BMJ Open...Baer, Erica ; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital Primary Subject Heading: Paediatrics Secondary

For peer review only

A study protocol: Early prediction of typical outcome and mild developmental delay for prioritisation of service

delivery for very preterm and very low birth weight infants.

Journal: BMJ Open

Manuscript ID bmjopen-2015-010726

Article Type: Protocol

Date Submitted by the Author: 21-Jan-2016

Complete List of Authors: Caesar, Rebecca; School of Medicine, Faculty of Medicine and Biomedical Science, University of Queensland, Queensland Cerebral Palsy and Rehabilitation Research Centre,; Sunshine Coast Hospital and Health

Service, Allied Health Womens and Families, Nambour General Hospital Boyd, Roslyn; School of Medicine, Faculty of Medicine and Biomedical Science, University of Queensland, Queensland Cerebral Palsy and Rehabilitation Research Centre, Colditz, Paul; University of Queensland, The University of Queensland Centre for Clinical Research (UQCCR), Faculty of Health Sciences, Royal Brisbane and Womens Hospital; Royal Brisbane and Womens Hospital Cioni, Giovani; Stella Maris Scientific Institute, Department of Developmental Neuroscience Ware, Robert; University of Queensland, School of Population Health Salthouse, Kaye; Sunshine Coast Hospital and Health Service, Allied Health Womens and Families, Nambour General Hospital

Doherty, Julie ; Sunshine Coast Hospital and Health Service, Allied Health Womens and Families, Nambour General Hospital Jackson, Maxine ; Sunshine Coast Hospital and Health Service, Allied Health Womens and Families, Nambour General Hospital Matthews, Leanne; Sunshine Coast Hospital and Health Service, Allied Health Womens and Families, Nambour General Hospital Hurley, Tom; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital Morosini, Anthony; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital Thomas, Clare; Sunshine Coast Hospital and Health Service, Department of

Paediatrics, Nambour General Hospital Camadoo, Laxmi ; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital Baer, Erica ; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital

<b>Primary Subject Heading</b>:

Paediatrics

Secondary Subject Heading: Neurology

Keywords: Developmental neurology & neurodisability < PAEDIATRICS, NEONATOLOGY, Paediatric neurology < PAEDIATRICS

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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STUDY PROTOCOL

Title: A Study Protocol: Early prediction of typical outcome and mild developmental delay

for prioritisation of service delivery for very preterm and very low birth weight infants.

Acronym: PREMTiME (Prediction of Mild Developmental Delay and Typical Outcome) in

at risk preterm infants

Authors

Chief Investigators:

1. Mrs Rebecca Caesar, PhD scholar (Med Sci), MPhty (Paediatrics), BAppSci Phty1,5

2. Professor Roslyn Boyd (Corresponding Author), PhD, MSc (Physio), Pgrad Dip

(Biomech), BAppSci (PT), BSc (Anatomy), NHMRC Early Career Development

Fellow, Scientific Director1

Faculty of Health and Biomedical Sciences

The University of Queensland

Level 6, Oral Health Centre (Building 883)

Herston Rd, Herston

QLD, 4006, Australia

[email protected]

Telephone: (07) 3069 7372

Fax: (07) 3365 5533

3. Professor Paul Colditz, MBBS, FRACP (Royal Australian College of Physicians),

BBiomedE, DPhil, FRCPCH (Royal College of Paediatrics and Child Health)2,3

4. Professor Giovani Cioni, MD4

5. Dr. Robert S. Ware, PhD, BSci (Hons)1,6

Associate Investigators:

6. Mrs Kaye Salthouse, BPhty5

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7. Mrs Julie Doherty, BPhty5

8. Mrs Maxine Jackson, BOccThy5

9. Ms Leanne Matthews, BHSci (OT)5

10. Dr Tom Hurley, MBBS, FRACP (Royal Australian College of Physicians)7

11. Dr Anthony Morosini, MBBS, FRACP (Royal Australian College of Physicians)7

12. Dr Clare Thomas, MBBS, FRACP (Royal Australian College of Physicians)7

13. Dr Laxmi Camadoo, BSc (Hons), MBBS, DCH, MRCPCH, FRACP7

14. Dr Erica Baer, MBBS, FRACP (Royal Australian College of Physicians)7

Collaborators:

The PREMTiME Study Group:

1. Mrs Louise Tambling, BSc Hons Phty5

2. Mrs Susanne Cuddihy, BA, Grad Dip Psych, Grad Dip SpEduc, MAppPsych 8

3. Ms Kellee Gee, BScPsych, Post Grad Dip Psych 8

4. Mrs Julie Creen, BOccThy 5

5. Dr Heidi Webster, MBBS, FRACP (Royal College of Physicians) 8

Affiliations:

1School of Medicine, Faculty of Medicine and Biomedical Science, The University of

Queensland, Queensland Cerebral Palsy and Rehabilitation Research Centre (QCPRRC),

South Brisbane, QLD, Australia.

2 The University of Queensland, The University of Queensland Centre for Clinical Research,

Faculty of Health Sciences, Royal Brisbane and Women’s Hospital, Brisbane, QLD,

Australia

3Royal Brisbane and Women’s Hospital, Herston, QLD, Australia.

4Stella Maris Scientific Institute, Department of Developmental Neuroscience, Pisa, Italy.

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5 Sunshine Coast Hospital and Health Service, Allied Health Women’s and Families,

Nambour General Hospital, Nambour, QLD, Australia

6University of Queensland, School of Population Health, Herston, QLD, Australia

7 Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General

Hospital, Nambour, QLD, Australia

8Sunshine Coast Hospital and Health Service, Child Development Service, Maroochydore,

QLD, Australia

Email addresses:

RC: [email protected]

RB: [email protected]

PC [email protected]

GC: [email protected]

RW: [email protected]

KS: [email protected]

JD: [email protected]

MJ: [email protected]

LM: [email protected]

TH: [email protected]

AM: [email protected]

CT: [email protected]

LC: [email protected]

EB: [email protected]

LT: [email protected]

SC: [email protected]

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KG: [email protected]

JC: [email protected]

HW: [email protected]

Journal: BMJ Open

Key words: Very Preterm, Very Low Birth Weight, Typical Development, Mild

Developmental Delay, Clinical Biomarkers, General Movements

Ethics: Ethical permission to conduct the study has been obtained from the Queensland

Children’s Health Services (RCH) Human Research Ethics Committee

(HREC/13/QRCH/66), the University of Queensland (2013001019) and the Sunshine Coast

Hospital and Health Service, SC-Research Governance (SSA/13/QNB/66)

Dissemination: Publications of all outcomes will be published in peer reviewed journals.

Trial Registration: ACTRN12614000480684

Web address of trial: http://www.ANZCTR.org.au/ACTRN12614000480684.aspx

ABSTRACT

Introduction: Over 80% of very preterm (<32 weeks) and very low birth weight (<1500g)

infants will have either typical development (TD) or mild developmental delay (MDD) in

multiple domains. As differentiation between TD and MDD can be difficult, infants with

MDD often miss opportunities for intervention. For many clinicians the ongoing challenge is

early detection of MDD without over servicing the population. This study aims to: 1) Identify

early clinical biomarkers for use in this population to predict and differentiate between TD

and MDD at 24 months corrected age. 2) Determine the extent to which family and caregiver

factors will contribute to neurodevelopmental and behavioural outcomes.

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Methods and Analysis: Participants will be a prospective cohort of 90 infants (<32 weeks

and/or <1500g). Between 34 weeks gestational age and 16 weeks post term, infants will have

a series of five neurological, neuromotor, neurobehavioural and perceptual assessments

including General Movement assessment at preterm, writhing and fidgety age. Primary

caregivers will complete questionnaires to identify social risk, maternal depression and

family strain. Extensive perinatal data will be collected from the medical record. At 24

months corrected age (c.a) infants will be assessed using standardised tools including the

Bayley Scales of Infant and Toddler Development – Third Edition (Bayley III). Longitudinal

trajectories of early assessment findings will be examined to determine any predictive

relationship with motor and cognitive outcomes at 24 months c.a. Published data of a cohort

of Australian children assessed with the Bayley III at 24 months c.a will provide a reference

group of term born controls.

Discussion: As families, clinicians and health services continue to want and need more

immediate information regarding the short and long term outcomes of at risk infants, finding

the best clinical biomarkers has the potential to streamline and effectively prioritise

premature infant follow up programs.

Abstract word count: 299

Number of Tables: 3

Number of Figures: 1

Supplementary Appendices: 1

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INTRODUCTION

The absolute number of children born very preterm and very low birth weight (VLBW) is

increasing in developed countries as neonatal intensive care continues to improve.[1,2] As

survival rates increase, the focus moves to consideration of quality of life.[1-8] The incidence

of severe outcomes in the very preterm/VLBW population is beginning to decline but the

overall risk of developmental delay across multiple domains remains steady at 47 %.[2,5,9

10] With rates of typical outcome at approximately 52%, clinical practitioners are now

challenged by the need to differentiate between infants with mild delay and TD.[1,2,5,11]

Given the current pressure on public health resources, population intervention is no longer

practical nor cost efficient. Robust early prediction and diffentiation is warranted to prevent

over servicing of very preterm/VLBW infants who are typically developing and facilitate

targeted interventions for infants in the population with higher risk for developmental delay.

In Australia, very preterm children with mild deficits are less likely to receive services than

children with more severe outcomes.[12] Lack of service engagement is even more evident

for very preterm children living in situations of higher social or environmental risk.[12] This

is cause for concern as early delays do not dissipate, rather they become more apparent with

age alongside increasing functional demands in educational and social contexts.[4,6,7,13-16]

Late referral often means that infants completely miss out on vital input during critical

periods of development when enriched experiences provided by parents and therapists may

optimise neuroplasticity.[17,18]

Mild impairment in very low birth weight and very preterm infants

Children born very preterm have an increased risk of mild motor delay (MMD) not associated

with cerebral palsy.[19] Prevalence of MMD in children born preterm is three to four times

greater than in term born infants.[8,19] At 8-12 months c.a nearly half of very preterm

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infants (47%) have mildly delayed scores on the Gross Motor Subscale of the Bayley III. (< 1

Standard Deviation (SD)).[20] At 2.5 years c.a, 29 % of children score 1SD below the

control mean on the gross motor and 34 % on the fine motor scale of the Bayley III.[21]

Studies at school age show similar outcomes with one study reporting 32 % and another 50 %

of very preterm born children scoring ≤ 15th

centile on the Movement Assessment Battery for

Children (MABC) at 5 years c.a.[7]

Consistent findings of mild delay in the preterm population from birth to 5 years suggest that

motor delays do not improve with time. Instead, early delays progress to motor impairments

at school entry that then persist into adolescence.[4,22] Developmental co-ordination

disorder is highly prevalent in the VLBW/very preterm population with children 6 times

more likely to score at or below the 5th

centile on the MABC, and 8 times more likely to

score below the 15th

centile.[14] A meta-analysis of 41 articles encompassing 9653 very

preterm/VLBW from infancy to 15 years found that these children are, on average, −0.57 to

−0.88 SD behind their term-born peers or typically developing children in motor

development.[4]

Mild motor impairment is rarely experienced in isolation. Children who are born very

preterm or VLBW are more likely than term born infants to perform below average in two or

more developmental domains.[5-7,20,21] Comorbidities that frequently accompany MMD

include mild deficits and delay in the cognitive, communication, behavioural, personal-social

and perceptual domains including sensory processing differences.[1, 5-7, 9-11, 20-24] In

very preterm infants where motor delay is identified at 5 years of age, there is a substantially

higher rate of impairment in other domains compared to very preterm infants who do not

have motor impairment.[7] Deficits associated with MMD at this age include lower IQ,

decreased processing speed, poor visuomotor co-ordination and increased incidence of

complex minor neurological dysfunction.[7]

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Biological rationale for multi domain neurodevelopmental deficits

Preterm birth is timed against a background of significant maturational processes. Between

24 and 40 weeks gestation, multiple developmental events are taking place that include the

pre-oligodendrocytes, microglia, axons, sub plate neurons, germinal epithelium of the

ganglionic eminence, thalamus, cortex and cerebellum.[25] Add to this the fragility of a

nervous system not prepared for the impact of the extra uterine environment and the result is

an immature and actively developing brain vulnerable to insults such as hypoxia,

inflammation, ischaemia, excitotoxicity and free radical attack.[25-28]

The high vascularity of the germinal matrix makes it prone to congestion and its fragile

capillary system is vulnerable to damage from hypoxia, fluctuations in blood flow velocity,

and venous congestion. The resulting haemorrhage may leak into the adjacent ventricles or

even further into the surrounding white matter. In severe cases there may be persisting

hydrocephalus.[28]

In periventricular leukomalacia, hypoxia causes activation of microglia leading to secretion

of toxic oxygen and nitrogen radicals and the release of glutamate. Inflammation secondary

to maternal, placental or foetal infection sets in motion the same reaction, releasing the same

toxins produced with hypoxia.[25,28] The principle target of these free radicals and

glutamate are the premyelinating oligodendrocytes (Pre-OLs). Cell loss at this crucial stage

results in a deficit of mature oligodendrocytes and impairment of myelination.[25,27,28]

There may be accompanying axonal injury resulting in loss and disarray of axons and damage

to sub plate neurons that will impair connections between the thalamus and cortex.[25,26]

The outcome of this widespread and multifaceted primary and secondary brain injury is

impaired white matter development and a decrease in total brain volumes persisting through

childhood and into adolescence.[18,25,26,29,30] On average, brain volume in very

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preterm/VLBW infants is 0.58 SD lower than in term children, with white matter volume

reductions of 0.53SD and grey matter volume reductions of 0.62SD. Reductions are seen in

cerebellar volumes, hippocampal volumes and the size of the corpus callosum as well as

reduced volumes of the thalamus and basal ganglia.[26]

It is becoming evident that motor, cognitive and perceptual deficits may be more inter related

than previously appreciated.[26,31] The thalamus and cerebellum, particularly vulnerable to

preterm insult, appear to be vital nodes in brain networks playing important roles in

cognitive, motor and perceptual tasks.[31,32] Early impacts to the cerebellum may result in

impairment of motor control as well as cognitive ability to learn or organise tasks that are

new, difficult, unpredictable, require concentration or need quick responses.[31]

Damage to the thalamus will potentially impact attention, awareness, visually guided actions

and perceptual matching of visual space across eye movement.[32,33] It may also

compromise memory and cognition including the cognitive aspects of motor control.[34,35]

White matter damage to the posterior thalamic radiations, the corpus callosum, basal ganglia

and superior longitudinal fasciculus is strongly correlated with atypical unimodal and

multisensory integration manifest in sensory processing disorders.[36] The thalamus also

acts with the basal ganglia as a central monitor for language-specific cortical activities and

injury may impact on perceptual and productive language execution.[37].

In summary, the interactions occurring between neurological development and biological

disturbance in the very preterm/VLBW infant brain are complicated and variable. There are

many potential mechanisms for negative impacts on neural structures and connections that

are crucial for organisation and co-ordination of multiple tasks and functions. Subsequently,

it is hypothesised, that prediction of typical and mildly delayed motor and cognitive outcomes

at 24 months c.a will require a combination of fit for purpose clinical tools used across the

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early developmental trajectory to assess the neurologic, neuromotor, neurobehavioral and

perceptual functions.

Social risk and environmental impact

The International Classification of Functioning, Disability and Health clearly indicates that

contextual factors have an important influence on activity level and participation.[38] The

very preterm/VLBW infant’s developmental outcome is dependent on many variables,

including social and environmental influences.[1,11,16,19,39] The impact of gestational age,

perinatal factors and biological insult is mitigated by level of maternal/parental education.[22,

40] Lower socio-economic status (SES) is also associated with a poorer developmental

outcome.[12,16,39,40] Children with lower SES have significantly lower composite scores

on the cognitive, language and motor indices of the Bayley Scales of Infant and Toddler

Development III (Bayley III) than children with higher SES.[16]

Premature birth is a stressful event with negative psychological and emotional effects on the

family.[41] This effect is greatest in the first month of life and remains a substantial

burden.[1,42] At seven years of age parents of very preterm children report higher levels of

total parenting stress, total parent-related stress and total child-related stress as well as poorer

family functioning when compared to families of term born infants.[42] As higher rates of

stress are associated with lower socio-economic status and lower parental education, stress

can compound pre-existing environmental and social risk factors.[1] An important aim of

this study is to investigate the extent to which family and caregiver factors will contribute to

developmental outcome.

The need for early biomarkers

By definition, a biomarker, or “biological marker”, is an objective indicator of medical state

observed from outside the patient which can be measured accurately and reproducibly.[43]

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Biomarkers are used to monitor and predict health states in individuals or across populations

so that appropriate therapeutic intervention can be planned. They can be used separately or in

combination to provide a detailed picture of how healthy a person is and whether or not a

diagnosis needs to be made.[44] Biomarkers are used to predict both the healthy and the

disease state.[43,44] They should be fit for purpose, safe and easy to measure, cost efficient,

modifiable with treatment and consistent across gender and ethnic groups.[44,45]

The risk of developmental delay in the preterm population increases exponentially as

gestational age decreases.[6,11] There is no particular threshold below which risk starts to

increase and no gestational age that is wholly exempt.[1,6] As the causative pathway for

developmental delay is multifaceted and there are increasing numbers of infants to consider,

clinicians need early biomarkers they can rely on to accurately predict outcomes in order to

efficiently and effectively prioritise early intervention services.[11]

There is no single standardised neurodevelopmental assessment tool, or combination of tools,

currently advocated or recognised as the “gold standard” for use with infants in the early

months of life to predict typical outcome and mild delay at 24 months c.a.[46] Instead there

are numerous assessments that vary in their physiological basis, pre requisite training and

expertise, time allotted to perform and score and clinical utility and validity.[45,47,48] Few

of these clinical tools are well suited for use with fragile or sick VLBW/very preterm

neonates or in clinical rather than research settings.[48,49]

In this study our plan is to explore the potential of five clinical tests, used in combination

across the early developmental trajectory, to act as biomarkers for typical and mild outcome

in the motor and cognitive domains for very preterm and VLBW infants at 24 months c.a.

