Current and Emerging Therapies for Prevention and Treatment of Bronchopulmonary Dysplasia in Preterm Infants

Abstract

Although advances in the care of extremely preterm born infants have yielded improvements in survival and reductions in important morbidities, rates of bronchopulmonary dysplasia (BPD) have remained relatively unchanged. As BPD can have a long-lasting impact on the quality of life for survivors of prematurity and their families, this remains a continuing challenge. Treatments that have consistently shown efficacy in preventing either BPD or the composite outcome of BPD and death prior to 36 weeks post menstrual age (PMA) in large-scale randomized clinical trials (RCTs) include caffeine [adjusted odds ratio aOR for BPD, 0.63; 95% confidence interval (95% CI) 0.52–0.76; p < 0.001)], vitamin A [relative risk (RR) for death or BPD 0.89; 95% CI 0.80–0.99], low-dose hydrocortisone in the first week of life [OR for survival without BPD, 1.45; 95% CI 1.11–1.90; p = 0.007], and post-natal dexamethasone [RR for BPD or mortality; 0.76; 95% CI 0.66–0.87]. Although early caffeine therapy is now a widely used strategy to prevent BPD, the potentially severe side effects of post-natal glucocorticoids and the concerns regarding the cost–benefit of vitamin A have led to inconsistent use of these drugs in clinical practice. Inhaled bronchodilators and diuretics provide differing degrees of symptomatic relief for patients according to their phenotypic pattern of lung injury; however, these medications do not prevent BPD. Currently available pharmaceuticals do not sufficiently address the degree of structural immaturity and immune dysregulation that is present in the growing population of survivors born prior to 25 weeks gestational age. In this article, we provide both an evidence-based summary of pharmacological treatments currently available to prevent and manage BPD and a discussion of emerging therapies that could help preserve normal lung development in infants born preterm.

Key Points

Except for caffeine, all other current drugs being used for management of BPD such as systemic glucocorticoids, vitamin A, inhaled corticosteroids, diuretics and inhaled broncodilators have variable use and efficacy.

Emerging therapies for prevention/treatment of BPD that have been clinically tested include high-dose vitamin C administered to pregnant smokers, N-acetylcysteine, stem cells, intratracheal budesonide mixed with surfactant and IGF1/IGFBP3.

Preclinical studies of AVR-48, micro-RNA-based therapies, ciclesonide, and inhaled probiotics have shown promise for potential use to prevent BPD in preterm infants.

Introduction

Bronchopulmonary dysplasia (BPD) is a multifactorial pulmonary condition that affects approximately 50,000 preterm infants each year in the USA [1]. Currently defined by the Neonatal Research Network (NRN) as continued dependence on respiratory support until at least 36 weeks post menstrual age (PMA) [2], BPD occurs most frequently in extremely preterm (EP) infants born < 28 weeks gestational age (GA) [3]. BPD is associated with a higher risk for hospital readmission, neurodevelopmental impairment (NDI), and mortality [4]. Infants with BPD incur higher healthcare costs during their initial hospitalization [5] and outpatient course [4, 6] compared with those off respiratory support by 36 weeks PMA. Although the severity of respiratory symptoms improves with age for most patients, BPD has been linked to reduced exercise tolerance [7] and quality of life [8] in children and adults. Data from the US NRN and other developed nations indicate that, while survival of EP  infants continues to improve, rates of BPD have either remained static or slightly increased [9–11]. BPD continues to place significant burden on survivors of prematurity, their families, and society, and new approaches are urgently needed to address this debilitating condition. Challenges in finding novel therapies to prevent or mitigate BPD severity include the marked phenotypic heterogeneity [12] and an inability to identify the contributions of specific pathological mechanisms at an early stage in the disease [13]. Interventions that have proven to be successful in preventing or reducing the severity of BPD in randomized clinical trials (RCTs) such as caffeine [14], vitamin A [15], and post-natal steroids [16, 17] either do not appear to show equal benefit for all preterm infants or may be associated with potentially unwanted side effects. BPD, as defined above, has been shown to correlate with adverse outcomes in early life [18]; however, it is unclear whether interventions that reduce oxygen dependency at 36 weeks have a significant impact on adult health parameters. In this review, we outline the evidence behind current pharmacological treatments and describe novel therapies under development that may be used to prevent BPD in the future.

Pathology and Pathogenesis of BPD

BPD was initially described as a fibrocystic lung condition occurring predominantly in infants born during the third trimester of pregnancy who required aggressive management of respiratory distress syndrome (RDS) [19]. Other pathological findings included bronchial cell metaplasia, increased muscularization of the pulmonary vasculature and cor pulmonale [19]. Advances such as antenatal steroid administration, surfactant replacement therapy, and improvements in respiratory support technology have made it possible for extremely preterm infants with lungs in the late canalicular and early saccular phases of development to survive the RDS phase, often without exposure to high levels of invasive positive pressure ventilation or supplemental oxygen. As a result, the typical histological features of the disease have altered into a picture characterized by impaired alveolarization with a relative paucity of oversized airspaces [20], milder but more diffuse degree of septal fibrosis [20], dysregulated vascular growth with abnormal leaky capillaries [21, 22], and pulmonary edema [20, 22, 23]. Excessive muscularization of the peripheral airways coupled with edema generated by inflammatory responses [24] increases the resistance of the respiratory system and contributes to the obstructive pattern of lung disease most frequently observed in people with BPD at all ages [25–27]. Preterm birth, coupled with exposure to invasive mechanical ventilation (IMV) has the potential to impair the development of central airways [28]. This can lead to tracheomalacia, bronchomalacia, tracheomegaly, or subglottic stenosis [28, 29], predisposing affected infants to increased morbidity and mortality [30, 31].

Although the need for respiratory support rarely lasts beyond early childhood, there is evidence that disturbances in early lung development put individuals with BPD at increased risk of developing chronic obstructive airways disease [26]. In addition to early life factors such as degree of prematurity and intrauterine growth restriction or IUGR [32], lower respiratory tract infections [33], suboptimal housing conditions [34, 35], and adverse environmental exposures [36] make significant contributions to long-term pulmonary morbidity in those born preterm. Further work is needed to understand the evolution of lung disease in survivors of prematurity following discharge to identify interventions that can optimize ongoing development.

The extent to which the airspaces, pulmonary vasculature, interstitial tissues, and conducting airways are affected varies between individuals, leading to marked phenotypic heterogeneity[12].

Genetic predisposition [37], features of the in utero environment, and post-natal exposures all can have an impact on respiratory development; however, GA at birth remains the most important factor determining the risk for and severity of BPD [38]. This finding is unsurprising as the need for deleterious exposures such as supplemental oxygen and IMV is more likely for individuals with a more structurally and functionally immature respiratory system. Infants born EP, particularly those delivered < 24 weeks GA, are also at higher risk of other major morbidities such as necrotizing enterocolitis (NEC), sepsis, and prolonged patency of the ductus arteriosus (DA) that increase the risk for BPD [39]. Figure 1 provides a summary of how various pre- and post-natal exposures influence the development of BPD. Broadly, these insults can be categorized into those that disrupt the delicate balance of immune regulation leading to inflammation, those that contribute to abnormal cell growth and differentiation, and those that have a deleterious effect on cellular metabolism. These processes are linked and overlapping as normal lung development is dependent on intricate paracrine communication between epithelial, endothelial, and interstitial cells [40]. Interventions that only address one category of pathogenic responses such as inflammation are unlikely to be sufficient to prevent or mitigate abnormal lung development in the most immature infants. Treatments with multifaceted effects administered early in the neonatal intensive care unit (NICU) course are more likely to have a significant impact on outcomes for the infants at highest risk for BPD. A recognized limitation of currently used clinical definitions of BPD is the relative lack of information given regarding the specific phenotype of disease. Early identification of infants at risk of, or who have already developed the different specific BPD phenotypes described in Fig. 1, has the potential to guide treatment more effectively [12]. For example, features in the perinatal history such as placental insufficiency and IUGR [41], combined with findings on echocardiogram performed at 1 week of life [42], are helpful in identifying infants at risk of a later diagnosis of BPD associated pulmonary hypertension. Pulmonary function tests can be useful in identifying patients with established BPD who may respond more effectively to bronchodilator therapies [43]. Table 1 provides an updated version of a previously published summary of currently used pharmacological agents, including the level of evidence supporting their use and recommendations based on the US Preventive Services Task Force grading [44].

