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 MRI, 3D MR spectroscopic imaging (MRSI) and diffusion tensor imaging (DTI): scan 1 early in life (median 32.1 weeks) and scan 2 at termequivalent age (median 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/ choline), lactate to choline ratios, average diffusivity (D AV ) and white matter fractional anisotropy (FA) from up to seven white and four subcortical grey matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analysed using generalized estimating equation modelling 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 grey 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.

The majority of infants born very preterm (24–32 weeks 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 versus 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.

WHAT'S KNOWN ON THIS SUBJECT: Greater numbers of invasive procedures from birth to term-equivalent age, adjusted for clinical confounders, are associated with altered brain microstructure during neonatal care and poorer cognitive outcome at 18 months' corrected age in children born very preterm.WHAT THIS STUDY ADDS: Altered myelination at school age is associated with greater numbers of invasive procedures during hospitalization in very preterm children without severe brain injury or neurosensory impairment. Greater numbers of invasive procedures and altered brain microstructure interact to predict lower IQ. abstract BACKGROUND: Very preterm infants (born 24-32 weeks' gestation) undergo numerous invasive procedures during neonatal care. Repeated skin-breaking procedures in rodents cause neuronal cell death, and in human preterm neonates higher numbers of invasive procedures from birth to term-equivalent age are associated with abnormal brain development, even after controlling for other clinical risk factors. It is unknown whether higher numbers of invasive procedures are associated with long-term alterations in brain microstructure and cognitive outcome at school age in children born very preterm. METHODS:Fifty children born very preterm underwent MRI and cognitive testing at median age 7.6 years (interquartile range, 7.5-7.7). T 1 -and T 2 -weighted images were assessed for the severity of brain injury. Magnetic resonance diffusion tensor sequences were used to measure fractional anisotropy (FA), an index of white matter (WM) maturation, from 7 anatomically defined WM regions. Child cognition was assessed using the Wechsler Intelligence Scale for Children-IV. Multivariate modeling was used to examine relationships between invasive procedures, brain microstructure, and cognition, adjusting for clinical confounders (eg, infection, ventilation, brain injury). RESULTS:Greater numbers of invasive procedures were associated with lower FA values of the WM at age 7 years (P = .01). The interaction between the number of procedures and FA was associated with IQ (P = .02), such that greater numbers of invasive procedures and lower FA of the superior WM were related to lower IQ. CONCLUSIONS:Invasive procedures during neonatal care contribute to long-term abnormalities in WM microstructure and lower IQ. Pediatrics 2014;133:412-421

Slower postnatal growth is an important predictor of adverse neurodevelopmental outcomes in infants born preterm. However, the relationship between postnatal growth and cortical development remains largely unknown. Therefore, we examined the association between neonatal growth and diffusion tensor imaging measures of microstructural cortical development in infants born very preterm. Participants were 95 neonates born between 24 and 32 weeks gestational age studied twice with diffusion tensor imaging: scan 1 at a median of 32.1 weeks (interquartile range, 30.4 to 33.6) and scan 2 at a median of 40.3 weeks (interquartile range, 38.7 to 42.7). Fractional anisotropy and eigenvalues were recorded from 15 anatomically defined cortical regions. Weight, head circumference, and length were recorded at birth and at the time of each scan. Growth between scans was examined in relation to diffusion tensor imaging measures at scans 1 and 2, accounting for gestational age, birth weight, sex, postmenstrual age, known brain injury (white matter injury, intraventricular hemorrhage, and cerebellar hemorrhage), and neonatal illness (patent ductus arteriosus, days intubated, infection, and necrotizing enterocolitis). Impaired weight, length, and head growth were associated with delayed microstructural development of the cortical gray matter (fractional anisotropy: P < 0.001), but not white matter (fractional anisotropy: P = 0.529), after accounting for prenatal growth, neonatal illness, and brain injury. Avoiding growth impairment during neonatal care may allow cortical development to proceed optimally and, ultimately, may provide an opportunity to reduce neurological disabilities related to preterm birth.

Children born very preterm (≤32 weeks gestation) show 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) seen 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 using 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 controls (P =0.02). Parent Sensitivity and Nonhostility moderated the relationship between neonatal pain and Internalizing behavior (all P <0.05); higher parent education (P <0.03), lower Parenting Stress (P =0.001), and fewer children in the home (P <0.01) were associated with lower Internalizing behavior in very preterm children, after adjusting for neonatal medical confounders, gender and child cognitive ability (all P >0.05). Parent Emotional Availability and stress were not associated with Internalizing behaviors in full-term controls. Positive parent interaction and lower stress appears to ameliorate negative effects of neonatal pain on stress-sensitive behaviors in this vulnerable population.

Background Greater neonatal pain is associated with higher internalizing behaviours in very preterm infants at 18 months corrected age, but it is unknown whether this relationship persists to school age. Moreover, it is unclear whether morphine ameliorates or exacerbates the potential influence of neonatal pain/stress on internalizing behaviours. We examined whether neonatal pain-related stress is associated with internalizing behaviours at age 7 years in children born very preterm, and whether morphine affects this relationship. Methods 101 children born very preterm (≤ 32 weeks gestation) were seen at mean age 7.7 years. A parent completed the Parenting Stress Index and Child Behavior Checklist questionnaires. Neonatal pain-related stress (the number of skin-breaking procedures adjusted for clinical factors associated with prematurity) was examined in relation to internalizing behaviour, separately in subjects mechanically ventilated and exposed to both pain and morphine (n = 57) and those never mechanically ventilated, exposed to pain but not morphine (n = 44). Results In the non-ventilated group, higher skin-breaking procedures (p = 0.037) and parenting stress (p = 0.004) were related to greater internalizing behaviours. In the ventilated group, greater morphine exposure (p = 0.004) was associated with higher child internalizing scores. Conclusions In very preterm children who undergo mechanical ventilation, judicious use of morphine is important, since morphine may mitigate the negative effects of neonatal pain on nociception but adversely affect internalizing behaviours at school age. Management of procedural pain needs to be addressed in very preterm infants in the NICU, to prevent long-term effects on child behaviour.

Chronic pain during childhood and adolescence can lead to persistent pain problems and mental health disorders into adulthood. Posttraumatic stress disorders and depressive and anxiety disorders are mental health conditions that co-occur at high rates in both adolescent and adult samples, and are linked to heightened impairment and disability. Comorbid chronic pain and psychopathology has been explained by the presence of shared neurobiology and mutually maintaining cognitive-affective and behavioral factors that lead to the development and/or maintenance of both conditions. Particularly within the pediatric chronic pain population, these factors are embedded within the broader context of the parent–child relationship. In this review, we will explore the epidemiology of, and current working models explaining, these comorbidities. Particular emphasis will be made on shared neurobiological mechanisms, given that the majority of previous research to date has centered on cognitive, affective, and behavioral mechanisms. Parental contributions to co-occurring chronic pain and psychopathology in childhood and adolescence will be discussed. Moreover, we will review current treatment recommendations and future directions for both research and practice. We argue that the integration of biological and behavioral approaches will be critical to sufficiently address why these comorbidities exist and how they can best be targeted in treatment.

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.