Ideally, tools that are predictive, valid, safe and easy to administer are a good fit for

developmental follow up in neonatal intensive care, special care, outpatient and community

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follow up programs. Tools that can be used during routine clinical contact offer an easily

administered, resource efficient means of early detection and provide important opportunities

for earlier referral to intervention services.[50]

The General Movements Assessment of spontaneous movement (GMs) is the most predictive

clinical test of neuromotor function available for use between birth and 20 weeks post

term.[45,48] The assessment is purely observational and easily administered in clinical

settings. Longitudinal assessment of GMs from 34 weeks until 16 weeks post term will be

combined with four other assessment measures; a preterm neurologic/neurobehavioural

assessment, a neurobehavioural assessment at 2 weeks c.a and then motor and perceptual

function assessment at 16 weeks post term.

The Premie-Neuro Examination (P-NE) neurologic/neurobehavioural assessment is selected

for inclusion at 34 weeks based on excellent clinical utility for use with very preterm infants.

It is the only preterm neurologic/neurobehavioral assessment with standardized norms from

23 weeks to 37 weeks g.a. Early research suggests evidence of ability to discriminate between

high and low risk infants.[49,51]

The Neonatal Intensive Care Unit Network Neurobehavioural Scale (NNNS) will be included

at 2 weeks post term. The NNNS is a neurobehavioural assessment specifically developed for

use with ‘at risk’ and preterm infants.[52] When used at term equivalent age it has

demonstrated ability to predict motor, cognitive, behavioral and school readiness outcomes

between18 months and 4.5 years.[53-55]

The Alberta Infant Motor Scale (AIMS) is included as the motor assessment with the best

combination of clinical utility and predictive validity for outcomes in the second year of life

at 16 weeks post term.[45] The Infant Sensory Profile 2 (Infant SP2) is a short parent

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questionnaire and recent revision of the Infant Toddler Sensory Profile.[56,57] It is included

as the best sensory processing measure available for use from birth.[58]

Broad Aim

The primary aim of this study is to identify clinical biomarkers that can be used between

preterm birth and 16 weeks post term to accurately predict typical development and mild

developmental delay in the very preterm and VLBW population at 24 months c.a. Clinicians

need reliable biomarkers to make earlier accurate prediction of outcomes to improve

prioritisation and promote timely service delivery. A logical strategy is to predict normal

outcome and then direct resources towards the smaller pool of “at risk” infants. The next step

is to predict mild delay as distinct from typical and severe outcomes. As mild delay is the

result of complex, intertwined, biological and environmental variables a combination of

biomarkers used across the developmental trajectory is most likely to correlate with later

outcomes.

The secondary aim of this study is to determine the extent to which family and caregiver

factors including social risk, maternal mental health and education and family strain will

contribute to neurodevelopmental and behavioural outcomes at 24 months c.a.

Primary Hypothesis: Key clinical biomarkers used to assess the developmental trajectory of

neurological, neurobehavioural, neuromotor and perceptual function between 34 weeks g.a

and 16 weeks post term will allow accurate prediction of typical outcome and mild

developmental delay in the motor and cognitive domains at 24 months c.a.

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OVERVIEW OF AIMS

Aim 1

To assess the ability of five clinical assessments, General Movements (GMs), Premie-Neuro

(P-NE), NICU Network Neurobehavioral Scale (NNNS), Alberta Infant Motor Scale (AIMS)

and the Infant Sensory Profile 2 (Infant SP2), administered between 34 weeks gestational age

and 16 weeks post term, to predict typical outcomes and mild motor and cognitive delay at 24

months c.a.

Typical outcome is defined as motor and cognitive composite scores above 1 standard

deviation (SD) below the mean on the Bayley III. Mild developmental delay is defined as

scores between 1SD and 2SD below the mean, moderate delay by scores between 2SD and

3SD below the mean and severe delay as scores more than 3SD below the mean.(5)

Typical outcome on the NSMDA is defined as a motor classification score of 1 or 2.(59) A

score of 1 is defined as within normal limits, a score of 2 as minimal deviation not impacting

function. Developmental delay on the NSMDA is defined as a motor classification score

greater than 2. A score of 3 indicates a mild dysfunction requiring treatment, 4 indicates

moderate disability, 5 severe disability and a score of 6 indicates profound impairment.(59)

Hypotheses:

H1a. Higher raw scores on the P-NE (> 95) combined with a “low risk” trajectory of GMs,

typical profile on the NNNS subscales (10th

to 90th

percentile) and a normal classification on

the AIMS (> 10th

centile) will predict typical performance (greater than 1SD below the mean)

on the motor and cognitive subscales of the Bayley III at 24 months c.a and a functional

grade of 1or 2 on the NSMDA.(51, 60)

H1b. Lower scores on the P-NE (<95), combined with a “moderate” or “high” risk trajectory

of GMs, atypical profile on the NNNS subscales (percentile <10 or > 90) and a

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suspicious/abnormal classification on the AIMS (< 10th

centile) will predict scores 1SD or

more below the mean on the motor and cognitive subscales of the Bayley III at 24 months c.a

and a functional grade greater than 2 on the NSMDA.

H1c. Children identified with mild delays (between 1SD and 2SD below the mean) on the

cognitive and motor subscales of the Bayley III subscale will be more likely to have lower

scores (1SD or more below the mean) on the language, adaptive behaviour and social

emotional subscales of the Bayley III.

H1d. A typical sensory profile on the Infant SP2 at 16 weeks post term will be associated

with typical motor and cognitive outcomes outcome on the Bayley III at 24 months c.a.

Aim 2

To examine any associations between the PN-E neurologic examination and GMs at preterm

and between the PN_E at preterm and longitudinal classification of GM trajectories at 16

weeks post term. To further determine any predictive association between the PN-E at

preterm, the NNNS at 2 weeks post term and the AIMS and Infant SP2 at 16 weeks post term.

Hypotheses:

H2a. Higher raw scores on the PN-E at 34-35 weeks g.a (>95) will correlate with normal

GMs classification at 34-35 weeks g.a. Lower raw scores on the PN-E at 34-35 weeks g.a

will correlate with poor repertoire and cramped synchronised classification on the GMs at 34-

35 weeks g.a.

H2b. Raw scores on the PN-E at 34-35 weeks g.a. will predict subscale scores on the NNNS

(typical or atypical) at 2 weeks post term.

H2c. Raw scores on the PN-E at 34 weeks will predict classification of risk on GM

trajectories (low, moderate, high), classification on the AIMS (normal, suspicious/abnormal)

and typical or atypical sensory processing on the Infant SP2 at 16 weeks post term.

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Aim 3

To determine any predictive association between the NNNS at 2 weeks post term and GM

classification at 16 weeks post term. To further determine any association between the NNNS

at 2 weeks post term and the AIMS and Infant Sensory profile at 16 weeks post term.

Hypothesis:

H3a. Subscale scores on the NNNS at 2 weeks post term (typical or atypical) will predict

classification of risk on GM trajectories (low, moderate, high), classification on the AIMS

(normal, suspicious/abnormal) and typical or atypical sensory processing on the Infant SP2 at

16 weeks post term.

Aim 4

To determine any predictive association between the NNNS at 2 weeks post term and

behavioural outcome at 24 months c.a. (Bayley III, ITSEA) To further determine any

association between the NNNS at 2 weeks post term and sensory profile at 24 months c.a.

Hypothesis:

H4a. Subscale scores on the NNNS (typical or atypical) at 2 weeks post term will predict

behavioural and social emotional competencies on the ITSEA and typical or atypical sensory

profile on the Infant SP2 at 24 months c.a.

Aim 5

To examine any association between the Bayley III motor subscale and the motor

classification score on the NSMDA at 24 months c.a.

Hypothesis:

H5a. Bayley III motor composite scores will correlate with NSMDA motor classification

scores at 24 months c.a.

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Aim 6

To determine the extent to which environmental and social factors including social risk, level

of education, incidence of post-natal depression and family strain will be associated with

neurodevelopmental and behavioural outcomes at 16 weeks post term and 24 months c.a.

Hypotheses:

H6a. Early environmental and social factors identified by a Social Risk Index (SRI), the

Impact on Family Scale (IOF-G) and the Edinburgh Post Natal Depression scale (EPDS), will

have a predictive association with neurodevelopmental outcome at 16 weeks post term

(AIMS, GMs, Infant SP2) and at 24 months c.a. (Bayley III, NSMDA) as well as behavioural

outcomes (Bayley III, ITSEA) at 24 months c.a.

H6b. Higher social risk scores, lower maternal level of education and incidence of maternal

depression are likely to be confounding variables for predicting cognitive outcome on the

Bayley III at 24 months c.a.

Aim 7

To evaluate the ability of perinatal variables, in particular brain injury on cranial ultrasound

(CUS), intrauterine growth restriction (IUGR), bronchopulmonary dysplasia (BPD),

necrotising enterocolitis (NEC), severe retinopathy of prematurity (ROP), sex, gestational

age, late onset sepsis and breastfeeding status at discharge, to predict mild motor and mild

cognitive delay at 24 months c.a. (Bayley III, NSMDA). To further evaluate any predictive

association between perinatal variables and behavioural outcomes and sensory profile at 24

months c.a. (Bayley III, Toddler Sensory Profile 2 (Toddler SP2), ITSEA)

Hypotheses:

H7a. Perinatal factors including brain injury on CUS, BPD, NEC, severe ROP, late onset

sepsis, gestational age, sex and breastfeeding status at discharge will predict

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neurodevelopmental and behavioural outcomes at 24 months c.a (Bayley III, NSMDA,

Toddler SP2, ITSEA).

Aim 8

To determine any predictive relationship between sensory processing profile (Infant SP2) at

16 weeks post term and sensory processing or motor profile at 24 months c.a. (Toddler SP2,

Bayley III)

Hypotheses:

H8a. A typical sensory processing profile at 16 weeks post term on the Infant SP2 (infant

total score less than 1SD from the mean) will remain stable over time and predict a typical

sensory profile at 24 months c.a on the Toddler SP2.

H8b. An atypical sensory processing profile at 16 weeks post term on the Infant SP2 (infant

total score greater than 2SD from the mean) will be associated with an atypical sensory

profile at 24 months c.a on the Toddler SP2 (scores greater than 2 SD from the mean in any

quadrant, sensory or behavioural domain)

H8c. An atypical sensory processing profile at 16 weeks post term on the Infant SP2 (infant

total score greater than 2SD away from the mean) will be associated with motor delay at 24

months c.a on the Bayley III (motor composite score 1SD or more below the mean).

METHODS

Participants

Subjects will be a prospective cohort of infants born at less than 32 weeks and/or 1500g

admitted to the Special Care Nursery (SCN), NGH. Over a period of 24 to 36 months, 90

infants will be entered into the study.

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Inclusion Criteria

• Infants born at less than 1500g and or less than 32 weeks gestation who are admitted to

the SCN and can be recruited prior to 37 weeks g.a.

Exclusion Criteria

• Infants with major congenital or chromosomal abnormalities.

• Families living outside a 100km radius from the NGH.

• Families where no English is spoken.

Sample Size

The primary aim of this study is to use longitudinal trajectories of GMs from 34-35 weeks

gestation until 16 weeks post term to predict typical or delayed neurodevelopmental outcome

at 2 years c.a in very preterm/VLBW infants. The General Movement assessment was chosen

as it is the “gold standard” measure for prediction of neurodevelopmental outcome in this

population.[61]

The expected ratio of normal to non-normal GMs assessments is 3:1. This figure is derived

from pilot data collected in clinical practice at NGH, where a clinical cohort of 86 preterm

infants < 32 weeks and/or less than 1500g was assessed using GMs at 34-35 weeks g.a and

then at 2, 5, 11-12 and 16 weeks post term. Fifty nine infants had normal GMs at each time

point compared to 21 infants with at least one abnormal finding in their assessment trajectory.

Four infants were lost to follow up.

The ability of GMs to predict neurodevelopmental outcome (typical/delayed) was determined

by calculating mean negative and positive predictive values (NPV and PPV) from published

studies with similar participant characteristics and outcome measures. Two recent systematic

reviews evaluating the predictive validity of the General Movement assessment were

searched to find studies with comparable subjects, measures and age at outcome.[62, 63]

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Only two studies with similar attributes were identified.[64, 65] A third study, identified in

additional searches, was also included.[66] (Table 1)

Table 1. Predictive values of General Movements (GMs), negative predictive values (NPV) and positive predictive values (PPV), with respect to neurodevelopmental outcome between

18 months and 24 months corrected age

*GMs at 1 month post term, writhing age ^GMs at 3 months post term, fidgety age

Mean NPV and PPV were compared at each predictive time point (preterm, writing and

fidgety age). (Table 2) The PS- Power and Sample Size Calculation Software v.3.1.2, 2014

was then used to generate the sample size calculations for preterm, writhing and fidgety ages

using alpha 0.01, power of 0.95 and a ratio of 3:1.

Results suggest that the predictive time point of fidgety age (8-20 weeks) will require the

largest sample size to identify a statistically significant association between GM’s and

neurodevelopmental outcome. Data from the literature indicates that a normal GM result at

Studies included Sample

Size

(n)

Participants Outcome

measure and age

at outcome

Pre-

term

NPV

(%)

Post

term

NPV

(%)

Pre-

term

PPV

(%)

Post

term

PPV

(%)

Stahlmann et al.

2007

103 Preterm

infants

<1500g

Motor outcome on

the Griffiths

Developmental

Motor Scale at 20

months

^84 ^89

Constantinou et

al. 2007

102 Preterm

infants

< 1500g

Neurological

examination and

Bayley II scores at

18 months

90 ^90 29 ^41

Spittle et al.

2013

94 Preterm

infants

< 30 weeks

Cognitive outcome

on the Bayley III

at 2 years

*94

^96

*14

^35

Language outcome

on the Bayley III

at 2 years

*91

^93

*14

^35

Motor outcome on

the Bayley III at 2

years

*100

^96

*16

^35

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fidgety age leads to typical neurodevelopmental outcome at 24 months c.a in 92% of infants.

Assuming that GMs at fidgety age correctly identify mild neurodevelopmental outcomes at

24 months ca. in 47% of occasions, we will need to collect data on 80 participants at 24

months c.a. (20 with abnormal GM assessment and 60 with normal GM assessment) to

demonstrate a statistically significant association between GM results at fidgety age and TD

and MDD at 24 months c.a.

Table 2. Mean negative and positive predictive values using GMs at 3 time points to predict typical or delayed neurodevelopmental outcome in the second year of life.

Time point Mean NPV Mean PPV

Preterm 90 29

2-7 weeks post term - writhing 95 15

8-20 weeks post term - fidgety 92 47

NPV = negative predictive value PPV = positive predictive value

GMs = General Movements

By the nature of their design, longitudinal cohort studies are vulnerable to subject attrition

and missing data; a potential cause of bias.[67] In order to minimise any possible impact we

will add an extra 10 subjects (12.5%) into our study design and recruit a total of 90 infants

into the PREMTiME study.

Recruitment process

Infants will be enrolled in the study between 34 and 36 weeks g.a. An administrative staff

member in the SCN, not affiliated with the research project, will introduce the study to

parents or caregivers of infants who meet eligibility criteria. If families are interested and

provide permission for contact, the principal investigator or a member of the research team

will supply a full information pack including the parent information statement. When

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providing the pack, a researcher, not associated with the infant’s clinical care, will explain the

study in more detail and answer all parent questions before seeking informed consent for

study participation. Once signed consent is obtained, the infant will be enrolled in the study,

parents will complete the relevant forms and questionnaires and the infant will receive the

relevant assessments.

Data Collection Methods

Data collection will commence following consent and enrolment. (See Figure 1 for study

timeline) Perinatal data will be collected by a member of the research team. Primary

caregivers will complete baseline questionnaires; the EPDS, SRI and IOF-G.

Should a parent/caregiver score above 9 points on the EPDS, a member of the research team

will refer the mother/caregiver to the SCN social worker. The social worker will discuss the

results with the parent/caregiver, provide information about post-natal depression, explain the

need for further monitoring and request consent to send a letter of notification to the carer’s

general practitioner (GP). Both the assessment findings and the follow up plan will be

documented in the mother’s hospital chart. An opportunity to monitor progress is embedded

within the study design. All mothers or primary caregivers will repeat the test when their

infant reaches 45 weeks post term.

Between 34 and 36 weeks g.a infants will be assessed in the SCN using the Premie-Neuro

Examination (P-NE) and the General Movement Assessment (GMs). All assessors will be

masked to the identity, and medical history of the infants. GMs and PN-E assessments will be

recorded using procedural guidelines developed by the research team. The clinical

photographer at NGH is trained in the use of these guidelines. GM assessments will be

viewed and scored offline by two to four assessors trained by the General Movement Trust.

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After discharge, baseline data collection will occur during 4 return appointments to the Allied

Health Paediatric Outpatient clinic, NGH. General Movements will be videotaped by the

NGH Clinical Photographer while supervised by a member of the research team and viewed

offline by expert assessors masked to the infant’s identity, medical history, perinatal data and

previous assessment findings. The visits will be timed for 2, 5, 11-12 and 16 weeks post term

providing an opportunity for repeat assessment of GMs during both the writhing and fidgety

age. This may reduce the potential impact of missing data in the writhing age when infants

are occasionally too unsettled to complete video assessment. Importantly it meets the

requirement for assessment of fidgety movement on at least two occasions to definitively

classify GMs as absent fidgety.[68]

Additional data collection will occur at the 2, 5 and 16 week post term appointments. At 2

weeks post term infants will complete the NNNS. The assessment will be administered by an

NNNS accredited trainer masked to the identity and medical history of the infant. The

assessment will be videotaped to allow offline scoring as appropriate.

At 5 weeks post term the primary caregivers will repeat the EPDS questionnaire. Should the

caregiver score above 9 on this occasion, a social worker will be on site to discuss the results

in session. The social worker will recommend that the mother/caregiver seek follow up and

consent will be sought to provide the GP with the assessment findings. The assessment

results and negotiated health plan will be documented in the hospital chart.

At 16 weeks post term an occupational therapist will explain the Infant Sensory Profile 2

(Infant SP2) and provide parents with a copy of the questionnaire to complete in session. A

physiotherapist will then administer the Alberta Infant Motor Scale (AIMS). Video footage

collected during the 16 week visit will include both the GMs and the AIMS assessment

allowing masked assessors to view and score the assessments offline. Following the 16 week

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post term appointment infants will be categorised according to longitudinal trajectories of

GM’s into low, moderate and high risk groups. (Table 3)

Table 3. Classification of neurodevelopmental risk according to trajectory of longitudinal GMs between 34 to 35 weeks g.a and 16 weeks post term.

