Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia in preterm infants

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Background

Bronchopulmonary dysplasia (BPD) is a serious complication of preterm birth, affecting around 40% of infants born before 29 weeks gestational age (GA) ^[1][2]. Recent advances in neonatal care have improved the survival of extremely preterm infants. At least in part due to improved survival, the incidence of BPD has not decreased in Canada in the past 10 years ^[2]. BPD is associated with life-long respiratory and neurodevelopmental morbidity.

Historically, postnatal corticosteroids have been used in the first week post-birth for prevention, or later for treatment, of evolving or established BPD. However, clinical trials and systematic reviews of this practice have highlighted its long-term side effects and specifically, an increased risk for cerebral palsy (CP). The previous revision of this statement in 2012 recommended against the routine use of corticosteroids in the first week after birth to prevent BPD, due to safety concerns ^[3], and recommended caution when using corticosteroids after the first week post-birth. It further suggested having an informed discussion with parents about risks and benefits, and underlined the need for evidence regarding the safety and efficacy of low-dose dexamethasone and inhaled corticosteroids.

This statement reviews studies published since 2012 to guide clinical use of postnatal corticosteroids in infants at risk for or with evolving or established BPD.

Statement development

Searches were designed and conducted by a librarian experienced with systematic review. MEDLINE searches included e-publications ahead of print, papers in-process, and other non-indexed citations (1946 to June 14, 2018). Embase (1980 to June 14, 2018) and the CENTRAL Trials Registry of the Cochrane Collaboration (May 2018 issue) were also searched. Randomized controlled trials (RCTs), cohort studies, and systematic reviews were sought specifically. Searches were not restricted by language, but were limited to material entering the databases since 2012. Search terms included ‘bronchopulmonary dysplasia’, ‘chronic lung disease’, ‘dexamethasone’, ‘hydrocortisone’, ‘inhaled corticosteroids’, ‘postnatal corticosteroids’, and ‘preterm infants’.

In general, studies to prevent BPD have examined potential therapies administered in the first week post-birth, whereas studies aiming to treat evolving or established BPD have examined therapies administered beyond this period. This statement makes the same differentiation.

Levels of evidence and grading of recommendations are based on criteria from the Canadian Task Force on Preventive Health ^[4].

Systemic corticosteroids in the first 7 days post-birth to prevent BPD

No new clinical trials of dexamethasone use in neonates to prevent BPD have been published since 2012. One large clinical trial of early hydrocortisone use, with two ancillary publications and one follow-up at 5 to 7 years of an RCT, have been published since ^[5]–[8]. One updated Cochrane systematic review and an individual patient data meta-analysis of four trials assessing physiological doses of hydrocortisone (HC) in the first days post-birth to prevent BPD, have been recently published ^[9][10]. Details of these studies are shown in Table 1.

Summary

Overall, the potential benefits of dexamethasone in the first week post-birth are offset by substantial side effects. Dexamethasone is therefore not recommended for prevention of BPD. (Level of evidence 1.)

Based on current evidence, physiological HC, at replacement doses, initiated in the first 24 to 48 h post-birth in infants born ˂28 weeks GA, when not associated with prophylactic indomethacin, increases survival without BPD at 36 weeks and survival before discharge without harmful effects on neurodevelopment at 2 years. These beneficial effects were more pronounced in infants exposed to maternal chorioamnionitis and in those born ≥26 weeks. An increased incidence of late-onset sepsis was observed in hydrocortisone-treated infants, a finding which was more pronounced in infants exposed to chorioamnionitis and in those born ˂26 weeks GA. Conversely, in the largest trial, infants born ˂26 weeks had better neurodevelopmental outcomes than those who received placebo. High-risk infants (e.g., those born ˂28 weeks GA, and particularly those exposed to chorioamnionitis) may benefit from physiological HC at replacement doses. Clinician assessment of each individual case is advised.

