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\begin{document}

\title{Lung function deficits and bronchodilator reversibility at 12 years of
age in children born very preterm compared with controls born at term}



\author[1]{Ellen Tufvesson}%
\author[2]{Cecilia Hagman}%
\author[2]{Lars Bjorklund}%
\author[1]{Leif Bjermer}%
\author[2]{Ingrid Hansen-Pupp}%
\affil[1]{Lunds universitet Lungmedicin och Allergologi}%
\affil[2]{Skanes universitetssjukhus Lund}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction} Very preterm birth is associated with lung
function impairment later in life, but several aspects have not been
studied. We aimed to comprehensively assess lung function at school age
in very preterm infants and term controls, with special emphasis on
bronchopulmonary dysplasia (BPD), sex and bronchodilator response.
\textbf{Methods} At 12 years of age, 136 children born very preterm (85
with and 51 without BPD), and 56 children born at term performed
spirometry, body plethysmography, impulse oscillometry, measurement of
diffusion capacity and multiple breath washout, before and after
bronchodilator inhalation. \textbf{Results} Airway symptoms and a
diagnosis of asthma were more common in children born very preterm.
These children had more airflow limitation, seen as lower FEV
\textsubscript{1} (p\textless{}0.001), FEV \textsubscript{1}/FVC
(p=0.011) and FEF \textsubscript{25-75} (p\textless{}0.001), and a
higher total and peripheral airway resistance compared to term born
controls. There was no difference in total lung capacity, but air
trapping and lung clearance index were higher in children born very
preterm. Diffusion capacity was lower in children born very preterm,
especially in those with a diagnosis of BPD. In most other tests, the
differences between preterm-born children with or without BPD were
smaller than between children born preterm versus at term. Boys born
preterm had more lung function deficits than preterm born girls. In
children born very preterm, airway obstruction was to a large extent
reversible. \textbf{Conclusion} At 12 years of age, children born very
preterm had lower lung function than children born at term in most
aspects. Airway obstruction improved markedly after bronchodilator
inhalation, and there was only little difference between children with
or without BPD.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Long-term pulmonary outcome in preterm infants usually involve chronic
respiratory impairment such as airway
obstruction\textsuperscript{(1)}and low diffusion
capacity\textsuperscript{(2)}. Perinatal inflammation, fetal growth
restriction, bronchopulmonary dysplasia (BPD) and gender are risk
factors affecting the immature lung during the first years of
life\textsuperscript{(3-5)}. There is evidence that persistence of
respiratory symptoms, lung function impairment and abnormalities of the
lung structure may persist into adulthood\textsuperscript{(6, 7)}.
Infants with BPD have low respiratory compliance in the first month of
life, but with some normalization at 2 years of
age\textsuperscript{(8)}. Up to 8 years of age, there is still a
reduction of forced flows and volumes in these
children\textsuperscript{(4, 9)}. In an 11-year follow-up of extremely
preterm infants, the children had reduced forced expiratory volume in 1
second (FEV\textsubscript{1}) and forced expiratory flow between 25-75\%
(FEF\textsubscript{25-75}) compared to term born
classmates\textsuperscript{(10)}. It has been suggested that the
observed increase in airway obstruction could be an expression of early
impaired airway development during childhood, whereas there seem to be
some catch-up through early life\textsuperscript{(7, 11)}. Furthermore,
small airway abnormalities, could be a risk for future chronic lung
disease and further decrease the respiratory outcome after preterm
birth\textsuperscript{(12)}, since prematurity per se is also a
well-known risk factor. A reduced lung function already at childhood,
may lead to a lower lung function throughout life\textsuperscript{(13)}.

Since BPD is a poor predictor of prematurity-associated lung
disease\textsuperscript{(11)}, and the respiratory outcomes after
preterm birth seem to be more dependent on the prematurity per se, it is
important to investigate preterm-born children also beyond
BPD.\textsuperscript{(14)}

The primary aim of the study was to extensively investigate lung
function pattern at 12 years of age in children born very preterm, with
or without BPD during infancy as compared to term born controls. The
secondary aim was to study how different neonatal comorbidities and sex
may affect lung function and prevalence of airway symptoms during
childhood in preterm children.