Level of risk Method of Classification

Low All normal GMs at preterm, writhing and fidgety age

Medium At least one finding of abnormal movement (poor repertoire or

cramped synchronized) at preterm or writhing age combined with either normal fidgety or abnormal fidgety movement at

fidgety age.

High At least one finding of abnormal movement (poor repertoire or

cramped synchronized) at preterm or writhing period combined

with absent fidgety movement at fidgety age.

The outcome of all baseline assessments will be forwarded in report format to the Paediatric

Specialist Outpatient Clinic, NGH where a consulting Paediatrician will review all infants

enrolled in the research project between 18 and 20 weeks post term. At this visit the

Paediatrician will have an opportunity to discuss baseline assessment findings with parents or

caregivers. He/she may initiate referral to early intervention services and organise any

additional medical investigations required. A request for magnetic resonance imaging (MRI)

will be ordered by the Paediatrician in cases where infants are assessed as absent fidgety on

the GMs at 12 and 16 weeks.

Multidisciplinary case conferencing with the allied health team will be organised for all

infants identified as high risk. The content and intensity of any concurrent therapy received

whilst enrolled in the PREMTiME project will be documented by parents/caregivers in a

study calendar and measured in a parent recall questionnaire provided at study completion.

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At 24 months c.a (±1 month) all participants will attend two final appointments at NGH.

Approximately four weeks prior, families participating in the study will receive an

appointment letter and the Toddler SP2 questionnaire to complete and return at the first

appointment. Appointments will be scheduled within a two week period. Children will be

assessed by examiners masked to the child’s identified level of risk, previous assessment

findings, medical history and perinatal data.

At the first appointment children will receive the cognitive, motor and language scales of the

Bayley III and the Toddler SP2 questionnaire will be scored. Caregivers will be provided

with the Infant –Toddler Social Emotional Assessment (ITSEA) to complete at home and

return at the second session. At the second visit, parent/caregivers will complete the Adaptive

Behaviour (ABAS II) and the Social Emotional Scales of the Bayley III while a member of

the research team administers the NSMDA. The Bayley III and NSMDA assessments will be

video recorded by the NGH clinical photographer.

All results of outcome assessment will be forwarded to the child’s Paediatrician at NGH,

Paediatric Specialist Outpatient Department. The Paediatrician will review each child within

one month of study completion. At this visit, final study results will be conveyed to the

parents/caregivers. Any diagnosis of cerebral palsy (CP) will be documented, defined and

classified according to the Surveillance of CP in Europe Network Guidelines and the Gross

Motor Function Classification Scale.[69-73] Classification of motor type of CP and Gross

Motor Function Classification Scale (GMFCS) will be confirmed after review of video

footage of the NSMDA by independent expert assessors at the QCPRRC.[70,74]

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MEASURES AND PROCEDURES

Baseline Measures

1. Perinatal Data

An extensive record of antenatal and birth history and the neonatal course will be collected

from the Nambour Hospital medical file at enrolment and then at discharge from the

SCN.[75,76] Data collected will include primary perinatal factors with known associations

with neurodevelopmental delay including early brain injury (intraventricular haemorrhage

identified on CUS or brain injury identified on MRI), intrauterine growth restriction (weight

<10th

centile for g.a), BPD (definition for infants born at < 32 weeks g.a as per criteria

outlined by the National Institute for Health, USA), retinopathy of prematurity (classified by

stages 1 to 5), severe necrotising enterocolitis (requiring surgery), late-onset sepsis (onset >

48 hours post birth), preterm premature rupture of membranes, postnatal infant steroid

therapy and gestational age at birth.[1,9-11,77-83]

Nambour General Hospital (NGH) is a regional facility located 100km north of the nearest

neonatal intensive care unit. Only a portion of high risk babies born or transferred from the

Royal Brisbane and Women’s hospital (RBWH) will receive MRI prior to transfer to

Nambour. A summary of MRI assessment findings will be included in transfer

documentation and will be collected with perinatal data when possible. All very

preterm/VLBW infants will have routine cranial ultrasound at day 3, 7 and 42 of life at the

RBWH prior to transfer to NGH. Early CUS findings are routinely included in transfer

documentation and graded and reported according to the conventions outlined in the Australia

and New Zealand Neonatal Network (ANZNN) data dictionary.[84]

(See Appendix 1 for a complete list of all perinatal variables included in data collection)

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2. Primary Caregiver Information

Edinburgh Post Natal Depression Scale (EPDS):

The EPDS is used to screen primary caregivers for risk of postnatal depression. It is a 10 item

self-reported scale that takes 5 minutes to administer.[85] Originally implemented in the UK

it has since been validated for use in Australia, demonstrating high sensitivity (100%) and

specificity (89%) at a cut off score of 12.5.[86] The EPDS appears to be acceptable to

women as a screening instrument with no complaints reported in an Australian study of 4148

administrations carried out over 3 years.[87] Facilitation of correct diagnosis is optimised by

a two-step strategy where those scoring above a predetermined cut off score on the first

occasion have another test readministered at a subsequent health visit.[87] In keeping with

this evidence based recommendation, the EPDS will be used twice during this study. Primary

caregivers will complete the questionnaire at 34-36 weeks and at 5 weeks post term.

Clearly defined processes have been developed around the event that a parent/caregiver

scores above a clinically conservative score of 9 points on the scale. Researchers will ensure

that caregivers are provided timely support by a social worker, consent is sought to inform

their GP, women are encouraged to seek follow-up and a negotiated health plan is

documented in the hospital chart.

Social Risk Index:

A 12-point SRI will be used between 34 and 36 weeks g.a to provide an overall social risk

score for each family.[12,75] Families will be informed in the parent information statement

that all responses on the questionnaire will be treated in a strictly confidential manner. The

index measures six aspects of social status:

1. Family structure (0 – two caregivers (nuclear); 1 – separated parents with dual custody, or

cared for by other intact family; 2 – single caregiver)

2. Education of primary caregiver (0 – tertiary educated; 1 – 11–12 years of formal

schooling; 2 – less than 11 years of formal schooling)

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3. Occupation of primary income earner (0 – skilled/professional; 1 – semiskilled; 2 –

unskilled)

4. Employment status of primary income earner (0 – full-time employment; 1 – part-time

employment; 2 – unemployed/pension)

5. Language spoken at home (0 – English only; 1 – some English; 2 – no English)

6. Maternal age at birth (0 – more than 21 years; 1 – 18–21 years; 2 – less than 18 years).

Families will be categorised as lower social risk (score ≤ 1) or higher social risk (≥2).[75]

Revised Impact on Family Scale (IOF-G Scale):

This questionnaire will be used between 34 and 36 weeks to assess the effect of a child’s

illness, in this case preterm birth, on the family system. The scale is an easily administered,

reliable, and valid measure of a family member’s perception of the effect of a child’s chronic

condition that can be used across diagnostic groups.[88-90] There are 15 items scored on a 4

point Likert scale (strongly agree to strongly disagree) that take 10 minutes to complete. It

can be used either as a questionnaire or read to the family if needed.[88,90]

3. Infant Assessments

The Premie-Neuro Examination (P-NE)

The PN-E is a new assessment tool designed in response to the relative scarcity of effective

neurologic assessments available for the extremely low birth weight (ELBW) and VLBW

infant.[49,51] It is a standardised clinical neurological and neurobehavioural examination

designed to assess brain function in fragile VLBW/very preterm infants from birth until 37

weeks of gestation.[49] The test is specifically designed to minimise the impact of handling

and can be modified for infants less than 28 weeks. It can be done whilst the baby is still in

isolette and electronically monitored and can be completed within approximately 10 minutes.

The test is administered between 30 minutes and one hour before a scheduled feed and takes

10-15 minutes to complete. It consists of 3 subscales; Neurologic, Movement and

Responsiveness - each with 8 items. Early research indicates good construct validity with

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good internal consistencies of the three subscales. (Cronbach α 75, .73 and .82). There is

evidence of predictive capability with raw scores at 34 to 36 weeks c.a. able to discriminate

between high and low risk groups of infants at term age and predict outcome on the Alberta

Infant Motor Scale at 3 months c.a.[46,49,51] In keeping with these findings infants in this

study will have the PN-E administered between 34 and 36 weeks g.a.

It is acknowledged that the PN-E has less published evidence for prediction than other

preterm assessments such as the Dubowitz Neurological Assessment or the Test of Infant

Motor performance (TIMP). The Dubowitz was not included in this study as its predictive

capability for normal outcomes is relatively modest and the primary aim of this study is to

predict typical outcome.[91] The TIMP has moderately better predictive validity for outcome

than the Dubowitz but less clinical utility than the PN-E.[45,48] The TIMP takes up to 40

minutes to administer while scoring 42 items, the majority of which are elicited. This is not

suited to many fragile preterm infants less than 36 weeks of age and does not fit well within

the ethos of a special care nursery where nursing and medical staff aim to keep handling and

cares to a bare minimum.

As the PN-E has high clinical utility with early indications of useful clinical validity, it has

potential for use as a very early biomarker of neurodevelopmental risk. Further research is

required to determine test reliability in the clinical setting, to determine concurrent validity

with other early neuromotor assessments (specifically GMs) and to further determine

predictive validity.[51] All P-NE assessments will be video recorded to increase accuracy of

measurement, especially on observational items. Our own inter-rater reliability will be

determined as part of the study using a sub-sample of 20 infants.

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Prechtl’s Method of Qualitative Assessment of General Movements (GMs)

The General Movement assessment is a predictive and discriminative tool that involves

longitudinal observations of the infant’s spontaneous motor activity.[45,92] GMs have high

specificity (96%) and sensitivity (95%) for predicting cerebral palsy and early evidence

suggests they have potential to predict normal or milder neurodevelopmental outcomes.[62,

63,93-96] GMs are assessed from preterm until 20 weeks c.a. The assessment is carried out

by videoing the infant in a calm alert state, without external stimulation. In the early preterm

stage this may require up to an hour of video recording but after the infant reaches term age,

5 minutes is the minimum requirement.

Examiners must determine if spontaneous movement is fluent, variable and complex before

defining GMs as normal or abnormal.[92] Normal GMs in the preterm period are gross

movements involving the whole body, including arm, leg, neck and trunk movements in

variable sequence. They “wax and wane” in intensity, force and speed and have a gradual

beginning and end.[92] From 40 weeks until approximately 8 weeks post term movements

are classified as “writhing” in nature. Normal writhing movements are characterised by small

to moderate amplitude and by slow to moderate speed and are elliptical in form. Abnormal

movements during the both the preterm and writing periods are described as poor repertoire,

chaotic or cramped synchronized.[92]

Between 6 and 9 weeks post term and continuing until approximately 20 weeks c.a, GMs

change to a “fidgety” pattern and are defined as “circular movements of small amplitude and

moderate speed and variable acceleration, of neck, trunk, and limbs, in all directions”.[92]

They are continual in the awake infant, except during focused attention, fussing and crying.

The infant will score as normal when fidgety movements are present. Abnormal movement is

scored when fidgety movements are absent or abnormal in pattern. Assessment at more than

one time point during the fidgety age is necessary to definitively score an infant as absent

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fidgety.[68] The infants in this study will have GMs assessed at 34-36 weeks, 2, 5, 11-12 and

16 weeks post term.

Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS)

The NNNS is a non-invasive clinical tool developed to assess neurobehaviour of “at risk”

infants and is suitable for use with very preterm/VLBW infants.[52,97] The assessment takes

between 15 to 20 minutes to administer, ideally in a quiet, dimly lit room, 2 hours after

feeding. The examination is state dependent with a standardised format. It assesses the full

range of infant neurobehavioral performance including neurological integrity, behavioural

functioning, and signs of stress/abstinence.[52,97]

Test items are presented in 13 packages providing summary scores/subscales for habituation,

attention, handling, quality of movement, regulation, non-optimal reflexes, arousal,

hypertonicity, hypotonicity, asymmetrical reflexes, excitability and lethargy.[52,97] The

NNNS has good internal consistency for item summary scores (Cronbachs α 0.87 to

0.90).[98] Published norms are available for summary scores of healthy term born infants at

term age (n=344) and for summary scores of very preterm infants at 1 month c.a. (n=204, 24

to 32 weeks g.a.).[98,99]

Evidence for prediction of motor and cognitive outcomes in very preterm and VLBW

populations is good.[53,54,100] Summary scores at term c.a. in a sample of 41 VLBW

infants were predictive of motor and cognitive outcomes on the Bayley Scales of Infant and

Toddler Development – Second Edition (Bayley II) at 18 months c.a.[53] In another study of

1248 infants < 37 weeks gestation, profiles of summary scores (profiles 1-5) were calculated

and used to predict outcome from birth to 4.5 years. At 1 month c.a, infants with a profile of

5 were more likely to have impaired Bayley II mental and psychomotor developmental index

scores at 2 years c.a.; chronic neurological abnormalities and brain-related illness or cerebral

palsy and behaviour problems at 3 years; motor, concept and language problems in school

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readiness at age 4 years; and lower IQ at 4 and half years.[54] The NNNS will be used to

assess infant neurobehaviour at 2 weeks c.a.

Alberta Infant Motor Scale (AIMS)

The AIMS is a discriminative, norm referenced tool that tests gross motor skills through the

components of weight bearing, posture and antigravity movements.[101,102] The test takes

20 minutes to administer and involves observation of the infant in prone, supine, sitting and

standing. The AIMS is an appropriate assessment tool for monitoring the gross motor

development of typically-developing infants and has normative data based on a population of

2200 infants from 0-18 months in Alberta, Canada.[101] Normative data for preterm infants

has also been published with a sample of 800 infants born at <32 weeks from the

Netherlands.[103]

The AIMS has excellent inter-rater, intra-rater and test-retest reliability for full term and

preterm infants.[104,105] The AIMS has excellent reliability, content, construct and

concurrent validity with the BSID-II (r = 0.98).[101,105,106] Although the AIMS was not

designed as a predictive tool, it has good predictive validity at 4 months for developmental

outcome at 18 months (sensitivity 77.3 %, specificity 81.7%).[107] The AIMS will be used

to classify each infant’s development as normal or suspicious/abnormal at 56 weeks g.a using

cut points at the 10th

centile on the term percentile scale and the 25th

centile on the premature

infant percentile scale.[101,103]

Sensory Profile 2 (SP2)

The SP2 is a newly revised edition of the Infant Toddler Sensory Profile.[56,57] It is a

standardised tool used to evaluate a child’s sensory processing patterns in the context of

participation. It enables professionals to gather information about the child’s sensory

processing abilities and how those patterns either support or interfere with functional

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performance.[58] It is based on a sensory integration and neuroscience frame of reference and

the author’s model of sensory processing.[108,109]

The tool supports family centred practice by actively engaging the primary caregiver in the

data gathering process.[110] Primary caregivers observe the infant or child engaging in a

number of different environmental contexts at home or other community settings and then

report on a range of behaviours on the item scoring sheet. The estimated time for completion

is 5 to 20 minutes based upon the caregiver completing the questionnaire in one sitting.

The SP2 was standardized between 2012 and 2013 using a normative sample of 1791 subjects

and a clinical sample of 771.[56,57] Where previously only raw scores were calculated, the

new version allows percentile ranking of infant total scores as well as quadrant scores for

toddlers and older children. Reliability of the measure is overall good to very good (internal

consistency 0.63-0.93, parent test-retest 0.83-0.97, inter-rater reliability 0.49-0.9/mostly

>0.7).[56] Correlation between the Infant Toddler Sensory Profile (ITSP) and the SP2 is

moderate to high.[56,57]

The new edition has several other improvements and advantages compared to the ITSP.[56,

57] The required reading level is grade 6 equivalent and parents have the option to complete

the forms online. In addition the questionnaire is now presented in two separate user friendly

forms for infants and for toddlers. The Infant Sensory Profile 2 is used for babies from birth

to six months and will be used as a baseline measure at 16 weeks post term. The Toddler

Sensory Profile 2 is for ages 7 to 35 months. It will be used as an outcome measure at 24

months c.a.

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Outcome Measures

1. The Bayley Scales of Infant Toddler Development – Third Edition (Bayley III)

This assessment is a relatively new revision of the Bayley Scales of Infant Development -

Second Edition. It is a norm referenced, discriminative measure used to describe the current

developmental functioning of the infant with good to strong validity and reliability.[111]

Other possible uses of the test include identification of possible developmental delay,

identification of relative strengths and weaknesses and monitoring of developmental

progress. The third edition consists of 5 distinct scales: Cognitive, Language, Motor, Social-

Emotional, and Adaptive Behaviour Scales (ABAS-II). All 5 scales will be utilised in this

study. Assessment is individually administered and may take up to 90 minutes to complete.

Caregivers are encouraged to remain present but not to influence the test proceedings.

