Background
Project overview
Aims
Methods
Design
Study population
Inclusion/exclusion criteria for preterm infants
Inclusion/exclusion criteria for term-born infants
Recruitment
Perinatal data collection
Child assessments
Serial neurobehavioural assessments up to term (preterm infants only)
Assessment | Purpose |
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NNNS [38] | The Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) assesses the neurological integrity, behavioural functioning, and responses to stress in high-risk infants using 45 items compared with norms for healthy term infants (n = 125). The NNNS provides an in-depth assessment of neurobehaviour and gives summary scores/subscales for attention, handling, quality of movement, regulation, nonoptimal reflexes, arousal, hypertonicity, hypotonicity, asymmetrical reflexes, excitability and lethargy. |
HNNE [39] | The Hammersmith Neonatal Neurologic Examination (HNNE) consists of 34 individual items with 6 subtotals including tone, tone patterns, reflexes, spontaneous movements, abnormal neurological signs and behaviour in newborns. It provides an overall “optimality score” which has been validated in healthy term (n = 224) and preterm (n = 380) infants. This assessment tool is used frequently in clinical practice and requires no formal training. |
GMs [40] | Prechtl’s General Movements (GMs) assessment is a non-invasive method for assessing global neurological development, particularly motor development. Video recordings are made of spontaneous whole body movements and assessed at a later time by independent assessors. GMs during the neonatal period have been shown to be predictive of cerebral palsy from birth in the preterm infant. This assessment has the advantage of obtaining an overall picture of neurological integrity without needing to handle the infant. |
Premie-Neuro [41] | The Premie-neuro is a brief neurological examination for preterm infants aged 23–37 weeks’ gestation. Consists of 24 items divided into neurological, movement and responsiveness subgroups. Validity has been shown in a small study (n = 34), however the inter-rater reliability was low. |
Assessment at term equivalent age (both preterm and term infants)
Serial neurobehavioural assessments
Magnetic resonance
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T2-weighted images: Transverse Restore turbo spin echo imaging: Flip angle = 120, Repetition Time = 8910 ms, Echo Time = 152 ms, Field Of View = 192 × 192 mm, Matrix = 192 × 192, 1 mm [3] isotropic voxels.
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T1-weighted images: Transverse multi-planar reconstruction imaging with noise suppression: Flip angle = 9°, Repetition Time = 2100 ms, Echo Time = 3.39 ms, Field Of View = 192 × 192 mm, Matrix = 192 × 192, 1.0 mm [3] isotropic voxels.
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Diffusion weighted imaging: Transverse echo planar imaging: Repetition Time = 20400 ms, Echo Time =120 ms, Field Of View =173 × 173 mm, Matrix = 144 × 144, 1.2 mm [3] isotropic voxels, 45 gradient directions (range b = 100 to b = 1200s/mm [2]), 3 b = 0 s/mm [2].
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Resting state functional connectivity MRI: Transverse 2D echo planar imaging with prospective acquisition correction: Repetition Time = 2910 ms, Echo Time = 28 ms, flip angle = 90°, Field Of View = 151 × 151 mm, Matrix = 64 × 64, 2.4 mm [3] isotropic voxels.
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Proton magnetic resonance spectroscopy: Transverse spin echo chemical shift imaging: Repetition Time = 2000, Echo Time = 135, flip angle = 90°, scan resolution = 12 × 12, interpolated 16 × 16, field of view = 103 × 125 mm, voxel size = 10.4 × 8.6 × 15.0 mm.
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Structural T1-weighted and T2-weighted MR image analyses: Grey and white matter and cerebrospinal fluid will be initially segmented using SPM8 software (http://www.fil.ion.ucl.ac.uk/spm/software/spm8) with tissue priors from a 40-week neonatal template [43], and then fed into a modified version of a previously published morphology-driven automatic segmentation pipeline [44] to obtain volumes of white matter, cortical grey matter, cerebrospinal fluid, deep nuclear gray matter, brainstem, hippocampus, amygdala and cerebellum [19]. These assessments will enable an assessment of size and morphological alterations to global and regional areas of the brain.
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Diffusion imaging and tractography: Vulnerable white matter fibre bundles of the visual, motor, language and attention pathways will be isolated by tractography. Diffusion tractography enables the characterisation of particular fibre tract populations which can then be related to early neurobehavioural functions. Tract-specific diffusion measures of fractional anisotropy, mean diffusivity, axial and radial diffusivity will be calculated. Diffusion measures provide insight into white matter tissue integrity reflecting microstructural organisation, water content, number and density of axons, and myelination, and are useful for gauging white matter maturity [45, 46]. Structural connectivity will also be performed, where white matter fibre networks will be analyzed using graph theory metrics [47].
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Resting state functional MRI: Resting state functional connectivity (fcMRI) will be assessed by detecting temporal correlations in spontaneous blood oxygen level dependent (BOLD) signal oscillations while subjects rest quietly in the scanner. Distinct resting-state networks related to vision, language, executive processing and other sensory and cognitive domains will be identified. This will allow relationships between specific neurodevelopmental impairments and functional brain networks to be determined [48].
