Assessment of Postnatal Corticosteroids for the Prevention of Bronchopulmonary Dysplasia in Preterm Neonates: A Systematic Review and Network Meta-analysis | Critical Care Medicine | JAMA Pediatrics | JAMA Network
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Figure 1.  Network, Surface Under the Cumulative Ranking Curve (SUCRA), and Forest Plots for Bronchopulmonary Dysplasia or Mortality at Postmenstrual Age of 36 Weeks
Network, Surface Under the Cumulative Ranking Curve (SUCRA), and Forest Plots for Bronchopulmonary Dysplasia or Mortality at Postmenstrual Age of 36 Weeks

A, Different nodes represent the postnatal corticosteroid interventions. The size of the nodes is proportional to the number of patients who were assigned to the intervention. The thickness of the lines connecting the nodes is proportional to the number of pairwise trials that evaluated the interventions, which are shown as numbers along the lines. B, Higher ranking of treatment was associated with smaller outcome value. The SUCRA values (%) for each treatment were as follows: 49 for early-initiated systemic hydrocortisone (EHC); 30, early-initiated inhaled beclomethasone (EIBEC); 50, early-initiated inhaled budesonide (EIBUD); 65, early-initiated inhaled fluticasone (EIFLUT); 70, intratracheal budesonide (ITBUD); 76, late-initiated, high cumulative dose of systemic dexamethasone (LaHdDX); 34, late-initiated, low cumulative dose of systemic dexamethasone (LaLdDX); 29, late-initiated, medium cumulative dose of systemic dexamethasone (LaMdDX); 17, late-initiated systemic hydrocortisone (LHC); 59, late-initiated inhaled beclomethasone (LIBEC); 35, late-initiated inhaled budesonide (LIBUD); 86, moderately early-initiated, high cumulative dose of systemic dexamethasone (MoHdDX); 44, moderately early-initiated, low cumulative dose of systemic dexamethasone (MoLdDX); 91, moderately early-initiated, medium cumulative dose of systemic dexamethasone (MoMdDX); and 14, placebo. C, The forest plot shows the risk ratio (RR) relative to placebo. CrI indicates credible interval.

Figure 2.  League Plot of the Network Estimates of Postnatal Corticosteroid Comparisons for Bronchopulmonary Dysplasia or Mortality at a Postmenstrual Age of 36 Weeks
League Plot of the Network Estimates of Postnatal Corticosteroid Comparisons for Bronchopulmonary Dysplasia or Mortality at a Postmenstrual Age of 36 Weeks

Network estimates are depicted as risk ratio (RR) with 95% credible interval (CrI). EHC indicates early-initiated systemic hydrocortisone; EIBEC, early-initiated inhaled beclomethasone; EIBUD, early-initiated inhaled budesonide; EIFLUT, early-initiated inhaled fluticasone; ITBUD, intratracheal budesonide; LaHdDX, late-initiated, high cumulative dose of systemic dexamethasone; LaLdDX, late-initiated, low cumulative dose of systemic dexamethasone; LaMdDX, late-initiated, medium cumulative dose of systemic dexamethasone; LHC, late-initiated systemic hydrocortisone; LIBEC, late-initiated inhaled beclomethasone; LIBUD, late-initiated inhaled budesonide; MoHdDX, moderately early-initiated, high cumulative dose of systemic dexamethasone; MoMdDX, moderately early-initiated, medium cumulative dose of systemic dexamethasone; MoLdDX, moderately early-initiated, low cumulative dose of systemic dexamethasone.

aValues are statistically significant.

Figure 3.  Subdividing Dexamethasone Therapy by Total Duration of the Course
Subdividing Dexamethasone Therapy by Total Duration of the Course

A, Different nodes represent the postnatal corticosteroid interventions. The size of the nodes is proportional to the number of patients who were assigned to the intervention. The thickness of the lines connecting the nodes is proportional to the number of pairwise trials that evaluated the interventions, which are shown as numbers along the lines. B, Higher ranking of treatment was associated with smaller outcome value. The surface under the cumulative ranking curve (SUCRA) values (%) for each treatment were as follows: 44 for early-initiated systemic hydrocortisone (EHC); 29, early-initiated inhaled beclomethasone (EIBEC); 53, early-initiated inhaled budesonide (EIBUD); 56, early-initiated inhaled fluticasone (EIFLUT); 59, intratracheal budesonide (ITBUD); 62, late-initiated, high cumulative dose, long course of systemic dexamethasone (LaHdLcDX); 29, late-initiated, low cumulative dose, medium course of systemic dexamethasone (LaLdMcDX); 58, late-initiated, low cumulative dose, short course of systemic dexamethasone (LaLdScDX); 22, late-initiated, medium cumulative dose, long course of systemic dexamethasone (LaMdLcDX); 50, late-initiated, medium cumulative dose, medium course of systemic dexamethasone (LaMdMcDX); 56, late-initiated, medium cumulative dose, short course of systemic dexamethasone (LaMdScDX); 19, late-initiated systemic hydrocortisone (LHC); 46, late-initiated inhaled beclomethasone (LIBEC); 50, late-initiated inhaled budesonide (LIBUD); 69, moderately early-initiated, high cumulative dose, long course of systemic dexamethasone (MoHdLcDX); 63, moderately early-initiated, high cumulative dose, medium course of systemic dexamethasone (MoHdMcDX); 41, moderately early-initiated, low cumulative dose, short course of systemic dexamethasone (MoLdScDX); 74, moderately early-initiated, medium cumulative dose, long course of systemic dexamethasone (MoMdLcDX); 68, moderately early-initiated, medium cumulative dose, medium course of systemic dexamethasone (MoMdMcDX); 82, moderately early-initiated, medium cumulative dose, short course of systemic dexamethasone (MoMdScDX); and 17, placebo. C, The forest plot shows the risk ratio (RR) relative to placebo. CrI indicates credible interval; RR, risk ratio.