Several recent studies recommend the precautionary use of a term born control group and/or

different cut points when using the Bayley III as a primary outcome measure.[112-115]

Studies conducted in Australia and the United States have found that significantly fewer

infants are identified with neurodevelopmental delay with the Bayley III when compared to

previous findings using the Bayley Scales of Infant Toddler Development II (Bayley II).[95-

102] Several explanations are possible but it is still unclear whether the Bayley III is

overestimating developmental performance, whether it is a more valid assessment of

neurodevelopmental impairment than the Bayley II or if premature infant outcomes are

improving. In keeping with these recommendations, scores obtained in this cohort of very

preterm/VLBW infants will be compared to published reference data of an Australian cohort

of 202 term born controls.[116]

The ABAS-II is one of the 5 subscales in the Bayley III.[111] Adaptive behaviour is defined

as the collection of conceptual, social, and practical skills that have been learned by people in

order to function in their everyday lives.[117] It is a parent reported, norm referenced and

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standardised measure of adaptive skills measuring a child’s functioning ability in the areas of

Communication, Community Use, Health and Safety, Leisure, Self-Care, Self-Direction,

Functional Pre-Academics, Home Living, Social, and Motor.[111]

Consisting of a total of 241 items, it takes 15 to 20 minutes to complete. Caregivers rate the

extent to which their child performs the adaptive skill when needed. Ratings include the

following options: 0 = not able to do it, 1 = able yet never does it when needed, 2 = does it

sometimes when needed and 3 = does it always or almost always when needed. Norm

referenced scaled scores are used to interpret results in the skills area and standardised scores

are used to rate performance across the 3 domains to create a total composite score. The

ABAS-II has strong psychometric properties with good to excellent content validity, test-

retest reliability and internal consistency.[117]

2. The Neuro-Sensory and Motor Developmental Assessment (NSMDA)

This a discriminative and predictive criterion referenced measure with a functional grading

system that scores overall motor performance classification as normal, mild not impacting

function, mild, moderate, severe or profound impairment.[45,118] It measures gross motor,

fine motor and sensory motor development, neurological status and postural control. The

examiner observes and administers items and the test takes up to 30 minutes to complete. A

published study of 148 preterm infants demonstrates adequate construct validity with the

NSMDA able to discriminate between normal and abnormal outcome at 24 months c.a.[45,

119] Concurrent validity has been reported in relation to agreement with paediatric

classification of normal or atypical development at 24 months c.a. (χ²=0.08)[45,119]

Reliability has only been reported in terms of correlation (r = 0.80).[45]

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3. The Infant Toddler Social-Emotional Assessment (ITSEA)

The ITSEA is a comprehensive parent-report instrument for evaluating behavioural problems

and social emotional competencies in infants aged 12 to 36 months.[120] The complete

ITSEA includes 166 items that are rated on a 3-point scale: (0) Not true/rarely, (1) Somewhat

true/sometimes, and (2) Very true/often. A “No opportunity” code allows parents to indicate

that they have not had the opportunity to observe certain behaviours. If reading levels are

inadequate it can be presented in interview format without impeding test reliability.[120]

The test measures four broad domains of behaviour; Externalizing, Internalizing,

Dysregulation and Competencies. Three additional indices; Maladaptive, Atypical Behaviour

and Social Relatedness are used to aid identification of significant psychopathology including

attention deficit hyperactivity disorder or autistic spectrum disorder.[120] Test construct,

reliability and validity was examined in a population sample of 1,235 parents of

children.[120] The test has good internal consistency across all four major domains, good

validity and acceptable test-retest and inter-rater reliability.[75,120]

DATA ANALYSIS PLAN

Analysis will be carried out using R version 2.9.1 with the R-Commander and R Studio

statistical analysis packages. Predictor and outcome variables will be identified as continuous

or categorical. Initial analysis will explore the distributions, means and variability of

continuous variables and the rate of occurrence and distribution of categorical variables. Any

outlying data will be identified and the characteristics of any missing data explored.

Graphical representations (histograms, boxplots and scatter plots), tables of means and

standard deviation (SD) and cross tabulations will be used to understand any relationships

between variables.

Univariable regression analysis will be used to determine any associations between predictor

and outcome variables. A forward selection process, entering variables one by one, will help

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to determine any confounding pathways. Multivariable analysis will be performed to

understand major contributors and the effect of confounders. Generalised estimating

equations (GEEs) will be included to determine the extent that early assessment will predict

later outcomes of interest.[121] GEEs track the importance of potential predictor variables

over time, accounting for the dependence of observations recorded from the same participant.

Consideration will be given to any non-linear effects and interactions.

A scaled score of the baseline assessment measures will be used to determine the sensitivity,

specificity, PPV and NPV of early biomarkers to predict typical outcome and MDD at 24

months c.a. Typical outcome will be defined as motor and cognitive scores that are above

1SD below the mean on the Bayley III and a functional grade of 1 or 2 on the NSMDA.

Developmental delay will be defined as motor and cognitive scores 1SD or more below the

mean on the motor and cognitive subscales of the Bayley III and a functional grade greater

than 2 on the NSMDA.

DISCUSSION

Results of this study will inform health policy and service delivery of follow up pathways and

early intervention for very preterm/VLBW infants and their families and guide the provision

of targeted, evidence based service delivery in clinical settings. Findings will be of interest to

medical, allied health, nursing staff, hospital and health service districts.

Findings will also inform future studies with the intent to follow this cohort of very

preterm/VLBW infants until completion of the Queensland Studies Authority, Grade 2

Diagnostic NET test. The Diagnostic NET test is a monitoring and assessment program of

literacy and numeracy competencies administered state wide and typically undertaken at 7

years of age in Queensland schools.[122]

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ABBREVIATIONS

ABAS-II Adaptive Behaviour Assessment Scale – Second Edition

AIMS Alberta Infant Motor Scale

ANZNN Australian and New Zealand Neonatal Network

Bayley II Bayley Scales of Infant and Toddler Development – Second Edition

Bayley III Bayley Scales of Infant and Toddler Development – Third Edition

BPD Bronchopulmonary Dysplasia

c.a corrected age

CP Cerebral Palsy

CUS Cranial Ultrasound

EPDS Edinburgh Post Natal Depression Scale

g.a gestational age

GEEs Generalised Estimating Equations

GMs General Movements

GMFCS Gross Motor Function Classification Scale

GP General Practitioner

IOF-G Impact on Families Scale

Infant SP2 Infant Sensory Profile 2

ITSEA Infant Toddler Social-Emotional Assessment

ITSP Infant Toddler Social-Emotional Assessment

IUGR Intrauterine Growth Restriction

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IVH Intraventricular Haemorrhage

MABC Movement Assessment Battery for Children

MDD Mild Developmental Delay

MMD Mild Motor Delay

MRI Magnetic Resonance Imaging

NGH Nambour General Hospital

NNNS The Neonatal Intensive Care Unit Network Neurobehavioral Scale

NPV Negative Predictive Value

NSMDA Neuro-Sensory and Motor Developmental Assessment

P-NE Premie-Neuro Examination

PPV Positive Predictive Value

QCPRRC Queensland Cerebral Palsy and Rehabilitation Research Centre

ROP Retinopathy of Prematurity

RBWH Royal Brisbane and Women’s Hospital

SCHHS Sunshine Coast Hospital and Health Service

SCN Special Care Nursery

SD Standard Deviation

SES Social Economic Status

SRI Social Risk Index

TD Typical Development

Toddler SP2 Toddler Sensory Profile 2

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Very Preterm Less than 32 weeks gestational age at birth

VLBW Very low birth weight (infants born at less than 1500g)

Competing Interests

The authors declare they have no competing interests.

Authors’ Contributions

Chief investigators that have had substantial input into study design: RC, RB, PC, GC, RW

Associate investigators that have provided input into study design: MJ, KS, JD, TH

Study personnel responsible for ethics applications and reporting: RC, RB, PC, GC

Study personnel responsible for writing the protocol manuscript: RC, RB, PC, GC, RW

Study personnel responsible for recruitment, data collection and implementation of the study:

RC, KS, JD, MJ, LM, TH, AM, CT, LC, EB

Chief investigators that will take lead roles in publication of the clinical outcomes of the

study: RC, RB, PC, GC, RW

All authors have read and approved the final manuscript

Collaborator Contributions – PREMTiME Study Group

Collaborators that have provided scientific advice: SC, KG, HW

Collaborators who have provided assistance with patient care and data collection: LT, JC

ACKNOWLEDGEMENTS

The PREMTiME study is funded by grants from the Health Practitioner Research Scheme,

Queensland Health and by Wishlist, Sunshine Coast Health Foundation. It receives support

from Allied Health staff working in the Women’s and Families stream at NGH including

physiotherapists, occupational therapists, dieticians, social workers and speech pathologists.

Further support is provided by administrative, nursing and medical staff in the NGH SCN,

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administrative staff at the Sunshine Coast Clinical School and from the Medical Imaging

Department, Nambour General Hospital.

The team acknowledges the contributions of administrative officers in the Women’s and

Families Stream NGH, for co-ordination of outpatient appointment bookings. It thanks Mr

Geoffrey Eddy, Clinical Photographer, for video recording of research assessments. It also

acknowledges assistance from Mrs Lorelle Addison and Mrs Helen Moffat, administrative

officers in the NGH SCN, with study recruitment. It thanks Ms Megan Rutter, Research

Governance and Development Manager at Nambour General Hospital for her assistance with

ethics approval and grant applications.

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Figure 1. Study time line of recruitment and assessment time points. KEY: P-NE = The Premie-Neuro Examination [47,58]; GMs = General Movement Assessment [91]; EPDS = Edinburgh Post Natal Depression Scale [84] ; SRI = Social Risk Index [12,76]; IOF = Impact of Family Scale [87-89];NNNS = NICU Network

Neurobehavioral Scale [50]; Infant SP2 = Infant Sensory Profile 2 [54,55]; AIMS = Alberta Infant Motor Scale [100], Bayley III = Bayley Scales of Infant and Toddler Development – 3rd edition [110]; NSMDA = Neuro-Sensory and Motor Developmental Assessment [116]; ITSEA = Infant-Toddler Social Emotional Assessment [118]; Toddler SP2 = Toddler Sensory Profile 2 [54,55]; ABAS-II = Adaptive Behaviour

Assessment Scale – 2nd Edition [115]; c.a = corrected age 194x217mm (300 x 300 DPI)

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APPENDIX 1

Table 3. Detailed description and definition of perinatal data collected during participants

inpatient stay in the Special Care Nursery, Nambour General Hospital.

Variable Description Code

1. ID Subject ID 001-

2. Sex Sex of the child 1=Male

2=Female

3. Ethnic Ethnicity of the child 1 = Caucasian

2 = Aboriginal/Torres Strait

3 = Maori/Polynesian

4 = Asian

5 = Other

4. Multi Multiple birth status 1= singleton

2 = twin 3 = triplet

4 = quadruplet or >

Maternal Variables

5. Mat_diab History of diabetes 1= non diabetic

2= Type 1 diabetes

3 = Type 2 diabetes

4 = Gestational diabetes

6. Mat_inf Infection in pregnancy or at delivery 0 = No

1= Yes

7. Mat_depr History of depression 0 = No

1= Yes

8. Mat_pl Placental presentation in pregnancy or delivery

1 = nil complication 2 = placenta Previa

3 = abruption

9. APH Antepartum haemorrhage 0 = No 1 = Yes

10. Mat_pre Pre-eclampsia/eclampsia in pregnancy 1 = none

2 = Pre-eclampsia

3 = HELLP (haemolysis, elevated

liver enzymes, low platelets

4 = eclampsia

11. TTTS Twin to twin transfusion syndrome in

pregnancy

0 = No

1 = Yes

12. SPTL Spontaneous preterm labour 0 = No 1 = Yes

13. PROM Premature rupture of membranes 0 = No

1 = Yes

14. Chorio Chorioamnionitis in pregnancy 1 = none

2 = clinical

3 = histological

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15. Mat_IUGR Intrauterine growth restriction (IUGR)

as cause of preterm delivery

0 = No

1 = Yes

16. F_dist Foetal distress during pregnancy or

delivery

1 = none

2 = foetal distress in pregnancy 3 = foetal distress in delivery

17. Mat_subst Substance use in pregnancy 1 = no substance use

2 = smoking 3 = alcohol

4 = drug use

5 = combined substance use

18. Mat_med Medications prescribed in pregnancy 0 = No

2 = Yes

19. Mat_cort Maternal corticosteroids 0 = No

1 = Yes

20. Mat_MgSO4 Maternal magnesium sulphate 0 = No

1 = Yes

21. Mat_antib Maternal antibiotics 0 = No

1 = Yes

22. Mat_del Type of delivery 1 = spontaneous vaginal

2 = assisted vaginal (forceps or vacuum)

3 = caesarean section

Infant Variables 23. K Gestation at delivery In weeks (23 -36)

24. BW Birth weight In grams (400 – 2000)

25. Apgar 1 Apgar score at 1 minute Numbered score (0, worst - 9, best)

26. Apgar 5 Apgar score at 5 minutes Numbered score (0, worst - 9, best)

27. Resus Resuscitation requirement at birth 1 = nil requirement

2 = oxygen only 3 = oxygen and mask resuscitation

4 = CPAP

5 = intubation/ventilation

28. Inf_surf Surfactant requirement 1 = nil

2 = 1 dose

3 = 2 or more doses

29. Inf_IUGR IUGR status at birth 0 = birth weight > 10th centile

1 = birth weight < 10th centile

30. Inf_vent Total time intubated and ventilated In 15 minute intervals per hour (1.0, 1.25, 1.5, 1.75, 2.0 to ……)

31. Inf_CPAP Total time on CPAP In 15 minute intervals per hour (1.0,

1.25, 1.5, 1.75, 2.0 to ……)

32. Max_O2 Maximum concentration of Oxygen

administered during neonatal care

In percentage (0-100%)

33. Inf_CST Infant required corticosteroid

treatment

0 = No

1 = Yes

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34. Inf_mg Infant prescribed MgSO4 0 = No

1 = Yes

35. Inf_Ptx Incidence of pneumothorax 0 = No

1 = Yes

36. Inf_IVH Incidence of intraventricular

haemorrhage

1= no IVH

2= unilateral IVH

3= bilateral IVH

37. Inf_grade Highest grade of IVH diagnosed on

cranial ultrasound – using the

Australian and New Zealand Neonatal Network Data Definitions

+ classification by ANZNN

definition

0 = None 1= Grade 1

2 = Grade 2

3 = Grade 3

4 = Grade 4 Localised

5 = Grade 4 – Extensive

38. Inf_PVL Highest grade of periventricular

leukomalacia diagnosed on cranial

ultrasound or MRI

++ classification by ANZNN data

definitions

0 = no cysts

1 = porencephalic cysts 2 = PVL confined to one region

3 = PVL extending to two or more

regions

39. Inf_brain Other infant brain abnormality or

pathology (not IVH or PVL)

1 = no abnormality detected

2 = hydrocephalus

3 = porencephalic cyst formation

4 = absent corpus callosum

5 = other brain insult or abnormality

40. Inf_cardio Presence or absence of a congenital

heart abnormality

1 = not present

2 = PDA*, no treatment required

3 = PDA*, treated medically

4 = VSD** 5 = other abnormality ***

6 = more than 1 abnormality

41. Inf_NEC Presence and severity of necrotising

enterocolitis

1 = none

2 = clinical signs only

3 = clinical and radiologic signs

4 = perforation

5 = surgery required

42. Inf_blood Number of blood transfusions required

during neonatal care

1 = none

2 = 1

3 = 2 4 = 3 or more

43. Inf_sepsis Incidence of infection during neonatal

care

1 = no infection

2 = early infection < 48 hours 3 = late infection > 48 hours

4 = both early and late infection

44. Inf_antib Number of courses of antibiotic therapy required during neonatal care

0 = nil required 1 = 1 course

2 = 2 courses

3 = 3 courses

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4 = > 3 courses

45. Inf_ROP Retinopathy of prematurity, worst

grade recorded in medical chart

+++ classification summary

0 = no ROP

1 = stage I 2 = stage II

3 = stage III

4 = stage IV 5 = stage V

46. Inf_TPN Duration of total parenteral nutrition In days (1 - )

47. Feed_dc Feeding status at discharge 1 = exclusive breast feeding 2 = mixed breast/bottle feeding

3 = breast fed and nasogastric tube

4 = bottle fed only

5 = bottle fed and nasogastric tube

6 = nasogastric tube only

48. Nutri_dc Nutritional status at discharge 1 = breast milk

2 = mixed breast milk and formula

3 = formula only

49. Wt_dc Weight at discharge In grams (0 to )

50. Inf_BPD Presence and severity of

bronchopulmonary dysplasia

++++ Definition by severity for

infants born at < 32 weeks g.a

0 = no BPD 1 = mild

2 = moderate or severe

51. O2_dc Oxygen requirement at discharge In litres/minute (0 to )

52. Plagio_dc Plagiocephaly present at discharge 1 = no plagiocephaly

2 = mild

3 = severe

+ Highest level of Intraventricular Haemorrhage (using ANZNN data definitions)

0 = None − CUS/ post mortem shows no haemorrhage

1= Grade 1 − Subependymal germinal matrix haemorrhage

2 = Grade 2 − Intraventricular haemorrhage

3 = Grade 3 − Intraventricular haemorrhage with ventricle distended with blood

4 = Grade 4 – Localised parenchymal haemorrhage

5 = Grade 4 – Extensive intraparenchymal haemorrhage

++ Cerebral Cysts (using ANZNN data definitions)

0 = no cysts, no cystic lesions seen on CUS

1 = Porencephalic cyst(s)

2 = Periventricular leukomalacia primarily confined to one of the regions: anterior

frontal, posterior frontal, parietal, temporal or occipital region (same as defined for

periventricular haemorrhage)

3= Extensive leukomalacia involving two or more of the above regions

+++ ROP Classification

Stage 1 – Mildly abnormal blood vessel growth

Stage 2 – Moderately abnormal blood vessel growth

Stage 3 – Severely abnormal blood vessel growth

Stage 4 – Partially detached retina

Stage 5 – Completely detached retina and the end stage of the disease

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++++ Definition of BPD for infants born at < 32 weeks g.a

(based on the National Institute of Child Health and Human Development/National Heart, Lung, and

Blood Institute Workshop Summary, 2001)

Mild - in supplemental oxygen at 28 days of age, but in air by 36 weeks corrected age.

Moderate - requiring <30% supplemental oxygen at 36 weeks corrected age.

Severe - in >30% supplemental oxygen and/or requiring positive pressure support, CPAP or

ventilation, at 36 weeks corrected age.

* PDA = Patent Ductus Arteriosus

** VSD = Ventricular Septal Defect

*** Other cardiac abnormalities include: aortic stenosis, atrial septal defect, atrioventricular canal defect,

co-arctation of the aorta, hypoplastic left heart syndrome, patent foramen ovale, pulmonary atresia,

pulmonary stenosis, tetralogy of fallot, total anomalous pulmonary venous connection, transposition of

the great arteries, tricuspid atresia, truncus arteriosus

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Early prediction of typical outcome and mild developmental delay for prioritisation of service delivery for very preterm

and very low birth weight infants: a study protocol.