\textbf{Materials and methods}

\textbf{Study population}

The study population consisted of 136 children from three prospective
cohorts\textsuperscript{(9, 15, 16)} of very preterm infants
(gestational age \textless{}32 weeks), one also including 56 term born
controls (see Table 1 and online supplement for details). Antenatal and
neonatal data were collected prospectively from the patient records.
There were 85 children with and 51 without a previous diagnosis of
bronchopulmonary dysplasia (BPD), defined as being born at \textless{}
32 weeks gestation and still being treated with extra oxygen at 36 weeks
postmenstrual age. A history of respiratory symptoms, medication and
allergy was obtained from a questionnaire completed by the accompanying
parent/caregiver at the 12-year visit.

\textbf{Ethics}

All parents/caregivers and children received oral and written
information about the study, and parents/caregivers signed written
informed consents. The study was approved by the Regional Ethical Review
Board in Lund, Sweden.

\textbf{Lung function testing}

Comprehensive lung function testing was done at 12 years of age. Flow
volume spirometry was performed to measure forced expiratory volume in 1
s (FEV\textsubscript{1}), forced vital capacity (FVC), mean forced
expiratory flow between 25\% and 75\% of FVC (FEF\textsubscript{25-75}),
and slow vital capacity (VC). FEV\textsubscript{1}/FVC was calculated as
a measure of expiratory flow limitation. Dysanapsis ratio, an index of
discrepancy in size between the airway and the lung, was calculated as
FEF\textsubscript{25-75}/FVC divided by an estimate of static recoil
pressure at 50\% of FVC based on child age\textsuperscript{(17)}. Body
plethysmography was used to measure static lung volumes, i.e. total lung
capacity (TLC) and residual volume (RV), and the ratio RV/TLC was
calculated as a measure of air trapping. Diffusion capacity of the lung
for CO (DL\textsubscript{CO}) was measured with single breath technique,
being the product of the rate constant for uptake of CO
(K\textsubscript{CO}) and alveolar volume. Impulse oscillometry (IOS)
provides information about the mechanical properties of large as well as
small airways. Resistance was estimated at 5 Hz (R\textsubscript{5},
reflecting total resistance) and at 20 Hz (R\textsubscript{20},
reflecting central resistance), while
R\textsubscript{5}-R\textsubscript{20} reflects peripheral resistance.
During small airway obstruction, reactance (elastance) of the lung (X)
decreases at 5 Hz (giving a more negative value of X\textsubscript{5}),
while the resonant frequency (F\textsubscript{res}) increases together
with the area under the reactance curve (AX), which is a measured from X
at 5 Hz to F\textsubscript{res}. During multiple breath washout (MBW) of
N\textsubscript{2}, the number of lung volume turnovers required to
lower the end-tidal N\textsubscript{2}-concentration to 5\% and 2.5\% of
the initial concentration are termed lung clearance index
(LCI\textsubscript{5.0} and LCI\textsubscript{2.5} respectively) and is
a measure of overall ventilation inhomogeneity. Analysis of the
N\textsubscript{2} concentration during each breath provides more
detailed information of whether the inhomogeneity arises from conductive
(S\textsubscript{cond}) or acinar (S\textsubscript{acin}) airways.
Higher values of LCI, S\textsubscript{cond} and
S\textsubscript{acin}indicate more ventilation inhomogeneity. See
supplement for detailed description.

To investigate reversibility, in most subjects, all pulmonary function
measurements were performed before and 15 minutes after inhalation of
200 \selectlanguage{greek}µ\selectlanguage{english}g salbutamol.

Data is presented as medians with interquartile range (IQR) of absolute
values or \% of predicted values, proportion below lower limit of normal
or above upper limit of normal, and as proportion below the
5\textsuperscript{th} or above the 95\textsuperscript{th} centile in the
group of the term born controls. For more detailed information, see
supplement.

\textbf{Statistics}

Nonparametric tests were used due to asymmetric distribution in most
variables. Mann-Whitney U test was used for comparison between two
groups and Chi\textsuperscript{2}-test or Fisher's exact test (when at
least one cell had an expected count less than five) were used to
explore relationships between categorical variables. Change in lung
function variables before versus after bronchodilator were evaluated by
Wilcoxon signed rank test or McNemar's test. P-values \textless{}0.05
were considered significant.

\textbf{Results}

\textbf{Population characteristics and early respiratory morbidity}

The children born preterm had a median gestational age at birth of 26
weeks+1 day, 73\% were born extremely preterm, i.e. before 28 weeks, and
63\% had a diagnosis of BPD (Table 1). In comparison to children born
preterm without BPD, children with BPD had a lower gestational age at
birth, a lower birth weight and were more often male. In the neonatal
period, they were more often treated with surfactant and were more often
mechanically ventilated and for longer periods (E-table 1). Smoking
during early pregnancy was only reported in 13\% of mothers to preterm
infants.