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Proton magnetic resonance spectroscopy: Brain metabolites in specific brain regions will be measured using proton MR spectroscopy. Measurements will be made for (a) N-acetyl aspartate, which is reduced as a result of destruction of neurons or decreased neuronal integrity (b) Lactate, which is elevated in regions where cell and tissue necrosis have occurred (c) Choline which reflects cellularity and is elevated in response to demyelination and gliosis (d) Glutamine and glutamate, markers for neuronal damage, and (e) myo-inositol, a marker for myelin breakdown. Levels of these markers, in regions of interest from the frontal and occipital white matter will be important to elucidate the association between neurobiological abnormalities as a result of hypoxic ischaemic events or infection/inflammation and adverse early neurobehavioural characteristics.
Outcomes at one and two years’ corrected age (both preterm and term infants)
Developmental assessment
Assessment | Purpose |
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AIMS [49] | The Alberta Infant Motor Scale (AIMS) is an observational norm-referenced assessment that measures infant motor development between 0 to 18 months of age. There are 58 items across the four positional subscales of prone, supine, sit and stand. The infants least and most mature item in each subscale is identified and marked as observed, then a window is created to assess the items in between as either observed or not observed. Subscale scores are added to obtain a total score. This assessment has been used extensively in follow-up of preterm infants and has excellent psychometric properties [53]. |
NSMDA [50] | The Neuro-Sensory Motor Developmental Assessment (NSMDA) is a criterion-referenced assessment tool constructed to measure neurodevelopment between 1 month and 6 years of age. The five domains of neurological, postural, sensory, fine, and gross motor are summed to create a total NSMDA score. A functional grade is also given for each domain and totalled to provide a total functional grade of normal, minimal deviation, mild deviation, moderate deviation, severe deviation or profound deviation. The NSDMA has good predictive validity for long term motor development [54]. |
TINE [51] | The Touwen Infant Neurological Examination (TINE) is a neurological examination designed for use with infants post term age. There are five clusters of dysfunction assessed – reaching and grasping, gross motor development, brainstem, visuomotor and sensorimotor. The number of criteria fulfilled is recorded for each cluster with an overall dysfunctional cluster rating of yes or no determined. The number of dysfunctional clusters are then added together to determine a neurological classification of neurologically normal, normal sub-optimal, MND (minor neurological dysfunction) or abnormal. The TINE has been shown to predict both minor and major neurological dysfunction in at risk populations including preterm infants [55]. |
SOMA [52] | The Schedule for Oral Motor Assessment (SOMA) is a standardised and psychometrically robust measure of oral-motor skills for eating and drinking for infants aged 8 months to 2 years. It was designed primarily to assess a wide range of oral-motor skills in infants with a grossly intact neurological system. |
Bayley-III [56] | The Bayley Scales of Infant and Toddler Development 3
rd
edition (Bayley-III) is a norm referenced developmental scale of cognitive, language and motor development that has good psychometric properties when used with a local control group, and has been used extensively in the follow-up of preterm infants [53, 57]. |
Parent–child relationship assessment
Birth | Up to 32wk* | 32wk to term** | Term | 12mth (CA) | 24mth (CA) | |
---|---|---|---|---|---|---|
Neurobehavioural assessment | √ | √ | √ | √√ | ||
Perinatal data | √√ | |||||
MRI | √√ | |||||
Motor assessment – AIMS and NSMDA | √√ | |||||
Clinical feeding assessment - SOMA | √√ | |||||
Developmental assessment – Bayley III | √√ | |||||
Parent–child relationship assessment- EAS | √√ | √√ | ||||
Neurological and Paediatric assessment | √√ |
Parental assessment
Assessment | Purpose |
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CES-D | The Centre for Epidemiological Studies Depression Scale (CES-D)[62] will be used to measure depressive symptoms. The questionnaire consists of 20 questions (total score range 0 to 60) with higher scores representing greater depressive symptoms. A score ≥16 on the CES-D represents significant depressive symptoms. This threshold has been shown to correlate well with clinician ratings of depression [63]. The CES-D has been used extensively in general populations and has been used with parents of preterm infants [64, 65]. |
HADS | The Hospital Anxiety and Depression Scale (HADS)[66] will be used to assess anxiety. The HADS assesses symptoms of anxiety and depression using 7 items for each scale that are scored with a 4-point rating scale (total score range 0 to 21). Scores above 11 are considered to indicate significant symptoms of depression or anxiety. The HADS has been validated in a variety of settings and has been found to perform well in assessing the severity of anxiety disorders and depression, not only in primary care patients and the general population [67] but also in parents of preterm infants [68]. |
PCL-S | The Posttraumatic Stress Disorder Checklist Specific Version[69] (PCL-S) will be used to assess symptoms of posttraumatic stress disorder (PTSD). The PCL-S consists of 17 items (total score range 17 to 85). The questions are asked in relation to a nominated specific traumatic event, in this case, the birth of their very preterm infant. There is evidence for good test-retest reliability, internal consistency and convergent validity [70]. Only parents of preterm infants will complete the PCL-S. |
