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\begin{document}

\title{Physical activity level in children born extremely preterm: a comparison
between children with and without bronchopulmonary dysplasia}



\author[1]{Rhiana Roeper}%
\author[2]{Henrietta Blinder}%
\author[2]{Lamia Hayawi}%
\author[2]{Nicholas Barrowman}%
\author[3]{Thuy Mai Luu}%
\author[4]{Theo Moraes}%
\author[3]{Sze Man Tse}%
\author[5]{Grace Parraga}%
\author[4]{Giles Santyr}%
\author[6]{Jean-Philippe Chaput}%
\author[6]{Franco Momoli}%
\author[1]{Bernard Thebaud}%
\author[1]{Nishard Abdeen}%
\author[3]{Sylvain Deschenes}%
\author[7]{Marcus Couch J}%
\author[3]{Anne-Monique Nuyt}%
\author[1]{Nadya  Fadel }%
\author[1]{Sherri Katz}%
\affil[1]{Children's Hospital of Eastern Ontario}%
\affil[2]{Children's Hospital of Eastern Ontario Research Institute}%
\affil[3]{Centre Hospitalier Universitaire Sainte-Justine}%
\affil[4]{The Hospital for Sick Children}%
\affil[5]{Western University}%
\affil[6]{University of Ottawa Faculty of Medicine}%
\affil[7]{University of Toronto Department of Medical Biophysics}%


\vspace{-1em}



  
  \date{June 07, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Children with a history of bronchopulmonary
dysplasia (BPD) may have lower physical activity levels, but evidence to
date is based on self-report. This study compared physical activity
levels between children born extremely preterm with and without history
of BPD, and examined their associations with pulmonary magnetic
resonance imaging (MRI) and pulmonary function test (PFT) indices.
\textbf{Methods:} This multi-centre cross-sectional study included
children aged 7-9 years born extremely preterm, with and without BPD.
Children wore a pedometer for one week, then completed the Physical
Activity Questionnaire (PAQ), pulmonary MRI, and PFT. Spearman
correlations and multivariable linear regression modelling were
performed. \textbf{Results:} Of 45 children, 28 had a history of
moderate-severe BPD. There were no differences in any physical activity
outcomes by BPD status. Higher average daily step count and higher
average daily moderate-vigorous physical activity (MVPA) were each
correlated with greater forced vital capacity (r=0.41 and 0.58), greater
MRI lung proton density at full expiration (r=0.42 and 0.49), and lower
lung clearance index (r=-0.50 and -0.41). After adjusting for MRI total
proton density and BPD status, a 5\% increase in forced expiratory
volume at one second was associated with 738 (95\%CI: 208, 1268) more
steps per day and 0.1 (0.0, 0.2) more hours of MVPA, respectively.
\textbf{Conclusion:} School-aged children born extremely preterm have
similar physical activity levels to their peers, regardless of history
of BPD. MRI and PFT measures suggestive of gas trapping and/or airflow
obstruction are associated with lower physical activity levels.%
\end{abstract}%



\sloppy


\textbf{TITLE PAGE}

\textbf{Title:} Physical activity level in children born extremely
preterm: a comparison between children with and without bronchopulmonary
dysplasia

\textbf{Authors:} Rhiana Roeper MD\textsuperscript{1,2}, Henrietta
Blinder MSc\textsuperscript{3}, Lamia Hayawi MSc\textsuperscript{3},
Nicholas Barrowman PhD\textsuperscript{3}, Thuy Mai Luu MDCM
MSc\textsuperscript{4}, Theo J Moraes, MD PhD\textsuperscript{5,6}, Sze
Man Tse MDCM MSc\textsuperscript{4}, Grace Parraga PhD
FCAHS\textsuperscript{7,8}, Giles Santyr PhD\textsuperscript{5,6,9},
Jean-Philippe Chaput PhD\textsuperscript{2,3}, Franco Momoli
PhD\textsuperscript{2,3}, Bernard Th\selectlanguage{ngerman}ébaud MD
PhD\textsuperscript{1,2,3,10}, Nishard Abdeen MD\textsuperscript{1,2},
Sylvain Deschenes PhD\textsuperscript{4}, Marcus J Couch
PhD\textsuperscript{9,11}, Anne-Monique Nuyt MD PhD\textsuperscript{4},
Nadya Ben Fadel MD\textsuperscript{1,2,3}, Sherri L Katz, MDCM,
MSc\textsuperscript{1,2,3}

