The American Academy of Pediatrics continues to provide guidance on the use of postnatal corticosteroids to manage or prevent chronic lung disease following preterm birth (formerly referred to as bronchopulmonary dysplasia). Since the last revision of such guidance in 2010, several prospective randomized trials have been published. This revision provides a review of those studies as well as updated recommendations, which include the use of systemic low-dose corticosteroid in preterm neonates with or at high risk for chronic lung disease. High-dose dexamethasone (≥0.5 mg/kg per day) is not recommended. New evidence suggests that inhaled corticosteroids may confer benefit if provided with surfactant as a vehicle, but safety data are lacking. Evidence remains insufficient to make any recommendations regarding routine use of postnatal corticosteroids in preterm infants. Neonatologists and other hospital care providers must continue to use their clinical judgment in individual patients, balancing the potential adverse effects of corticosteroid treatment with those of chronic lung disease. The decision to use postnatal corticosteroids for this purpose should be made together with the infant’s parents, and the care providers should document their discussions with parents in the patient’s medical record.

Chronic lung disease (CLD) following preterm birth remains a major morbidity among preterm infants, particularly among extremely low gestational age (<28 weeks) newborns (ELGANs).1 The name “bronchopulmonary dysplasia” (BPD), assigned to this condition >50 years ago, reflected specific pathologic findings.2 Because most preterm infants now survive, current terminology focuses on clinical rather than pathologic correlates. Long-term respiratory, growth, and neurodevelopmental morbidities associated with CLD continue to be challenging.35 

Postnatal corticosteroids (PCSs) are a proven therapy for CLD but carry substantial risk. In a policy statement in 2002, the American Academy of Pediatrics (AAP) concluded that routine use of dexamethasone (DEX), the predominant PCS used to prevent or treat CLD, could not be recommended, and that PCSs continue to be studied in prospective, randomized clinical trials with long-term neurodevelopmental follow-up.6 Following the 2002 AAP statement, the use of PCSs declined; unfortunately, this was associated with an increase in the incidence and severity of CLD.7 

In 2010, following numerous clinical trials and several meta-analyses, the AAP revised its 2002 statement but continued not to recommend routine PCS use.8 It was noted that infants at higher risk of CLD (birth weight <1500 g and who remained on mechanical ventilation beyond 1 week of age) could benefit from a short course of PCS; a duration was not specified, although most studies reviewed in this revision administered a tapering course of PCS for 7 to 14 days. The 2010 policy statement concluded that available data were conflicting and inconclusive and that pediatricians and other pediatric care providers must use their own clinical judgment to balance the adverse effects of CLD with those of PCSs on an individual patient basis and that it be a shared decision with the infant’s parents.8 

Clinical research continues to focus on the use of PCSs in infants at risk for or with CLD, and several large clinical trials have been conducted in the past decade. Clinical investigators have looked at corticosteroids (CSs) other than DEX and alternate methods of administration to potentially minimize the adverse effects of CSs. The objectives of this revised statement are to present and review these new data and to update AAP recommendations regarding use of PCSs to prevent or treat CLD.

The discussion is focused on 4 areas: type of corticosteroid (DEX, hydrocortisone [HC], and other); intended purpose (prevention or treatment); dosing (low or high), and route of administration (systemic or inhaled). In general, the literature review was limited to randomized, prospective clinical trials and systematic reviews. When possible, odds ratios have been converted to either relative risk (RR) or relative benefit increase (RBI)a to facilitate interpretation.

Of the various PCSs, DEX and HC have been studied the most extensively. Randomized control trials of these systemic CSs have been arbitrarily divided into early (prevention; started ≤7 days of age) and late (treatment; started >7 and <28 days of age) in most systematic reviews and meta-analyses published, and this statement follows this approach.b Because dosing may alter the risk and benefit profile, a separate discussion of low versus high dosing has been added.

The most recent Cochrane review of the use of early PCS to prevent CLD concluded that the benefits of early DEX (successful extubation and survival without CLD at 36 weeks’ postmenstrual age [PMA]) may not outweigh adverse effects.9 There were no significant differences in mortality. However, there were higher rates of hyperglycemia, hypertension, hypertrophic cardiomyopathy, gastrointestinal bleeding or perforation, and growth failure. Long-term follow-up studies reported an increase in abnormal neurologic examinations and cerebral palsy, although the methodologic quality was inadequate in some studies with assessments limited to preschool age, and no study was powered to detect adverse long-term outcomes.

The most recent Cochrane review of the use of late PCS to treat CLD concluded that there was evidence of both benefit and harm of late DEX; that because of limitations in the evidence, it would be prudent to reserve the use of late PCS (including DEX) for infants who cannot be weaned from mechanical ventilation; and that, if DEX is used, the dose and duration should be minimized.10 This conclusion is similar to recent recommendations from a panel of European experts11 as well as the Canadian Pediatric Society Fetus and Newborn Committee.12 

Since these 2 Cochrane reviews, there have been 2 RCTs of DEX in ventilator-dependent preterm infants at 10 to 21 days of age. The first study, called MINIDEX, compared a very low dose (50 µg/kg per day) of DEX versus a placebo with extubation as the primary outcome.13 This multicenter study planned to enroll 94 infants, but because of frequent open-label PCS use and a high rate of sepsis, recruitment proved difficult, and the study was halted. Among evaluable subjects, a higher proportion of infants in the DEX group were extubated by study day 7 (63% vs 33%), but no conclusions should be drawn from such a limited sample size.13 