Fig. 1.

Extreme preterm birth is associated with both immune dysregulation and structural lung immaturity that may necessitate support with invasive mechanical ventilation and supplemental oxygen. Varying combinations of adverse pre- and post-natal environmental exposures together with the unique genetic make-up of individuals and variable epigenetic responses lead to the presence of different BPD phenotypes. As normal lung development is dependent on communication between different cell types, insults to epithelial, endothelial, or interstitial tissues can cause dysregulated growth of adjacent structures. This leads to the development of mixed phenotypes of lung disease. Abx, antibiotics; BPD, bronchopulmonary dysplasia; IMV, invasive mechanical ventilation; IUGR, intrauterine growth restriction; NEC, necrotizing enterocolitis; O₂, oxygen

Table 1.

Summary of medications used to prevent and/or manage BPD with levels of evidence and recommendations for use in clinical practice

Phase of care	Treatment	Current evidence	Evidence level	Recommendation	Considerations
Early (≤ 7days)	Caffeine	Receipt of caffeine within the first 3 days of life reduces the risk of BPD in preterm infants with birthweight 500g-1250g [aOR, 0.63; (95% CI 0.52–0.76; p < 0.001), NNT = 9.5 (95% CI 6.7–16.4)] [209]	I	A	Side effects include tachycardia, GI disturbances
	Vitamin A	Vitamin A given in the first 4 weeks of life reduces the risk of BPD [RR 0.87 (95% CI 0.77–0.99), NNT = 11, (95% CI 6–100; five studies, 986 infants)] [210]	I	A	High-cost treatment with relatively low effect size Involves repeated IM injections Not associated with improved long-term outcomes
	Low dose hydrocortisone	Receipt of total dose of 8.5 mg/kg over the first 10 days of life is associated with improved BPD-free survival [OR: 1.48, (95% CI 1.02–2.16, p = 0.04), NNT 12, (95% CI 6–200)] [75]	I	C	Increased risk of sepsis in infants < 25 weeks GA Risk of SIP if used with indomethacin Risks and relatively small effect size inform our recommendation
	Dexamethasone	Early initiation of dexamethasone prevents BPD but increases risk for NDI [77]	I	D	Guidance is to avoid dexamethasone prior to 7 days of life [113]
	Inhaled budesonide	Early initiation of inhaled budesonide prevents BPD but associated with increased risk of mortality [211, 212]	I	D	Treatment is not encouraged owing to link with increased mortality
	Azithromycin	Prophylactic azithromycin does not reduce the risk for BPD [94, 95, 213]	I	D	Possible that the deleterious effects on the microbiome outweigh other benefits
Evolving (> 7 days to 36 weeks PMA)	Dexamethasone	Dexamethasone probably reduces the risk of oxygen dependency at 36 weeks PMA [RR: 0.76, (95% CI 0.66–0.87); 12 studies, 553 infants; moderate-certainty evidence] [17] 10-day course of low-dose dexamethasone (0.89 mg/kg) > 7 days of life facilitates extubation but does not prevent BPD [109] Risk of NDI with dexamethasone treatment is modulated by risk of BPD. Infants with risk of grade 2–3 BPD > 53% are most likely to benefit [105] Dexamethasone should not be used when the risk of BPD is < 30% [122]	I I I I	C C C D	Side effects include hyperglycemia, hypertension, GI  perforation, osteopenia of prematurity, and reduced growth Risk of NDI may be underestimated owing to missing follow-up data, and most outcomes reported only in children 2 years and younger [17] Administration of dexamethasone should be guided by baseline risk of BPD
	Hydrocortisone	Administration of hydrocortisone to intubated preterm infants ≥ 14 days of life facilitates extubation but does not prevent BPD [120, 121]	I	C	Later treatment with hydrocortisone is associated with increased risk of significant hypertension but with NDI unchanged [121, 214, 215]
	Diuretics	May improve lung compliance and facilitate weaning in infants with pulmonary edema. Do not prevent BPD [133, 216, 217]	I	B	Side effects include electrolyte losses, growth failure, osteopenia of prematurity, and nephrocalcinosis
Established phase (> 36 weeks PMA)	Prednisolone	A 10-day course of prednisolone facilitates weaning of support in infants with established BPD [141] Courses of prednisolone that extend beyond 10 days have limited effectiveness in reducing respiratory support [142]	II-2 II-2	B C	30-day course of prednisolone was associated with reduced linear growth in infants with established BPD [142]
	Diuretics	As for evolving phase, consider allowing infant to outgrow dose	I	B
	Bronchodilators	Bronchodilators may have some efficacy in preterm infants who present with frequent respiratory symptoms [146]	II-3	B	Direct treatment toward preterm infants with active symptoms without strict consideration of BPD diagnosis
	Inhaled steroids	May improve symptoms in preterm infants with history of wheezing [144]. No evidence of benefit when used as standard therapy in BPD [143]	II-3	C	No indication that routine inhaled steroids prevent respiratory complications for asymptomatic patients with BPD

BPD, bronchopulmonary dysplasia; PMA, post menstrual age; H, hours; GI, gastrointestinal; IM, intramuscular; GA, gestational age; aOR, adjusted odds ratio; 95% CI, 95% confidence interval; NNT, number needed to treat; RR, relative risk; SIP, spontaneous intestinal perforation;  NDI, neurodevelopmental impairment

Current Therapeutic Approaches

Early Phase (First 7 Days of Life)

Caffeine

Caffeine is primarily an adenosine receptor antagonist that nonselectively blocks adenosine A1 and selectively blocks adenosine A2A receptors in the central nervous system and peripheral tissues [45]. By blocking these receptors, caffeine increases respiratory drive, prevents apnea, and reduces hypoxic episodes [46]. The CAP trial enrolled 2006 preterm infants with birthweight (BW) of 500–1500 g and randomized them to treatment with either caffeine or placebo during the first 10 days of life [14]. BPD was significantly lower in infants who received caffeine compared with those treated with placebo [36% versus 47% adjusted odds ratio (aOR) 0.63, 95% confidence interval (95% CI) 0.52–0.76, p < 0.001] [14]. Infants in the treatment group also spent a shorter duration on positive airway pressure [14]. Improved neurodevelopmental outcomes were noted in the treatment group [47, 48] with a lasting reduction in developmental coordination disorder [49]. Post hoc analysis of the trial suggested that infants who received caffeine within the first 3 days of life seemed to benefit more from a shorter duration of IMV than those in whom treatment was started later [50]. Retrospective studies indicate that early initiation of caffeine is associated with reduced duration of respiratory support and incidence of BPD [51–54]. The effect of caffeine in stimulating the respiratory system and promoting contraction of the diaphragm [55] and bronchodilation [56] likely contributes to these findings. The diuretic effects of caffeine may help counteract the development of a positive fluid balance that has been linked with an increased risk for BPD during the first week of life [57]. Studies performed in preclinical models have identified involvement of caffeine in leveraging anti-oxidant [58], anti-inflammatory [59, 60], and pro-angiogenic[61] pathways.

