Biobehavioural reactivity to pain in preterm infants: a marker of neuromotor development

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1 Biobehavioural reactivity to pain in preterm infants: a marker of neuromotor development Ruth E Grunau* PhD, Centre for Community Child Health Research, Child and Family Research Institute; Michael F Whitfield MD, Department of Pediatrics, University of British Columbia; Taryn Fay MSc, Centre for Community Child Health Research, Child and Family Research Institute; Liisa Holsti PhD, School of Rehabilitation Sciences; Timothy Oberlander MD, Department of Pediatrics, University of British Columbia; Marilynn L Rogers BSR, Children s and Women s Health Centre of BC, Vancouver, British Columbia, Canada. *Correspondence to first author at Centre for Community Child Health Research, Room L , Oak Street, Vancouver, British Columbia, Canada, V6H 3V4. [email protected] 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 800g and/or 25 weeks gestational age (GA). Pain reactivity during routine heel lance for blood collection at 32 weeks GA was measured using a composite score derived from the Neonatal Facial Coding System, change in infant sleep/wake state, and spectral analysis of heart rate. Motor development was assessed using the Movement Assessment of Infants scale and the Bayley Scales of Infant Development. Low biobehavioural pain reactivity at 32 weeks PCA was associated with poorer overall quality of motor function at 8 months CCA, but not at 4 months CCA. It was concluded that pain reactivity before discharge from the neonatal intensive care unit may be a useful marker of neuromotor development in infancy. See end of paper for list of abbreviations. Biobehavioural pain reactivity of preterm infants in the neonatal period may reflect the capacity of the central nervous system (CNS) to regulate arousal and neurobiological organization. Regulation of arousal can be assessed through physiological and behavioural responses which reflect changes in CNS activation. CNS activation is central to the processing of sensory input and to engaging and maintaining attention (Mayes 2000, Posner 2002). Early prolonged exposure to pain and stress is proposed as one of the contributing factors to later difficulties with self-regulation and attention in infants born at extremely low gestational age (GA; Als 1995; Grunau 2002, 2003), but being a marker of neurobehavioural organization, may also predict later outcome. Lower-risk preterm infants display more vigorous pain responses in the neonatal period (Johnston and Stevens 1996, Grunau et al. 2001); therefore, it was hypothesized that greater neonatal pain response would be associated with better neurodevelopmental outcome later in infancy. Perinatal factors (e.g. birthweight, GA at birth, and neonatal illness) and neonatal assessment tools (Dubowitz et al. 1981, Amiel-Tison 2002) have limited value in predicting later neurodevelopment in high-risk infants. Assessment of quality of infant movements is more predictive of neurological dysfunction than traditional neurological examination (Cioni et al. 1997, Hadders-Algra and Groothuis 1999, Prechtl 2001, Campbell et al. 2002). There has been a shift away from a search for risk factors towards focus on how the infant s CNS functions in response to extrauterine stimuli (Porges 1992, Als 1995, Doussard-Roosevelt et al. 1997). The aim of the present study was to examine whether infant behavioural and cardiac reactivity to stress of acute pain in the neonatal intensive care unit (NICU) provides a marker of the infant s neuromotor functioning later in infancy, above and beyond perinatal and medical factors. Behavioural and autonomic reactivity to blood collection by heel lance at 32 weeks postconceptional age (PCA) and neonatal risk factors were examined in relation to neurodevelopmental functioning at 4 and 8 months corrected chronological age (CCA). Thirty-two weeks PCA was chosen as infants are clinically stable, and past the acute phase of intensive management. This appears to be the first study to examine whether pain reactivity in the NICU, as an indicator of infant regulatory capability, predicts later neurodevelopment in high-risk infants. Method PARTICIPANTS Infants were recruited in the tertiary NICU in the Children s and Women s Health Centre of British Columbia, Canada for a study of pain reactivity at 32 weeks PCA (Grunau et al. 2001). Infants were