Received: 12 April 2023

DOI: 10.1002/pdi3.6

REVIEW
- -
Revised: 11 May 2023 Accepted: 12 May 2023

An updated review on systemic glucocorticoids in the

prevention and treatment of bronchopulmonary dysplasia

Xinyi Wang1,2,3,4,5 | Yuan Shi1,2,3,4,5

1
Department of Neonatology, Children's
Hospital of Chongqing Medical University, Abstract
Chongqing, China Bronchopulmonary dysplasia (BPD) is a severe chronic pulmonary disease
2
Ministry of Education Key Laboratory of affecting premature infants and their families. The main pathogenesis of BPD
Child Development and Disorders,
Chongqing, China
is the abnormal inflammatory response in immature lungs, resulting in the
3
National Clinical Research Center for distortion of lung development and influencing the formation of alveoli and
Child Health and Disorders, Chongqing, vascular structures. Based on anti‐inflammatory mechanisms, glucocorticoids
China
may reduce the incidence and mortality of BPD in premature infants, but
4
China International Science and
different types and administrations of glucocorticoids may lead to various
Technology Cooperation Base of Child
Development and Critical Disorders, short‐term or long‐term outcomes, especially the most concerning neuro-
Chongqing, China developmental abnormalities. Dexamethasone is currently recognized as a
5
Chongqing Key Laboratory of Pediatrics, first‐choice drug for BPD, but the different administration methods may affect
Chongqing, China
the efficacy and safety of the regimen. Hydrocortisone is currently considered
Correspondence to minimize both short‐term and long‐term adverse outcomes, but its effec-
Yuan Shi, Department of Pediatric
tiveness needs to be confirmed by further trials. Numerous alternative stra-
Intensive Care Unit, Children’s Hospital
of Chongqing Medical University, tegies have been proposed to reduce adverse reactions, such as moderate early
Zhongshan Road 136#, Yuzhong District, dosing, lower cumulative doses, and individualized dosing, but the high‐
Chongqing, CN 400014, China.
quality evidence is still not enough. This review is trying to summarize
Email: shiyuan@hospital.cqmu.edu.cn
some new developments in mechanisms of action, adverse effects, and other
Funding information treatment regimens of systemic glucocorticoids for the prevention and treat-
National Key Research and Development
ment of BPD in the recent few years.
Program of China, Grant/Award Number:
2022YFC2704805
Keywords
BPD, bronchopulmonary dysplasia, preterm, systemic glucocorticoids

1 | INTRODUCTION superimposed healing of mechanical ventilation (MV)‐

induced damage and respiratory distress syndrome.2
The incidence of bronchopulmonary dysplasia (BPD) is With the successful application of exogenous surfactant
still increasing each year,1 which severely affects pre- therapy, the “old BPD” mainly characterized by airway
mature infants, especially those born at less than injury, inflammation, and parenchymal fibrosis is no
28 weeks of gestation. Northway et al. were the first to longer applicable and replaced by the “new BPD”, which
describe BPD. Initially, “BPD” was utilized to describe is characterized by reduced fibrosis, airway injury, and
the pulmonary manifestations that emerge from the uniform alveolar expansion during simplification.3

-
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. Pediatric Discovery published by John Wiley & Sons Australia, Ltd on behalf of Children's Hospital of Chongqing Medical University.

Pediatric Discovery. 2023;1:e6. wileyonlinelibrary.com/journal/pdi3 1 of 9

https://doi.org/10.1002/pdi3.6
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Therefore, BPD has been redefined as lung injury in characterized by reduced fibrosis, airway damage, and
preterm infants who require supplemental oxygen for homogeneous alveolar expansion during simplification.13
more than 28 days after birth. Based on the amount of The “new BPD” primarily affects infants born at less than
supplemental oxygen required at 36 weeks postmenstrual 1500 g and 32 weeks of gestation and is now rare in in-
age (GA < 32 weeks) or after 28 days (GA ≥ 32 weeks), fants born at more than 1500 g and 32 weeks of gestation.
BPD is categorized as mild, moderate, and severe.1,2 Since 2000, some reports suggest that BPD incidence
Neonatologists worldwide have made many efforts to has begun to decline, but most studies suggest that BPD
prevent it from causing severe harm to patients and rates have remained stable or even increased over the
their families, but the currently available treatment for past 2–30 years likely due to improved survival rates for
BPD is still limited. The inflammatory response is ge- at‐risk infants with advances in modern medicine. Inci-
nerally considered to be the primary pathogenesis of dence rates of BPD for babies born 501–1500 g between
BPD,4 and thus, glucocorticoids are often used for the 1997 and 2018 have been reported at 23.2%–32.6%.14
prevention and treatment of BPD5 with their potent anti‐ There was no clinically relevant decline during this
inflammatory effects. The current clinical use of gluco- period.
corticoids for BPD mainly includes inhaled and systemic Although several individual risk factors have been
use, prenatal and postnatal administration, and postnatal identified, BPD may result from a complex interaction
glucocorticoids have been certified and proven as the only between immature lungs and multiple perinatal and
pharmacologic interventions.6 Dexamethasone and hy- postnatal exposures. Patients with BPD are at risk for
drocortisone are the most commonly used postnatal sys- chronic sequelae, including long‐term lung deficits,
temic corticosteroids. Numerous previous trials have been neurodevelopmental disorders, and late neonatal mor-
conducted to assess the best administration time and dose tality. There is evidence that many of these sequelae
of dexamethasone and hydrocortisone in the management persist into adulthood even in children born in the “new
of BPD. Unfortunately, these findings have demonstrated BPD” era.13
significant variations. In addition, systemic glucocorti- To reduce the risk of BPD, the main clinical ap-
coids (SG) have been reported to be associated with proaches are prevention of preterm birth, use of nonin-
some short‐term and long‐term adverse outcomes while vasive ventilatory measures, administration of surfactant,
lowering the risk of BPD, such as neurodevelopmental caffeine, vitamin A, and glucocorticoids, and recent
problems.7,8 Current research is focusing on whether emerging treatment strategies, such as inhaled nitric ox-
postnatal corticosteroids should be used and how to be ide and cell therapy, but their efficacy and safety need to
used effectively so that the benefits can outweigh the risks. be confirmed by further clinical trials.15
Therefore, this review aims to summarize the existing
literature and try to provide some further evidence‐based
suggestions for SG management in the prevention and 3 | MECHANISM OF ACTION OF
treatment of BPD. GLUCOCORTICOIDS