Table 1.  Characteristics of the Included Studies
Characteristics of the Included Studies
Table 2.  Assessment of the Quality of Evidence for the Different Comparisons for Bronchopulmonary Dysplasia (BPD) or Mortality at Postmenstrual Age (PMA) of 36 Weeks
Assessment of the Quality of Evidence for the Different Comparisons for Bronchopulmonary Dysplasia (BPD) or Mortality at Postmenstrual Age (PMA) of 36 Weeks
Supplement.

eFigure 1. Literature Search/PRISMA Flow

eFigure 2. Mean Gestational Age of the Enrolled Neonates

eFigure 3. Risk of Bias Summary and Graph of the Included Trials

eFigure 4. Direct Evidence from the Pair Wise Comparisons for the Primary Outcome BPD or Mortality at 36 Weeks’ PMA

eFigure 5. Split Between Direct and Indirect Evidence for the Primary Outcome BPD or Mortality at 36 Weeks’ PMA

eFigure 6. Network Plot for BPD at 36 Weeks’ PMA (A), SUCRA Plot with SUCRA Values (%) for BPD at 36 Weeks’ PMA (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for BPD at 36 Weeks’ PMA (C)

eFigure 7. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for BPD at 36 Weeks’ PMA

eFigure 8. Direct Evidence from the Pair Wise Comparisons for BPD at 36 Weeks’ PMA

eFigure 9. Split Between Direct and Indirect Evidence for BPD at 36 Weeks’ PMA

eFigure 10. Network Plot for BPD at 28 Days (A), SUCRA Plot with SUCRA Values (%) for BPD at 28 Days (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for BPD at 28 Days (C)

eFigure 11. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for BPD at 28 Days

eFigure 12. Direct Evidence from the Pair Wise Comparisons for BPD at 28 Days

eFigure 13. Split Between Direct and Indirect Evidence for BPD at 28 Days

eFigure 14. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Mortality (C)

eFigure 15. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Mortality

eFigure 16. Direct Evidence from the Pair Wise Comparisons for Mortality

eFigure 17. Split Between Direct and Indirect Evidence for Mortality

eFigure 18. Network Plot for BPD (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Successful Extubation (C)

eFigure 19. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Successful Extubation

eFigure 20. Direct Evidence from the Pair Wise Comparisons for Successful Extubation

eFigure 21. Split Between Direct and Indirect Evidence for Successful Extubation

eFigure 22. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for NDI at 18-24 Months (C)

eFigure 23. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for NDI at 18-24 Months

eFigure 24. Direct Evidence from the Pair Wise Comparisons for NDI at 18-24 Months

eFigure 25. Split Between Direct and Indirect Evidence for NDI at 18-24 Months

eFigure 26. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for GI Perforation (C)

eFigure 27. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for GI Perforation

eFigure 28. Direct Evidence from the Pair Wise Comparisons for GI Perforation

eFigure 29. Split Between Direct and Indirect Evidence for GI Perforation

eFigure 30. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Hypertrophic Cardiomyopathy (C)

eFigure 31. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Hypertrophic Cardiomyopathy

eFigure 32. Direct Evidence from the Pair Wise Comparisons for Hypertrophic Cardiomyopathy

eFigure 33. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Hypertension (C)

eFigure 34. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Hypertension

eFigure 35. Direct Evidence from the Pair Wise Comparisons for Hypertension

eFigure 36. Split Between Direct and Indirect Evidence for Hypertension

eFigure 37. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Sepsis (C)

eFigure 38. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Sepsis

eFigure 39. Direct Evidence from the Pair Wise Comparisons for Sepsis

eFigure 40. Split Between Direct and Indirect Evidence for Sepsis

eFigure 41. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Severe ROP (C)

eFigure 42. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Severe ROP

eFigure 43. Direct Evidence from the Pair Wise Comparisons for Severe ROP

eFigure 44. Split Between Direct and Indirect Evidence for Severe ROP

eFigure 45. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for NEC (C)

eFigure 46. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for NEC

eFigure 47. Direct Evidence from the Pair Wise Comparisons for NEC

eFigure 48. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for IVH >II (C)

eFigure 49. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for IVH >II

eFigure 50. Direct Evidence from the Pair Wise Comparisons for IVH >II

eFigure 51. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for PVL (C)

eFigure 52. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for PVL

eFigure 53. Direct Evidence from the Pair Wise Comparisons for PVL

eFigure 54. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for CP (C)

eFigure 55. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for CP

eFigure 56. Direct Evidence from the Pair Wise Comparisons for CP

eFigure 57. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Sensitivity Analysis - Duration of Course of Dexamethasone

eFigure 58. Split Between Direct and Indirect Evidence for Duration of Course of Dexamethasone

