Infancy. 2008 Dec;13(6):570-95.
Oberlander TF, Grunau R, Mayes L, Riggs W, Rurak D, Papsdorf M, Misri S, Weinberg J.: Hypothalamic-pituitary-adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure. Early Hum Dev. 2008 Oct;84(10):689-97.
Grunau RE, Tu MT. Long-term consequences of pain in human neonates. In K.J.S. Anand, B.J. Stevens, & P.J. McGrath (Eds.) Pain in Neonates, 2007, 3rd edition. Amsterdam: Elsevier Science, 45-55.
Grunau RE, Haley DW, Whitfield MF, Weinberg J, Yu W, Thiessen P. Altered basal cortisol levels at 3, 6, 8 and 18 months in infants born extremely low gestational age. J Pediatrics 2007;150:151-156.
Tu MT, Grunau RE, Petrie-Thomas J, Haley DW, Weinberg J, Whitfield MF. Maternal stress and behavior modulate relationships between neonatal stress, attention and basal cortisol at 8 months in preterm infants. Developmental Psychobiology 2007; 49:150-164.
Grunau RE, Whitfield MF, Fay T, Holsti L., Oberlander T, Rogers ML. Biobehavioural reactivity to pain in preterm infants: a marker of neuromotor development. Developmental Medicine & Child Neurology. 2006;48:471-476.
Grunau RE, Holsti L, Peters JW. Long-term consequences of pain in human neonates. In D Tibboel, R Bhat (Guest editors) Pain Control and Sedation, Seminars in Fetal and Neonatal Medicine. 2006;11:268-275.
Holsti L, Grunau RE, Whitfield MF, Oberlander TF, Lindh V. Behavioral responses to pain are heightened after clustered care in preterm infants born between 30 and 32 weeks gestational age. Clinical Journal of Pain 2006;22:757-764.
Haley DW, Weinberg J, Grunau RE. Cortisol, contingency learning, and memory in preterm and full-term infants. Psychoneuroendocrinology 2006;31:108-117.
Grunau RE , Holsti L, Haley DW, Oberlander TF, Weinberg J, Solimano A, Whitfield MF, Papsdorf, M, Fitzgerald C, Yu W. Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain 2005; 113:293-300.
Grunau RE , Whitfield MF, Fay TB. Psycho-Social and Academic Characteristics of ELBW (greater than or equal to 800g) Survivors In Late Adolescence Compared To Term-Born Controls. Pediatrics 2004;114:e725-e732.
Grunau RE, Weinberg J, Whitfield MF. Neonatal procedural pain and preterm infant cortisol response to novelty at 8 months. Pediatrics 2004;114(1), e77-e84.
Distinguished Scholar, Child & Family Research Institute, 2007 – present
Senior Scholar, Human Early Learning Partnership, 2007 - present
Senior Scholar, Michael Smith Foundation for Health Research, 2002-2007
Joint Research Scholar Award, BC Health Research Foundation and BC Research Institute for Children's & Women's Health, 1999-2002