The second study compared a 42 day dosing regimen with a 9 day dosing regimen.14 Infants in the 9-day group could receive up to 2 additional 9 day courses if respiratory criteria were met; after 42 study days, open-label PCSs were permitted in both groups. Rates of survival without CLD and rates of rehospitalization for respiratory illness were similar. By age 7 years, 2 of 30 infants in the 42 day group were lost to follow-up, and 3 of 29 infants in the 9 day group had died. Of survivors who were evaluated, mean Wechsler Intelligence Scale scores were similar; however, significantly more infants in the 42 day group were in regular classrooms without individualized education plans (75% vs 38%, P < .05). The authors concluded that attempts to minimize PCS exposure may not be beneficial, although the small sample size, large number of exclusions (34% of eligible infants were excluded because of low 5 minute Apgar scores and/or birth weight below the 10th percentile), high percentage of multiple DEX courses in the 9 day group (33%), and frequent open-label use of PCSs (27%) among both groups suggest that this conclusion may not be generalizable.

Review of the literature for the 2010 AAP policy statement concluded that high daily doses (≥0.5 mg/kg) of DEX were linked to adverse neurodevelopmental outcomes, but because there had not been a linkage reported in low-dose trials, additional studies of lower-dose DEX were warranted. Authors of a 2017 Cochrane review analyzing RCTs that compared different dosing regimens concluded that recommendations on the optimal dosage and timing could not be made on the basis of the current level of evidence and suggested that if late PCSs are used, both dose and duration should be minimized.9,10 There have been no new RCTs published since that Cochrane review.c

Although DEX was the focus of most of the earlier studies, interest has turned to HC, given the numerous adverse effects associated with DEX use and a growing understanding of the physiologic differences between DEX, a synthetic glucocorticoid, and endogenous cortisol. DEX, unlike cortisol, has little mineralocorticoid effect but high potency and a long half-life; these features combine to increase the risk of deleterious effects on the developing nervous, cardiac, pulmonary, and gastrointestinal systems.15,16 The developing brain has both mineralocorticoid and glucocorticoid receptors; exogenous glucocorticoids, like DEX, suppress endogenous cortisol secretion but do not substantially bind to mineralocorticoid receptors, leaving these receptors unoccupied for prolonged periods, which leads to neuronal apoptosis.17,18 HC, which has both glucocorticoid and mineralocorticoid activity, acts more like endogenous cortisol and has been under intensive study in recent years as a potentially safer alternative to DEX.

The 2010 AAP policy statement concluded that existing data were insufficient to make any recommendation regarding the use of HC to prevent CLD, although there was evidence to suggest that giving HC for the first 2 weeks of life might increase survival without CLD, particularly for infants delivered in the setting of perinatal inflammation.8 A 2017 Cochrane review of early PCS to prevent CLD includes 3 RCTs published since the 2010 AAP policy statement.9,10 Two were small feasibility trials in ELGANs with low blood pressure;19,20 the third was the PREMILOC study, a large, multicenter randomized controlled trial (RCT) of low-dose HC in ELGANs for the first 10 postnatal days.21 The PREMILOC authors reported a statistically significant increase in survival without CLD at 36 weeks’ gestation (60% vs 51%; RBI, 0.22; 95% confidence interval [CI], 0.01 to 0.59; P = .04). However, in the subgroup of infants born at 24 to 25 weeks of gestation, the authors noted a statistically higher rate of late-onset sepsis in the HC group (40% vs 23%; RR, 1.70; 95% CI, 1.08 to 2.70; P = .02). Mortality was not significantly different between groups. Inclusion of these studies into the 2017 Cochrane review meta-analysis resulted in a small but statistically significant increase in survival without CLD at 36 weeks’ gestation (RBI, 0.04; 95% CI, 0.01 to 0.09), similar to that observed in trials using DEX (RBI, 0.08; 95% CI, 0.03 to 0.12). As with DEX, the authors concluded that the beneficial effects of early HC (either high or low dose) may not outweigh the adverse effects. In a predefined secondary analysis, the PREMILOC trial study authors found no predictive value of baseline cortisol levels with CLD. However, high cortisol levels early after birth were associated with an increased risk of severe intraventricular hemorrhage and spontaneous intestinal perforation in infants treated with hydrocortisone.22 

In a separate meta-analysis of 4 RCTs designed specifically to test the efficacy of early HC for prophylaxis against relative adrenal insufficiency in preterm infants, the authors analyzed individual patient data from 982 study patients.23 Similar to previous reports, they concluded that early, low-dose HC significantly improves rates of survival without CLD (RBI, 0.20, 95% CI, 0.06 to 0.35; P = .007) and survival to hospital discharge (RBI, 0.07; 95% CI, 0.01 to 0.12; P = .03). They also found significantly increased rates of spontaneous intestinal perforation (RR, 2.39; 95% CI, 1.32 to 4.22; P = .004) and late-onset sepsis (RR, 1.22; 95% CI, 1.01 to 1.43; P = .04), but there was no association of HC with spontaneous intestinal perforation in the absence of concurrent indomethacin treatment, and the observed difference in sepsis was not associated with increased mortality or other in-hospital adverse outcomes. The authors concluded that these adverse effects did not negate the overall benefit of HC therapy in this population.