excluded if they had a major congenital abnormality, parenchymal brain injury on cranial ultrasound (grade IV intraventricular hemorrhage or cystic periventricular leukomalacia), maternal illicit drug use, or received analgesia or sedation within 72 hours before the pain assessment. Infants born 800g or 25 weeks GA (n=42) were targeted. Of these 42 infants, one died at 3 months CCA, two moved out of the province, and two did not return for follow-up. The 37 infants who attended the 4-month and/or the 8-month follow-up visits comprised the study sample, and did not differ in neonatal or demographic characteristics from those who did not return. Of the 37 infants, 29 were seen at 4 months, Developmental Medicine & Child Neurology 2006, 48:

2 31 at 8 months, and 23 were seen at both visits. Participant characteristics are shown in Table I. Written informed consent was obtained from a parent or legal guardian according to a protocol approved by the Clinical Research Ethics Board of the University of British Columbia. PROCEDURES Pain reactivity data were acquired during routine blood collection in the NICU at 32 weeks PCA, as described previously (Grunau et al. 2001). Continuous behavioural coding and cardiac signal aquisition was carried out for a 3-minute baseline period before the procedure, during cleansing of the heel, during lance and squeeze phases of blood collection, and for a 3- minute recovery period following last contact by the laboratory technician. Developmental evaluation at 4 and 8 months CCA was carried out in the Neonatal Follow-up Programme of the Children s and Women s Health Centre of British Columbia by a physiotherapist or occupational therapist, both of whom were certified on the Movement Assessment of Infants scale (MAI; Chandler et al. 1980) and the Bayley Scales of Infant Development, 2nd edition (BSID-II; Bayley 1993). MEASURES The following assessments and measures of pain reactivity at 32 weeks PCA were taken: behaviour, autonomic, composite pain scores, NICU chart review, and developmental outcome. Behaviour Facial activity. The Neonatal Facial Coding System (NFCS) was coded at bedside (Grunau et al. 1998). Face actions were summed to provide a total facial activity score for each event (baseline, contact, swab, lance, squeeze, and recovery), with a possible range of 0 to 9. Table I: Neonatal and sociodemographic characteristics of infants at 4 or 8 months corrected chronological age (n=35) a Characteristics Neonatal Gestational age at delivery, (mean [SD]) wks (1.5) Infant birthweight, (mean [SD]) g (105.4) SNAP-II day 1, mean (SD) 24.2 (13.3) SNAP-II day 3, mean (SD) 8.5 (7.6) Morphine exposure, (mean [SD]) mg/kg days 5.0 (6.6) Postnatal dexamethasone exposure, (mean [SD]) d 18.8 (11.8) Mechanical ventilation, (mean [SD]) d 30.3 (12.9) Invasive procedures, (mean [SD]) n (50.6) Apgar 1, mean (SD) 5.0 (2.1) Apgar 5, mean (SD) 7.7 (1.2) Males, n (%) 17 (49) SGA, n (%) 8 (23) Singleton, n (%) 27 (77) Sociodemographic Mother s age at delivery, (mean [SD]) y 29.4 (5.5) Mother s race, (n [%]) White 30 (86) Mother s education, (mean [SD]) y 13.5 (2.4) a Two outliers excluded. SNAP-II, Score for Neonatal Acute Physiology (Richardson et al. 2001); SGA, small for gestational age (gestational age at birth <10th centile for birthweight). Sleep/waking state. Sleep/waking state (Grunau et al. 1998) was coded from 1 to 7: 1, deep sleep; 2, light sleep; 3, drowsy; 4, quiet awake; 5, active awake; 6, highly aroused, agitated, upset and/or crying; 7, prolonged respiratory pause >8sec. Autonomic Continuous electrocardiographic (ECG) activity was recorded from a single surface ECG (lead II) and digitally sampled at 360Hz off-line using a computer acquisition system and custom signal processing software. Power spectral estimates in the low frequency region ( Hz) were measured as described previously (Grunau et al. 2001). During baseline and blood collection, epochs of heart rate variability of stable 2.2 minute periods were used. To examine cardiac reactivity, changes were measured from baseline to invasive phase of blood collection. Composite pain scores Biobehavioural responses to pain were evaluated using the NFCS, low frequency power range of cardiac output, and infant sleep/wake state. Composite pain scores were used to reduce the number of outcome measures, due to the relatively low sample size in the present study, constraining the number of predictor variables. Principal