Caffeine remains one of the most prescribed medications in US neonatal units [62], with early use becoming part of normative practice. Smaller studies indicate that infants may attain greater benefit from higher maintenance therapy of 10 mg/kg [63, 64]; however, individual differences in caffeine metabolism may predispose patients to side effects such as feeding intolerance, irritability, and tachycardia [45]. Future studies to identify optimal practices in caffeine dosing and timing of administration are necessary to fully leverage the use of caffeine in the prevention of BPD.

Vitamin A

Vitamin A has been shown to play a vital role in the development of the lung epithelium and has potent anti-oxidant properties [65]. It works by binding to retinoic acid receptors and retinoid X receptors in the cell nucleus, influencing gene transcription and promoting the differentiation of epithelial cells in the respiratory tract [66]. Among preterm infants, reduced levels of vitamin A at birth have been found to correlate with increased risk for BPD [67], with infants born at extremely low BW (ELBW; BW < 1000 g) being at particularly high risk of deficiency. Data from a multicenter placebo-controlled randomized clinical trial (RCT) (n = 807 infants; BW 401–1000 g) linked administration of vitamin A 5000 international units given by intramuscular (IM) injection three times a week for the first 4 weeks of life with a significant reduction in the composite outcome of BPD or death prior to 36 weeks PMA [55% versus 62%, relative risk (RR) 0.89, 95% CI 0.80–0.99] [15]. Despite this finding, many clinicians remain reluctant to adopt routine vitamin A administration, citing concerns regarding the effectiveness of the treatment [68] and pain from repeated injections. Unfortunately, oral preparations of vitamin A have not had an impact on respiratory outcomes, making IM dosing the only effective route of administration [69]. The finding that BPD rates did not increase during a vitamin A shortage also suggests that the effect size of this therapy is relatively small [70]. A post hoc analysis of trial data indicated that ELBWs at relatively lower risk of BPD tended to show greater benefit from vitamin A than those in higher-risk patients [71]. These data suggest that the multimodal effects of vitamin A are unlikely to have a significant impact in reducing BPD but that it can be considered as part of a comprehensive preventative approach.

Prophylactic Hydrocortisone

Reduced endogenous production of cortisol makes the EP infant more prone to developing an early exaggerated inflammatory response and may reduce the efficiency of circulatory adaptation, predisposing to early hypotension and prolonged patency of the DA [72]. Cortisol also plays an important role in normal lung development [73], and lower levels of serum cortisol at birth/during the first few days of life have been linked to an increased risk for BPD [74]. Results from a single-patient metanalysis containing data from over 900 infants born between 24 and 29 weeks GA showed that low-dose hydrocortisone (total 8.5 mg/kg) given during the first 10 days of life is associated with a small but statistically significant increase in BPD-free survival [OR: 1.48, 95% CI 1.02–2.16, p=0.04]. This benefit may be most significant in female infants and those exposed to chorioamnionitis [75]. More recent metanalyses have failed to show any significant benefit for early high-dose hydrocortisone in preventing BPD [17, 76–79]. Of note, there was a higher degree of heterogeneity between the studies included in these analyses, several of which were designed to evaluate the circulatory response to hydrocortisone rather than the impact on respiratory outcome. Retrospective studies of hydrocortisone in preventing BPD suggest that this treatment is safe [80, 81], with one study showing a significant impact in BPD-free survival [81].

Adverse effects associated with early prophylactic hydrocortisone include increased risk of late-onset sepsis in infants < 26 weeks GA [16, 75] and spontaneous intestinal perforation [82] when used in combination with indomethacin. To date, there is no evidence linking receipt of early hydrocortisone with NDI, with some data suggesting an improvement in outcomes in infants born between 24 and 25 weeks GA [83]. In contrast, the potent glucocorticoid agonist dexamethasone is effective in preventing BPD if used in the first week of life but is associated with increased risk for cerebral palsy [77]. Subgroup analysis of patients from the PREMILOC trial—the largest RCT evaluating early low-dose hydrocortisone therapy [16]—indicates that patients with higher baseline cortisol were more likely to sustain adverse effects such as spontaneous gastrointestinal perforation and intraventricular hemorrhage [84]. When subjects of the PREMILOC trial were stratified according to their baseline risk for BPD using a predictive model that included GA at birth, BW, respiratory support at baseline, sex, center effect, and multiple pregnancy [85], treatment with early prophylactic hydrocortisone was found to have a greater impact in improving BPD-free survival when compared with the original trial data [OR 2.053, 95% CI 1.602–2.501, p = 0.002, number needed to treat (NNT) = 5.8, 95% CI 4.1–23.0 [86] versus OR 1.48, 95% CI 1.02–2.16, p = 0.04, NNT = 12, 95% CI 6–200] [16]. Although the numbers of infants in each severity group were too low to provide robust analysis, investigators noted a trend toward greater BPD-free survival with early hydrocortisone in infants with less than 75% chance of achieving this outcome [85]. One major limitation of this study is that it did not study the adverse effects of hydrocortisone; however, these findings suggest the utility of using predictive models to predict the risk of BPD at birth to direct low-dose hydrocortisone treatment toward infants with the greatest likelihood of benefit.

Early Inhaled Budesonide

Given the concerns regarding the long-term effects of early systemic glucocorticoid exposure, local delivery of steroids by inhalation seemed like a safer strategy to reduce the deleterious impact of inflammation on lung development. When the effect of early inhaled budesonide was evaluated in a population of 863 extremely preterm infants enrolled in a multicenter RCT, early treatment with 400 μg budesonide starting within the first 12 h of life was associated with reduced risk of BPD [RR 0.74, 95% CI 0.60–0.91, p = 0.004)] but not the composite outcome of death prior to 36 weeks PMA or BPD [RR: 0.85, 95% CI 0.75–1.00, p = 0.05] [87]. A trend toward increased mortality in the treatment group reached statistical significance at 2-year follow-up. This finding is peculiar as BPD is typically associated with increased mortality, and so as the intervention was effective in reducing BPD in trial participants, survival would be expected to be at the very least similar, if not improved, in that group relative to the placebo group. Although exposure to inhaled budesonide in the first 12 h of life may be effective in preventing BPD, the association with increased mortality makes it difficult to recommend routine use in the early neonatal period.

Azithromycin

The link between in utero and perinatal infection with Ureaplasma and Mycoplasma spp. and BPD is strongly supported by data from laboratory models [88, 89] and clinical studies [90, 91]. Data from placebo-controlled RCTs do not, however, support a role for universal azithromycin prophylaxis in the prevention of BPD [92–95]. Any benefit that azithromycin might have in clearing Ureaplasma from the respiratory tract may be outweighed by potentially deleterious effects on the microbiome. In general, antibiotic use beyond the first 48 h of life should be limited to infants with positive cultures.

Inhaled Nitric Oxide (iNO)

Several preclinical studies have indicated that derangements in NO production could play an important role in the pathogenesis of BPD [22, 96]. Disappointingly, RCTs of iNO in preterm populations have failed to show a benefit in reducing BPD [97–99]. Use of iNO was associated with improvement in survival in a cohort of 55 infants < 34 weeks GA with confirmed pulmonary hypertension without any impact on BPD [100]. Those that showed the most pronounced response were infants who presented with pulmonary hypertension in the first 72 h of life and those with a prenatal diagnosis of oligohydramnios [100]. Another retrospective study that evaluated the outcomes of 84 preterm infants who received iNO in the setting of acute hypoxic respiratory failure noted that degree of prematurity, pulmonary hemorrhage, and systemic hypotension were independent risk factors for mortality [101]. Treatment of preterm infants with iNO should be considered carefully on a case-by-case basis [102].

