The Val66Met brain-derived neurotrophic factor gene variant interacts with early pain exposure to predict cortisol dysregulation in 7-year-old children born very preterm: Implications for cognition.

Early stress in the form of repetitive neonatal pain, in infants born very preterm, is associated with long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and with poorer cognitive performance. Brain-derived neurotrophic factor (BDNF) which is important in synaptic plasticity and cognitive functions is reduced by stress. Therefore the BDNF Val66Met variant, which affects secretion of BDNF, may interact with early exposure to pain-related stress in children born very preterm, to differentially affect HPA regulation that in turn may be associated with altered cognitive performance. The aims of this study were to investigate whether in children born very preterm, the BDNF Val66Met variant modulates the association between neonatal pain-related stress and cortisol levels at age 7years, and if cortisol levels were related to cognitive function. Furthermore, we examined whether these relationships were sex-specific. Using a longitudinal cohort design, N=90 children born very preterm (24-32weeks gestation) were followed from birth to age 7years. Cortisol was assayed from hair as an index of cumulative stress and from saliva to measure reactivity to a cognitive challenge. BDNF Val66Met variant was genotyped at 7years using real-time polymerase chain reaction (PCR). Using generalized linear modeling, in boys with the Met allele, greater neonatal pain-related stress (adjusted for clinical risk factors) predicted lower hair cortisol (p=0.006) and higher reactivity salivary cortisol (p=0.002). In both boys and girls with the Met allele, higher salivary cortisol reactivity was correlated with lower IQ (r=-0.60; p=0.001) and poorer visual-motor integration (r=-0.48; p=0.008). Our findings show associations between lower BDNF availability (presence of the Met allele) and vulnerability to neonatal pain/stress in boys, but not girls. This exploratory study suggests new directions for research into possible mechanisms underlying how neonatal pain/stress is related to cognitive performance in children born very preterm.

Tract-Based Spatial Statistics in Preterm-Born Neonates Predicts Cognitive and Motor Outcomes at 18 Months.

BACKGROUND AND PURPOSE: Adverse neurodevelopmental outcome is common in children born preterm. Early sensitive predictors of neurodevelopmental outcome such as MR imaging are needed. Tract-based spatial statistics, a diffusion MR imaging analysis method, performed at term-equivalent age (40 weeks) is a promising predictor of neurodevelopmental outcomes in children born very preterm. We sought to determine the association of tract-based spatial statistics findings before term-equivalent age with neurodevelopmental outcome at 18-months corrected age. MATERIALS AND METHODS: Of 180 neonates (born at 24-32-weeks' gestation) enrolled, 153 had DTI acquired early at 32 weeks' postmenstrual age and 105 had DTI acquired later at 39.6 weeks' postmenstrual age. Voxelwise statistics were calculated by performing tract-based spatial statistics on DTI that was aligned to age-appropriate templates. At 18-month corrected age, 166 neonates underwent neurodevelopmental assessment by using the Bayley Scales of Infant Development, 3rd ed, and the Peabody Developmental Motor Scales, 2nd ed. RESULTS: Tract-based spatial statistics analysis applied to early-acquired scans (postmenstrual age of 30-33 weeks) indicated a limited significant positive association between motor skills and axial diffusivity and radial diffusivity values in the corpus callosum, internal and external/extreme capsules, and midbrain (P < .05, corrected). In contrast, for term scans (postmenstrual age of 37-41 weeks), tract-based spatial statistics analysis showed a significant relationship between both motor and cognitive scores with fractional anisotropy in the corpus callosum and corticospinal tracts (P < .05, corrected). Tract-based spatial statistics in a limited subset of neonates (n = 22) scanned at <30 weeks did not significantly predict neurodevelopmental outcomes. CONCLUSIONS: The strength of the association between fractional anisotropy values and neurodevelopmental outcome scores increased from early-to-late-acquired scans in preterm-born neonates, consistent with brain dysmaturation in this population.

Internalizing behaviours in school-age children born very preterm are predicted by neonatal pain and morphine exposure.

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: One hundred one 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 neonatal intensive care unit, to prevent long-term effects on child behaviour.