eFigure 59. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Sensitivity Analysis Excluding Trials with Antenatal Corticosteroid Coverage <70% (C)

eFigure 60. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Sensitivity Analysis Excluding Trials with Antenatal Corticosteroid Coverage <70%

eFigure 61. Split Between Direct and Indirect Evidence for Sensitivity Analysis Excluding Trials with Antenatal Corticosteroid Coverage <70%

eFigure 62. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Sensitivity Analysis by Excluding Trials with High Risk of Bias (C)

eFigure 63. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Sensitivity Analysis by Excluding Trials with High Risk of Bias

eFigure 64. Split Between Direct and Indirect Evidence for Sensitivity Analysis by Excluding Trials with High Risk of Bias

eFigure 65. Network Plot (A), SUCRA Plot with SUCRA Values (%) (B), and Forest Plot Depicting the Network Estimates [RR (95% CrI)] of the Various Interventions with “Placebo” as the Common Comparator for Sensitivity Analysis by Combining Different Types of Inhaled Corticosteroids (C)

eFigure 66. League Plot Depicting the Network Estimates [RR (95% CrI)] of Postnatal Corticosteroids Comparisons for Sensitivity Analysis by Combining Different Types of Inhaled Corticosteroids

eFigure 67. Split Between Direct and Indirect Evidence for Sensitivity Analysis by Combining Different Types of Inhaled Corticosteroids

eTable 1. Literature Search Strategy for Two Electronic Databases

eTable 2. Some of the Studies That Were Excluded for Valid Reasons

eTable 3. Network Characteristics for All the Outcomes and Sensitivity Analysis

eTable 4. GRADE/Quality of Evidence for Some of the Secondary Outcomes

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    Original Investigation
    March 15, 2021

    Assessment of Postnatal Corticosteroids for the Prevention of Bronchopulmonary Dysplasia in Preterm Neonates: A Systematic Review and Network Meta-analysis

    Author Affiliations
    • 1Newborn Services, John Radcliffe Hospital, Oxford University Hospitals National Health Service (NHS) Foundation Trust, Oxford, United Kingdom
    • 2Ankura Hospital for Women and Children, Hyderabad, India
    • 3Department of Neonatology, Dr Ram Manohar Lohia Hospital and Post Graduate Institute of Medical Education and Research, New Delhi, India
    • 4Department of Neonatology, Institute of Medical Sciences and SUM Hospital, Orissa, India
    • 5Department of Neonatology, Indira Gandhi Institute of Child Health, Bengaluru, India
    • 6Women’s Wellness and Research Centre, Hamad Medical Corporation, Doha, Qatar
    • 7Department of Neonatology, James Cook University Hospital, Middlesbrough, United Kingdom
    • 8National Perinatal Epidemiology Unit, Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
    • 9Department of Neonatology, Lady Hardinge Medical College, New Delhi, India
    JAMA Pediatr. 2021;175(6):e206826. doi:10.1001/jamapediatrics.2020.6826
    Key Points

    Question  Which is the most appropriate postnatal corticosteroid regimen for preventing mortality or bronchopulmonary dysplasia (BPD) in preterm neonates at 36 weeks’ postmenstrual age?

    Findings  In this systematic review and network meta-analysis of 62 studies with 5559 neonates, a moderately early-initiated, medium cumulative dose of systemic dexamethasone had the highest relative risk reduction of mortality or BPD among 14 regimens, with a low confidence in the evidence.

    Meaning  Results of this study suggested that a moderately early-initiated, medium cumulative dose of systemic dexamethasone appeared to be the best regimen for preventing mortality or BPD at 36 weeks’ postmenstrual age.

    Abstract

    Importance  The safety of postnatal corticosteroids used for prevention of bronchopulmonary dysplasia (BPD) in preterm neonates is a controversial matter, and a risk-benefit balance needs to be struck.

    Objective  To evaluate 14 corticosteroid regimens used to prevent BPD: moderately early-initiated, low cumulative dose of systemic dexamethasone (MoLdDX); moderately early-initiated, medium cumulative dose of systemic dexamethasone (MoMdDX); moderately early-initiated, high cumulative dose of systemic dexamethasone (MoHdDX); late-initiated, low cumulative dose of systemic dexamethasone (LaLdDX); late-initiated, medium cumulative dose of systemic dexamethasone (LaMdDX); late-initiated, high cumulative dose of systemic dexamethasone (LaHdDX); early-initiated systemic hydrocortisone (EHC); late-initiated systemic hydrocortisone (LHC); early-initiated inhaled budesonide (EIBUD); early-initiated inhaled beclomethasone (EIBEC); early-initiated inhaled fluticasone (EIFLUT); late-initiated inhaled budesonide (LIBUD); late-initiated inhaled beclomethasone (LIBEC); and intratracheal budesonide (ITBUD).

    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.

    Study Selection  In this systematic review and network meta-analysis, the randomized clinical trials selected included preterm neonates with a gestational age of 32 weeks or younger and for whom a corticosteroid regimen was initiated within 4 weeks of postnatal age. Peer-reviewed articles and abstracts in all languages were included.

    Data Extraction and Synthesis  Two independent authors extracted data in duplicate. Network meta-analysis used a bayesian model.

    Main Outcomes and Measures  Primary combined outcome was BPD, defined as oxygen requirement at 36 weeks’ postmenstrual age (PMA), or mortality at 36 weeks’ PMA. The secondary outcomes included 15 safety outcomes.