\textbf{Affiliations:}

1. Department of Pediatrics, Children's Hospital of Eastern Ontario,
Ottawa, Ontario, Canada,

2. Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

3. Children's Hospital of Eastern Ontario Research Institute, Ottawa,
Ontario, Canada

4. Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec,
Canada

5. Department of Pediatrics, Hospital for Sick Children, University of
Toronto, Toronto, Ontario, Canada

6. Translational Medicine Program, Hospital for Sick Children, Toronto,
Ontario, Canada

7. Department of Medical Biophysics, Western University, London,
Ontario, Canada

8. Robarts Research Institute, London, Ontario, Canada

9. Department of Medical Biophysics, University of Toronto, Toronto,
Ontario, Canada

10. Regenerative Medicine Program, Ottawa Hospital Research Institute,
Ottawa, Ontario

11. Siemens Healthcare Limited, Montreal, Canada

\textbf{Corresponding author:}

Dr. Sherri Katz

Children's Hospital of Eastern Ontario

401 Smyth Road Rm. W1403

Ottawa, ON K1H 8L1

Tel: (613) 737-7600 x 2956

Fax: (613) 738-4297

Email: skatz@cheo.on.ca

\textbf{Primary institute:} Children's Hospital of Eastern Ontario,
Ottawa, Ontario, Canada

\textbf{Financial support} : This study was supported by the Ontario
Lung Association Grant in Aid Award and the CHEO Research Institute
Resident Research Award.

\textbf{Ethics approval:} Local research ethics board approval and
Health Canada approval was obtained at each of the three participating
sites (Children's Hospital of Eastern Ontario Research Ethics Board
(REB) \#16/31E; The Hospital for Sick Children REB \# 1000055745; and
Centre hospitalier universitaire Sainte-Justine \#2017-1486).

\textbf{Consent to participate:} Written informed consent and/or assent
was obtained from all children and their parents included in this study.

\textbf{Conflicts of interest:} The authors have no relevant conflicts
of interest to declare.

\textbf{Author contribution statement:} This study was conceptualized by
Dr. Katz, and designed by Drs. Roeper, Chaput, Katz, Barrowman, and
Momoli. Recruitment and acquisition of the respiratory symptom
questionnaire, pulmonary function tests, and pedometer data was
conducted by Drs. Katz, Luu, Nuyt, Thebaud, Moraes, Tse, Ben Fadel, and
Roeper. Drs. Santyr, Abdeen, Deschenes, and Couch contributed to MRI
data acquisition and interpretation. Dr. Parraga was responsible for the
MRI data analysis and interpretation. Ms. Blinder was responsible for
project management, data acquisition, and data validation. Statistical
analysis was performed by Ms. Hayawi, with oversight by Dr. Barrowman.
Dr. Roeper wrote the initial manuscript draft. All authors contributed
to data interpretation and revision of the manuscript, and approved the
final version being submitted.

\textbf{Keywords:} physical activity, bronchopulmonary dysplasia,
prematurity, magnetic resonance imaging, pediatric, pulmonary function
test

\textbf{Running head:} Physical activity in children with and without
BPD

\textbf{SUMMARY/ABSTRACT}

\textbf{Introduction:} Children with a history of bronchopulmonary
dysplasia (BPD) may have lower physical activity levels, but evidence to
date is based on self-report. This study compared physical activity
levels between children born extremely preterm with and without history
of BPD, and examined their associations with pulmonary magnetic
resonance imaging (MRI) and pulmonary function test (PFT) indices.

\textbf{Methods:} This multi-centre cross-sectional study included
children aged 7-9 years born extremely preterm, with and without BPD.
Children wore a pedometer for one week, then completed the Physical
Activity Questionnaire (PAQ), pulmonary MRI, and PFT. Spearman
correlations and multivariable linear regression modelling were
performed.