Prenatal and postnatal inflammation in relation to cortisol levels in preterm infants at 18 months corrected age.

OBJECTIVE: To examine whether early inflammation is related to cortisol levels at 18 months corrected age (CA) in children born very preterm. STUDY DESIGN: Infants born ≤ 32 weeks of gestational age were recruited in the neonatal intensive care unit (NICU), and placental histopathology, magnetic resonance imaging (MRI) and chart review were obtained. At 18 months CA, developmental assessment and collection of three salivary cortisol samples were carried out. Generalized least squares was used to analyze data from 85 infants providing 222 cortisol samples. RESULT: Infants exposed to chorioamnionitis with funisitis had a significantly different pattern of cortisol across the samples compared with infants with chorioamnionitis alone or no prenatal inflammation (F(4, 139)=7.3996, P<0.0001). Postnatal infections, necrotizing enterocolitis and chronic lung disease were not significantly associated with the cortisol pattern at 18 months CA. CONCLUSION: In children born very preterm, prenatal inflammatory stress may contribute to altered programming of the hypothalamic-pituitary-adrenal (HPA) axis.

Long-term outcome after neonatal intraparenchymal echodensities with porencephaly.

OBJECTIVE: To compare long-term neurodevelopmental and functional outcomes of neonatal intensive care unit (NICU) survivors with neonatal intraparenchymal echodensities (IPE) with porencephaly on cranial ultrasonography with matched controls. To compare the developmental trajectories of these infants over the childhood years with those of matched controls. DESIGN: Cohort study. SETTING: Tertiary level NICU and the Neonatal Follow-Up Programme (NFUP) in Vancouver, Canada. PATIENTS: NICU survivors with birth weights <1250 g, born between 1983 and 1985. METHODS: Cranial ultrasound scans of NICU subjects with grade 4 intraventricular haemorrhage (IVH) were reviewed by a neuroradiologist and cases were defined, using stringent criteria, as IVH with IPE with porencephaly. Controls with normal cranial ultrasound findings were selected case-matched for birth weight and sex. Prospective sequential multidisciplinary assessments were performed up to 17 years in the NFUP. Mann-Whitney U test was used to compare outcomes between cases and controls. RESULTS: Of 385 eligible patients, 14 met IPE and porencephaly criteria and 10 survived to discharge. All cases with IPE and porencephaly had one or more impairments, significantly different from preterm controls (p<0.001). At all ages assessed, rates of motor, cognitive and overall impairment were significantly higher in the cases (p< or =0.002 for all tests). Most cases at adolescence were ambulatory, required learning assistance in school and had social challenges. CONCLUSIONS: Children with neonatal IPE and porencephaly have a much worse long-term neurodevelopmental outcome than children with normal cranial ultrasound findings.

Magnetoencephalography study of brain dynamics in young children born extremely preterm.

Magnetoencephalography (MEG) was recorded while 5-7 year-old children were performing a visual-spatial memory recognition task. Full-term children showed greater gamma-band (30-50 Hz) amplitude in the right temporal region during the task, than children who were born extremely preterm. These results may represent altered brain processing in extremely preterm children who escape major impairment.

Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 Weeks' postconceptional Age.

BACKGROUND: Management of pain in very low birth weight infants is limited by a lack of empiric knowledge about the multiple determinants of biobehavioral reactivity in infants receiving neonatal intensive care. OBJECTIVE: To examine relationship of early neonatal factors and previous medication exposure to subsequent biobehavioral reactivity to acute pain of blood collection. DESIGN: Prospective cohort study. Methods. One hundred thirty-six very low birth weight (

Relations between behavioral and cardiac autonomic reactivity to acute pain in preterm neonates.