Since those meta-analyses mentioned previously were conducted, there has been 1 newly reported RCT of HC in preterm infants. The STOP-BPD study compared early HC versus placebo, starting between 7 and 14 days of age, and continuing for 22 days.24 The initial dose of HC was 5 mg/kg per day for 7 days, followed by a scheduled taper. The primary outcome, survival without CLD at 36 weeks’ PMA, occurred in 28% of the 372 study patients, and was not statistically different between groups (RBI, 0.11; 95% CI, 0.20 to 0.55; P = .52). However, there was a significant reduction in mortality by 36 weeks PMA in infants in the HC group (RR, 0.65; 95% CI, 0.43 to 1.00; P = .0498). These modest results may not significantly alter the conclusions from previous meta-analyses regarding the short-term risk and benefit profile of early HC in preterm infants. However, a preplanned analysis of long-term, 2-year corrected age outcomes for this study cohort may soon be available.

A recent meta-analysis examined the question of whether chorioamnionitis was an independent predictor of response to early HC.25 The authors identified 3 RCTs published between 1999 and 2018 in which the presence of histologic chorioamnionitis was reported. In each study, enrollment was limited to ELGANs and/or infants with birth weight <1000 g. In the combined cohort of 407 infants exposed to chorioamnionitis, the rate of survival without CLD was significantly higher in the HC group (56% vs 42%; RBI, 0.32; 95% CI, 0.08 to 0.61; P = .0071) compared with 373 infants not exposed to chorioamnionitis (50% vs 47%; RBI, 0.06; 95% CI, −0.14 to 0.31; P = .58).

The 2010 AAP policy statement concluded that existing data were insufficient to make any recommendation regarding the use of HC to treat CLD.8 A 2017 Cochrane review included 1 additional pilot RCT, published since the 2010 AAP policy statement.9,10 In that study, the authors were unable to discern any effect of a 1 week course of low-dose HC on pulmonary outcomes or regional brain volumes among 64 ventilator-dependent ELGANs.26 Eight infants died in each study group, and there was no difference in the composite outcome of death or severe CLD, defined as oxygen and/or pressure support at 36 weeks’ PMA. The Cochrane review went on to note the limitations in the evidence to-date and concluded that it would be prudent to reserve the late use of PCS (including HC) for infants who cannot be weaned from mechanical ventilation and to minimize the dose and duration.

In an ongoing RCT study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network that enrolled 800 infants born at <30 weeks’ gestational age who remained intubated for >7 days and intubated at 7 to 14 days, HC facilitated extubation; however, survival without CLD was not significantly improved. Also, survival without moderate or severe neurodevelopmental impairment in the group receiving HC was similar to that in the placebo group.27 

There have been no RCTs directly comparing different doses of HC to prevent or treat CLD in preterm infants. Of all RCTs published to date, none have shown an increase in short-term adverse outcomes compared with placebo; this includes studies using low (≤2 mg/kg per day) and high (>2 mg/kg per day) doses of HC. This is reassuring, particularly in light of a recent observational study with more than 1427 preterm infants exposed to early HC in which the authors found an independent association between higher early HC doses and mortality.28 

To our knowledge, other systemic CSs commonly used in clinical practice have not been studied to prevent or treat CLD in preterm infants in RCTs.

To maximize pulmonary benefit while avoiding systemic adverse effects, there has been growing interest in the use of inhaled CSs to prevent or treat CLD in preterm infants.

The 2010 AAP policy statement concluded that existing data were insufficient to make any recommendation regarding the use of inhaled CS to treat CLD.8 A 2017 Cochrane Review of “early” (≤14 days of age) inhaled CS to prevent CLD included 2 new RCTs published since the 2010 AAP policy statement.29,30 The authors noted increasing evidence for increased survival without CLD at 36 weeks’ PMA (RBI, 0.09; 95% CI, 0.01 to 0.33; P = .04), although the upper confidence limit around the number needed to treat to benefit 1 infant was infinity.

One new trial included in the 2017 Cochrane Review was the NEuroSIS trial, the largest RCT of inhaled steroids to date.31 This placebo-controlled trial enrolled 863 ELGANs; 437 received budesonide starting within 24 hours of age and continuing until they no longer required supplemental oxygen or positive pressure support or until they reached 32 weeks’ PMA. The authors found that the rates of survival without CLD at 36 weeks’ PMA were not statistically significant (60% vs 54%; RBI, 0.12; 95% CI, 0.01 to 0.26; P = .07). The risk of CLD at 36 weeks’ PMA was significantly reduced (RR, 0.74; 95% CI, 0.60 to 0.91; P = .004), but the authors noted that this advantage may have been gained at the expense of increased mortality (RR, 1.24; 95% CI, 0.91 to 1.69; P = .17).31 

The second new RCT was a placebo-controlled trial that enrolled 211 ventilator-dependent ELGANs; infants in the inhaled group received fluticasone daily until extubation or 6 weeks of age.32 The overall rate of survival without supplemental oxygen need at discharge (the study definition of severe CLD) was 82% and was not significantly different between groups (RBI, 0.10; 95% CI, −0.03 to 0.25; P = .13). However, in preplanned subgroup analyses, the authors found a significantly higher rate of this composite outcome for treated infants in the 24- to 26-weeks’ gestational age strata (93% vs 83%; RBI, 0.12; 95% CI, 0.01 to 0.24; P = .03); this benefit appeared to be limited to infants in whom chorioamnionitis was confirmed by placental pathology (86% vs 59%; RBI, 0.44; 95% CI, 0.05 to 0.99; P = .02).32 

Since 2017, there have been no new published RCTs of inhaled CSs to prevent CLD.d

In a 2017 Cochrane review of latee (≥7 days of age) inhaled CSs, the authors analyzed results from 8 RCTs that enrolled 232 preterm infants.33 They found that inhaled CSs did not significantly increase the rate of survival without CLD at 36 weeks’ PMA.

