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Background: Altered sensory processing is commonly reported in children born very preterm (≤32 weeks' gestational age [GA]). The immature nervous system, particularly the development of connections from the thalamus to the cortex, may show enhanced vulnerability to excessive sensory stimulation, and may contribute to altered sensory processing. Our objective was to determine whether sensory processing assessed at preschool-aged in children born very preterm was predicted by neonatal procedural pain and thalamic development., Methods: In a prospective longitudinal cohort study, N = 140 very preterm infants (median GA at birth 28 weeks) underwent MRI early-in-life and again at term-equivalent age. Children returned for assessment at 4.5 years. Parents reported on child sensory processing behaviors on the Short Sensory Profile. General linear models were used to assess factors associated with sensory processing behaviors, adjusting for clinical and demographic factors., Results: Among extremely preterm neonates (born 24-28 weeks' GA), but not very-preterm neonates (29-32 weeks' GA), more invasive procedures were associated with poorer sensory processing (B = -0.09, 95%CI [-0.17, -0.01] p = 0.03). In the overall cohort, fewer sensory processing problems were associated with greater thalamic growth between birth and term-equivalent age (B = 0.3, 95%CI [0.11, 0.42], p < 0.001). Extremely preterm neonates exposed to a high number of skin-breaking procedures who exhibited slower neonatal thalamic growth displayed the highest sensory processing problems (B = -26.2, 95%CI [-45.96, -6.38], p = 0.01)., Conclusion: Early exposure to pain and related alterations in the developing thalamus may be a key factor underlying later sensory problems in children born extremely preterm., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To test the hypothesis that a strategy of prolonged arterial line (AL) and central venous line (CVL) use is associated with reduced neonatal invasive procedures and improved growth of the thalamus in extremely preterm neonates (<28 weeks' gestation)., Methods: Two international cohorts of very preterm neonates (n = 143) with prolonged (≥14 days) or restricted (<14 days) use of AL/CVL were scanned serially with MRI. General linear models were used to determine the association between skin breaks and thalamic volumes, accounting for clinical confounders and site differences. Children were assessed at preschool age on standardized tests of motor and cognitive function. Outcome scores were assessed in relation to neonatal thalamic growth., Results: Prolonged AL/CVL use in neonates (n = 86) was associated with fewer skin breaks (median 34) during the hospital stay compared to restricted AL/CVL use (n = 57, median 91, 95% confidence interval [CI] 60.35-84.89). Neonates with prolonged AL/CVL use with fewer skin breaks had significantly larger thalamic volumes early in life compared to neonates with restricted line use (B = 121.8, p = 0.001, 95% CI 48.48-195.11). Neonatal thalamic growth predicted preschool-age cognitive (B = 0.001, 95% CI 0.0003-0.001, p = 0.002) and motor scores (B = 0.01, 95% CI 0.001-0.10, p = 0.02). Prolonged AL/CVL use was not associated with greater incidence of sepsis or multiple infections., Conclusions: Prolonged AL/CVL use in preterm neonates may provide an unprecedented opportunity to reduce invasive procedures in preterm neonates. Pain reduction in very preterm neonates is associated with optimal thalamic growth and neurodevelopment., (© 2020 American Academy of Neurology.)

Oral sucrose is administered routinely to reduce pain of minor procedures in premature infants and is recommended as standard care in international guidelines. No human or animal studies on effects of early repeated sucrose exposure on long-term brain development have been done in the context of pain. We evaluated the effects of repeated neonatal sucrose treatment before an intervention on long-term brain structure in mouse pups. Neonatal C57Bl/6J mice (n = 109) were randomly assigned to one of 2 treatments (vehicle vs sucrose) and one of 3 interventions (handling, touch, or needle-prick). Mice received 10 interventions daily from postnatal day 1 to 6 (P1-6). A dose of vehicle or 24% sucrose was given orally 2 minutes before each intervention. At P85-95, brains were scanned using a multichannel 7.0 T MRI. Volumes of 159 independent brain regions were obtained. Early repetitive sucrose exposure in mice (after correcting for whole brain volume and multiple comparisons) lead to smaller white matter volumes in the corpus callosum, stria terminalis, and fimbria (P < 0.0001). Cortical and subcortical gray matter was also affected by sucrose with smaller volumes of hippocampus and cerebellum (P < 0.0001). These significant changes in adult brain were found irrespective of the type of intervention in the neonatal period. This study provides the first evidence of long-term adverse effects of repetitive sucrose exposure and raises concerns for the use of this standard pain management practice during a period of rapid brain development in very preterm infants.

Introduction: Children born very preterm display altered pain thresholds. Little is known about the neonatal clinical and psychosocial factors associated with their later pain perception., Objective: We aimed to examine whether the number of neonatal invasive procedures, adjusted for other clinical and psychosocial factors, was associated with self-ratings of pain during a blood collection procedure at school age in children born very preterm., Materials and Methods: 56 children born very preterm (24 to 32 weeks gestational age), followed longitudinally from birth, and free of major neurodevelopmental impairments underwent a blood collection by venipuncture at age 7.5 years. The children's pain was self-reported using the Coloured Analog Scale and the Facial Affective Scale. Parents completed the Child Behavior Checklist and the State-Trait Anxiety Inventory. Pain exposure (the number of invasive procedures) and clinical factors from birth to term-equivalent age were obtained prospectively. Multiple linear regression was used to predict children's pain self-ratings from neonatal pain exposure after adjusting for neonatal clinical and concurrent psychosocial factors., Results: A greater number of neonatal invasive procedures and higher parent trait-anxiety were associated with higher pain intensity ratings during venipuncture at age 7.5 years. Fewer surgeries and lower concurrent child externalizing behaviors were associated with a higher pain intensity., Conclusions: In very preterm children, exposure to neonatal pain was related to altered pain self-ratings at school age, independent of other neonatal factors. Neonatal surgeries and concurrent psychosocial factors were also associated with pain ratings., Competing Interests: statement The authors report no conflict of interest.

Objective: To examine whether specific neonatal factors differentially influence cerebellar subregional volumes and to investigate relationships between subregional volumes and outcomes in very preterm children at 7 years of age., Study Design: Fifty-six children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-dimensional T(1)-weighted neuroimaging at median age 7.6 years. Children with severe brain injury were excluded. Cerebellar subregions were automatically segmented using the multiple automatically generated templates algorithm. The relation between cerebellum subregional volumes (adjusted for total brain volume and sex) and neonatal clinical factors were examined using constrained principal component analysis. Cognitive and visual-motor integration functions in relation to cerebellar volumes were also investigated., Results: Higher neonatal procedural pain and infection, as well as other clinical factors, were differentially associated with reduced cerebellar volumes in specific subregions. After adjusting for clinical risk factors, neonatal procedural pain was distinctively associated with smaller volumes bilaterally in the posterior VIIIA and VIIIB lobules. Specific smaller cerebellar subregional volumes were related to poorer cognition and motor/visual integration., Conclusions: In very preterm children, exposure to painful procedures, as well as additional neonatal risk factors such as infection, were associated with reduced cerebellar volumes in specific subregions and poorer outcomes at school age., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Functional MRI studies suggest that healthy full-term newborn babies experience some aspects of pain in a similar way to adults.

