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Confidential: For Review O

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The continuum of neurobehavior and its associations with

brain MRI in infants born preterm

Journal: BMJ Paediatrics Open

Manuscript ID bmjpo-2017-000136

Article Type: Original article

Date Submitted by the Author: 31-May-2017

Complete List of Authors: Eeles, Abbey; Murdoch Childrens Research Institute, Victorian Infant Brain Study Walsh, Jennifer; The Royal Women's Hospital, Newborn Research Olsen, Joy; Murdoch Childrens Research Institute Cuzzilla, Rocco Thompson, Deanne

Anderson, Peter Doyle, Lex; Royal WOmen's Hospital, Cheong, Jeanie Spittle, Alicia; University of Melbourne School of Health Services, Physiotherapy

Keywords: Neurodevelopment

https://mc.manuscriptcentral.com/bmjpo

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The continuum of neurobehavior and its associations with brain MRI in infants

born preterm

Abbey L Eeles,b,c

Jennifer M Walsh,b,c,d

Joy E Olsen,b,c,e

Rocco Cuzzilla,b,c,e

Deanne

K Thompson,b,f,h

Peter J Anderson, b,f,g

Lex W Doyle, b,c,e,f

Jeannie L Y Cheong,b,c,f

Alicia J Spittlea,b,c

Author Affiliations: aDepartment of Physiotherapy, University of Melbourne,

Melbourne, Vic; bMurdoch Childrens Research Institute, Melbourne, Vic;

cNewborn

Research, Royal Women’s Hospital, Melbourne, Vic; dPaediatric Infant Perinatal

Emergency Retrieval (PIPER), The Royal Children’s Hospital, Melbourne, Vic; eDepartment of Obstetrics and Gynaecology, University of Melbourne, Melbourne,

Vic; fDepartment of Paediatrics, University of Melbourne, Melbourne, Vic;

gMonash

Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne,

Vic; hFlorey Institute of Neuroscience and Mental Health, Melbourne, Vic

Corresponding Author:

Alicia J Spittle

7th Floor, Alan Gilbert Building, University of Melbourne, Grattan Street, Parkville,

Vic, Australia, 3052.

E-mail: [email protected]

Copyright:

The Corresponding Author has the right to grant on behalf of all authors and does

grant on behalf of all authors, a worldwide licence to the Publishers and its licensees

in perpetuity, in all forms, formats and media (whether known now or created in the

future), to i) publish, reproduce, distribute, display and store the Contribution, ii)

translate the Contribution into other languages, create adaptations, reprints, include

within collections and create summaries, extracts and/or, abstracts of the

Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to

exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links

from the Contribution to third party material where-ever it may be located; and, vi)

licence any third party to do any or all of the above.

What is known about this subject?

Infants born very preterm are at increased risk of long-term neurodevelopmental

deficits. Early interventions can improve developmental outcomes and thus early

identification of infants at greatest need for these services is paramount. Brain MRI

abnormalities has been associated with neurobehaviour functioning in very preterm

infants, however, this relationship is yet to be explored in moderate-to-late preterm

infants.

What this study adds:

This study highlights a clear continuum of neurobehaviour with increased suboptimal

functioning on three neurobehavioral assessments with decreasing gestational age.

The relationships between brain abnormality scores and suboptimal neurobehavior

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provides evidence that neurobehavioral assessments may be useful in earlier

identification of the highest-risk infants.

Word count: 2857

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ABSTRACT

Background

Infants born very preterm (VPT) and moderate-to-late preterm (MLPT) are at

increased risk of long-term neurodevelopmental deficits, but how these deficits relate

to early neurobehavior in MLPT children is unclear. The aims of this study were to

compare the neurobehavioral performance of infants born across 3 different

gestational age groups: VPT (<30 weeks’ gestational age); MLPT (32 to 36 weeks’

gestational age); and term age ≥37 weeks’ gestational age), and explore the

relationships between MRI brain abnormalities and neurobehavior at term-equivalent

age.

Methods

Neurobehaviour was assessed at term equivalent age in 149 VPT, 200 MLPT, and 200

term born infants using the NICU Network Neurobehavioral Scale (NNNS), the

Hammersmith Neonatal Neurological Exam (HNNE), and Prechtl’s Qualitative

Assessment of General Movements (GMA). A subset of 110 VPT and 198 MLPT

infants had concurrent brain MRI.

Results

Proportions with abnormal neurobehavior on the NNNS and the HNNE, and

abnormal GMA all increased with decreasing gestational age. Higher brain MRI

abnormality scores in some regions were associated with suboptimal neurobehavior

on the NNNS and HNNE. The relationships between brain MRI abnormality scores

and suboptimal neurobehavior were similar in both VPT and MLPT infants. The

relationship between brain MRI abnormality scores and abnormal GMA was stronger

in VPT infants.

Conclusions

There was a continuum of neurobehaviour across gestational ages. The relationships

between brain abnormality scores and suboptimal neurobehavior provide evidence

that neurobehavioral assessments offer insight into the integrity of the developing

brain, and may be useful in earlier identification of the highest-risk infants.

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BACKGROUND AND RATIONALE

Infants born preterm are at increased risk of long-term neurodevelopmental deficits in

cognitive, neurosensory, physical, and social-emotional development, as well as

impairments in academic functioning compared with their term-born peers.1-4

Early

interventions to mitigate some of these adverse neurodevelopmental deficits are

promising,5,6

and thus, clinicians working with preterm infants and their families aim

to identify those infants at greatest need for early intervention services. Whilst major

preterm brain injuries, such as high-grade intraventricular hemorrhage (IVH) and

cystic periventricular leukomalacia (cPVL), are highly prognostic for adverse

neurodevelopmental outcomes,6,7

other clinical predictors of long-term development

have only modest prognostic utility. Magnetic resonance imaging (MRI) can detect

more subtle preterm brain injury associated with adverse neurodevelopment, however

its use in routine clinical care is limited by availability and cost.8 Clinicians are

increasingly using neonatal neurobehavioral assessments to identify high-risk infants

and to help guide referrals for early intervention. Neurobehavioral assessments are

valid and reliable tools which offer insights into the neurological integrity and

behavioral functioning of an infant.9,10

Compared with their term-born peers, infants born very preterm (VPT: <32 weeks’

gestation) and moderate-to-late preterm (MLPT: 32 to 36 weeks’ gestation) present

with increased rates of atypical neurobehavior at term-equivalent age.11,12

Importantly, these neurobehavioral difficulties have been associated with later

developmental deficits,13,14

providing support for the neurobehavioral assessment as a

predictive tool for later neurodevelopmental outcome. Whilst there is some evidence

that MRI brain abnormalities are associated with neurobehavior in VPT infants at

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term-equivalent age,15-17

this brain-neurobehavior relationship has yet to be explored

in MLPT infants.

The primary aim of this study was to compare the neurobehavioral performance of

infants born across 3 different gestational age groups: VPT (<30 weeks’ gestational

age); MLPT (32 to 36 weeks’ gestational age); and term age (>37 weeks’ gestational

age) using the NICU Network Neurobehavioral Scale (NNNS), the Hammersmith

Neonatal Neurological Exam (HNNE), and Prechtl’s Qualitative Assessment of

General Movements (GMA).18

Secondary aims were to explore the relationships

between MRI brain abnormalities (development and injury) and neurobehavior at

term-equivalent age between gestational age groups (VPT, MLPT and term-born

infants).

METHODS

Participants

Participants were derived from two longitudinal cohorts of infants recruited from the

Royal Women’s Hospital in Melbourne, Australia, between November 2009 and

December 2013. The first cohort comprised 149 VPT infants born <30 weeks’

gestation19

and the second cohort included 201 MLPT infants born between 32 to 36

weeks’ gestation.20

In addition, a cohort of 201 term controls born >37 weeks’

gestation were recruited across the two cohorts. Infants with congenital abnormalities

and/or infants with non-English speaking parents were excluded due to limited

funding for interpreters. In the term control group, infants requiring admission to the

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special care or intensive care nurseries were excluded. Informed parental consent was

obtained for all participants, and both studies were approved by the Royal Women’s

Hospital’s and Royal Children’s Hospital’s Human Research Ethics Committees.

Perinatal data were recorded by research nurses, including gestation at birth, sex,

birthweight z-score (calculated according to gestational age and sex using the British

Growth Reference norms),21

multiple birth, use of antenatal corticosteroids, and

respiratory support.

Neurobehavioral measures

At term-equivalent age (38-44 weeks’ postmenstrual age), neurobehavior was

assessed by one of five trained and certified assessors using NNNS,22

HNNE,23

and

GMA. All assessors had advanced GMA certification and were masked to the

participants’ clinical history. All assessments were administered according to their

standardized procedures, as previously published in the study protocol.19

Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS)

The NNNS is a neurobehavioral assessment that examines the neurological integrity,

behavioral functioning, and responses to stress in high-risk infants using 45 items

which correspond to 13 summary scales including habituation, attention, arousal,

regulation, handling, quality of movement, excitability, lethargy, non-optimal

reflexes, asymmetrical reflexes, hypertonicity, hypotonicity, and stress.24,25

The

habituation scale was not included in this study as infants were not consistently in an

appropriate state (sleep) to administer the scale at the start of the assessment. The

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scoring and classification of infants’ performance on the NNNS summary scales has

been described previously by our group.

Hammersmith Neonatal Neurological Examination (HNNE)

The HNNE is primarily a neurological exam developed for term and preterm infants.

It consists of 34 individual items with six subtotals including tone, tone patterns,

reflexes, spontaneous movements, abnormal neurological signs, and behavior, which

are added for a total score. Suboptimal performance on the HNNE was categorized as

previously published.26

Prechtl’s qualitative assessment of General Movements (GMA)

The GMA is an observational assessment of the infant’s spontaneous movements

(GMs) with good predictive validity for neurodevelopmental outcomes, including

cerebral palsy, motor impairment and cognitive outcomes.27

GMs were scored from

video recordings according to Prechtl’s method of qualitative assessment.18

GMs were

categorized as normal or abnormal, with abnormal GMs further categorized as poor

repertoire, cramped synchronized, or chaotic. GMs were classified unscorable if the

infant was crying or hypokinetic.

