Prevalence, Prevention and Management of Bronchopulmonary Dysplasia

Figures & data

Table 1 Summary of Studies Evaluating Trends in BPD Incidence and/or Relationships with Associated Risk Factors

Study Population	Time Period of Study	BPD Criteria	BPD Outcome (% Population)	Significant Trends Identified During Study Period (RR, 95% CI)	Associations with BPD (OR, 95% CI)	Ref
10,877 infants born at 22–28 weeks GA in US hospitals belonging to NICHD NRN	2013–16 Comparison: 2008–2012 outcomes	NRN^Citation37	BPD: 49.8% Grade 1: 31.8% Grade 2: 21% Grade 3: 8%	BPD increased: 44.7–49.8%, (AD: 4.3, 2.8–5.8) Survival increased: 76.0–78.4%, (AD: 2.0,1.0–2.9) Exposure to IMV decreased: 87.0–84.3%, (AD: −2.1, −3.2 to −0.9) Exposure to PNS increased 12.2–18.6%, (AD: 4.0, 3.1–4.9)	N/A	[4]
19,370 infants born at 22–27 weeks GA in hospitals affiliated with the Neonatal Research Network of Japan	2003–16 2003 outcomes compared to 2016	NICHD 2001^Citation38	2003–16: 45.5% 2003: 41.4% (n=660) 2016: 52% (n=1122)	BPD increased: 41.4–52%, (p≤0.001) Mortality rates decreased (19–8%, (p≤0.001) IMV ≥4 weeks decreased: 70.3–57.3%, (p≤0.001) NIPPV ≥4 weeks increased: 13.9–64.6%, (p≤0.001) Higher % adverse perinatal factors: SGA, chorioamnionitis, BW <750g in 2016 population versus 2003	Supplemental O2 ≥4 weeks (aOR: 6.98, 5.8–8.41) IMV ≥4 weeks (aOR: 3.42, 3.04–3.86) BW <750g (aOR: 1.62, 1.43–1.84) SGA (aOR: 1.40, 1.22–1.61) NIPPV ≥4 weeks (aOR: 1.38, 1.25–1.52) Chorioamnionitis (aOR: 1.29, 1.17–1.43) GA<26 weeks (aOR: 1.18, 1.04–1.33) Treated PDA (aOR: 1.12, 1.02–1.23) Center volume <20 cases/yr (aOR: 1.16, 1.06–1.27)	[5]
40,268 infants born at 22–32 weeks GA at Hospitals in CA, USA	2008–2017	Shennan 1988^Citation39	BPD: 23.5% overall <28 weeks: 44.9%	Overall incidence of BPD unchanged BPD in infants >26 weeks GA decreased: (18.1% in 2008–2011 vs 16.6% in 2014–17, p =0.002 for trend) BPD in infants <750g decreased: (18.5% in 2008–2011 vs 16.6% in 2014–17, p <0.001 for trend) Mortality decreased: (31.6/100 live births to 25.5/100 live births (p<0.001 for trend) IMV in DR decreased by 46% (p=0.002) NRS increased by 75% (p<0.001)	IPPV in DR (aOR: 2.64, 2.22–3.13) predicted probability of BPD: 13.96, (10.54–18.27) NRS in DR (aOR 1.73, 1.46–2.05) Predicted probability of BPD 9.53 (7.1–12.69) IMV after DR (aOR: 10.01, 7.4–13.58) Predicted probability of BPD: 14.83 (10.97–19.75) iNO use: (aOR 3.79, 3.3–4.35) Predicted probability of BPD: 31.6 (24.23–40.01) Surfactant: (aOR: 2.88, 2.68–3.09) Predicted probability of BPD 14.94 (11–19.91)	[24]
Infants 24–27^+6 weeks GA born in Germany with data in National Database	Epoch 1: 2010–2013 n=9058 Epoch 2: 2014–2017 n=10,924	NICHD 2001^Citation38 moderate to severe with O2 needs targeting SpO2 ≥90%^Citation40	Epoch 1: 34.9% Epoch 2: 24.2%	Mortality decreased: 15.1–12.7%, (RR: 0.841, 0.784–0.901, p<0.0001) BPD decreased: 34.9–24.2%, (RR 0.693, 0.662–0.727, p<0.0001) % requiring NRS only increased: 20.7–27.8% (RR 1.342, 1.276–1.411)	N/A	[19]
379 Infants <28 weeks GA born at a single US academic center	Epoch 1: prophylactic surfactant 2010–2014 n=233 Epoch 2: Selective surfactant n=146	Shennan 1988^Citation39 NICHD 2001^Citation38 CNN^Citation41 NRN^Citation37	Epoch 1: Shennan: 32% NICHD 2001: 68% Moderate or severe: 39% CNN: 16% NRN: 41% Grade 2/3: 21% Epoch 2: Shennan: 35% NICHD 2001: 58% Moderate or severe: 37% CNN:22% NRN: 49% Grade 2/3: 19%	Significant differences in incidence were noted with varied use of definition within each epoch No significant differences noted between epochs in BPD incidence Use of PNS increased: 6–17% (p=0.002) Intubation in DR decreased: 87–52% (p<0.001) CPAP days increased: 22±16 to 40±19 (p<0.001) NIPPV days decreased: 22±17 to 14±13 (p=0.007) IMV decreased but not significantly	N/A	[22]