\textbf{History of airway disease}

Children born very preterm had significantly more respiratory symptoms
than term controls (Table 1). Caregivers reported that 59/136 (43\%)
children born very preterm had experienced at least one out of four
symptoms related to airflow obstruction (any history of wheezing,
exercise-induced wheezing, nocturnal cough without infection, sleep
disturbed by wheezing) compared to 12/56 (21\%) children born at term
(p=0.004). Wheezing was the most common symptom, reported in 52/136
(38\%) children born very preterm compared to 8/56 (14\%) children born
at term (p=0.001). There were no differences in symptoms within the
preterm group between children with or without a diagnosis of BPD.

There were no associations between antenatal exposures and later airway
symptoms except that children born preterm after maternal infection or
after clinical chorioamnionitis had twice as often experienced nocturnal
wheezing (34\% versus 16\% for maternal infection, p=0.042, and 50.0\%
versus 23.5\% for chorioamnionitis, p=0.052) than children without these
exposures. There were no associations between respiratory support (CPAP
or ventilator days) in the neonatal period and airway symptoms at school
age.

A diagnosis of asthma was more common in children born very preterm than
in the term-born controls (36\% versus 11\%, p\textless{}0.001), but
equally common in very preterm children with or without BPD. None of the
children had any mechanical respiratory support or supplemental oxygen
at the time of the lung function study.

\textbf{Lung function deficits in children born very preterm versus at
term}

Children born very preterm had more airway obstruction, higher airway
resistance, lower diffusion capacity and more ventilation inhomogeneity
at 12 years of age than their term born controls. This was most evident
before bronchodilator inhalation and was seen in a majority of the tests
performed and both as absolute values and as percent of predicted normal
values (Figure 1 and Tables 2 and 3).

Spirometry showed significantly more airway obstruction, measured as
reductions in FEV\textsubscript{1}, FEV\textsubscript{1}/FVC and
FEF\textsubscript{25-75}, in children born very preterm compared to
term, both as absolute values and as percent of predicted (Figure 1A-C,
Table 2). FEV\textsubscript{1} below the lower limit of normal occurred
in 23.5\% of children born very preterm but only in 3.6\% of children
born at term (p=0.001). The corresponding proportions for
FEV\textsubscript{1}/FVC were 25.0\% versus 9.1\% (p=0.014) and for
FEF\textsubscript{25-75} 39.7\% versus 10.9\% (p\textless{}0.001).
Dysanapsis ratio was lower in children born very preterm than in
children born at term (p=0.004, Table 2).

Measurement of static lung volumes showed lower VC and higher RV as
percent of predicted in very preterm infants, and also higher RV/TLC
(Table 2 and 3). However, TLC and alveolar volume were not significantly
different between children born preterm or at term.

Inspiratory, expiratory, and total airway resistance, as measured by
body plethysmography, were higher in children born preterm (Table 3).
Impulse oscillometry similarly showed a higher total resistance
(R\textsubscript{5}, Figure 1D), frequency dependence of resistance
(R\textsubscript{5}-R\textsubscript{20}) and resonant frequency
(F\textsubscript{res}), a lower reactance at 5 Hz (more negative
X\textsubscript{5}), and an increased area under the reactance curve
(AX; all p\textless{}0.001, Table 3), all indicating dysfunction of
peripheral airways.

Diffusion capacity (DL\textsubscript{CO}) and the diffusion coefficient
for CO (K\textsubscript{CO}) were significantly lower in preterm- than
in term-born children (Table 3 and Figure 1E). However, the proportion
of preterm-born children with measurements below the lower limit of
normal was much smaller for DL\textsubscript{CO} (5.7\% for children
born preterm and 0\% for term born controls, E-table 2) than for
expiratory flows.

During N\textsubscript{2} washout, children born very preterm had a
significantly higher lung clearance index (both
LCI\textsubscript{2.5}and LCI\textsubscript{5.0}) than children born at
term (Table 3 and Figure 1F). This was most prominent for
LCI\textsubscript{2.5}, indicating an increased ventilation
inhomogeneity most evident in the peripheral airways.

Within the whole study population, children with
FEV\textsubscript{1}/FVC or FEF\textsubscript{25-75} below the lower
limit of normal had significantly more often experienced wheezing,
disturbed sleep or at least one of the symptoms listed in Table 1 (all
p\textless{}0.05). A previous diagnosis of asthma was almost twice as
common in children found to have FEF\textsubscript{25-75} below the
lower limit of normal than in those with a normal
FEF\textsubscript{25-75} (42.4\% vs. 22.0\%, p=0.004).