    Results  A total of 62 studies involving 5559 neonates (mean [SD] gestational age, 26 [1] weeks) were included. Several regimens were associated with a decreased risk of BPD or mortality, including EHC (risk ratio [RR], 0.82; 95% credible interval [CrI], 0.68-0.97); EIFLUT (RR, 0.75; 95% CrI, 0.55-0.98); LaHdDX (RR, 0.70; 95% CrI, 0.54-0.87); MoHdDX (RR, 0.64; 95% CrI, 0.48-0.82); ITBUD (RR, 0.73; 95% CrI, 0.57-0.91); and MoMdDX (RR, 0.61; 95% CrI, 0.45-0.79). Surface under the cumulative ranking curve (SUCRA) value ranking showed that MoMdDX (SUCRA, 0.91), MoHdDX (SUCRA, 0.86), and LaHdDX (SUCRA, 0.76) were the 3 most beneficial interventions. ITBUD (RR, 4.36; 95% CrI, 1.04-12.90); LaHdDX (RR, 11.91; 95% CrI, 1.64-44.49); LaLdDX (RR, 6.33; 95% CrI, 1.62-18.56); MoHdDX (RR, 4.96; 95% CrI, 1.14-14.75); and MoMdDX (RR, 3.16; 95% CrI, 1.35-6.82) were associated with more successful extubation from invasive mechanical ventilation. EHC was associated with a higher risk of gastrointestinal perforation (RR, 2.77; 95% CrI, 1.09-9.32). MoMdDX showed a higher risk of hypertension (RR, 3.96; 95% CrI, 1.10-30.91). MoHdDX had a higher risk of hypertrophic cardiomyopathy (RR, 5.94; 95% CrI, 1.95-18.11).

    Conclusions and Relevance  This study suggested that MoMdDX may be the most appropriate postnatal corticosteroid regimen for preventing BPD or mortality at a PMA of 36 weeks, albeit with a risk of hypertension. The quality of evidence was low.

    Introduction

    Bronchopulmonary dysplasia (BPD) remains one of the most common, complex, and intriguing diseases among preterm neonates. Bronchopulmonary dysplasia is associated with an increased risk of mortality as well as short- and long-term morbidity, especially in extremely low-gestational-age neonates (ELGANs).1-3 Although the pathogenesis of BPD has yet to be fully deciphered, an imbalance between ongoing pulmonary inflammation and simultaneous repair seems to play a major role.4,5 In ELGANs, postnatal corticosteroids (PNCs) have been used for both the prevention and treatment of BPD. The anti-inflammatory action of PNCs on the pulmonary system has been postulated to improve gas exchange and lung mechanics, thus facilitating weaning from invasive mechanical ventilation.6 However, the use of PNCs in ELGANs remains controversial because of fear of adverse neurodevelopmental effects.7

    Multiple studies have indicated that BPD is associated with risk of poor long-term neurological outcomes, such as cerebral palsy, as well as cognitive, visual, speech, and learning impairments and behavioral problems.1 Doyle et al,2 in their follow-up to a longitudinal study of extremely preterm infants born during the past 3 decades, found that the rates of BPD did not decrease despite an increase in the use of noninvasive respiratory support in the latter years. Doyle et al2 postulated that less use of PNCs, even in infants who were at the highest risk of BPD, might be a contributing factor. As such, clinicians often have to negotiate between the risks of adverse outcomes associated with long-term ventilation and the potential adverse outcomes of PNCs.

    Field studies report a varying prevalence of PNC use (3%-50%).8,9 Appreciating the chasm, different academic bodies provide advice on the use of both systemic and inhaled PNCs for preterm neonates who are at risk of BPD.10-12 As a common denominator, the recommendations unanimously warn against the early use of systemic dexamethasone at fewer than 8 days of life. However, the policy statements for other regimens of systemic dexamethasone or different corticosteroids, including hydrocortisone and inhaled corticosteroids, differ widely among advisory bodies.10-12

    An abundance of systematic reviews and meta-analyses that compare different PNCs using pairwise comparisons are available.13-18 However, evaluating such a complex intervention in a network meta-analysis would ease interpretation and enable the ranking of PNCs according to improved outcomes and safety.19 To our knowledge, only a single network meta-analysis has covered this subject.20 To guide safe clinical practice, we performed a comprehensive systematic review and network meta-analysis to scrutinize the existing body of evidence as well as to evaluate and compare treatments that have not been compared against each other in randomized clinical trials (RCTs).

    Methods

    The study protocol was registered with PROSPERO (CRD42020205685).21 We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.22

    Interventions and Studies

    This systematic review and network meta-analysis evaluated 14 interventions for BPD: (1) moderately early-initiated (8-14 days), low cumulative dose (<2 mg/kg) of systemic dexamethasone (MoLdDX); (2) moderately early-initiated, medium cumulative dose (2-4 mg/kg) of systemic dexamethasone (MoMdDX); (3) moderately early-initiated, high cumulative dose (>4 mg/kg) of systemic dexamethasone (MoHdDX); (4) late-initiated (15-27 days), low cumulative dose of systemic dexamethasone (LaLdDX); (5) late-initiated, medium cumulative dose of systemic dexamethasone (LaMdDX); (6) late-initiated, high cumulative dose of systemic dexamethasone (LaHdDX); (7) early-initiated (<8 days) systemic hydrocortisone (EHC); (8) late-initiated (≥8 days) systemic hydrocortisone (LHC); (9) early-initiated (<8 days) inhaled budesonide (EIBUD); (10) early-initiated inhaled beclomethasone (EIBEC); (11) early-initiated inhaled fluticasone (EIFLUT); (12) late-initiated (≥8 days) inhaled budesonide (LIBUD); (13) late-initiated inhaled beclomethasone (LIBEC); and (14) intratracheal budesonide (ITBUD; using surfactant as a vehicle). The cumulative dose and duration of systemic dexamethasone were categorized on the basis of previously published systematic reviews.14