481 Infants <32 weeks and <1500g born in a 2 NICUs in Jerusalem, Israel	Epoch 1: 2012–2013 Epoch 2: 2018–2019	NICHD 2001^Citation38	Epoch 1: Moderate or Severe: 11% <28 weeks GA Moderate or Severe: 36% Epoch 2: Moderate or Severe: 14% <28 weeks GA Moderate or Severe: 40%	No significant changes in BPD rates Mortality rates decreased: 13.1–10.7% IMV rates increased: 33–47%, p = 0.016 Average NRS days increased: 9.24–14.08 days p=0.016% infants receiving any respiratory support increased: 63–77% (p=0.001) O2 use decreased: 10.02±17.49 vs 5.47±11.13 days (p=0.001) Total duration of respiratory support was unchanged	BW: OR: 0.0998 (0.996–0.999, p=0.003) IMV days: OR: 1.21 (1.14–1.30, p<0.001)	[42]
9181 Infants born at 23–28^+6 weeks GA, BW 501–1250g born in US Hospitals belonging to NICHD NRN	2011–2017	NRN^Citation37	BPD:60% Grade 1:34.3% Grade 2:18.8% Grade 3:6.7% n=8129 survivors at 36 weeks PMA	N/A	On DOL 1 BW was most predictive of death or BPD severity Mode of respiratory support most predictive factor on days 3,7,14 and 28	[32]
24,896 Infants born at 22–29 weeks GA at 715 US hospitals belonging to VON	2018	NRN^Citation37	BPD:45.4% Grade 1/2: 36.9% Grade 3: 3.7% n=22,322 survivors to 36 weeks PMA	N/A	Incidence of mortality and grade 3 BPD decreased proportionally as GA increased Grade 1 or 2 BPD diagnosis peaked at 25 weeks GA (51.8%) Various morbidities higher in survivors with BPD versus those with No BPD including IVH or cystic PVL, surgical NEC, LOS, severe ROP and need for home oxygen therapy	[26]
266 ELBW infants ≤28 weeks cared for at a tertiary center in Singapore	2012–2015	NICHD 2001^Citation38	Moderate or severe BPD 67%	N/A	IMV on DOL 7: (OR: 1.97, 1.3–3.1) was the only independent risk factors for the composite outcome of mortality or BPD Significant factors on univariate analysis included: Low GA, Low BW, PDA needing treatment, air leaks, FiO2 >0.25	[28]
202 VLBW infants born ≤32 weeks GA at a Level III NICU in Spain	January 1st 2013-August 30th 2020	NICHD 2001^Citation38	BPD: 28.7% Moderate or severe: 10.4%	N/A	IMV DOL 1: (OR 5.39, 1.54–18.89, p=0.008) IMV DOL 3: (OR 9.99, 2.47–40.44, p=0.001) LOS: (OR: 9.51, 2.99–30.28, p<0.001) IMV through DOL 1 and DOL 3 and LOS were independent risk factors for moderate-severe BPD	[27]
1755 preterm infants with BPD born in public and private hospitals included in a national database Median GA 27.1 weeks	January 2016-August 2020	NICHD 2001^Citation38	Mild: 52.5% Moderate: 25.3% Severe:22.2%	N/A	Factors associated with increased risk for moderate/severe versus mild BPD: Male sex (OR: 1.425, 1.134–1.791, p=0.003) Oligohydramnios (OR: 1.547, 1.120–2.212, p=0.009) Histological chorioamnionitis (OR: 1.714, 1.250–2.348, p=0.001) FiO2 >0.3 at birth (OR: 1.434, 1.098–1.874, p =0.008) FiO2 >0.6 at birth (OR:1.607, 1.211–2.132, p<0.001) IMV exposure: (OR:1.515, 1.104–2.604, p=0.01) Nosocomial pneumonia: (OR:3.231, 2.192–4.764, p<0.001) Received iNO: (OR1.76, 1.189–2.079, p=0.005)	[29]
471 <32 weeks GA infants with BPD admitted to Level IV NICU in Shanghai, China	2016–2020	NICHD 2001^Citation38	Mild: 59.2% Moderate 31.2% Severe: 9.6%	N/A	GDM: (aOR: 2.272, 1.080–4.780, p=0.031) Initial FiO2: (aOR: 1.032, 1.012–1.052, p=<0.001) IMV: (aOR: 2.593, 1.400–4.802, p=0.002) pH-min: (aOR: 0.005, 0.001–0.189, p=0.005) Cl-min: (aOR: 0.904, 0.851–0.961, p=0.001) CRP-max: (aOR: 1.026, 1.016–1.036, p<0.001) Gram negative organism in respiratory culture: (aOR: 2.311, 1.273–4.197, p=0.006) PDA: (aOR: 6.328, 2.937–13.631, p<0.001)	[30]