\textbf{BPD in association to lung function at school age}

At 12 years of age, children born very preterm with a former diagnosis
of BPD had more airflow obstruction, higher airway resistance and a
lower diffusion capacity than preterm infants without BPD (Tables 2 and
3, and Figure 1).

More airway obstruction was read as a lower FEV\textsubscript{1}/FVC and
FEF\textsubscript{25-75} in children with than in children without BPD
(p=0.022 and p=0.021, respectively), but there was no difference in
FEV\textsubscript{1}, FVC, or in static volumes. However, the dysanapsis
ratio were lower in children with than in children without BPD (p=0.023,
Table 2).

Children with a history of BPD had an increased peripheral resistance
(measured as R\textsubscript{5}-R\textsubscript{20} and
R\textsubscript{5}-R\textsubscript{20} \% of predicted by IOS) compared
to children born without BPD. The higher airway resistance in children
born preterm versus term was mainly explained by specifically higher
resistance among children with BPD.

Diffusion capacity was lower in children with BPD compared to children
with no BPD, both as D\textsubscript{LCO} and DL\textsubscript{CO} \% of
predicted. The lower level of diffusion capacity in very preterm born
children compared to term born was mainly explained by the lower values
in children with BPD (Table 3).

Children with a history of BPD also had a larger ventilation
inhomogeneity of the conductive airways, measured as
S\textsubscript{cond} than in children without BPD. In addition,
preterm-born children with a diagnosis of BPD, but not children without
BPD, had worse LCI\textsubscript{5.0}, S\textsubscript{cond} and
S\textsubscript{acin} than children born at term (Table 3).

\textbf{Antenatal markers and neonatal events in association to lung
function}

In very preterm infants, antenatal events associated with BPD
(chorioamnionitis and maternal infection) were not associated with
impaired lung function at 12 years of age, neither was premature rupture
of membrane.

Children that had been mechanically ventilated in the neonatal period
showed increased airflow obstruction at school age;
FEV\textsubscript{1}(p=0.005) and FEF\textsubscript{25-75} (p=0.027).
These children also had lower diffusing capacity, DL\textsubscript{CO}
(p=0.005), DL\textsubscript{CO} \% of predicted (p=0.019),
K\textsubscript{CO}(p=0.16) and K\textsubscript{CO} \% of predicted
(p=0.034). Surfactant treatment was not associated with later lung
function impairment.

\textbf{Effect of bronchodilator inhalation on lung function}

Reversibility, here meaning an improvement in lung function after
inhalation of 200 \selectlanguage{greek}µ\selectlanguage{english}g salbutamol, occurred both in children born at term
and in children born very preterm (Figure 1), but the effect was
generally larger in the very preterm group, so that after bronchodilator
the difference between the two groups was, for some parameters, no
longer significant. Table 4 shows \% of predicted values, E-table 3
shows absolute values, and E-table 4 proportion of children with values
outside the normal range before versus after bronchodilator. E-table 5
shows reversibility in percent and E-table 6 absolute reversibility,
also in relation to BPD.

Children born preterm were more reversible in FEV\textsubscript{1}/FVC
and FEF\textsubscript{25-75} compared to full term controls (E-table 5
and 6), but after bronchodilator, there remained a significant
difference between children born preterm versus at term for
FEV\textsubscript{1} and FEF\textsubscript{25-75}, but not for
FEV\textsubscript{1}/FVC (Tables 4 and E-table 3). After bronchodilator,
the proportion of children born very preterm with
FEV\textsubscript{1}below the lower limit of normal fell from 23.5\% to
7.6\% (p=0.001). For FEV\textsubscript{1}/FVC, the similar proportions
were 25.0\% versus 7.6\%, and for FEF\textsubscript{25-75} they were
39.7 \% versus 16.3\% (both p\textless{}0.001, Table 4).

Bronchodilator inhalation caused no significant change in lung
volumes,\emph{i.e.} FVC, TLC, RV or alveolar volume in children born
very preterm (Table 4).