Infected lung damage, oxygen toxicity, and MV all

2 | PREVALENCE AND CLINICAL contribute to the pathogenesis of BPD in premature
FEATURES OF BPD newborns; the crucial mechanism is that the above events
cause an excessive inflammatory response.16 The in-
BPD is one of the most common sequelae of prematurity flammatory response induced in immature lungs is
and has significant prognostic implications. Birth weight essential in distorting pulmonary development. It affects
and gestational age are the two main risk factors for BPD alveolar, mesenchymal, and vascular structures, ulti-
with the incidence rising with falling birth weight and mately leading to abnormal tissue repair and arrest of
gestational age. Sepsis, intrauterine growth restriction, pulmonary development, causing newly developed BPD,
oxygen delivery, and prolonged mechanical breathing are whose pathological basis is vascular dysregulation and
additional significant risk factors.9–11 BPD affects at least defective alveolar development.4
a quarter of infants with birth weights of less than 1500 g. The excessive inflammatory response involves many
In the United States, it affects 10,000–18,000 infants per mechanisms, most studied of which are the breaking of
year, including approximately 50% of those with a birth the balance between pro‐inflammatory cytokines and
weight of less than 1000 g.12 lung development‐promoting factors, the attraction of
In the following decades, the introduction of prenatal innate immune cells to the immature lung, breaking of
glucocorticoids, milder ventilation strategies, and sur- the balance of cytokine signaling networks, phenotypic
factant therapy altered the pathophysiology of BPD, distortion of lung‐resident mesenchymal stem cells, and
replacing the original concept with a “new BPD” the dual feature of inflammatory cytokine signaling
WANG and SHI
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pathways.4 In the inflammatory response, pro‐ and thus forming the pathological basis of newly
inflammatory cytokines are overproduced, including emerging BPD.15
interleukin‐1β (IL‐1ß), interleukin‐6 (IL‐6), interleukin‐8 Glucocorticoids exert their anti‐inflammatory roles
(IL‐8), and tumor necrosis factor‐α (TNF‐α), granulocyte primarily through the transcriptional effect of the
colony‐stimulating factor (GCSF), macrophage inflam- glucocorticoid receptor (GR), which alters the transcrip-
matory proteins (MIP), and monocyte chemotactic pro- tion of numerous genes in leukocytes, including their up
teins (MCP). In contrast, anti‐inflammatory cytokines, or downregulation.5 Glucocorticoids cause a net increase
such as interleukin‐10, are downregulated.17 Meanwhile, in leukocyte numbers, resulting in decreased neutrophil
the overexpression of pro‐inflammatory mediators at- migration into tissues; they also inhibit interleukin‐2
tracts alveolar macrophages and neutrophils as well, (IL‐2) signaling, thereby suppressing T‐cell proliferation
leading to an innate immune response that induces a and inducing apoptosis; inhibit the activity of NF‐kB, a
shift from an initial M2 anti‐inflammatory state to an M1 critical transcriptional regulator of pro‐inflammatory
inflammatory state, which predominates and releases genes, thereby reducing cytokine gene expression; and
more pro‐inflammatory cytokines, continuing to enhance inhibit mast cell desmoplasia.21 The most critical mech-
the inflammatory process in the lung.18–20 At the same anism is glucocorticoid‐inhibiting transcription of many
time, the overactivation of the TGF‐β inhibits lung vital enzymes encoding pro‐inflammatory cytokines and
myofibroblast function and platelet‐derived growth factor chemokines, cell adhesion molecules, and those involved
(PDGF) receptor α‐mediated vascular endothelial growth in initiating or maintaining the host inflammatory re-
factor A (VEGFA) secretion, resulting in the dysregula- sponse.22 A more detailed understanding of the patho-
tion of vascular development. Inflammatory cytokines genesis of BPD and the mechanism of glucocorticoid
play a double role in lung development and injury. action may provide a reference to better utilize the roles
However, they may exacerbate damage of the lungs when of glucocorticoids. Figure 1 briefly summarizes the
overstimulated, resulting in distorted lung development pathogenesis of BPD and the mode of action of SG.