    We included studies of preterm neonates with a gestational age of 32 weeks or younger that compared any of the previously mentioned interventions in an RCT. Published and peer-reviewed full-text articles and abstracts in all languages were included. The characteristics of the included studies are provided in Table 1.23-83 Studies that evaluated early-initiated dexamethasone (<8 days of postnatal age) or dexamethasone in established cases of BPD (≥28 days) were excluded.

    Primary and Secondary Outcomes

    The primary combined outcome was mortality or BPD, which was defined as oxygen dependency, at a postmenstrual age (PMA) of 36 weeks. The secondary outcomes were incidences of BPD at a PMA of 36 weeks, BPD at 28 days of age, successful extubation from invasive mechanical ventilation, mortality before discharge, an intraventricular hemorrhage grade of III or IV,84 periventricular leukomalacia, hyperglycemia, hypertension (defined as systolic or diastolic blood pressure >2 SDs above the mean for neonates’ gestational and postnatal age), necrotizing enterocolitis (stage ≥II per Bell et al85), gastrointestinal perforation, retinopathy of prematurity stage 3 or higher,86 blood culture–proven sepsis, hypertrophic cardiomyopathy, cerebral palsy or neurodevelopmental impairment (NDI) at 18 to 24 months (cerebral palsy or mental development index <70 per Bayley Scales of Infant Development II), or visual or hearing impairment.

    Literature Search, Study Selection, and Risk-of-Bias Assessment

    We searched the online databases MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Embase, World Health Organization’s International Clinical Trials Registry Platform (ICTRP), and CINAHL (via CENTRAL) from inception through August 25, 2020. The citations from previously published systematic reviews on PNCs for prevention and treatment of BPD were also searched. The search strategy used is shown in eTable 1 in the Supplement.

    Two of us (T.B. and J.A.) independently screened titles, abstracts, and full-text articles. Full-text articles of relevant RCTs were selected and evaluated for inclusion. In case of differences of opinion between the 2 reviewers, we consulted a third author (V.V.R.).

    The risk of bias for the included studies was assessed by 2 of us (T.B. and V.V.R.) using the Cochrane Collaboration risk-of-bias tool.87 The domains of selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias were evaluated. Disagreements between the 2 assessors were resolved by consulting a third reviewer (C.C.R.).

    Quality of Evidence

    The quality of evidence for the primary and secondary outcomes was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group approach for network meta-analysis.88 The direct evidence from pairwise comparisons was first evaluated on risk of bias, inconsistency (heterogeneity), imprecision, indirectness, and publication bias. The quality of indirect evidence was evaluated from the lowest quality of direct evidence (of pairwise comparisons) from the first-order loops. When 2 or more first-order loops were detected, the highest quality of evidence among them was used. If no first-order loops were present, the quality of indirect evidence was inferred from the lowest quality of direct evidence from the higher-order loops. The highest quality of evidence between direct and indirect evidence was adjudged to be the quality of the evidence for the final network estimate. The quality of evidence was ranked as follows: high (high confidence in the evidence), moderate (moderate confidence), low (some confidence), and very low (little confidence) (Table 2).

    Statistical Analysis

    Network meta-analysis using bayesian and frequentist approaches was performed using R, version 3.6.2; netmeta; BUGSnet; and gemtc packages (R Foundation for Statistical Computing).89,90 The bayesian network meta-analysis was performed with Markov chain Monte Carlo simulation using vague priors. We used generalized linear models with 4 chains, burn-in of 50 000 iterations followed by 100 000 iterations, and 10 000 adaptations.90 Network geometry was evaluated with network plots. Model fit was assessed with leverage plots, total residual deviance, and deviance information criterion. Gelman-Rubin as well as trace and density plots were inspected for model convergence.91 Node-splitting and inconsistency model method in the bayesian approach as well as net-splitting in the frequentist approach were used to look for any inconsistency between the direct and indirect evidence.92 A P < .05 was considered as statistically significant. The sensitivity of the bayesian results was assessed by comparing them with the results of the frequentist approach.

    Pairwise comparisons were depicted using forest plots and the I2 statistic to detect heterogeneity. Estimates were reported as risk ratios (RRs, with 95% credible intervals [CrIs] or 95% CIs). Forest plots, league plots, and matrix plots were used to illustrate the network estimates of various comparisons. Ranking of the interventions was performed with the surface under the cumulative ranking curve (SUCRA) plots.93 Caution is warranted when interpreting the SUCRA. The SUCRA values can vary across outcomes for the same regimen, and the differences might be attributed to chance alone; the values should be interpreted along with the quality of evidence and do not capture the magnitude of differences in outcomes between 2 regimens.93

    In addition, we performed the following sensitivity analyses: (1) excluding RCTs that enrolled neonates on noninvasive respiratory support; (2) subdividing dexamethasone therapy according to the total duration of the treatment course into short course (<8 days), medium course (8-14 days) and long course (>14 days); (3) excluding RCTs with antenatal corticosteroid coverage of less than 70%; (4) excluding RCTs with a high risk of bias; (5) excluding RCTs that evaluated intratracheal budesonide; and (6) combining the different types of inhaled corticosteroids.