Early life stress can alter hypothalamic pituitary adrenal (HPA) axis function. Differences in cortisol levels have been found in preterm infants exposed to substantial procedural stress during neonatal intensive care, compared to infants born full-term, but only a few studies investigated whether altered programming of the HPA axis persists past toddler age. Further, there is a dearth of knowledge of what may contribute to these changes in cortisol. This prospective cohort study examined the cortisol profiles in response to the stress of cognitive assessment, as well as the diurnal rhythm of cortisol, in children (n=129) born at varying levels of prematurity (24-32 weeks gestation) and at full-term (38-41 weeks gestation), at age 7 years. Further, we investigated the relationships among cortisol levels and neonatal procedural pain-related stress (controlling for multiple medical confounders), concurrent maternal factors (parenting stress, depressive and anxiety symptoms) and children's behavioral problems. For each aim we investigate acute cortisol response profiles to a cognitive challenge as well as diurnal cortisol patterns at home. We hypothesized that children born very preterm will differ in their pattern of cortisol secretion from children born full-term, possibly depended on concurrent child and maternal factors, and that exposure to neonatal pain-related stress would be associated with altered cortisol secretion in children born very preterm, possibly in a sex-dependent way. Saliva samples were collected from 7-year old children three times during a laboratory visit for assessment of cognitive and executive functions (pretest, mid-test, end-study day acute stress profile) and at four times over two consecutive non-school days at home (i.e. morning, mid-morning, afternoon and bedtime-diurnal rhythm profile). We found that cortisol profiles were similar in preterm and full-term children, albeit preterms had slightly higher cortisol at bedtime compared to full-term children. Importantly, in the preterm group, greater neonatal procedural pain-related stress (adjusted for morphine) was associated with lower cortisol levels on the study day (p=.044) and lower diurnal cortisol at home (p=.023), with effects found primarily in boys. In addition, child attention problems were negatively, and thought problems were positively, associated with the cortisol response during cognitive assessment on the study day in preterm children. Our findings suggest that neonatal pain/stress contributes to altered HPA axis function up to school-age in children born very preterm, and that sex may be an important factor., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background and Objectives: Pain in Child Health (PICH) is a transdisciplinary, international research training consortium. PICH has been funded since 2002 as a Strategic Training Initiative in Health Research of the Canadian Institutes of Health Research, with contributions from other funding partners and the founding participation of five Canadian universities. The goal of PICH has been to create a community of scholars in pediatric pain to improve child health outcomes., Methods: Quantitative analyses enumerated PICH faculty, trainees, training activities and scientific outputs. Interviews with PICH stakeholders were analyzed using qualitative methods capturing perceptions of the program's strengths, limitations, and opportunities for development and sustainability., Results: PICH has supported 218 trainee members from 2002 through 2013, from 14 countries and more than 16 disciplines. The faculty at the end of 2013 comprised nine co-principal investigators, 14 Canadian coinvestigators, and 28 Canadian and international collaborators. Trainee members published 697 peer-reviewed journal articles on pediatric pain through 2013, among other research dissemination activities including conference presentations and webinars. Networks have been established between new and established researchers across Canada and in 13 other countries. Perceptions from stakeholders commended PICH for its positive impact on the development of pediatric pain researchers. Stakeholders emphasized skills and abilities gained through PICH, the perceived impact of PICH training on this research field, and considerations for future training in developing researchers in pediatric pain., Conclusions: PICH has been successfully developing highly qualified health research personnel within a Canadian and international community of pediatric pain scholarship.

The majority of infants born very preterm (24-32 wk gestational age) now survive; however, long-term neurodevelopmental and behavioral problems remain a concern. As part of their neonatal care, very preterm infants undergo repeated painful procedures during a period of rapid brain development and programming of stress systems. Infants born this early have the nociceptive circuitry required to perceive pain, however, their sensory systems are functionally immature. An imbalance of excitatory vs. inhibitory processes leads to increased nociceptive signaling in the central nervous system. Specific cell populations in the central nervous system of preterm neonates are particularly vulnerable to excitoxicity, oxidative stress, and inflammation. Neonatal rat models have demonstrated that persistent or repeated pain increases apoptosis of neurons, and neonatal pain and stress lead to anxiety-like behaviors during adulthood. In humans, greater exposure to neonatal pain-related stress has been associated with altered brain microstructure and stress hormone levels, as well as with poorer cognitive, motor, and behavioral neurodevelopment in infants and children born very preterm. Therefore, it is important that pain-related stress in preterm neonates is accurately identified, appropriately managed, and that pain management strategies are evaluated for protective or adverse effects in the long term.

Preclinical and clinical studies have demonstrated the adverse consequences of untreated pain and stress on brain development in the preterm infant. Sucrose has widely been implemented as standard therapy for minor procedural pain. Anesthetics are commonly utilized in preterm infants during major surgery. Pharmacologic agents (benzodiazepines and opioids) have been examined in clinical trials of preterm infants requiring invasive mechanical ventilation. Controversy exists regarding the safety and long-term impact of these interventions. Ongoing multidisciplinary research will help define the impact of these agents and identify potential alternative therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Infants born preterm (<37 weeks of gestation) are particularly vulnerable to procedural stress and pain exposure during neonatal intensive care, at a time of rapid and complex brain development. Concerns regarding effects of neonatal pain on brain development have long been expressed. However, empirical evidence of adverse associations is relatively recent. Thus, many questions remain to be answered. This review discusses the short- and long-term effects of pain-related stress and associated treatments on brain maturation and neurodevelopmental outcomes in children born preterm. The current state of the evidence is presented and future research directions are proposed.

Objectives: Preterm infants undergo frequent painful procedures in the neonatal intensive care unit. Electroencephalography (EEG) changes in reaction to invasive procedures have been reported in preterm and full-term neonates. Frontal EEG asymmetry as an index of emotion during tactile stimulation shows inconsistent findings in full-term infants, and has not been examined in the context of pain in preterm infants. Our aim was to examine whether heel lance for blood collection induces changes in right-left frontal asymmetry, suggesting negative emotional response, in preterm neonates at different gestational age (GA) at birth and different duration of stay in the neonatal intensive care unit., Materials and Methods: Three groups of preterm infants were compared: set 1: group 1 (n=24), born and tested at 28 weeks GA; group 2 (n=22), born at 28 weeks GA and tested at 33 weeks; set 2: group 3 (n=25), born and tested at 33 weeks GA. EEG power was calculated for 30-second artifact-free periods, in standard frequency bandwidths, in 3 phases (baseline, up to 5 min after heel lance, 10 min after heel lance)., Results: No significant differences were found in right-left frontal asymmetry, or in ipsilateral or contralateral somatosensory response, across phases. In contrast, the Behavioral Indicators of Infant Pain scores changed across phase (P<0.0001). Infants in group 1 showed lower Behavioral Indicators of Infant Pain scores (P=0.039)., Discussion: There are technical challenges in recording EEG during procedures, as pain induces motor movements. More research is needed to determine the most sensitive approach to measure EEG signals within the context of pain in infancy.