Journal: BMJ Open

Manuscript ID bmjopen-2015-010726.R1

Article Type: Protocol

Date Submitted by the Author: 08-Apr-2016

Complete List of Authors: Caesar, Rebecca; School of Medicine, Faculty of Medicine and Biomedical Science, University of Queensland, Queensland Cerebral Palsy and Rehabilitation Research Centre,; Sunshine Coast Hospital and Health

Service, Allied Health Womens and Families, Nambour General Hospital Boyd, Roslyn; School of Medicine, Faculty of Medicine and Biomedical Science, University of Queensland, Queensland Cerebral Palsy and Rehabilitation Research Centre, Colditz, Paul; University of Queensland, The University of Queensland Centre for Clinical Research (UQCCR), Faculty of Health Sciences, Royal Brisbane and Womens Hospital; Royal Brisbane and Womens Hospital Cioni, Giovani; Stella Maris Scientific Institute, Department of Developmental Neuroscience Ware, Robert; University of Queensland, School of Population Health Salthouse, Kaye; Sunshine Coast Hospital and Health Service, Allied Health Womens and Families, Nambour General Hospital

Doherty, Julie ; Sunshine Coast Hospital and Health Service, Allied Health Womens and Families, Nambour General Hospital Jackson, Maxine ; Sunshine Coast Hospital and Health Service, Allied Health Womens and Families, Nambour General Hospital Matthews, Leanne; Sunshine Coast Hospital and Health Service, Allied Health Womens and Families, Nambour General Hospital Hurley, Tom; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital Morosini, Anthony; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital Thomas, Clare; Sunshine Coast Hospital and Health Service, Department of

Paediatrics, Nambour General Hospital Camadoo, Laxmi ; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital Baer, Erica ; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital

<b>Primary Subject Heading</b>:

Paediatrics

Secondary Subject Heading: Neurology

Keywords: NEONATOLOGY, Developmental neurology & neurodisability < PAEDIATRICS, Paediatric neurology < PAEDIATRICS


BMJ Open on M

arch 6, 2021 by guest. Protected by copyright.

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STUDY PROTOCOL

Title: Early prediction of typical outcome and mild developmental delay for prioritisation of

service delivery for very preterm and very low birth weight infants: a study protocol.

Acronym: PREMTiME (Prediction of Mild Developmental Delay and Typical Outcome) in

at risk preterm infants

Authors

Chief Investigators:

1. Mrs Rebecca Caesar, PhD scholar (Med Sci), MPhty (Paediatrics), BAppSci Phty1,5

2. Professor Roslyn N Boyd (Corresponding Author), PhD, MSc (Physio), NHMRC

Research Fellow, Scientific Director, Queensland Cerebral Palsy and Rehabilitation

Research Centre1

Faculty of Health and Biomedical Sciences

The University of Queensland

Rm 611, Level 6, Centre for Children’s Health Research,

62 Graham Street,

South Brisbane,

QLD, 4101, Australia

[email protected]

Telephone: (07) 3069 7372

Fax: (07) 3069 7109

3. Professor Paul Colditz, MBBS, FRACP (Royal Australian College of Physicians),

BBiomedE, DPhil, FRCPCH (Royal College of Paediatrics and Child Health)2,3

4. Professor Giovani Cioni, MD4

5. Dr. Robert S. Ware, PhD, BSci (Hons)1,6

Associate Investigators:

6. Mrs Kaye Salthouse, BPhty5

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7. Mrs Julie Doherty, BPhty5

8. Mrs Maxine Jackson, BOccThy5

9. Ms Leanne Matthews, BHSci (OT)5

10. Dr Tom Hurley, MBBS, FRACP (Royal Australian College of Physicians)7

11. Dr Anthony Morosini, MBBS, FRACP (Royal Australian College of Physicians)7

12. Dr Clare Thomas, MBBS, FRACP (Royal Australian College of Physicians)7

13. Dr Laxmi Camadoo, BSc (Hons), MBBS, DCH, MRCPCH, FRACP7

14. Dr Erica Baer, MBBS, FRACP (Royal Australian College of Physicians)7

Collaborators:

The PREMTiME Study Group:

1. Mrs Louise Tambling, BSc Hons Phty5

2. Mrs Susanne Cuddihy, BA, Grad Dip Psych, Grad Dip SpEduc, MAppPsych 8

3. Ms Kellee Gee, BScPsych, Post Grad Dip Psych 8

4. Mrs Julie Creen, BOccThy 5

5. Dr Heidi Webster, MBBS, FRACP (Royal College of Physicians) 8

Affiliations:

1School of Medicine, Faculty of Medicine and Biomedical Science, The University of

Queensland, Queensland Cerebral Palsy and Rehabilitation Research Centre (QCPRRC),

South Brisbane, QLD, Australia.

2 The University of Queensland, The University of Queensland Centre for Clinical Research,

Faculty of Health Sciences, Royal Brisbane and Women’s Hospital, Brisbane, QLD,

Australia

3Royal Brisbane and Women’s Hospital, Herston, QLD, Australia.

4Stella Maris Scientific Institute, Department of Developmental Neuroscience, Pisa, Italy.

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5 Sunshine Coast Hospital and Health Service, Allied Health Women’s and Families,

Nambour General Hospital, Nambour, QLD, Australia

6University of Queensland, School of Population Health, Herston, QLD, Australia

7 Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General

Hospital, Nambour, QLD, Australia

8Sunshine Coast Hospital and Health Service, Child Development Service, Maroochydore,

QLD, Australia

Email addresses:

RC: [email protected]

RB: [email protected]

PC [email protected]

GC: [email protected]

RW: [email protected]

KS: [email protected]

JD: [email protected]

MJ: [email protected]

LM: [email protected]

TH: [email protected]

AM: [email protected]

CT: [email protected]

LC: [email protected]

EB: [email protected]

LT: [email protected]

SC: [email protected]

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KG: [email protected]

JC: [email protected]

HW: [email protected]

Journal: BMJ Open

Key words: Very Preterm, Very Low Birth Weight, Typical Development, Mild

Developmental Delay, Clinical Biomarkers, General Movements

ABSTRACT

Introduction: Over 80% of very preterm (<32 weeks) and very low birth weight (<1500g)

infants will have either typical development (TD) or mild developmental delay (MDD) in

multiple domains. As differentiation between TD and MDD can be difficult, infants with

MDD often miss opportunities for intervention. For many clinicians the ongoing challenge is

early detection of MDD without over servicing the population. This study aims to: 1) Identify

early clinical biomarkers for use in this population to predict and differentiate between TD

and MDD at 24 months corrected age. 2) Determine the extent to which family and caregiver

factors will contribute to neurodevelopmental and behavioural outcomes.

Methods and Analysis: Participants will be a prospective cohort of 90 infants (<32 weeks

and/or <1500g). Between 34 weeks gestational age and 16 weeks post term, infants will have

a series of five neurological, neuromotor, neurobehavioural and perceptual assessments

including General Movement assessment at preterm, writhing and fidgety age. Primary

caregivers will complete questionnaires to identify social risk, maternal depression and

family strain. Extensive perinatal data will be collected from the medical record. At 24

months corrected age (c.a) infants will be assessed using standardised tools including the

Bayley Scales of Infant and Toddler Development – Third Edition (Bayley III). Longitudinal

trajectories of early assessment findings will be examined to determine any predictive

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relationship with motor and cognitive outcomes at 24 months c.a. Published data of a cohort

of Australian children assessed with the Bayley III at 24 months c.a will provide a reference

group of term born controls.

Ethics: Ethical approval has been obtained from the Queensland Children’s Health Services

Human Research Ethics Committee (HREC/13/QRCH/66), the University of Queensland

(2013001019) and the Sunshine Coast Hospital and Health Service, SC-Research Governance

(SSA/13/QNB/66). Publication of all study outcomes will be in peer reviewed journals.

Abstract word count: 299

Number of Tables: 3

Number of Figures: 1

Supplementary Appendices: 1

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INTRODUCTION

The absolute number of children born very preterm and very low birth weight (VLBW) is

increasing in developed countries as neonatal intensive care continues to improve.[1,2] As

survival rates increase, the focus moves to consideration of quality of life.[1-8] The

incidence of severe outcomes in the very preterm/VLBW population is beginning to decline

but the overall risk of developmental delay across multiple domains remains steady at 47

percent.[2,5,9,10] With rates of typical outcome at approximately 52%, clinical practitioners

are now challenged by the need to differentiate between infants with mild delay and

TD.[1,2,5,11]

Given the current pressure on public health resources, population intervention is no longer

practical nor cost efficient. Robust early prediction and differentiation is warranted to prevent

over servicing of very preterm/VLBW infants who are typically developing and facilitate

targeted interventions for infants in the population with higher risk for developmental delay.

In Australia, very preterm children with mild deficits are less likely to receive services than

children with more severe outcomes.[12] Lack of service engagement is even more evident

for very preterm children living in situations of higher social or environmental risk.[12] This

is cause for concern as early delays do not dissipate, rather they become more apparent with

age alongside increasing functional demands in educational and social contexts.[4,6,7,13-16]

Late referral often means that infants completely miss out on vital input during critical

periods of development when enriched experiences provided by parents and therapists may

optimise neuroplasticity.[17,18]

Mild impairment in very low birth weight and very preterm infants

Children born very preterm have an increased risk of mild motor delay (MMD) not associated

with cerebral palsy.[19] Prevalence of MMD in children born preterm is three to four times

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greater than in term born infants.[8,19] At 8-12 months c.a nearly half of very preterm

infants (47%) have mildly delayed scores on the Gross Motor Subscale of the Bayley III. (< 1

Standard Deviation (SD)).[20] At 2.5 years c.a, 29 % of children score 1SD below the

control mean on the gross motor and 34 % on the fine motor scale of the Bayley III.[21]

Studies at school age show similar outcomes with one study reporting 32 % and another 50 %

of very preterm born children scoring ≤ 15th

centile on the Movement Assessment Battery for

Children (MABC) at 5 years c.a.[7]

Consistent findings of mild delay in the preterm population from birth to 5 years suggest that

motor delays do not improve with time. Instead, early delays progress to motor impairments

at school entry that then persist into adolescence.[4,22] Developmental co-ordination

disorder is highly prevalent in the VLBW/very preterm population with children 6 times

more likely to score at or below the 5th

centile on the MABC, and 8 times more likely to

score below the 15th

centile.[14] A meta-analysis of 41 articles encompassing 9653 very

preterm/VLBW from infancy to 15 years found that these children are, on average, −0.57 to

−0.88 SD behind their term-born peers or typically developing children in motor

development.[4]

Mild motor impairment is rarely experienced in isolation. Children who are born very

preterm or VLBW are more likely than term born infants to perform below average in two or

more developmental domains.[5-7,20,21] Comorbidities that frequently accompany MMD

include mild deficits and delay in the cognitive, communication, behavioural, personal-social

and perceptual domains including sensory processing differences.[1,5-7,9-11,20-24] In very

preterm infants where motor delay is identified at 5 years of age, there is a substantially

higher rate of impairment in other domains compared to very preterm infants who do not

have motor impairment.[7] Deficits associated with MMD at this age include lower IQ,

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decreased processing speed, poor visuomotor co-ordination and increased incidence of

complex minor neurological dysfunction.[7]

Biological rationale for multi domain neurodevelopmental deficits

Preterm birth is timed against a background of significant maturational processes. Between

24 and 40 weeks gestation, multiple developmental events are taking place that include the

pre-oligodendrocytes, microglia, axons, sub plate neurons, germinal epithelium of the

ganglionic eminence, thalamus, cortex and cerebellum.[25] Add to this the fragility of a

nervous system not prepared for the impact of the extra uterine environment and the result is

an immature and actively developing brain vulnerable to insults such as hypoxia,

inflammation, ischaemia, excitotoxicity and free radical attack.[25-28]

The high vascularity of the germinal matrix makes it prone to congestion and its fragile

capillary system is vulnerable to damage from hypoxia, fluctuations in blood flow velocity,

and venous congestion. The resulting haemorrhage may leak into the adjacent ventricles or

even further into the surrounding white matter. In severe cases there may be persisting

hydrocephalus.[28]

In periventricular leukomalacia, hypoxia causes activation of microglia leading to secretion

of toxic oxygen and nitrogen radicals and the release of glutamate. Inflammation secondary

to maternal, placental or foetal infection sets in motion the same reaction, releasing the same

toxins produced with hypoxia.[25,28] The principle target of these free radicals and

glutamate are the premyelinating oligodendrocytes (Pre-OLs). Cell loss at this crucial stage

results in a deficit of mature oligodendrocytes and impairment of myelination.[25,27,28]

There may be accompanying axonal injury resulting in loss and disarray of axons and damage

to sub plate neurons that will impair connections between the thalamus and cortex.[25,26]

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The outcome of this widespread and multifaceted primary and secondary brain injury is

impaired white matter development and a decrease in total brain volumes persisting through

childhood and into adolescence.[18,25,26,29,30] On average, brain volume in very

preterm/VLBW infants is 0.58 SD lower than in term children, with white matter volume

reductions of 0.53SD and grey matter volume reductions of 0.62SD. Reductions are seen in

cerebellar volumes, hippocampal volumes and the size of the corpus callosum as well as

reduced volumes of the thalamus and basal ganglia.[26]

It is becoming evident that motor, cognitive and perceptual deficits may be more inter related

than previously appreciated.[26,31] The thalamus and cerebellum, particularly vulnerable to

preterm insult, appear to be vital nodes in brain networks playing important roles in

cognitive, motor and perceptual tasks.[31,32] Early impacts to the cerebellum may result in

impairment of motor control as well as cognitive ability to learn or organise tasks that are

new, difficult, unpredictable, require concentration or need quick responses.[31]

Damage to the thalamus will potentially impact attention, awareness, visually guided actions

and perceptual matching of visual space across eye movement.[32,33] It may also

compromise memory and cognition including the cognitive aspects of motor control.[34,35]

White matter damage to the posterior thalamic radiations, the corpus callosum, basal ganglia

and superior longitudinal fasciculus is strongly correlated with atypical unimodal and

multisensory integration manifest in sensory processing disorders.[36] The thalamus also

acts with the basal ganglia as a central monitor for language-specific cortical activities and

injury may impact on perceptual and productive language execution.[37]

In summary, the interactions occurring between neurological development and biological

disturbance in the very preterm/VLBW infant brain are complicated and variable. There are

many potential mechanisms for negative impacts on neural structures and connections that

are crucial for organisation and co-ordination of multiple tasks and functions. Subsequently,

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it is hypothesised, that prediction of typical and mildly delayed motor and cognitive outcomes

at 24 months c.a will require a combination of fit for purpose clinical tools used across the

early developmental trajectory to assess the neurologic, neuromotor, neurobehavioral and

perceptual functions.

Social risk and environmental impact

The International Classification of Functioning, Disability and Health clearly indicates that

contextual factors have an important influence on activity level and participation.[38] The

very preterm/VLBW infant’s developmental outcome is dependent on many variables,

including social and environmental influences.[1,11,16,19,39] The impact of gestational age,

perinatal factors and biological insult is mitigated by level of maternal/parental

education.[22,40] Lower socio-economic status (SES) is also associated with a poorer

developmental outcome.[12,16,39,40] Children with lower SES have significantly lower

composite scores on the cognitive, language and motor indices of the Bayley Scales of Infant

and Toddler Development III (Bayley III) than children with higher SES.[16]

Premature birth is a stressful event with negative psychological and emotional effects on the

family.[41] This effect is greatest in the first month of life and remains a substantial

burden.[1,42] At seven years of age parents of very preterm children report higher levels of

total parenting stress, total parent-related stress and total child-related stress as well as poorer

family functioning when compared to families of term born infants.[42] As higher rates of

stress are associated with lower socio-economic status and lower parental education, stress

can compound pre-existing environmental and social risk factors.[1] An important aim of

this study is to investigate the extent to which family and caregiver factors will contribute to

developmental outcome.

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The need for early biomarkers

By definition, a biomarker, or “biological marker”, is an objective indicator of medical state

observed from outside the patient which can be measured accurately and reproducibly.[43]

Biomarkers are used to monitor and predict health states in individuals or across populations

so that appropriate therapeutic intervention can be planned. They can be used separately or in

combination to provide a detailed picture of how healthy a person is and whether or not a

diagnosis needs to be made.[44] Biomarkers are used to predict both the healthy and the

disease state.[43,44] They should be fit for purpose, safe and easy to measure, cost efficient,

modifiable with treatment and consistent across gender and ethnic groups.[44,45]

The risk of developmental delay in the preterm population increases exponentially as

gestational age decreases.[6,11] There is no particular threshold below which risk starts to

increase and no gestational age that is wholly exempt.[1,6] As the causative pathway for

developmental delay is multifaceted and there are increasing numbers of infants to consider,

clinicians need early biomarkers they can rely on to accurately predict outcomes in order to

efficiently and effectively prioritise early intervention services.[11]

There is no single standardised neurodevelopmental assessment tool, or combination of tools,

currently advocated or recognised as the “gold standard” for use with infants in the early

months of life to predict typical outcome and mild delay at 24 months c.a.[46] Instead there

are numerous assessments that vary in their physiological basis, pre requisite training and

expertise, time allotted to perform and score and clinical utility and validity.[45,47,48] Few

of these clinical tools are well suited for use with fragile or sick VLBW/very preterm

neonates or in clinical rather than research settings.[48,49]

In this study our plan is to explore the potential of five clinical tests, used in combination

across the early developmental trajectory, to act as biomarkers for typical and mild outcome

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in the motor and cognitive domains for very preterm and VLBW infants at 24 months c.a.

Ideally, tools that are predictive, valid, safe and easy to administer are a good fit for

developmental follow up in neonatal intensive care, special care, outpatient and community

follow up programs. Tools that can be used during routine clinical contact offer an easily

administered, resource efficient means of early detection and provide important opportunities

for earlier referral to intervention services.[50]

The General Movements Assessment of spontaneous movement (GMs) is the most predictive

clinical test of neuromotor function available for use between birth and 20 weeks post

term.[45,48] The assessment is purely observational and easily administered in clinical

settings. Longitudinal assessment of GMs from 34 weeks until 16 weeks post term will be

combined with four other assessment measures; a preterm neurologic/neurobehavioural

assessment, a neurobehavioural assessment at 2 weeks c.a and then motor and perceptual

function assessment at 16 weeks post term.

The Premie-Neuro Examination (P-NE) neurologic/neurobehavioural assessment is selected

for inclusion at 34 weeks based on excellent clinical utility for use with very preterm infants.