component analysis was applied from an earlier study in which two composite scores were validated in a study of pain on 136 infants at 32 weeks PCA (Grunau et al. 2001). One composite pain score primarily comprised pain behaviour (facial activity and sleep/wake state), referred to in this study as Pain Behaviour. The other composite score primarily reflected the low frequency power range of cardiac autonomic output, referred to in this study as Pain Autonomic. The weightings for the Pain Behaviour composite score were 0.73 on the NFCS during lance, 0.87 during squeeze, 0.79 sleep/wake state during squeeze, and 0.19 change in low frequency power from baseline to squeeze. Pain Autonomic weightings were 0.31 on the NFCS during lance, 0.07 during squeeze, 0.13 sleep/waking state during squeeze, and 0.95 change in low frequency power from baseline to squeeze. Therefore, Pain Behaviour mainly reflected the behavioural response and Pain Autonomic mainly reflected the change in low frequency power. Normal pain reactivity in healthy preterm neonates at 32 weeks PCA is reflected as higher Pain Behaviour scores. As lower low-frequency power indicates greater sympathetic arousal, a lower Pain Autonomic score indicates greater cardiac pain reactivity. NICU chart review A neonatal research nurse carried out a prospective medical chart review from birth to the pain reactivity test day at 32 weeks PCA including, but not limited to, GA, birthweight, Apgar score, illness severity on days 1 and 3 using the Score of Neonatal Acute Physiology (SNAP-II; Richardson et al. 2001), number of invasive (skin breaking) procedures, morphine exposure (daily average mg/kg days of exposure), days of postnatal dexamethasone, and days of mechanical ventilation. Developmental outcome The primary outcome measure of neurodevelopment at age 4 and 8 months CCA was the MAI which evaluates quality of motor movement and is predictive of later motor outcome 472 Developmental Medicine & Child Neurology 2006, 48:

3 (Chandler et al. 1980, Swanson et al. 1992). Neuromotor outcome was the focus because motor functioning provides an early quantifiable window on development in high-risk preterm infants. The MAI was administered at 4 and 8 months CCA, and is comprised of 65 items which assess motor behaviours in four categories: muscle tone, primitive reflexes, automatic reactions, and volitional movement. A score for each category and a total risk score was derived; higher scores indicating a greater deviation from normal. The Mental (MDI) and Psychomotor (PDI) scales of the BSID-II were administered at 8 months CCA only. Interobserver and test retest reliability on the MAI were r=0.72 and r=0.76 respectively in samples which included term and preterm infants (Harris et al. 1984), and on the BSID- II interobserver and test retest reliability were r=0.75 to 0.96 and r=0.84 to 0.88 respectively (Bayley 1993). DATA ANALYSIS Associations between perinatal data, Pain Behaviour, Pain Autonomic, and MAI measures at 4 and 8 months were examined. Spearman s rho (non-parametric) correlations were used as the MAI is an ordinal scale, and the BSID-II scores were not normally distributed. Hierarchical regression analysis was conducted to examine relationships between neonatal risk factors, pain reactivity, and MAI motor risk score. Key neonatal factors were identified and entered together in block 1. Pain reactivity was entered in block 2 to examine the degree to which it would predict the MAI above and beyond the neonatal variables entered in step 1. Significance was set at p<0.05. Results OUTLIERS The distributions of the Pain Behaviour and Pain Autonomic scores were examined for outliers. Two infants whose scores were at the extreme ends of the distribution of the Pain Autonomic scores ( and ) were considered outliers and were excluded from data analyses. Data were analyzed separately with and without the outliers. Both sets of analyses gave results in the same direction: the results were exaggerated with the outliers included. Because this is a preliminary study, more conservative results are presented with outliers excluded. After excluding outliers, the Pain Behaviour scores ranged from 2.21 to (mean [SD 4.75]) and Pain Autonomic scores ranged from to (mean 4.16 [SD 9.75]). NEONATAL MEDICAL RISK AND OUTCOME Early illness severity (SNAP-II on day 1 and 3 since birth), GA at birth, birthweight, morphine exposure, Apgar scores, and