Evolving Phase (> 7 Days of Life to 36 Weeks PMA)

Moderately Early Systemic Steroids

Dexamethasone

Although suppression of deleterious inflammatory responses at the earliest opportunity would appear to be an optimal approach to prevent BPD, dexamethasone exposure before 7 days of life has been consistently associated with an increased risk for NDI [77, 103]. Systematic reviews and metanalyses indicate that moderately early use of dexamethasone in preterm infants between 7 and 21 days of life reduces the risk for both BPD and the combined outcome of BPD and mortality [17, 78, 79] with no significant impact on NDI. Severe BPD is strongly associated with neuro-disability [104], and administration of dexamethasone is associated with reduced incidence of NDI in patients for whom the risk for grade 2–3 BPD exceeds 53% [105]. Findings from multicenter retrospective studies indicate that receipt of steroids within 8 and 28 days of life is more effective in preventing grade 2 or grade 3 BPD than postponing treatment to a later time [106, 107]. Standardized use of the NRN BPD calculator [38] as a tool to guide initiation of dexamethasone therapy can be incorporated as part of a comprehensive quality improvement bundle to encourage optimal timing of therapy to reduce BPD [108]; however, dose selection remains controversial. While delivery of a relatively low dose (0.89 mg/kg over 10 days) was associated with increased rates of extubation among preterm infants > 7 days old who were dependent on IMV [109], this treatment did not reduce the risk of BPD. A network metanalysis that included a total of 6441 infants enrolled in 59 RCTs indicated that high-dose regimens that included > 4 mg/kg cumulative dose of dexamethasone administered > 7 days of life have more efficacy in preventing oxygen dependency at 36 weeks PMA than low- or moderate-dose courses of dexamethasone [(control, RR 0.69, (95% CI 0.59–0.80, high-certainty evidence); low-dose dexamethasone, RR 0.73, (95% CI 0.60–0.88, low-certainty evidence); moderate-dose dexamethasone, RR 0.76, (95% CI 0.62–0.93, low-certainty evidence)] [110]. No significant association with NDI was noted; however, heterogeneity between studies and limited follow-up data indicate that these results should be viewed with caution. Retrospective analysis of data from extremely preterm infants enrolled in the PENUT trial showed that scores on the Bayley Scales of Infant and Toddler Development (BSID-III) evaluation were found to be 7.4 (95% CI − 12.3 to − 2.5) points lower in the motor domain (p = 0.003) and 5.8 (95% CI − 10.9 to − 0.6) points lower in the language domain (p = 0.03) in infants who received dexamethasone for at least 14 days compared with nonexposed infants [111]. Repeated use of the low-dose Dexamethasone: A Randomized Trial (DART) protocol has been associated with increased risk for NDI [112]. Current American Academy of Pediatrics guidelines advocate for a personalized approach with consideration of a short-duration, relatively low-dose course of dexamethasone in preterm infants who remain ventilator dependent between 7 and 28 days of life [113]. This strategy appears to contrast with contemporary practice, where steroid courses are being given for a wide variety of indications that are often not evidence based [114, 115]. BPD rates have continued to rise in UK neonatal units [116] despite increased use of postnatal steroids [117]. While steroids have short-term pulmonary benefits, data from animal studies suggest that treatment with glucocorticoids could contribute to long-term impairment in alveolar development [118]. Findings that lung function parameters were more severely reduced in preterm-born adolescents who received dexamethasone for prevention and/or management of BPD also indicate that this treatment should be utilized with caution [119].

Hydrocortisone

Unfortunately, RCTs evaluating the use of hydrocortisone in preterm infants who remain intubated beyond the first week of life have not demonstrated success in reducing BPD [120, 121]. Although higher doses of dexamethasone (> 4 mg/kg) appear to have greater efficacy in preventing oxygen dependency at 36 weeks PMA than moderately late hydrocortisone treatment [110], follow-up studies from two relatively large RCTs of hydrocortisone use > 7 days of life have not indicated any increased risk for NDI [120, 121]. While routine use of hydrocortisone to reduce the risk of BPD beyond the first week of life is not recommended [113], this approach has been shown to be efficacious in facilitating extubation and could be considered as an alternative to the DART protocol.

To summarize, application of short, low-dose courses of systemic corticosteroids should be strongly considered in preterm infants born at < 32 weeks GA and at least 14 days old who are unable to wean from IMV. Dexamethasone appears to have a more robust evidence base in terms of preventing BPD; however, it appears that the degree of benefit is dependent on both dose and timing of therapy [110]. The infants who derive the most global benefit from treatment are those at highest risk for severe BPD and associated NDI [105, 122]. Reserving higher-dose courses of dexamethasone in patients whose risk of grade 2–3 BPD > 70% might be a reasonable strategy, whereas either low-dose dexamethasone or hydrocortisone regimens could be considered when the primary goal is to wean from IMV.

Inhaled Bronchodilators

Over the last 37 years, several reports have emerged indicating that preterm infants in the evolving phase of BPD may respond to beta-2-adrenergic receptor agonist albuterol and the cholinergic receptor antagonist ipratropium with favorable changes in vital signs and/or lung function parameters [123–125]. Practices surrounding the prescriptions of these medications vary substantially between centers [126] as the evidence supporting their routine use to either prevent BPD or ameliorate symptoms remains inconsistent. Studies have been conducted in relatively small numbers of patients with marked variation between the timing of initiation with respect to GA, dosage, and delivery devices used [125]. Endpoints in studies have also differed markedly, with few trials using development of BPD as a primary outcome measure [127]. An RCT that compared inhaled albuterol alone or in combination with inhaled beclomethasone in 173 infants born at < 31 weeks GA receiving respiratory support on the 10th postnatal day did not reveal any advantage of these therapies over placebo in preventing BPD [128]. A subgroup analysis from the NEUROSIS trial failed to show any effect of early use of bronchodilators on respiratory outcomes [129]. Retrospective studies conducted in centers where lung function testing is part of routine practice do, however, suggest a role for bronchodilator therapies in select patients, with improvement in lung function test parameters noted [123, 124]. Nebulized treatments are more frequently used in the inpatient population of infants with BPD.

Diuretics

Diuretics are frequently prescribed in the NICU to improve pulmonary mechanics and oxygenation in preterm infants with evolving [130] and established BPD [131]. Despite widespread use of furosemide in critically ill neonates [130], there is no consistent evidence that this drug can prevent BPD [132, 133]. Diuretic use varies considerably between centers caring for infants with established BPD [134], and no advantage is associated with higher rates of treatment in terms of mortality or length of stay [135]. Loop diuretics are associated with several side effects, including increased electrolyte losses [136], nephrocalcinosis [137], severe osteopenia of prematurity [138], and hearing loss[139]. Thiazide diuretics such as chlorothiazide are calcium sparing and may be a better choice for chronic symptomatic management of pulmonary edema in preterm infants with evolving or established BPD. Attention to adequate electrolyte supplementation is still necessary to offset increased losses of sodium and chloride [140]. In general, diuretic use should be limited to infants with clinical and/or radiographic evidence of pulmonary edema who show an objective response to therapy. The need for continued treatment should be frequently reassessed throughout the hospitalization and beyond.

Established Phase (> 36 Weeks GA)

Prednisolone

The Bhandari regimen of 2 mg/kg/day of prednisolone divided into two doses for 5 days followed by a taper given over the following 6 days was shown to be effective in facilitating weaning off respiratory support in oxygen-dependent preterm infants with established BPD [141]. Administrating a 28-day course of prednisolone to ventilator-dependent patients with BPD was associated with weaning in support over the first week of therapy; however, no significant improvements were noted beyond this point [142]. Linear growth failure was noted toward the end of the steroid course, and 50% of infants in the cohort went on to require a tracheostomy, suggesting that improvements did not have a significant effect in altering the clinical course [142]. Use of prednisolone can therefore be considered in patients with established BPD; however, duration of therapy should be limited to maximize benefits and minimize risks.