Abbreviations: GA, gestational age; US, United States; BPD, bronchopulmonary dysplasia; CI, confidence interval; RR, relative risk; AD, adjusted difference; aOR, adjusted odds ratio; OR, odds ratio; BW, birth weight; SGA, small for gestational age; NIPPV, nasal intermittent positive pressure ventilation; NRS, non-invasive respiratory support; IMV, invasive mechanical ventilation; IPPV, invasive positive pressure ventilation; NICHD, National Institute for Child Health and Human Development; NRN, Neonatal Research Network; NICU, Neonatal Intensive Care Unit; PDA, patent ductus arteriosus; iNO, inhaled nitric oxide; PNS, post-natal steroids; CNN, Canadian Neonatal Network; CPAP, continuous positive airways pressure; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; NEC, necrotizing enterocolitis; LOS, late onset sepsis; ROP, retinopathy of prematurity; FiO₂, fraction of inspired oxygen; O₂, oxygen; SpO₂, oxygen saturation; DR, delivery room; Cl, chloride; CRP, C-reactive protein.

Table 2 A Summary of Evidence-Based Recommendations for Prevention and Management of BPD

Therapeutic Intervention	Current Status	Evidence Level	Recommendation Level
Early phase (up to 1 postnatal week)
Oxygen supplementation	Resuscitation:	I	B
	Titrate supplemental oxygen to obtain preductal oxygen saturation >80% by five minutes of life^Citation86
	Maintain oxygen saturations 90–95%^Citation87	I	A
Ventilatory strategy	Trial of CPAP for spontaneously breathing infants	I	A
	Aim to give surfactant within 2 hours of life^Citation88,Citation89	I	A
	Surfactant administration for infants requiring intubation in DR^Citation89	II	A
	Consider surfactant administration if FiO2 remains consistently ≥0.3 on PEEP +6 cm H20^Citation89–91	II	A
	Use InSurE/LISA technique to administer surfactant^Citation89	I	B
	Use early NIPPV^Citation92	I	A
	Lung protective strategies: Consider volume targeted ventilation strategies – TV 4–6mL/kg^Citation93 or HFOV^Citation94	I	A
	Use short inspiratory times (0.3–0.4 s),^Citation95 rapid rates (40–60 per min) and low PIP on pressure control settings (14 −20 cm H2O), moderate PEEP (4–6 cm H2O)^Citation96	III	B
	PaO2: 40–60mmHg; PaCO2:45–55 mmHg^Citation97
	No proven advantage to higher CO2 limits^Citation98
	Trial of extubation to NIPPV prior to 7 days in infants who tolerate weaning to minimal settings^Citation99	II-2	B
Methylxanthines	Administration of caffeine within first 3 days of life decreases BPD,^Citation100,Citation101 improves neurodevelopmental outcome^Citation102	I	A
	Improves successful extubation rate^Citation103	I	A
Intratracheal administration of budesonide and surfactant	Associated with an increase in BPD free survival (NNT 4.1 [95% CI: 2.8–7.8])^Citation104	I	B
	Studies to date not adequately powered to assess long term neurodevelopmental outcome
Vitamin A	Improves BPD free survival with reported NNT 14–15^Citation105 Not associated with long term improved respiratory outcome^Citation106 Dose: 5000 IU given intramuscularly 3 times a week for 4 weeks	I	A
Low dose hydrocortisone	Low dose hydrocortisone (total dose 8.5mg over 10 days) is associated with increased BPD free survival^Citation107	I	C