FIGURE 1 The pathogenesis of BPD and the mode of action of systemic glucocorticoids. BPD, bronchopulmonary dysplasia.
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4 | APPLICATIONS OF SYSTEMIC early in life (12 h), and a prolonged course (49 days) of
GLUCOCORTICOIDS Dexamethasone resulted in short‐term adverse effects,
such as transient hyperglycemia, hypertension, sepsis,
Glucocorticoids have potent anti‐inflammatory functions hyperparathyroidism, and growth retardation.3 In 2000,
and are pivotal in respiratory epithelial cell development Yeh et al. reported a significant decrease in indicators
and lung maturation. Therefore, these efficient anti‐ of neurodevelopment, including motor skills and IQ
inflammatory drugs have long been used for BPD. Since scores, in children receiving dexamethasone therapy
the 1980s, we often use SG in managing infants with BPD early in their life, causing awareness of early dexameth-
in clinical practice.1 Systemic glucocorticosteroids, which asone application that may have long‐term negative
largely use dexamethasone and hydrocortisone, and consequences—neurodevelopmental disorders. There-
inhaled glucocorticosteroids, which include beclometha- fore, early SG therapy for BPD is not recommended.
sone, budesonide, fortikasone, fornizotide, and dexa- In 2021, to verify the effect of dexamethasone and
methasone, are the two major classes of hydrocortisone during the first six days, Doyle et al.
glucocorticosteroids most commonly used in clinical elected 32 randomized controlled trials involving 4395
settings.23 preterm newborns. The main results showed that early
The current clinical protocols for prophylaxis and SG had little or no overall effect on mortality; on the
curing BPD with glucocorticoids are prenatal and post- contrary, early SG increased the risk of cerebral palsy
natal glucocorticoids, including systemic and inhaled (CP), gastrointestinal perforation, and combined mortal-
glucocorticoids. However, the risk/benefit ratio of their ity. Besides, strong data showed that dexamethasone
use remains controversial. Antepartum glucocorticoid alone and early SG had the same effect on the combined
administration has been proven to promote fetal lung outcome of mortality or BPD at 36 weeks. Furthermore,
maturation in preterm infants, reducing respiratory in the Doyle et al. study, early dexamethasone use had
distress syndrome and mortality.24 However, there are no negligible influence on the combined outcome or BPD,
recent developments regarding their effect on lowering contrary to the prevailing view that early dexamethasone
the BPD incidence rate, so they are not highlighted in this appears to increase this combined outcome.26
article. Postnatal systemic administration (PNS) of glu- While there was substantial evidence that hydrocorti-
cocorticoids reduces the incidence and severity of BPD. sone alone could lower mortality, it had no impact on
However, it is accompanied by long‐term neuro- reducing the total incidence of BPD at postmenstrual age
developmental and respiratory consequences, so routine (PMA) 36 weeks (high‐certainty evidence). Contrarily,
drug administration is not recommended. Glucocor- hydrocortisone had little influence on the combined
ticoids may lead to an increased risk of neuro- outcome of death and decreased the combined outcome of
developmental disorders.24 Alternative glucocorticoid mortality or BPD at 36 weeks (high‐certainty evidence).26
regimens have been investigated over the last few years, Briefly, Doyle et al. concluded that early SG is helpful as
covering the timing and duration of steroid initiation, well as harmful for BPD in preterm children with a high‐
pulsed or non‐pulsed administration, and cumulative risk condition and that administering dexamethasone
cortisol regimens to maximize the benefits of glucocor- early was relevant to both advantageous and detrimental
ticoids and to avoid short‐term and long‐term negative effects but did not seem to lower mortality. The benefit of
consequences.7 Hydrocortisone is a synthetic cortisol early hydrocortisone use for BPD control has not been
analog with glucocorticoid activity, but it exhibits saline clinically proven, while it perhaps will help prevent death
corticosteroid activity at supraphysiological doses. While without impairing neurodevelopment. Because the evi-
hydrocortisone has nothing to do with long‐term detri- dence is insufficient, further trials are needed on neuro-
mental neurodevelopmental impacts, its early use developmental disorders and other long‐range impacts.
might reduce the incidence or death of BPD.25 There is In 2022, Thangaraj et al. concluded that early sys-
insufficient evidence to demonstrate the efficacy of hy- temic steroid use, whether dexamethasone or hydrocor-
drocortisone against BPD, and thus further trials are tisone, was associated with a lower risk of BPD or
needed. mortality (moderate strength of evidence), and strong
data indicated that early systemic dexamethasone use
was associated with a lower risk of BPD or mortality at
4.1 | Early administration of SG PMA 36 weeks PMA, but that use of dexamethasone early
was associated with a poor long‐term neurologic prog-
Initially, SG were first applied to facilitate extubation. In nosis.6 Thus, up to now, there remains an international
the 1990s, when Dexamethasone began to be used, high consensus against the application of systemic dexameth-
cumulative doses (i.e., 6.16 mg/kg) were administered asone in the first week of life in neonates.
WANG and SHI
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4.2 | Late administration of SG systemic steroids for BPD after the first week in a retro-
spective cohort study.28 The results showed no significant
In 2021, Doyle et al. evaluated 21 randomized controlled correlation between mortality or the composite outcome
trials involving 1382 infants, incorporating two random- of sNDI and the PNA of sPNS. Beyond that, a delay in the
ized controlled trials (435 infants) evaluating hydrocor- timing of the initial application of systemic steroids
tisone alone. High‐certainty data showed a significant among survivors might have increased the odds of sNDI