It is the only preterm neurologic/neurobehavioral assessment with standardized norms from

23 weeks to 37 weeks g.a. Early research suggests evidence of ability to discriminate between

high and low risk infants.[49,51]

The Neonatal Intensive Care Unit Network Neurobehavioural Scale (NNNS) will be included

at 2 weeks post term. The NNNS is a neurobehavioural assessment specifically developed for

use with ‘at risk’ and preterm infants.[52] When used at term equivalent age it has

demonstrated ability to predict motor, cognitive, behavioral and school readiness outcomes

between18 months and 4.5 years.[53-55]

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The Alberta Infant Motor Scale (AIMS) is included as the motor assessment with the best

combination of clinical utility and predictive validity for outcomes in the second year of life

at 16 weeks post term.[45] The Infant Sensory Profile 2 (Infant SP2) is a short parent

questionnaire and recent revision of the Infant Toddler Sensory Profile.[56,57] It is included

as the best sensory processing measure available for use from birth.[58]

Broad Aim

The primary aim of this study is to identify clinical biomarkers that can be used between

preterm birth and 16 weeks post term to accurately predict typical development and mild

developmental delay in the very preterm and VLBW population at 24 months c.a. Clinicians

need reliable biomarkers to make earlier accurate prediction of outcomes to improve

prioritisation and promote timely service delivery. A logical strategy is to predict normal

outcome and then direct resources towards the smaller pool of “at risk” infants. The next step

is to predict mild delay as distinct from typical and severe outcomes. As mild delay is the

result of complex, intertwined, biological and environmental variables a combination of

biomarkers used across the developmental trajectory is most likely to correlate with later

outcomes.

The secondary aim of this study is to determine the extent to which family and caregiver

factors including social risk, maternal mental health and education and family strain will

contribute to neurodevelopmental and behavioural outcomes at 24 months c.a.

Primary Hypothesis: Key clinical biomarkers used to assess the developmental trajectory of

neurological, neurobehavioural, neuromotor and perceptual function between 34 weeks g.a

and 16 weeks post term will allow accurate prediction of typical outcome and mild

developmental delay in the motor and cognitive domains at 24 months c.a.

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OVERVIEW OF AIMS

Aim 1

To assess the ability of five clinical assessments, General Movements (GMs), Premie-Neuro

(P-NE), NICU Network Neurobehavioral Scale (NNNS), Alberta Infant Motor Scale (AIMS)

and the Infant Sensory Profile 2 (Infant SP2), administered between 34 weeks gestational age

and 16 weeks post term, to predict typical outcomes and mild motor and cognitive delay at 24

months c.a.

Typical outcome is defined as motor and cognitive composite scores not lower than 1

standard deviation (SD) below the mean on the Bayley III. Mild developmental delay is

defined as scores between 1SD and 2SD below the mean, moderate delay by scores between

2SD and 3SD below the mean and severe delay as scores more than 3SD below the mean.[5]

Typical outcome on the NSMDA is defined as a motor classification score of 1 or 2.[59] A

score of 1 is defined as within normal limits, a score of 2 as minimal deviation not impacting

function. Developmental delay on the NSMDA is defined as a motor classification score

greater than 2. A score of 3 indicates a mild dysfunction requiring treatment, 4 indicates

moderate disability, 5 severe disability and a score of 6 indicates profound impairment.[59]

Hypotheses:

H1a. Higher raw scores on the P-NE (> 95) combined with a “low risk” trajectory of GMs,

typical profile on the NNNS subscales (10th

to 90th

percentile) and a normal classification on

the AIMS (> 10th

centile) will predict typical performance (scores above -1SD) on the motor

and cognitive subscales of the Bayley III at 24 months c.a and a functional grade of 1or 2 on

the NSMDA.[51,60]

H1b. Lower scores on the P-NE (<95), combined with a “moderate” or “high” risk trajectory

of GMs, atypical profile on the NNNS subscales (percentile <10 or > 90) and a

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suspicious/abnormal classification on the AIMS (< 10th

centile) will predict scores -1SD or

more below the mean on the motor and cognitive subscales of the Bayley III at 24 months c.a

and a functional grade greater than 2 on the NSMDA.

H1c. Children identified with mild delays (between -1SD and -2SD below the mean) on the

cognitive and motor subscales of the Bayley III subscale will be more likely to have lower

scores (-1SD or more below the mean) on the language, adaptive behaviour and social

emotional subscales of the Bayley III.

H1d. A typical sensory profile on the Infant SP2 at 16 weeks post term will be associated

with typical motor and cognitive outcomes outcome on the Bayley III at 24 months c.a.

Aim 2

To examine any associations between the PN-E neurologic examination and GMs at preterm

and between the PN_E at preterm and longitudinal classification of GM trajectories at 16

weeks post term. To further determine any predictive association between the PN-E at

preterm, the NNNS at 2 weeks post term and the AIMS and Infant SP2 at 16 weeks post term.

Hypotheses:

H2a. Higher raw scores on the PN-E at 34-35 weeks g.a (>95) will correlate with normal

GMs classification at 34-35 weeks g.a. Lower raw scores on the PN-E at 34-35 weeks g.a

will correlate with poor repertoire and cramped synchronised classification on the GMs at 34-

35 weeks g.a.

H2b. Raw scores on the PN-E at 34-35 weeks g.a. will predict subscale scores on the NNNS

(typical or atypical) at 2 weeks post term.

H2c. Raw scores on the PN-E at 34 weeks will predict classification of risk on GM

trajectories (low, moderate, high), classification on the AIMS (normal, suspicious/abnormal)

and typical or atypical sensory processing on the Infant SP2 at 16 weeks post term.

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Aim 3

To determine any predictive association between the NNNS at 2 weeks post term and GM

classification at 16 weeks post term. To further determine any association between the NNNS

at 2 weeks post term and the AIMS and Infant Sensory profile at 16 weeks post term.

Hypothesis:

H3a. Subscale scores on the NNNS at 2 weeks post term (typical or atypical) will predict

classification of risk on GM trajectories (low, moderate, high), classification on the AIMS

(normal, suspicious/abnormal) and typical or atypical sensory processing on the Infant SP2 at

16 weeks post term.

Aim 4

To determine any predictive association between the NNNS at 2 weeks post term and

behavioural outcome at 24 months c.a. (Bayley III, ITSEA) To further determine any

association between the NNNS at 2 weeks post term and sensory profile at 24 months c.a.

Hypothesis:

H4a. Subscale scores on the NNNS (typical or atypical) at 2 weeks post term will predict

behavioural and social emotional competencies on the ITSEA and typical or atypical sensory

profile on the Infant SP2 at 24 months c.a.

Aim 5

To examine any association between the Bayley III motor subscale and the motor

classification score on the NSMDA at 24 months c.a.

Hypothesis:

H5a. Bayley III motor composite scores will correlate with NSMDA motor classification

scores at 24 months c.a.

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Aim 6

To determine the extent to which environmental and social factors including social risk, level

of education, incidence of post-natal depression and family strain will be associated with

neurodevelopmental and behavioural outcomes at 16 weeks post term and 24 months c.a.

Hypotheses:

H6a. Early environmental and social factors identified by a Social Risk Index (SRI), the

Impact on Family Scale (IOF-G) and the Edinburgh Post Natal Depression scale (EPDS), will

have a predictive association with neurodevelopmental outcome at 16 weeks post term

(AIMS, GMs, Infant SP2) and at 24 months c.a. (Bayley III, NSMDA) as well as behavioural

outcomes (Bayley III, ITSEA) at 24 months c.a.

H6b. Higher social risk scores, lower maternal level of education and incidence of maternal

depression are likely to be confounding variables for predicting cognitive outcome on the

Bayley III at 24 months c.a.

Aim 7

To evaluate the ability of perinatal variables, in particular brain injury on cranial ultrasound

(CUS), intrauterine growth restriction (IUGR), bronchopulmonary dysplasia (BPD),

necrotising enterocolitis (NEC), severe retinopathy of prematurity (ROP), sex, gestational

age, late onset sepsis and breastfeeding status at discharge, to predict mild motor and mild

cognitive delay at 24 months c.a. (Bayley III, NSMDA). To further evaluate any predictive

association between perinatal variables and behavioural outcomes and sensory profile at 24

months c.a. (Bayley III, Toddler Sensory Profile 2 (Toddler SP2), ITSEA)

Hypotheses:

H7a. Perinatal factors including brain injury on CUS, BPD, NEC, severe ROP, late onset

sepsis, gestational age, sex and breastfeeding status at discharge will predict

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neurodevelopmental and behavioural outcomes at 24 months c.a (Bayley III, NSMDA,

Toddler SP2, ITSEA).

Aim 8

To determine any predictive relationship between sensory processing profile (Infant SP2) at

16 weeks post term and sensory processing or motor profile at 24 months c.a. (Toddler SP2,

Bayley III)

Hypotheses:

H8a. A typical sensory processing profile at 16 weeks post term on the Infant SP2 (infant

total score less than 1SD from the mean) will remain stable over time and predict a typical

sensory profile at 24 months c.a on the Toddler SP2.

H8b. An atypical sensory processing profile at 16 weeks post term on the Infant SP2 (infant

total score greater than 2SD from the mean) will be associated with an atypical sensory

profile at 24 months c.a on the Toddler SP2 (scores greater than 2 SD from the mean in any

quadrant, sensory or behavioural domain)

H8c. An atypical sensory processing profile at 16 weeks post term on the Infant SP2 (infant

total score greater than 2SD away from the mean) will be associated with motor delay at 24

months c.a on the Bayley III (motor composite score 1SD or more below the mean).

METHODS

Participants

Subjects will be a prospective cohort of infants born at less than 32 weeks and/or 1500g

admitted to the Special Care Nursery (SCN), NGH. Over a period of 24 to 36 months, 90

infants will be entered into the study.

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Inclusion Criteria

• Infants born at less than 1500g and or less than 32 weeks gestation who are admitted to

the SCN and can be recruited prior to 37 weeks g.a.

Exclusion Criteria

• Infants with major congenital or chromosomal abnormalities.

• Families living outside a 100km radius from the NGH.

• Families where no English is spoken.

Sample Size

The primary aim of this study is to use longitudinal trajectories of GMs from 34-35 weeks

gestation until 16 weeks post term to predict typical or delayed neurodevelopmental outcome

at 2 years c.a in very preterm/VLBW infants. The General Movement assessment was chosen

as it is the “gold standard” measure for prediction of neurodevelopmental outcome in this

population.[61]

The expected ratio of normal to non-normal GMs assessments is 3:1. This figure is derived

from pilot data collected in clinical practice at NGH, where a clinical cohort of 86 preterm

infants < 32 weeks and/or less than 1500g was assessed using GMs at 34-35 weeks g.a and

then at 2, 5, 11-12 and 16 weeks post term. Fifty nine infants had normal GMs at each time

point compared to 21 infants with at least one abnormal finding in their assessment trajectory.

Four infants were lost to follow up.

The ability of GMs to predict neurodevelopmental outcome (typical/delayed) was determined

by calculating mean negative and positive predictive values (NPV and PPV) from published

studies with similar participant characteristics and outcome measures. Two recent systematic

reviews evaluating the predictive validity of the General Movement assessment were

searched to find studies with comparable subjects, measures and age at outcome.[62,63]

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Only two studies with similar attributes were identified.[64,65] A third study, identified in

additional searches, was also included.[66] (Table 1)

Table 1. Predictive values of General Movements (GMs), negative predictive values (NPV) and positive predictive values (PPV), with respect to neurodevelopmental outcome between

18 months and 24 months corrected age

*GMs at 1 month post term, writhing age ^GMs at 3 months post term, fidgety age

Mean NPV and PPV were compared at each predictive time point (preterm, writing and

fidgety age). (Table 2) The PS- Power and Sample Size Calculation Software v.3.1.2, 2014

was then used to generate the sample size calculations for preterm, writhing and fidgety ages

using alpha 0.01, power of 0.95 and a ratio of 3:1.

Results suggest that the predictive time point of fidgety age (8-20 weeks) will require the

largest sample size to identify a statistically significant association between GM’s and

neurodevelopmental outcome. Data from the literature indicates that a normal GM result at

Studies included Sample

Size

(n)

Participants Outcome

measure and age

at outcome

Pre-

term

NPV

(%)

Post

term

NPV

(%)

Pre-

term

PPV

(%)

Post

term

PPV

(%)

Stahlmann et al.

2007

103 Preterm

infants

<1500g

Motor outcome on

the Griffiths

Developmental

Motor Scale at 20

months

^84 ^89

Constantinou et

al. 2007

102 Preterm

infants

< 1500g

Neurological

examination and

Bayley II scores at

18 months

90 ^90 29 ^41

Spittle et al.

2013

94 Preterm

infants

< 30 weeks

Cognitive outcome

on the Bayley III

at 2 years

*94

^96

*14

^35

Language outcome

on the Bayley III

at 2 years

*91

^93

*14

^35

Motor outcome on

the Bayley III at 2

years

*100

^96

*16

^35

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fidgety age leads to typical neurodevelopmental outcome at 24 months c.a in 92% of infants.

Assuming that GMs at fidgety age correctly identify mild neurodevelopmental outcomes at

24 months ca. in 47% of occasions, we will need to collect data on 80 participants at 24

months c.a. (20 with abnormal GM assessment and 60 with normal GM assessment) to

demonstrate a statistically significant association between GM results at fidgety age and TD

and MDD at 24 months c.a.

Table 2. Mean negative and positive predictive values using GMs at 3 time points to predict typical or delayed neurodevelopmental outcome in the second year of life.

Time point Mean NPV Mean PPV

Preterm 90 29

2-7 weeks post term - writhing 95 15

8-20 weeks post term - fidgety 92 47

NPV = negative predictive value PPV = positive predictive value

GMs = General Movements

By the nature of their design, longitudinal cohort studies are vulnerable to subject attrition

and missing data; a potential cause of bias.[67] In order to minimise any possible impact we

will add an extra 10 subjects (12.5%) into our study design and recruit a total of 90 infants

into the PREMTiME study.

Recruitment process

Infants will be enrolled in the study between 34 and 36 weeks g.a. An administrative staff

member in the SCN, not affiliated with the research project, will introduce the study to

parents or caregivers of infants who meet eligibility criteria. If families are interested and

provide permission for contact, the principal investigator or a member of the research team

will supply a full information pack including the parent information statement. When

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providing the pack, a researcher, not associated with the infant’s clinical care, will explain the

study in more detail and answer all parent questions before seeking informed consent for

study participation. Once signed consent is obtained, the infant will be enrolled in the study,

parents will complete the relevant forms and questionnaires and the infant will receive the

relevant assessments.

Data Collection Methods

Data collection will commence following consent and enrolment. (See Figure 1 for study

timeline) Perinatal data will be collected by a member of the research team. Primary

caregivers will complete baseline questionnaires; the EPDS, SRI and IOF-G.

Should a parent/caregiver score above 9 points on the EPDS, a member of the research team

will refer the mother/caregiver to the SCN social worker. The social worker will discuss the

results with the parent/caregiver, provide information about post-natal depression, explain the

need for further monitoring and request consent to send a letter of notification to the carer’s

general practitioner (GP). Both the assessment findings and the follow up plan will be

documented in the mother’s hospital chart. An opportunity to monitor progress is embedded

within the study design. All mothers or primary caregivers will repeat the test when their

infant reaches 45 weeks post term.

Between 34 and 36 weeks g.a infants will be assessed in the SCN using the Premie-Neuro

Examination (P-NE) and the General Movement Assessment (GMs). All assessors will be

masked to the identity, and medical history of the infants. GMs and PN-E assessments will be

recorded using procedural guidelines developed by the research team. The clinical

photographer at NGH is trained in the use of these guidelines. GM assessments will be

viewed and scored offline by two to four assessors trained by the General Movement Trust.

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After discharge, baseline data collection will occur during 4 return appointments to the Allied

Health Paediatric Outpatient clinic, NGH. At each visit growth trajectories will be monitored

by recording body weight and length. General Movements will be videotaped by the NGH

Clinical Photographer while supervised by a member of the research team and then viewed

offline by expert assessors masked to the infant’s identity, medical history, perinatal data and

previous assessment findings. The visits will be timed for 2, 5, 11-12 and 16 weeks post term

providing an opportunity for repeat assessment of GMs during both the writhing and fidgety

age. This may reduce the potential impact of missing data in the writhing age when infants

are occasionally too unsettled to complete video assessment. Importantly it meets the

requirement for assessment of fidgety movement on at least two occasions to definitively

classify GMs as absent fidgety.[68]

Additional data collection will occur at the 2, 5 and 16 week post term appointments. At 2

weeks post term infants will complete the NNNS. The assessment will be administered by an

NNNS accredited trainer masked to the identity and medical history of the infant. The

assessment will be videotaped to allow offline scoring as appropriate.

At 5 weeks post term the primary caregivers will repeat the EPDS questionnaire. Should the

caregiver score above 9 on this occasion, a social worker will be on site to discuss the results

in session. The social worker will recommend that the mother/caregiver seek follow up and

consent will be sought to provide the GP with the assessment findings. The assessment

results and negotiated health plan will be documented in the hospital chart.

At 16 weeks post term an occupational therapist will explain the Infant Sensory Profile 2

(Infant SP2) and provide parents with a copy of the questionnaire to complete in session. A

physiotherapist will then administer the Alberta Infant Motor Scale (AIMS). Video footage

collected during the 16 week visit will include both the GMs and the AIMS assessment

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allowing masked assessors to view and score the assessments offline. Following the 16 week

post term appointment infants will be categorised according to longitudinal trajectories of

GM’s into low, moderate and high risk groups. (Table 3)

Table 3. Classification of neurodevelopmental risk according to trajectory of longitudinal GMs between 34 to 35 weeks g.a and 16 weeks post term.

Level of risk Method of Classification

Low All normal GMs at preterm, writhing and fidgety age

Medium At least one finding of abnormal movement (poor repertoire or

cramped synchronized) at preterm or writhing age combined

with either normal fidgety or abnormal fidgety movement at

fidgety age.

High At least one finding of abnormal movement (poor repertoire or

cramped synchronized) at preterm or writhing period combined

with absent fidgety movement at fidgety age.

The outcome of all baseline assessments will be forwarded in report format to the Paediatric

Specialist Outpatient Clinic, NGH where a consulting Paediatrician will review all infants

enrolled in the research project between 18 and 20 weeks post term. At this visit the

Paediatrician will have an opportunity to discuss baseline assessment findings with parents or

caregivers. He/she may initiate referral to early intervention services and organise any

additional medical investigations required. A request for magnetic resonance imaging (MRI)

will be ordered by the Paediatrician in cases where infants are assessed as absent fidgety on

the GMs at 12 and 16 weeks.