Table 1. Trials and systematic reviews of systemic corticosteroid use in the first week post-birth to prevent BPD
Study	Methods	Sample size and number of centres	Eligibility criteria	Intervention	Results
Baud et al. [5][6][8]	Randomized controlled trial (RCT)	523 21 centres Planned sample of 786; DSMB  stopped recruitment due to technical and financial issues	24+0-27+6 weeks GA, <24 h of age; small for GA (<3rd centile) were excluded	Hydrocortisone hemisuccinate 1 mg/kg per day x 7 days, then 0.5 mg/kg per day x 3 days (total: 8.5 mg/kg)	Survival without BPD* 60% vs. 51% (RR 1.48, 95% CI 1.02 to 2.16) No difference in rates of GI perforation Sub-group analysis: More sepsis in 24 to 25 weeks in treatment group Follow-up at 2 years: No difference in neurodevelopmental impairment or CP† Sub-group analysis: Better global neurodevelopment in infants born at 24 to 25 weeks who received hydrocortisone vs. those who did not
Peltoniemi et al. [7]	RCT	51 (37 followed up at 5 to 7 years) single-centre	501 to 1250 g, 23+0 to 30+0 weeks GA, ventilated in first 24 h after birth	Hydrocortisone 2.0 mg/kg per day x 2 days, 1.5 mg/kg per day x 2 days, 0.75 mg/kg per day x 6 days (total: 11.5 mg/kg)	Study interrupted due to higher rate of GI perforations in the hydrocortisone-treated infants Follow-up at 5 to 7 years: Mean verbal IQ and functional IQ not different. Mean performance IQ lower in the hydrocortisone-treated children (88.3 (14.5) vs. 99.1 (14.0); p = 0.034)
Doyle, LW et al. [9]	Systematic review	4395 32 trials Follow-up data for 13 trials	Preterm infants at risk for developing BPD	21 trials of dexamethasone 11 trials of hydrocortisone	Earlier extubation, decreased risk for BPD, patent ductus arteriosus (PDA), and severe retinopathy of prematurity (ROP) offset by short- (GI perforation) and long-term (increased risk for CP) harms. Most benefits and harms attributed to dexamethasone. Risk of GI perforation attributed to hydrocortisone Methodological quality of follow-up studies limited, due to follow-up before school age or lack of power
Shaffer et al. [10]	Individual patient data meta-analysis (includes trials by Baud and Peltoniemi)	982 patients, 4 trials	Preterm infants (<30 weeks GA) or birth weight under 1 kg in first 48 h post-birth	Hydrocortisone prophylactic replacement for adrenal insufficiency over 10 to 15 days (total dose 8.5 to 13.5 mg/kg)	Hydrocortisone treated infants had: Improved survival without BPD at 36 weeks: OR 1.45 (95% CI 1.11 to 1.9); p = 0.007; NNT 11 Less death before discharge: OR 0.70 (95% CI 0.51 to 0.97); p = 0.0327 Less treatment for PDA: OR 0.72 (95% CI 0.56 to 0.93); p = 0.012 More late-onset sepsis: OR 1.34 (95% CI 1.02 to1.75); p = 0.0357 Sub-group analysis: Spontaneous GI perforation increased with indomethacin and hydrocortisone, but not with hydrocortisone alone. Effects on survival to 36 weeks without BPD, death before discharge more pronounced in infants exposed to chorioamnionitis or those born at ≥26 weeks.
* Physiologic definition of BPD † Standardized neurological examination and revised Brunet-Lezine scale BPD Bronchopulmonary dysplasia; CI Confidence interval; CP cerebral palsy; DSMB Data and Safety Monitoring Board; GI Gastro-intestinal; NNT Number needed to treat; OR Odds ratio; RR Relative risk

Early inhaled corticosteroids to prevent BPD

Two RCTs and one systematic review have been published since 2012 ^[11]–[14]. Details of these studies are shown in Table 2.