Since 2017, there have been no new published RCTs of inhaled CSs to treat CLD.

The theoretical advantages of inhaled versus systemic PCSs would include a lower absolute dose, enhanced pulmonary benefit, and reduced systemic effects. However, a pair of 2017 Cochrane reviews that included RCTs that directly compared inhaled versus systemic PCSs found no evidence of differences in either effectiveness or adverse event profiles.29,30 The authors concluded that inhaled CSs do not confer any net advantage over systemic CSs for the prevention or treatment of CLD in preterm infants.

A recent systematic review comparing pulmonary versus systemic delivery of PCSs included 2 RCTs of endotracheal instillation of CS using surfactant as a vehicle, in addition to the RCTs of inhaled CS included in the 2017 Cochrane review.34 Studies of CS instilled with a vehicle had not previously been included in any systematic review. Meta-analysis of outcomes for 1716 preterm infants among 8 RCTs found that those who received direct pulmonary administration of CS had a significantly higher rate of survival without CLD at 36 weeks’ PMA (62% vs 52%; RBI 0.18; 95% CI, 0.09 to 0.29; P = .0001).

Clinical trials of inhaled CSs to prevent or treat CLD have used a variety of CSs, including beclomethasone, budesonide, fluticasone, flunisolide, and DEX, but there have been no RCTs directly comparing different inhaled CSs in preterm infants. In a recent systematic review limited only to 5 RCTs that used budesonide, the authors found marked heterogeneity between trials and could find no evidence that inhaled budesonide attenuates the severity of CLD.35 

Although cumulative data suggest that PCSs may increase survival without CLD among ELGANs, the interaction of various factors in determining the risk and benefit profile has made it difficult to determine the optimal approach. Type, dose, route, and duration of PCS all seem to be important modulators of response as well as the risk of both short-term and long-term adverse effects. Although one could not conduct an RCT or even a series of RCTs that adequately address all these parameters, it may be possible to employ novel analytical techniques to use the data we have accumulated thus far and gain new insights. One such technique is a Bayesian network meta-analysis, an extension of the classic pairwise meta-analysis that allows comparison of multiple interventions based on both head-to-head comparisons within trials and indirect comparisons across trials.36 For example, if 1 set of trials compared A versus B and another set of trials compared B versus C, a Bayesian network analysis enables us to make comparisons between A and C, with B as the common comparator for both A and C. This technique has recently been applied to RCTs of PCSs to prevent or treat CLD in preterm infants. In 1 network meta-analysis that included 47 RCTs and 6747 participants, the authors found that DEX was more effective at reducing CLD than either HC or inhaled beclomethasone, and that early (≤7 days of age) initiation of high dose DEX (total dose >3.0 mg/kg) was associated with the most significant reductions in CLD.37 Although the risk of cerebral palsy was not statistically significant between types of PCS, the combination of high dose and long-term DEX use was associated with an increased risk of adverse neurodevelopmental outcome.37 In a more recent network meta-analysis that included 62 RCTs and 5559 participants, the authors parsed the data into 3 levels of PCS initiation (early, moderately early, and late) and total dose (low, medium, and high), and found that DEX provided moderately early (8–14 days of age) and at a medium total dose (2–4 mg/kg) was associated with the best overall reduction in mortality and/or CLD with hypertension as the only significantly increased adverse outcome.38 

Despite the limitations of network meta-analysis (eg, indirect comparisons must be considered observational evidence), such novel approaches may bring us closer to the optimal use of PCSs.

Because the risks associated with PCS use cannot be eliminated, patient selection is critical so as not to expose infants who are unlikely to benefit, ie, infants not likely to develop CLD. The importance of patient selection is underscored by an analysis first reported in 2005 and updated in 2014 in which the authors performed a weighted meta-regression between the risk differences for the combined outcome of death or cerebral palsy and the rate of CLD in controls from RCTs.39,40 As in 2005, the authors found a strong negative relationship that favored PCS use if the incidence of CLD in the pretreatment population was >50%. With this information, one could apply clinical prediction models at an early postnatal age and treat only those infants at relatively high risk for CLD; however, this would still result in exposing vulnerable preterm infants who are not going to develop CLD, while also missing some infants who will go on to develop CLD. Ideally, a model that predicts CLD with an extremely high sensitivity and specificity at or soon after birth would maximize an individual infant’s risk and benefit profile. Although several models exist that use various demographic and clinical parameters, gestational age alone remains the strongest predictor within the first week of age.41 

Initiating PCSs soon after birth has the advantage of interrupting the inflammatory cascade that leads to the development of CLD. Delaying treatment and using more selective criteria, such as continued need for respiratory support, has the advantage of capturing those infants most likely to develop CLD. The disadvantage to delayed intervention, however, is that infants with more severe CLD are less likely to benefit from PCS.42 

Many RCTs of PCSs have not reported long-term outcomes, and those that have are limited to 18 to 24 months’ PMA. To better assess the impact of PCSs on preterm infant outcomes, longer-term assessments are needed; unfortunately, only a handful of RCTs have reported outcomes at school age (Table 1). In sum, these studies suggest that PCSs do not increase the risk of adverse outcomes at school age. Although preterm cohorts exposed to PCSs generally showed decreased growth, impaired lung function, and increased rates of neurodevelopmental impairment relative to term infants, they did not significantly differ from control cohorts for their respective RCTs. However, many studies were contaminated by relatively high rates of open-label PCS use; of the 3 placebo-controlled studies with low or no open-label PCS contamination, the 2 larger studies found increased rates of growth and/or neurodevelopmental impairment;43,44 hence, the overall safety of PCS remains in question. A large, multicenter RCT by the Neonatal Research Network just completed 2-year follow-up, with plans to conduct school-aged outcomes assessment, which may provide data on nearly 800 infants, about the same as all previous studies combined.f