Multidisciplinary case conferencing with the allied health team will be organised for all

infants identified as high risk. The content and intensity of any concurrent therapy received

whilst enrolled in the PREMTiME project will be documented by parents/caregivers in a

study calendar and measured in a parent recall questionnaire provided at study completion.

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At 24 months c.a (±1 month) all participants will attend two final appointments at NGH.

Approximately four weeks prior, families participating in the study will receive an

appointment letter and the Toddler SP2 questionnaire to complete and return at the first

appointment. Appointments will be scheduled within a two week period. Children will be

assessed by examiners masked to the child’s identified level of risk, previous assessment

findings, medical history and perinatal data.

At the first appointment children will receive the cognitive, motor and language scales of the

Bayley III and the Toddler SP2 questionnaire will be scored. Caregivers will be provided

with the Infant –Toddler Social Emotional Assessment (ITSEA) to complete at home and

return at the second session. Height and weight measurements will be recorded.

At the second visit, parent/caregivers will complete the Adaptive Behaviour (ABAS II) and

the Social Emotional Scales of the Bayley III while a member of the research team

administers the NSMDA. Both the Bayley III and NSMDA assessments will be video

recorded by the NGH clinical photographer.

All results of outcome assessment will be forwarded to the child’s Paediatrician at NGH,

Paediatric Specialist Outpatient Department. The Paediatrician will review each child within

one month of study completion. At this visit, final study results will be conveyed to the

parents/caregivers. Any diagnosis of cerebral palsy (CP) will be documented, defined and

classified according to the Surveillance of CP in Europe Network Guidelines and the Gross

Motor Function Classification Scale.[69-73] Classification of motor type of CP and Gross

Motor Function Classification Scale (GMFCS) will be confirmed after review of video

footage of the NSMDA by independent expert assessors at the QCPRRC.[70,74]

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MEASURES AND PROCEDURES

Baseline Measures

1. Perinatal Data

An extensive record of antenatal and birth history and the neonatal course will be collected

from the Nambour Hospital medical file at enrolment and then at discharge from the

SCN.[75,76] Data collected will include primary perinatal factors with known associations

with neurodevelopmental delay including early brain injury (intraventricular haemorrhage

identified on CUS or brain injury identified on MRI), intrauterine growth restriction (weight

<10th

centile for g.a), BPD (definition for infants born at < 32 weeks g.a as per criteria

outlined by the National Institute for Health, USA), retinopathy of prematurity (classified by

stages 1 to 5), severe necrotising enterocolitis (requiring surgery), late-onset sepsis (onset >

48 hours post birth), preterm premature rupture of membranes, postnatal infant steroid

therapy and gestational age at birth.[1,9-11,77-83]

Nambour General Hospital (NGH) is a regional facility located 100km north of the nearest

neonatal intensive care unit. Only a portion of high risk babies born or transferred from the

Royal Brisbane and Women’s hospital (RBWH) will receive MRI prior to transfer to

Nambour. A summary of MRI assessment findings will be included in transfer

documentation and will be collected with perinatal data when possible. All very

preterm/VLBW infants will have routine cranial ultrasound at day 3, 7 and 42 of life at the

RBWH prior to transfer to NGH. Early CUS findings are routinely included in transfer

documentation and graded and reported according to the conventions outlined in the Australia

and New Zealand Neonatal Network (ANZNN) data dictionary.[84]

(See Appendix 1 for a complete list of all perinatal variables included in data collection)

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2. Primary Caregiver Information

Edinburgh Post Natal Depression Scale (EPDS):

The EPDS is used to screen primary caregivers for risk of postnatal depression. It is a 10 item

self-reported scale that takes 5 minutes to administer.[85] Originally implemented in the UK

it has since been validated for use in Australia, demonstrating high sensitivity (100%) and

specificity (89%) at a cut off score of 12.5.[86] The EPDS appears to be acceptable to

women as a screening instrument with no complaints reported in an Australian study of 4148

administrations carried out over 3 years.[87] Facilitation of correct diagnosis is optimised by

a two-step strategy where those scoring above a predetermined cut off score on the first

occasion have another test readministered at a subsequent health visit.[87] In keeping with

this evidence based recommendation, the EPDS will be used twice during this study. Primary

caregivers will complete the questionnaire at 34-36 weeks and at 5 weeks post term.

Clearly defined processes have been developed around the event that a parent/caregiver

scores above a clinically conservative score of 9 points on the scale. Researchers will ensure

that caregivers are provided timely support by a social worker, consent is sought to inform

their GP, women are encouraged to seek follow-up and a negotiated health plan is

documented in the hospital chart.

Social Risk Index:

A 12-point SRI will be used between 34 and 36 weeks g.a to provide an overall social risk

score for each family.[12,75] Families will be informed in the parent information statement

that all responses on the questionnaire will be treated in a strictly confidential manner. The

index measures six aspects of social status:

1. Family structure (0 – two caregivers (nuclear); 1 – separated parents with dual custody, or

cared for by other intact family; 2 – single caregiver)

2. Education of primary caregiver (0 – tertiary educated; 1 – 11–12 years of formal

schooling; 2 – less than 11 years of formal schooling)

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3. Occupation of primary income earner (0 – skilled/professional; 1 – semiskilled; 2 –

unskilled)

4. Employment status of primary income earner (0 – full-time employment; 1 – part-time

employment; 2 – unemployed/pension)

5. Language spoken at home (0 – English only; 1 – some English; 2 – no English)

6. Maternal age at birth (0 – more than 21 years; 1 – 18–21 years; 2 – less than 18 years).

Families will be categorised as lower social risk (score ≤ 1) or higher social risk (≥2).[75]

Revised Impact on Family Scale (IOF-G Scale):

This questionnaire will be used between 34 and 36 weeks to assess the effect of a child’s

illness, in this case preterm birth, on the family system. The scale is an easily administered,

reliable, and valid measure of a family member’s perception of the effect of a child’s chronic

condition that can be used across diagnostic groups.[88-90] There are 15 items scored on a 4

point Likert scale (strongly agree to strongly disagree) that take 10 minutes to complete. It

can be used either as a questionnaire or read to the family if needed.[88,90]

3. Infant Assessments

The Premie-Neuro Examination (P-NE)

The PN-E is a new assessment tool designed in response to the relative scarcity of effective

neurologic assessments available for the extremely low birth weight (ELBW) and VLBW

infant.[49,51] It is a standardised clinical neurological and neurobehavioural examination

designed to assess brain function in fragile VLBW/very preterm infants from birth until 37

weeks of gestation.[49] The test is specifically designed to minimise the impact of handling

and can be modified for infants less than 28 weeks. It can be done whilst the baby is still in

isolette and electronically monitored and can be completed within approximately 10 minutes.

The test is administered between 30 minutes and one hour before a scheduled feed and takes

10-15 minutes to complete. It consists of 3 subscales; Neurologic, Movement and

Responsiveness - each with 8 items. Early research indicates good construct validity with

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good internal consistencies of the three subscales. (Cronbach α 75, .73 and .82). There is

evidence of predictive capability with raw scores at 34 to 36 weeks c.a. able to discriminate

between high and low risk groups of infants at term age and predict outcome on the Alberta

Infant Motor Scale at 3 months c.a.[46,49,51] In keeping with these findings infants in this

study will have the PN-E administered between 34 and 36 weeks g.a.

It is acknowledged that the PN-E has less published evidence for prediction than other

preterm assessments such as the Dubowitz Neurological Assessment or the Test of Infant

Motor performance (TIMP). The Dubowitz was not included in this study as its predictive

capability for normal outcomes is relatively modest and the primary aim of this study is to

predict typical outcome.[91] The TIMP has moderately better predictive validity for outcome

than the Dubowitz but less clinical utility than the PN-E.[45,48] The TIMP takes up to 40

minutes to administer while scoring 42 items, the majority of which are elicited. This is not

suited to many fragile preterm infants less than 36 weeks of age and does not fit well within

the ethos of a special care nursery where nursing and medical staff aim to keep handling and

cares to a bare minimum.

As the PN-E has high clinical utility with early indications of useful clinical validity, it has

potential for use as a very early biomarker of neurodevelopmental risk. Further research is

required to determine test reliability in the clinical setting, to determine concurrent validity

with other early neuromotor assessments (specifically GMs) and to further determine

predictive validity.[51] All P-NE assessments will be video recorded to increase accuracy of

measurement, especially on observational items. Our own inter-rater reliability will be

determined as part of the study using a sub-sample of 20 infants.

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Prechtl’s Method of Qualitative Assessment of General Movements (GMs)

The General Movement assessment is a predictive and discriminative tool that involves

longitudinal observations of the infant’s spontaneous motor activity.[45,92] GMs have high

specificity (96%) and sensitivity (95%) for predicting cerebral palsy and early evidence

suggests they have potential to predict normal or milder neurodevelopmental

outcomes.[62,63,93-96] GMs are assessed from preterm until 20 weeks c.a. The assessment

is carried out by videoing the infant in a calm alert state, without external stimulation. In the

early preterm stage this may require up to an hour of video recording but after the infant

reaches term age, 5 minutes is the minimum requirement.

Examiners must determine if spontaneous movement is fluent, variable and complex before

defining GMs as normal or abnormal.[92] Normal GMs in the preterm period are gross

movements involving the whole body, including arm, leg, neck and trunk movements in

variable sequence. They “wax and wane” in intensity, force and speed and have a gradual

beginning and end.[92] From 40 weeks until approximately 8 weeks post term movements

are classified as “writhing” in nature. Normal writhing movements are characterised by small

to moderate amplitude and by slow to moderate speed and are elliptical in form. Abnormal

movements during the both the preterm and writing periods are described as poor repertoire,

chaotic or cramped synchronized.[92]

Between 6 and 9 weeks post term and continuing until approximately 20 weeks c.a, GMs

change to a “fidgety” pattern and are defined as “circular movements of small amplitude and

moderate speed and variable acceleration, of neck, trunk, and limbs, in all directions”.[92]

They are continual in the awake infant, except during focused attention, fussing and crying.

The infant will score as normal when fidgety movements are present. Abnormal movement is

scored when fidgety movements are absent or abnormal in pattern. Assessment at more than

one time point during the fidgety age is necessary to definitively score an infant as absent

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fidgety.[68] The infants in this study will have GMs assessed at 34-36 weeks, 2, 5, 11-12 and

16 weeks post term.

Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS)

The NNNS is a non-invasive clinical tool developed to assess neurobehaviour of “at risk”

infants and is suitable for use with very preterm/VLBW infants.[52,97] The assessment takes

between 15 to 20 minutes to administer, ideally in a quiet, dimly lit room, 2 hours after

feeding. The examination is state dependent with a standardised format. It assesses the full

range of infant neurobehavioral performance including neurological integrity, behavioural

functioning, and signs of stress/abstinence.[52,97]

Test items are presented in 13 packages providing summary scores/subscales for habituation,

attention, handling, quality of movement, regulation, non-optimal reflexes, arousal,

hypertonicity, hypotonicity, asymmetrical reflexes, excitability and lethargy.[52,97] The

NNNS has good internal consistency for item summary scores (Cronbachs α 0.87 to

0.90).[98] Published norms are available for summary scores of healthy term born infants at

term age (n=344) and for summary scores of very preterm infants at 1 month c.a. (n=204, 24

to 32 weeks g.a.).[98,99]

Evidence for prediction of motor and cognitive outcomes in very preterm and VLBW

populations is good.[53,54,100] Summary scores at term c.a. in a sample of 41 VLBW

infants were predictive of motor and cognitive outcomes on the Bayley Scales of Infant and

Toddler Development – Second Edition (Bayley II) at 18 months c.a.[53] In another study of

1248 infants < 37 weeks gestation, profiles of summary scores (profiles 1-5) were calculated

and used to predict outcome from birth to 4.5 years. At 1 month c.a, infants with a profile of

5 were more likely to have impaired Bayley II mental and psychomotor developmental index

scores at 2 years c.a.; chronic neurological abnormalities and brain-related illness or cerebral

palsy and behaviour problems at 3 years; motor, concept and language problems in school

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readiness at age 4 years; and lower IQ at 4 and half years.[54] The NNNS will be used to

assess infant neurobehaviour at 2 weeks c.a.

Alberta Infant Motor Scale (AIMS)

The AIMS is a discriminative, norm referenced tool that tests gross motor skills through the

components of weight bearing, posture and antigravity movements.[101,102] The test takes

20 minutes to administer and involves observation of the infant in prone, supine, sitting and

standing. The AIMS is an appropriate assessment tool for monitoring the gross motor

development of typically-developing infants and has normative data based on a population of

2200 infants from 0-18 months in Alberta, Canada.[101] Normative data for preterm infants

has also been published with a sample of 800 infants born at <32 weeks from the

Netherlands.[103]

The AIMS has excellent inter-rater, intra-rater and test-retest reliability for full term and

preterm infants.[104,105] The AIMS has excellent reliability, content, construct and

concurrent validity with the BSID-II (r = 0.98).[101,105,106] Although the AIMS was not

designed as a predictive tool, it has good predictive validity at 4 months for developmental

outcome at 18 months (sensitivity 77.3 %, specificity 81.7%).[107] The AIMS will be used

to classify each infant’s development as normal or suspicious/abnormal at 56 weeks g.a using

cut points at the 10th

centile on the term percentile scale and the 25th

centile on the premature

infant percentile scale.[101,103]

Sensory Profile 2 (SP2)

The SP2 is a newly revised edition of the Infant Toddler Sensory Profile.[56,57] It is a

standardised tool used to evaluate a child’s sensory processing patterns in the context of

participation. It enables professionals to gather information about the child’s sensory

processing abilities and how those patterns either support or interfere with functional

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performance.[58] It is based on a sensory integration and neuroscience frame of reference and

the author’s model of sensory processing.[108,109]

The tool supports family centred practice by actively engaging the primary caregiver in the

data gathering process.[110] Primary caregivers observe the infant or child engaging in a

number of different environmental contexts at home or other community settings and then

report on a range of behaviours on the item scoring sheet. The estimated time for completion

is 5 to 20 minutes based upon the caregiver completing the questionnaire in one sitting.

The SP2 was standardized between 2012 and 2013 using a normative sample of 1791 subjects

and a clinical sample of 771.[56,57] Where previously only raw scores were calculated, the

new version allows percentile ranking of infant total scores as well as quadrant scores for

toddlers and older children. Reliability of the measure is overall good to very good (internal

consistency 0.63-0.93, parent test-retest 0.83-0.97, inter-rater reliability 0.49-0.9/mostly

>0.7).[56] Correlation between the Infant Toddler Sensory Profile (ITSP) and the SP2 is

moderate to high.[56,57]

The new edition has several other improvements and advantages compared to the

ITSP.[56,57] The required reading level is grade 6 equivalent and parents have the option to

complete the forms online. In addition, the questionnaire is now presented in two separate

user friendly forms for infants and for toddlers. The Infant Sensory Profile 2 is used for

babies from birth to six months and will be used as a baseline measure at 16 weeks post term.

The Toddler Sensory Profile 2 is for ages 7 to 35 months. It will be used as an outcome

measure at 24 months c.a.

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Outcome Measures

1. The Bayley Scales of Infant Toddler Development – Third Edition (Bayley III)

This assessment is a relatively new revision of the Bayley Scales of Infant Development -

Second Edition. It is a norm referenced, discriminative measure used to describe the current

developmental functioning of the infant with good to strong validity and reliability.[111]

Other possible uses of the test include identification of possible developmental delay,

identification of relative strengths and weaknesses, monitoring of developmental progress

and prediction of cognitive function at preschool entry.[112] The third edition consists of 5

distinct scales: Cognitive, Language, Motor, Social-Emotional, and Adaptive Behaviour

Scales (ABAS-II). All 5 scales will be utilised in this study. Assessment is individually

administered and may take up to 90 minutes to complete. Caregivers are encouraged to

remain present but not to influence the test proceedings.

Several recent studies recommend the precautionary use of a term born control group and/or

different cut points when using the Bayley III as a primary outcome measure.[113-116]

Studies conducted in Australia and the United States have found that significantly fewer

infants are identified with neurodevelopmental delay with the Bayley III when compared to

previous findings using the Bayley Scales of Infant Toddler Development II (Bayley II).[95-

102] Several explanations are possible but it is still unclear whether the Bayley III is

overestimating developmental performance, whether it is a more valid assessment of

neurodevelopmental impairment than the Bayley II or if premature infant outcomes are

improving. In keeping with these recommendations, scores obtained in this cohort of very

preterm/VLBW infants will be compared to published reference data of an Australian cohort

of 202 term born controls.[114]

The ABAS-II is one of the 5 subscales in the Bayley III.[111] Adaptive behaviour is defined

as the collection of conceptual, social, and practical skills that have been learned by people in

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order to function in their everyday lives.[117] A newly revised edition, The ABAS-3 is now

available for use.[118] Retaining all of the essential feature of the ABAS -II, the new edition

is even easier to administer and score. It is a parent reported, norm referenced and

standardised measure of adaptive skills measuring a child’s functioning ability in the areas of

Communication, Community Use, Health and Safety, Leisure, Self-Care, Self-Direction,

Functional Pre-Academics, Home or School Living, Social, Work and Motor.[118]

The ABAS-3 takes 15 to 20 minutes to complete. Caregivers rate the extent to which their

child performs the adaptive skill when needed using a 4-point reference scale. Norm

referenced scaled scores are used to interpret results in the skills area and norm-referenced

standard scores, confidence intervals for standard scores, and percentile ranks are used to rate

performance across the 3 adaptive domains and calculate a General Adaptive Composite

score. [119] The ABAS-3 builds on the ABAS-II which has strong psychometric properties

with good to excellent content validity, test-retest reliability and internal consistency.[117]

2. The Neuro-Sensory and Motor Developmental Assessment (NSMDA)

This a discriminative and predictive criterion referenced measure with a functional grading

system that scores overall motor performance classification as normal, mild not impacting

function, mild, moderate, severe or profound impairment.[45,119] It measures gross motor,

fine motor and sensory motor development, neurological status and postural control. The

examiner observes and administers items and the test takes up to 30 minutes to complete. A

published study of 148 preterm infants demonstrates adequate construct validity with the

NSMDA able to discriminate between normal and abnormal outcome at 24 months

c.a.[45,120] Concurrent validity has been reported in relation to agreement with paediatric

classification of normal or atypical development at 24 months c.a. (χ²=0.08).[45,120]

Reliability has only been reported in terms of correlation (r = 0.80).[45]

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3. The Infant Toddler Social-Emotional Assessment (ITSEA)

The ITSEA is a comprehensive parent-report instrument for evaluating behavioural problems

and social emotional competencies in infants aged 12 to 36 months.[121] The complete

ITSEA includes 166 items that are rated on a 3-point scale: (0) Not true/rarely, (1) Somewhat

true/sometimes, and (2) Very true/often. A “No opportunity” code allows parents to indicate

that they have not had the opportunity to observe certain behaviours. If reading levels are

inadequate it can be presented in interview format without impeding test reliability.[121]

The test measures four broad domains of behaviour; Externalizing, Internalizing,

Dysregulation and Competencies. Three additional indices; Maladaptive, Atypical Behaviour

and Social Relatedness are used to aid identification of significant psychopathology including

attention deficit hyperactivity disorder or autistic spectrum disorder.[121] Test construct,

reliability and validity was examined in a population sample of 1,235 parents of children.[121]

The test has good internal consistency across all four major domains, good validity and

acceptable test-retest and inter-rater reliability.[75,121]

DATA ANALYSIS PLAN

Analysis will be carried out using R version 2.9.1 with the R-Commander and R Studio

statistical analysis packages. Predictor and outcome variables will be identified as continuous

or categorical. Initial analysis will explore the distributions, means and variability of

continuous variables and the rate of occurrence and distribution of categorical variables. Any

outlying data will be identified and the characteristics of any missing data explored.