Background: Altered brain development is evident in children born very preterm (24-32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age., Methods: 42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling., Results: After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes., Conclusions: In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.

Children born very prematurely (< or =32 weeks) often exhibit visual-perceptual difficulties at school-age, even in the absence of major neurological impairment. The alterations in functional brain activity that give rise to such problems, as well as the relationship between adverse neonatal experience and neurodevelopment, remain poorly understood. Repeated procedural pain-related stress during neonatal intensive care has been proposed to contribute to altered neurocognitive development in these children. Due to critical periods in the development of thalamocortical systems, the immature brain of infants born at extremely low gestational age (ELGA; < or =28 weeks) may have heightened vulnerability to neonatal pain. In a cohort of school-age children followed since birth we assessed relations between functional brain activity measured using magnetoencephalogragy (MEG), visual-perceptual abilities and cumulative neonatal pain. We demonstrated alterations in the spectral structure of spontaneous cortical oscillatory activity in ELGA children at school-age. Cumulative neonatal pain-related stress was associated with changes in background cortical rhythmicity in these children, and these alterations in spontaneous brain oscillations were negatively correlated with visual-perceptual abilities at school-age, and were not driven by potentially confounding neonatal variables. These findings provide the first evidence linking neonatal pain-related stress, the development of functional brain activity, and school-age cognitive outcome in these vulnerable children., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤ 32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm.

Children born very preterm (≤ 32 weeks gestation) exhibit greater internalizing (anxious/depressed) behaviors compared to term-born peers as early as 2 years corrected age (CA); however, the role of early stress in the etiology of internalizing problems in preterm children remains unknown. Therefore, we examined the relationship between neonatal pain and internalizing behavior at 18 months CA in children born very preterm and examined whether parent behavior and stress moderated this relationship. Participants were 145 children (96 very preterm, 49 full term) assessed at 18 months CA. Neonatal data were obtained from medical and nursing chart review. Neonatal pain was defined as the number of skin-breaking procedures. Cognitive ability was measured with the Bayley Scales of Infant Development II. Parents completed the Parenting Stress Index III, Child Behavior Checklist 1.5-5, and participated in a videotaped play session with their child, which was coded using the Emotional Availability Scale IV. Very preterm children displayed greater Internalizing behaviors compared to full-term control children (P=.02). Parent Sensitivity and Nonhostility moderated the relationship between neonatal pain and Internalizing behavior (all P<.05); higher parent education (P<.03), lower Parenting Stress (P=.001), and fewer children in the home (P<.01) were associated with lower Internalizing behavior in very preterm children, after adjusting for neonatal medical confounders, gender, and child cognitive ability (all P>.05). Parent Emotional Availability and stress were not associated with Internalizing behaviors in full-term control children. Positive parent interaction and lower stress appears to ameliorate negative effects of neonatal pain on stress-sensitive behaviors in this vulnerable population., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Premature infants are at risk for adverse motor outcomes, including cerebral palsy and developmental coordination disorder. The purpose of this study was to examine the relationship of antenatal, perinatal, and postnatal risk factors for abnormal development of the corticospinal tract, the major voluntary motor pathway, during the neonatal period. In a prospective cohort study, 126 premature neonates (24-32 weeks' gestational age) underwent serial brain imaging near birth and at term-equivalent age. With diffusion tensor tractography, mean diffusivity and fractional anisotropy of the corticospinal tract were measured to reflect microstructural development. Generalized estimating equation models examined associations of risk factors on corticospinal tract development. The perinatal risk factor of greater early illness severity (as measured by the Score for Neonatal Acute Physiology-II [SNAP-II]) was associated with a slower rise in fractional anisotropy of the corticospinal tract (P = 0.02), even after correcting for gestational age at birth and postnatal risk factors (P = 0.009). Consistent with previous findings, neonatal pain adjusted for morphine and postnatal infection were also associated with a slower rise in fractional anisotropy of the corticospinal tract (P = 0.03 and 0.02, respectively). Lessening illness severity in the first hours of life might offer potential to improve motor pathway development in premature newborns., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Procedural pain is associated with poorer neurodevelopment in infants born very preterm (≤ 32 weeks gestational age), however, the etiology is unclear. Animal studies have demonstrated that early environmental stress leads to slower postnatal growth; however, it is unknown whether neonatal pain-related stress affects postnatal growth in infants born very preterm. The aim of this study was to examine whether greater neonatal pain (number of skin-breaking procedures adjusted for medical confounders) is related to decreased postnatal growth (weight and head circumference [HC] percentiles) early in life and at term-equivalent age in infants born very preterm. Participants were n=78 preterm infants born ≤ 32 weeks gestational age, followed prospectively since birth. Infants were weighed and HC measured at birth, early in life (median: 32 weeks [interquartile range 30.7-33.6]) and at term-equivalent age (40 weeks [interquartile range 38.6-42.6]). Weight and HC percentiles were computed from sex-specific British Columbia population-based data. Greater neonatal pain predicted lower body weight (Wald χ(2)=7.36, P=0.01) and HC (Wald χ(2)=4.36, P=0.04) percentiles at 32 weeks postconceptional age, after adjusting for birth weight percentile and postnatal risk factors of illness severity, duration of mechanical ventilation, infection, and morphine and corticosteroid exposure. However, later neonatal infection predicted lower weight percentile at term (Wald χ(2)=5.09, P=0.02). Infants born very preterm undergo repetitive procedural pain during a period of physiological immaturity that appears to impact postnatal growth, and may activate a downstream cascade of stress signaling that affects later growth in the neonatal intensive care unit., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objective: Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants., Methods: Infants born very preterm (N=86; 24-32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery., Results: After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (β=-0.0002, p=0.028) and reduced subcortical gray matter NAA/choline (β=-0.0006, p=0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes., Interpretation: Early procedural pain in very preterm infants may contribute to impaired brain development., (Copyright © 2012 American Neurological Association.)

