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TY - JOUR

T1 - Late (≥ 7 days) inhaled corticosteroids to reduce bronchopulmonary dysplasia in preterm infants

AU - Onland, Wes

AU - Offringa, Martin

AU - van Kaam, Anton

N1 - Funding Information: Trial author provided additional information on randomisation process. Glaxo France provided the therapeutic units (placebo and drugs), and Trudell Medical London, Ontario, Canada supplied the ae-rochamber spacer devices. Supported by a grant from Assistance Publique Hopitaux de Paris. Funding Information: Trial authors provided data on extubation rate. Supported by a grant from Action Research UK. MDIs were provided by Astra Draco, Edinburgh, UK, and the spacers by Trudell Medical, London, Canada. Funding Information: We would like to thank Dr P Lister, Dr R Iles, Dr B Shaw, and Dr F Ducharme for writing the previous version of this review, named 'Inhaled steroids for neonatal chronic lung disease' (Lister 2000). 
We are grateful to Dr David Schwartz, Dr T Giep, Prof M Silverman, and Dr Spencer Brudno for providing additional information for the previous version of this review.
We would also like to thank Prof Silverman and Dr Jonsson, who provided precious additional data for the first update of the review.
The search strategy was designed by Cochrane Neonatal, and Colleen Ovelman ran the searches. We would like to thank the following members of Cochrane Neonatal for providing editorial and administrative support: Colleen Ovelman and Jane Cracknell (Managing Editors), Michelle Fiander and Chris Cooper (Information Specialists), and Roger Soll and William McGuire (Co-ordinating Editors). Cochrane Neonatal supported the review authors in the development of this updated review. The following people conducted the editorial process for this article: Sign-off Editor (final editorial decision): Robert Boyle, Imperial College London, UK; Co-ordinating Editor of the Cochrane Skin Group. Managing Editor (selected peer reviewers, provided comments, collated peer-reviewer comments, provided editorial guidance to the review authors, edited the article): Lara Kahale, Cochrane Central Editorial Service Editorial Assistant (conducted editorial policy checks and supported editorial team): Lisa Wydrzynski, Cochrane Central Editorial Service Copy Editor (copy-editing and production): Julia Turner Peer-reviewers (provided comments and recommended an editorial decision): Augusto F Schmidt, University of Miami Miller School of Medicine, USA; Jana Tukova, Charles University in Prague and General University Hospital in Prague, Czech Republic; Faouzi I Maalouf, American University of Beirut, Lebanon (clinical/content review); Jamale Eleid, American University of Beirut, Lebanon (consumer review); Nuala Livingstone, Associate Editor, Cochrane Evidence Production and Methods Directorate (methods review); and Robin Featherstone, Cochrane Central Editorial Service (search review). Sign-off Editor (final editorial decision): Robert Boyle, Imperial College London, UK; Co-ordinating Editor of the Cochrane Skin Group. Managing Editor (selected peer reviewers, provided comments, collated peer-reviewer comments, provided editorial guidance to the review authors, edited the article): Lara Kahale, Cochrane Central Editorial Service Editorial Assistant (conducted editorial policy checks and supported editorial team): Lisa Wydrzynski, Cochrane Central Editorial Service Copy Editor (copy-editing and production): Julia Turner Peer-reviewers (provided comments and recommended an editorial decision): Augusto F Schmidt, University of Miami Miller School of Medicine, USA; Jana Tukova, Charles University in Prague and General University Hospital in Prague, Czech Republic; Faouzi I Maalouf, American University of Beirut, Lebanon (clinical/content review); Jamale Eleid, American University of Beirut, Lebanon (consumer review); Nuala Livingstone, Associate Editor, Cochrane Evidence Production and Methods Directorate (methods review); and Robin Featherstone, Cochrane Central Editorial Service (search review). Funding Information: Trial authors did not respond to queries. Supported by GlaxoSmithKline. Dr Piedboeuf was supported by the Fonds de Recherche en Santé de Québec. Funding Information: Trial author provided additional outcome data and checked data extraction. Trial received grants from Sällskapet Barnavård and Stilftesen Barnhuset, Stockholm. Publisher Copyright: Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