cut‐down in mortality with late SG, and the incidence and motor delay, but confounding factors like birth
of BPD also decreased at 36 weeks of PMA (moderate‐ weight, gestational age, and whether they were affected
certainty data). The same result was observed for the by exposure to antenatal steroids have not been excluded,
combined outcome of mortality or BPD at 36 weeks of so the effects need to be proven in additional clinical
PMA. For another, the high‐certainty data showed that trials. Noura et al. analyzed 3662 newborns of whom 901
late SG had almost no effect on CP and mortality or the (24.6%) were diagnosed with BPD. According to Noura
combined outcome. Dexamethasone has been demon- et al., PNS was linked to a significant rise in the incidence
strated in subgroup analysis to reduce the incidence of of dyskinesia in the BPD group at the highest risk despite
BPD at PMA 36 weeks, but hydrocortisone has not been the fact that this effect persisted regardless of the steroid
shown to have the same impact. Therefore, Doyle et al. utilized.29 Regiment with dexamethasone or betametha-
concluded that late SG is beneficial for BPD, and late SG sone was connected with an additional risk of cognitive
reduces mortality or BPD at 36 weeks of PMA without abnormalities, whereas no danger of neurodevelopmental
significantly increasing CP.27 However, more prognosis abnormalities was observed with hydrocortisone. This
data are lacking; thus, late SGs ought to be used with observation has yet to be confirmed in a randomized
caution in newborns who are unable to be weaned from controlled trial. Meanwhile, the severity of BPD may also
mechanical breathing, beginning at exceeding 7 days of have an impact on the neurodevelopmental outcome,
age and for the shortest possible time and dose. which is related to both glucocorticoid usage and BPD
In 2022, a systematic review and meta‐analysis of 14 severity. In a single‐center retrospective cohort study of
SG regimens revealed that the most appropriate regimen GA <30 weeks patients who survived to 36 weeks of
of treatment for lowering mortality or the development of PMA, Trixie et al. made the following assertions: NDI
BPD at 36 weeks of PMA was moderately early use (8– was statistically significant for all BPD severities
14 days), moderate cumulative dose (2–4 mg/kg), and compared with babies without BPD; among all infants
short duration (<8 days).6 There was no evidence that the with BPD, the risk of NDI increased 5‐fold between 2 and
evaluated interventions were associated with the risk of 5 years of age; the strength of the association between
neurodevelopmental disorders. Nevertheless, no studies NDI and BPD severity did not change over time.23
are available to research clinical diversities in the Second, postnatal systemic steroid use increases the
occurrence of remote neurologic adverse events. Inter- severity of retinopathy of prematurity (ROP). ROP is a
national advisory bodies currently recommend an accu- leading reason of childhood blindness in developed
mulated dose of 1–2 mg/kg of dexamethasone for countries, and it is now accepted that oxygen supply and
exceeding 7–10 days.7 Overall, late SG is thought to be prematurity are the main risk factors for ROP.30 Other
favorable for BPD in preterm newborns, lowering mor- identified risk factors include MV, BPD, intraventricular
tality and incidence of BPD at 36 weeks of PMA, although hemorrhage (IVH), necrotizing tiny bowel colitis (NSC),
there is little evidence to support its long‐term impact on blood transfusions, and sepsis. Postnatal systemic steroids
neurologic events. Therefore, further clinical trials are are known to increase the risk of ROP. However, it is
needed to evaluate the appropriate start date, cumulative not known whether the accumulated dose and type of
dose, and duration of treatment. postnatal systemic steroids are connected with the
development and severity of ROP.30 Katsuo included 75
newborns born at <28 postmenstrual weeks (PMA) in a
4.3 | Adverse reactions of SG multifactorial logistic regression analysis showing that
gross systemic steroid dose was the single risk factor for
The first is the most concerning issue of neurological severe ROP requiring photocoagulation (PC) and that a
development. Hemasree et al. examine the relationship cutoff value of 8.95 mg/kg for postnatally administered
between postnatal age (PNA) at the first use of systemic systemic steroids could be used as a valuable marker for
steroids at 29 weeks gestation and mortality at corrected predicting severe ROP requiring PC.31
age 18–24 months or significant neurodevelopmental Third, postnatal glucocorticoid use affects renal func-
disorders (sNDI) at corrected age 18–24 months by tion and blood pressure in very low birth weight (VLBW)
analyzing follow‐up data from 6200 babies exposed to neonates. In a retrospective cohort study, Christiane et al.
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examined medical records of infants born from January Glucocorticoid regimens have been studied, including
2015 to December 2019 (≤35 weeks GA) to examine the the timing of treatment initiation, cumulative dose effect,
cumulative dose and duration of glucocorticoids on blood pulse dosing, and individualized regimens. First, regarding
pressure and renal function in VLBW infants. They the timing of treatment initiation, Onland et al. included 16
discovered that when cumulative steroid dose rose, it tests, five of which included 797 newborns, examining
caused systolic blood pressure and significantly increased early (<7 days) versus moderately early (8–14 days) or
creatinine clearance in newborns being discharged from delayed (>3 weeks) initiation of dexamethasone therapy.7
the hospital. It suggests that the duration of postnatal Another study found no variation in the combined out-
steroid use and accumulated dose are connected with comes of death at PMA 36 weeks or occurrence of BPD,
increased systolic blood pressure. Although this effect PMA at 28 days, and death at PMA 36 weeks between the
may disappear after discontinuation of treatment, so we allocation groups. For the incidence of BPD at 28 days PMA