\textbf{Results:} Of 45 children, 28 had a history of moderate-severe
BPD. There were no differences in any physical activity outcomes by BPD
status. Higher average daily step count and higher average daily
moderate-vigorous physical activity (MVPA) were each correlated with
greater forced vital capacity (r=0.41 and 0.58), greater MRI lung proton
density at full expiration (r=0.42 and 0.49), and lower lung clearance
index (r=-0.50 and -0.41). After adjusting for MRI total proton density
and BPD status, a 5\% increase in forced expiratory volume at one second
was associated with 738 (95\%CI: 208, 1268) more steps per day and 0.1
(0.0, 0.2) more hours of MVPA, respectively.

\textbf{Conclusion:} School-aged children born extremely preterm have
similar physical activity levels to their peers, regardless of history
of BPD. MRI and PFT measures suggestive of gas trapping and/or airflow
obstruction are associated with lower physical activity levels.

\textbf{Word count:} 243

\textbf{INTRODUCTION}

In recent decades, there has been a significant reduction in mortality
associated with premature birth, allowing for a greater number of
survivors of extremely preterm birth\textsuperscript{1}.
Bronchopulmonary dysplasia (BPD; defined as a need for oxygen at or
beyond 28 days of life, and characterized in severity by degree of
support required at 36 weeks post-menstrual age)\textsuperscript{2} is a
common comorbidity in preterm neonates, associated with long-term
effects on respiratory function\textsuperscript{3,4}. As the survival of
extremely preterm children increases, there is a need to evaluate the
outcomes of these children in all aspects of life and health, and how
different clinical and behavioural factors might mitigate morbidity.
Participation in physical activity can impact the health and well-being
of school-aged children\textsuperscript{5}, and engagement in physical
activity in childhood increases the likelihood of ongoing physical
activity in adulthood\textsuperscript{6}. Evaluating and encouraging
physical activity in preterm born children and youth is therefore
important for improving long-term health outcomes.

Prior studies on the physical activity of children with BPD have
demonstrated lower participation in physical activity through
self-report\textsuperscript{5,7,8}. Study findings have been mixed,
showing both normal and reduced exercise
tolerance\textsuperscript{9,10}and similar aerobic
capacity\textsuperscript{7} in children born preterm (with and without
BPD) when compared to children born at term. Children with BPD have been
shown to have pulmonary function abnormalities including reduced forced
expiratory volume in one second (FEV1)\textsuperscript{7,8,11} and
mid-expiratory flows (FEF\textsubscript{25-75})\textsuperscript{8},
moderate-to-severe airflow obstruction and
hyperinflation\textsuperscript{9,11}. They may also have an increased
respiratory rate\textsuperscript{11}, lower tidal
volumes\textsuperscript{11}, and decreased peak oxygen
saturation\textsuperscript{9,11} during aerobic activity, compared to
their full term peers without BPD. Furthermore, most adolescents and
young adults who had BPD in infancy have some degree of pulmonary
dysfunction (airway obstruction, hyper-reactivity, hyperinflation), even
if they were clinically asymptomatic\textsuperscript{12}. Given these
findings of reduced lung function and exercise capacity in children with
BPD, it is important to understand physical activity in this population
and its relationship to measures of lung disease.

To date, studies evaluating degree of participation in physical activity
have been through self-report assessment tools, rather than by objective
means. There may be important differences between perceived and actual
participation in physical activity in this population, and physical
activity may be mitigated by other clinical or behavioural factors. This
study therefore sought to compare perceived exercise tolerance and
objective physical activity data in a home environment in children born
extremely preterm (\textless{}28 weeks gestation), who are now
school-aged (7-9 years), with and without history of BPD. We also
examined associations of physical activity with pulmonary magnetic
resonance imaging (MRI) and lung function. Our hypothesis was that
children with a history of BPD would have decreased physical activity
compared to those without a history of BPD.



\textbf{MATERIALS AND METHODS}

\textbf{Study design and setting}

This study was performed in conjunction with the PICTURE study
(Pulmonary Magnetic Resonance Imaging of Ex-preterm Children with and
without Bronchopulmonary Dysplasia to Understand Risk of Emphysematous
Changes; clinicaltrials.gov: NCT02921308)\textsuperscript{13}. The
PICTURE study is a multicentre, cross-sectional study which aimed to
evaluate the use of ultra-short echo time MRI to assess lung structure
in children born extremely preterm with and without BPD. This study was
performed at three tertiary pediatric hospitals: the Children's Hospital
of Eastern Ontario (Ottawa, Ontario), The Hospital for Sick Children
(Toronto, Ontario), and the Centre Hospitalier Universitaire
Sainte-Justine (Montreal, Quebec). Local research ethics board approval
was obtained at each of the participating sites.

