EBNEO Commentary: Umbrella Review Evaluating Interventions to Decrease Risk of Bronchopulmonary Dysplasia in Preterm Neonates

MANUSCRIPT CITATION

Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, Somanath SH, Shaik NB, Pullattayil AK, Weiner GM. Interventions to Prevent Bronchopulmonary Dysplasia in Preterm Neonates: An Umbrella Review of Systematic Reviews and Meta-analyses. JAMA Pediatrics 2022; 176:502-516. PMID 35226067.

REVIEWED BY

Sara Stucker, MD
Neonatal-Perinatal Medicine Fellow
University of Minnesota
Stuck085@umn.edu

Ellen Diego, MD
Assistant Professor of Pediatrics
University of Minnesota
Diego008@umn.edu 

QUESTION

What interventions are effective for preventing bronchopulmonary dysplasia (BPD) or mortality at 36 weeks’ postmenstrual age (PMA) in preterm neonates as evaluated in systematic reviews with meta-analyses?

P: Preterm infants born at less than 37 weeks’ gestation

I: Clinical care interventions in the delivery room or Neonatal Intensive Care Unit (NICU)

C: Current unit practice standard

O: Bronchopulmonary dysplasia (BPD) or mortality

T: 36 weeks’ PMA

METHODS

• Design: Umbrella review of systematic reviews with meta-analyses
• Allocation: Varies with individual study, all randomized control trials (RCTs)
• Blinding: Varies based on individual study
• Follow-up period: 36 weeks’ PMA
• Setting: All studies conducted in a hospital setting in the NICU with some studies also conducted in the delivery room.
• Patients: Premature infants at risk for BPD

o   Inclusion Criteria: Systematic reviews with meta-analyses of RCTs evaluating interventions in preterm infants <37 weeks’ gestation that reported BPD as a primary or secondary outcome.

o   Exclusion Criteria: RCTs pooled with nonrandomized trials or systematic reviews based on network meta-analyses. When systematic reviews evaluated the same research question, authors included the most recent high-quality review with the highest number of RCTs.

• Intervention: Clinical care interventions in the delivery room or NICU
• Outcomes:

o   Primary outcome: BPD or mortality at 36 weeks’ PMA and BPD at 36 weeks’ PMA.

o   Secondary outcomes: BPD at 28 days of life and BPD or mortality at 28 days of life

• Analysis and Sample Size: The AMSTAR2 tool assessed the quality of the systematic reviews and reported study quality as high, moderate, low, or critically low. GRADE methodology assessed the certainty of evidence (COE) of the effect estimates in the meta-analyses and reported the effect estimate certainty as high, moderate, low, or very low. Two authors independently evaluated each study.
• Patient follow-up: Varied across studies, not reported in umbrella review.

MAIN RESULTS

This umbrella review included 154 systematic reviews with meta-analyses of RCTs evaluating 251 research questions.

AMSTAR2 Assessment of Systematic Reviews: The authors utilized AMSTAR2 (A MeaSurement Tool to Assess systematic Reviews) methodology to assess systematic review quality. The authors graded 110 (71.4%) studies as high-quality systematic reviews and 38 (24.6%) studies as low or very low-quality reviews based on AMSTAR2 rating. The use of individual patient data in the meta-analysis excluded 6 systematic reviews.

GRADE Assessment of Meta-analyses: The study evaluated meta-analyses utilizing the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology. For the primary outcome of BPD or mortality at 36 weeks’ PMA, 12 comparisons showed significant benefits from the intervention with high COE, indicating a high level of confidence that the true effect is close to the estimate. Twenty-three comparisons had moderate COE, with 8 of those supporting the benefit of the intervention and 15 indicating no difference between the intervention and comparison. Moderate COE signifies moderate confidence that the true effect is close to the estimate, but there is a possibility of substantial difference. For the primary outcome of BPD at 36 weeks’ PMA, 8 comparisons supported a significant benefit of intervention with high COE. Sixty comparisons had moderate COE, with 14 indicating a benefit of intervention and 46 indicating no difference.

Interventions: Results from high-quality systematic reviews with high COE determined that the following interventions are associated with decreased risk of BPD or mortality at 36 weeks’ PMA: delivery room continuous positive airway pressure (CPAP) over intubation with or without routine surfactant, early selective surfactant over delayed selective surfactant, early inhaled corticosteroids, early systemic hydrocortisone, avoiding endotracheal intubation with delivery room CPAP and less invasive surfactant administration (LISA), and volume-targeted ventilation over pressure-limited ventilation.

Table 1. Interventions associated with decreased risk of BPD or mortality at 36 weeks’ PMA with high certainty of evidence (COE).

 ^*Prophylactic surfactant: infants determined to be at-risk for respiratory distress syndrome (RDS) intubated and surfactant administered independent of initial RDS severity

⁺Selective surfactant: surfactant only administered to infants requiring intubation for RDS symptoms

^{^}Early selective surfactant: surfactant administered within 3 hours for infants requiring intubation for RDS symptoms

⁺⁺Delayed selective surfactant: surfactant administration delayed until worsening RDS symptoms appreciated for infants requiring intubation for RDS symptoms.

^# Early inhaled corticosteroids (budesonide, fluticasone, or other formulations) have conflicting safety data requiring further evaluation of dosing and adverse outcome analysis ahead of implementation.