	Increased risk of late onset sepsis in infants <26 weeks^Citation107
	Increased risk of SIP in infants who receive indomethacin^Citation107
Antibiotics	Consider withholding early antibiotic treatment in infants delivered in the absence of preterm labor, preterm ROM or concerns for chorioamnionitis^Citation108	II	B
Fluids	Avoiding excessively positive fluid balance may prevent BPD^Citation109,Citation110	II-2	B
Nutrition	Exclusive human milk feeding reduces the risk for BPD^Citation111	I	A
	Provide increased energy intake^Citation110,Citation112	II-2	A
Evolving BPD (> 1 postnatal week to 36 weeks PMA)
Dexamethasone	Low dose dexamethasone (0.89 mg/kg over 10 days) facilitates extubation but does not reduce BPD^Citation113	I	C
	High dose dexamethasone (0.5mg/kg – 1mg/kg) reduces BPD but may increase the risk of NDI and CP^Citation114	I	C
	Greatest global benefit is for infants with combined risk of mortality and Grade 2/3 BPD >52% - ie those who remain intubated at 3–4 weeks post-natal age.^Citation115
Ventilatory strategy	Avoid endotracheal tube ventilation, encourage non-invasive support strategies (NIPPV, SNIPPV, nCPAP)^Citation116	I	A
	Blood gas targets: pH 7.25–7.35; PaO2 50–70mmHg; PCO2 50–60 mmHg^Citation97	I	A
	No advantage to allowing higher CO2 limit^Citation98	II	B
	Continue CPAP/NIPPV/NIV-NAVA until 32 weeks PMA may help optimize FRC^Citation117	II	A
Diuretics	May improve respiratory mechanics and facilitate weaning of support. Do not prevent BPD. Continue use only if clear response demonstrated^Citation118	I	B
Antibiotics	Same as for early phase
	Preterm infants remain at risk for sepsis, but antibiotics used in the absence of infection can increase risk for BPD^Citation119	I	A
	Strongly consider discontinuing antibiotics at 48h if cultures are negative
Nutrition	Same as for early phase
Methylxanthines	Same as for early phase	I	A
Established phase (>36 weeks PMA)
Echocardiographic screening for BPD PH Ventilatory strategy	25% of infants with moderate or severe BPD have echocardiographic evidence of pulmonary hypertension^Citation120	III	A
	SIMV or NAVA modalities over HFOV	III	A
	Use large tidal volumes (8–15mL/kg), long I-time (0.5–1s), low respiratory rates (12–20 per minute), high PEEP (8–12 cmH2O)Wean slowly, with goals to reduce work of breathing, improve growth and participation in developmental therapies
Bronchodilators	May improve symptoms in subpopulations of affected infants^Citation121	II-3	B
Inhaled steroidsSystemic steroids	Later use may improve symptoms in subpopulations of infants^Citation121	III	B
	Brief use of prednisolone may help wean support or provide symptomatic relief during exacerbation^Citation122	II	B
Diuretics	Chronic therapy as for the evolving phase^Citation118	I	B
	Consider allowing infant to outgrow dose^Citation121	III	B
Nutrition	Monitor linear growth closely^Citation123	II	A
	Adjust approach according to clinical phase, avoid holding of enteral feeds^Citation124	III	A
	Avoid excessive weight gain.
Immunization	Prophylaxis against RSV and influenza decreases re-hospitalization and morbidity	II-2	A
	RSV prophylaxis is cost-effective^Citation125	I	A