number of prior invasive procedures, were not significantly correlated with the MAI risk score at 4 or 8 months CCA (see Table II). The only statistically significant correlation with MAI risk score was that higher number of days of postnatal dexamethasone was associated with higher MAI risk score (greater risk) at 4 months (r=0.41, p=0.035). None of the perinatal variables was significantly correlated with the 8-month MAI total risk score. Values for developmental measures at 4 and 8 months CCA are given in Table III. Three MAI category scores were significantly correlated with medical risk factors. Volitional movement was significantly correlated at 4 months with infant birthweight (r=0.40, p=0.04) and at 8 months with GA at delivery (r=0.39, p=0.05). SNAP-II on day 1 of life was also correlated with muscle tone at 8 months (r=0.39, p=0.05). PAIN REACTIVITY AT 32 WEEKS PCA AND OUTCOME Correlations between Pain Behaviour and Pain Autonomic at 32 weeks PCA and the outcome measures at both ages are presented in Tables IV and V. At 4 months, CCA Pain Behaviour was significantly correlated (r= 0.42, p=0.03) with volitional movement. At 8 months CCA Pain Behaviour was significantly correlated with the MAI risk score (r= 0.54, p=0.004), muscle tone (r= 0.47, p=0.016), and primitive reflexes (r= 0.64, p=0.001). Pain Autonomic was significantly correlated (r=0.52, p=0.007) with primitive reflexes. There was no significant correlation between either Pain Behaviour or Pain Autonomic and the 8-month BSID-II MDI or PDI. NEONATAL MEDICAL RISK, PAIN REACTIVITY, AND OUTCOME To examine whether pain reactivity (Pain Behaviour) predicted overall motor risk at 8 months CCA above and beyond Table II: Spearman s correlations for neonatal factors and Movement Assessment of Infants (MAI; Chandler et al. 1980) scores at 4 and 8 months CCA 4mo MAI categories 8mo MAI categories MAI risk Muscle Primitive Automatic Volitional MAI risk Muscle Primitive Automatic Volitional score tone reflexes reactions movement score tone reflexes reactions movement Gestational age at delivery a Birthweight, g a SNAP-II day a SNAP-II day Morphine exposure Dexamethasone, d 0.41 a Mechanical ventilation, d Invasive procedures, n Apgar 1min Apgar 5min a p<0.05. SNAP-II, Score for Neonatal Acute Physiology (Richardson et al. 2001). Early Pain Reactivity and Neuromotor Development Ruth E Grunau et al. 473

4 perinatal medical variables, hierarchical linear regression was carried out. Pain Behaviour was used for this analysis as it was more related to outcome than Pain Autonomic. Three perinatal medical risk variables (SNAP-II on day 1, days on mechanical ventilation, days of postnatal dexamethasone) were entered together in block 1, but were not significantly related to the 8-month total MAI risk score (F[3,22]=1.32, p=0.29). Pain Behaviour was added at block 2, resulting in a significant relationship with the MAI 8-month total risk score (F[4, 21]=3.605, p=0.02). Thus, Pain Behaviour significantly predicted motor outcome at 8 months CCA above and beyond perinatal risk factors. The perinatal risk factors accounted for only 15% of the variance (ns), and Pain Behaviour accounted for an additional 26% of the variance (p=0.02). Thus, 41% of the variance in the MAI motor risk status was accounted for by combining the perinatal and Pain Behaviour data. Table III: Developmental outcomes for participants Measure Mean Range MAI risk score 4mo CCA MAI risk score 8mo CCA BSID-II PDI 8mo BSID-II MDI 8mo MAI, Movement Assessment of Infants scale (Chandler et al. 1980); CCA, corrected chronological age; BSID-II, Bayley Scales of Infant Development, 2nd Edition (Bayley 1993); PDI, Psychomotor scale of BSID-II; MDI, Mental scale of BSID-II. PREDICTION OF BSID-II MDI AND PDI There was no statistically significant relationship between neonatal factors, Pain Behaviour, Pain Autonomic, and the 8-month BSID-II MDI and PDI. Discussion Healthy preterm infants with little prior pain exposure typically react to acute pain at 32 weeks PCA with a robust response characterized by facial grimacing, a shift towards greater arousal in behavioural state, and heightened autonomic activity (Grunau et al. 2001). Conversely, preterm infants born considerably earlier, and exposed to more procedural pain in the NICU, show dampened reactivity at 32 weeks PCA (Johnston and Stevens 1996, Grunau et al. 2001) and stress hormone response (Grunau et al. 2005). Early pain