Magnetic Resonance Imaging

Brain MRI was performed using the Siemens 3T Magnetom Trio MRI system

(Siemens, Erlangen, Germany) during natural sleep, on the same day as

neurobehavioral assessments. The details of the imaging protocol have previously

been published, and the T1 and T2-weighted structural brain images were used for the

current study.20

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A validated neonatal brain MRI scoring system was used to assess brain maturation,

injury and size, utilizing two dimensional brain metrics28

and conventional methods

of assessing brain injury.29

Four regional abnormality scores were calculated based on

assessment of injury, growth and maturation: cerebral white matter, cortical grey

matter, deep grey matter (basal ganglia & thalamus), and cerebellar abnormality.30

A

global abnormality score was computed using the sum of the four regional

abnormality scores; higher scores indicate greater abnormality. Brain MRI were

scored independently by one of four experienced neuroradiologists and neonatologists

who had received training in this scoring system with excellent inter- and intra-rater

reliability.20

Statistical analysis

Data were analyzed using Stata Version 14 (StatCorp, Texas, USA). To explore the

relationships between gestational age group and neurobehavior at term-equivalent

age, proportions with suboptimal neurobehavior within gestational age groups were

compared by chi-square test for trend. Relationships between brain MRI

abnormalities and suboptimal neurobehavior in the preterm infants (<37 weeks’

gestational age) were explored using logistic regression, fitted using generalized

estimating equations to allow for multiple births, and adjusted for sex and age at brain

MRI. For any significant relationships between neonatal brain abnormality and

suboptimal neurobehavior, an interaction term was included in the model to explore

whether the relationship differed according to the preterm infants’ gestational age

group (VPT or MLPT). We have previously demonstrated a strong relationship

between brain abnormality scores and abnormal GMA in VPT infants,31

thus, an

interaction term was included in this model, irrespective of the initial findings.

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RESULTS

Neurobehavioral assessments were performed at term-equivalent age in 140 of 149

VPT infants, 200/201 MLPT infants, and 200/201 term controls recruited for this

study. Participant characteristics are summarized in Table 1. A subset of VPT (n=110)

and MLPT (n=198) infants had concurrent brain MRI. Infants ≥45 weeks’

postmenstrual age at the time of neurobehavioral assessment and brain MRI were

excluded, as were infants who were not in an appropriate state to allow their GMA to

be reliably scored (see Figure 1). Differences between infants with and without

neurobehavioral data are shown in Supplementary Table 1a-c. In the VPT group, six

infants died prior to term-equivalent age and were not included in this baseline

analysis.

INSERT Figure 1: Participant Recruitment and Neurobehavior Assessment and

MRI Follow-up

Table 1: Participant Characteristics of Infants Assessed at Term Equivalent Age

(Based on HNNE sample size)

VPT

n=133

MLPT

n=196

Term Control

n=186

Postnatal corticosteroids – n (%)

12 (9) 0 0

Multiple birth – n (%) 59 (44) 73 (37) 2 (1)

Caesarean delivery – n

(%) 75 (72) 134 (68) 72 (39)

Gestational age at birth

(weeks) – mean (SD) 27.9 (1.4) 34.4 (1.3) 39.7 (1.2)

Birth weight z-score –

mean (SD) -0.33 (1) -0.33 (1.2) 0.23 (0.82)

Male – n (%) 54 (52) 93 (47) 99 (53)

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Respiratory distress at birth – n (%)

102 (98) 44 (22) 0

Postmenstrual age at

neurobehaviour

assessment (weeks) – mean (SD)

41.5 (1.9) 41.4 (1.1)

41.9 (1.5)

13 days (10

days)


MRI (weeks) – mean (SD)

42.4 (1.5) 41.4 (1.1)

Suboptimal Neurobehavior

There were statistically significant linear trends between several suboptimal

neurobehavior subscales and decreasing gestational age group (Error! Reference

source not found.). On the NNNS, the proportion with suboptimal neurobehavior

increased with decreasing gestational age group for the following subscales:

regulation, quality of movement, non-optimal reflexes, hypertonicity and stress.

Excluding abnormal signs and behavior, which were nonlinear, suboptimal

neurobehavior on the HNNE subscales increased with decreasing age. There was a

strong linear trend for decreasing gestational age group and abnormal GMA.

INSERT Figure 1: Sub-optimal Neurobehavior and Abnormal GMs across

Gestational Age Groups

Brain MRI Abnormality and Suboptimal Neurobehavior

Higher brain MRI abnormality scores were associated with suboptimal neurobehavior

on the NNNS and HNNE, with the exception of the deep grey matter abnormality

score (Table 2). A higher global brain abnormality score was associated with greater

odds of suboptimal lethargy and non-optimal reflexes on the NNNS, and greater odds

of suboptimal reflexes, abnormal signs and total score on the HNNE. Similarly, a

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higher cerebral white matter abnormality score was associated with greater odds of

suboptimal lethargy and non-optimal reflexes on the NNNS, and greater odds of

suboptimal reflexes, suboptimal spontaneous movements and total score on the

HNNE. A higher cortical grey matter abnormality score was associated with non-

optimal reflexes on the NNNS. A higher cerebellar abnormality score was associated

with greater odds of suboptimal lethargy on the NNNS and total score on the HNNE.

The cerebellar abnormality score was the only brain MRI abnormality score

associated with suboptimal tone on the HNNE. Brain abnormality scores were not

associated with increased odds of abnormal GMA.

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Table 2: Relationship between brain abnormality scores and suboptimal neurobehavior

Suboptimal

neurobehaviour

Global brain abnormality

score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value

Cortical GM abnormality

score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value

Cerebellar abnormality

score

OR (95%CI), p-value

NNNS

Attention

1.03 (0.87 to 1.21), 0.67 1.18 (0.91 to 1.53), 0.20 0.75 (0.50 to 1.13), 0.16 1.59 (0.42 to 5.95), 0.50 1.08 (0.61 to 1.90), 0.80

NNNS Arousal 0.93 (0.82 to 1.04), 0.21 0.89 (0.72 to 1.09), 0.26 1 (0.77 to 1.28), 0.98 0.74 (0.29 to 1.92), 0.54 0.77 (0.48 to 1.25), 0.30

NNNS

Regulation

0.99 (0.89 to 1.11), 0.88 1.01 (0.84 to 1.21), 0.94 0.98 (0.76 to 1.27), 0.90 0.21 (0.03 to 1.30), 0.09 1.01 (0.69 to 1.47), 0.97

NNNS

Handling

0.85 (0.68 to 1.07), 0.16 0.72 (0.42 to 1.23), 0.23 1.08 (0.78 to 1.51), 0.65 Omitted* 0.51 (0.18 to 1.44), 0.20

NNNS Quality

of Movement

1.07 (0.94 to 1.21), 0.31 1.07 (0.87 to 1.32), 0.51 1.02 (0.78 to 1.34), 0.88 0.44 (0.11 to 1.70), 0.23 1.45 (0.97 to 2.16), 0.07

NNNS

Excitability

0.93 (0.83 to 1.05), 0.25 0.87 (0.71 to 1.06), 0.17 1.05 (0.83 to 1.35), 0.67 0.20 (0.03 to 1.50), 0.12 0.85 (0.57 to 1.27), 0.43

NNNS Lethargy

1.20 (1.01 to 1.43), 0.04 1.44 (1.09 to 1.89), 0.01 0.78 (0.47 to 1.27), 0.32 Omitted* 2.22 (1.38 to 3.59), <0.01

NNNS Non-

optimal

Reflexes

1.23 (1.07 to 1.41), <0.01 1.30 (1.06 to 1.59), 0.01 1.33 (1.03 to 1.72), 0.03 1.12 (0.36 to 3.53), 0.85 1.47 (0.97 to 2.23), 0.07

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Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

NNNS Asymmetrical

Reflexes

0.86 (0.69 to 1.08), 0.20 0.89 (0.63 to 1.26), 0.52 0.83 (0.50 to 1.36), 0.45 Omitted* 0.43 (0.18 to 1), 0.05

NNNS

Hypertonicity


NNNS Hypotonicity

1.05 (0.93 to 1.19), 0.40 1.21 (1 to 1.46), 0.05 0.92 (0.67 to 1.27), 0.62 Omitted* 1.08 (0.67 to 1.73), 0.75

NNNS Stress 1.10 (0.98 to 1.22), 0.11 1.15 (0.96 to 1.38), 0.12 1.05 (0.84 to 1.32), 0.66 0.90 (0.37 to 2.16), 0.81 1.35 (0.91 to 1.99), 0.13

HNNE Total

Score

1.19 (1.05 to 1.33), <0.01 1.29 (1.06 to 1.57), 0.01 1.16 (0.91 to 1.49), 0.23 0.68 (0.23 to 2.02), 0.49 1.61 (1.09 to 2.38), 0.02

HNNE Tone

Optimality

1.10 (0.97 to 1.23), 0.14 1.14 (0.94 to 1.38), 0.17 1 (0.77 to 1.29), 0.97 1.38 (0.58 to 3.29), 0.46 1.55 (1.02 to 2.34), 0.04

HNNE Tone

Patterns

1.13 (0.98 to 1.31), 0.10 1.09 (0.86 to 1.37), 0.48 1.22 (0.87 to 1.70), 0.25 0.54 (0.09 to 3.06) 0.48 1.50 (0.91 to 2.46), 0.11

HNNE

Reflexes

1.17 (1.03 to 1.33), 0.01 1.37 (1.09 to 1.71), 0.01 1.05 (0.80 to 1.39), 0.72 0.38 (0.05 to 2.76), 0.34 1.41 (0.94 to 2.12), 0.10

HNNE

Spontaneous

Movement

1.11 (0.98 to 1.25), 0.09 1.26 (1.04 to 1.52), 0.02 1.04 (0.81 to 1.35), 0.74 0.42 (0.10 to 1.88), 0.26 1.15 (0.77 to 1.72), 0.50

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Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

HNNE Abnormal

Signs

1.14 (1.01 to 1.28), 0.03 1.12 (0.93 to 1.34), 0.24 1.23 (0.94 to 1.61), 0.13 1.09 (0.44 to 2.69), 0.86 1.34 (0.88 to 2.06), 0.18

HNNE

Behaviour


Abnormal GMs 1.12 (0.99 to 1.26) 0.07 1.21 (1.00 to 1.46) 0.05 1.15 (0.91 to 1.45) 0.24 0.92 (0.41 to 2.05) 0.84 1.04 (0.71 to 1.53) 0.83

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Statistically significant relationships between brain MRI abnormality scores and

suboptimal neurobehavior on the NNNS and HNNE were similar in both the VPT and

MLPT groups (all p values for interaction >0.05). The relationships between brain

MRI abnormality scores and abnormal GMA were stronger in the VPT group for

global brain (OR 1.39; 95% CI 1.04, 1.86; p=0.03) and cortical grey matter (OR 1.75;

95% CI 1.05, 2.93; p=0.03) abnormality scores.