\textbf{Participants}

Children were identified from local neonatal follow-up databases at the
respective study sites and consent/assent was obtained by the research
coordinator. Children were eligible if they were 7-9 years of age and
born at less than 28 weeks' gestation, with and without history of BPD,
and were enrolled in the PICTURE study\textsuperscript{13}. Participants
were ineligible if they had 1) known lung anomalies or genetic
conditions which may affect pulmonary function or MRI findings 2)
contraindications for MRI, 3) any severe neurosensory impairment which
might prevent test completion, or 4) a recent bacterial/viral
respiratory illness (within the preceding 6 weeks)\textsuperscript{13}.

\textbf{Study measures and procedures}

Children wore a pedometer for one week, then came into the hospital for
a study visit to complete a questionnaire, pulmonary MRI, and pulmonary
function testing (PFT) on a single day.

\emph{Pedometer:} Participants were sent a StepsCount Piezo Rx pedometer
in the mail to wear at their waist for 7 consecutive days, including 2
weekend days. The pedometer collected daily step count (steps per day)
as well as moderate-to-vigorous physical activity (MVPA) data, which is
the duration of time (in hours) spent in moderate (100 steps per minute)
or vigorous (120 steps per minute) activity\textsuperscript{14}. This
pedometer has been validated\textsuperscript{14}, and pedometer data has
been shown to be a valid assessment of physical activity in school-aged
children\textsuperscript{15-18}. The pedometer was returned to the study
team on the day of their study visit. Data was considered valid if a
participant had at least 4 valid days (including one weekend day) of
data.

\emph{Physical Activity Questionnaire (PAQ):} The PAQ is a validated,
self-report, recall questionnaire which documents the physical activity
performed by a child in the most recent 7 days\textsuperscript{19}. The
outcome of interest was the PAQ global score, which is a composite score
averaging the participation in several different activities to provide
an indication of the degree of physical activity performed. A score of 1
indicates low physical activity, while a score of 5 indicates high
physical activity\textsuperscript{19}.

\emph{Pulmonary MRI:} Participants underwent a lung MRI to assess for
average total proton density (at a lung volume of functional residual
capacity plus one litre), which is a marker of lung tissue
inhomogeneity, and average proton density at full expiration, which is
an exploratory surrogate measure of gas trapping\textsuperscript{13,20}.
Novel research has identified correlations between pulmonary function
and proton density,\textsuperscript{21-23} but MRI measures provide
different information about lung architecture\textsuperscript{13}.

\emph{Pulmonary function test:} PFT included spirometry, which was
conducted according to American Thoracic Society
protocols\textsuperscript{24}. Measurements included percent-predicted
forced expiratory volume in one second (FEV1), forced vital capacity
(FVC), forced expiratory flow at 25 and 75\% of the pulmonary volume
(FEF\textsubscript{25-75}), residual volume (RV), and lung clearance
index (LCI) using Global Lung Function Initiative (GLI)
norms\textsuperscript{25}.

\emph{Medical chart review:} Throughout the course of the study, a
research coordinator collected medical history, including maternal and
neonatal history, and medications.

\textbf{Statistical analysis}

The primary exercise measures were average daily steps, average daily
MVPA measured by the pedometer, and the PAQ questionnaire score.
Activity values that were extreme (2 standard deviations above or below
average) were discarded to account for any technical errors or induced
bias.

Associations between the average daily steps, average MVPA and PAQ
score, with PFT and MRI measures, were conducted using Spearman
correlations. We interpreted the absolute values of correlation
coefficients as the following: 0.10-0.39 (weak), 0.40-0.69 (moderate),
0.70-0.89 (strong), and \textgreater{}0.9 (very strong)
associations\textsuperscript{26}. All statistical analyses were carried
out using R version 4.0.3 (R Core Team, Vienna, Austria).

