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 FEV1/FVC or
FEF25-75 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(6, 7) and reduced diffusion
capacity(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
DLCO 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(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(17). In
addition, the lower dysanapsis ratio in preterm-born children may
suggest that their airways are undersized in relation to the
lungs(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(3, 6, 22). There were
differences in lung function between children with versus without BPD,
notably more airway obstruction and a lower DLCO, 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(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(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 FEV1, and in some
cases also the effect on FEV1/FVC and
FEF25-75(25), and the conclusion is
that bronchodilators improve the FEV1 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.(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(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.