DISCUSSION

This study demonstrates the continuum of neurobehavior across gestational age

groups, demonstrating more infants with suboptimal neurobehavior for many items on

the HNNE, NNNS and GMA with decreasing gestational age. This study extends

previous research that has shown differences in neurobehavior between VPT and

term-born infants at term-equivalent age by exploring brain-behavior relationships on

concurrent neurobehavioral assessment and brain MRI.

Regulation and Behavioral Domains of the NNNS and HNNE

The current study demonstrated a linear relationship between suboptimal regulation

on the NNNS (which assesses the infant’s capacity to organize motor activity,

physiology and state during the examination)24

and decreasing gestational age, and is

consistent with other reports describing VPT infants as more irritable with poorer

self-regulation at term-equivalent age than their term-born peers.32

Compromises to

the development of preterm infants’ self-regulation may influenced by the ‘chaotic

context’ of the neonatal intensive care unit environment,33

which includes perinatal

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care experiences associated with pain and stress to a system undergoing rapid growth

and organization.34

Previous studies have demonstrated a relationship between lower

gestational age and greater exposure to stress in the neonatal period,35

which may

explain the current study’s finding of increasing rates of suboptimal regulation at

term-equivalent age in infants born at lower gestations.

Poor regulation is often exhibited through infant behaviors known as stress cues.36

Accordingly, it is not surprising that the current study also demonstrated a linear

relationship between greater suboptimal levels of stress-related behaviors on the

NNNS and decreasing gestational age. The NNNS stress scale provides information

about the infant’s capacity to regulate and organize multiple systems (e.g. visual,

state, physiological, motor) in response to handling and interaction demands of their

environment. Interestingly, a significant proportion of the MLPT infants showed

suboptimal stress responses on the NNNS (36%), suggesting that despite their greater

gestational age, MLPT infants, like their VPT infant peers, are vulnerable to

environmental stressors and may require external support to regulate their developing

regulatory systems.37

Influenced in part by an infant’s regulatory capacity, it is not surprising that compared

with their term-born peers, both VPT and MLPT infants had higher rates of

suboptimal arousal and excitability on the NNNS. This relationship was not, however,

linear, which may be explained by the bidirectional nature of these scales, with higher

scores representing over-arousal or over-excitability and lower scores reflecting

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under-arousal or under-excitability. The suboptimal score does not differentiate the

direction of the pattern.

Other non-linear relationships in the current study may be explained by the age of

term infants at assessment. Compared with the MLPT infants, term infants had higher

proportions of suboptimal lethargy and hypotonicity on the NNNS. These infants

were often assessed before hospital discharge, when the physiological changes that

occur in the first days after birth may have influenced the presentation of lethargy and

apparent hypotonicity.38

The NNNS handling scale includes the strategies used to

obtain focused attention and the non-linear relationship is somewhat surprising. Term

infants did not require as much supportive handling, as expected, but MLPT infants

required more handling than the VPT infants, which may reflect their different

responses to stress. On the HNNE, the proportions of suboptimality in the abnormal

signs domain were similar between VPT and MLPT infants and the behavior domain

had low levels of suboptimality in all three groups.

The orientation and attention performance of infants across the three gestational age

groups, whilst linear, was similar between groups. Despite the effects of gestational

age at birth on regulation at term-equivalent age, all three groups demonstrated

similar orientation and attentional responses to visual and auditory stimuli, although

perhaps at the cost of the VPT and MLP infants’ stress and regulation performance.

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Neurological Domains of the NNNS and HNNE, and the General Movements

Assessment

Having spent longer in physiological flexion in-utero, term-born infants often present

with greater flexion and smoother movement patterns compared with preterm

peers.16,39,40

Higher rates of tone abnormalities, both hypertonicity and hypotonicity,

are reported in preterm infants at term-equivalent age.16

Consistent with this pattern,

the current study demonstrated a linear trend with suboptimal hypertonicity on the

NNNS, suboptimal tone optimality and suboptimal tone patterns on the HNNE, and

decreasing gestational age. Similarly, there was a linear trend for poorer quality of

movement and decreasing gestational age on all three neurobehavioral assessments.

On the HNNE, VPT infants demonstrated significantly higher rates of suboptimal

spontaneous movement (41%) compared with MLPT and term infants (14% and 4%,

respectively) and higher rates of abnormal GMA with decreased gestational age.

Reduced quality of movement at lower gestational ages may reflect differences in

central nervous system integrity and the extra-uterine environment, including limited

opportunities for movement.

Similarly, the reflex scales of the NNNS and HNNE also reflect maturation of the

infants’ central nervous system with a linear trend observed between decreasing

gestational age and increasing suboptimal reflexes on the NNNS and HNNE. Infants

born VPT had a significantly higher rate of suboptimal reflexes (32%) compared with

MLPT and term-born infants (9% and 7%, respectively). Furthermore, the rates of

suboptimal total scores on the HNNE, a reflection of an infant’s overall performance

on the more neurologically-based assessment, increased significantly with decreasing

gestational age, highlighting the impact of VPT birth on the maturation and integrity

of the central nervous system. This finding contrasts with other studies having

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reported that motor reflexes do not seem to be differentially affected by a short

gestation, severity of illness, or brain injury.41

Brain behavior relationships

A number of relationships between brain MRI abnormality scores and suboptimal

neurobehavior were identified in the current study. These brain behavior

relationships were more common on the HNNE than the NNNS, which may reflect its

greater neurological focus (ref Alicia paper).

On the NNNS, various brain abnormality scores were associated with greater odds of

non-optimal reflexes and suboptimal lethargy. In particular, the global, cerebral white

matter, and cortical grey matter abnormality scores were associated with suboptimal

reflexes and the global, cerebral white matter and cerebellar with suboptimal lethargy

on the NNNS. This is consistent with the study by Brown,17

who also reported both

white matter signal abnormality and delayed gyral maturation to be associated with

worse performance on the NNNS non-optimal reflex scale.

Previous studies have linked poor quality of movement with cerebral injury, in

particular, white matter abnormality and poor outcome.10

Similarly, the current study

demonstrated a significant relationship between white matter abnormality and

suboptimal performance on the HNNE spontaneous movement scale. This is

consistent with the study by Brown who reported a linear relationship between grade

of white matter abnormality and HNNE spontaneous movement scores. In keeping

with the current study’s findings, previous studies found no relationship between

brain abnormality scores and the NNNS quality of movement scale.16,17

No other

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regional abnormality scores were associated with suboptimal movement in contrast

with two earlier studies that reported delayed gyral maturation and higher grey matter

abnormality were associated with lower HNNE spontaneous movement scores.17,42

On the GMA, however, global brain abnormality and cortical grey abnormality, a

composite of signal abnormality, delayed gyration and dilated extra-cerebral space,

was associated with abnormal GMA.

Limitations of the current study are important to consider in the interpretation of the

findings. In particular, the low rates of brain abnormality scores may have influenced

the power to detect relationships between brain abnormality and suboptimal

neurobehavioral outcomes.

CONCLUSION

The current study demonstrated a clear continuum of neurobehavior across three

gestational age groups, with poorer behavior regulation, increased stress response,

greater tone abnormality, abnormal reflexes, and poorer quality of movement with

decreasing gestational age. A number of relationships between brain abnormality

scores and suboptimal neurobehavior were found, particularly the global, white

matter, and cerebellar abnormality scores with the more neurologically focused

domains of the NNNS and HNNE, evidence that the neurobehavioral assessment can

provide insight into the integrity of the developing brain and can both supplement

imaging findings when available, or, in the absence of MRI, provide guidance to

clinicians who are identifying high risk infants for early intervention services.

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Competing Interests: All authors have completed the ICMJE uniform disclosure form at

www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for

the submitted work; no financial relationships with any organisations that might have

an interest in the submitted work in the previous three years; no other relationships or

activities that could appear to have influenced the submitted work.

Funding source:

This work was supported in part by the Australian National Health and Medical

Research Council (NHMRC) (Project Grant ID 1028822); Centre of Clinical

Research Excellence Grant ID 546519; Centre of Research Excellence Grant ID

1060733; Senior Research Fellowship ID 1081288 to PJA.; Early Career Fellowship

ID 1053787 to JLYC, ID 1053767 to AJS; Career Development Fellowship ID

1108714 to AJS; Australian Postgraduate Scholarship to JEO, Murdoch Children’s

Research Institute, Clinical Sciences Theme Grant, the Victorian Government

Operational Infrastructure Support Program.

Financial Disclosure: The authors have no financial relationships relevant to this

article to disclose.

We attest that we have obtained appropriate permissions and paid any required fees

for use of copyright protected materials.