Objective: Pain response may be altered in infants born very preterm owing to repeated exposure to procedures in the neonatal intensive care unit. Findings have been inconsistent in studies of behavioral and cardiac responses to brief pain in preterm versus full-term infants following neonatal intensive care unit discharge. To our knowledge, cortisol reactivity to pain has not been compared in preterm and full-term infants. We examined pain reactivity to immunization in preterm and full-term infants., Method: Cortisol, facial behavior, and heart rate reactivity before, during, and after immunization were examined in infants born preterm at extremely low gestational age (ELGA 24 to 28 wk), very low gestational age (VLGA 29 to 32 wk), and full-term, at corrected age 4 months., Results: In all groups, cortisol, behavior, and heart rate increased during immunizations. Cortisol concentrations were lower in preterm ELGA and VLGA boys, compared with full-term boys. In contrast, facial and heart rate responses to immunization did not differ between preterm and full-term infants., Discussion: Although earlier reports found differences in pain processing in preterm infants earlier and later in development, the present findings indicate that pain responses, indexed by behavior and heart-rate, do not seem to differ in preterm compared with full-term infants at 4 months corrected age. Importantly, however, stress regulation seems altered in preterm male infants. As cortisol impacts development and functioning of the brain, altered stress regulation has important implications beyond pain systems.

Preterm and critically ill newborns admitted to a NICU undergo repeated skin-breaking procedures that are necessary for their survival. Sucrose is rapidly becoming the accepted clinical standard nonpharmacologic intervention for managing acute procedural pain for these infants. Although shown to be safe in single doses, only 4 studies have evaluated the effects of repeated doses of sucrose over relatively short periods of time. None has examined the use of sucrose throughout the NICU stay, and only 1 study evaluated the neurodevelopmental outcomes after repeated doses of sucrose. In that study, infants born at <31 weeks' gestational age and exposed to >10 doses per day in the first week of life were more likely to show poorer attention and motor development in the early months after discharge from the NICU. Results of studies in animal models have suggested that the mechanism of action of sucrose is through opioid pathways; however, in human infants, little has been done to examine the physiologic mechanisms involved, and the findings reported thus far have been ambiguous. Drawing from the growing animal literature of research that has examined the effects of chronic sugar exposure, we describe alternative amine and hormone pathways that are common to the processing of sucrose, attention, and motor development. In addition, a review of the latest research to examine the effects of repeated sucrose on pain processing is presented. These 2 literatures each can inform the other and can provide an impetus to initiate research to examine not only the mechanisms involved in the calming mechanisms of sucrose but also in the long-term neurodevelopmental effects of repeated sucrose in those infants born extremely preterm or critically ill.

Objectives: To examine biobehavioral responses to an acute pain event in a Cape Town, South Africa, cohort consisting of 28 Cape Colored (mixed ancestry) newborns (n = 14) heavily exposed to alcohol during pregnancy (exposed), and born to abstainers (n = 14) or light (< or = 0.5 oz absolute alcohol/d) drinkers (controls)., Methods: Mothers were recruited during the third trimester of pregnancy. Newborn data were collected on postpartum day 3 in the maternity obstetrical unit where the infant had been delivered. Heavy prenatal alcohol exposure was defined as maternal consumption of at least 14 drinks/wk or at least 1 incident of binge drinking/mo. Acute stress-related biobehavioral markers [salivary cortisol, heart rate (HR), respiratory sinus arrhythmia (RSA), spectral measures of heart rate variability (HRV), and videotaped facial actions] were collected thrice during a heel lance blood collection (baseline, lance, and recovery). After a feeding and nap, newborns were administered an abbreviated Brazelton Neonatal Behavioral Assessment Scale., Results: There were no between-group differences in maternal age, marital status, parity, gravidity, depression, anxiety, pregnancy smoking, maternal education, or infant gestational age at birth (all ps > 0.15). In both groups, HR increased with the heel lance and decreased during the postlance period. The alcohol-exposed group had lower mean HR than controls throughout, and showed no change in RSA over time. Cortisol levels showed no change over time in controls but decreased over time in exposed infants. Although facial action analyses revealed no group differences in response to the heel lance, behavioral responses assessed on the Brazelton Neonatal Scale showed less arousal in the exposed group., Conclusions: Both cardiac autonomic and hypothalamic-pituitary-adrenal stress reactivity measures suggest a blunted response to an acute noxious event in alcohol-exposed newborns. This is supported by results on the Brazelton Neonatal Scale indicating reduced behavioral arousal in the exposed group. To our knowledge, these data provide the first biobehavioral examination of early pain reactivity in alcohol-exposed newborns and have important implications for understanding neuro-/biobehavioral effects of prenatal alcohol exposure in the newborn period.

Background: Pain reactivity may reflect underlying mechanisms of constitutional aspects of temperament., Aim: To examine whether the neonatal biobehavioral reactivity and recovery responses from pain and distress, as well as the gestational age, the illness severity and the amount of painful procedures undergone the Neonatal Intensive Care Unit (NICU) stay, predict temperament later in toddlerhood, in vulnerable children born preterm., Study Design: Prospective-longitudinal study., Subjects: Twenty-six preterm and very low birth weight infants followed from birth to toddlerhood., Outcome Measures: Illness severity was assessed with the Clinical Risk Index for Babies (CRIB) score. The medical charts were reviewed prospectively for obtaining the amount of pain exposure in NICU. For assessing the behavioral and cardiac reactivity and recovery from pain and distress, the neonates were evaluated during routine blood collection in the NICU in the first 10 days of life. Pain and distress reactivity and recovery was measured using the Neonatal Facial Coding System score, the duration of crying, and the magnitude of average heart rate. At toddlerhood, mothers answered the Early Childhood Behavior Questionnaire., Results: Higher biobehavioral reactivity to pain and distress predicted higher temperamental Negative Affect, above and beyond gestational age, illness severity and amount of pain exposure in NICU. However, we did not find a predictive relation between gestational age, CRIB score and number of painful procedures undergone NICU and toddler's temperament., Conclusions: The findings highlight the relevance of the neonatal individual characteristics of reactivity for identifying more vulnerable infants for future problems in biobehavioral regulation.

Procedural pain in the neonatal intensive care unit triggers a cascade of physiological, behavioral and hormonal disruptions which may contribute to altered neurodevelopment in infants born very preterm, who undergo prolonged hospitalization at a time of physiological immaturity and rapid brain development. The aim of this study was to examine relationships between cumulative procedural pain (number of skin-breaking procedures from birth to term, adjusted for early illness severity and overall intravenous morphine exposure), and later cognitive, motor abilities and behavior in very preterm infants at 8 and 18 months corrected chronological age (CCA), and further, to evaluate the extent to which parenting factors modulate these relationships over time. Participants were N=211 infants (n=137 born preterm 32 weeks gestational age [GA] and n=74 full-term controls) followed prospectively since birth. Infants with significant neonatal brain injury (periventricular leucomalacia, grade 3 or 4 intraventricular hemorrhage) and/or major sensori-neural impairments, were excluded. Poorer cognition and motor function were associated with higher number of skin-breaking procedures, independent of early illness severity, overall intravenous morphine, and exposure to postnatal steroids. The number of skin-breaking procedures as a marker of neonatal pain was closely related to days on mechanical ventilation. In general, greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months CCA, however, specific protocols for morphine administration were not evaluated. Lower parenting stress modulated effects of neonatal pain, only on cognitive outcome at 18 months.