Inhaled Steroids

In one small RCT, infants with BPD treated with twice daily fluticasone propionate did not show any improvement in respiratory symptoms over a 12-month period compared with infants who received placebo [143]. Another trial conducted in patients with prematurity-associated respiratory disease, several of whom had a diagnosis of BPD, did note both objective improvement in functional residual capacity and a 37% decrease in reported symptoms following 6-week treatment course of inhaled beclomethasone [144]. These findings suggest that treatment with inhaled steroids should be targeted toward preterm-born patients with respiratory symptoms, as indicated in the most recently issued American Thoracic Society (ATS) guidelines [145].

Inhaled Bronchodilators

Studies performed in the outpatient setting also support a role for inhaled bronchodilators either alone [146] or in combination with an inhaled steroid [147, 148] for the purpose of alleviating respiratory symptoms. Children with a predominantly obstructive phenotype of post-prematurity lung disease were found to have a more limited exercise capacity when compared with preterm-born subjects with a preserved ratio of impaired spirometry, preterm-born subjects without lung disease and term-born controls [43]. An obstructive phenotype of lung disease was also associated with a more pronounced response to short-acting beta agonist therapy, suggesting that lung function testing may be helpful in identifying individuals likely to benefit more from bronchodilator therapy [43]. A relatively small placebo controlled trial of a preparation containing the steroid fluticasone propionate with the long acting beta-agonist salmeterol may benefit school-aged children with BPD [148].The muscarinic receptor antagonist ipratropium bromide was shown to be effective in improving objective measures of lung function and parent-reported measures in a small population of preterm-born infants with active respiratory symptoms [146]. Infants without active signs of illness did, however, experience a paradoxical response to nebulized therapy with an increase in airway resistance reported [149]. The long-acting M2 receptor antagonist tiotropium bromide is frequently used in adults with asthma and chronic obstructive pulmonary disease (COPD), with use becoming more frequent in the treatment of childhood wheezing [150]. Inhibition of acetylcholine-induced bronchoconstriction and mucus secretion may be particularly advantageous in the management of viral-induced wheezing that occurs in infants and young children. Although tiotropium use was associated with a significant increase in symptom-free days in infants and toddlers with two to four physician-reported episodes of wheezing, this RCT did not include any infants born at < 36 weeks GA [151]. A role for tiotropium bromide in the management of infants and children with BPD is still not clear but could be considered in those with frequent symptoms of cough and wheeze who respond well to ipratropium. In general, bronchodilator therapy should be targeted toward individuals with active symptoms as suggested in the ATS guidelines for the management of post-prematurity lung disease [145]. Evidence shows that superior drug delivery is achieved for all age groups through use of a multidrug inhaler (MDI) and a spacer [152].

Azithromycin

Immune dysregulation caused by bacterial dysbiosis or exposure to respiratory viruses has been identified as a factor leading to wheezing during infancy and early childhood [153]. Azithromycin has both anti-bacterial and anti-inflammatory properties and has been shown to shorten the duration of asthma-like episodes by approximately 50% in children aged 1–3 years [154]. Follow-up studies from this RCT identified that the effect of azithromycin was modulated by the airway microbiome, with greater benefits obtained in children with increased microbiota richness [155]. As only 3% of the study cohort from which these trials were recruited were born < 36 weeks GA [156], a direct role for azithromycin in the management of respiratory exacerbations in infants with prematurity-associated respiratory disease is not indicated. A course of azithromycin can, however, be considered in situations where atypical pneumonia is strongly considered.

Emerging Treatments

Early (First 7 Days of Life)

Prenatal High-Dose Vitamin C Supplementation

Placebo-controlled RCTs have shown that treatment of women who smoked during pregnancy with high-dose vitamin C is associated with improved infant lung function indices at birth [157, 158], enhanced trajectory of pulmonary function parameters over the first 60 months of life, and reduced respiratory symptoms [159]. Lower levels of vitamin C in the first week of life have been linked to increased risk for BPD [160], and post-natal supplementation has been considered as a potentially useful intervention in premature infants [161]. A placebo-controlled RCT investigating the effects of early post-natal vitamin C supplementation noted a trend toward a reduction in BPD that did not reach statistical significance [161].

N-Acetylcysteine

A single-center RCT recently showed a significant reduction in the risk for BPD in preterm infants born to mothers with suspected chorioamnionitis who received N-acetylcysteine prior to delivery (BPD, NAC: 3% versus placebo: 32%, RR 0.10; 95% CI 0.01–0.73) [162]. This study contained only 67 participants; however, it suggests that modification of perinatal exposures could potentially have a significant impact in a select group of patients. Confirmation in a larger multicenter trial is required before this can become a widely recommended intervention.

Surfactant and Budesonide

A pilot RCT that evaluated the efficacy of intratracheal instillation of a preparation containing 100 mg/kg Survanta^® (beractant) mixed with 25 mcg/kg budesonide showed a significant reduction in the incidence of BPD diagnosed at 36 weeks PMA (19/60 versus 34/56) [163]. A larger international multicenter RCT reported that the combination of surfactant and budesonide was significantly associated with reduced risk for BPD compared with standard treatment with surfactant alone [55 of 131 (42.0%) versus 89 of 134 (66%); RR 0.58; 95% CI 0.44–0.77, p < 0.001, NNT 4.1, 95% CI 2.8–7.8)] [164]. Results from a recently published metanalysis that included 10 studies and 527 preterm infants indicated that intratracheal administration of surfactant and budesonide is effective in reducing the incidence of BPD OR = 0.52, 95% CI 0.39–0.68, p < 0.00001) [165]. Recently published results from a multicenter international RCT including 1059 infants born < 28 weeks GA did not, however, show any advantage of surfactant and budesonide on the primary outcome of BPD-free survival [166]. Another large-scale multicenter trial is ongoing in the USA (NCT04545866), with results expected in the next 2 years; until further data are forthcoming, clinical use of surfactant and budesonide is not recommended.

Insulin-Like Growth Factor 1 (IGF-1)/IGF Binding Protein 3 (IGFBP-3)

Low levels of IGF-1 and a slow increase in IGF-1 levels have been linked to increased risk for BPD [167]. EP infants between 23+0 to 27+6 weeks GA who received an intravenous infusion of IGF-1/IGFBP-3 in a phase 2 RCT were found to be significantly less likely to develop BPD compared with those in the placebo group [168]. Severe BPD occurred in 13/61 of the subjects in the IGF-1/IGFBP-3 treatment compared with 27/60 of the patients who received standard care (p = 0.04). Only 1/24 patients who achieved target exposure conditions developed BPD, representing an 89% decrease in this outcome when compared with the control group (p = 0.02) [168]. These findings were unexpected as the trial was designed to evaluate the impact of this treatment on retinopathy of prematurity (ROP). A larger phase 2 clinical trial designed to evaluate the efficacy of IGF-1/IGFBP-3 in preventing the combined outcome of severe BPD or death prior to 36 weeks is currently underway, with results expected within the next 2 years (NCT03253263).

Evolving (> 7 Days to 36 Weeks PMA)

Stem-Cell-Based Therapies

Preclinical studies have demonstrated that administration of mesenchymal stromal cells (MSCs) and/or MSC-derived conditioning media can effectively preserve normal lung and pulmonary vascular development in rodent models of neonatal hyperoxia-induced lung injury and/or BPD [169]. Results from phase I and phase II clinical trials indicate that intratracheal administration of MSCs [170, 171] is safe and potentially efficacious [172] in preventing BPD in specific populations of preterm infants. A recently reported double-blind, multicenter, phase II study showed a trend toward reduced incidence of severe BPD in infants born < 25 weeks GA in the treatment group [172]. A second phase II RCT evaluating the use of PNEUMOSTEM^® in infants 23–25 weeks with a goal to recruit at least 60 patients is currently still recruiting (NCT03392467), with results expected within the next 2 years. Another phase II RCT evaluating the efficacy of IV administration of MSCs for prevention of BPD in extremely preterm infants is also underway (NCT06270199). In the interim, long-term follow-up is continuing for patients studied in the published phase I [170, 171] and phase II RCT [172] of intratracheal MSC administration.