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Supplementary Table 1a: Differences in infant characteristics for those infants with and without HNNE data across three gestational age groups

VPT

with

HNNE

data

VPT

no

HNNE

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

HNNE

data

MLPT

no

HNNE

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

HNNE

data

TERM

no

HNNE

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=133 n=10 n=196 n=5 n=186 n=15

Postnatal

corticosteroids

n (%)

12 (9) 4 (40) 8.98

(0.003) 0 0 0 0

Multiple birth

n (%) 59 (44) 4 (40) 0.07 (0.79) 71 (36) 3 (60) 1.18 (0.28) 2 (1) 0 (0) 0.16 (0.69)

Caesarean

delivery

n (%)

97 (73) 8 (80) 0.24 (0.63) 133 (68) 4 (80) 0.33 (0.57) 72 (39) 5 (33) 0.17 (0.68)

Gestational age

at birth (weeks)

mean (SD)

27.8 (1.5) 27.2 (1.5)

-0.59 (-1.54

to 0.37),

0.23

34.4 (1.3) 34.1

(0.4)

-0.35 (-1.46 to

0.76), 0.53 39.7 (1.2)

40.2

(1.3)

0.52 (-0.12

to 1.16),

0.11

Birth weight z-

score

mean (SD)

-0.41

(1.02)

-0.97

(1.11)

-0.57 (-1.23

to 0.10),

0.09

-0.35

(1.2)

-0.43

(0.6)

-0.08 (-1.12 to

0.96), 0.88

0.23

(0.82)

0.04

(0.84)

-0.19 (-0.62

to 0.25),

0.39

Male

n (%) 66 (50) 5 (50)

0.0005

(0.98) 94 (48) 2 (40) 0.12 (0.73) 99 (53) 8 (53)

0.0001

(0.99)

Respiratory

distress at birth

n (%)

130 (98) 10 (100) 0.23 (0.63) 44 (22) 1 (20) 0.02 (0.90) 0 0

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Supplementary Table 1b: Differences in infant characteristics for those infants with and without NNNS data across three gestational age groups

VPT

with

NNNS

data

VPT

no

NNNS

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

NNNS

data

MLPT

no

NNNS

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

NNNS

data

TERM

no

NNNS

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=130 n=13 n=187 n=14 n=183 n=18

Postnatal

corticosteroids

n (%)

11 (8) 5 (38) 10.70

(0.001) 0 0 0 0

Multiple birth

n (%) 57 (44) 6 (46) 0.03 (0.87) 65 (35) 9 (64) 4.88 (0.02) 2 (1) 0 (0) 0.20 (0.66)

Caesarean

delivery

n (%)

96 (74) 9 (69) 0.13 (0.72) 128 (68) 9 (64) 0.10 (0.75) 71 (39) 6 (33) 0.21 (0.65)

Gestational age

at birth (weeks)

mean (SD)

27.9 (1.4) 26.8 (1.6)

-1.07 (-1.90

to -0.24),

0.01

34.4 (1.3) 34.3

(0.8)

-0.14 (-0.83 to

0.54), 0.67 39.7 (1.2)

40.3

(1.2)

0.56 (-0.03

to 1.14),

0.06

Birth weight z-

score

mean (SD)

-0.39

(1.01)

-0.98

(1.10)

-0.59 (-1.18

to -0.00),

0.05

-0.32

(1.2)

-0.74

(1)

-0.41 (-1.04 to

0.22), 0.20

0.22

(0.82)

0.16

(0.85)

-0.09 (-0.46

to 0.34),

0.77

Male

n (%) 64 (49) 7 (54) 0.10 (0.75) 88 (47) 8 (57) 0.53 (0.47) 97 (53) 10 (56) 0.04 (0.84)

Respiratory

distress at birth

n (%)

127 (98) 13 (100) 0.31 (0.58) 43 (23) 2 (14) 0.57 (0.45) 0 0

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Supplementary Table 1c: Differences in infant characteristics for those infants with and without GMA data across three gestational age groups

VPT

with

GMA

data

VPT

no GMA

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

GMA

data

MLPT

no

GMA

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

GMA

data

TERM

no

GMA

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=113 n=30 n=154 n=47 n=142 n=59

Postnatal

corticosteroids

n (%)

14 (12) 2 (7) 0.78 (0.38) 0 0 0 0

Multiple birth

n (%) 47 (42) 16 (53) 1.33 (0.25) 56 (36) 18 (38) 0.06 (0.81) 0 (0) 2 (3) 4.86 (0.03)

Caesarean

delivery

n (%)

79 (70) 26 (87) 3.41 (0.07) 106 (69) 31 (66) 0.14 (0.71) 52 (37) 25 (42) 0.58 (0.45)

Gestational age

at birth (weeks)

mean (SD)

27.7 (1.6) 28.0 (1.1)

0.34 (-0.25

to 0.94),

0.26

34.5 (1.3) 34.1

(1.0)

-0.37 (-0.78 to

0.03), 0.07 39.8 (1.2)

39.6

(1.3)

-0.28 (-0.65

to 0.09),

0.14

Birth weight z-

score

mean (SD)

-0.43

(1.02)

-0.53

(1.10)

-0.10 (-0.52

to 0.32).

0.64

-0.35

(1.2)

-0.36

(1.1)

-0.01 (-0.39 to

0.37), 0.97

0.23

(0.82)

0.17

(0.82)

-0.06 (-0.31

to 0.19),

0.63

Male

n (%) 55 (49) 16 (53) 0.21 (0.65) 73 (47) 23 (49) 0.03 (0.85) 79 (56) 28 (47) 1.12 (0.29)

Respiratory

distress at birth

n (%)

112 (99) 28 (93) 3.86 (0.05) 34 (22) 11 (23) 0.04 (0.85) 0 0

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Manuscript ID bmjpo-2017-000136.R1


Date Submitted by the Author: 05-Jul-2017


Anderson, Peter Doyle, Lex; Royal WOmen's Hospital, Cheong, Jeanie Spittle, Alicia; Murdoch Childrens Research Institute, Victorian Infant Brian Study





jpaedsopen.bmj.com

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ctober 2017. Dow

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1


born preterm

Abbey L Eeles,b,c


Joy E Olsen,b,c,e


Deanne

K Thompson,b,f,h







cNewborn




gMonash




Alicia J Spittle




Copyright:

















infants.





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Word count: 2891

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ABSTRACT

Background





gestational age groups: Preterm <30 weeks’ gestational age (PT<30); MLPT (32 to 36

weeks’ gestational age); and term age (≥37 weeks’ gestational age), and explore the


age.

Methods

Neurobehaviour was assessed at term equivalent age in 149 PT<30, 200 MLPT, and

200 term born infants using the NICU Network Neurobehavioral Scale (NNNS), the


Assessment of General Movements (GMA). A subset of 110 PT<30 and 198 MLPT


Results





and suboptimal neurobehavior were similar in both PT<30 and MLPT infants. The


in PT<30 infants.

Conclusions





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Early


promising,5,6






















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in MLPT infants.


infants born across 3 different gestational age groups: Preterm <30 weeks’

gestational age (PT<30); MLPT (32 to 36 weeks’ gestational age); and term age (≥37

weeks’ gestational age) using the NICU Network Neurobehavioral Scale (NNNS), the


Assessment of General Movements (GMA).18

Secondary aims were to explore the

relationships between MRI brain abnormalities (development and injury) and

neurobehavior at term-equivalent age in infants born preterm (PT<30 and MLPT).

METHODS

Participants



December 2013. The first cohort comprised 149 preterm infants born <30 weeks’

gestation (PT<30)19

and the second cohort included 201 MLPT infants born between

32 to 36 weeks’ gestation.20

In addition, a cohort of 201 term controls born ≥37

weeks’ gestation were recruited across the two cohorts. Infants with congenital

abnormalities and/or infants with non-English speaking parents were excluded due to

limited funding for interpreters. In the term control group, infants requiring admission

to the special care or intensive care nurseries were excluded. Informed parental

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consent was obtained for all participants, and both studies were approved by the

Royal Women’s Hospital’s and Royal Children’s Hospital’s Human Research Ethics

Committees.









HNNE,23

and










The




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been described previously by our group.26













GMs were









current study.20




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A





reliability.20












group (PT<30 or MLPT). We have previously demonstrated a strong relationship

between brain abnormality scores and abnormal GMA in infants born <30 weeks’

gestational age,32

thus, an interaction term was included in this model, irrespective of

the initial findings.

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RESULTS


PT<30 infants, 200/201 MLPT infants, and 200/201 term controls recruited for this

study. Participant characteristics are summarized in Table 1. A subset of PT<30

(n=110) and MLPT (n=198) infants had concurrent brain MRI. Infants ≥45 weeks’




neurobehavioral data are shown in Supplementary Table 1a-c. In the PT<30 group,

six infants died prior to term-equivalent age and were not included in this baseline

analysis.


MRI Follow-up



PT<30

n=133

MLPT

n=196

Term Control

n=186


12 (9) 0 0

Multiple birth – n (%) 59 (44) 73 (37) 2 (1)


(%) 75 (72) 134 (68) 72 (39)


(weeks) – mean (SD) 27.9 (1.4) 34.4 (1.3) 39.7 (1.2)


mean (SD) -0.33 (1) -0.33 (1.2) 0.23 (0.82)

Male – n (%) 54 (52) 93 (47) 99 (53)

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102 (98) 44 (22) 0


neurobehaviour


41.5 (1.9) 41.4 (1.1) 41.9 (1.5)



42.4 (1.5) 41.4 (1.1) N/A

Global brain abnormality score

n, mean (SD)

101, 4.30 (2.02) 187, 1.82 (1.87) N/A

Cerebral WM brain

abnormality score

n, mean (SD)

101, 2.29 (1.35) 187, 0.98 (1.17) N/A


score

n, mean (SD)

102, 1.39 (1.28) 193, 0.62 (0.78) N/A

Deep Nuclear GM

abnormality score

n, mean (SD)

102, 0.11 (0.34) 194, 0.04 (0.19) N/A

Cerebellar abnormality score

n, mean (SD)

102, 0.51 (0.73) 192, 0.19 (0.58) N/A

SD: standard deviation; MRI: Magnetic resonance imaging; N/A: Not applicable (term infants

did not have an MRI for this study)


There were statistically significant decreasing trends across the gestational age groups

for several suboptimal neurobehavior subscales (Figure 2). On the NNNS, the

proportions with suboptimal neurobehavior decreased with increasing gestational age

group for the following subscales: regulation, quality of movement, non-optimal

reflexes, hypertonicity and stress. Excluding abnormal signs and behavior,

suboptimal neurobehavior on the remaining HNNE subscales decreased with

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increasing age. There was a strong decreasing trend across the gestational age groups

for abnormal GMA.







odds of being suboptimal on the lethargy domain and non-optimal reflexes on the

NNNS, and greater odds of suboptimal reflexes, abnormal signs and total score on the

HNNE. Similarly, a higher cerebral white matter abnormality score was associated

with greater odds of being suboptimal on the lethargy domain and non-optimal

reflexes on the NNNS, and greater odds of suboptimal reflexes, suboptimal

spontaneous movements and total score on the HNNE. A higher cortical grey matter

abnormality score was associated with non-optimal reflexes on the NNNS. A higher

cerebellar abnormality score was associated with greater odds of being suboptimal on

the lethargy domain on the NNNS and total score on the HNNE. The cerebellar

abnormality score was the only brain MRI abnormality score associated with

suboptimal tone on the HNNE. Brain abnormality scores were not associated with

increased odds of abnormal GMA.

