Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia in preterm infants

Abstract

Historically, postnatal corticosteroids have been used to prevent and treat bronchopulmonary dysplasia (BPD), a significant cause of morbidity and mortality in preterm infants. Administering dexamethasone to prevent BPD in the first 7 days post-birth has been associated with increasing risk for cerebral palsy, while early inhaled corticosteroids appear to be associated with an increased risk of mortality. Neither medication is presently recommended to prevent BPD. New evidence suggests that prophylactic hydrocortisone, when initiated in the first 48 hours post-birth, at a physiological dose, and in the absence of indomethacin, improves survival without BPD, with no adverse neurodevelopmental effects at 2 years. This therapy may be considered by clinicians for infants at highest risk for BPD. Routine dexamethasone therapy for all ventilator-dependent infants is not recommended, but after the first week post-birth, clinicians may consider a short course of low-dose dexamethasone (0.15 mg/kg/day to 0.2 mg/kg/day) for individual infants at high risk for, or with evolving, BPD. There is no evidence that hydrocortisone is an effective or safe alternative to dexamethasone for treating evolving or established BPD. Current evidence does not support inhaled corticosteroids for the treatment of BPD.

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 lifelong 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 nonindexed 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, has 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 in the first days post-birth to prevent BPD have been recently published (9,10). Details of these studies are shown in Supplementary Table 1 in the Appendix.

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 hydrocortisone, at replacement doses, initiated in the first 24 to 48 hours 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 hydrocortisone at replacement doses. Clinician assessment of each individual case is advised.

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 Supplementary Table 2 in the Appendix.

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 multicentre 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 Supplementary Table 3 in the Appendix. 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).

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; five 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 subgroup 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 subgroup 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 is 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/day × 7 days, then 0.5 mg/kg/day × 3 days) beginning in the first 24 to 48 hours 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.)

All Canadian Paediatric Society position statements and practice points are reviewed regularly and revised as needed. Consult the Position Statements section of the CPS website www.cps.ca/en/documents for the most current version. Retired statements are removed from the website.

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