OBJECTIVE: The purpose of this study was to assess relations and concordance between behavioral and physiologic reactivity to pain in preterm neonates at 32 weeks postconceptional age as a function of gestational age at birth. SETTING: Level III neonatal intensive care unit. DESIGN/PATIENTS: The study group comprised 136 preterm neonates (mean [range] birthweight, 1,020 g [445-1,500 g]: gestational age at birth, 28 weeks [23-32 weeks]) separated into three groups according to gestational age at birth as follows: 23 to 26 weeks (n = 48), 27 to 29 weeks (n = 52), and 30 to 32 weeks (n = 36). OUTCOME MEASURES: Reactivity to routine blood collection at 32 weeks postconceptional age was assessed using bedside-recorded behavioral and autonomic measures. Coders who were blinded to the study design scored behavioral responses (facial activity using the Neonatal Facial Coding System, sleep/waking state, and finger splay). Autonomic reactivity was assessed by change in heart rate and spectral analysis of heart rate variability (change in low-frequency and high-frequency power, and the ratio of low-frequency to high-frequency power during blood collection). RESULTS: Facial activity and state correlated moderately with change in heart rate across gestational age groups (r = 0.41-0.62). Facial activity and state did not correlate significantly with change in low-frequency and high-frequency power, or the ratio of low-frequency to high-frequency power (r = 0.00-0.31). Finger splay did not correlate with any autonomic recording (r = 0.03-0.41). Concordance between established biobehavioral measures of pain revealed individual differences. Although some neonates showed high behavioral but low physiologic reactivity, other neonates displayed the opposite reaction; however, the majority displayed concordant reactions. CONCLUSIONS: The study findings confirm the value of measuring domains independently, especially in neonates born at a very young gestational age.

Behavior, pain perception, and the extremely low-birth weight survivor.

This article explores the literature concerning responses to pain of both premature and term-born newborn infants, the evidence for short-term and long-term effects of pain, and behavioral sequelae in individuals who have experienced repeated early pain in neonatal life as they mature. There is no doubt that pain causes stress in babies and this in turn may adversely affect long-term neurodevelopmental outcome. Although there are methods for assessing dimensions of acute reactivity to pain in an experimental setting, there are no very good measures available at the present time that can be used clinically. In the clinical setting repeated or chronic pain is more likely the norm rather than infrequent discrete noxious stimuli of the sort that can be readily studied. The wind-up phenomenon suggests that, exposed to a cascade of procedures as happens with clustering of care in the clinical setting in an attempt to provide periods of rest for stressed babies, an infant may in fact perceive procedures that are not normally viewed as noxious, as pain. Pain exposure during lifesaving intensive medical care of ELBW neonates may also affect subsequent reactivity to pain in the neonatal period, but behavioral differences are probably not likely to be clinically significant in the long term. Prolonged and repeated untreated pain in the newborn period, however, may produce a relatively permanent shift in basal autonomic arousal related to prior NICU pain experience, which may have long-term sequelae. In the long run, the most significant clinical effects of early pain exposure may be on neurodevelopment, contributing to later attention, learning, and behavior problems in these vulnerable children. Although there is considerable evidence to support a variety of adverse effects of early pain, there is less information about the long-term effects of opiates and benzodiazepines on the developing central nervous system. Current evidence reviewed suggests that judicious use of morphine for adjustment to mechanical ventilation may ameliorate the altered autonomic response. It may be very important, however, to distinguish stress from pain. Animal evidence suggests that the neonatal brain is affected differently when exposed to morphine administered in the absence of pain than in the presence of pain. Pain control may be important for many reasons but overuse of morphine or benzodiazepines may have undesirable long-term effects. This is a rapidly evolving area of knowledge of clear relevance to clinical management likely to affect long-term outcomes of high-risk children.

Are twitches, startles, and body movements pain indicators in extremely low birth weight infants?