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12


Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

NNNS

Attention

1.03 (0.87 to 1.21), 0.67 1.18 (0.91 to 1.53), 0.20 0.75 (0.50 to 1.13), 0.16 1.59 (0.42 to 5.95), 0.50 1.08 (0.61 to 1.90), 0.80


NNNS

Regulation

0.99 (0.89 to 1.11), 0.88 1.01 (0.84 to 1.21), 0.94 0.98 (0.76 to 1.27), 0.90 0.21 (0.03 to 1.30), 0.09 1.01 (0.69 to 1.47), 0.97

NNNS

Handling


NNNS Quality

of Movement

1.07 (0.94 to 1.21), 0.31 1.07 (0.87 to 1.32), 0.51 1.02 (0.78 to 1.34), 0.88 0.44 (0.11 to 1.70), 0.23 1.45 (0.97 to 2.16), 0.07

NNNS

Excitability

0.93 (0.83 to 1.05), 0.25 0.87 (0.71 to 1.06), 0.17 1.05 (0.83 to 1.35), 0.67 0.20 (0.03 to 1.50), 0.12 0.85 (0.57 to 1.27), 0.43

NNNS Lethargy


NNNS Non-

optimal

Reflexes

1.23 (1.07 to 1.41), <0.01 1.30 (1.06 to 1.59), 0.01 1.33 (1.03 to 1.72), 0.03 1.12 (0.36 to 3.53), 0.85 1.47 (0.97 to 2.23), 0.07

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13

Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

NNNS Asymmetrical

Reflexes


NNNS

Hypertonicity


NNNS Hypotonicity



HNNE Total

Score

1.19 (1.05 to 1.33), <0.01 1.29 (1.06 to 1.57), 0.01 1.16 (0.91 to 1.49), 0.23 0.68 (0.23 to 2.02), 0.49 1.61 (1.09 to 2.38), 0.02

HNNE Tone

Optimality

1.10 (0.97 to 1.23), 0.14 1.14 (0.94 to 1.38), 0.17 1 (0.77 to 1.29), 0.97 1.38 (0.58 to 3.29), 0.46 1.55 (1.02 to 2.34), 0.04

HNNE Tone

Patterns

1.13 (0.98 to 1.31), 0.10 1.09 (0.86 to 1.37), 0.48 1.22 (0.87 to 1.70), 0.25 0.54 (0.09 to 3.06) 0.48 1.50 (0.91 to 2.46), 0.11

HNNE

Reflexes

1.17 (1.03 to 1.33), 0.01 1.37 (1.09 to 1.71), 0.01 1.05 (0.80 to 1.39), 0.72 0.38 (0.05 to 2.76), 0.34 1.41 (0.94 to 2.12), 0.10

HNNE

Spontaneous

Movement

1.11 (0.98 to 1.25), 0.09 1.26 (1.04 to 1.52), 0.02 1.04 (0.81 to 1.35), 0.74 0.42 (0.10 to 1.88), 0.26 1.15 (0.77 to 1.72), 0.50

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14

Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

HNNE Abnormal

Signs

1.14 (1.01 to 1.28), 0.03 1.12 (0.93 to 1.34), 0.24 1.23 (0.94 to 1.61), 0.13 1.09 (0.44 to 2.69), 0.86 1.34 (0.88 to 2.06), 0.18

HNNE

Behaviour



NNNS: Neonatal Intensive Care Unit Network Neurobehavioral Scale; HNNE: Hammersmith Neonatal Neurological Examination; WM: white matter; OR:

odds ratio; GM: grey matter; CI: confidence interval; GMs: General Movements; *Result omitted as too few numbers with suboptimal neurobehavior and

deep nuclear GM abnormality to analyze.

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When an interaction term was included in the model to explore whether the

relationship differed according to the preterm infants’ gestational age group,

statistically significant relationships between brain MRI abnormality scores and

suboptimal neurobehavior on the NNNS and HNNE were similar in both the PT<30

and MLPT groups (all p values for interaction >0.05). The relationships between

brain MRI abnormality scores and abnormal GMA were stronger in the PT<30 group

for global brain (OR 1.39; 95% CI 1.04, 1.86; p=0.03) and cortical grey matter (OR

1.75; 95% CI 1.05, 2.93; p=0.03) abnormality scores.

DISCUSSION








The current study demonstrated that suboptimal regulation on the NNNS (which

assesses the infant’s capacity to organize motor activity, physiology and state during

the examination)24

was more common with decreasing gestational age, and is



Compromises to

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and organization.35



which may




Accordingly, it is not surprising that the current study also demonstrated greater

suboptimal levels of stress-related behaviors on the NNNS with decreasing

gestational age. The NNNS stress scale provides information about the infant’s

capacity to regulate and organize multiple systems (e.g. visual, state, physiological,

motor) in response to handling and interaction demands of their environment.

Interestingly, a significant proportion of the MLPT infants showed suboptimal stress

responses on the NNNS (36%), suggesting that despite their greater gestational age,

MLPT infants, like their PT<30 infant peers, are vulnerable to environmental stressors

and may require external support to regulate their developing regulatory systems.38


with their term-born peers, both PT<30 and MLPT infants had higher rates of

suboptimal arousal and excitability on the NNNS, however the trend across groups

was not significant, which may be explained by the bidirectional nature of these

scales, with higher scores representing over-arousal or over-excitability and lower

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scores reflecting under-arousal or under-excitability. The suboptimal score does not

differentiate the direction of the pattern.

The lack of significant trends across groups for some variables in the current study

may be explained by the age of term infants at assessment. Compared with the MLPT

infants, term infants had higher proportions of suboptimal lethargy and hypotonicity

on the NNNS. These infants were often assessed before hospital discharge, when the

physiological changes that occur in the first days after birth may have influenced the

presentation of lethargy and apparent hypotonicity.39

The NNNS handling scale

includes the strategies used to obtain focused attention and the non-significant

relationship across groups is somewhat surprising. Term infants did not require as

much supportive handling, as expected, but MLPT infants required more handling

than the PT<30 infants, which may reflect their different responses to stress. On the

HNNE, the proportions of suboptimality in the abnormal signs domain were similar

between PT<30 and MLPT infants and the behavior domain had low levels of

suboptimality in all three groups.

Despite the effects of gestational age at birth on regulation at term-equivalent age, all

three groups demonstrated similar orientation and attentional responses to visual and

auditory stimuli, although perhaps at the cost of the PT<30 and MLPT infants’ stress

and regulation performance.

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Assessment



peers.16,40,41




the current study demonstrated higher rates of suboptimal hypertonicity on the

NNNS, suboptimal tone optimality and suboptimal tone patterns on the HNNE with

decreasing gestational age. Similarly, there was poorer quality of movement with

decreasing gestational age on all three neurobehavioral assessments. On the HNNE,

PT<30 infants demonstrated substantially higher rates of suboptimal spontaneous

movement (41%) compared with MLPT and term infants (14% and 4%, respectively),

and there were higher rates of abnormal GMA with decreasing gestational age.





infants’ central nervous system with increasing suboptimal reflexes on the NNNS and

HNNE with decreasing gestational age. Infants born PT<30 had a substantially

higher rate of suboptimal reflexes (32%) compared with MLPT and term-born infants

(9% and 7%, respectively). Furthermore, the rates of suboptimal total scores on the

HNNE, a reflection of an infant’s overall performance on the more neurologically-

based assessment, increased significantly with decreasing gestational age,

highlighting the impact of preterm birth on the maturation and integrity of the central

nervous system. This finding contrasts with other studies having reported that motor

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reflexes do not seem to be differentially affected by a short gestation, severity of

illness, or brain injury.42





greater neurological focus.9














consistent with the study by Brown et al who reported an association between a worse

grade of white matter abnormality and suboptimal HNNE spontaneous movement

scores. In keeping with the current study’s findings, previous studies found no

relationship between brain abnormality scores and the NNNS quality of movement

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scale.16,17

No other regional abnormality scores were associated with suboptimal

movement in contrast with two earlier studies that reported delayed gyral maturation

and higher grey matter abnormality were associated with lower HNNE spontaneous

movement scores.17,43

On the GMA, however, global brain abnormality and cortical

grey abnormality, a composite of signal abnormality, delayed gyration and dilated

extra-cerebral space, was associated with abnormal GMA.




neurobehavioral outcomes. Also, not all infants were able to have all assessments.

CONCLUSION











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Funding source:













References



2003;289(24):3264-3272.





2012;48(9):784–788.













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2008;121:1184-1189.






1998;51(3):235-245.



in very low birth weight preterm infants. J Dev Behav Pediatr. Oct

1995;16(5):309-317.






Development. 1/1/2010 2010;86:1-5.



























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2):676-678.



Pediatrics. 2012;161:1073-1079.

26. Spittle AJ, Jennifer W, Olsen JE, et al. Neurobehaviour in the first weeks after

birth for infants born between 32-42 weeks’ gestation. Early Human

Development. 2015;paper in submission






2013;55(5):418-426.






Nov-Dec 2013;34(11):2208-2214.









2006;118(6):2461-2471.




12/1/December 2015 2015;91:769-775.



2000;77(2):69-82.



2011;70(4):541-549.


1977;27(2):66-73.







1999.


1990(3):393.

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2005;25(12):788-793 786p.