Although MSC-based therapies have the potential to address multiple pathomechanisms leading to the development of BPD, deployment of these treatments on a large scale without sacrificing safety or quality poses several challenges [173]. The International Society of Cell Therapy (ISCT) have proposed minimal criteria to define MSCs; however, a recent scoping review of the literature suggests that these guidelines are not consistently being followed [174]. The lack of consensus on how to characterize MSCs limits progress toward complete understanding of their therapeutic potential [173]. There is also limited understanding of how environmental factors can influence the composition of the MSC secretosome. Single-cell RNA sequencing of MSCs derived from a murine model of chronic hyperoxia is consistent with a pro-inflammatory, pro-fibrotic phenotype [175]. Tracheal aspirates obtained from ventilated preterm infants contain MSCs with similar characteristics [176]. Using single-cell RNA sequencing to evaluate the relationship between the transcriptomic profile of umbilical cord MSCs and their function will be important to effectively leverage their beneficial effects.

To date, all the clinical trials of MSCs have taken an allogenic approach, utilizing purified MSCs derived from healthy infants born at term. Using banked allogenic cells allows for greater logistical efficiency and cost savings than an autologous strategy where the patient’s own cells are harvested, purified, and used for treatment. Differences in major histocompatibility complexes between healthy donor-derived cells and the recipient could, however, lead to alloimmunization and the possibility of acute or chronic rejection [173]. Ensuring adequate long-term follow-up data of infants who received MSCs in phase 1 and phase 2 RCTs is therefore essential if safety is to be maintained. Preclinical research suggests that MSCs derived from preterm infants may have increased regenerative capacity when compared with those from term infants [177]; however, the opposite may be true for infants born to mothers diagnosed with pre-eclampsia [178]. Understanding the impact of the prenatal environment in determining MSC phenotypes is an area that also needs to be thoroughly explored in the consideration of autologous approaches to MSC source selection.

Maintaining consistent purity and quality of MSC products on a large scale poses highly significant challenges [179]. Optimal practices in source selection, isolation, expansion, culture conditions, and cryopreservation still need to be determined, including the potential for pre-conditioning MSCs to optimize their content [180]. Even if ongoing clinical trials reveal favorable results, extensive research and development are needed before MSC-based therapies can be widely used to prevent BPD.

Ciclesonide

Ciclesonide is a pro-drug that is metabolized to a glucocorticoid that has been shown to preserve normal alveolar development in a rodent model of hyperoxia-induced BPD without associated suppression of IGF-1, somatic growth failure, and hippocampal apoptosis associated with dexamethasone therapy [181]. Early administration of ciclesonide provides potential for infants to receive the protective benefits of glucocorticoid therapy without risking adverse neurodevelopmental outcomes, metabolic disturbance, or growth failure. A phase II nonrandomized dose escalation trial that aims to evaluate the feasibility and safety of inhaled ciclesonide administration to preterm infants > 8 days of life has recently commenced (NCT06589245).

Probiotics

There is evidence that patterns of microbial colonization present in the airway early in the neonatal course can be predictive for BPD [182]. Although no single organism or microbiological signature has emerged that consistently predicts poor respiratory outcomes [183], patterns of reduced biodiversity [184], and increased abundance of Gammaproteobacteria and decreased populations of Lactobacilli can persist in infants with established severe BPD [185, 186]. Treatments to address airway dysbiosis with the goal of preventing BPD are currently under development. Use of an inhaled live biotherapeutic preparation containing Lactobacilli was shown to be highly effective in preserving normal pulmonary architecture in newborn mice studied in a model of inhaled Escherichia coli derived lipopolysaccharide (LPS) and hyperoxia-induced BPD [185]. Although there is evidence indicating that oral administration of probiotics reduces the incidence of mortality, NEC, late onset sepsis, time to full enteral feeds, and length of stay, no benefit has been noted in reducing BPD [187].

Micro-RNA (miR)-Based Therapies

Our group has identified miR-34a as an important regulator of several diverse pathways leading to the development of BPD [188, 189]. We have shown that miR-34a expression is increased in the tracheal aspirates of infants diagnosed with RDS who went on to develop BPD and have localized increased miR-34a expression to type II pulmonary epithelial cells in post mortem specimens obtained from preterm infants with RDS and evolving BPD [189]. Experiments performed using a murine model of hypoxia-induced BPD have linked exposure to hyperoxia to a p53-mediated rise in miR-34a expression in type II epithelial cells that, in turn, is associated with dysregulated pulmonary vascular grown, right ventricular remodeling, and abnormal airspace development [189]. These changes were ameliorated either by deletion of miR-34a or by treatment with a specific antagomir [189]. We identified angiopoietin-1 - a pro-angiogenic protein that maintains structural integrity in developing blood vessels - as a key target for miR-34a-mediated pathogenic changes. Additional targets for miR-34a include sirtuin-1, a key regulator of mitochondrial autophagy and protector against cell senescence [190], and B-cell leukemia/lymphoma protein-2, a negative regulator of apoptosis [191]. miR-34a also inhibits expression of platelet-derived growth factor receptor A (PDGFR-A) by PDGFR-A-expressing myofibroblasts and disrupts alveolar development [192].

Interestingly, our experiments have indicated sexual dimorphism in miR-34a responses, with higher levels reported in male infants with BPD [189] and in male newborn mice studied in a model of hyperoxia-induced BPD [193]. This pattern may contribute to the observation that male infants are at higher risk of developing BPD than females of equivalent BW and GA [9]. Increased expression of miR-30^AA noted in female mice in response to hyperoxia has recently been shown to play a protective role in maintaining normal alveolarization and may serve as another potential target for intervention [194]. Other miRs that have been implicated as potentially important in the pathogenesis of BPD include miR-195 [195], miR-45 [196], and miR-219-5p [197]. Reduced levels of miR-876-3p were noted in exosomes isolated from infants with severe BPD and were subsequently linked to increased exposure to proteobacterial LPS [198]. These data link disturbances in the microbiome to loss of protective miR-mediated responses and show how many of the exposures leading to BPD are closely linked.

Exosomes released by MSCs are an important source of miRs, and the activity of MSCs themselves can be, in turn, directed by alterations in miRNA expression [199]. Work from our laboratory has demonstrated that effective inhibition of miR-34a can be achieved noninvasively through nasal administration without any discernable adverse consequences on other organs, including the retina and the brain [200]. This strategy may not be as effective in human subjects as studies evaluating the use of inhaled medications frequently demonstrate variability in how effectively these agents reach the airspaces. Further studies in large-animal models are required to confirm the safety and effectiveness of miR-based therapies before trials in human subjects can take place.

AVR-48

Chitohexaose is a hexomeric oligosaccharide that exerts immunomodulatory effects by binding to Toll-like receptor (TLR)-4, inhibiting production of the pro-inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-6 and prompting macrophages to switch to an anti-inflammatory M2 phenotype [201]. Studies from our laboratory demonstrate that administration of the chitohexaose analog AVR-48 to neonatal mice studied in a model of hypoxia-induced severe BPD is associated with a reduced inflammatory response, preservation of normal alveologenesis, increased cell proliferation, and healthy angiogenesis [202]. An investigational new drug (IND) application for AVR-48 as a treatment for BPD was recently approved by the Food and Drug Administration (FDA). AVR-48 has the potential to have a considerable impact in preventing BPD.