should pay attention to prevent long‐term cardiovascular and 36 weeks PMA, newborns with delayed start (>21 days
and renal diseases. Beyond that, in susceptible infants, PMA) were more numerous than those with a moderately
increases in creatinine clearance and GFR in infants early start (8–21 days PMA).8 There are no neuro-
exposed to postnatal steroids have the possibility to cause developmental findings for infants whose medications
short‐term improvements in renal function. This effect were started at different times.
can mask the fact that renal injury is occurring. Animal Second, for the effect of cumulative dose, a total of 306
studies have shown that exposure to high doses of gluco- participants were enrolled in eight cumulative dose
corticoids leads to renal cyst formation, renal unit loss, studies. According to cumulative dose, these studies were
and renal morphogenesis.32 We should be more cautious divided into three categories: low cumulative dose (2 mg/
when using postnatal cortisol in these extremely fragile kg), medium cumulative dose (between 2 and 4 mg/kg),
newborns since its effects on renal function are currently and high cumulative dose (>4 mg/kg). No discrepancy
underappreciated. existed between the high and low accumulated doses
Finally, postnatal use of cortisol may result in concerning abnormal neurodevelopmental outcomes
metabolic disturbances. It has been demonstrated in assessed in BPD survivors, composite outcome, death, or
animal experiments that postnatal administration of low BPD. On the contrary, there was no proof that a high
doses of dexamethasone to neonatal rats results in cumulative dose increased the incidence of CP when
growth retardation and impaired thermogenesis, which compared to a low‐dose strategy.
causes cold intolerance in neonatal pups. The cause of The danger of CP was more severe with the highest
these impacts could be related to interference with accumulated dose than with the medium accumulated
brown adipocyte differentiation.33 In addition, by dose. In subgroup analyses comparing high‐dose dexa-
recording daily temperature changes in infants on glu- methasone with the medium accumulated dose regimen,
cocorticoids, postnatal systemic corticosteroid use was there was more evidence of an elevated risk of death or
connected with more significant temperature fluctua- CP with the highest cumulative dose. There was no dif-
tions, suggesting that glucocorticoids may impair ference in the primary outcome between the moderate
neonatal thermoregulation. and low cumulative doses.
Third, to the pulsed‐dose studies, which essentially
refer to the administration of 0.5 mg/kg/day of dexa-
4.4 | Different SG regimens methasone for 3 days followed by 7 days without corti-
costeroid therapy, two studies comparing pulsed therapy
Because hydrocortisone's ability to minimize the occur- with a continuous regimen of reduced doses showed an
rence of BPD is unknown and dexamethasone's short‐ increased risk of death or BPD when using pulsed ther-
term and long‐term effects remain a concern, there has apy with no difference in primary outcome or long‐term
recently been a series of clinical searches for alternative neurodevelopmental outcomes.34
components and SG regimens. Trials have been con- Finally, as for the research on individualized regi-
ducted with betamethasone, prednisolone, or methyl- mens, it has been demonstrated that BPD has different
prednisolone as alternatives to dexamethasone and pathological types and that patients differ in terms of
hydrocortisone. Unfortunately, the quality of the data is gestational age, birth weight, prenatal steroid exposure,
too low to indicate their connection to a decline in and mechanical or non‐mechanical ventilation, which
mortality and the incidence rate of BPD. As a result, the means that the characteristics of BPD vary from indi-
Canadian Pediatric Society's recent position statement vidual to individual.35 In response to this characteristic,
does not suggest using these agents. individualized drug administration has been proposed in
WANG and SHI
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recent years. However, a systematic review and meta‐ in newborns born at less than 32 weeks, whereas high
analysis did not show significant differences between COE showed that the early use of low doses of hydro-
different dexamethasone regimens. The duration of MV cortisone had something to do with a reduced danger of
was the only referenced short‐term outcome that differed, BPD or mortality at 36 weeks. The moderate COE sug-
and it was significantly reduced by personalized and gests that the late use of hydrocortisone helps reduce the
adjusted dosage regimens. risk of BPD or mortality at 36 weeks of PMA; the benefit
of late hydrocortisone use is not supported by random-
ized controlled trials.6 The efficacy and safety of hydro-
4.5 | Applications of systemic cortisone were evaluated by Onland et al., who divided
hydrocortisone infants into three groups based on start times, cumulative
doses, and administration times. Although the obvious
Hydrocortisone is a synthetic cortisol analog with distinction in the frequency of BPD and the distribution
glucocorticoid activity but exhibits saline corticosteroid of BPD severity between the hydrocortisone group and
activity at physiologic doses. The current clinical practice the control group were unfounded, the data indicated
is early use with low doses of hydrocortisone, which at that the extubation rate was more significant on day 3 in
low doses can circumvent some of the short‐term and the hydrocortisone group than in the placebo group.7 The
long‐term adverse impacts of dexamethasone. However, scientists also discovered that babies receiving hydro-
the efficacy and safety of hydrocortisone have yet to be cortisone treatment had a higher risk of having severe
fully established. IVH and necrotizing enterocolitis (NEC), which may
In a systematic review and meta‐analysis, high COE be related to higher cortisol levels. More randomized
showed that hydrocortisone administration in the first controlled trials are needed to help identify these highly
week was relevant to a reduced risk of BPD or mortality susceptible babies so that clinical decisions about the