Objectives: To evaluate the ability of the Behavioral Indicators of Infant Pain (BIIP) scale to discriminate between skin-breaking and nonskin breaking procedures, and to identify sensitized pain responses in preterm infants in the neonatal intensive care unit (NICU)., Methods: Sixty-nine infants born between 24 and 32 weeks gestational age were assessed at 32 weeks postconceptional age during blood collection on one day (procedure A), and then on another day during blood collection preceded by a diaper change (procedure B). Procedure order was randomized. Outcome measures were changes in BIIP coded from continuous bedside video recordings and changes in heart rate (HR)., Results: During blood collection (procedure A), BIIP scores (P<0.0001) and mean HR (P<0.0001) were higher than during the diaper change and higher when the infants had had a preceding diaper change (procedure B vs. procedure A) (P<0.03). HR changed from baseline to the stressors for each procedure. No differences in mean HR were observed during Lance phase between the procedure A and the B blood collection; however, HR remained elevated significantly during the Recovery phase when blood collection was preceded by the diaper change (P<0.03)., Discussion: The BIIP scale is reliable, accurate, and valid assessment for measuring acute pain in preterm infants in the NICU. This assessment combines the relatively most specific, anatomically based, theoretically derived indicators; and it allows evaluation of behavioral and physiologic pain responses separately.

Accurate pain assessment in preterm infants in the neonatal intensive care unit (NICU) is complex. Infants who are born at early gestational ages (GA), and who have had greater early pain exposure, have dampened facial responses which may lead to under-treatment. Since behavioral and physiological responses to pain in infants are often dissociated, using multidimensional scales which combine these indicators into a single score may limit our ability to determine the effects of interventions on each system. Our aim was to design a unidimensional scale which would combine the relatively most specific, individual, behavioral indicators for assessing acute pain in this population. The Behavioral Indicators of Infant Pain (BIIP) combines sleep/wake states, 5 facial actions and 2 hand actions. Ninety-two infants born between 23 and 32 weeks GA were assessed during 3, 1 min Phases of blood collection. Outcome measures included changes in BIIP and in Neonatal Infant Pain Scale (NIPS) scores coded in real time from continuous bedside video recordings; changes in heart rate (HR) were obtained using custom physiological processing software. Scores on the BIIP changed significantly across Phases of blood collection (p<0.01). Internal consistency (0.82) and inter-rater reliability (0.80-0.92) were high. Correlations between the BIIP and NIPS were modest (r=0.64, p<0.01) as were correlations between the BIIP and mean heart rate (r=0.45, p<0.01). In this initial study, the BIIP has been shown to be a reliable, valid scale for assessing acute pain in preterm infants in the NICU.

Background: Accurate assessment and treatment of pain and stress in preterm infants in neonatal intensive care units (NICU) is vital because pain and stress responses have been linked to long-term alterations in development in this population., Purpose: To review the evidence of specific extremity movements in preterm infants as observed during stressful procedures., Methods: Five on-line databases were searched for relevant studies. For each study, levels of evidence were determined and effect size estimates were calculated. Each study was also evaluated for specific factors that presented potential threats to its validity., Results: Eighteen studies were identified and seven comprised the review. The combined sample included 359 preterm infants. Six specific movements were associated with painful and intrusive procedures., Clinical Implications: A set of specific extremity movements, when combined with other reliable biobehavioural measures of pain and stress, can form the basis for future research and development of a clinical stress scale for preterm infants.

Objective: To compare biobehavioral pain responses of preterm infants born at differing gestational ages (GAs) when pain was preceded by a rest period or by a series of routine nursing interventions., Methods: In a randomized, within subjects, cross-over design, facial (Neonatal Facial Coding System), sleep/wake state and heart rate (HR) responses of 43 preterm infants [mean birth weight: 1303 g (range 590 g to 2345 g); mean GA at birth: 30 weeks (range 25 to 32)] were examined across 3 phases of blood collection (Baseline, Lance, and Recovery) under 2 conditions: pain after a 30-minute rest period versus pain after a series of routine nursing interventions (clustered care). Infant behavioral responses were coded from continuous bedside videotapes. HR was analyzed using custom physiologic signal processing software., Results: Infants born at earlier GA (<30 wk) had equally intense facial responses during the Lance phase regardless of condition. However, later born infants (> or =30 wk GA) showed heightened facial responses indicative of sensitized responses during blood collection when it was preceded by clustered care (P=0.05). Moreover, later born infants had significantly lower facial (P=0.05) and HR (P=0.04) reactivity during Recovery when blood collection followed clustered care., Discussion: Earlier born preterm infants showed heightened states of arousal and poor ability to modulate HR during Recovery when an invasive procedure was preceded by routine tactile nursing procedures. Alternatively, later born infants exhibited sensitized responses when clustered care preceded blood collection. Our findings support the importance of cue based individualized approaches to care.

The low tactile threshold in preterm infants when they are in the neonatal intensive care unit (NICU), while their physiological systems are unstable and immature, potentially renders them more vulnerable to the effects of repeated invasive procedures. There is a small but growing literature on pain and tactile responsivity following procedural pain in the NICU, or early surgery. Long-term effects of repeated pain in the neonatal period on neurodevelopment await further research. However, there are multiple sources of stress in the NICU, which contribute to inducing high overall 'allostatic load', therefore determining specific effects of neonatal pain in human infants is challenging.

