Long-term consequences of pain in human neonates
Introduction
With advances in medical care over the past two decades, survival of infants born extremely premature, infants with life-threatening medical conditions and infants with congenital malformations has increased substantially. However, as part of this life-saving care, these infants are exposed to multiple stressors in the neonatal period. Extremely preterm birth results in lengthy hospitalization of infants who are physiologically unprepared for the stress outside the protective intrauterine environment.1 Such stress includes extended exposure to light and noise, acute and chronic illness, maternal separation, invasive procedures, handling, and multiple medications, for each of which the long-term effects are unclear. At the same time, there has been growing concern that the invasive procedures that are intrinsic to management in the neonatal intensive care unit (NICU) and the pediatric intensive care unit (PICU), such as endotracheal intubation, repeated blood tests, insertion of peripheral lines and surgery, might induce changes to the CNS.2, 3 It is well established that preterm neonates show greater sensitivity to pain compared to full-term infants.4 For infants with extremely immature physiological and neurobehavioural systems, continual adaptation to repeated challenges induces long-term alterations in pain sensitivity,4, 5 might affect generalized stress-arousal systems,6, 7 and potentially affects the developing cytoarchitecture of the brain.2, 9, 10 Pain-related stress during many weeks or months in the NICU might in turn be one contributing factor to alterations in neurodevelopment and behavior in extremely preterm infants who escape major neurosensory impairment, although this link remains largely speculative at this point.
The neurobiology of pain in the developing organism is addressed in Chapter 1 of this volume, and pain while infants are in the NICU is covered in Chapter 3. This chapter first presents the overall context of pain-related stress; second, it addresses potential links between neonatal pain and brain development; and third, it examines long-term effects of procedural pain and surgery on later pain sensitivity. The animal literature on effects of neonatal pain has recently been reviewed elsewhere,4 therefore we primarily address pain in human infants.
Section snippets
Prematurity and allostatic load
Recently, the concepts of ‘allostasis’ and ‘allostatic load’ have been developed to define more clearly the cumulative effects of exposure to repeated stress from any source.11 ‘Allostasis’ applies to systems that maintain homeostasis, integrating responses of the hypothalamic–pituitary–adrenal (HPA) axis, the immune system and the autonomic nervous system, which constantly adapt to variations in response to perceived and anticipated environmental demands. In the long term, high demands on
Vulnerability of the developing preterm brain
The etiology of neurobehavioral problems in preterm infants who escape major sensory, motor and cognitive impairments is unclear. However, these problems are probably attributable, at least in part, to disturbances in the expected organizational events in brain development, and/or injury to basal ganglia or hippocampus,38 and/or subtle white matter changes, which are far more common than previously thought among infants who escape periventricular leukomalacia or severe intraventricular
Stress and vulnerability of the hippocampal and prelimbic prefrontal regions
The HPA axis and cardiovascular, metabolic and immune systems respond to external and internal threat.42 As we have described above, one type of allostatic load is the inability to shut off responses after a stress is terminated. The mechanisms of the shift from down-regulation of cortisol in the NICU32 in preterm infants born at extremely low gestational age (ELGA; <28 weeks gestation) to sustained up-regulation later long after discharge home7 are unknown. However, high basal cortisol, as we
Neuroimaging, electrophysiology and prematurity
Imaging studies are beginning to describe structural differences in the brains of children born before term. Using advanced volumetric MRI, preterm children have smaller brain volume in specific regions at age 7 years,55 and poorer cognitive outcome was correlated with reduced brain volume.57 There are regions of particular vulnerability in the developing brain. For example, adolescents born <30 weeks gestation had comparable head circumference and neurologic exams (compared to term-born
Pre-emptive analgesia in the NICU
A critical question continues to be whether analgesics play a role in long-term changes to the CNS.60 Pre-emptive morphine might ameliorate, have no effect, or potentially even exacerbate adverse neurodevelopment associated with prematurity. Pharmacologic treatment of neonatal pain was reviewed recently61 and is addressed elsewhere in this volume, therefore we will only touch on these issues here.
Analgesic agents directly suppress neuronal activation, and reduce extracellular concentrations of
Surgery
Relatively few studies have assessed long-term effects of early surgery on pain sensitivity later in life. Although a large body of literature has shown that analgesics prevent pain and blunt the physiological effects of pain and stress at the short term (see, for example, refs 68 and 69) their capability to prevent hypersensitivity in the long term is not clear. In one of the most cited studies, term-born males who had undergone unanesthetized neonatal circumcision, responded more intensely to
Summary
Causal effects of neonatal pain on later pain sensitivity have been established through animal models. However, the findings are complex and show that outcomes vary in relation to timing, type and extent of insult. In human infants, there is a growing body of work on pain sensitivity in infants exposed to neonatal pain and/or surgery. The animal findings are essential for interpreting and confirming human studies, due to the difficulties of establishing causality in follow-up of human infants.
Acknowledgement
We express our appreciation to Dr Michael Whitfield for his very helpful comments on an earlier draft of this paper. Supported in part by grant HD39783-01 (R.E.G.) from the National Institute of Child Health and Human Development, a Senior Scholar award from the Michael Smith Foundation for Health Research (R.E.G.), and a Canadian Child Health Clinician-Scientist award (L.H.).
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