TABLE 1 Pathologic and clinical features of different systemic glucocorticoids.

Type of treatment Evidence Clinical features Comment

Early systemic Large meta‐analyses26 Almost no effect on death/ Not recommended

glucocorticoids BPD at 28 days PNA
(dexamethasone and 36 weeks PMA
or hydrocortisone) ↑Cerebral palsy
↑Gastrointestinal perforation
↑Combined mortality
↓Failure to extubate
↑Hyperglycemia
↑Hypertension
Early systemic Systematic review ↓BPD/mortality Not recommended,
hydrocortisone and meta‐analysis7,20 ↑Extubation rate needing
↑Severe IVH and NEC further studies
↑Hyperglycemia
↑Hypertension
Doubt on neurodevelopment
Late systemic Large meta‐analyses27 ↓BPD at 28 days PNA and To evaluate the benefit
glucocorticoids 36 weeks PMA and the risk
(dexamethasone ↓Mortality
or hydrocortisone) ↑Extubation rate
Almost no effect on cerebral
palsy and the combined outcome
↓IVH
↑Hyperglycemia
↑Hypertension
Late systemic Meta‐analysis and RCT6,7 ↓BPD or mortality but RCT does not support. Not recommended
hydrocortisone
Abbreviations: BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; PMA, postmenstrual age; PNA,
postnatal age; RCT, randomized controlled trial.
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advantages and disadvantages of tailoring hydrocortisone pulsed dosing, and individualized dosing, has not yet
treatment can be made. In these highly susceptible produced high‐quality evidence of their efficacy and
newborns, the potentially fatal negative consequences safety, and further clinical trials are necessary. On ac-
linked to hydrocortisone treatment are of greater concern count of the available evidence, careful clinical judgment
than the advantages of improved BPD‐free survival.20 It is needed to weigh the benefits and risks of SG in the
is unknown whether using hydrocortisone after the sec- management of BPD.
ond week of life improves survival in the absence of BPD
and the absence of adverse neurodevelopmental ef- A U T H OR CON T R I B U T I ON S
fects. The survival without moderate or severe BPD at Xinyi Wang collected and sorted out the literature and
36 weeks of PMA with hydrocortisone was not statisti- wrote the first manuscript draft. Yuan Shi was the
cally different from that of the placebo group, according guarantor and revised it critically for important intellec-
to a study of 800 babies under 30 weeks' GA who were tual content.
intubated for at least seven days at 14–28 days (396 of
whom received hydrocortisone).25 That hydrocortisone A C KN OW L E DG M E N T S
cure did not alter the severity of BPD assessed then, All the authors provided intellectual input, contributed to
which could be related to identified inflammatory dam- manuscript revisions, and approved the final version.
age at late treatment. This article was completed with the support of “National
Hydrocortisone now appears promising for improving Key Research and Development Program of China”
short‐term prognosis without affecting long‐term neuro- (2022YFC2704805).
development, which may be related to its mechanism of
action. In animal studies, hydrocortisone did not show C O NF L I C T OF I N T E R E S T S T AT E ME N T
brain growth‐limiting impacts or apoptotic impacts on Yuan Shi is the Deputy Editor‐in‐Chief of Pediatric Dis-
the hippocampus like dexamethasone, so hydrocortisone covery. He was excluded from all editorial decision‐
could be able to replace dexamethasone in terms of long‐ making related to the acceptance of this article for pub-
term neurodevelopmental outcomes.36 However, the lication. The remaining authors declare no conflict of
long‐term safety of hydrocortisone has not been demon- interest.
strated. Few adverse effects have been reported with
hydrocortisone with short‐term adverse effects being D A T A A V AI L AB I LI T Y S T AT E M EN T
hyperglycemia and hypertension. Concerns about long‐ Data sharing is not applicable to this article as no datasets
term neurodevelopmental outcomes, many trials have were generated or analyzed during the current study.
found no proof of long‐term neurologic damage through
follow‐up visits of neurocognitive outcomes at 2 and E T H I CS S T A T EM E N T
5 years of age. More extended follow‐up periods are Not applicable.
needed to determine the long‐term safety of hydrocorti-
sone. Table 1 summarizes the current clinical features O R C ID
regarding the use of SG. Xinyi Wang https://orcid.org/0009-0000-3042-7206