Children born very preterm were more reversible than children born at
term in total airway resistance, as measured by body plethysmography,
and frequency dependence of resistance (R\textsubscript{5-20}) and
airway reactance (X\textsubscript{5}, AX and F\textsubscript{res}) as
measured by IOS (E-table 6). Total airway resistance (measured by body
plethysmography and as R\textsubscript{5} by impulse oscillometry)
decreased significantly after bronchodilator inhalation, so that no
difference remained in comparison with children born at term. Small
airway dysfunction measured by impulse oscillometry also improved after
bronchodilator (all p\textless{}0.001) but remained significantly higher
than in children born at term (Tables 4 and E-table 3).

In children born preterm, DL\textsubscript{CO} and
K\textsubscript{CO}increased after bronchodilator inhalation but
remained significantly lower than in term infants (Tables 4 and E-table
3). However, after bronchodilator inhalation, almost all children had
values within a normal range (E-table 4).

Multiple breath wash-out in children born preterm showed a significant
fall in S\textsubscript{cond} and S\textsubscript{acin} after
bronchodilator (Table 4 and E-table 3). Notably, the proportion of
children born very preterm with S\textsubscript{cond} above the
95\textsuperscript{th} centile fell from 17.3\% to 4.4\% (p=0.035,
E-table 4).

In a subgroup analysis of children born very preterm with or without
BPD, the bronchodilator response was found to be similar with the same
significance levels in both subgroups for measurements made during
spirometry, body plethysmography and diffusion capacity (E-tables 5 and
6).

\textbf{Sex in association to lung function at school age}

Overall, the boys born preterm had in many aspects worse lung function
than the boys born at term, which was not seen to the same extent in the
girls born preterm compared to girls born at term. Boys born very
preterm had more airflow limitation during spirometry, more air
trapping, higher airway resistance, more peripheral airway dysfunction,
lower diffusion capacity, and more ventilation inhomogeneity than boys
born at term (Tables 5, E-tables 7 and 8). In comparison with preterm
girls, preterm boys had significantly lower expiratory flows, lower
dysanapsis ratio, lower diffusion capacity, and more ventilation
inhomogeneity.

In girls born very preterm, expiratory flows, dysanapsis ratio, air
trapping, and ventilation inhomogeneity were not significantly different
from what was measured in girls born at term. However, both boys and
girls born very preterm had significantly more small airway dysfunction,
as measured by IOS, than their term-born counterparts (Table 5).''

\textbf{Discussion}

By using a broad approach of lung function measurements, we show that
children born very preterm have an increased risk for impaired lung
function in many aspects at 12 years of age compared to children born at
term. Airway obstruction was evident, and a high proportion of children
born very preterm had FEV\textsubscript{1}/FVC or
FEF\textsubscript{25-75} below the lower limit of normal. They also had
an increased airway resistance and IOS findings compatible with small
airway dysfunction. A higher lung clearance index revealed a higher
ventilation inhomogeneity in the group of preterm children, which is in
line with the increased obstructive pattern shown by spirometry. We have
got a more complete picture of the lung function at 12 years of age, and
all together, this reflects deficits in the lung after very preterm
birth.

Airflow limitation\textsuperscript{(6, 7)} and reduced diffusion
capacity\textsuperscript{(2, 7, 18, 19)}, has also previously been
reported in children born preterm and in young adults with a history of
BPD. In this study, a significant reduction in diffusion capacity was
seen in children born very preterm, but few children had a
DL\textsubscript{CO} below the lower limit of normal. Static volumes,
such as alveolar volume and total lung capacity, were not significantly
reduced in children born very preterm, which is in accordance with
previous reports\textsuperscript{(6, 20)}. However, RV/TLC, an estimate
of air trapping, was higher in children born preterm than in term-born
controls, supporting evidence of changes in the peripheral airways. The
dysanapsis ratio has been suggested to describe the relationship between
airway calibre and lung size, and has been shown in adults to be a
predictor of expiratory flow limitation\textsuperscript{(17)}. In
addition, the lower dysanapsis ratio in preterm-born children may
suggest that their airways are undersized in relation to the
lungs\textsuperscript{(21)}.

The lower gestational age and more pulmonary morbidity in children with
BPD did not translate into a markedly more severe lung function
impairment at school age\textsuperscript{(3, 6, 22)}. There were
differences in lung function between children with versus without BPD,
notably more airway obstruction and a lower DL\textsubscript{CO}, but
generally the difference between children within the very preterm group
were smaller than the differences between the whole preterm group and
their term controls. The definition of BPD has been modified to maximize
the possibility to predict future respiratory morbidity up to
approximately two years of age, but the later natural history of BPD, at
school age and early adulthood, is less well
understood\textsuperscript{(23, 24)}. Previous follow-up studies have
sometimes reported long-term effects of BPD in relation only to term
controls, and the effects of prematurity per se may have been
underestimated.