Table 2. Trials and systematic reviews of early inhaled corticosteroids to prevent BPD
Study	Methods	Sample size and number of centres	Eligibility criteria	Intervention	Results and effect size
Bassler et al. [11][14]	Randomized controlled trial (RCT)	863 (40 centres)	23+0-27+6 weeks GA, <12 h  post-birth on positive pressure respiratory support	Budesonide by metered-dose inhaler 800 mcg per day x 14 days; 400 micrograms per day until 32 weeks GA or no longer needing oxygen or respiratory support	Death or BPD reduced in infants who received budesonide: 40% vs. 46% (RR 0.71, 95% CI 0.53 to 0.97) Survival without BPD higher in infants who received budesonide: 27.8% vs. 38%; p = 0.004 Death 16.9% vs. 13.8%; p = 0.17 Neurodevelopmental disability at 18 to 22 months corrected age: 48.1% vs. 51.4%; p = 0.40 Death by 18 to 22 months 19.9% vs. 14.5%; p = 0.04, favoring the control group
Nakamura et al. [12]	RCT	211 (12 centres)	Birth weight (BW)<1000 g, requiring intubation and ventilation in first 24 h post-birth	Fluticasone propionate 100 mcg per day x 6 weeks, or until extubation	Death or oxygen dependence at discharge 14% vs. 22%; p = 0.15
Shah et al. [13] (includes studies by Bassler and Nakamura)	Cochrane systematic review	1644 (10 trials)	Preterm infants with BW˂1501 g, on respiratory support, and randomized within the first 1 to 2 weeks post-birth (only 2 trials allowed enrollment from 7 to 14 days of age)	Budesonide, beclomethasone dipropionate, fluticasone propionate, or flunisolide by inhalation for at least 2 weeks	Infants treated with inhaled corticosteroids had: No difference in BPD overall at 36 weeks: RR 0.97 (95% CI 0.62 to 1.52) Less BPD at 36 weeks among survivors: RR 0.76 (95% CI 0.63 to 0.93); NNT 14 (95% CI 8 to 50) Less death or BPD at 36 weeks: RR 0.86 (95% CI 0.75 to 0.99); (p = 0.04); NNTB 17 (95% CI 9 to infinity)
BPD Bronchopulmonary dysplasia; CI Confidence interval; NNT Number needed to treat; NNTB Number needed to benefit; RR Relative risk

Although a reduction in BPD in survivors was observed in the largest trial performed to date ^[11], more infants randomized to inhaled corticosteroids had died by the 2-year follow-up time point ^[14]. Trial authors have cautioned that reducing the incidence of BPD may have been achieved at the expense of increased mortality.

Summary

Based on current evidence, any beneficial effects on BPD rates appear to be offset by increased risk for mortality. Administering inhaled corticosteroids (such as budesonide and fluticasone) the first 2 weeks post-birth to prevent BPD is not recommended. (Level of evidence 1.)

Systemic corticosteroids after the first week post-birth to treat evolving or established BPD

No new trial of later dexamethasone treatment has been published since 2012. One single centre pilot RCT and one multi-centre RCT investigating hydrocortisone succinate were reported since then ^[15][16]. A 2019 RCT reported no difference in the combined outcome of death or BPD at 36 weeks corrected GA, but found a decrease in death in infants who received hydrocortisone (16% versus 24%) ^[16]. These results are encouraging and suggest that later hydrocortisone may benefit preterm infants with evolving BPD. However, more research to confirm this possibility is required before treatment can be recommended.

One Cochrane systematic review and meta-analysis to assess both dexamethasone and hydrocortisone succinate was updated in 2017 ^[17]. Details are presented in Table 3. Concerns have been raised about the potential toxicity of dexamethasone, including the possible toxic effects of sulfite preservatives used in its preparation. While some investigators have studied betamethasone or methylprednisolone as an alternative to dexamethasone for infants with evolving BPD, the quality of evidence provided by these studies is insufficient to endorse these medications ^[18]–[22].

