Abstract
Decreases in future lung function are a hallmark of preterm birth, but studies for management of decreased lung function are limited. To determine whether 12 weeks of treatment with inhaled corticosteroids (ICS) alone or in combination with long-acting β2 agonists (LABA) improves spirometry and exercise capacity in school-aged preterm-born children who had percent predicted forced expiratory volume in 1 second (%FEV1) less than or equal to 85% compared with inhaled placebo treatment. A double-blind, randomized, placebo-controlled trial was conducted to evaluate ICS and ICS/LABA against placebo. Preterm-born children (age, 7-12 years; gestation ≤34 weeks at birth) who did not have clinically significant congenital, cardiopulmonary, or neurodevelopmental abnormalities underwent spirometry, exercise testing, and measurement of fractional exhaled nitric oxide before and after treatment. A total of 144 preterm-born children at the Children's Hospital for Wales in Cardiff, UK, were identified and enrolled between July 1, 2017, and August 31, 2019. Each child was randomized to 1 of 3 cohorts: fluticasone propionate, 50 μg, with placebo; fluticasone propionate, 50 μg, with salmeterol, 25 μg; or placebo inhalers, all given as 2 puffs twice daily for 12 weeks. Children receiving preexisting ICS treatment underwent washout prior to randomization to ICS or ICS/LABA. The primary outcome was between-group differences assessed by adjusted pretreatment and posttreatment differences of %FEV1 using analysis of covariance. Intention-to-treat analysis was conducted. Of 144 preterm-born children who were identified with %FEV1 less than or equal to 85%, 53 were randomized. Treatment allocation was 20 children receiving ICS (including 5 with prerandomization ICS), 19 children receiving ICS/LABA (including 4 with prerandomization ICS), and 14 children receiving placebo. The mean (SD) age of children was 10.8 (1.2) years, and 29 of the randomized children (55%) were female. The posttreatment %FEV1 was adjusted for sex, gestation, bronchopulmonary dysplasia, intrauterine growth restriction, pretreatment corticosteroid status, treatment group, and pretreatment values. Posttreatment adjusted means for %FEV1, using analysis of covariance, were 7.7% (95% CI, -0.27% to 15.72%; P = .16) higher in the ICS group and 14.1% (95% CI, 7.3% to 21.0%; P = .002) higher in the ICS/LABA group compared with the placebo group. Active treatment decreased the fractional exhaled nitric oxide and improved postexercise bronchodilator response but did not improve exercise capacity. One child developed cough when starting inhaler treatment; no other adverse events reported during the trial could be attributed to the inhaler treatment. The results of this randomized clinical trial suggest that combined ICS/LABA treatment is beneficial for prematurity-associated lung disease in children. EudraCT number: 2015-003712-20.
Highlights
Of 144 preterm-born children identified with %forced expiratory volume in 1 second (FEV1) less than or equal to 85%, 53 (37%) could not be recontacted or declined participation (Figure 1)
From the remaining 87 children, including 9 with successful washout from inhaled corticosteroids (ICS) therapy, 4 did not complete satisfactory spirometry tests, and 33 (38%) were excluded because their %FEV1 value was greater than 85% at the pretreatment visit
Because late preterm-born children, especially those born at 33 to 34 weeks’ gestation, are at risk of developing lung disease,[1] we focused on pretermborn children born at 34 weeks’ or less who had low lung function close to the lower limit of normal rather than just focusing on those with bronchopulmonary dysplasia (BPD) especially as a significant proportion of those with BPD have normal lung function in childhood and beyond
Summary
Participants The Respiratory Health Outcomes in Neonates (RHiNO) study is a comprehensive study of respiratory disease of pretermborn children evaluating mechanisms, hyperpolarized xenon 129 magnetic resonance imaging, and the current randomized clinical trial.[11] The protocol and statistical analysis plan of this randomized blinded trial are available in Supplement 1. To identify the participants with %FEV1 less than or equal to 85%, we supplemented the responders from a 2013 questionnaire study[3,12] with additional potential participants identified from the National Welsh Informatics Service and invited them to join the RHiNO study if they were born at 34 weeks’ gestation or less, were aged 7 to 12 years, and did not have substantial congenital abnormalities or severe cardiopulmonary or neurodevelopmental impairment. Recruitment to the trial occurred between July 1, 2017, and August 31, 2019, for children from South Wales who were assessed at the Children’s Hospi-
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