5 | CONCLUSION R E F E R E N CE S
1. Gilfillan M, Bhandari A, Bhandari V. Diagnosis and manage-
ment of bronchopulmonary dysplasia. BMJ. 2021;375:n1974.
Postnatal SG, particularly dexamethasone, may reduce
2. Northway WH, Rosan RC, Porter DY. Pulmonary disease
the incidence and severity of BPD. However, the early following respirator therapy of hyaline‐membrane disease. N
use of dexamethasone often leads to long‐term abnormal Engl J Med. 1967;276(7):357‐368.
neurodevelopmental abnormalities, and its routine use is 3. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J
not recommended. The early use of hydrocortisone may Respir Crit Care Med. 2001;163(7):1723‐1729.
be associated with a low risk of BPD or mortality, and 4. Holzfurtner L, Shahzad T, Dong Y, et al. When inflammation
no obvious neurodevelopmental abnormalities have meets lung development‐an update on the pathogenesis of
been observed in children aged 2–5 years. Late SG re- bronchopulmonary dysplasia. Mol Cell Pediatr. 2022;9(1):7.
5. Coutinho AE, Chapman KE. The anti‐inflammatory and im-
duces mortality or BPD at PMA of 36 weeks without a
munosuppressive effects of glucocorticoids, recent develo-
significant increase in CP. However, a longer follow‐up pments and mechanistic insights. Mol Cell Endocrinol.
is still needed to ensure long‐term safety. Current 2011;335(1):2‐13.
research on alternative regimens to glucocorticoids, such 6. Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, et al.
as alternative formulations, lower cumulative doses, Interventions to prevent bronchopulmonary dysplasia in
WANG and SHI
- 9 of 9

