MANUSCRIPT CITATION
Ramaswamy VV, Bandyopadhyay T, Nanda D, Bandiya P, Ahmed J, Garg A, Roehr CC, Nangia S. Assessment of Postnatal Corticosteroids for the Prevention of Bronchopulmonary Dysplasia in Preterm Neonates: A Systematic Review and Network Meta-analysis. JAMA Pediatr 2021; 175 (6): e206826. PMID 33720274.
REVIEWED BY
Nicolas A. Bamat, MD, MSCE
Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania
Erik A. Jensen, MD, MSCE
Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania
Souvik Mitra, MD, MSc
Dalhousie University & IWK Health
TYPE OF INVESTIGATION
Systematic review and network meta-analysis
QUESTION
In (P) preterm infants of gestational age 32 weeks or less, how do (I/C) various postnatal corticosteroid exposures compare in preventing (O) death prior to or bronchopulmonary dysplasia at (T) 36 weeks postmenstrual age?
METHODS
- Design: systematic review and network meta-analysis of randomized clinical trials.
- Allocation: various, see “Interventions.”
- Blinding: varied by trial.
- Follow-up period: varied by trial.
- Data Sources:
- PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, World Health Organization’s International Clinical Trials Registry Platform (ICTRP), and CINAHL were searched from inception through August 25, 2020.
- Citations from prior systematic reviews on postnatal corticosteroids.
- Participants: preterm infants with a gestational age of 32 weeks or less.
- Interventions: see Table. Trials that initiated dexamethasone therapy prior to 8 or after 28 days of age were excluded from the meta-analysis.
Table. Characteristics of interventions compared in systematic review and network meta-analysis by Ramaswamy et al. and comparative effect to placebo for select outcomes
| Corticosteroid | Postnatal age at exposure initiation | Cumulative dose | Route | Abbreviation | BPD or Death (Primary) | Death by discharge | NDI at
18 – 24 mo. |
| Relative risk (95% Credible Interval)
Compared to placebo |
|||||||
| Dexamethasone | Moderate Early
(8 – 14 days) |
Low
(< 2 mg/kg) |
Systemic | MoLdDX | 0.87
(0.55 – 1.27) |
0.89
(0.30 – 2.01) |
1.33
(0.02 – 6.79) |
| Dexamethasone | Moderate Early
(8 – 14 days) |
Medium
(2-4 mg/kg) |
Systemic | MoMdDX | 0.61
(0.45 – 0.79) |
0.43
(0.18 – 0.82) |
1.08
(0.04 – 4.22) |
| Dexamethasone | Moderate Early
(8 – 14 days) |
High
(> 4 mg/kg) |
Systemic | MoHdDX | 0.64
(0.48 – 0.82) |
0.51
(0.20 – 1.01) |
0.53
(0.03 – 1.93) |
| Dexamethasone | Late (15 – 27 days) | Low
(< 2 mg/kg) |
Systemic | LaLdDX | 0.91
(0.66 – 1.21) |
0.84
(0.19 – 2.32) |
1.23
(0.43 – 2.72) |
| Dexamethasone | Late (15 – 27 days) | Medium
(2-4 mg/kg) |
Systemic | LaMdDX | 0.93
(0.71 – 1.19) |
0.80
(0.35 – 1.40) |
1.77
(0.61 – 4.52) |
| Dexamethasone | Late (15 – 27 days) | High
(> 4 mg/kg) |
Systemic | LaHdDX | 0.70
(0.54 – 0.87) |
0.60
(0.29 – 1.06) |
0.50
(0.05 – 1.67) |
| Hydrocortisone | Early (< 8 days)
|
– | Systemic | EHC | 0.82
(0.68 – 0.97) |
0.69
(0.44 – 0.98) |
0.81
(0.42 – 1.36) |
| Hydrocortisone | Late (≥ 8 days) | – | Systemic | LHC | 1.01
(0.79 – 1.28) |
0.80
(0.42 – 1.43) |
0.73
(0.20 – 1.83) |
| Budesonide | Early (< 8 days)
|
– | Inhaled | EIBUD | 0.83
(0.63 – 1.02) |
0.89
(0.46 – 1.36) |
1.02
(0.39 – 2.17) |
| Beclomethasone | Early (< 8 days)