Table 3. Studies of systemic corticosteroids initiated after the first week post-birth to treat evolving BPD
Study	Methods	Sample size and number of centres	Eligibility criteria	Intervention	Results and effect size
Parikh et al. [15]	Randomized controlled trial (RCT)	64, single centre	BW ≤1000 g at birth, ventilator dependent at 10 to 21 days of age with a  respiratory index score ≥2 or score ≥3 with improvement in last 24 h	Hydrocortisone succinate 3 mg/kg/day x 4 days; 2 mg/kg/day x 2 days; 1 mg/kg/day x 1 day (cumulative dose: 17 mg/kg over 7 days)	Brain volume at 38 weeks of age: no difference No difference in BPD or duration of mechanical ventilation
Onland et al. (abstract) [16]	RCT	372, multi-centre	<30 weeks at birth, ventilated at 7 to14 days, respiratory index score ≥2.5	Hydrocortisone weaning over 22 days; cumulative dose 72 mg/kg. Open label steroids permitted: 28% in treatment group; 56% in placebo group	Death or BPD at 36 weeks: 70% vs. 74%: RR 0.95 (95% CI 0.84 to 1.08) Mortality at 36 weeks: 16% vs. 24%: RR 0.65 (95% CI 0.43 to 0.99)
Doyle LW et al. [17] (does not include the trial by Onland et al.)	Cochrane systematic review	1424 patients; 21 trials	Preterm infants with evolving or established BPD, defined as oxygen-dependent, ventilator-dependent (or both), with or without radiographic changes in BPD status	Dexamethasone or hydrocortisone, IV or per os for 7 to 42 days. Total dose varied across trials	Infants treated with late corticosteroids had: Facilitated extubation on study days 3, 7, and 28 Less BPD at 36 weeks: RR 0.77; 95% CI 0.67 to 0.88 Less need for rescue corticosteroids Less discharge on home oxygen: RR 0.71; 95% CI 0.54 to 0.94 Increased risk of severe ROP (no increase in blindness) No difference in death rates at 36 weeks: RR 0.82 (95% CI 0.50 to 1.35) No difference in CP rates
BPD Bronchopulmonary dysplasia; CI Confidence interval; CP Cerebral palsy; ROP Retinopathy of prematurity; RR Relative risk

Summary

The routine use of dexamethasone for all infants who require assisted ventilation after 7 days of age to treat evolving BPD is not recommended. Nor can hydrocortisone to treat evolving BPD be recommended at this time. The results of ongoing trials are awaited.

Inhaled corticosteroids after the first week post-birth to treat evolving or established BPD

No post-2012 trial of late inhaled steroids was identified. One updated Cochrane systematic review in 2017 included eight trials and 232 patients ^[23]. Some infants were ventilated while others were not. Treatment was initiated between 7 and 21 days post-birth. Meta-analysis showed a reduced risk of failure to extubate at 7 days (RR 0.80, 95% CI 0.66 to 0.98; 5 studies, 79 infants) in infants who received inhaled corticosteroids. No difference was noted in the rate of death or BPD, in death at 36 weeks of age, or in BPD at 36 weeks of age. Conclusions are limited by the small number of infants enrolled and heterogeneity of patients and inhalation therapy.

Inhaled corticosteroids cannot be recommended to treat BPD. (Level of evidence 1.)

Ancillary analyses conducted to help guide practice for prevention or treatment of evolving or established BPD

Although an adequate number of trials have been conducted with a sufficient number of infants enrolled to allow for meta-analyses and help guide practice, the widespread use of open-label treatments and significant variance among  patients being assessed (e.g., regarding eligibility criteria, type and course of steroid used, comparison groups, and outcomes) have prompted a number of ancillary analyses to help refine recommendations for clinical use.

Comparisons between various treatment regimens

One recent meta-analysis concluded that evidence was insufficient to determine an optimal dexamethasone dosing regimen (i.e., higher versus lower cumulative dose, in the first week versus after 1 week, pulse versus a continuous regimen) ^[24]. Two further meta-analyses comparing inhaled with systemic corticosteroids reported no advantage for either medication ^[25][26].

Efficacy and safety in relation to risk of developing BPD

One updated meta-regression found that the higher the rate of BPD in the control group, the lower the risk difference  in the rate of death or CP between the control and dexamethasone-treated groups, suggesting that with a high baseline risk of BPD, treatment with dexamethasone may convey benefit ^[27]. Study authors concluded that when the risk for BPD was >60%, dexamethasone treatment appeared to lower the rate of death or CP. This possibility has an important clinical implication: for a sub-group of infants at high risk for BPD, the benefits of the treatment appear to outweigh risks.

Determining the effect of open-label use of corticosteroids on study outcomes

To adjust for the confounding effect of open-label corticosteroid use in RCTs, one meta-regression was performed to compare dexamethasone with placebo in infants over 7 days old ^[28]. Twenty-seven per cent  to 65% of infants assigned to the placebo group, and 10% to 33% of those assigned to active treatment, received open-label dexamethasone. Overall, infants in the active treatment group had lower rates of death or BPD without increasing the incidence of adverse neurodevelopmental outcomes, and this apparent benefit was inversely related to the degree of open-label usage in the placebo group (i.e., the more the use of open label, the less observed benefit). As an additional caution, dexamethasone treatment was associated with an increase in CP when treatment was delayed beyond 21 days of age.