Separate multiple linear regression analyses were conducted to assess
the association between each of our primary outcomes (average daily
steps and average daily MVPA), respectively, with predictors of
interest, including history of BPD (yes/no), FEV1\% predicted and MRI
total proton density. Sensitivity analyses examining the impact of
recruitment site were conducted for each multiple linear regression.
Unadjusted and adjusted estimates with 95\% CI were reported.

To explore the impact of ADHD medication use on daily step count, we
conducted an exploratory descriptive analysis comparing daily step count
between children taking ADHD medication and those not taking ADHD
medications, as well as a subgroup analysis only within the group with
BPD.



\textbf{RESULTS}

There were 45 participants enrolled in this study, of which 28 met
criteria for BPD in infancy, and 17 did not. Among several differences
in the two groups of children, those with BPD had a lower gestational
age at delivery, lower average birth weight, a greater percentage of
males and lower height percentile at the time of evaluation (Table 1).

Of the 45 participants, 37 children had valid pedometer data and were
included in the pedometer analyses. Five children were excluded due to
insufficient days of recording, 2 children did not return their
pedometer, and 1 had their data accidentally deleted prior to upload. An
additional 4 participants of the 37 were missing data on MVPA due to
pedometer data uploading issues at a single site.

Comparing children with and without history of BPD, there were no clear
differences between the average number of daily steps, MVPA, or PAQ
score (Table 2). Of the 37 participants with valid step count data, 27
had also had reliable PFT and MRI data. A Spearman correlation matrix
was conducted to assess the correlation between daily step count, daily
MVPA, PAQ score, PFT measures, and MRI measures (Table 3). While PAQ
score was weakly correlated with both pedometer outcomes, there was a
very strong correlation between average daily step count and average
daily MVPA (r=0.90). A higher average daily step count was moderately
correlated with higher FVC \% predicted, lower LCI, and greater proton
density at full expiration. A higher average daily MVPA was moderately
correlated with higher FVC \% predicted, higher TLC \% predicted, lower
LCI, and greater proton density at full expiration. All other pulmonary
function measure associations were weak or negligible.

A linear regression analysis demonstrated an association between FEV1 \%
predicted and daily step count, after adjusting for MRI total proton
density and BPD status. MRI total proton density and BPD status were not
associated with average daily step count (Table 4a). A separate linear
regression analysis with average daily MVPA as the outcome found similar
results, with FEV1 \% predicted marginally associated with average daily
MVPA, after adjusting for MRI total proton density and BPD status (Table
4b). Sensitivity analyses examining the impact of site found that while
it resulted in wider confidence intervals, the direction of association
between FEV1 \% predicted and both pedometer outcomes remained the same.

Of the 45 participants, 42 had medication data available. Of the 42
participants with available medication data, 6 were taking ADHD
medications -- 1 in the non-BPD group, and 5 in the BPD group. When we
compared the average daily step count data by ADHD medication status,
there were no differences between groups (Figure 1). Among children with
BPD, the mean (standard deviation) daily step count of the 3/5 children
who were taking ADHD medication for whom a valid step count was
available, was 15772 (5054) compared to 16416 (4288) in the 21 children
who were not taking ADHD medication (Figure 2).

\textbf{DISCUSSION}

With this study, we demonstrated a similar level of physical activity in
children born extremely preterm, with and without BPD, both from
objective pedometer data and self-reported activity level. Notably,
after adjusting for both MRI total proton density and BPD status, a
5\%-predicted increase in FEV1 was associated with approximately 750
more steps taken per day, suggesting that airflow limitation affects
physical activity. Further, both higher daily step count and greater
daily MVPA were moderately correlated with greater proton density at
full expiration, suggesting less gas trapping.