|
– | Inhaled | EIBEC | 0.95
(0.65 – 1.33) |
1.21
(0.50 – 2.47) |
1.57
(0.43 – 4.10) |
| Fluticasone | Early (< 8 days)
|
– | Inhaled | EIFLUT | 0.75
(0.55 – 0.98) |
0.62
(0.31 – 1.10) |
0.76
(0.19 – 2.03) |
| Budesonide | Late (≥ 8 days) | – | Inhaled | LIBUD | 0.91
(0.62 – 1.25) |
0.68
(0.24 – 1.32) |
– |
| Beclomethasone | Late (≥ 8 days) | – | Inhaled | LIBEC | 0.78
(0.57 – 1.09) |
0.69
(0.23 – 1.58) |
– |
| Budesonide (with surfactant as a vehicle) | – | – | Tracheal | ITBUD | 0.73
(0.57 – 0.91) |
0.65
(0.33 – 1.16) |
0.80
(0.38 – 1.48) |
- Primary outcome: bronchopulmonary dysplasia (BPD), defined as the use of supplemental oxygen, or mortality, assessed at 36 weeks postmenstrual age (PMA).
- Secondary outcomes: BPD at 36 weeks PMA, BPD at 28 days of age, mortality at discharge, successful extubation from invasive mechanical ventilation, neurodevelopmental impairment (NDI) at 18 to 24 months, gastrointestinal perforation, hypertrophic cardiomyopathy, hypertension, blood culture–proven sepsis, severe retinopathy of prematurity, necrotizing enterocolitis, grade III or IV intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, hyperglycemia.
- Analysis and Sample Size: network meta-analysis of 62 trials enrolling 5559 infants.
MAIN RESULTS
- 62 studies enrolling 5559 infants were included
- Included infants had a mean (SD) gestational age of 26 (1) weeks.
- Only 18 of 62 trials (29%) reported antenatal corticosteroid use in greater than 70% of enrolled infants.
- 5236 infants from 45 studies were included in the analysis of the primary outcome of BPD or mortality at 36 weeks PMA.
- See the Table for a summary of results of each comparison relative to placebo.
- Six of the compared interventions were associated with a decreased risk of BPD or mortality compared to placebo:
- moderately early-initiated medium cumulative dose systemic dexamethasone (low quality of evidence).
- moderately early-initiated high cumulative dose systemic dexamethasone (moderate quality of evidence).
- late-initiated high dose systemic dexamethasone (moderate quality of evidence).
- early systemic hydrocortisone (moderate quality of evidence).
- early inhaled fluticasone (moderate quality of evidence).
- tracheal budesonide with surfactant (low quality of evidence).
- Of all compared interventions, moderately early-initiated medium cumulative dose (2-4 mg/kg) systemic dexamethasone (MoMdDx) had the lowest risk ratio (95% credible interval) for BPD or mortality compared to placebo: 0.61 (0.45 – 0.79).
- Two of the compared interventions were associated with a decreased risk of mortality compared to placebo:
- moderately early-initiated medium cumulative dose systemic dexamethasone.
- early systemic hydrocortisone.
- 2127 infants from 18 studies reported on moderate to severe NDI at 18-24 months
- No interventions were associated with a decreased risk of NDI.
- Effect estimates for all compared interventions were imprecise.
CONCLUSION
The authors conclude that moderately early medium cumulative dose systemic dexamethasone may be the most appropriate postnatal corticosteroid regimen for preventing BPD or mortality at 36 weeks, but acknowledge the low quality of evidence that informed this assertion.