exposure at extremely low GA may alter infant regulatory capability (Grunau 2003), and pain reactivity may thereby reflect neurodevelopmental vulnerability. The major contribution of the present study was that among high-risk preterm infants ( 800g and/or 25 weeks GA) greater behavioural pain reactivity at 32 weeks PCA predicted better quality of neuromotor outcome at age 8 months CCA, over and above neonatal risk factors, such as GA and early illness severity, accounting for 41% of the variance. Therefore, the relationship between pain reactivity and neuromotor outcome at 8 months CCA appears to be of significance. There were few statistically significant correlations when individual neonatal factors were compared with MAI category scores. A higher risk score on the volitional movement category at 4 months CCA was positively correlated with higher infant birthweight, and at 8 months CCA with higher GA, consistent with previous work predicting abnormal outcome (Swanson et al. 1992). Table IV: Spearman s correlations for Pain Behaviour, Pain Autonomic, and Movement Assessment of Infants (MAI; Chandler et al. 1980) category scores at 4 months corrected chronological age MAI categories Muscle tone Primitive reflexes Automatic reactions Volitional movement BSID-II MDI BSID-II PDI Pain Behaviour a N/A N/A Pain Autonomic N/A N/A Higher Pain Behaviour indicates greater pain reactivity. Lower Pain Autonomic indicates greater pain reactivity. Higher score on MAI indicates higher developmental risk. Lower score on BSID-II indicates higher developmental risk. a p<0.05. BSID-II, Bayley Scales of Infant Development, 2nd Edition (Bayley 1993); PDI, Psychomotor scale of BSID-II; MDI, Mental scale of BSID-II; N/A, non-applicable. Table V: Spearman s correlations for Pain Behaviour, Pain Autonomic, and Movement Assessment of Infants (MAI; Chandler et al. 1980) category scores and BSID-II scores at 8 months corrected chronological age MAI categories Muscle tone Primitive reflexes Automatic reactions Volitional movement BSID-II MDI BSID-II PDI Pain Behaviour 0.47 a 0.63 b Pain Autonomic b Higher Pain Behaviour indicates greater pain reactivity. Lower Pain Autonomic indicates greater pain reactivity. Higher score on MAI indicates higher developmental risk. Lower score on BSID-II indicates higher developmental risk. a p<0.05; b p<0.01. BSID-II, Bayley Scales of Infant Development, 2nd Edition (Bayley 1993); PDI, Psychomotor scale of the BSID-II; MDI, Mental scale of the BSID-II. 474 Developmental Medicine & Child Neurology 2006, 48:

5 The association between greater behavioural pain reactivity and better motor outcome increased over time: it was not significant at 4 months CCA but was significant at 8 months. This finding is expected, as the 8-month MAI is a more sensitive predictor of later outcome than the 4-month MAI, and results in fewer false positives (Swanson et al. 1992). Improved sensitivity at 8 months is likely to reflect wider motor repertoire of older infants (Swanson et al. 1992). Pain reactivity predicted the MAI, but not the BSID-II PDI or MDI. A likely explanation is that the MAI measures quality of motor movement, as well as milestone achievement, whereas the BSID-II scales measure only milestone achievement. Autonomic response can provide information about infant physiological regulation in response to internal and environmental demands for infants born >1000g, however, not for extremely low birthweight infants 1000g (Porges 1992). Thus, the findings in these high-risk infants born 800g or 25 weeks GA are consistent with previous studies. Furthermore, results in the present study are consistent with emerging evidence suggesting that acute pain responses are reduced in children with developmental delay (Gilbert-MacLeod et al. 2000), and in adolescents with cerebral palsy (CP; Oberlander et al. 1999). However, lower pain response was not found in a very small sample of infants with documented parenchymal brain injury in the newborn period, many of whom had CP at follow-up (Oberlander et al. 2002). Early identification of those at developmental risk is a major goal in the follow-up of high-risk infants. However, outcomes of individual infants are diverse even in the smallest survivors. Most preterm infants escape major sensory, motor, or multiple impairments but are at high risk of long-term cognitive, academic, and behavioural problems, especially the smallest and least mature