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.