Summary

These findings strongly suggest that for a sub-group of infants at high risk for BPD (e.g., who remain ventilated beyond the first week post-birth with increasing oxygen requirements and worsening lung disease), a short course of dexamethasone (0.15 mg/kg/day to 0.2 mg/kg/day tapered over 7 to 10 days) should be considered. The timing of initiation and initial dose should be based on postnatal age and severity of condition. Treatment before BPD is fully established and titration based on illness severity are advised (Level of Evidence 5).

Future treatments

Recent trials have reported on mixing corticosteroids with surfactant and administering this combination early via endotracheal tube for infants born very preterm ^[29][30]. Although the beneficial effects of this combined therapy on reducing death or BPD were marked, relatively few infants were being studied. Results from ongoing research are needed before a recommendation on this practice can be issued.

Recommendations

• The use of dexamethasone in the first week post-birth to prevent BPD is not recommended. (Grade A recommendation.)
• Clinicians may consider prescribing a course of low-dose hydrocortisone (physiologic replacement dose: 1 mg/kg per day x 7 days, then 0.5 mg/kg per day x 3 days) beginning in the first 24 to 48 h after birth, for 10 days, to infants at the highest risk for BPD (e.g., <28 weeks GA or exposed to chorioamnionitis). There may be an increased risk for late-onset sepsis associated with this practice. Hydrocortisone should not be combined with indomethacin prophylaxis. (Grade B recommendation.)
• The routine use of inhaled corticosteroids to prevent BPD is not recommended. (Grade A recommendation.)
• The routine use of dexamethasone after the first week of life for evolving BPD is not recommended. (Grade A recommendation.) For infants who remain ventilated after the first week post-birth with increasing oxygen requirements and worsening lung disease, the benefits of dexamethasone therapy appear to outweigh the potential adverse effects. In these circumstances, low-dose dexamethasone (with an initial dose of 0.15 mg/kg/day to 0.2 mg/ kg/day, tapered over a short course [7 to 10 days]) should be considered. (Grade C recommendation.)
• Hydrocortisone to treat infants with evolving BPD beyond the first week post-birth, or infants with prolonged ventilator dependence, is not recommended. (Grade B recommendation.)
• Use of inhaled corticosteroids to treat BPD is not recommended. (Grade B recommendation.)
• More research is needed to identify the most at-risk population and on the utility of alternative corticosteroid preparations and regimens. (Grade A recommendation.)

Acknowledgements

The authors would like to thank Margaret Sampson, MLIS, PhD, AHIP (with the Children’s Hospital of Eastern Ontario), for developing our electronic search strategies. This position statement has been reviewed by the Respiratory Health Section of the Canadian Paediatric Society. It was also reviewed by the Canadian Thoracic Society and by members of the Canadian Pediatric Endocrine Group: Dr. Rose Girgis (University of Alberta), Dr. Alex Ahmet (Children’s Hospital of Eastern Ontario), and Dr. Julia Von Oettigen (Montreal Children’s Hospital).

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CANADIAN PAEDIATRIC SOCIETY FETUS AND NEWBORN COMMITTEE

Members: Heidi Budden MD (Board Representative), Mireille Guillot MD (Resident member), Leonora Hendson MD, Thierry Lacaze-Masmonteil MD, PhD (past Chair), Brigitte Lemyre MD, Michael R. Narvey MD (Chair), Vibhuti Shah MD
Liaisons: Radha Chari MD, The Society of Obstetricians and Gynaecologists of Canada; James Cummings MD, Committee on Fetus and Newborn, American Academy of Pediatrics; William Ehman MD, College of Family Physicians of Canada; Roxanne Laforge RN, Canadian Perinatal Programs Coalition; Chantal Nelson PhD, Public Health Agency of Canada; Eugene H. Ng MD, CPS Neonatal-Perinatal Medicine Section; Doris Sawatzky-Dickson RN, Canadian Association of Neonatal Nurses
Principal authors: Brigitte Lemyre MD, Michael Dunn MD, Bernard Thebaud MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.