Graphical representations (histograms, boxplots and scatter plots), tables of means and

standard deviation (SD) and cross tabulations will be used to understand any relationships

between variables.

Univariable regression analysis will be used to determine any associations between predictor

and outcome variables. A forward selection process, entering variables one by one, will help

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to determine any confounding pathways. Multivariable analysis will be performed to

understand major contributors and the effect of confounders. Generalised estimating

equations (GEEs) will be included to determine the extent that early assessment will predict

later outcomes of interest.[122] GEEs track the importance of potential predictor variables

over time, accounting for the dependence of observations recorded from the same participant.

Consideration will be given to any non-linear effects and interactions.

A scaled score of the baseline assessment measures will be used to determine the sensitivity,

specificity, PPV and NPV of early biomarkers to predict typical outcome and MDD at 24

months c.a. Typical outcome will be defined as motor and cognitive scores that are above

1SD below the mean on the Bayley III and a functional grade of 1 or 2 on the NSMDA.

Developmental delay will be defined as motor and cognitive scores 1SD or more below the

mean on the motor and cognitive subscales of the Bayley III and a functional grade greater

than 2 on the NSMDA.

DISCUSSION

As families, clinicians and health services continue to want and need more immediate

information regarding the short and long term outcomes of at risk infants, finding the best

clinical biomarkers has the potential to streamline and effectively prioritise premature infant

follow up programs.

Results of this study will inform health policy and service delivery of follow up pathways and

early intervention for very preterm/VLBW infants and their families and guide the provision

of targeted, evidence based service delivery in clinical settings. Findings will be of interest to

medical, allied health, nursing staff, hospital and health service districts.

Findings will also inform future studies with the intent to follow this cohort of very

preterm/VLBW infants until completion of the Queensland Studies Authority, Grade 2

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Diagnostic NET test. The Diagnostic NET test is a monitoring and assessment program of

literacy and numeracy competencies administered state wide and typically undertaken at 7

years of age in Queensland schools.[123]

ABBREVIATIONS

ABAS-II Adaptive Behaviour Assessment Scale – Second Edition

ABAS-3 Adaptive Behaviour Assessment Scale – Third Edition

AIMS Alberta Infant Motor Scale

ANZNN Australian and New Zealand Neonatal Network

Bayley II Bayley Scales of Infant and Toddler Development – Second Edition

Bayley III Bayley Scales of Infant and Toddler Development – Third Edition

BPD Bronchopulmonary Dysplasia

c.a corrected age

CP Cerebral Palsy

CUS Cranial Ultrasound

EPDS Edinburgh Post Natal Depression Scale

g.a gestational age

GEEs Generalised Estimating Equations

GMs General Movements

GMFCS Gross Motor Function Classification Scale

GP General Practitioner

IOF-G Impact on Families Scale

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Infant SP2 Infant Sensory Profile 2

ITSEA Infant Toddler Social-Emotional Assessment

ITSP Infant Toddler Social-Emotional Assessment

IUGR Intrauterine Growth Restriction

IVH Intraventricular Haemorrhage

MABC Movement Assessment Battery for Children

MDD Mild Developmental Delay

MMD Mild Motor Delay

MRI Magnetic Resonance Imaging

NGH Nambour General Hospital

NNNS The Neonatal Intensive Care Unit Network Neurobehavioral Scale

NPV Negative Predictive Value

NSMDA Neuro-Sensory and Motor Developmental Assessment

P-NE Premie-Neuro Examination

PPV Positive Predictive Value

QCPRRC Queensland Cerebral Palsy and Rehabilitation Research Centre

ROP Retinopathy of Prematurity

RBWH Royal Brisbane and Women’s Hospital

SCHHS Sunshine Coast Hospital and Health Service

SCN Special Care Nursery

SD Standard Deviation

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SES Social Economic Status

SRI Social Risk Index

TD Typical Development

Toddler SP2 Toddler Sensory Profile 2

Very Preterm Less than 32 weeks gestational age at birth

VLBW Very low birth weight (infants born at less than 1500g)

COMPETING INTERESTS

The authors declare they have no competing interests.

AUTHOR’S CONTRIBUTIONS

Chief investigators that have had substantial input into study design: RC, RB, PC, GC, RW

Associate investigators that have provided input into study design: MJ, KS, JD, TH

Study personnel responsible for ethics applications and reporting: RC, RB, PC, GC

Study personnel responsible for writing the protocol manuscript: RC, RB, PC, GC, RW

Study personnel responsible for recruitment, data collection and implementation of the study:

RC, KS, JD, MJ, LM, TH, AM, CT, LC, EB

Chief investigators that will take lead roles in publication of the clinical outcomes of the

study: RC, RB, PC, GC, RW

All authors have read and approved the final manuscript

COLLABORATOR CONTRIBUTIONS – PREMTiME Study Group

Collaborators that have provided scientific advice: SC, KG, HW

Collaborators who have provided assistance with patient care and data collection: LT, JC

ACKNOWLEDGEMENTS

The PREMTiME study is funded by grants from the Health Practitioner Research Scheme,

Queensland Health and by Wishlist, Sunshine Coast Health Foundation. It receives support

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from Allied Health staff working in the Women’s and Families stream at NGH including

physiotherapists, occupational therapists, dieticians, social workers and speech pathologists.

Further support is provided by administrative, nursing and medical staff in the NGH SCN,

administrative staff at the Sunshine Coast Clinical School and from the Medical Imaging

Department, Nambour General Hospital.

The team acknowledges the contributions of administrative officers in the Women’s and

Families Stream NGH, for co-ordination of outpatient appointment bookings. It thanks Mr

Geoffrey Eddy, Clinical Photographer, for video recording of research assessments. It also

acknowledges assistance from Mrs Lorelle Addison and Mrs Helen Moffat, administrative

officers in the NGH SCN, with study recruitment. It thanks Ms Megan Rutter, Research

Governance and Development Manager at Nambour General Hospital for her assistance with

ethics approval and grant applications.

ETHICS AND DISSEMINATION

Ethical permission to conduct the study has been obtained from the Queensland Children’s

Health Services (RCH) Human Research Ethics Committee (HREC/13/QRCH/66), the

University of Queensland (2013001019) and the Sunshine Coast Hospital and Health Service,

SC-Research Governance (SSA/13/QNB/66). Publications of all outcomes will be published

in peer reviewed journals.

Trial Registration: ACTRN12614000480684

Web address of trial: http://www.ANZCTR.org.au/ACTRN12614000480684.aspx

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Figure 1. Study time line of recruitment and assessment time points. KEY: P-NE = The Premie-Neuro Examination [47,58]; GMs = General Movement Assessment [91]; EPDS = Edinburgh Post Natal Depression Scale [84] ; SRI = Social Risk Index [12,76]; IOF = Impact of Family Scale [87-89];NNNS = NICU Network

Neurobehavioral Scale [50]; Infant SP2 = Infant Sensory Profile 2 [54,55]; AIMS = Alberta Infant Motor Scale [100], Bayley III = Bayley Scales of Infant and Toddler Development – 3rd edition [110]; NSMDA = Neuro-Sensory and Motor Developmental Assessment [116]; ITSEA = Infant-Toddler Social Emotional Assessment [118]; Toddler SP2 = Toddler Sensory Profile 2 [54,55]; ABAS-3 = Adaptive Behaviour

Assessment Scale – 3rd Edition [118]; c.a = corrected age 181x190mm (300 x 300 DPI)

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APPENDIX 1

Table 3. Detailed description and definition of perinatal data collected during participants

inpatient stay in the Special Care Nursery, Nambour General Hospital.

Variable Description Code

1. ID Subject ID 001-

2. Sex Sex of the child 1=Male

2=Female

3. Ethnic Ethnicity of the child 1 = Caucasian

2 = Aboriginal/Torres Strait

3 = Maori/Polynesian

4 = Asian

5 = Other

4. Multi Multiple birth status 1= singleton

2 = twin

3 = triplet

4 = quadruplet or >

5. Siblings Number of siblings 0 = only child

1 = 1 sibling

2 = 2 siblings

3 = 3 siblings

4 = 4 or more siblings

Maternal Variables

6. Mat_diab History of diabetes 1= non diabetic

2= Type 1 diabetes

3 = Type 2 diabetes

4 = Gestational diabetes

7. Mat_inf Infection in pregnancy or at delivery 0 = No

1= Yes

8. Mat_depr History of depression 0 = No

1= Yes

9. Mat_pl Placental presentation in pregnancy or

delivery

1 = nil complication

2 = placenta Previa

3 = abruption

10. APH Antepartum haemorrhage 0 = No

1 = Yes

11. Mat_pre Pre-eclampsia/eclampsia in pregnancy 1 = none

2 = Pre-eclampsia

3 = HELLP (haemolysis, elevated

liver enzymes, low platelets

4 = eclampsia

12. TTTS Twin to twin transfusion syndrome in

pregnancy

0 = No

1 = Yes

13. SPTL Spontaneous preterm labour 0 = No

1 = Yes

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14. PROM Premature rupture of membranes 0 = No

1 = Yes

15. Chorio Chorioamnionitis in pregnancy 1 = none

2 = clinical

3 = histological

16. Mat_IUGR Intrauterine growth restriction (IUGR)

as cause of preterm delivery

0 = No

1 = Yes

17. F_dist Foetal distress during pregnancy or

delivery

1 = none

2 = foetal distress in pregnancy

3 = foetal distress in delivery

18. Mat_subst Substance use in pregnancy 1 = no substance use

2 = smoking

3 = alcohol

4 = drug use

5 = combined substance use

19. Mat_med Medications prescribed in pregnancy 0 = No

2 = Yes

20. Mat_cort Maternal corticosteroids 0 = No

1 = Yes

21. Mat_MgSO4 Maternal magnesium sulphate 0 = No

1 = Yes

22. Mat_antib Maternal antibiotics 0 = No

1 = Yes

23. Mat_del Type of delivery 1 = spontaneous vaginal

2 = assisted vaginal

(forceps or vacuum)

3 = caesarean section

Infant Variables

24. K Gestation at delivery In weeks (23 -36)

25. BW Birth weight In grams (400 – 2000)

26. Apgar 1 Apgar score at 1 minute Numbered score (0, worst - 9,

best)

27. Apgar 5 Apgar score at 5 minutes Numbered score (0, worst - 9,

best)

28. Resus Resuscitation requirement at birth 1 = nil requirement

2 = oxygen only

3 = oxygen and mask resuscitation

4 = CPAP

5 = intubation/ventilation

29. Inf_surf Surfactant requirement 1 = nil

2 = 1 dose

3 = 2 or more doses

30. Inf_IUGR IUGR status at birth 0 = birth weight > 10th centile

1 = birth weight < 10th centile

31. Inf_vent Total time intubated and ventilated In 15 minute intervals per hour

(1.0, 1.25, 1.5, 1.75, 2.0 to ……)

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32. Inf_CPAP Total time on CPAP In 15 minute intervals per hour

(1.0, 1.25, 1.5, 1.75, 2.0 to ……)

33. Max_O2 Maximum concentration of Oxygen

administered during neonatal care

In percentage (0-100%)

34. Inf_CST Infant required corticosteroid

treatment

0 = No

1 = Yes

35. Inf_mg Infant prescribed MgSO4 0 = No

1 = Yes

36. Inf_Ptx Incidence of pneumothorax 0 = No

1 = Yes

37. Inf_IVH Incidence of intraventricular

haemorrhage

1= no IVH

2= unilateral IVH

3= bilateral IVH

38. Inf_grade Highest grade of IVH diagnosed on

cranial ultrasound – using the

Australian and New Zealand Neonatal

Network Data Definitions

+ classification by ANZNN

definition

0 = None

1= Grade 1

2 = Grade 2

3 = Grade 3

4 = Grade 4 Localised

5 = Grade 4 – Extensive

39. Inf_PVL Highest grade of periventricular

leukomalacia diagnosed on cranial

ultrasound or MRI

++ classification by ANZNN data

definitions

0 = no cysts

1 = porencephalic cysts

2 = PVL confined to one region

3 = PVL extending to two or more

regions

40. Inf_brain Other infant brain abnormality or

pathology (not IVH or PVL)

1 = no abnormality detected

2 = hydrocephalus

3 = porencephalic cyst formation

4 = absent corpus callosum

5 = other brain insult or

abnormality

41. Inf_cardio Presence or absence of a congenital

heart abnormality

1 = not present

2 = PDA*, no treatment required

3 = PDA*, treated medically

4 = VSD**

5 = other abnormality ***

6 = more than 1 abnormality

42. Inf_NEC Presence and severity of necrotising

enterocolitis

1 = none

2 = clinical signs only

3 = clinical and radiologic signs

4 = perforation

5 = surgery required

43. Inf_blood Number of blood transfusions required

during neonatal care

1 = none

2 = 1

3 = 2

4 = 3 or more

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44. Inf_sepsis Incidence of infection during neonatal

care

1 = no infection

2 = early infection < 48 hours

3 = late infection > 48 hours

4 = both early and late infection

45. Inf_antib Number of courses of antibiotic

therapy required during neonatal care

0 = nil required

1 = 1 course

2 = 2 courses

3 = 3 courses

4 = > 3 courses

46. Inf_ROP Retinopathy of prematurity, worst

grade recorded in medical chart

+++ classification summary

0 = no ROP

1 = stage I

2 = stage II

3 = stage III

4 = stage IV

5 = stage V

47. Inf_TPN Duration of total parenteral nutrition In days (1 - )

48. Feed_dc Feeding status at discharge 1 = exclusive breast feeding

2 = mixed breast/bottle feeding

3 = breast fed and nasogastric tube

4 = bottle fed only

5 = bottle fed and nasogastric tube

6 = nasogastric tube only

49. Nutri_dc Nutritional status at discharge 1 = breast milk

2 = mixed breast milk and formula

3 = formula only

50. Wt_dc Weight at discharge In grams (0 to )

51. Inf_BPD Presence and severity of

bronchopulmonary dysplasia

++++ Definition by severity for

infants born at < 32 weeks g.a

0 = no BPD

1 = mild

2 = moderate or severe

52. O2_dc Oxygen requirement at discharge In litres/minute (0 to )

53. Plagio_dc Plagiocephaly present at discharge 1 = no plagiocephaly

2 = mild

3 = severe

+ Highest level of Intraventricular Haemorrhage (using ANZNN data definitions)

0 = None − CUS/ post mortem shows no haemorrhage

1= Grade 1 − Subependymal germinal matrix haemorrhage

2 = Grade 2 − Intraventricular haemorrhage

3 = Grade 3 − Intraventricular haemorrhage with ventricle distended with blood

4 = Grade 4 – Localised parenchymal haemorrhage

5 = Grade 4 – Extensive intraparenchymal haemorrhage

++ Cerebral Cysts (using ANZNN data definitions)

0 = no cysts, no cystic lesions seen on CUS

1 = Porencephalic cyst(s)

2 = Periventricular leukomalacia primarily confined to one of the regions: anterior

frontal, posterior frontal, parietal, temporal or occipital region (same as defined for

periventricular haemorrhage)

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3= Extensive leukomalacia involving two or more of the above regions

+++ ROP Classification

Stage 1 – Mildly abnormal blood vessel growth

Stage 2 – Moderately abnormal blood vessel growth

Stage 3 – Severely abnormal blood vessel growth

Stage 4 – Partially detached retina

Stage 5 – Completely detached retina and the end stage of the disease

++++ Definition of BPD for infants born at < 32 weeks g.a

(based on the National Institute of Child Health and Human Development/National Heart, Lung, and

Blood Institute Workshop Summary, 2001)

Mild - in supplemental oxygen at 28 days of age, but in air by 36 weeks corrected age.

Moderate - requiring <30% supplemental oxygen at 36 weeks corrected age.

Severe - in >30% supplemental oxygen and/or requiring positive pressure support, CPAP or

ventilation, at 36 weeks corrected age.

* PDA = Patent Ductus Arteriosus

** VSD = Ventricular Septal Defect

*** Other cardiac abnormalities include: aortic stenosis, atrial septal defect, atrioventricular canal defect,

co-arctation of the aorta, hypoplastic left heart syndrome, patent foramen ovale, pulmonary atresia,

pulmonary stenosis, tetralogy of fallot, total anomalous pulmonary venous connection, transposition of

the great arteries, tricuspid atresia, truncus arteriosus

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BMJ Open...Baer, Erica ; Sunshine Coast Hospital and Health Service, Department of Paediatrics, Nambour General Hospital Primary Subject Heading: Paediatrics Secondary