Note: Adapted by permission from BMJ Publishing Group Limited. Diagnosis and management of bronchopulmonary dysplasia. Gilfillan M, Bhandari A, Bhandari V, 375:n1974, copyright notice 2021.³³

Abbreviations: nCPAP, nasal continuous positive airway pressure; FiO₂, fraction of inspired oxygen; PEEP, positive end-expiratory pressure; InSurE, intubation, surfactant administration, extubation; LISA, less invasive surfactant administration; TV, tidal volume; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PIP, peak inspiratory pressure; NIPPV, nasal intermittent positive pressure ventilation; SIP, spontaneous intestinal perforation; NDI, neurodevelopmental impairment; CP, cerebral palsy; RSV, respiratory syncytial virus, FRC, functional residual capacity; NIV-NAVA, non-invasive ventilation-neurally adjusted ventilatory assist.

Table 3 A Summary of the Strategies and Results of three Recent QI Projects That Successfully Reduced Adverse Pulmonary Outcome

Site and Population	Global Aim	Key Drivers	Bundle Components	Outcomes	Ref
42 bed level III NICU, USA 132 infants <32 weeks GA admitted during study period Mean GA 29 weeks	To reduce number of patients discharged on supplemental O2	Limitation of high PIPs on conventional IMV Consistency in use of different IMV modalities Consistency in use of medications Consistency in delivery room management	1st PDSA Cycle: (January 2018 – April 2019) Indications for initial surfactant administration and repeat dosing HFOV as primary mode in infants <28 weeks GA, HFOV until extubation or ≥2 weeks of age Caffeine on admission in all infants <32 weeks GA 2nd PDSA Cycle (May 2019-January 2020) Indications for DR intubation: PPV for >5 mins or FiO2 >0.6 SIMV-VG as primary mode in infants ≥28 weeks GA, limit PIPs to 24–25cmH2O Extubation and reintubation guidelines -Settings for pressure and rate that should prompt extubation -Failure defined by blood gas parameters and frequency of apneic events -Guidelines regarding NRS initiation and weaning process, CPAP until 32 weeks for infants who fail RA trial - Bronchodilators and diuretics limited to patients who showed benefit	Infants <32 weeks GA discharged on O2: 19.5% to 8.3% Grade II/III BPD in infants <32 weeks: 54.4% to 28.6%	[84]
24-bed, Level III NICU, USA 449 infants<33 weeks admitted during study period Mean GA 28.5 weeks	Decrease BPD according to VON BPD <33wk criteria (O2 dependency at 36 weeks PMA in infants <33 weeks GA)	A shared mental model that BPD is preventable Consistent GA and PMA specific practices	Initial Responses (2010–2014) “Shared mental model that BPD is avoidable but requires aggressive preventative care” – Enhanced communication re protocol compliance, consensus building regarding management changes GA and PMA specific interventions: Early CPAP, surfactant administration guidelines, SIMV-VG as primary mode, HFOV for rescue Extubation criteria, CPAP or NIPPV phasing into NIV-NAVA post extubation, delay weaning to HFNC until 