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254x190mm (96 x 96 DPI)

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VPT

with

HNNE

data

VPT

no

HNNE

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

HNNE

data

MLPT

no

HNNE

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

HNNE

data

TERM

no

HNNE

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=133 n=10 n=196 n=5 n=186 n=15

Postnatal

corticosteroids

n (%)

12 (9) 4 (40) 8.98

(0.003) 0 0 0 0

Multiple birth

n (%) 59 (44) 4 (40) 0.07 (0.79) 71 (36) 3 (60) 1.18 (0.28) 2 (1) 0 (0) 0.16 (0.69)

Caesarean

delivery

n (%)

97 (73) 8 (80) 0.24 (0.63) 133 (68) 4 (80) 0.33 (0.57) 72 (39) 5 (33) 0.17 (0.68)

Gestational age

at birth (weeks)

mean (SD)

27.8 (1.5) 27.2 (1.5)

-0.59 (-1.54

to 0.37),

0.23

34.4 (1.3) 34.1

(0.4)

-0.35 (-1.46 to

0.76), 0.53 39.7 (1.2)

40.2

(1.3)

0.52 (-0.12

to 1.16),

0.11

Birth weight z-

score

mean (SD)

-0.41

(1.02)

-0.97

(1.11)

-0.57 (-1.23

to 0.10),

0.09

-0.35

(1.2)

-0.43

(0.6)

-0.08 (-1.12 to

0.96), 0.88

0.23

(0.82)

0.04

(0.84)

-0.19 (-0.62

to 0.25),

0.39

Male

n (%) 66 (50) 5 (50)

0.0005

(0.98) 94 (48) 2 (40) 0.12 (0.73) 99 (53) 8 (53)

0.0001

(0.99)

Respiratory

distress at birth

n (%)

130 (98) 10 (100) 0.23 (0.63) 44 (22) 1 (20) 0.02 (0.90) 0 0

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VPT

with

NNNS

data

VPT

no

NNNS

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

NNNS

data

MLPT

no

NNNS

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

NNNS

data

TERM

no

NNNS

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=130 n=13 n=187 n=14 n=183 n=18

Postnatal

corticosteroids

n (%)

11 (8) 5 (38) 10.70

(0.001) 0 0 0 0

Multiple birth

n (%) 57 (44) 6 (46) 0.03 (0.87) 65 (35) 9 (64) 4.88 (0.02) 2 (1) 0 (0) 0.20 (0.66)

Caesarean

delivery

n (%)

96 (74) 9 (69) 0.13 (0.72) 128 (68) 9 (64) 0.10 (0.75) 71 (39) 6 (33) 0.21 (0.65)

Gestational age

at birth (weeks)

mean (SD)

27.9 (1.4) 26.8 (1.6)

-1.07 (-1.90

to -0.24),

0.01

34.4 (1.3) 34.3

(0.8)

-0.14 (-0.83 to

0.54), 0.67 39.7 (1.2)

40.3

(1.2)

0.56 (-0.03

to 1.14),

0.06

Birth weight z-

score

mean (SD)

-0.39

(1.01)

-0.98

(1.10)

-0.59 (-1.18

to -0.00),

0.05

-0.32

(1.2)

-0.74

(1)

-0.41 (-1.04 to

0.22), 0.20

0.22

(0.82)

0.16

(0.85)

-0.09 (-0.46

to 0.34),

0.77

Male

n (%) 64 (49) 7 (54) 0.10 (0.75) 88 (47) 8 (57) 0.53 (0.47) 97 (53) 10 (56) 0.04 (0.84)

Respiratory

distress at birth

n (%)

127 (98) 13 (100) 0.31 (0.58) 43 (23) 2 (14) 0.57 (0.45) 0 0

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VPT

with

GMA

data

VPT

no GMA

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

GMA

data

MLPT

no

GMA

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

GMA

data

TERM

no

GMA

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=113 n=30 n=154 n=47 n=142 n=59

Postnatal

corticosteroids

n (%)

14 (12) 2 (7) 0.78 (0.38) 0 0 0 0

Multiple birth

n (%) 47 (42) 16 (53) 1.33 (0.25) 56 (36) 18 (38) 0.06 (0.81) 0 (0) 2 (3) 4.86 (0.03)

Caesarean

delivery

n (%)

79 (70) 26 (87) 3.41 (0.07) 106 (69) 31 (66) 0.14 (0.71) 52 (37) 25 (42) 0.58 (0.45)

Gestational age

at birth (weeks)

mean (SD)

27.7 (1.6) 28.0 (1.1)

0.34 (-0.25

to 0.94),

0.26

34.5 (1.3) 34.1

(1.0)

-0.37 (-0.78 to

0.03), 0.07 39.8 (1.2)

39.6

(1.3)

-0.28 (-0.65

to 0.09),

0.14

Birth weight z-

score

mean (SD)

-0.43

(1.02)

-0.53

(1.10)

-0.10 (-0.52

to 0.32).

0.64

-0.35

(1.2)

-0.36

(1.1)

-0.01 (-0.39 to

0.37), 0.97

0.23

(0.82)

0.17

(0.82)

-0.06 (-0.31

to 0.19),

0.63

Male

n (%) 55 (49) 16 (53) 0.21 (0.65) 73 (47) 23 (49) 0.03 (0.85) 79 (56) 28 (47) 1.12 (0.29)

Respiratory

distress at birth

n (%)

112 (99) 28 (93) 3.86 (0.05) 34 (22) 11 (23) 0.04 (0.85) 0 0

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Date Submitted by the Author: 30-Jul-2017







jpaedsopen.bmj.com

/bm


ctober 2017. Dow

nloaded from



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1


born preterm

Abbey L Eeles,b,c


Joy E Olsen,b,c,e


Deanne

K Thompson,b,f,h







cNewborn




gMonash




Alicia J Spittle




Copyright:

















infants.





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Word count: 2891

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ABSTRACT

Background








age.

Methods






Results







in PT<30 infants.

Conclusions





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Early


promising,5,6






















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in MLPT infants.










METHODS

Participants




gestation (PT<30)19








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Committees.









HNNE,23

and










The




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GMs were









current study.20




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A





reliability.20














gestational age,32



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9

RESULTS










analysis.


MRI Follow-up



PT<30

n=133

MLPT

n=196

Term Control

n=186


12 (9) 0 0

Multiple birth – n (%) 59 (44) 73 (37) 2 (1)


(%) 75 (72) 134 (68) 72 (39)


(weeks) – mean (SD) 27.9 (1.4) 34.4 (1.3) 39.7 (1.2)


mean (SD) -0.33 (1) -0.33 (1.2) 0.23 (0.82)

Male – n (%) 54 (52) 93 (47) 99 (53)

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102 (98) 44 (22) 0


neurobehaviour


41.5 (1.9) 41.4 (1.1) 41.9 (1.5)



42.4 (1.5) 41.4 (1.1) N/A


n participants, mean

score (SD)

101, 4.30 (2.02) 187, 1.82 (1.87) N/A

Cerebral WM brain

abnormality score


score (SD)

101, 2.29 (1.35) 187, 0.98 (1.17) N/A


score


score (SD)

102, 1.39 (1.28) 193, 0.62 (0.78) N/A

Deep Nuclear GM

abnormality score n participants, mean

score (SD)

102, 0.11 (0.34) 194, 0.04 (0.19) N/A


score


score (SD)

102, 0.51 (0.73) 192, 0.19 (0.58) N/A




There were statistically significant trends across the gestational age groups for several

suboptimal neurobehavior subscales (Figure 2). On the NNNS, the proportions with

suboptimal neurobehavior decreased with increasing gestational age group for the

following subscales: regulation, quality of movement, non-optimal reflexes,

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hypertonicity and stress. Excluding abnormal signs and behavior, suboptimal

neurobehavior on the remaining HNNE subscales decreased with increasing age.

There was a strong decreasing trend across the gestational age groups for abnormal

GMA.



















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12


Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

NNNS

Attention

1.03 (0.87 to 1.21), 0.67 1.18 (0.91 to 1.53), 0.20 0.75 (0.50 to 1.13), 0.16 1.59 (0.42 to 5.95), 0.50 1.08 (0.61 to 1.90), 0.80


NNNS

Regulation

0.99 (0.89 to 1.11), 0.88 1.01 (0.84 to 1.21), 0.94 0.98 (0.76 to 1.27), 0.90 0.21 (0.03 to 1.30), 0.09 1.01 (0.69 to 1.47), 0.97

NNNS

Handling


NNNS Quality

of Movement

1.07 (0.94 to 1.21), 0.31 1.07 (0.87 to 1.32), 0.51 1.02 (0.78 to 1.34), 0.88 0.44 (0.11 to 1.70), 0.23 1.45 (0.97 to 2.16), 0.07

NNNS

Excitability

0.93 (0.83 to 1.05), 0.25 0.87 (0.71 to 1.06), 0.17 1.05 (0.83 to 1.35), 0.67 0.20 (0.03 to 1.50), 0.12 0.85 (0.57 to 1.27), 0.43

NNNS Lethargy


NNNS Non-

optimal

Reflexes

1.23 (1.07 to 1.41), <0.01 1.30 (1.06 to 1.59), 0.01 1.33 (1.03 to 1.72), 0.03 1.12 (0.36 to 3.53), 0.85 1.47 (0.97 to 2.23), 0.07

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13

Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

NNNS Asymmetrical

Reflexes


NNNS

Hypertonicity


NNNS Hypotonicity



HNNE Total

Score

1.19 (1.05 to 1.33), <0.01 1.29 (1.06 to 1.57), 0.01 1.16 (0.91 to 1.49), 0.23 0.68 (0.23 to 2.02), 0.49 1.61 (1.09 to 2.38), 0.02

HNNE Tone

Optimality

1.10 (0.97 to 1.23), 0.14 1.14 (0.94 to 1.38), 0.17 1 (0.77 to 1.29), 0.97 1.38 (0.58 to 3.29), 0.46 1.55 (1.02 to 2.34), 0.04

HNNE Tone

Patterns

1.13 (0.98 to 1.31), 0.10 1.09 (0.86 to 1.37), 0.48 1.22 (0.87 to 1.70), 0.25 0.54 (0.09 to 3.06) 0.48 1.50 (0.91 to 2.46), 0.11

HNNE

Reflexes

1.17 (1.03 to 1.33), 0.01 1.37 (1.09 to 1.71), 0.01 1.05 (0.80 to 1.39), 0.72 0.38 (0.05 to 2.76), 0.34 1.41 (0.94 to 2.12), 0.10

HNNE

Spontaneous

Movement

1.11 (0.98 to 1.25), 0.09 1.26 (1.04 to 1.52), 0.02 1.04 (0.81 to 1.35), 0.74 0.42 (0.10 to 1.88), 0.26 1.15 (0.77 to 1.72), 0.50

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14

Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

HNNE Abnormal

Signs

1.14 (1.01 to 1.28), 0.03 1.12 (0.93 to 1.34), 0.24 1.23 (0.94 to 1.61), 0.13 1.09 (0.44 to 2.69), 0.86 1.34 (0.88 to 2.06), 0.18

HNNE

Behaviour






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DISCUSSION










the examination)24




Compromises to

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and organization.35



which may















suboptimal arousal and excitability on the NNNS, however the trend across groups

was not significant, which may be explained by the bidirectional nature of these


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The lack of significant trends across groups for some variables in the current study


















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Assessment



peers.16,40,41























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scale.16,17












CONCLUSION











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Funding source:













References



2003;289(24):3264-3272.