survivors compared with term-born socially comparable peers (Whitfield et al. 1997, Hack and Fanaroff 1999). Earliest possible identification of those infants at greater risk would provide the opportunity of early intervention and effective use of available resources. The results of this study indicate a new direction in early identification of risk, namely, that early pain behaviour may reflect neuromotor outcome in infancy. A limitation of the current study was the small sample size. This was an exploratory study to evaluate the possible relationship between capacity to respond to pain and later neurodevelopment. Conclusion Behavioural reactivity to pain at 32 weeks PCA appears to be a marker of quality of motor development at 8 months CCA. Dampened pain response in an infant in a NICU may indicate a higher risk of subsequent problems with neuromotor development. Further studies are needed to determine the specific characteristics of biobehavioural systems that provide the best clues to later developmental outcome. In future studies, multiple assessments of pain reactivity, rather than a single event, should be evaluated. While causal relations between early pain exposure and later motor difficulties are not directly suggested in this study, alteration of the capacity to self-regulate is a unifying construct for considering the early sequelae of pain exposure. DOI: /S Accepted for publication 18th August Acknowledgements The authors gratefully acknowledge the contributions of the parents and infants who participated, Colleen Fitzgerald who coordinated the neonatal phase of this project, and the staff of the Neonatal Follow-up Programme at the Children s and Women s Health Centre of British Columbia. We appreciate the advice of Dr Mike Papsdorf who advised us on the statistical analyses. This study was funded by operating Grant from the British Columbia Medical Services Foundation to the first author. Ruth E Grunau was supported by a Senior Scholar Award from the Michael Smith Foundation for Health Research, and Liisa Holsti was supported by a Canadian Institutes of Health Research/Canadian Occupational Therapy Foundation Post-Doctoral Fellowship. References Als H. (1995) The preterm infant: a model for the study of fetal brain expectation. In: Lecanuet JP, Fifer WP, Krasnegor NA, Smotherman WP, editors. Fetal Development: a Psychobiological Perspective. Hillsdale, NJ: Lawrence Erlbaum Associates. p Amiel-Tison C. (2002) Update of the Amiel-Tison neurologic assessment for the term neonate or at 40 weeks corrected age. Pediatr Neurol 27: Bayley N. (1993) Manual for the Bayley Scales of Infant Development. 2nd edn. San Antonio, TX: The Psychological Corporation. Campbell SK, Kolobe TH, Wright BD, Linacre JM. (2002) Validity of the Test of Infant Motor Performance for prediction of 6-, 9- and 12-month scores on the Alberta Infant Motor Scale. Dev Med Child Neurol 44: Chandler L, Andrews M, Swanson M, Larson A. (1980) Movement Assessment of Infants (MAI). Rolling Bay, WA: Infant Movement Research. Cioni G, Prechtl HF, Ferrari F, Paolicelli PB, Einspieler C, Roversi MF. (1997) Which better predicts later outcome in full-term infants: quality of general movements or neurological examination? Early Hum Dev 50: Doussard-Roosevelt JA, Porges SW, Scanlon JW, Alemi B, Scanlon KB. (1997) Vagal regulation of heart rate in the prediction of developmental outcome for very low birth weight preterm infants. Child Dev 68: Dubowitz LM, Levene MI, Morante A, Palmer P, Dubowitz V. (1981) Neurologic signs in neonatal intraventricular hemorrhage: a correlation with real-time ultrasound. J Pediatr 99: Gilbert-MacLeod CA, Craig KD, Rocha EM. (2000) Everyday pain responses in children with and without developmental delays. J Pediatr Psychol 25: Grunau R. (2002) Early pain in preterm infants. A model of longterm effects. Clin Perinatol 29: Grunau RE. (2003) Self-regulation and behavior in preterm children: Effects of early pain. In: McGrath PJ, Finley GA, editors. Pediatric Pain: Biological and Social Context, Progress in Pain Research and Management. Seattle: IASP Press. Grunau RE, Holsti L, Haley DW, Oberlander TF, Weinberg J, Solimano A, Whitfield MF, Fitzgerald C, Yu W. (2005) Neonatal procedural pain exposure predicts lower cortisol and behavioural reactivity in preterm infants in the NICU. Pain 113: Grunau RE, Oberlander T, Holsti L, Whitfield MF. (1998) Bedside application of the Neonatal Facial Coding