More children born very preterm had experienced wheezing or had been
given a diagnosis of asthma, but there was no difference in airway
symptoms in preterm born children with or without a diagnosis of BPD.
Prematurity per se and not a diagnosis of BPD seems to be a more
valuable factor for a variety of symptoms regarding the airways, which
have also been shown in younger ages\textsuperscript{(22)}. Most
important is to be aware that BPD and asthma are two different entities
with disparity in ongoing airway inflammation.

Lung function impairment of children born preterm is often believed to
be structurally determined and unaffected by treatment, and due to lack
of evidence there is no recommendation about the routine use of
bronchodilators. Reversibility of lung function impairment in
preterm-born children by bronchodilator inhalation has not been more
widely studied than for the effect on FEV\textsubscript{1}, and in some
cases also the effect on FEV\textsubscript{1}/FVC and
FEF\textsubscript{25-75}\textsuperscript{(25)}, and the conclusion is
that bronchodilators improve the FEV\textsubscript{1} in short term. Our
study is, to the best of our knowledge, the first to report short-term
bronchodilator effect on a multitude of modalities of pulmonary function
testing. We showed that a substantial proportion of preterm-born
children normalized their airflows after a single dose bronchodilator
inhalation. These findings indicate that some preterm-born children may
be undertreated, and more studies on treatment effects are warranted.

In children born very preterm, our study shows a male disadvantage in
lung function, especially for measures of airflow obstruction and total
airway resistance. Harris et al.\textsuperscript{(26)} identified a
similar pattern of airway obstruction.

The main strengths of our study are that it included consecutively
recruited inborn infants with a high acceptance rate and all born at a
single regional Centre with little variation in treatment and has a long
observational period. Term born controls were born in the same region as
the preterm infants and collected according to a well-defined
system\textsuperscript{(27)}. Comprehensive pulmonary function tests
were performed at a narrow age span around 12 years of age and covered
different aspects of lung function. To our knowledge this is the first
study covering all these different modalities of lung function
parameters including reversibility.

The design of the study with an antenatal informed consent may have
introduced a selection bias in the original study population, since
informed consent could not be obtained for infants born after unexpected
deliveries. The wide gestational age span in our cohort (23-31 weeks),
with a majority of the children born extremely preterm, may confound our
results, as well as different reasons for preterm birth. We are aware of
the risks of making multiple comparisons and that our findings need to
be confirmed in a larger population. It would be of value to follow lung
function over time during childhood, as a timeline of lung development.

In conclusion, in this study we have defined a comprehensive lung
function pattern in children 12 years of age, born term or preterm, with
or without BPD. We show differences in lung function and reversibility
between these groups, from airway obstruction to resistance and
reactance to ventilation inhomogeneity and diffusion capacity, which has
not been done previously in this broad perspective. The importance of
follow-up during childhood to determine lung function and establish
guidelines on comprehensive monitoring strategies beyond the neonatal
period seems to be vital for the future.

\textbf{Figure legend:}

Figure 1. Lung function at 12 years of age before and after
bronchodilator inhalation in children born very preterm with or without
a previous diagnosis of BPD, and children born at term. Data is
presented as individual values and horizontal lines are median of \% of
predicted values for FEV\textsubscript{1} (A), FEV\textsubscript{1}/FVC
(B), FEF\textsubscript{25-75} (C), R\textsubscript{5} (D),
DL\textsubscript{CO} (E) and LCI\textsubscript{2.5} (F). The dotted line
represents the lower limit of normal in A, B, C and E, and upper limit
of normal in D and F. *p\textless{}0.05, **p\textless{}0.01 and
***p\textless{}0.001.

\textbf{Author contribution}

All authors contributed to the conception and design of this work as
well as the analysis and interpretation of data. Data acquisition was
done by IH-P (neonatal data) and ET (lung function testing). All authors
have had complete access to the study data. CH wrote the first draft.
All authors revised the text, have approved the version to be published,
and agree to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved.

\textbf{Conflict of interests}

CH has no conflict of interest. LJB has received honoraria from Chiesi
Pharma AB, Sweden, for being a member of the steering committee for the
Nordic Neonatal Meetings, and from AbbVie AB for lectures and for
previously being a member of the steering committee for the NEOSPEX
educational project. LB has no conflict of interest. IH-P holds
stock/stock options in Premalux AB and has received honoraria from
Baxter International for lectures. ET has no conflict of interest.

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