PY - 2022/12/15

Y1 - 2022/12/15

N2 - Background: Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks' postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation may be an effective and safe alternative. Objectives: To assess the benefits and harms of inhaled corticosteroids versus placebo, initiated between seven days of postnatal life and 36 weeks' postmenstrual age, to preterm infants at risk of developing bronchopulmonary dysplasia. Search methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trials registries to August 2022. We searched conference proceedings and the reference lists of retrieved articles for additional studies. Selection criteria: We included randomised controlled trials (RCTs) comparing inhaled corticosteroids to placebo, started between seven days' postnatal age (PNA) and 36 weeks' PMA, in infants at risk of BPD. We excluded trials investigating systemic corticosteroids versus inhaled corticosteroids. Data collection and analysis: We collected data on participant characteristics, trial methodology, and inhalation regimens. The primary outcomes were mortality, BPD, or both at 36 weeks' PMA. Secondary outcomes included short-term respiratory outcomes (mortality or BPD at 28 days' PNA, failure to extubate, total days of mechanical ventilation and oxygen use, and need for systemic corticosteroids) and adverse effects. We contacted the trial authors to verify the validity of extracted data and to request missing data. We analysed all data using Review Manager 5. Where possible, we reported the results of meta-analyses using risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, along with their 95% confidence intervals (CIs). We analysed ventilated and non-ventilated participants separately. We used the GRADE approach to assess the certainty of the evidence. Main results: We included seven trials involving 218 preterm infants in this review. We identified no new eligible studies in this update. The evidence is very uncertain regarding whether inhaled corticosteroids affects the combined outcome of mortality or BPD at 36 weeks' PMA (RR 1.10, 95% CI 0.74 to 1.63; RD 0.07, 95% CI −0.21 to 0.34; 1 study, 30 infants; very low-certainty) or its separate components: mortality (RR 3.00, 95% CI 0.35 to 25.78; RD 0.07, 95% CI −0.08 to 0.21; 3 studies, 61 infants; very low-certainty) and BPD (RR 1.00, 95% CI 0.59 to 1.70; RD 0.00, 95% CI −0.31 to 0.31; 1 study, 30 infants; very low-certainty) at 36 weeks' PMA. Inhaled corticosteroids may reduce the need for systemic corticosteroids, but the evidence is very uncertain (RR 0.51, 95% CI 0.26 to 1.00; RD −0.22, 95% CI −0.42 to −0.02; number needed to treat for an additional beneficial outcome 5, 95% CI 2 to 115; 4 studies, 74 infants; very low-certainty). There was a paucity of data on short-term and long-term adverse effects. Despite a low risk of bias in the individual studies, we considered the certainty of the evidence for all comparisons discussed above to be very low, because the studies had few participants, there was substantial clinical heterogeneity between studies, and only three studies reported the primary outcome of this review. Authors' conclusions: Based on the available evidence, we do not know if inhaled corticosteroids initiated from seven days of life in preterm infants at risk of developing BPD reduces mortality or BPD at 36 weeks' PMA. There is a need for larger randomised placebo-controlled trials to establish the benefits and harms of inhaled corticosteroids.

AB - Background: Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks' postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation may be an effective and safe alternative. Objectives: To assess the benefits and harms of inhaled corticosteroids versus placebo, initiated between seven days of postnatal life and 36 weeks' postmenstrual age, to preterm infants at risk of developing bronchopulmonary dysplasia. Search methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trials registries to August 2022. We searched conference proceedings and the reference lists of retrieved articles for additional studies. Selection criteria: We included randomised controlled trials (RCTs) comparing inhaled corticosteroids to placebo, started between seven days' postnatal age (PNA) and 36 weeks' PMA, in infants at risk of BPD. We excluded trials investigating systemic corticosteroids versus inhaled corticosteroids. Data collection and analysis: We collected data on participant characteristics, trial methodology, and inhalation regimens. The primary outcomes were mortality, BPD, or both at 36 weeks' PMA. Secondary outcomes included short-term respiratory outcomes (mortality or BPD at 28 days' PNA, failure to extubate, total days of mechanical ventilation and oxygen use, and need for systemic corticosteroids) and adverse effects. We contacted the trial authors to verify the validity of extracted data and to request missing data. We analysed all data using Review Manager 5. Where possible, we reported the results of meta-analyses using risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, along with their 95% confidence intervals (CIs). We analysed ventilated and non-ventilated participants separately. We used the GRADE approach to assess the certainty of the evidence. Main results: We included seven trials involving 218 preterm infants in this review. We identified no new eligible studies in this update. The evidence is very uncertain regarding whether inhaled corticosteroids affects the combined outcome of mortality or BPD at 36 weeks' PMA (RR 1.10, 95% CI 0.74 to 1.63; RD 0.07, 95% CI −0.21 to 0.34; 1 study, 30 infants; very low-certainty) or its separate components: mortality (RR 3.00, 95% CI 0.35 to 25.78; RD 0.07, 95% CI −0.08 to 0.21; 3 studies, 61 infants; very low-certainty) and BPD (RR 1.00, 95% CI 0.59 to 1.70; RD 0.00, 95% CI −0.31 to 0.31; 1 study, 30 infants; very low-certainty) at 36 weeks' PMA. Inhaled corticosteroids may reduce the need for systemic corticosteroids, but the evidence is very uncertain (RR 0.51, 95% CI 0.26 to 1.00; RD −0.22, 95% CI −0.42 to −0.02; number needed to treat for an additional beneficial outcome 5, 95% CI 2 to 115; 4 studies, 74 infants; very low-certainty). There was a paucity of data on short-term and long-term adverse effects. Despite a low risk of bias in the individual studies, we considered the certainty of the evidence for all comparisons discussed above to be very low, because the studies had few participants, there was substantial clinical heterogeneity between studies, and only three studies reported the primary outcome of this review. Authors' conclusions: Based on the available evidence, we do not know if inhaled corticosteroids initiated from seven days of life in preterm infants at risk of developing BPD reduces mortality or BPD at 36 weeks' PMA. There is a need for larger randomised placebo-controlled trials to establish the benefits and harms of inhaled corticosteroids.

UR - http://www.scopus.com/inward/record.url?scp=85144175937&partnerID=8YFLogxK

U2 - 10.1002/14651858.CD002311.pub5

DO - 10.1002/14651858.CD002311.pub5

M3 - Review article

C2 - 36521169

VL - 2022

JO - Cochrane database of systematic reviews (Online)

JF - Cochrane database of systematic reviews (Online)

SN - 1469-493X

IS - 12

M1 - CD002311

ER -