Established Disease (> 36 Weeks PMA)

Bacterial Lysates

Lower respiratory tract infections sustained during infancy and early childhood are closely linked with the development of chronic cough and wheezing [203]. The commercially available bacterial lysates OMV-85 and MV130 contain lysophilized particles of common upper respiratory tract pathogens and have been shown to reduce the incidence of respiratory tract infections associated with wheezing in infants and young children [204]. This is achieved through increased stimulation of T-helper cell (T_H) 1 activity and suppression of T_H 2-cell-mediated IL-4 release associated with allergic sensitization [205]. Although patients who have been included in trials of bacterial lysates have been as young as 3 months of age, most studies have used pre-existing lung disease as an exclusion criteria [204]. It is possible that immunotherapy with bacterial lysates may be useful in preventing long-term respiratory morbidity in preterm infants with and without BPD. An RCT evaluating the efficacy of OMV-85 in reducing the frequency of respiratory tract infections and wheeze in moderate preterm infants is currently underway in the Netherlands, with results expected within the next 2 years (NCT05063149).

Conclusions

BPD is a condition that is challenging to prevent and treat for many reasons, as controversies in the optimal application of current therapies, limitations in the diagnostic criteria, and phenotypical heterogeneity make it difficult to definitively assess the relative effectiveness of different medications. Table 2 provides a summary of current treatments available for the prevention and management of BPD with recommended dose ranges and timing of therapy. Combining these treatments with gentle ventilation strategies and optimization of nutrition as part of a quality improvement project has been shown to be effective in reducing the impact of BPD at a local level [206, 207]. These initiatives have, however, had less impact for infants born < 24 weeks GA, where structural immaturity of the lung and functional immaturity of the immune system likely play a more significant role in determining the risk for adverse pulmonary outcome. Table 3 provides a summary of the emerging treatments discussed in this article and includes their mechanism of action, current clinical trial status, and barriers to implementation. All the novel therapies in development exert multidimensional effects on the developing respiratory system. Instead of suppressing inflammatory responses, paracrine mediators released from stem cells, miR-34a, inhaled probiotics, bacterial lysates, and AVR-48 have immunomodulatory effects that could make responses to pathogens more effective. IGF-1/IGBP-3, vitamin C, miR-34a, and contents of extracellular vesicles have the potential to preserve normal patterns of cellular differentiation, thus avoiding dysregulated reparative responses. With continued research and development, it is possible that one or more of these treatment approaches will eventually lessen the deleterious impact of EP birth on the developing respiratory system and provide a growing population of survivors with a healthier future.

Table 2.

Current medications used for management of BPD

Treatment	Mode(s)of action	Recommended dose and timing	Adverse effects
Caffeine	No-selective adenosine A1-receptor antagonist Selective A2 receptor antagonist Increases respiratory drive [218] Increases diaphragmatic contractility [55] Reduces duration of IMV [51] Potential anti-inflammatory [219], anti-oxidant [220], and pro-angiogenic properties [61]	Early—first 72 h of life 20 mg/kg loading dose 5–10 mg/kg/day maintenance dose Stop around 34–36 weeks corrected PMA	Tachycardia, GI upset, irritability
Vitamin A	Plays critical role in epithelial cell differentiation and lung maturation [65, 221] Retinoic acid has a protective effect in animal models of hyperoxia-induced BPD [222]	Early—first 24–72 h of life Consider in infants < 1000 g 5000 IU IM every MWF for 4 weeks	Pain from injections
Hydrocortisone	Plays key role in normal lung development [73] Reduces excessive inflammatory responses[223] Aids circulatory transition to ex utero life, facilitates closing of the PDA [16, 73, 83, 223]	Early—first 24 of life Consider for infants 25–27 weeks GA exposed to chorioamnionitis 0.5 mg/kg q12h IV × 7 days then 0.5 mg/kg q24h × 3 days [16]	Hyperglycemia, GI bleeding and perforation, particularly when used with indomethacin [82], association with late onset sepsis in infants < 25 weeks GA [16]
Dexamethasone	Potent anti-inflammatory properties [224] Improves lung function by increasing surfactant production [225] and accelerating thinning of the pulmonary mesenchyme [226] Activation of glucocorticoid receptors in the hippocampus can lead to apoptosis in absence of mineralocorticoid stimulation [227]	Consider a short course of dexamethasone to facilitate extubation in ventilator-dependent infants 14–28 days of life [113] Avoid treatment < 7 days of life owing to association with CP [77] Avoid high-dose regimens (≥ 0.5 mg/kg/day) [113] Avoid cumulative doses ≥ 2 mg/kg [111] DART regimen (IV or enteral): 0.075 mg/kg q12h × 3 days, 0.05 mg/kg divided q12h × 3 days, 0.025 mg/kg q12h × 2 days, 0.025 mg/kg q24h × 2 days [109]	Use < 7 days of life associated with increased risk for CP [77] Cumulative doses > 2 mg/kg associated with lower BSID scores [111] Other side effects include delayed growth, GI bleeding/perforation, hyperglycemia, hypertension, osteopenia of prematurity, immunosuppression
Inhaled budesonide	Reduce inflammation and edema in peripheral airways, decrease resistance and airway reactivity [211, 228]	Consider during evolving stage of BPD (≥ 7 days of life to 36 weeks PMA) and in patients with established BPD Budesonide 0.125–0.25 mg q12h inhaled via nebulizer	Exposure in first 24 h of life associated with increased mortality [212] Oral thrush
Inhaled bronchodilators	Relax smooth muscle in peripheral airways either through activation of β2 adrenoceptors (albuterol) or by counteracting the bronchoconstriction caused by acetylcholine at muscarinic receptors (ipratropium) [125]	Consider using during evolving and established phases of BPD according to symptoms [229] Albuterol 2.5 mg q6-12h nebulized Ipratropium 0.125mg q6-12h nebulized	Tachycardia, irritability
Furosemide	Loop diuretic, acts to inhibit reabsorption of sodium, potassium and chloride in the thick ascending loop of Henlé [140] May improves symptoms of pulmonary edema but does not prevent BPD [133]	Consider use to manage symptomatic pulmonary edema in infants with evolving or established BPD 1 mg/kg IV or 2 mg/kg enterally up to every 6 h	Hearing loss, osteopenia, renal calcifications, electrolyte imbalance, growth failure [140]
Hydrochlorothiazide	Diuretic that acts to block absorption of sodium in the distal nephron [140] May improve symptoms of pulmonary edema but does not prevent BPD [217]	Consider use to manage symptomatic pulmonary edema in infants with evolving or established BPD 20–40 mg/kg/day divided q12H PO/NGT	Electrolyte imbalances, growth failure
Prednisolone	Reduces inflammation, accelerates lung maturation [230]	Consider Bhandari regimen to facilitate weaning support in patients with established BPD [141] 1 mg/kg q12h × 5 days, 1 mg/kg q24h × 3 days, 1 mg/kg q48H × 3 doses [141]	Hypertension, hyperglycemia, immunosuppression

BPD, bronchopulmonary dysplasia; IMV, invasive mechanical ventilation; PMA, post menstrual age; H, hours; GI, gastrointestinal; IM, intramuscular; IV, intravenous; PO, per oral; NGT, nasogastric tube; IU, international units; MWF, Monday, Wednesday, Friday; GA, gestational age; PDA, patent ductus arteriosus; CP, cerebral palsy;  BSID, Bayley Scales of Infant Development

Table 3.

