In our cohort of school-aged children born preterm lung function measured by IOS and spirometry was significantly impaired as compared to predicted values. Notably, we found an increase in airway impedance with higher values of resistance and lower values of reactance, larger area under the reactance curve AX and higher resonant frequency Fres. Spirometry revealed normal forced expiratory volume and forced vital capacity but reduced values of FEF25 − 75 compared to predicted values. Children with a diagnosis of BPD showed a significant lower FEV1 than children without BPD. Having BPD did not influence IOS parameters while being born SGA was associated to higher increase in the value of peripheral airway resistance R5-R20 compared to children born AGA. In children born with a BW < 1500 g airway impedance Z and airway resistance at 5 Hz were inversely related to BW z-score. Respiratory symptoms were reported by almost one third of our population.
The impairment of lung function in children born preterm is a well-known finding. Over the years, longitudinal studies demonstrated significant reduction of FEV1 in cohorts of children born extremely preterm, especially in those with BPD5,7,8,18,19, and also in children born late preterm20. Anomalies in airway elastic properties and resistance have been assessed in preterm children by different techniques such as the interrupter resistance Rint21,22, the forced oscillation technique (FOT)7, 23–26 and IOS20,26−30.
One study conducted in a group of 6–8 years old Swedish children born preterm with a BW < 1500 g showed that, even if asymptomatic, those with BPD had worse IOS parameters with higher airway resistance and more negative reactance compared to children without BPD28. Same results were obtained in a similar cohort of 49 Finnish children studied at the age of 5–10 years29. Findings in adolescents born preterm between 24 and 31 weeks of gestation confirmed that those with a diagnosis of BPD had higher R5-R20 compared to peers without BPD26. In all the three studies FEV1 was lower and often impaired in subjects with BPD. Thunqvist et al. found in 151 extremely preterm children aged 6 years a higher airway resistance R5-R20 compared to controls born at term irrespective of a diagnosis of BPD20. Compared to controls born at term, greater airway resistance was described in young children born late preterm (34–36 weeks of gestation) and higher values of R5, R5-R20 and AX were reported in male adolescents born moderate to late preterm (32–36 weeks of gestation)30 suggesting that also slight prematurity can have a negative effect on pulmonary function.
Our results are in line with these previous findings with a certain degree of respiratory impairment found in 7-9-year-old children born preterm. The IOS findings of increased resistance of central and peripheral airways, lower reactance and increased AX and Fres suggest that children born preterm may have an increase in airway tone particularly in peripheral airways. Imaging studies performed in school children born very preterm revealed structural lung abnormalities of the peripheral airways such as airway wall thickening, increased subpleural opacities (that usually stand for alveolar septal fibrosis), mosaic perfusion and air trapping both in children with BPD31 and in children without BPD8 suggesting a fixed peripheral airway narrowing32. These changes might be present especially in children who might have suffered from anatomical damages during fetal life like those with intrauterine growth restriction (IUGR).
IUGR is commonly suspected when BW is classified as SGA. IUGR is often the result of nutritional fetal deficiency and impaired oxygenation due to placental insufficiency33 that usually manifests in the last phases of gestation when pulmonary parenchyma encounters acinar and alveolar phases. As a result, the growth of distal airways is the portion of the lung mainly affected as confirmed in animal studies33. Our population included 12 children born SGA and 8 of these were born moderate to late preterm. The mean difference between observed and predicted values of R5-R20 was higher in children born SGA, suggesting a possible greater impairment in small airway resistance in these children compared to children born AGA. In the study by Thunqvist et al. children born SGA had higher values of R5-R20 than those born AGA while no difference was noted in spirometry20. Similarly, Greenough et al. found higher airway resistance measured by pletismography in children born preterm (23–25 wks) and SGA34. Furthermore, in children with a VLBW (< 1500 g) we found that airway impedance Z and airway resistance R5 negatively correlated with BW z-score and that in the multivariable linear regression analysis BW z-score was an independent predictor for Z5, R5 and AX values. The relationship between low BW and impaired lung function has been extensively studied in infants34,35, childhood5,8,36,37 and adults38. Our data may further confirm the association between fetal and airway growth, particularly in children with VLBW.
We speculate that the finding of lower FEF25 − 75 in our cohort may reflect the impairment of small airways demonstrated with the increased values of the IOS indices. Previous studies showed concordant information between the oscillometric method and spirometry26,28,29 but IOS is considered to be more sensitive in evaluating peripheral airways13. However, while we found a significant lower FEV1 in subjects with BPD compared to those without BPD (-0.93 z-score), we did not find a significant difference with IOS. However, all IOS indices were slightly but not significantly higher in children with BPD. In our population children born extremely preterm were only 9.2% of total while more than half (51.9%) was born moderate to late preterm; 10 children were diagnosed with BPD because exposed to long-term oxygen therapy. These data point out that the number of subjects at risk for severe respiratory complications was small and that the not significant data obtained from IOS parameters when comparting children with and without BPD may be due to the small size of the sample. However, a recent prospective cohort study based in Italy on a large population of very preterm children (n 194) also reported no significant difference in airway resistance in subjects with and without BPD22. Regardless a diagnosis of BPD, preterm birth alone, interrupting the last phases of lung development, may have contributed to the abnormalities observed in our study in lung function tests.
Almost one third of children in our cohort reported at least one episode of wheezing confirming the higher prevalence of respiratory symptoms in preterms with and without BPD4,25,36. However, in contrast with other authors27, we did not find higher airway resistance in children who had experienced wheezing in the previous year.
Our study has certain limitations. The cohort did not include a control population and we compared our IOS data with the published reference values of a Brasilian pediatric population. Our population cannot be considered representative of the total population of preterm children born in our area because we studied only those in regular follow-up in our respiratory clinic. Furthermore, we excluded from the study children with severe neurological impairment likely excluding the most severe cases. Our limited number of participants might have contributed to the non-significant associations between all the range of BW and the various IOS parameters because of power issues. The effect of bronchodilators on airway resistance was not evaluated, making it difficult to exclude that the higher resistance found in our study can be due to reversible airway obstruction. In addition, we did not assess lung function serially over time. Further studies are needed to confirm our results.