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

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.

Figure 1.. 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

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

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.