Summary of emerging treatments currently in development

Emerging therapy	Mechanism(s) of action	Clinical trial status	Barriers to implementation
Prenatal administration of N-acetylcysteine (NAC)	Supports anti-oxidant activities by replenishing glutathione	In a placebo-controlled trial that included 67 pregnant women in preterm labor with a diagnosis of chorioamnionitis, receipt of NAC was associated with reduced risk for BPD (NAC:3% versus placebo 32%, RR: 0.10; 95% CI 0.01–0.73) [162]	Larger RCT is required to support prenatal administration of NAC Accurate diagnosis of chorioamnionitis can be challenging
High-dose vitamin C	Antioxidant, immunomodulator, pre-natal administration reverses over-muscularization of peripheral airways in primate model of in utero nicotine exposure [231]	Phase 3 RCTs showed that infants born to women who smoked during pregnancy who received high-dose vitamin C had superior lung function and improved pulmonary outcomes during infancy and early childhood [159] Post-natal supplementation in preterm infants was associated with a trend toward reduction in BPD that did not reach statistical significance [161]	Lack of demonstrated benefit in the setting of prematurity and BPD. Theoretical concerns regarding harmful pro-oxidant effects of vitamin C, but this has not been reported in any of the clinical trials
Surfactant and budesonide	Local anti-inflammatory effects [232]. Selective for infants with significant RDS.	Phase 3 RCT with 256 infants did show a reduction in the composite outcome of BPD or death [164] Recent phase 3 RCT with 1059 infants did not show a benefit on survival free of BPD [166] A US-based phase 3 RCT with estimated enrollment of 1160 infants is currently ongoing. Preliminary results are expected within the next 2 years (NCT04545866)	Unconvincing evidence of benefit in reducing BPD Would not be indicated in infants with BPD who did not have significant RDS
Insulin-like growth factor/insulin like growth factors binding protein 3 (IGF-1/IGFBP-3)	Regulates somatic growth, cell differentiation, and metabolism [233]	Phase 2 clinical trial with 61 preterm infants showed significant association between IGF-1/IGFBP-3 administration and reduced risk for severe BPD (13/61 versus 26/60, p = 0.04) [168]. Large multicenter trial currently in progress (NCT03253263)	Administered by continuous IV infusion over first 6 weeks of life. Challenging to maintain IV access in preterm infants for such a lengthy time period. Will need to be highly effective in reducing BPD in order not to be cost prohibitive
Stem-cell-based therapies	Mesenchymal stromal cells (MSCs) secrete extracellular vesicles that have anti-inflammatory, immunomodulatory, anti-oxidant, anti-apoptotic, and anti-fibrotic properties [234]	Phase 1 and 2 clinical trials indicate that intratracheal administration of allogenic MSCs is well tolerated and safe in the short term [170–172]. A trend toward reduced severe BPD was noted in infants < 25 weeks GA who received intratracheal stem cells [172]. A phase 2 clinical trial evaluating this treatment in infants 23–25 weeks GA has recently been completed (NCT03392467). Phase 2 clinical trial of intravenous MSCs is also underway (NCT06270199)	Theoretical risk of acute and/or chronic rejection with the allogenic approach that has been used. Concerns that autologous donation would increase cost and that exposure to an adverse in utero environment could adversely influence the secretory profile of MSCs obtained from preterm infants Controversies remain regarding optimal practices in MSC harvesting, purification, storage, and transport
Ciclesonide	Pro-drug that is metabolized into a glucocorticoid. Anti-inflammatory effects and acceleration of lung development	Pre-clinical studies indicate that ciclesonide has similar effects as dexamethasone without inhibition of growth or neurotoxic effects [181]. Phase 2 clinical trial for use in preterm infants currently enrolling (NCT06589245)	FDA approved for use in adults and children but not in infants. May not inhibit growth in infants but could still have immunosuppressive effects
Inhaled probiotics	Lactobacilli sp. have immunomodulatory properties and counteract the proinflammatory and adverse metabolic effects of Gammaproteobacteria	Preclinical studies demonstrate Lactobacilli sp. can effectively preserve lung architecture and reduce neutrophilic inflammation [185]	Oral probiotic regimens are still not approved for use by the FDA, and it is likely that inhaled probiotics will meet with similar regulatory challenges Maintaining appropriate purity and quality of a live biotherapeutic product manufactured on a large scale will also be difficult
Bacterial lysates	Bacterial extracts containing lysophilized fractions of inactivated bacteria help modulate the immune system to enhance protective TH1-mediated activity and reduce pro-allergenic TH2 responses	Phase 3 trials show that commercially available bacterial OMV-85 and MV130 reduce wheezing episodes in infants and children without chronic respiratory conditions [204] Phase 3 RCT of OMV-85 in moderate to late preterm infants starting at 6–10 weeks of life currently underway (NCT05063149)	Lack of evidence for safety and tolerance in preterm infants No specific evidence that this therapy would benefit individuals with prematurity-associated respiratory conditions
Micro-RNA (miR) based therapies	miRs are short single-stranded ribonucleotide molecules that regulate gene expression through interactions with multiple mRNA transcripts. Manipulation of miRNA expression can therefore have an impact on multiple processes including angiogenesis, alveolarization, and immunoregulation	Preclinical studies indicate that inhibition of miR-34a expression by delivery of an inhaled antagomir has beneficial effects on alveolar and pulmonary vascular development [189]. Other miRs that show promise include miR-30AA [194], miR-451 [196], miR-195 [195], miR-219-p [197], and miR-876-3p [198]. No clinical trials currently in progress	A single miR regulates multiple different pathways with potential for serious side effects Information from large-animal models, including evaluation of long-term side effects, is needed before clinical trials can commence
AVR-48	Exerts immunomodulatory effects through interactions with TLR-4 receptors on macrophages	AVR-48 improves bacterial clearance and host survival in animal models of pneumonia and polymicrobial sepsis [235]. AVR-48 preserves normal lung development in murine models of BPD [202]. Preclinical studies in large-animal models are currently in progress	FDA has granted fast-track designation to AVR-48, which will lead to expedited review. Lack of clinical data in human subjects is the main barrier to use at present

RR, relative risk; BPD, bronchopulmonary dysplasia; RCT, randomized clinical trial; 95% CI, 95% confidence interval; RDS, respiratory distress syndrome; FDA, Food and Drug Administration; TLR4, Toll-like receptor 4; miR: micro-RNA

Clinical Implications

Caffeine is the agent with the largest effect size in reducing the risk of BPD and has a relatively favorable side-effect profile [14]. Vitamin A has no serious side effects but is expensive and painful to administer and has relatively low efficacy in preventing BPD [15, 208]. Early hydrocortisone shows a relatively small benefit in reducing BPD; however, this needs to be balanced with an increased risk of late-onset sepsis in infants < 25 weeks GA [75]. Dexamethasone use is associated with NDI, but the risk of this adverse effect is reduced when treatment is started after 7 days of life [17]. The risk of NDI may even be reduced when dexamethasone is used to treat infants at high risk of grade 2–3 BPD [105, 122]. As the prevalence of BPD rises, the need for novel therapies for infants in all phases of the disease process becomes increasingly important. While agents such as IGF-1/IGBP3 or AVR-48 may prove to be efficacious in protecting normal lung development, immunotherapeutic approaches such as administration of bacterial lysates and inhaled probiotics may reduce symptoms and improve lung function in patients with established BPD. In the meantime, early provision of caffeine and judicious use of post-natal steroids along with other symptomatic treatments remain the mainstays of therapy, and quality improvement approaches should be used to optimize consistency in the initiation, timing, and dosing of these agents.

Declarations

Funding

Open access funding provided by Rowan University.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

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Author contributions

A.K. wrote the first draft of specific subsections of the manuscript and contributed to Table 3. M.G. edited sections written by A.K., wrote the first draft of the remaining parts of the manuscript, and designed Fig. 1. V.B. edited the first and subsequent drafts of the manuscript. All authors have read and approve the final version of the manuscript and agree to be accountable for the work.