Although we expected that there may be a difference between groups,
levels of physical activity did not differ between children with and
without BPD. Previous research has shown that children with BPD and
lower FEV1 have reduced exercise capacity\textsuperscript{5,10}, and
that children with BPD have pulmonary function abnormalities compared to
their peers without BPD\textsuperscript{7-9,11}, which may correlate
with physical activity limitations. Our study did find that lower
physical activity levels were associated with pulmonary function
abnormalities consistent with gas trapping, across both groups. This
suggests that there may be factors related to extreme prematurity and
lung function that affect physical activity, independent of the
diagnosis of BPD, some of which may not be captured in this study, such
as leg discomfort or being shorter than children without BPD, which may
result in a greater number of steps needed to travel the same
distance\textsuperscript{27}. Diagnosing BPD relies on clinical
characteristics and treatment, rather than physiologic or histologic
changes, which may lead to misdiagnosis or misclassification of
disease\textsuperscript{28-30}. Tests which evaluate the lung function
or structure, such as pulmonary MRI, may provide us with new information
for diagnosis and classification of prematurity-associated lung disease,
and may correlate better with functional measures such as physical
activity\textsuperscript{20,22,31-33}.

Our study found that both lower daily step count and lower MVPA were
correlated with diminished proton density at full expiration on MRI, a
measure of gas trapping. In our previous PICTURE study, diminished MRI
proton density at full expiration was correlated with PFT measures
suggestive of gas trapping (higher RV/TLC and lower
FEV1)\textsuperscript{13}, which have been shown to be associated with
impaired exercise capacity in a previous study\textsuperscript{34}. As
pulmonary MRI measures may provide different and useful information
compared to a clinical BPD diagnosis, further research is needed to
understand factors that determine physical activity in this
population\textsuperscript{13}.

Nonetheless, it was encouraging that the average number of steps taken
by this cohort was significantly higher than expected when compared to
CanPlay normative data for average step counts (11500-12200, depending
on gender) in this age group\textsuperscript{35}. Overall, our data
suggest that children born extremely prematurely are more active than
their peers, regardless of whether they were given a diagnosis of BPD in
infancy. This is in contrast to a previous study suggesting that
children born extremely preterm are less active than their term-born
peers\textsuperscript{5}.

Given the high prevalence of ADHD and hyperactivity in children with
history of extreme prematurity\textsuperscript{36}, we conducted
analyses to determine if ADHD diagnosis explained differences in
physical activity. While we observed a lower step count in children with
BPD who were treated with ADHD medications compared to their peers
without ADHD medications, treated individuals still had a daily step
count well above the average based on normative data. Ultimately, we
found that there does not seem to be an effect of a diagnosis of or
treatment for ADHD on overall activity level, although the prevalence of
ADHD in the study population may be underreported or
underdiagnosed\textsuperscript{37}. This may account for the difference
between our cohort and normative range data.

Our study was limited by small sample size. Although we increased the
rigour of our study data by only considering children with valid
pedometer data (i.e. at least 4 days of recording, including 1 weekend
day), this further limited our sample. As such, our study was not
powered to detect small differences between variables. Furthermore, our
sub-analysis examining the impact of ADHD medications was unable to
assess whether children with ADHD who are not treated with medication
were present, limiting the reliability of this analysis. Children with
untreated ADHD may be more active than their peers in all cohorts, which
may account for the variation seen, however this is purely speculative.
Lastly, due to the cross-sectional nature of this study, we could not
evaluate the causal nature of the relationship between physical
activity, BPD, PFT measures, and MRI indices.

Larger studies are needed to further evaluate the associations between
pulmonary structure on MRI, pulmonary function and physical activity in
children born extremely pre-term, with and without BPD. It would also be
beneficial to reassess the physical activity level of this and similar
cohorts of children as they approach adolescence and adulthood to
determine if the participation and perception of physical activity level
remains comparable to their peers, both between groups of BPD/non-BPD,
and compared to non-preterm peers. These findings also support further
research into novel imaging strategies which may provide alternate means
to identify those at risk of impaired pulmonary function and lower
physical activity, as the current clinical diagnostic classifications
are limited in their ability to identify these
children\textsuperscript{31,32}.

CONCLUSIONS

This study suggests that school-aged children born extremely prematurely
have similar physical activity to their peers, regardless of a diagnosis
of BPD in infancy. Nonetheless, pulmonary function measures suggestive
of gas trapping and diminished proton density on MRI were associated
with lower physical activity. These findings support ongoing
encouragement of participation in physical activity programs in children
born prematurely, particularly for children with more pulmonary
abnormalities, who may become less physically active as they age.

\textbf{ACKNOWLEDGEMENTS}

We would like to thank the children and families who participated in
this study as well as our entire study team.

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