In this preliminary study, it was examined whether capacity to react to external stress (acute pain) during neonatal intensive care predicts later neuromotor development at 4 and 8 months corrected chronological age (CCA) in high-risk preterm infants. Behavioural and cardiac reactivity to blood collection at 32 weeks postconceptional age (PCA) were recorded in addition to developmental outcomes at 4 and 8 months CCA in 35 preterm infants (17 males, 18 females) born

Objectives: To describe developmentally appropriate, specific body movements and other biobehavioral responses of preterm infants to a group of routine care giving tasks (Clustered Care), and to compare responses to acute pain with those of Clustered Care., Methods: In a randomized design, 54 preterm infants were assessed at 32 weeks gestational age during 3 phases of blood collection (Baseline, Lance/squeeze, Recovery) and of diaper changing, measuring abdominal girth and axillary temperature, and mouth care (Baseline, Clustered Care, Recovery) in a neonatal intensive care unit. The Newborn Individualized Developmental Care and Assessment Program and 1 facial action from the Neonatal Facial Coding System, Brow Bulge, were coded from separate continuous bedside video recordings. Heart rate and oxygen saturation were also acquired continuously., Results: Brow Bulge, heart rate, and a subset of 9 Newborn Individualized Developmental Care and Assessment Program movements increased and oxygen saturation decreased significantly to Lance/squeeze compared to Baseline. Similar facial and physiological changes occurred during Clustered Care, but with less intensity. However, infants showed greater frequencies and variety of Newborn Individualized Developmental Care and Assessment Program stress cues during Clustered Care than during Lance/squeeze. Stress cues persisted after Clustered Care, whereas the infants returned to Baseline following Lance/squeeze., Discussion: Changes in facial activity and heart rate remain the most sensitive markers of pain in preterm infants. Tactile procedures, such as diaper changing, produce lower intensity facial and physiological responses than pain procedures, but greater body reactions. Also, the effects from tactile procedures appear to last longer. Adding observations of a small number of specific body movements to the assessment of pain and stress provides complementary information particularly for those infants who may show dampened facial reactivity as a result of repeated pain exposure.

Background: Acute pain is a significant stressor for preterm infants in neonatal intensive care units (NICU); however, little is known about the effects of acute pain on subsequent motor responses during clusters of tactile handling., Aims: (1) To compare facial, body and heart rate reactivity in preterm infants at 32 weeks gestational age (GA) during routine care-giving tasks following a rest period (RCC: diapering, measuring abdominal girth and axillary temperature, mouth care) with their responses to Clustered Care following blood collection (PCC). (2) To examine how GA at birth affects patterns of stress and self-regulatory behaviors during RCC and PCC., Study Design: Within-group crossover design (random order)., Subjects: Preterm infants, N=54 (mean GA at birth 29.3 +/- 2.2 weeks; mean birth weight 1257 +/- 423 g) were assessed at 32 weeks GA in the NICU., Outcome Measures: The Newborn Developmental Care and Assessment Program (NIDCAP) and Neonatal Facial Coding System (NFCS) were coded from continuous bedside video recordings. Changes in mean heart rate (HR) were computed using custom physiologic software., Results: All infants had heightened facial, body and HR responses when CC followed a painful procedure compared to when they had not been handled prior to CC. Infants born at earlier GA (<30 weeks) had equal numbers of stress cues during RCC and PCC, but dampened self-regulatory behaviors during PCC., Conclusion: Prior pain induces heightened biobehavioral reactivity in preterm infants during subsequent tactile procedures. In addition, clustering care is particularly stressful for infants born at earlier GA.

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 week) 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

Objective: The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) is widely used in neonatal intensive care units and comprises 85 discrete infant behaviors, some of which may communicate infant distress. The objective of this study was to identify developmentally relevant movements indicative of pain in preterm infants., Methods: Forty-four preterm infants were assessed at 32 weeks' gestational age (GA) during 3 phases (baseline, lance/squeeze, and recovery) of routine blood collection in the neonatal intensive care unit. The NIDCAP and Neonatal Facial Coding System (NFCS) were coded from separate continuous bedside video recordings; mean heart rate (mHR) was derived from digitally sampled continuous electrographic recordings. Analysis of variance (phase x gender) with Bonferroni corrections was used to compare differences in NIDCAP, NFCS, and mHR. Pearson correlations were used to examine relationships between the NIDCAP and infant background characteristics., Results: NFCS and mHR increased significantly to lance/squeeze. Eight NIDCAP behaviors also increased significantly to lance/squeeze. Another 5 NIDCAP behaviors decreased significantly to lance/squeeze. Infants who had lower GA at birth, had been sicker, had experienced more painful procedures, or had greater morphine exposure showed increased hand movements indicative of increased distress., Conclusions: Of the 85 NIDCAP behaviors, a subset of 8 NIDCAP movements were associated with pain. Particularly for infants who are born at early GAs, addition of these movements to commonly used measures may improve the accuracy of pain assessment.

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.

Objective: Children with neurologic impairments have shown diminished pain response compared with control subjects; however, it remains unclear what mechanisms underlie this response or when it develops. If this were also true with premature infants who undergo neonatal intensive care, then infants with parenchymal brain injury (PBI) would be at increased risk of underrecognition and undertreatment of procedural pain. The purpose of this study was to determine whether infants with PBI display altered responses to acute procedural pain at 32 weeks' postconceptional age (PCA), compared with control subjects., Methods: We compared responses to blood collection by heel lance at 32 weeks' PCA in 12 very low birth weight infants (mean [range] birth weight: 876 g [630-1240 g]; gestational age: 26.3 weeks (24-28 weeks) who had sustained PBI in the neonatal period, with 12 control subjects matched for gestational age at birth and gender (838 g [625-990 g]; 26.3 weeks [24-28 weeks[) who had normal neonatal brain imaging. PBI was defined as cerebral parenchymal infarction (grade 4 intraventricular hemorrhage) or cystic periventricular leukomalacia on serial cranial ultrasound scans conducted in the neonatal period. Biobehavioral responses to pain were measured using facial activity (Neonatal Facial Coding System) and measures of heart rate (HR) variability (low-frequency [LF] power [0.04-0.15], high-frequency [HF] power [0.15-0.8 Hz], and LF/HF ratio) as a measure of cardiac autonomic modulation. Neurodevelopmental follow-up was undertaken at 18 months., Results: The infants with PBI had significantly higher illness severity scores at day 1 compared with day 3 (Score of Neonatal Acute Physiology II: 32.1 vs 19.8) but similar previous pain experiences (109 vs 115) and total morphine exposure (0.29 vs 0.30 mg/kg). Both groups of children mounted similar responses to heel lance at 32 weeks' PCA with no difference in facial response or HR variability. Mean HR and facial action scores increased from baseline to the lance, whereas LF, HF, and the LF/HF ratio decreased significantly. No group differences were found. The only statistically significant difference between groups was that infants with PBI had more tongue protrusion at lance. Neurodevelopmental follow-up showed 8 of 11 toddlers with PBI had cerebral palsy compared with 0% of control toddlers. Psychomotor Developmental Index score on the Bayley Scales of Infant Development II was significantly lower in the PBI group. Five of 11 toddlers with PBI had Mental Developmental Index score <2 standard deviations below mean compared with 0% of the control toddlers., Conclusion: Contrary to expectations, we did not find any evidence of an altered pain response pattern in infants with proven brain injury in the neonatal period. Although most infants with PBI developed cerebral palsy, these findings suggest that cerebral injury predominantly to the central white matter leaves brainstem responses intact in the neonatal period. Furthermore, it seems that the injured brain of the preterm infant has not yet expressed the identifiable differences in pain display and the functional impairment observed at later ages.