TABLE 1

RCTs of PCSs That Reported School-Aged Outcomes

Original Study CohortSchool-Aged Follow-Up Study Cohort
SourcePCSInitiationControlOpen-Label UseaLength(days)SourceNAge(y)Treated versus Control, P < .05
≤7 d>7 dGrowthLungFunctionNeurodevelopmental Outcomes
Cummings et al45 (1989) DEX — √ Saline None 42 or 18
 
Gross et al52 (2005) 22 15 Nob No No 
Collaborative DTG46 (1991) DEX — √ Saline 39% 7–16 Jones53 (2005) 142 13–17 No No NA 
Jones54 (2005) 150 13–17 NA NA No 
Kari et al47 (1993) DEX — √ Saline 34% Mieskonen55 et al (2003) 15 7–9 No No NA 
Yeh et al48 (1997) DEX √ — Saline 9% 28 Yeh et al56 (2004) 146 6–10 ↓ Height ↓ HC NA ↑NDI 
Kothadia et al49 (1999) DEX — √ Saline None 42 Nixon et al57 (2007) 68 8–11 No No NA 
O’Shea et al58 (2007) 95 4–11 NA NA ↑ NDI 
Halliday et al50 (2001) DEX √ √ BUD None 12 Wilson et al59 (2006) 434 4.5–9.5 No No No 
Marr et al51 (2011) DEX — √ Short-course DEX 27% 42 Marr et al (2019)14  57 No NA ↓NDI 
Original Study CohortSchool-Aged Follow-Up Study Cohort
SourcePCSInitiationControlOpen-Label UseaLength(days)SourceNAge(y)Treated versus Control, P < .05
≤7 d>7 dGrowthLungFunctionNeurodevelopmental Outcomes
Cummings et al45 (1989) DEX — √ Saline None 42 or 18
 
Gross et al52 (2005) 22 15 Nob No No 
Collaborative DTG46 (1991) DEX — √ Saline 39% 7–16 Jones53 (2005) 142 13–17 No No NA 
Jones54 (2005) 150 13–17 NA NA No 
Kari et al47 (1993) DEX — √ Saline 34% Mieskonen55 et al (2003) 15 7–9 No No NA 
Yeh et al48 (1997) DEX √ — Saline 9% 28 Yeh et al56 (2004) 146 6–10 ↓ Height ↓ HC NA ↑NDI 
Kothadia et al49 (1999) DEX — √ Saline None 42 Nixon et al57 (2007) 68 8–11 No No NA 
O’Shea et al58 (2007) 95 4–11 NA NA ↑ NDI 
Halliday et al50 (2001) DEX √ √ BUD None 12 Wilson et al59 (2006) 434 4.5–9.5 No No No 
Marr et al51 (2011) DEX — √ Short-course DEX 27% 42 Marr et al (2019)14  57 No NA ↓NDI 

BUD indicates budesonide; DEX, dexamethasone; HC, hydrocortisone; NA, not assessed; NDI, neurodevelopmental impairment. —, not applicable.

a

Open-label use refers to percent of infants who received open label PCS after study intervention period.

b

Two steroid treatment groups (42 d and 18 d duration) combined.

  1. PCSs, either to prevent or treat early CLD, may increase the rate of survival without severe CLD but carry significant short- and long-term risks.

  2. Early (≤7 days) low-dose HC may prevent CLD or death in infants weighing less than 1000 g exposed to chorioamnionitis.

  3. Late (>7 and <28 days of age) low-dose DEX may improve outcomes for preterm infants who remain on significant respiratory support but without evidence of severe CLD.

  4. Inhaled CSs do not appear to offer any advantage over systemic corticosteroids and may be associated with increased mortality.

  5. CSs may be more effective when delivered directly into the lung with surfactant as a vehicle, but data on long-term outcomes are lacking.

  6. Data from RCTs are population based and may not apply to individual patients.

  7. More data regarding long-term, school-aged outcomes are needed to guide the use of PCSs to prevent or treat CLD in preterm infant.

  1. Routine use of PCSs cannot be recommended.

  2. The decision to use PCSs to prevent or treat CLD should be individualized and made together with the parents, and the discussions should be documented in the patient’s medical record.

  3. If a decision is made to administer a PCS, a low dose provided for a short, predefined duration (eg, extubation) is recommended. If the infant does not show a clinical response to the PCS within 72 hours of initiation, continued treatment is not recommended.

  4. High-dose PCSs are not recommended to prevent or treat CLD in preterm infants.

  5. Indomethacin should not be used concurrently with PCSs.

______________________________

  • James J. Cummings, MD, MS, FAAP

  • Arun K. Pramanik, MD, FAAP

  • Eric Eichenwald, MD, Chairperson

  • Charleta Guillory, MD

  • Ivan Hand, MD

  • Mark Hudak, MD

  • David Kaufman, MD

  • Camilia Martin, MD

  • Ashley Lucke, MD

  • Margaret Parker, MD

  • Arun Pramanik, MD

  • Kelly Wade, MD

  • Timothy Jancelewicz, MD – AAP Section on Surgery

  • Michael Narvey, MD – Canadian Pediatric Society

  • Russell Miller, MD – American College of Obstetricians and Gynecologists

  • RADM Wanda Barfield, MD, MPH – Centers for Disease Control and Prevention

  • Lisa Grisham, APRN, NNP-BC – National Association of Neonatal Nurses

Jim Couto, MA

a

RBI = relative benefit increase = [exposed events-control events]/control events (a measure of relative benefit).