    Results

    Of the 2211 studies screened, 62 studies (involving 5559 neonates) were included in the final analysis23-83 (Table 1 and eFigure 1 in the Supplement). The mean (SD) gestational age of the enrolled neonates was 26 (1) weeks (eFigure 2 in the Supplement). We contacted 19 authors for additional information regarding their studies, and 2 responded. The included studies consisted of two 3-group RCTs,24,63 and 41 had enrolled ventilated neonates,23-29,31,34,35,38-42,44,46,48,51,55-57,59,60,62-66,68-71,74-76,78-81,83 but only 18 had included neonates with an antenatal corticosteroid coverage of more than 70%.25,26,28,29,31,34,42-44,46,51,59,60,62,65,66,75,79 Excluded studies are listed in eTable 2 in the Supplement.

    Thirteen studies were judged to have a high risk of bias.25,32,33,37,50,54,55,58,65,68,75,81,82 Three studies were classified as having variable risk of bias,24,28,69 and 45 studies had a low risk of bias.23,26,27,29-31,34-36,38-49,51-53,56,57,59-64,66,67,70-74,76-80,83 The RCTs with a high risk of bias predominantly had concerns regarding random sequence generation and allocation concealment. The risk-of-bias summary and graph are shown in eFigure 3 in the Supplement.

    Primary Outcome

    A total of 45 studies with 5236 neonates and 2768 events (53% event rate) were included for the assessment of the primary outcome (Figure 1 and eTable 3 in the Supplement).23-29,31,34,35,38-44,46,59,49-51,55-57,60,62-66,68-71,74-76,78-81,83 When compared with placebo, EHC (RR, 0.82; 95% CrI, 0.68-0.97); EIFLUT (RR, 0.75; 95% CrI, 0.55-0.98); LaHdDX (RR, 0.70; 95% CrI, 0.54-0.87); MoHdDX (GRADE: moderate) (RR, 0.64; 95% CrI, 0.48-0.82); ITBUD (RR, 0.73; 95% CrI, 0.57-0.91); and MoMdDX (GRADE: low) (RR, 0.61; 95% CrI, 0.45-0.79) decreased the risk of the primary outcome, mortality or BPD at 36 weeks’ PMA (Figure 1). Furthermore, MoMdDX was better than LaMdDX (GRADE: low) (RR, 0.67; 95% CrI, 0.45-0.94), and MoHdDX was better than LaMdDX (GRADE: low) (RR, 0.70; 95% CrI, 0.48-0.99) (Figure 2).

    SUCRA values ranked MoMdDX (SUCRA, 0.91); MoHdDX (SUCRA, 0.86); and LaHdDX (SUCRA, 0.76) as the 3 most beneficial interventions. The least beneficial intervention was LHC (SUCRA, 0.17) (Figure 1). Direct evidence from the pairwise comparisons and the split between direct and indirect evidence are shown in eFigures 4 and 5 in the Supplement. The quality of evidence for the various comparisons for the primary outcome is described in Table 2.

    Secondary Outcomes

    The network characteristics for all 15 secondary outcomes are provided in eTable 3 in the Supplement. The network plots; SUCRA plots; forest plots depicting the network estimate compared with placebo, split between direct and indirect evidence, and direct pairwise comparisons; and the league plots or matrix plots are shown in eFigures 6 to 56 in the Supplement. The quality-of-evidence assessment is outlined in eTable 4 in the Supplement. Because of the sparseness of some of the networks, node-splitting to assess inconsistency was not possible for some of the 15 outcomes (intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, hypertrophic cardiomyopathy, and cerebral palsy at 18-24 months).

    EIBUD was associated with decreased incidence of BPD at a PMA of 36 weeks (GRADE: moderate) (RR, 0.71; 95% CrI, 0.51-0.94). Furthermore, EHC showed a pattern of lesser incidence of BPD at 36 weeks’ PMA but did not reach statistical significance (RR, 0.86; 95% CrI, 0.71-1.02).

    When compared with placebo, MoMdDX (GRADE: low) (RR, 0.43; 95% CrI, 0.18-0.82) and EHC (GRADE: moderate) (RR, 0.69; 95% CrI, 0.44-0.98) were associated with reduced mortality before discharge. EIBUD did not show any significant difference in the incidence of mortality compared with placebo (RR, 0.89; 95% CrI, 0.46-1.36).

    The following regimens were associated with more extubations: ITBUD (RR, 4.36; 95% CrI, 1.04-12.90); LaHdDX (RR, 11.91; 95% CrI, 1.64-44.49); LaLdDX (RR, 6.33; 95% CrI, 1.62-18.56); MoHdDX (RR, 4.96; 95% CrI, 1.14-14.75); and MoMdDX (GRADE: very low to low) (RR, 3.16; 95% CrI, 1.35-6.82). According to SUCRA ranking, LaHdDX was the best intervention.