System in pain assessment of premature neonates. Pain 76: Grunau RE, Oberlander TF, Whitfield MF, Fitzgerald C, Lee SK. (2001) Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 weeks postconceptional age. Pediatrics 107: Hack M, Fanaroff AA. (1999) Outcomes of children of extremely low birthweight and gestational age in the 1990s. Early Hum Dev 53: Hadders-Algra M, Groothuis AM. (1999) Quality of general movements in infancy is related to neurological dysfunction, ADHD, and aggressive behaviour. Dev Med Child Neurol 41: Harris SR, Haley SM, Tada WL, Swanson MW. (1984) Reliability of observational measures of the Movement Assessment of Infants. Phys Ther 64: Early Pain Reactivity and Neuromotor Development Ruth E Grunau et al. 475

6 Johnston CC, Stevens BJ. (1996) Experience in a neonatal intensive care unit affects pain response. Pediatrics 98: Mayes LC. (2000) A developmental perspective on the regulation of arousal states. Semin Perinatol 24: Oberlander TF, Gilbert CA, Chalmers CT, O Donnell ME, Craig KD. (1999) Biobehavioral responses to acute pain in adolescents with a significant neurologic impairment. Clin J Pain 15: Oberlander TF, Grunau RE, Fitzgerald C, Whitfield MF. (2002) Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks post conceptional age? Pediatrics 110: Posner MI. (2002) Convergence of psychological and biological development. Dev Psychobiol 40: Porges SW. (1992) Vagal tone: a physiologic marker of stress vulnerability. Pediatrics 90 (3 Pt 2): Prechtl HF. (2001) General movement assessment as a method of developmental neurology: new paradigms and their consequences. The 1999 Ronnie Mac Keith Lecture. Dev Med Child Neurol 43: Richardson DK, Corcoran JD, Escobar GJ, Lee SK. (2001) SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores. J Pediatr 138: Swanson M, Bennett F, Shy K, Whitfield M. (1992) Identification of neurodevelopmental abnormality at four and eight months by the movement assessment of infants. Dev Med Child Neurol 34: Whitfield MF, Grunau RV, Holsti L. (1997) Extremely premature (<801g) schoolchildren: multiple areas of hidden disability. Arch Dis Child Fetal Neonatal Ed 77: F85 F90. List of abbreviations BSID-II CCA MAI MDI NFCS NICU PCA PDI SNAP-II Bayley Scales of Infant Development Corrected chronological age Movement Assessment of Infants scale Mental scale of the BSID-II Neonatal Facial Coding System Neonatal intensive care unit Postconceptional age Psychomotor scale of the BSID-II Score of Neonatal Acute Physiology This is Mac Keith Press s new website and we invite you to visit us there. It is not a product site and though there are fast links from it to our part of the Cambridge University Press site, the centre for information about DMCN, our book publishing, and how to subscribe to or buy what we produce remains at CUP. ( The aim of our new site is to be a centre for the exchange of views, information, and news about developmental medicine and paediatric neurology. Here are some of the contents: Mac Keith Meetings: this section gives details of forthcoming meetings in this highly-regarded programme and will enable you to book early for the Meetings in your field. Meetings: this is a noticeboard for anyone to use to advertise appropriate meetings. There is no charge for this just send the details of what you would like to advertise to [email protected] Links: another free notice board if you would like your organization to be included, please tell us at the same address. Forum: the aim of this key part of the site is to enable exchanges of view about a wide range of topics. At the moment there is very little in this section and its success will depend on input from our readers and the site s users. We will invite comment on, for example, proposed consensus statements like the new CP definition document or postural management for children with cerebral palsy; terminology mental retardation vs learning disability ; live new areas of research such as the role of the placenta in disability; comment on individual issues of DMCN; and other topics as they arise. There will be a simple online tool for sending comments in to us. Our plan for our new site is that it should be a practical and useful resource for everyone working in our area. We do hope you will visit it, use it, and let us know what else you think it should have in it. Comments and suggestions to: [email protected] 476 Developmental Medicine & Child Neurology 2006, 48: