Commentary on “Early (<7 Days) Systemic Postnatal Corticosteroids for Prevention of Bronchopulmonary Dysplasia in Preterm Infants”

Twenty years ago, the American Academy of Pediatrics Committee on Fetus and Newborn published guidance on the use of systemic postnatal corticosteroids to treat or prevent bronchopulmonary dysplasia (BPD) [1]. Corticosteroid use – particularly dexamethasone, was common prior to the 2002 guideline [2, 3]. The hope was these medications could interrupt the inflammatory cascade underlying the pathogenesis of BPD, reducing this common and consequential morbidity. Citing a 2001 Cochrane review, the guideline concluded that while no differences in mortality were noted, early postnatal corticosteroids did indeed reduce BPD and the composite outcome of death or BPD. Yet, the committee recommended against routine use, in part due to a “number of serious short- and long-term complications” [1]. Most concerning were increased risks of neurodevelopmental impairment, particularly cerebral palsy (CP) [4]. Although unstated, implicit in this recommendation was that long-term neurodevelopment is more important to infants and their families than BPD and that an increase in CP outweighs a decrease in BPD when moving from evidence synthesis to practice guidance. Use of early postnatal corticosteroids in preterm infants decreased sharply after publication [5].

Despite the recommendation against routine clinical use, the 2002 guidelines recommended additional randomized controlled trials (RCTs) of alternative early corticosteroid regimens, allowing for the possibility that the right drug and dose, in carefully selected populations, could lead to a favorable risk-benefit profile. Meta-regression of data from trials of early or late postnatal corticosteroids suggests population characteristics – namely baseline risk of developing BPD – may modify the risk-benefit balance [6]. Over the last two decades, RCTs have contributed additional data, which have now been aggregated in an updated 2021 Cochrane review by Doyle et al. [7] and colleagues (abstract below). This update now includes 4,395 infants from 32 RCTs. The main results report that overall, early systemic corticosteroids reduce the risk of BPD (Fig. 1) and the combined outcome of death or BPD. There are no certain differences on mortality, and the risk of several short- and long-term complications, most notably CP, is increased. In short, the summary results are remarkably similar 20 years later.

New considerations, however, have emerged when considering individual corticosteroids separately. Although dexamethasone reduces BPD and the combined outcome of death or BPD, no certain differences are identified for hydrocortisone, with the effect estimates trending toward modest potential benefit (Fig. 1). In turn, while no difference in mortality at the latest reported age is noted for dexamethasone, the review reports high-certainty evidence that hydrocortisone reduces mortality (Fig. 2). While dexamethasone clearly increases the risk of cerebral palsy, no differences are identified for hydrocortisone, and the effect estimate lacks suggestion of a clinically meaningful difference.

The inconsistencies between dexamethasone and hydrocortisone complicate the path between evidence synthesis and practice guidance. The latter has also been updated, with the most recent guidelines from the American Academy of Pediatrics Committee on Fetus and Newborn issued in 2022 [8]. The update cites systematic review data concluding a mortality benefit for early systemic hydrocortisone and suggests that conclusions on the risks and benefits of dexamethasone and hydrocortisone may need to be distinct [9]. The overall recommendation, nonetheless, is that “routine use of (postnatal corticosteroids) cannot be recommended” [8]. This message is consistent with the “Implications for practice” in the updated Cochrane review, which concludes that “given the potential short-term and long-term adverse effects versus potential short-term benefits, this review supports curtailment of early systemic corticosteroid treatment for prevention of BPD” [7]. The uncertainty regarding the impact of postnatal corticosteroids on long-term neurodevelopment into school age is highlighted in the immediately preceding text, suggesting an important influence in shaping the conclusions.

There is increasing recognition that families should play an integral role in the prioritization, design, and interpretation of neonatal clinical research. A recent review of familial perspectives on research outcomes found inadequate emphasis on measures of global day-to-day function beyond early childhood [10], supporting the cautious stance taken by the Cochrane authors in the absence of such data. However, few would argue that normal global function in childhood is more important to most families than survival or that increased neurosensory disability should outweigh decreased death when moving from evidence synthesis to practice guidance. The Cochrane review finds no difference between postnatal hydrocortisone and control on major neurosensory disability at 2 years, while the point estimate favors hydrocortisone. What future neurodevelopmental data are likely to emerge, whether ascertained at 2 or 5 years, that will outweigh the high-certainty evidence that hydrocortisone reduces mortality?

So where on the path between evidence and guidance have the findings of less death with early postnatal hydrocortisone stalled? Has the legacy of unanticipated harm with early dexamethasone led us to dig in, extrapolate, and double-down on the principle of “first, do no harm?” for all early postnatal corticosteroids, irrespective of the pharmacologic differences that encouraged further study? Is it that despite the “high” certainty of evidence GRADE assignment, our true certainty surrounding a hydrocortisone mortality benefit is far less? Though more research is needed, addressing these questions will help clarify the path between the considerable efforts required to generate high-quality evidence and the practice guidance that influences the impact of those efforts on patients.

Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence-based care of the highest quality for newborn infants and their families.

The authors serve in the editorial group of Cochrane Neonatal.

No funding was received.

Drs. Nicolas A. Bamat and Roger F. Soll planned and wrote the commentary on the Cochrane review of “Early (<7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.”

Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Early (<7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database of Systematic Reviews 2021, Issue 10. Art. No.: CD001146. DOI: 10.1002/14651858.CD001146.pub6. Background: Bronchopulmonary dysplasia (BPD) remains a major problem for infants born extremely preterm. Persistent inflammation in the lungs is important in its pathogenesis. Systemic corticosteroids have been used to prevent or treat BPD because of their potent anti‐inflammatory effects. Objectives: The aim of the review was to examine the relative benefits and adverse effects of systemic postnatal corticosteroids commenced within the first 6 days after birth for preterm infants at risk of developing BPD. Search Methods: We ran an updated search of the following databases on September 25, 2020: CENTRAL via CRS Web and MEDLINE via OVID. We also searched clinical trial databases and reference lists of retrieved articles for randomized controlled trials (RCTs). We did not include cluster randomized trials, cross‐over trials, or quasi‐RCTs. Selection Criteria: For this review, we selected RCTs examining systemic (intravenous or oral) postnatal corticosteroid treatment started within the first 6 days after birth (early) in high‐risk preterm infants. We included studies that evaluated the use of dexamethasone, as well as studies that assessed hydrocortisone, even when the latter was used primarily for management of hypotension, rather than for treatment of lung problems. We did not include trials of inhaled corticosteroids. Data Collection and Analysis: We used standard Cochrane methods. We extracted and analyzed data regarding clinical outcomes that included mortality, BPD, mortality or BPD, failure to extubate, complications during the primary hospitalization, and long‐term health and neurodevelopmental outcomes. We used the GRADE approach to assess the certainty of evidence. Main Results: Use of the GRADE approach revealed that the certainty of evidence was high for the major outcomes considered, except for BPD at 36 weeks for all studies combined, which was downgraded one level to moderate because of evidence of publication bias. We included 32 RCTs (4,395 infants). The overall risk of bias of included studies was low; all were RCTs, and most trials used rigorous methods. Early systemic corticosteroids overall have little or no effect on mortality to the latest reported age (risk ratio [RR] 0.95, 95% confidence interval [CI] 0.85–1.06; 31 studies, 4,373 infants; high‐certainty evidence), but hydrocortisone alone reduces mortality (RR 0.80, 95% CI 0.65–0.99; 11 studies, 1,433 infants; high‐certainty evidence). Early systemic corticosteroids overall probably reduce BPD at 36 weeks’ postmenstrual age (PMA) (RR 0.80, 95% CI 0.73–0.88; 26 studies, 4,167 infants; moderate‐certainty evidence), as does dexamethasone (RR 0.72, 95% CI 0.63–0.82; 17 studies, 2,791 infants; high‐certainty evidence), but hydrocortisone has little to no effect (RR 0.92, 95% CI 0.81–1.06; 9 studies, 1,376 infants; high‐certainty evidence). Early systemic corticosteroids overall reduce the combined outcome of mortality or BPD at 36 weeks’ PMA (RR 0.89, 95% CI 0.84–0.94; 26 studies, 4,167 infants; high‐certainty evidence), as do both dexamethasone (RR 0.88, 95% CI 0.81–0.95; 17 studies, 2,791 infants; high‐certainty evidence) and hydrocortisone (RR 0.90, 95% CI 0.82–0.99; 9 studies, 1,376 infants; high‐certainty evidence). Early systemic corticosteroids overall increase gastrointestinal perforation (RR 1.84, 95% CI 1.36–2.49; 16 studies, 3,040 infants; high‐certainty evidence), as do both dexamethasone (RR 1.73, 95% CI 1.20–2.51; 9 studies, 1,936 infants; high‐certainty evidence) and hydrocortisone (RR 2.05, 95% CI 1.21–3.47; 7 studies, 1,104 infants; high‐certainty evidence). Early systemic corticosteroids overall increase cerebral palsy (RR 1.43, 95% CI 1.07–1.92; 13 studies, 1,973 infants; high‐certainty evidence), as does dexamethasone (RR 1.77, 95% CI 1.21–2.58; 7 studies, 921 infants; high‐certainty evidence) but not hydrocortisone (RR 1.05, 95% CI 0.66–1.66; 6 studies, 1,052 infants; high‐certainty evidence). Early systemic corticosteroids overall have little to no effect on the combined outcome of mortality or cerebral palsy (RR 1.03, 95% CI 0.91–1.16; 13 studies, 1,973 infants; high‐certainty evidence), nor does hydrocortisone (RR 0.86, 95% CI 0.71–1.05; 6 studies, 1,052 infants; high‐certainty evidence). However, early dexamethasone probably increases the combined outcome of mortality or cerebral palsy (RR 1.18, 95% CI 1.01–1.37; 7 studies, 921 infants; high‐certainty evidence), In sensitivity analyses by primary intention for treatment with hydrocortisone (lung problems vs. hypotension), there was little evidence of differences in effects on major outcomes of mortality, BPD, or combined mortality or BPD, by indication for the drug. Authors’ Conclusions: Early systemic postnatal corticosteroid treatment (started during the first 6 days after birth) prevents BPD and the combined outcome of mortality or BPD. However, it increases risks of gastrointestinal perforation, cerebral palsy, and the combined outcome of mortality or cerebral palsy. Most beneficial and harmful effects are related to early treatment with dexamethasone rather than to early treatment with hydrocortisone, but early hydrocortisone may prevent mortality, whereas early dexamethasone does not. Longer term follow‐up into late childhood is vital for assessment of important outcomes that cannot be assessed in early childhood, such as effects of early corticosteroid treatment on higher order neurological functions, including cognitive function, executive function, academic performance, behavior, mental health, motor function, and lung function. Further RCTs of early corticosteroids, particularly hydrocortisone, should include longer term survival free of neurodevelopmental disability as the primary outcome.