OBJECTIVE: The goal of this study was to examine whether body activity such as postural, trunk, and limb movements may be potential pain cues in preterm infants. DESIGN: Convenience sample. SETTING: Level III neonatal intensive care unit (NICU). PATIENTS: Extremely low birth weight (< or = 1,000 g) preterm infants (n = 64) undergoing routine NICU medical care. OUTCOME MEASURES: Procedures likely to differ in evoking distress (i.e., endotracheal suctioning, chest physical therapy, diaper change, or nasogastric feed) were observed. Behaviors were recorded at bedside using the Neonatal Individualized Developmental Care and Assessment Program system. RESULTS: Changes in heart rate and sleep/waking state were related to the procedures, supporting the assumption of differing relative disruption to the infant. Arching, squirming, startles, and twitching were not observed significantly more during procedures than at baseline. After controlling for background variables, finger splay and leg extension were significantly related to ongoing procedures. Facial brow raising was a function of the number of invasive procedures in the past 24 hours; thus, it may be a useful cue of sensitization. CONCLUSIONS: Some extensor movements seemed to be distress signals, whereas tremors, startles, and twitches were not related to discomfort during the observation period. These behaviors may differ qualitatively during longer lasting tissue invasive events. The results of this study indicate the need for more in-depth study of patterns of motor activity in preterm infants over longer observation periods to evaluate potential signs of stress and pain in babies undergoing NICU medical care.

Biobehavioral pain responses in former extremely low birth weight infants at four months' corrected age.

OBJECTIVE: To compare biobehavioral responses to acute pain at 4 months' corrected age between former extremely low birth weight (ELBW) infants and term-born controls. METHODOLOGY: Measures of facial behavioral and cardiac autonomic reactivity in 21 former ELBW infants (mean birth weight = 763 g) were compared with term-born infants (n = 24) during baseline, lance, and recovery periods of a finger-lance blood collection. Further, painful procedures experienced during neonatal care were quantified in both groups. RESULTS: Overall, behavioral and cardiac autonomic responses to the lance were similar between groups. However, the ELBW group seemed to have a less intense parasympathetic withdrawal in the lance period and a more sustained sympathetic response during recovery than the control group. Further, in the recovery period, two behavioral patterns (early recovery and a late recovery) were apparent among the ELBW group. CONCLUSIONS: Biobehavioral pain responses were similar overall between both groups of infants. Subtle differences were observed in cardiac autonomic responses during the lance period and in behavioral recovery among ELBW infants. Whether these findings represent a long-term effect of early pain experience or a developmental lag in pain response remains unclear. The lack of an overall difference runs counter to previously reported findings of reduced behavioral response in former ELBW infants. biobehavioral pain response, premature infants, repetitive pain, heart rate variability.

Predicting IQ of biologically "at risk" children from age 3 to school entry: sensitivity and specificity of the Stanford-Binet Intelligence Scale IV.

Predictive validity of the Stanford-Binet Intelligence Scale Fourth Edition (S-B IV) from age 3 years to ages 4-5 years was evaluated with biologically "at risk" children without major sensory or motor impairments (n = 236). Using the standard scoring, children with full scale IQ < or = 84 on the Wechsler Preschool and Primary Scale of Intelligence at age 4-5 years were poorly identified (sensitivity 54%) from the composite S-B IV score at age 3. However, sensitivity improved greatly to 78% by including as a predictor the number of subtests the child was actually able to perform at age 3 years. Measures from the Home Screening Questionnaire and ratings of mother-child interaction further improved sensitivity to 83%. The standard method for calculating the composite score on the S-B IV excludes subtests with a raw score of 0, which overestimates cognitive functioning in young biologically high risk children. Accuracy of early identification was improved significantly by considering the number of subtests the child did not perform at age 3 years.

Long-term effects of pain in infants.

Pain and stress have been shown to induce significant physiological and behavioral reactions in newborn infants, even in those born prematurely. Infants who are born prematurely or seriously ill are commonly exposed to multiple painful and stressful events as part of their prolonged hospitalizations and required medical procedures. There is now evidence that these early events not only induce acute changes, but that permanent structural and functional changes may also result. This article reviews the growing body of evidence of likely long-term effects of early pain and stress on the human infant. It is hoped that a better understanding of this literature will promote more responsive and sensitive management of infants and young children during their encounters with the medical community and will ultimately facilitate the healthy growth and development of all children.

The developmental character of cardiac autonomic responses to an acute noxious event in 4- and 8-month-old healthy infants.