    None of the interventions were associated with either a decreased or an increased risk of NDI. In addition, LaHdDX showed a lower incidence of NDI at 18 to 24 months compared with LaMdDX (GRADE: low) (RR, 0.31; 95% CrI, 0.03-0.90).

    Compared with placebo, EHC was associated with a higher risk of gastrointestinal perforation (GRADE: moderate) (RR, 2.77; 95% CrI, 1.09-9.32). The network was sparse, and inconsistency assessment was not possible. The direct pairwise analysis revealed a higher risk of hypertrophic cardiomyopathy with MoHdDX compared with placebo (GRADE: low) (RR, 5.94; 95% CrI, 1.95-18.11).

    Compared with placebo, MoMdDX was associated with higher risk of hypertension (GRADE: low) (RR, 3.96; 95% CrI, 1.10-30.91). Inconsistency was detected in the network meta-analysis.

    Sensitivity Analyses

    Moderately early-initiated, medium cumulative dose, short course of systemic dexamethasone (RR, 0.54; 95% CrI, 0.30-0.86); moderately early-initiated, high cumulative dose, long course of systemic dexamethasone (RR, 0.65; 95% CrI, 0.42-0.95); and late-initiated, high cumulative dose, long course of systemic dexamethasone (RR, 0.71; 95% CrI, 0.52-0.94) were associated with decreased risk of the primary outcome, mortality or BPD at PMA of 36 weeks (Figure 3). On the basis of SUCRA values, a moderately early-initiated, medium cumulative dose, short course of systemic dexamethasone was found to be the best intervention (SUCRA, 0.82). The network characteristics for all of the sensitivity analyses are shown in eTable 3 in the Supplement. Inconsistency assessment by splitting direct and indirect evidence as well as the league plot depicting the network estimates for the different comparisons are given in eFigures 57 and 58 in the Supplement.

    In excluding RCTs that enrolled neonates on noninvasive respiratory support, we found that the results for the primary outcome were similar to those of the primary analysis. When RCTs with antenatal corticosteroid coverage of less than 70% were excluded, only ITBUD showed a significant decrease in the incidence of the primary outcome (RR, 0.64; 95% CrI, 0.44-0.89) (eFigures 59-61 in the Supplement).

    The results for the primary outcome were similar to those of the primary analysis when RCTs that evaluated ITBUD were excluded. When trials with a high risk of bias were excluded, the network estimates for both EHC (RR, 0.75; 95% CrI, 0.53-1.01) and EIFLUT (RR, 0.84; 95% CrI, 0.67-1.02) compared with placebo did not show any significant decrease in the mortality or BPD at a PMA of 36 weeks (eFigures 62-64 in the Supplement).

    By combining the different types of inhaled corticosteroids, we found that early-initiated inhaled corticosteroid was associated with a decreased risk of the primary outcome measure when compared with placebo (RR, 0.81; 95% CrI, 0.69-0.94). All of the other results for different comparisons were similar to those of the primary analysis (eFigures 65-67 in the Supplement).

    Discussion

    This systematic review and network meta-analysis included 62 RCTs that evaluated the outcomes and safety of different regimens of PNCs administered through various routes (systemic, inhaled, and intratracheal). The primary outcome measure was the combined outcome of BPD or mortality at a PMA of 36 weeks.

    These results indicate that moderately early initiation (8-14 days of postnatal age) of systemic dexamethasone with a medium cumulative dose (2-4 mg/kg) appeared to be the most successful intervention in preventing mortality or BPD. In contrast, Zeng et al20 in their network meta-analysis found the early initiation (<8 days) of systemic dexamethasone in a high dose (>3 mg/kg/d) to be the most successful in preventing BPD at 36 weeks. Substantial differences exist between the present network meta-analysis and that of Zeng et al.20 First, we excluded studies that had evaluated early systemic dexamethasone because this therapy is unanimously touted as an unsafe intervention by different academic bodies and by authors of several systematic reviews.7,8,10,94 Second, the interventions that we evaluated were different with the addition of LHC and ITBUD, as well as splitting inhaled corticosteroids (EIBUD, EIBEC, EIFLUT, LIBEC, and LIBUD) and subdividing systemic dexamethasone into different regimens based on a previously published Cochrane review.14 Third, although Zeng et al20 had evaluated safety by assessing cerebral palsy alone, we assessed 11 short- and long-term adverse effects. Fourth, we included 25 trials28-34,36,37,40,41,43,49,52-54,57,58,62,72,75,78,80,82,83 that were not evaluated by Zeng et al20 because of the different inclusion criteria.

    The 2020 Canadian Paediatric Society recommendation advises initiating systemic dexamethasone at a dose of 0.15 to 0.2 mg/kg/d for a total duration of 7 to10 days in preterm neonates who require continued invasive mechanical ventilation beyond the first week of life.12 In keeping with this recommendation, our findings also suggested that moderately early initiation (8-14 days) of dexamethasone is better than late initiation (>14 days). However, the cumulative dose suggested by the Canadian Paediatric Society is anywhere between 1 and 2 mg/kg, whereas findings in the present study favored a dose of 2 to 4 mg/kg. The 2020 Canadian Paediatric Society recommendation relied on evidence from pairwise meta-analyses. In addition, a guidelines panel takes into consideration multiple other parameters when moving from evidence to recommendation, such as clinician and parental preference, adverse effects profile, and cost-benefit ratio.95