CONCLUSION

This umbrella review supports the combined approach of delivery room CPAP instead of routine intubation, early selective surfactant administration within three hours of life over prophylactic surfactant, avoiding endotracheal intubation, early hydrocortisone prophylaxis initiated in the first week of life in high-risk patients, inhaled corticosteroids within the first two weeks of life, and volume-targeted ventilation instead of pressure-limited ventilation in decreasing the risk of BPD and mortality at 36 weeks’ PMA with high COE. LISA, porcine surfactant, intratracheal corticosteroids, and late systemic steroids are associated with decreased risk of BPD or mortality at 36 weeks’ PMA with moderate COE. Further studies are needed to evaluate nutritional interventions and FiO2 and CPAP thresholds for LISA. Additional evaluation of early inhaled corticosteroids is required before widespread use due to conflicting safety data for budesonide and limited data evaluating fluticasone.

COMMENTARY

Bronchopulmonary Dysplasia (BPD) continues to affect preterm infants despite medical advances. Identifying effective prevention strategies is difficult due to the multifactorial nature of the disease. This umbrella review evaluated 154 systematic reviews with meta-analyses of randomized control trials (RCTs) to identify interventions effective at preventing BPD or mortality at 36 weeks’ postmenstrual age (PMA) in preterm infants. One hundred and ten of those systematic reviews are rated as high quality with 12 comparisons showing significant benefits from the intervention in reducing the risk of BPD or mortality at 36 weeks’ PMA with high certainty of evidence (COE).

 

Essential components of assessing umbrella reviews include evaluating for a focused question, appropriate study inclusion, and quality assessment of included studies (1). The authors of this paper selected a focused question and conducted a comprehensive literature review from multiple databases, likely capturing the majority of relevant studies. Established quality scoring tools (GRADE and AMSTAR2) assessed meta-analyses and systematic reviews with independent evaluation by 2 authors and detailed descriptions of grading criteria provided in the supplemental materials (2, 3).

 

Umbrella reviews only evaluate interventions previously studied in systematic reviews with meta-analyses of RCTs, limiting available studies for inclusion and the ability to perform in-depth adverse outcome analysis. Correctly interpreting consolidated statistical data is essential for accurate analysis and evaluation. For example, iNO, oxygen saturations of 85-89%, and vitamin A were associated with decreased risk of BPD, but not the combined outcome of BPD or mortality. The authors concluded this may suggest an increased risk of mortality, however, an editorial reply from Dr. Romero Lopez provided an alternative analysis using the example of Vitamin A (4). The editorial reply importantly emphasizes that observing the effect of an intervention on some but not all elements of a composite outcome does not imply the intervention has the opposite effect on the remaining elements. In this case, the study reported mortality data and did not see an increased risk (5). Facilitating an open dialogue discussing statistical analysis and conclusions is essential for deepening provider understanding of literature analysis and appropriate application to clinical practice to improve care.

 

This study provides the clinician with valuable scaffolding to guide further literature evaluation focusing on adverse outcome analysis and applying as appropriate to clinical decision-making. Adherence to high COE strategies for BPD reduction can be assessed at the facility-level by performing a best practice gap analysis for clinical protocol development and targeted quality improvement. Quality improvement studies have successfully decreased BPD rates by combining multiple interventions supported in this umbrella review into respiratory care bundles, including the use of delivery room CPAP and avoiding endotracheal intubation. At least one center has successfully maintained BPD rates of 5-7% for decades, supporting the feasibility and sustainability of utilizing a bubble CPAP care bundle to optimize care (6). Other studies have successfully decreased rates of intubation and BPD via respiratory care bundle implementation that includes initiation of CPAP in the delivery room, strict intubation and extubation criteria, and standardization of respiratory care provided (7,8,9)..

REFERENCES

1. Critical Appraisal Skills Programme. CASP Systematic Review Checklist. Available at: casp-uk.net/casp-tools-checklists/ 2022. Accessed: August 3rd, 2023.
2. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: A critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017; 358: j4008.
3. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011; 64: 401–406.
4. Mar Romero Lopez M. Comment on “Interventions to Prevent Bronchopulmonary Dysplasia in Preterm Neonates.” JAMA Network, 2022. Available at: jamanetwork.com/journals/jamapediatrics/article-abstract/2789460
5. Darlow BA, Graham PJ, Rojas-Reyes MX. Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2016; 8:CD000501.
6. Aly H, Mohamed MA. An experience with a bubble CPAP bundle: is chronic lung disease preventable? Pediatric Research 2020; 88: 444–450.
7. Levesque BM, Kalish LA, LaPierre J, Welch M, Porter V. Impact of implementing 5 potentially better respiratory practices on neonatal outcomes and costs. Pediatrics 2011; 128.
8. Kakkilaya VB, Weydig HM, Smithhart WE, Renfro SD, Garcia KM, Brown CM, et al. Decreasing continuous positive airway pressure failure in preterm infants. Pediatrics 2021; 148.
9. Kubicka Z, Zahr E, Rousseau T, Feldman HA, Fiascone J. Quality improvement to reduce chronic lung disease rates in very-low birth weight infants: High compliance with a respiratory care bundle in a small NICU. Journal of Perinatology 2018; 38: 285–292.