b

This policy pertains to neonates ranging in age from 0 to 28 days.

c

PubMed search, April 19, 2021.

d

PubMed search, May 1, 2021.

e

The definition of early and late for the 2017 Cochrane reviews of inhaled PCS overlap, as early was defined as 14 days of age and late as >7 days of age. As a result, there are 2 RCTs that are included in both reviews.

f

https://www.clinicaltrials.gov/ct2/show/NCT01353313?cond=hydrocortisone+NICHD&DRAW=2&RANK=3

Dr Cummings conducted the literature review and prepared the initial draft of this report; Dr Pramanik revised the draft and updated references; and both authors prepared the final manuscript.

Policy statements from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However, policy statements from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent.

The guidance in this statement does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

All policy statements from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

     
  • AAP

    American Academy of Pediatrics

  •  
  • BPD

    bronchopulmonary dysplasia

  •  
  • CI

    confidence interval

  •  
  • CLD

    chronic lung disease following preterm birth

  •  
  • CS

    corticosteroid

  •  
  • DEX

    dexamethasone

  •  
  • ELGAN

    extremely low gestational age (<28 weeks) newborn

  •  
  • HC

    hydrocortisone

  •  
  • PCS

    postnatal corticosteroid

  •  
  • PMA

    postmenstrual age

  •  
  • RBI

    relative benefit increase

  •  
  • RCT

    randomized controlled trial

  •  
  • RR

    relative risk

1
Morris
BH
,
Gard
CC
,
Kennedy
K
;
NICHD Neonatal Research Network
.
Rehospitalization of extremely low birth weight (ELBW) infants: are there racial/ethnic disparities?
J Perinatol
.
2005
;
25
(
10
):
656
663
2
Northway
WH
Jr
,
Rosan
RC
,
Porter
DY
.
Pulmonary disease following respirator therapy of hyaline-membrane disease. bronchopulmonary dysplasia
.
N Engl J Med
.
1967
;
276
(
7
):
357
368
3
Islam
JY
,
Keller
RL
,
Aschner
JL
,
Hartert
TV
,
Moore
PE
.
Understanding the short- and long-term respiratory outcomes of prematurity and bronchopulmonary dysplasia
.
Am J Respir Crit Care Med
.
2015
;
192
(
2
):
134
156
4
Biniwale
MA
,
Ehrenkranz
RA
.
The role of nutrition in the prevention and management of bronchopulmonary dysplasia
.
Semin Perinatol
.
2006
;
30
(
4
):
200
208
5
Schmidt
B
,
Asztalos
EV
,
Roberts
RS
,
Robertson
CM
,
Sauve
RS
,
Whitfield
MF
;
Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators
.
Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms
.
JAMA
.
2003
;
289
(
9
):
1124
1129
6
Committee on Fetus and Newborn
.
Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants
.
Pediatrics
.
2002
;
109
(
2
):
330
338
7
Yoder
BA
,
Harrison
M
,
Clark
RH
.
Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants
.
Pediatrics
.
2009
;
124
(
2
):
673
679
8
Watterberg
KL
;
American Academy of Pediatrics. Committee on Fetus and Newborn
.
Policy statement--postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia
.
Pediatrics
.
2010
;
126
(
4
):
800
808
9
Doyle
LW
,
Cheong
JL
,
Ehrenkranz
RA
,
Halliday
HL
.
Early (<8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants
.
Cochrane Database Syst Rev
.
2017
;
10
(
10
):
CD001146
10
Doyle
LW
,
Cheong
JL
,
Ehrenkranz
RA
,
Halliday
HL
.
Late (>7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants
.
Cochrane Database Syst Rev
.
2017
;
10
(
10
):
CD001145
11
Sweet
DG
,
Carnielli
V
,
Greisen
G
, et al
.
European consensus guidelines on the management of respiratory distress syndrome - 2019 update
.
Neonatology
.
2019
;
115
(
4
):
432
450
12
Lemyre
B
,
Dunn
M
,
Thebaud
B
.
Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia in preterm infants
.
Paediatr Child Health
.
2020
;
25
(
5
):
322
331
13
Yates
HL
,
Newell
SJ
.
Minidex: very low dose dexamethasone (0.05 mg/kg/day) in chronic lung disease
.
Arch Dis Child Fetal Neonatal Ed
.
2011
;
96
(
3
):
F190
F194
14
Marr
BL
,
Mettelman
BB
,
Bode
MM
,
Gross
SJ
.
Randomized trial of 42-day compared with 9-day courses of dexamethasone for the treatment of evolving bronchopulmonary dysplasia in extremely preterm infants
.
J Pediatr
.
2019
;
211
:
20
26.e1
15
Cole
TJ
,
Short
KL
,
Hooper
SB
.
The science of steroids
.
Semin Fetal Neonatal Med
.
2019
;
24
(
3
):
170
175
16
Baud
O
,
Watterberg
KL
.
Prophylactic postnatal corticosteroids: early hydrocortisone
.
Semin Fetal Neonatal Med
.
2019
;
24
(
3
):
202
206
17
Crochemore
C
,
Lu
J
,
Wu
Y
, et al
.
Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation
.