Heart rate (HR) has been widely studied as a measure of an individual's response to painful stimuli. It remains unclear whether changes in mean HR or the variability of HR are specifically related to the noxious stimulus (i.e. pain). Neither is it well understood how such changes reflect underlying neurologic control mechanisms that produce these responses, or how these mechanisms change during the first year of life. To study the changes in cardiac autonomic modulation that occur with acute pain and with age during early infancy, the relationship between respiratory activity and short-term variations of HR (i.e. respiratory sinus arrhythmia) was quantified in a longitudinal study of term born healthy infants who underwent a finger lance blood collection at 4 months of age (n = 24) and again at 8 months of age (n = 20). Quantitative respiratory activity and HR were obtained during baseline, lance, and recovery periods. Time and frequency domain analyses from 2.2-min epochs of data yielded mean values, spectral measures of low (0.04-0.15 Hz) and high (0.15-0.80 Hz) frequency power (LF and HF), and the LF/HF ratio. To determine sympathetic and parasympathetic cardiac activity, the transfer relation between respiration and HR was used. At both 4 and 8 months, mean HR increased significantly with the noxious event (p > 0.01). There were age-related differences in the pattern of LF, HF, and LF/HF ratio changes. Although these parameters all decreased (p > 0.01) at 4 months, LF and LF/HF increased at 8 months and at 8 months HF remained stable in response to the noxious stimulus. Transfer gain changes with the lance demonstrated a change from predominant vagal baseline to a sympathetic condition at both ages. The primary finding of this study is that a response to an acute noxious stimulus appears to produce an increase in respiratory-related sympathetic HR control and a significant decrease in respiratory-related parasympathetic control at both 4 and 8 months. Furthermore, with increasing age, the sympathetic and parasympathetic changes appear to be less intense, but more sustained.

Children's judgements about pain at age 8-10 years: do extremely low birthweight (< or = 1000 g) children differ from full birthweight peers?

Children's judgements about pain at age 8-10 years were examined comparing two groups of children who had experienced different exposure to nociceptive procedures in the neonatal period: extremely low birthweight (ELBW) < or = 1000 g (N = 47) and full birthweight (FBW) > or = 2500 g (N = 37). The 24 pictures that comprise the Pediatric Pain Inventory, depicting events in four settings: medical, recreational, daily living, and psychosocial, were used as the pain stimuli. The subjects rated pain intensity using the Color Analog Scale and pain affect using the Facial Affective Scale. Child IQ and maternal education were statistically adjusted in group comparisons. Pain intensity and pain affect related to activities of daily living and recreation were significantly higher than psychosocial and medically related pain on both scales in both groups of children. Although the two groups of children did not differ overall in their perceptions of pain intensity or affect, the ELBW children rated medical pain intensity significantly higher than psychosocial pain, unlike the FBW group. Also, duration of neonatal intensive care unit stay for the ELBW children was related to increased pain affect ratings in recreational and daily living settings. Despite altered response to pain in the early years reported by parents, on the whole at 8-10 years of age ELBW children judged pain in pictures similarly to their term peers. However, differences were evident, which suggests that studies are needed of biobehavioural reactivity to pain beyond infancy, as well as research into beliefs, attitudes, and perceptions about pain during the course of childhood in formerly ELBW children.

The expression of pain in infants and toddlers: developmental changes in facial action.

Age-related changes in the facial expression of pain during the first 18 months of life have important implications for our understanding of pain and pain assessment. We examined facial reactions video recorded during routine immunization injections in 75 infants stratified into 2-, 4-, 6-, 12-, and 18-month age groups. Two facial coding systems differing in the amount of detail extracted were applied to the records. In addition, parents completed a brief questionnaire that assessed child temperament and provided background information. Parents' efforts to soothe the children also were described. While there were consistencies in facial displays over the age groups, there also were differences on both measures of facial activity, indicating systematic variation in the nature and severity of distress. The least pain was expressed by the 4-month age group. Temperament was not related to the degree of pain expressed. Systematic variations in parental soothing behaviour indicated accommodation to the age of the child. Reasons for the differing patterns of facial activity are examined, with attention paid to the development of inhibitory mechanisms and the role of negative emotions such as anger and anxiety.