32 weeks PMA Caffeine, Vitamin A and IVIG for ELBW and <28 weeks GA, dexamethasone criteria and protocol, inhaled medications as rescue, avoidance of diuretics, Azithromycin prophylaxis pending cultures, limit use of other antibiotics MBM/DBM as base for feeds with bovine supplements Additions to protocols - Full implementation (2015–2019 “No BPD Roadmap”, Surfactant criteria expanded, HFOV as primary mode for ELBW <28 weeks, NIV-NAVA until 32 weeks PMA, human milk for both base and fortifier, avoid pharmacological treatment of reflux and PDA	BPD in infants <33wk (VON): 31% to 1.6% (p <0.001) BPD in infants <28 wk (VON): 50% to 1.2% (p <0.001) BPD in infants <26 wk VON): 35.7 to 2.6% (p=0.03) O2 at D/C:13.8 to 2.2% (p =0.03)	[83]
49 bed academic Level III NICU, USA 611 infants <32 weeks GA admitted during the baseline and study periods Median GA 29 weeks	Decrease moderate to severe BPD by NICHD 2001 criteria^Citation38 by 35%	Effective team communication re: DR plan and preparation Standardization of DR resuscitation Awareness of InSurE guideline Comfort using NRS equipment Standardization of orders sets Care team guideline support Uncertainty regarding optimal timing of surfactant	DR care bundle Q1 2017-Q4 2017 -Pre-delivery huddle before every <32 weeks GA delivery -GA specific guidelines for initiation and escalation of NRS and threshold for surfactant administration -Caffeine within 24 hr of life Compliance with weaning pathway Q1 2018-Q2 2020 -Maintain infants <32 weeks GA on NRS until at least ≥32 weeks PMA Revision of surfactant guideline Q3 2020-Q1 2021 -Revised GA specific protocol to include early selective surfactant administration determined by NRS requirements in the DR and at 90 minutes of age -Surfactant in all infants intubated unless for respiratory depression -Surfactant by InSurE method for infants on NRS meeting selective treatment criteria	Moderate to severe BPD: 38 to 15% (p <0.0001) Moderate to severe BPD or death: 48 to 26% (p =0.0009) IMV requirement: 52 to 27% (p = 0.0025) Postnatal steroids: 19 to 10% (p = 0.02)	[85]

Abbreviations: NICU, neonatal intensive care unit; USA, United States of America; GA, gestational age; O₂, oxygen; PIP, positive inspiratory pressure; IMV, invasive mechanical ventilation; PDSA, “plan, do, study, act” cycle; HFOV, high frequency oscillatory ventilation; DR, delivery room; FiO₂, fraction of inspired oxygen; PPV, positive pressure ventilation; SIMV-VG, synchronized intermittent ventilation volume guarantee; NRS, non-invasive respiratory support; RA, room air; VON, Vermont Oxford Network; NIV-NAVA, non-invasive ventilation-neurally adjusted ventilatory assist; PMA, post menstrual age; IVIG, intravenous immunoglobulin; ELBW, extremely low birthweight (<1000g); MBM, maternal breast milk; DBM, donor breastmilk; mins, minutes; NICHD, National Institute of Child Health and Human Development; InSurE, Intubate Surfactant Extubate; PDA, patent ductus arteriosus; Q, quarter.