Mol Psychiatry
.
2005
;
10
(
8
):
790
798
18
Hassan
AH
,
von Rosenstiel
P
,
Patchev
VK
,
Holsboer
F
,
Almeida
OF
.
Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone
.
Exp Neurol
.
1996
;
140
(
1
):
43
52
19
Batton
BJ
,
Li
L
,
Newman
NS
, et al
.;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Feasibility study of early blood pressure management in extremely preterm infants
.
J Pediatr
.
2012
;
161
(
1
):
65
9.e1
20
Hochwald
O
,
Palegra
G
,
Osiovich
H
.
Adding hydrocortisone as 1st line of inotropic treatment for hypotension in very low birth weight infants
.
Indian J Pediatr
.
2014
;
81
(
8
):
808
810
21
Baud
O
,
Maury
L
,
Lebail
F
, et al
.;
PREMILOC trial study group
.
Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial
.
Lancet
.
2016
;
387
(
10030
):
1827
1836
22
Renolleau
C
,
Toumazi
A
,
Bourmaud
A
, et al
.;
PREMILOC Trial Study Group
.
Association between baseline cortisol serum concentrations and the effect of prophylactic hydrocortisone in extremely preterm infants
.
J Pediatr
.
2021
;
234
:
65
70.e3
23
Shaffer
ML
,
Baud
O
,
Lacaze-Masmonteil
T
,
Peltoniemi
OM
,
Bonsante
F
,
Watterberg
KL
.
Effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone in very preterm infants: an individual patient data meta-analysis
.
J Pediatr
.
2019
;
207
:
136
142.e5
24
Onland
W
,
Cools
F
,
Kroon
A
, et al
.;
STOP-BPD Study Group
.
Effect of hydrocortisone therapy initiated 7 to 14 days after birth on mortality or bronchopulmonary dysplasia among very preterm infants receiving mechanical ventilation: a randomized clinical trial
.
JAMA
.
2019
;
321
(
4
):
354
363
25
Zhou
J
,
Yu
Z
,
Chen
C
.
Hydrocortisone for preventing mortality and bronchopulmonary dysplasia in preterm infants with or without chorioamnionitis exposure: a meta-analysis of randomized trials
.
Am J Perinatol
.
2021
;
38
(
7
):
662
668
26
Parikh
NA
,
Kennedy
KA
,
Lasky
RE
,
McDavid
GE
,
Tyson
JE
.
Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes
.
J Pediatr
.
2013
;
162
(
4
):
685
690.e1
27
Watterberg
KL
,
Walsh
MC
,
Li
L
, et al
Hydrocortisone to improve survival without bronchopulmonary dysplasia
.
N Engl J Med
.
2022
;
386
:
1121
1131
28
Tolia
VN
,
Bahr
TM
,
Bennett
MM
, et al
.
The association of hydrocortisone dosage on mortality in infants born extremely premature
.
J Pediatr
.
2019
;
207
:
143
147.e3
29
Shah
SS
,
Ohlsson
A
,
Halliday
HL
,
Shah
VS
.
Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates
.
Cochrane Database Syst Rev
.
2017
;
10
(
10
):
CD002058
30
Shah
SS
,
Ohlsson
A
,
Halliday
HL
,
Shah
VS
.
Inhaled versus systemic corticosteroids for the treatment of bronchopulmonary dysplasia in ventilated very low birth weight preterm infants
.
Cochrane Database Syst Rev
.
2017
;
10
(
10
):
CD002057
31
Bassler
D
,
Plavka
R
,
Shinwell
ES
, et al
.;
NEUROSIS Trial Group
.
Early inhaled budesonide for the prevention of bronchopulmonary dysplasia
.
N Engl J Med
.
2015
;
373
(
16
):
1497
1506
32
Nakamura
T
,
Yonemoto
N
,
Nakayama
M
, et al
.;
and The Neonatal Research Network, Japan
.
Early inhaled steroid use in extremely low birthweight infants: a randomised controlled trial
.
Arch Dis Child Fetal Neonatal Ed
.
2016
;
101
(
6
):
F552
F556
33
Onland
W
,
Offringa
M
,
van Kaam
A
.
Late (≥7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants
.
Cochrane Database Syst Rev
.
2017
;
8
(
8
):
CD002311
34
Delara
M
,
Chauhan
BF
,
Le
ML
,
Abou-Setta
AM
,
Zarychanski
R
,
'tJong
GW
.
Efficacy and safety of pulmonary application of corticosteroids in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis
.
Arch Dis Child Fetal Neonatal Ed
.
2019
;
104
(
2
):
F137
F144
35
Andrews
E
,
Sur
A
.
Is inhaled budesonide a useful adjunct for the prevention or management of bronchopulmonary dysplasia?
Arch Dis Child
.
2020
;
105
(
5
):
508
511
36
Uhlmann
L
,
Jensen
K
,
Kieser
M
.
Hypothesis testing in Bayesian network meta-analysis
.
BMC Med Res Methodol
.
2018
;
18
(
1
):
128
37
Zeng
L
,
Tian
J
,
Song
F
, et al
.
Corticosteroids for the prevention of bronchopulmonary dysplasia in preterm infants: a network meta-analysis
.
Arch Dis Child Fetal Neonatal Ed
.
2018
;
103
(
6
):
F506
F511
38
Ramaswamy
VV
,
Bandyopadhyay
T
,
Nanda
D
, et al
.
Assessment of postnatal corticosteroids for the prevention of bronchopulmonary dysplasia in preterm neonates: a systematic review and network meta-analysis
.
JAMA Pediatr
.
2021
;
175
(
6
):
e206826
39
Doyle
LW
,
Halliday
HL
,
Ehrenkranz
RA
,
Davis
PG
,
Sinclair
JC
.
An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of bronchopulmonary dysplasia
.