Exposure to pain‐related stress from frequent invasive procedures in the neonatal intensive care unit (NICU) has been associated with altered physiological stress regulation, neurodevelopment, and behavior in children born very preterm (≤32 weeks gestation). Previously, in a cohort born 2003–2006 (Cohort 1), we found that, at 18 months corrected age (CA), children born extremely low gestational age (ELGA; 24–28 weeks) and very low gestational age (VLGA; 29–32 weeks), had higher pre‐test cortisol levels and a different pattern of cortisol output across a developmental assessment involving cognitive challenge compared to children born full‐term (FT; 39–41 weeks). Also, greater neonatal pain‐related stress exposure among the preterm children was related to higher pre‐test cortisol levels. Given the adverse long‐term effects of neonatal pain in preterm infants and the ensuing rise in clinical concerns to appropriately manage pain in the NICU in recent years, we aimed to examine whether our findings from Cohort 1 would still be evident in an independent cohort (Cohort 2) born 2006–2011 and recruited from the same tertiary NICU in Vancouver, Canada. We also compared the cortisol patterns, clinical and socio‐demographic factors, and their interrelationships between the two cohorts. In Cohort 2, our findings using multi‐level modeling support and extend our earlier findings in Cohort 1, demonstrating that children born ELGA display higher pre‐test cortisol levels than FT. As well, greater cortisol output across assessment was related to more anxiety/depressive behaviors in children born VLGA. Importantly, children born ELGA were exposed to less neonatal pain/stress, mechanical ventilation, and morphine in Cohort 2 than Cohort 1. In both cohorts, however, cortisol levels and patterns were related to neonatal pain/stress and clinical factors (days on mechanical ventilation, overall morphine exposure). Despite less exposure to pain/stress and adverse clinical factors in Cohort 2 compared to Cohort 1, cortisol levels and patterns across cognitive challenge in preterm children at 18‐month CA were consistent across the two independent cohorts. These findings highlight that, despite improvements to neonatal care, children born extremely preterm continue to display altered HPA axis activity, which is associated with their poorer neurodevelopmental and behavioral outcomes. [ABSTRACT FROM AUTHOR]

Background: Children born very preterm often display selective cognitive difficulties at school age even in the absence of major brain injury. Alterations in neurophysiological activity underpinning such difficulties, as well as their relation to specific aspects of adverse neonatal experience, remain poorly understood. In the present study, we examined interregional connectivity and spectral power in very preterm children at school age, and their relationship with clinical neonatal variables and long‐term outcomes (IQ, executive functions, externalizing/internalizing behavior, visual‐motor integration). Methods: We collected resting state magnetoencephalographic (MEG) and psychometric data from a cohort at the age of 8 years followed prospectively since birth, which included three groups: Extremely Low Gestational Age (ELGA, 24–28 weeks GA n = 24, age 7.7 ± 0.38, 10 girls), Very Low Gestational Age (VLGA, 29–32 weeks GA n = 37, age 7.7 ± 0.39, 24 girls), and full‐term children (38–41 weeks GA n = 39, age 7.9 ± 1.02, 24 girls). Interregional phase synchrony and spectral power were tested for group differences, and associations with neonatal and outcome variables were examined using mean‐centered and behavioral Partial Least Squares (PLS) analyses, respectively. Results: We found greater connectivity in the theta band in the ELGA group compared to VLGA and full‐term groups, primarily involving frontal connections. Spectral power analysis demonstrated overall lower power in the ELGA and VLGA compared to full‐term group. PLS indicated strong associations between neurophysiological connectivity at school age, adverse neonatal experience and cognitive performance, and behavior. Resting spectral power was associated only with behavioral scores. Conclusions: Our findings indicate significant atypicalities of neuromagnetic brain activity and connectivity in very preterm children at school age, with alterations in connectivity mainly observed only in the ELGA group. We demonstrate a significant relationship between connectivity, adverse neonatal experience, and long‐term outcome, indicating that the disruption of developing neurophysiological networks may mediate relationships between neonatal events and cognitive and behavioral difficulties at school age. [ABSTRACT FROM AUTHOR]

Altered hippocampal morphology and reduced volumes have been found in children born preterm compared to full-term. Stress inhibits neurogenesis in the hippocampus, and neonatal stress/noxious stimulation in rodent pups are associated with long-term alterations in hippocampal volumes. We have previously shown reduced cortical thickness and cerebellar volumes in relation to more exposure to pain-related stress of neonatal invasive procedures in children born very preterm. We have reported targeted gene-by-pain environment interactions that contribute to long-term brain development and outcomes in this population. We now aim to determine whether exposure to pain-related stress (adjusted for clinical factors and genotype) differentially impacts regional structures within the limbic system and thalamus, and investigate relationships with outcomes in very preterm children. Our study included 57 children born very preterm (<32 weeks GA) followed longitudinally from birth who underwent 3-D T1 MRI neuroimaging at ∼8 years. Hippocampal subfields and white matter tracts, thalamus and amygdala were automatically segmented using the MAGeT Brain algorithm. The relationship between those subcortical brain volumes (adjusted for total brain volume) and neonatal invasive procedures, gestational age (GA), illness severity, postnatal infection, days of mechanical ventilation, number of surgeries, morphine exposure, and genotype (COMT, SLC6A4 , and BDNF) was examined using constrained principal component analysis. We found that neonatal clinical factors and genotypes accounted for 46% of the overall variance in volumes of hippocampal subregions, tracts, basal ganglia, thalamus and amygdala. After controlling for clinical risk factors and total brain volume, greater neonatal invasive procedures was associated with lower volumes in the amygdala and thalamus (p = 0.0001) and an interaction with COMT genotype predicted smaller hippocampal subregional volume (p = 0.0001). More surgeries, days of ventilation, and lower GA were also related to smaller volumes in various subcortical regions (p < 0.002). These reduced volumes were in turn differentially related to poorer cognitive, visual-motor and behavioral outcomes. Our findings highlight the complexity that interplays when examining how exposure to early-life stress may impact brain development both at the structural and functional level, and provide new insight on possible novel avenues of research to discover brain-protective treatments to improve the care of children born preterm. [ABSTRACT FROM AUTHOR]