Table 4 A Summary of Emerging Therapies for BPD Currently Being Evaluated in Clinical Trials

Novel Treatment	Current Evidence	Mechanisms of Benefit	Future Directions
High dose vitamin C to pregnant smoking women 500mg/day	RCT n=159 newborns. Increased ratio of time to peak tidal expiratory peak flow and increased compliance/kg in newborns. Decreased wheezing in first year of life.^Citation249 RCT n=222 Increased forced expiratory flows at 3 months of age and at 12 months of age in prenatal high dose vitamin C group.^Citation250	Reduces effect of nicotine in promoting increased collagen deposition in small airways of fetus. Exposure to vitamin C alters DNA methylation patterns. Hyper-methylation of DIP2C, APOH/PRKCA genes noted in placental DNA specimens from women who received vitamin C was associated with decreased wheezing and improved lung function.^Citation251 Potential reduction in morbidity from small airway disease phenotype of BPD.	RCT with more patients enrolled currently underway. Follow up of lung function tests from infancy to adolescence. Tracking of DNA methylation patterns linked with maternal smoking. (NCT03206710)
N-Acetylcysteine (NAC) to women with chorioamnionitis at risk of preterm delivery	RCT n=67. NAC exposed newborns required less intensive resuscitation at birth. BPD reduced: 3% versus 32% (RR:0.1, 95% CI:0.01–0.73).^Citation252	NAC acts as a free radical scavenger and inhibitor of histone deacetylase. Has anti-fibrotic and anti-inflammatory properties. Potential to reduce early sensitization of the lung to further inflammatory exposures such as IMV and supplemental O2.	Needs evaluation in a larger prospective RCT.
Budesonide mixed with surfactant for RDS	RCT n=265 VLBW infants with RDS. 0.25mg/kg budesonide associated with reduced risk for BPD and mortality (RR 0.58, 95% CI: 0.44–0.77; p <0.001), NNT 4.1 (95% CI 2.8–7.8)].^Citation104	Reduces cytokine expression in TA aspirates of preterm infants.^Citation104,Citation253 Modulates inflammatory responses induced by prenatal^Citation254 and postnatal^Citation255 inflammatory stimuli and accelerates lung maturity^Citation256 in preterm lambs. Benefits lung parenchyma and small airways.	Existing RCTs underpowered for long term outcomes. Phase 3 RCT currently underway (NCT04545866).
rhIGF-1/rhIGFBP-3 infusion from birth to 29^+6 weeks GA	RCT n=121 EP 23–27+6 wks GA. Associated with reduced BPD (23% vs 44.9%, p = 0.04).^Citation257	rhIGF-1/rhIGFBP-3 preserved alveolar development and RV remodeling in rats exposed to two different experimental models of BPD-PH.^Citation258 Potential to benefit parenchymal, interstitial and pulmonary vascular development.	Phase 2b RCT underway. (NCT03253263)
Mesenchymal stem cell (MSC) based therapies	Phase II RCT n=66. Infants 23–28 wks GA on IMV randomized at 5–14 days of life to intra-tracheal administration of umbilical cord blood MSCs. Moderate to severe BPD reduced in 23–24 weeks GA subgroup (53–18%) but not in the 25–28 wks GA subgroup.^Citation259	Multiple data from animal studies indicate the benefits derived from MSC exposure are mediated by the content of exosomes.^Citation260 Exosomes contain miRs and regulatory proteins that reduce inflammation. Pulmonary vascular and alveolar development is maintained even in the presence of inflammatory and anti-angiogenic insults.^Citation261 Potential to preserve normal alveolar and pulmonary vascular development.	Multiple Phase 1 and Phase 2 RCT studies underway. (NCT04255147) (NCT03645525) (NCT03631420) (NCT03392467)

Abbreviations: RCT, randomized controlled trial; DIP2C, disco interacting protein 2 C; APOH, apolipoprotein; PRKCA, protein kinase C alpha; DNA, deoxyribonucleic acid; NAC, N-acetylcysteine; VLBW, very low birth weight; RDS, respiratory distress syndrome; rhIGF-1, recombinant human insulin growth factor-1; rhIGFBP3, recombinant human insulin binding protein 3; GA, gestational age; wks, weeks; IMV, invasive mechanical ventilation; EP, extremely preterm; BPD, bronchopulmonary dysplasia; PH, pulmonary hypertension; RR, relative risk; NNT, number needed to treat; CI, confidence interval; miR, microRNA; MSC, mesenchymal stem cells.