    In this study, the quality of evidence for MoMdDX or MoLdDX compared with placebo was low, implying that the true effect (or the reality, as defined by the GRADE group) might be substantially different from the estimated outcome. Risk of bias and imprecision were the reasons for downgrading the quality of evidence for MoMdDX vs placebo. The sensitivity analysis that evaluated the duration of dexamethasone course indicated that a moderately early-initiated, medium dose, and short course (<8 days) of systemic dexamethasone might be the best intervention. A short course has also been advocated in the 2019 update of the European Consensus Guidelines on the Management of Respiratory Distress Syndrome.11

    Of the different regimens with late initiation, only LaHdDX was associated with a significant decrease in risk of the primary outcome. Although LaLdDX appeared to be a good intervention to facilitate extubation, it did not translate into better clinical outcomes (GRADE: low). Thus, late initiation might warrant a relatively high dose for a better outcome than moderately early initiation. In their prediction model of the various risk factors of BPD, Laughon et al96 concluded that, with advancing age, the risk of BPD of all severity increased with continued mechanical ventilation. This risk might be secondary to the ongoing pulmonary inflammation from a ventilator-induced lung injury and hence requiring a higher dose of systemic dexamethasone in the third rather than the second week of life. This analysis of long-term outcomes indicated that none of the interventions were associated with an increased risk of NDI when compared with placebo (GRADE: low). We also found that LaHdDX had a lower incidence of NDI compared with LaMdDX. In a sparse network, the evidence was derived from a single study published 3 decades ago, and the overall quality of evidence was judged to be low.63

    This study showed that, although LHC did not have any benefits for short-term outcomes, EHC had a decreased risk of the combined outcome of BPD or mortality at 36 weeks that was attributable to a decreased risk of mortality. These findings are in agreement with the 2010 American Academy of Paediatrics and 2020 Canadian Paediatric Society policy statements.10,12 In addition, EHC was associated with higher rates of gastrointestinal perforation. It was suggested that this increased risk of perforation was associated with concomitant indomethacin use.12 The present analysis also indicated that EIFLUT might be associated with a decreased risk of mortality or BPD. Moderate-quality evidence points toward a decreased risk of BPD at a PMA of 36 weeks associated with EIBUD. However, EIBUD was not found to have a lower risk of the competing outcome of BPD or mortality at a PMA of 36 weeks. The possibility of this finding being associated with an increase in the risk of mortality could not be ruled out.

    In the present analysis, ITBUD appeared to be beneficial, a finding that is in sync with other pairwise meta-analyses.15,16 However, intratracheal budesonide is used very early in postnatal life during the window of surfactant administration, when a higher proportion of the neonates are successfully extubated. Further studies are warranted to investigate this intervention’s benefits in neonates who remain ventilated beyond the first week of life.

    Limitations

    This study has several limitations. Most of the included RCTs had used open-label dexamethasone. Analysis of some of the postnatal systemic dexamethasone regimens (pulse, individualized, or based on daily dose) could not be performed. We could not conduct a meta-regression analysis similar to that of Doyle et al97 by assessing neonates according to their baseline risk of BPD. Some of the networks assessing the safety outcomes were sparse, with low to very low quality of evidence.

    Conclusions

    Although it presents a risk of hypertension, a moderately early-initiated (8-14 days), medium cumulative dose (2-4 mg/kg), short course (<8 days) of systemic dexamethasone might be the most appropriate PNC regimen for preventing the risk of BPD or mortality at PMA of 36 weeks, with a low quality of evidence. In view of this low confidence in the evidence, the successful outcome and safety of this regimen need to be confirmed by an adequately powered multicentric RCT.

    Neither a moderately early-initiated nor late-initiated low dose of systemic dexamethasone (<2 mg/kg) appeared successful in decreasing the risk of BPD or mortality at a PMA of 36 weeks, with a low quality of evidence.

    EHC might confer a survival advantage, with a moderate quality of evidence. EIFLUT might be a better alternative to EIBUD, especially in lieu of the possibility of increased risk of mortality with EIBUD, with a moderate quality of evidence. Although ITBUD appeared to be a good intervention with a low quality of evidence, further research is warranted in neonates who require continued mechanical ventilation beyond the first week of life.

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    Article Information

    Accepted for Publication: October 27, 2020.

    Published Online: March 15, 2021. doi:10.1001/jamapediatrics.2020.6826

    Corresponding Author: Charles C. Roehr, MD, PhD, National Perinatal Epidemiology Unit, Nuffield Department of Population Health Medical Sciences Division, University of Oxford, Old Road Campus, Richard Doll Building, Oxford OX3 7LF, United Kingdom (charles.roehr@ouh.nhs.uk).

    Author Contributions: Dr Ramaswamy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Ramaswamy, Bandyopadhyay, Roehr, Nangia.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Ramaswamy, Bandyopadhyay, Bandiya, Roehr.

    Critical revision of the manuscript for important intellectual content: Ramaswamy, Bandyopadhyay, Nanda, Ahmed, Garg, Roehr, Nangia.

    Statistical analysis: Ramaswamy, Bandyopadhyay.

    Administrative, technical, or material support: Nanda, Bandiya, Ahmed, Roehr, Nangia.

    Supervision: Ramaswamy, Bandyopadhyay, Roehr, Nangia.

    Conflict of Interest Disclosures: None reported.

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