2012;48(9):784–788.













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2008;121:1184-1189.






1998;51(3):235-245.




1995;16(5):309-317.






Development. 1/1/2010 2010;86:1-5.



























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2):676-678.



Pediatrics. 2012;161:1073-1079.









2013;55(5):418-426.






Nov-Dec 2013;34(11):2208-2214.









2006;118(6):2461-2471.




12/1/December 2015 2015;91:769-775.



2000;77(2):69-82.



2011;70(4):541-549.


1977;27(2):66-73.







1999.


1990(3):393.

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2005;25(12):788-793 786p.




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254x190mm (96 x 96 DPI)

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VPT

with

HNNE

data

VPT

no

HNNE

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

HNNE

data

MLPT

no

HNNE

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

HNNE

data

TERM

no

HNNE

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=133 n=10 n=196 n=5 n=186 n=15

Postnatal

corticosteroids

n (%)

12 (9) 4 (40) 8.98

(0.003) 0 0 0 0

Multiple birth

n (%) 59 (44) 4 (40) 0.07 (0.79) 71 (36) 3 (60) 1.18 (0.28) 2 (1) 0 (0) 0.16 (0.69)

Caesarean

delivery

n (%)

97 (73) 8 (80) 0.24 (0.63) 133 (68) 4 (80) 0.33 (0.57) 72 (39) 5 (33) 0.17 (0.68)

Gestational age

at birth (weeks)

mean (SD)

27.8 (1.5) 27.2 (1.5)

-0.59 (-1.54

to 0.37),

0.23

34.4 (1.3) 34.1

(0.4)

-0.35 (-1.46 to

0.76), 0.53 39.7 (1.2)

40.2

(1.3)

0.52 (-0.12

to 1.16),

0.11

Birth weight z-

score

mean (SD)

-0.41

(1.02)

-0.97

(1.11)

-0.57 (-1.23

to 0.10),

0.09

-0.35

(1.2)

-0.43

(0.6)

-0.08 (-1.12 to

0.96), 0.88

0.23

(0.82)

0.04

(0.84)

-0.19 (-0.62

to 0.25),

0.39

Male

n (%) 66 (50) 5 (50)

0.0005

(0.98) 94 (48) 2 (40) 0.12 (0.73) 99 (53) 8 (53)

0.0001

(0.99)

Respiratory

distress at birth

n (%)

130 (98) 10 (100) 0.23 (0.63) 44 (22) 1 (20) 0.02 (0.90) 0 0

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VPT

with

NNNS

data

VPT

no

NNNS

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

NNNS

data

MLPT

no

NNNS

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

NNNS

data

TERM

no

NNNS

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=130 n=13 n=187 n=14 n=183 n=18

Postnatal

corticosteroids

n (%)

11 (8) 5 (38) 10.70

(0.001) 0 0 0 0

Multiple birth

n (%) 57 (44) 6 (46) 0.03 (0.87) 65 (35) 9 (64) 4.88 (0.02) 2 (1) 0 (0) 0.20 (0.66)

Caesarean

delivery

n (%)

96 (74) 9 (69) 0.13 (0.72) 128 (68) 9 (64) 0.10 (0.75) 71 (39) 6 (33) 0.21 (0.65)

Gestational age

at birth (weeks)

mean (SD)

27.9 (1.4) 26.8 (1.6)

-1.07 (-1.90

to -0.24),

0.01

34.4 (1.3) 34.3

(0.8)

-0.14 (-0.83 to

0.54), 0.67 39.7 (1.2)

40.3

(1.2)

0.56 (-0.03

to 1.14),

0.06

Birth weight z-

score

mean (SD)

-0.39

(1.01)

-0.98

(1.10)

-0.59 (-1.18

to -0.00),

0.05

-0.32

(1.2)

-0.74

(1)

-0.41 (-1.04 to

0.22), 0.20

0.22

(0.82)

0.16

(0.85)

-0.09 (-0.46

to 0.34),

0.77

Male

n (%) 64 (49) 7 (54) 0.10 (0.75) 88 (47) 8 (57) 0.53 (0.47) 97 (53) 10 (56) 0.04 (0.84)

Respiratory

distress at birth

n (%)

127 (98) 13 (100) 0.31 (0.58) 43 (23) 2 (14) 0.57 (0.45) 0 0

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VPT

with

GMA

data

VPT

no GMA

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

GMA

data

MLPT

no

GMA

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

GMA

data

TERM

no

GMA

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=113 n=30 n=154 n=47 n=142 n=59

Postnatal

corticosteroids

n (%)

14 (12) 2 (7) 0.78 (0.38) 0 0 0 0

Multiple birth

n (%) 47 (42) 16 (53) 1.33 (0.25) 56 (36) 18 (38) 0.06 (0.81) 0 (0) 2 (3) 4.86 (0.03)

Caesarean

delivery

n (%)

79 (70) 26 (87) 3.41 (0.07) 106 (69) 31 (66) 0.14 (0.71) 52 (37) 25 (42) 0.58 (0.45)

Gestational age

at birth (weeks)

mean (SD)

27.7 (1.6) 28.0 (1.1)

0.34 (-0.25

to 0.94),

0.26

34.5 (1.3) 34.1

(1.0)

-0.37 (-0.78 to

0.03), 0.07 39.8 (1.2)

39.6

(1.3)

-0.28 (-0.65

to 0.09),

0.14

Birth weight z-

score

mean (SD)

-0.43

(1.02)

-0.53

(1.10)

-0.10 (-0.52

to 0.32).

0.64

-0.35

(1.2)

-0.36

(1.1)

-0.01 (-0.39 to

0.37), 0.97

0.23

(0.82)

0.17

(0.82)

-0.06 (-0.31

to 0.19),

0.63

Male

n (%) 55 (49) 16 (53) 0.21 (0.65) 73 (47) 23 (49) 0.03 (0.85) 79 (56) 28 (47) 1.12 (0.29)

Respiratory

distress at birth

n (%)

112 (99) 28 (93) 3.86 (0.05) 34 (22) 11 (23) 0.04 (0.85) 0 0

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Date Submitted by the Author: 06-Sep-2017







jpaedsopen.bmj.com

/bm


ctober 2017. Dow

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born preterm

Abbey L Eeles,b,c,h


Joy E Olsen,b,c,e


Deanne

K Thompson,b,f,i







cNewborn




gMonash


Vic; hDepartment of Paediatrics, Monash University, Melbourne, Vic;

iFlorey

Institute of Neuroscience and Mental Health, Melbourne, Vic


Alicia J Spittle




Copyright:

















infants.




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Word count: 2891

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ABSTRACT

Background








age.

Methods






Results







in PT<30 infants.

Conclusions





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Early


promising,5,6






















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in MLPT infants.










METHODS

Participants




gestation (PT<30)19








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Committees.









HNNE,23

and










The




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GMs were









current study.20




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A





reliability.20














gestational age,32



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RESULTS










analysis.


MRI Follow-up



PT<30

n=133

MLPT

n=196

Term Control

n=186


12 (9) 0 0

Multiple birth – n (%) 59 (44) 73 (37) 2 (1)


(%) 75 (72) 134 (68) 72 (39)


(weeks) – mean (SD) 27.9 (1.4) 34.4 (1.3) 39.7 (1.2)


mean (SD) -0.33 (1) -0.33 (1.2) 0.23 (0.82)

Male – n (%) 54 (52) 93 (47) 99 (53)

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102 (98) 44 (22) 0


neurobehaviour


41.5 (1.9) 41.4 (1.1) 41.9 (1.5)



42.4 (1.5) 41.4 (1.1) N/A



score (SD)

101, 4.30 (2.02) 187, 1.82 (1.87) N/A

Cerebral WM brain

abnormality score


score (SD)

101, 2.29 (1.35) 187, 0.98 (1.17) N/A


score


score (SD)

102, 1.39 (1.28) 193, 0.62 (0.78) N/A

Deep Nuclear GM

abnormality score n participants, mean

score (SD)

102, 0.11 (0.34) 194, 0.04 (0.19) N/A


score


score (SD)

102, 0.51 (0.73) 192, 0.19 (0.58) N/A




Scores on several neurobehavior subscales were not independent of gestational age

(P<0.05) (Figure 2). On the NNNS, the proportions with suboptimal neurobehavior

decreased with increasing gestational age group for the following subscales:

regulation, quality of movement, non-optimal reflexes, hypertonicity and stress.

Excluding abnormal signs and behavior, suboptimal neurobehavior on the remaining

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HNNE subscales decreased with increasing age. Rates of abnormal GMA were higher

with decreasing gestational age.



