IPIP-NEO | Neuroticism, or negative affectivity, will be measured with the 10-item Neuroticism scale of the International Personality Item Pool Five Factor Personality Inventory (IPIP-NEO) [71]. The Neuroticism scale selected for the present study is from a 50-item self-report version of the NEO PI-R, named the IPIP-NEO [72]. Responses on the Neuroticism scale are scored on a 5-point scale. |
PSOC | The Parenting Sense of Competence Scale (PSOC) assesses parental satisfaction and efficacy in the parenting role, with higher scores representing higher satisfaction and efficacy in parenting. It is a 16 self-report measure with each item rated by parents on a 6-point rating scale. The PSOC has been widely used and there is good evidence for the validity of the measure [73]. |
CISS | The Coping Inventory of Stressful Situations (CISS) is a 48-item inventory which will be used to measure three major types of coping styles in an individual, including Task-Oriented (problem-solving), Emotion-Oriented (focuses on consequent emotions, becoming angry/upset), and Avoidance Coping (distraction and social diversion) [74]. Parents will be asked to rate each item on a 5-point scale ranging from (1) “not at all” to (5) “very much”. |
PSI-LSS | The Life Stress Scale from the Parenting Stress Index (PSI-LSS)[75] assesses how many of 19 significant life events have occurred for parents within the last 12 months such as divorce, went deeply into debt, entered new school. |
Demographic & family questionnaire | Items include relationship to child, whether the parent is the primary caregiver, number of other children in the home, cultural background. |
Parent mental health history questionnaire | Five items will assess parental cigarette, alcohol and recreational drug use, and mental health service access history. |
Parenting practices questionnaire | The Parenting Practices Questionnaire is a 16-item measure that assesses parental warmth, hostility and involvement with their child (Longitudinal Study of Australian Children, LSAC). |
ITSEA | The Infant Toddler Social and Emotional Assessment[76] (ITSEA) is a 135 item parental report measure of social–emotional problems and competencies in 1 to 3 year olds. It assesses 4 broad domains of behaviour: dysregulation, externalizing, internalizing and competencies. Mean scores below the 10th percentile for competence, or above the 90th percentile for externalising, internalising and dysregulation suggest the infant may be at risk for psychopathology. The ITSEA has good internal consistency, validity, and test-retest reliability, and has been used extensively, including with very preterm populations. |
MacArthur CDI | The MacArthur-Bates Communicative Development Inventories (CDI)[77] are standardised parent report forms for assessing early language (semantic and grammatical) development in 16 to 30 month old children. The CDI: Words and Sentences (Toddler form) will be completed by the primary care-giver. |
FAD | The Family Assessment Device (FAD)[78] requires the primary caregiver to indicate whether they “strongly agree”, “agree”, “disagree”, or “strongly disagree” with 60 statements about family functioning. The inventory yields 7 scales: problem solving, communication, roles, affective responsiveness, affective involvement, behaviour control and general functioning. Higher scores indicate poorer family functioning. |
ITSP | The Infant/Toddler Sensory Profile Questionnaire (ITSP) [79] consists of 48 questions, addressing 6 sensory processing sections, including: Auditory, Visual, Tactile, Vestibular, and Oral Sensory Processing, as well as a General measure. Questions within each sensory processing section yield information about how the child responds to stimuli in each sensory system. Its purpose is to evaluate the possible contributions of sensory processing to the child’s daily performance patterns, to provide information about his or her tendencies to respond to stimuli and to identify which sensory systems are likely to be contributing to or creating barriers to functional performance. The ITSP has excellent content validity and adequate to excellent reliability [80]. |
CSBS-DP | The Infant-Toddler checklist from the Communication and Symbolic Behavior Scales Developmental Profile (CSBS-DP) [81] is a 24 item screening tool designed to measure 7 predictors of language including emotion and eye gaze, communication, gestures, sounds, words, understanding and object use in children aged between 6 and 24 months of age. |
Social Risk Index | A Social Risk Index (family demographic questionnaire) [37] score will be calculated based on a combination of family structure, education of primary caregiver, employment of primary income earner, language spoken at home and maternal age at the birth of the child. Higher scores indicate higher social risk. |
Birth | F/night* | Term | 3mth (CA) | 6mth (CA) | 12mth (CA) | 18mth (CA) | 24mth (CA) | |
---|---|---|---|---|---|---|---|---|
CES-D | √ | √ | √√ | √√ | √√ | √√ | √√ | √√ |
HADS | √ | √ | √√ | √√ | √√ | √√ | √√ | √√ |
PCL-S | √ | √ | √ | |||||
IPIP-NEO | √ | |||||||
PSOC | √√ | √√ | √√ | |||||
PSI-LSS | √√ | √√ | √√ | |||||
CISS | √√ | √√ | ||||||
Demographic & family questionnaire | √√ | |||||||
Parent mental health history questionnaire | √√ | √√ | √√ | |||||
Parenting practices | √√ | √√ | √√ | |||||
ITSEA | √√ | √√ | ||||||
MacArthur CDI | √√ | |||||||
FAD | √√ | |||||||
ITSP | √√ | |||||||
CSBS-DP | √√ | |||||||
Social Risk Index | √√ | √√ | √√ |