Sucrose is recommended for the treatment of pain during minor procedures in preterm infants in the neonatal intensive care unit (NICU) and is currently used worldwide as the standard of care. We recently reported that adult mice repetitively exposed to sucrose compared to water during the first week of life, irrespective of exposure to an intervention, had significantly smaller brain volumes in large white matter, cortical and subcortical structures (e.g., hippocampus, striatum, fimbria). These structures are important for stress regulation and memory formation. Here, we report the effects of repeated neonatal exposure to pain and sucrose on adult behavior in mice. Neonatal C57BL/6J mice (N = 160, 47% male) were randomly assigned to one of two treatments (sucrose, water) and one of three interventions (needle-prick, tactile, handling). Pups received 10 interventions daily from postnatal day 1 (P1) to P6. A single dose of 24% sucrose or water was given orally 2 min before each intervention. At adulthood (P60-85) mice underwent behavioral testing to assess spatial memory, anxiety, motor function, pain sensitivity, and sugar preference. We found that mice that had received sucrose and handling only, had poorer short-term memory in adulthood compared to water/handling controls (p < 0.05). When exposed to pain, mice treated with repetitive sucrose or water did not differ on memory performance (p = 0.1). A sugar preference test showed that adult mice that received sucrose before an intervention as pups consumed less sugar solution compared to controls or those that received water before pain (p < 0.05). There were no significant group differences in anxiety, motor, or pain sensitivity. In a mouse model that closely mimics NICU care, we show for the first time that memory in adulthood was poorer for mice exposed to pain during the first week of life, irrespective of sucrose treatment, suggesting that sucrose does not protect memory performance when administered for pain. In the absence of pain, early repetitive sucrose exposure induced poorer short-term memory, highlighting the importance of accurate pain assessment. [ABSTRACT FROM AUTHOR]

Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and A-acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development. [ABSTRACT FROM AUTHOR]

Objective. To examine the comparative effectiveness of two topical anesthetics in controlling the pain associated with tongue-tie release (frenotomy) in young infants. Design. Randomized trial. Setting. A Pediatric Craniofacial Clinic. Subjects. Forty-two infants who were referred for frenotomy were randomly allocated to receive the topical anesthetic gel 2% tetracaine or 20% benzocaine applied prior to frenotomy. Frenotomies were videotaped. The primary outcome measure was the Neonatal Facial Coding System (NFCS) score. Secondary outcome measures included cry duration and a visual analog scale (VAS) assessed by the parents. Results. The two groups were comparable with regard to weight, age, gender, previous painful experience, and last feeding time. Median NFCS scores prior to frenotomy in the tetracaine and the benzocaine groups were 4.5 (IQR: 0.75-10.2) and 3.5 (IQR: 0-9.5), respectively (P50.89, 95% CI 23 to 4). During frenotomy, median NFCS score increased to 28 (IQR: 24.5-30.25) in the tetracaine group (P< 0.0001, median difference 222, 95% CI 224.5 to 219), and to 28 (IQR: 26-30) in the benzocaine group (P< 0.0001, median difference 223, 95% CI 227 to 217). Mean cry durations in the tetracaine and the benzocaine groups were 69.4 seconds and 63.9 seconds, respectively (P50.32, 95% CI 247 to 15), and mean VAS scores were 57.2 and 58.2, respectively (P50.89, 95% CI 215.2 to 13.4). Conclusions. These topical anesthetics seem ineffective in controlling the pain associated with frenotomy. Clinicians should continue to search for an effective treatment for this procedure. [ABSTRACT FROM AUTHOR]

Children born very preterm are exposed to repeated neonatal procedures that induce pain and stress during hospitalization in the neonatal intensive care unit (NICU). The COMT Val158Met genotype is involved with pain sensitivity, and early life stress is implicated in altered expression of methylation of the serotonin transporter.We examined: (1) whether methylation of the serotonin transporter gene (SLC6A4) promoter differs between very preterm children and full-term controls at school age, (2) relationships with child behavior problems, and (3) whether the extent of neonatal pain exposure interacts with the COMT Val158Met genotype to predict SLC6A4 methylation at 7 years in the very preterm children. We examined the associations between the COMT genotypes, neonatal pain exposure (adjusted for neonatal clinical confounders), SLC6A4 methylation and behavior problems. Very preterm children had significantly higher methylation at 7/10 CpG sites in the SLC6A4 promoter compared to full-term controls at 7 years. Neonatal pain (adjusted for clinical confounders) was significantly associated with total child behavior problems on the Child Behavior Checklist (CBCL) questionnaire (adjusted for concurrent stressors and 5HTTLPR genotype) (p = 0.035). CBCL Total Problems was significantly associated with greater SLC6A4 methylation in very preterm children (p = 0.01). Neonatal pain (adjusted for clinical confounders) and COMT Met/Met genotype were associated with SLC6A4 promoter methylation in very preterm children at 7 years (p = 0.001). These findings provide evidence that both genetic predisposition and early environment need to be considered in understanding susceptibility for developing behavioral problems in this vulnerable population. [ABSTRACT FROM AUTHOR]

Preterm and critically ill newborns admitted to a NICU undergo repeated skin-breaking procedures that are necessary for their survival. Sucrose is rapidly becoming the accepted clinical standard nonpharmacologic intervention for managing acute procedural pain for these infants. Although shown to be safe in single doses, only 4 studies have evaluated the effects of repeated doses of sucrose over relatively short periods of time. None has examined the use of sucrose throughout the NICU stay, and only 1 study evaluated the neurodevelopmental outcomes after repeated doses of sucrose. In that study, infants born at <31 weeks' gestational age and exposed to >10 doses per day in the first week of life were more likely to show poorer attention and motor development in the early months after discharge from the NICU. Results of studies in animal models have suggested that the mechanism of action of sucrose is through opioid pathways; however, in human infants, little has been done to examine the physiologic mechanisms involved, and the findings reported thus far have been ambiguous. Drawing from the growing animal literature of research that has examined the effects of chronic sugar exposure, we describe alternative amine and hormone pathways that are common to the processing of sucrose, attention, and motor development. In addition, a review of the latest research to examine the effects of repeated sucrose on pain processing is presented. These 2 literatures each can inform the other and can provide an impetus to initiate research to examine not only the mechanisms involved in the calming mechanisms of sucrose but also in the long-term neurodevelopmental effects of repeated sucrose in those infants born extremely preterm or critically ill. [ABSTRACT FROM AUTHOR]

There is evidence that the developmental trajectory of cortisol secretion in preterm infants is altered, with elevated basal cortisol levels observed postnatally through at least 18 months corrected age (CA). This alteration is possibly due to neonatal pain-related stress. High cortisol levels might contribute to greater risk of impaired neurodevelopment. Since maternal factors are important for the regulation of infant stress responses, we investigated relationships between infant (neonatal pain-related stress, attention, cortisol) and maternal (stress, interactive behaviors) factors at age 8 months CA. We found that interactive maternal behaviors buffered the relationship between high neonatal pain-related stress exposure and poorer focused attention in mothers who self-reported low concurrent stress. Furthermore, in preterm infants exposed to high concurrent maternal stress and overwhelming interactive maternal behaviors, higher basal cortisol levels were associated with poor focused attention. Overall, these findings suggest that maternal factors can influence the cognitive resilience at 8 months of preterm infants exposed to early life stress. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 150–164, 2007. [ABSTRACT FROM AUTHOR]