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12


Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

NNNS

Attention

1.03 (0.87 to 1.21), 0.67 1.18 (0.91 to 1.53), 0.20 0.75 (0.50 to 1.13), 0.16 1.59 (0.42 to 5.95), 0.50 1.08 (0.61 to 1.90), 0.80


NNNS

Regulation

0.99 (0.89 to 1.11), 0.88 1.01 (0.84 to 1.21), 0.94 0.98 (0.76 to 1.27), 0.90 0.21 (0.03 to 1.30), 0.09 1.01 (0.69 to 1.47), 0.97

NNNS

Handling


NNNS Quality

of Movement

1.07 (0.94 to 1.21), 0.31 1.07 (0.87 to 1.32), 0.51 1.02 (0.78 to 1.34), 0.88 0.44 (0.11 to 1.70), 0.23 1.45 (0.97 to 2.16), 0.07

NNNS

Excitability

0.93 (0.83 to 1.05), 0.25 0.87 (0.71 to 1.06), 0.17 1.05 (0.83 to 1.35), 0.67 0.20 (0.03 to 1.50), 0.12 0.85 (0.57 to 1.27), 0.43

NNNS Lethargy


NNNS Non-

optimal

Reflexes

1.23 (1.07 to 1.41), <0.01 1.30 (1.06 to 1.59), 0.01 1.33 (1.03 to 1.72), 0.03 1.12 (0.36 to 3.53), 0.85 1.47 (0.97 to 2.23), 0.07

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13

Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

NNNS Asymmetrical

Reflexes


NNNS

Hypertonicity


NNNS Hypotonicity



HNNE Total

Score

1.19 (1.05 to 1.33), <0.01 1.29 (1.06 to 1.57), 0.01 1.16 (0.91 to 1.49), 0.23 0.68 (0.23 to 2.02), 0.49 1.61 (1.09 to 2.38), 0.02

HNNE Tone

Optimality

1.10 (0.97 to 1.23), 0.14 1.14 (0.94 to 1.38), 0.17 1 (0.77 to 1.29), 0.97 1.38 (0.58 to 3.29), 0.46 1.55 (1.02 to 2.34), 0.04

HNNE Tone

Patterns

1.13 (0.98 to 1.31), 0.10 1.09 (0.86 to 1.37), 0.48 1.22 (0.87 to 1.70), 0.25 0.54 (0.09 to 3.06) 0.48 1.50 (0.91 to 2.46), 0.11

HNNE

Reflexes

1.17 (1.03 to 1.33), 0.01 1.37 (1.09 to 1.71), 0.01 1.05 (0.80 to 1.39), 0.72 0.38 (0.05 to 2.76), 0.34 1.41 (0.94 to 2.12), 0.10

HNNE

Spontaneous

Movement

1.11 (0.98 to 1.25), 0.09 1.26 (1.04 to 1.52), 0.02 1.04 (0.81 to 1.35), 0.74 0.42 (0.10 to 1.88), 0.26 1.15 (0.77 to 1.72), 0.50

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14

Suboptimal

neurobehaviour


score

OR (95%CI), p-value

Cerebral WM brain

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

Deep Nuclear GM

abnormality score

OR (95%CI), p-value


score

OR (95%CI), p-value

HNNE Abnormal

Signs

1.14 (1.01 to 1.28), 0.03 1.12 (0.93 to 1.34), 0.24 1.23 (0.94 to 1.61), 0.13 1.09 (0.44 to 2.69), 0.86 1.34 (0.88 to 2.06), 0.18

HNNE

Behaviour






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DISCUSSION










the examination)24




Compromises to

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and organization.35



which may















suboptimal arousal and excitability on the NNNS, however, the relationship between

these subscale scores and their dependence on gestational age did not reach statistical

significance (P<0.05). This may be explained by the bidirectional nature of these

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The lack of dependence on gestational age for some variables in the current study


















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Assessment



peers.16,40,41























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scale.16,17












CONCLUSION











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Contributorship Statement:

Dr Eeles collected data, carried out the analyses, drafted the initial manuscript, and

reviewed and revised the manuscript.

Dr Walsh collected data, drafted the initial manuscript, and reviewed and revised the

manuscript.

Dr Olsen collected data and reviewed and revised the manuscript.

Dr Cuzzilla critically reviewed and revised the manuscript.

Dr Thompson, Professor Anderson, Professor Doyle, A/Professor Cheong and

A/Professor Spittle conceptualized and designed the study and critically reviewed and

revised the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable

for all aspects of the work.






Funding source:













References



2003;289(24):3264-3272.

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2012;48(9):784–788.




















2008;121:1184-1189.






1998;51(3):235-245.




1995;16(5):309-317.






Development. 1/1/2010 2010;86:1-5.










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2):676-678.



Pediatrics. 2012;161:1073-1079.









2013;55(5):418-426.






Nov-Dec 2013;34(11):2208-2214.









2006;118(6):2461-2471.




12/1/December 2015 2015;91:769-775.

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2000;77(2):69-82.



2011;70(4):541-549.


1977;27(2):66-73.







1999.


1990(3):393.




2005;25(12):788-793 786p.




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254x190mm (96 x 96 DPI)

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VPT

with

HNNE

data

VPT

no

HNNE

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

HNNE

data

MLPT

no

HNNE

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

HNNE

data

TERM

no

HNNE

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=133 n=10 n=196 n=5 n=186 n=15

Postnatal

corticosteroids

n (%)

12 (9) 4 (40) 8.98

(0.003) 0 0 0 0

Multiple birth

n (%) 59 (44) 4 (40) 0.07 (0.79) 71 (36) 3 (60) 1.18 (0.28) 2 (1) 0 (0) 0.16 (0.69)

Caesarean

delivery

n (%)

97 (73) 8 (80) 0.24 (0.63) 133 (68) 4 (80) 0.33 (0.57) 72 (39) 5 (33) 0.17 (0.68)

Gestational age

at birth (weeks)

mean (SD)

27.8 (1.5) 27.2 (1.5)

-0.59 (-1.54

to 0.37),

0.23

34.4 (1.3) 34.1

(0.4)

-0.35 (-1.46 to

0.76), 0.53 39.7 (1.2)

40.2

(1.3)

0.52 (-0.12

to 1.16),

0.11

Birth weight z-

score

mean (SD)

-0.41

(1.02)

-0.97

(1.11)

-0.57 (-1.23

to 0.10),

0.09

-0.35

(1.2)

-0.43

(0.6)

-0.08 (-1.12 to

0.96), 0.88

0.23

(0.82)

0.04

(0.84)

-0.19 (-0.62

to 0.25),

0.39

Male

n (%) 66 (50) 5 (50)

0.0005

(0.98) 94 (48) 2 (40) 0.12 (0.73) 99 (53) 8 (53)

0.0001

(0.99)

Respiratory

distress at birth

n (%)

130 (98) 10 (100) 0.23 (0.63) 44 (22) 1 (20) 0.02 (0.90) 0 0

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VPT

with

NNNS

data

VPT

no

NNNS

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

NNNS

data

MLPT

no

NNNS

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

NNNS

data

TERM

no

NNNS

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=130 n=13 n=187 n=14 n=183 n=18

Postnatal

corticosteroids

n (%)

11 (8) 5 (38) 10.70

(0.001) 0 0 0 0

Multiple birth

n (%) 57 (44) 6 (46) 0.03 (0.87) 65 (35) 9 (64) 4.88 (0.02) 2 (1) 0 (0) 0.20 (0.66)

Caesarean

delivery

n (%)

96 (74) 9 (69) 0.13 (0.72) 128 (68) 9 (64) 0.10 (0.75) 71 (39) 6 (33) 0.21 (0.65)

Gestational age

at birth (weeks)

mean (SD)

27.9 (1.4) 26.8 (1.6)

-1.07 (-1.90

to -0.24),

0.01

34.4 (1.3) 34.3

(0.8)

-0.14 (-0.83 to

0.54), 0.67 39.7 (1.2)

40.3

(1.2)

0.56 (-0.03

to 1.14),

0.06

Birth weight z-

score

mean (SD)

-0.39

(1.01)

-0.98

(1.10)

-0.59 (-1.18

to -0.00),

0.05

-0.32

(1.2)

-0.74

(1)

-0.41 (-1.04 to

0.22), 0.20

0.22

(0.82)

0.16

(0.85)

-0.09 (-0.46

to 0.34),

0.77

Male

n (%) 64 (49) 7 (54) 0.10 (0.75) 88 (47) 8 (57) 0.53 (0.47) 97 (53) 10 (56) 0.04 (0.84)

Respiratory

distress at birth

n (%)

127 (98) 13 (100) 0.31 (0.58) 43 (23) 2 (14) 0.57 (0.45) 0 0

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VPT

with

GMA

data

VPT

no GMA

data

Mean

difference

(95% CI),

p-value

or

Chi 2

(p-value)

MLPT

with

GMA

data

MLPT

no

GMA

data

Mean

difference

(95% CI), p-

value

or

Chi 2

(p-value)

TERM

with

GMA

data

TERM

no

GMA

data

Mean

difference

(95% CI),

p-value

or

Chi 2 (p-

value)

n=113 n=30 n=154 n=47 n=142 n=59

Postnatal

corticosteroids

n (%)

14 (12) 2 (7) 0.78 (0.38) 0 0 0 0

Multiple birth

n (%) 47 (42) 16 (53) 1.33 (0.25) 56 (36) 18 (38) 0.06 (0.81) 0 (0) 2 (3) 4.86 (0.03)

Caesarean

delivery

n (%)

79 (70) 26 (87) 3.41 (0.07) 106 (69) 31 (66) 0.14 (0.71) 52 (37) 25 (42) 0.58 (0.45)

Gestational age

at birth (weeks)

mean (SD)

27.7 (1.6) 28.0 (1.1)

0.34 (-0.25

to 0.94),

0.26

34.5 (1.3) 34.1

(1.0)

-0.37 (-0.78 to

0.03), 0.07 39.8 (1.2)

39.6

(1.3)

-0.28 (-0.65

to 0.09),

0.14

Birth weight z-

score

mean (SD)

-0.43

(1.02)

-0.53

(1.10)

-0.10 (-0.52

to 0.32).

0.64

-0.35

(1.2)

-0.36

(1.1)

-0.01 (-0.39 to

0.37), 0.97

0.23

(0.82)

0.17

(0.82)

-0.06 (-0.31

to 0.19),

0.63

Male

n (%) 55 (49) 16 (53) 0.21 (0.65) 73 (47) 23 (49) 0.03 (0.85) 79 (56) 28 (47) 1.12 (0.29)

Respiratory

distress at birth

n (%)

112 (99) 28 (93) 3.86 (0.05) 34 (22) 11 (23) 0.04 (0.85) 0 0

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