preterm neonates: an umbrella review of systematic re- neurodevelopmental outcome at 2 and 5 years corrected age. J
views and meta‐analyses. JAMA Pediatr. 2022;176(5): Pediatr. 2022;243:40‐46.e2.
502‐516. 24. Strashun S, Seliga‐Siwecka J, Chioma R, et al. Steroid use for
7. Onland W, van de Loo M, Offringa M, van Kaam A. Systemic established bronchopulmonary dysplasia: study protocol for a
corticosteroid regimens for prevention of bronchopulmonary systematic review and meta‐analysis. BMJ Open. 2022;12(6):
dysplasia in preterm infants. Cochrane Database Syst Rev. e059553.
2023;3(3):CD010941. 25. Watterberg KL, Walsh MC, Li L, et al. Hydrocortisone to
8. Yao S, Uthaya S, Gale C, Modi N, Battersby C, UK Neonatal improve survival without bronchopulmonary dysplasia. N Engl
Collaborative (UKNC). Postnatal corticosteroid use for pre- J Med. 2022;386(12):1121‐1131.
vention or treatment of bronchopulmonary dysplasia in En- 26. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL, Soll R.
gland and Wales 2012‐2019: a retrospective population cohort Early (<7 days) systemic postnatal corticosteroids for preven-
study. BMJ Open. 2022;12(11):e063835. tion of bronchopulmonary dysplasia in preterm infants.
9. Tracy MK, Berkelhamer SK. Bronchopulmonary dysplasia and Cochrane Database Syst Rev. 2021;10(10):CD001146.
pulmonary outcomes of prematurity. Pediatr Ann. 2019;48(4): 27. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Late
e148‐e153. (≥7 days) systemic postnatal corticosteroids for prevention of
10. Voynow JA. “New” bronchopulmonary dysplasia and chronic bronchopulmonary dysplasia in preterm infants. Cochrane
lung disease. Paediatr Respir Rev. 2017;24:17‐18. Database Syst Rev. 2021;11(11):CD001145.
11. Jensen EA, Edwards EM, Greenberg LT, Soll RF, Ehret DE, 28. Kandraju H, Jasani B, Shah PS, et al. Timing of systemic ste-
Horbar JD. Severity of bronchopulmonary dysplasia among roids and neurodevelopmental outcomes in infants < 29 weeks
very preterm infants in the United States. Pediatrics. 2021; gestation. Children. 2022;9(11):1687.
148(1):e2020030007. 29. Zayat N, Truffert P, Drumez E, et al. Systemic steroids in
12. McGrath‐Morrow SA, Collaco JM. Bronchopulmonary preventing bronchopulmonary dysplasia (BPD): neurode-
dysplasia: what are its links to COPD? Ther Adv Respir velopmental outcome according to the risk of BPD in the
Dis. 2019;13:1753466619892492. EPICE cohort. Int J Environ Res Publ Health. 2022;19(9):5600.
13. Salimi U, Dummula K, Tucker MH, Dela Cruz CS, Sampath V. 30. Athikarisamy SE, Lam GC, Cooper MN, Strunk T. Retinopathy
Postnatal sepsis and bronchopulmonary dysplasia in prema- of prematurity and placental histopathology findings: a retro-
ture infants: mechanistic insights into "New BPD". Am J Respir spective cohort study. Front Pediatr. 2023;11:1099614.
Cell Mol Biol. 2022;66(2):137‐145. 31. Tao K. Postnatal administration of systemic steroids increases
14. Omar SA, Abdul‐Hafez A, Ibrahim S, et al. Stem‐cell therapy severity of retinopathy in premature infants. Pediatr Neonatol.
for bronchopulmonary dysplasia (BPD) in newborns. Cells. 2022;63(3):220‐226.
2022;11(8):1275. 32. Mhanna C, Pinto M, Koechley H, et al. Postnatal glucocorti-
15. Shahzad T, Radajewski S, Chao CM, Bellusci S, Ehrhardt H. coid use impacts renal function in VLBW neonates. Pediatr
Pathogenesis of bronchopulmonary dysplasia: when inflam- Res. 2022;91(7):1821‐1826.
mation meets organ development. Mol Cell Pediatr. 2016; 33. Chang YS, Hou SY, Yu SS, et al. Postnatal dexamethasone
3(1):23. therapy impairs brown adipose tissue thermogenesis and
16. Staude B, Oehmke F, Lauer T, et al. The microbiome and autophagy flux in neonatal rat pups. Theranostics. 2022;12(13):
preterm birth: a change in paradigm with profound implica- 5803‐5819.
tions for patho‐physiologic concepts and novel therapeutic 34. Szabó H, Baraldi E, Colin AA. Corticosteroids in the preven-
strategies. BioMed Res Int. 2018;2018:7218187. tion and treatment of infants with bronchopulmonary dy-
17. Martonik D, Parfieniuk‐Kowerda A, Rogalska M, Flisiak R. splasia: Part I. systemic corticosteroids. Pediatr Pulmonol.
The role of Th17 response in COVID‐19. Cells. 2021;10(6):1550. 2022;57(3):600‐608.
18. Sakaria RP, Dhanireddy R. Pharmacotherapy in broncho- 35. Pierro M, Van Mechelen K, van Westering‐Kroon E, Villamor‐
pulmonary dysplasia: what is the evidence? Front Pediatr. Martínez E, Villamor E. Endotypes of prematurity and phe-
2022;10:820259. notypes of bronchopulmonary dysplasia: toward personalized
19. Choi Y, Rekers L, Dong Y, et al. Oxygen toxicity to the im- neonatology. J Personalized Med. 2022;12(5):687.
mature lung‐Part I: pathomechanistic understanding and 36. Baud O, Maury L, Lebail F, et al. Effect of early low‐dose
preclinical perspectives. Int J Mol Sci. 2021;22(20):11006. hydrocortisone on survival without bronchopulmonary
20. Behnke J, Dippel CM, Choi Y, et al. Oxygen toxicity to the dysplasia in extremely preterm infants (PREMILOC): a
immature lung‐Part II: the unmet clinical need for causal double‐blind, placebo‐controlled, multicentre, randomised
therapy. Int J Mol Sci. 2021;22(19):10694. trial. Lancet. 2016;387(10030):1827‐1836.
21. Chapman KE, Coutinho A, Gray M, Gilmour JS, Savill JS,
Seckl JR. Local amplification of glucocorticoids by 11‐
hydroxysteroid dehydrogenase type 1 and its role in the in- How to cite this article: Wang X, Shi Y. An
flammatory response. Ann N Y Acad Sci. 2006;1088:265‐273.
updated review on systemic glucocorticoids in the
22. Hardy RS, Rabbitt EH, Filer A, et al. Local and systemic
glucocorticoid metabolism in inflammatory arthritis. Ann
prevention and treatment of bronchopulmonary
Rheum Dis. 2007;67(9):1204‐1210. dysplasia. Pediatr Discov. 2023;1(1):e6. https://doi.
23. Katz TA, Vliegenthart RJS, Aarnoudse‐Moens CSH, org/10.1002/pdi3.6
et al. Severity of bronchopulmonary dysplasia and