J Pediatr
.
2014
;
165
(
6
):
1258
1260
40
Doyle
LW
,
Halliday
HL
,
Ehrenkranz
RA
,
Davis
PG
,
Sinclair
JC
.
Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease
.
Pediatrics
.
2005
;
115
(
3
):
655
661
41
Onland
W
,
Debray
TP
,
Laughon
MM
, et al
.
Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study
.
BMC Pediatr
.
2013
;
13
:
207
42
Harmon
HM
,
Jensen
EA
,
Tan
S
, et al
.;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Timing of postnatal steroids for bronchopulmonary dysplasia: association with pulmonary and neurodevelopmental outcomes
.
J Perinatol
.
2020
;
40
(
4
):
616
627
43
Yeh
TF
,
Lin
YJ
,
Huang
CC
, et al
.
Early dexamethasone therapy in preterm infants: a follow-up study
.
Pediatrics
.
1998
;
101
(
5
):
E7
44
O’Shea
TM
,
Kothadia
JM
,
Klinepeter
KL
, et al
.
Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age
.
Pediatrics
.
1999
;
104
(
1 Pt 1
):
15
21
45
Cummings
JJ
,
D’Eugenio
DB
,
Gross
SJ
.
A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia
.
N Engl J Med
.
1989
;
320
(
23
):
1505
1510
46
Collaborative Dexamethasone Trial Group
.
Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial
.
Pediatrics
.
1991
;
88
(
3
):
421
427
47
Kari
MA
,
Heinonen
K
,
Ikonen
RS
,
Koivisto
M
,
Raivio
KO
.
Dexamethasone treatment in preterm infants at risk for bronchopulmonary dysplasia
.
Arch Dis Child
.
1993
;
68
(
5 Spec No
):
566
569
48
Yeh
TF
,
Lin
YJ
,
Hsieh
WS
, et al
.
Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clinical trial
.
Pediatrics
.
1997
;
100
(
4
):
E3
49
Kothadia
JM
,
O’Shea
TM
,
Roberts
D
,
Auringer
ST
,
Weaver
RG
III
,
Dillard
RG
.
Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants
.
Pediatrics
.
1999
;
104
(
1 Pt 1
):
22
27
50
Halliday
HL
,
Patterson
CC
,
Halahakoon
CW
;
European Multicenter Steroid Study Group
.
A multicenter, randomized open study of early corticosteroid treatment (OSECT) in preterm infants with respiratory illness: comparison of early and late treatment and of dexamethasone and inhaled budesonide
.
Pediatrics
.
2001
;
107
(
2
):
232
240
51
Marr
BL
,
Bode
MM
,
Gross
SJ
.
Trial of 42 day vs. 9 day courses of dexamethasone for the treatment of evolving bronchopulmonary dysplasia in extremely preterm infants
.
Proceedings of the Pediatric Academic Societies
;
April 30-May 3, 2011
;
Denver, CO
52
Gross
SJ
,
Anbar
RD
,
Mettelman
BB
.
Follow-up at 15 years of preterm infants from a controlled trial of moderately early dexamethasone for the prevention of chronic lung disease
.
Pediatrics
.
2005
;
115
(
3
):
681
687
53
Jones
RA
;
Collaborative Dexamethasone Trial Follow-up Group
.
Randomized, controlled trial of dexamethasone in neonatal chronic lung disease: 13- to 17-year follow-up study: I. neurologic, psychological, and educational outcomes
.
Pediatrics
.
2005
;
116
(
2
):
370
378
54
Jones
RA
;
Collaborative Dexamethasone Trial Follow-up Group
.
Randomized, controlled trial of dexamethasone in neonatal chronic lung disease: 13- to 17-year follow-up study: II. respiratory status, growth, and blood pressure
.
Pediatrics
.
2005
;
116
(
2
):
379
384
55
Mieskonen
S
,
Eronen
M
,
Malmberg
LP
,
Turpeinen
M
,
Kari
MA
,
Hallman
M
.
Controlled trial of dexamethasone in neonatal chronic lung disease: an 8-year follow-up of cardiopulmonary function and growth
.
Acta Paediatr
.
2003
;
92
(
8
):
896
904
56
Yeh
TF
,
Lin
YJ
,
Lin
HC
, et al
.
Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity
.
N Engl J Med
.
2004
;
350
(
13
):
1304
1313
57
Nixon
PA
,
Washburn
LK
,
Schechter
MS
,
O’Shea
TM
.
Follow-up study of a randomized controlled trial of postnatal dexamethasone therapy in very low birth weight infants: effects on pulmonary outcomes at age 8 to 11 years
.
J Pediatr
.
2007
;
150
(
4
):
345
350
58
O’Shea
TM
,
Washburn
LK
,
Nixon
PA
,
Goldstein
DJ
.
Follow-up of a randomized, placebo-controlled trial of dexamethasone to decrease the duration of ventilator dependency in very low birth weight infants: neurodevelopmental outcomes at 4 to 11 years of age
.
Pediatrics
.
2007
;
120
(
3
):
594
602
59
Wilson
TT
,
Waters
L
,
Patterson
CC
, et al
.
Neurodevelopmental and respiratory follow-up results at 7 years for children from the United Kingdom and Ireland enrolled in a randomized trial of early and late postnatal corticosteroid treatment, systemic and inhaled (the open study of early corticosteroid treatment)
.
Pediatrics
.
2006
;
117
(
6
):
2196
2205

Competing Interests

This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the board of directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.