COMMENTARY
Systemic postnatal corticosteroids (PNCs) reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants but may contribute to long-term neurodevelopmental harm. The need to identify a treatment regimen with a reassuring risk-benefit balance remains.(1) In an extraordinary feat of data aggregation, Ramaswamy and colleagues include 62 randomized clinical trials (RCTs) enrolling 5559 neonates in a systematic review and network meta-analysis (NMA) to determine which of 14 distinct PNC exposures (Table) may be most appropriate. (2) The authors suggest moderately early-initiated medium cumulative dose systemic dexamethasone is the best regimen.
Unlike traditional pairwise meta-analyses, NMAs compare multiple interventions, adding relevance to clinical scenarios with various alternative treatment options. NMAs also allow indirect comparisons between interventions, linking them through a common comparator. (3) For example, no RCTs have compared early systemic hydrocortisone (EHC) to late-initiated low cumulative dose systemic dexamethasone (LaLdDx), but a shared comparison to placebo in separate RCTs allows a relative risk estimation.
The validity of NMA results rely on specific assumptions. A critical one is that data linked to produce indirect evidence display “transitivity.” (3) In essence, that aggregation be justified by similarities in key population characteristics. Tools that guide this subjective judgment include assessment of whether the populations are similar on important effect modifiers and whether the indirect comparisons could be assessed in head-to-head trials. Extending the example above, we consider the tools against the PREMILOC (EHC) and DART (LaLdDx) trials .(4,5) A meta-regression identified the baseline risk of developing BPD as an important effect modifier for the effect of PNCs on death or cerebral palsy.(6) The rates of death or BPD in the control groups of PREMILOC and DART were 49% and 91%, respectively, questioning their similarity.(4,5) In turn, a hypothetical trial of EHC vs. LaLdDx would presumably compare prophylactic EHC to LaLdDx only among infants remaining on mechanical ventilation at 14 days. Exposing subjects to LaLdDx irrespective of respiratory status would raise ethical concerns. However, the indirect comparison generated by the NMA is not of prophylactic EHC vs expectant management with rescue LaLdDx. Though we focus on EHC vs LaLdDx as an example, these concerns extend to various comparisons. One could argue that transitivity is generally violated when comparing interventions applied in distinct stages of disease progression, and that use of PNCs as prophylaxis vs treatment of evolving severe BPD are distinct indications best suited to distinct comparisons.(3)
Lastly, we should avoid labeling the PNC regimen most effective against BPD as “most appropriate.” Although a reduction in BPD with various PNC regimens is probable, avoidance of risk for adverse long-term neurodevelopmental outcomes is uncertain, and the latter will guide appropriateness. Further, as the authors acknowledge, the quality of evidence supporting the conclusion is low. Despite these points of caution, Ramaswamy and colleagues add a rich contribution to the literature, shining a helpful light on the path forward. Conclusively arriving at best practice will require additional high-quality research, followed by cautious data synthesis that prioritizes long-term outcomes of importance to patients and their families.
REFERENCES
- Doyle LW. Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Neonatology. 2021;118(2):244–51.
- Ramaswamy VV, Bandyopadhyay T, Nanda D, Bandiya P, Ahmed J, Garg A, et al. Assessment of postnatal corticosteroids for the prevention of bronchopulmonary dysplasia in preterm neonates: a systematic review and network meta-analysis. JAMA Pediatr. 2021;175(6).
- Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Res Synth Methods. 2012;3(2):80–97.
- Baud O, Maury L, Lebail F, Ramful D, El Moussawi F, Nicaise C, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): A double-blind, placebo-controlled, multicentre, randomised trial. Lancet. 2016;387(10030):1827–36.
- Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB, Kaimakamis M, et al. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: A multicenter, international, randomized, controlled trial. Pediatrics. 2006;117(1):75–83.
- Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: Effect modification by risk of bronchopulmonary dysplasia. J Pediatr. 2014;165(6):1258–60.