Table 5 Summary of the Approach Used for Patients with Established BPD at Nationwide Children’s Hospital, Columbus, Ohio, USA

BPD Phase	Clinical Characteristics	Relative Cardiopulmonary Support Requirements	Nutritional Recommendations
I: Acute	Frequent desaturations Increased work of breathing Irritability Unable to tolerate developmental therapy Variable weight gain Poor linear growth	Increased FiO2 Increased positive pressure Systemic corticosteroids Pulmonary vasodilators in setting of BPH-PH Sedation Pharmacological paralysis	Fluids: 120–150mL/kg/day Energy: 120–150kcal/kg/day Protein: 4g/kg/day 24–26kcal/oz FBM or formula 24–30kcal/oz Consider MCT oil or liquid protein
II: Transitional	Improved work of breathing Brief time periods in quiet alert state Tolerates low-level activities Improving weight trend Slow linear growth	FiO2 typically ≤0.6 Tolerates slow weaning of respiratory support and de-escalation of medications	Fluids: 120–140mL/kg/day Energy: 110–120kcal/kg/day Protein: 2.5–4g/kg/day
III: Pro-growth	Comfortable work of breathing Tolerates therapies well Developmental progress Weight-for-length trend improves Consistent linear growth	Respiratory requirements stable Corticosteroid and sedation requirements minimal to none PH well controlled	Fluids: 110–130mL/kg/day Energy: 70–120kcal/kg/day Protein: 2.5–3g/kg/day

Notes: Data from Miller AN, Curtiss J, Taylor SN, Backes CH, Kielt MJ. A review and guide to nutritional care of the infant with established bronchopulmonary dysplasia. J Perinatol. 2023;43(3):402–410. doi:10.1038/s41372-022-01578-0.24¹²⁴

Abbreviations: BPD, bronchopulmonary dysplasia; FiO₂, fraction of inspired oxygen; BPD-PH, BPD associated pulmonary hypertension; mL, milliliters; Kg, kilogram; Kcal, kilocalories; FBM, fortified breast milk; MCT, medium chain triglycerides; g, grams.

Figure 1 Multiple exposures during the prenatal and postnatal periods contribute to the development of BPD. Stimuli encountered in the prenatal and early postnatal period appear to have the strongest influence in determining long-term pulmonary outcome. These exposures and their potential for generating inflammatory responses and altered lung development are outlined in the top part of the figure. The lower boxes summarize key strategies needed to prevent and manage early, evolving and established BPD in a system-based manner.

Abbreviations: BPD, bronchopulmonary dysplasia; wks, weeks; GA, gestational age; GDM, gestational diabetes mellitus; RDS, respiratory distress syndrome; hsPDA, hemodynamically significant patent ductus arteriosus; IMV, invasive mechanical ventilation; DOL, day of life; wks, weeks; PMA, postmenstrual age; LISA, less invasive surfactant administration; InSurE, Intubate; surfactant; extubate; NRS, non-invasive respiratory support; CPAP, continuous positive airways pressure; NIPPV, nasal intermittent positive pressure ventilation; HFOV, high frequency oscillatory ventilation; TV, tidal volume; Ti, inspiratory time; PEEP, positive end expiratory pressure; RR, respiratory rate; PNS, postnatal steroids; Wt, weight; abx, antibiotics; OMM, own mother’s milk.

Jensen EA, Dysart K, Gantz MG, et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. An evidence-based approach. Am J Respir Crit Care Med. 2019;200(6):751–759. doi:10.1164/rccm.201812-2348OC

 PubMed Web of Science ®Google Scholar

Bell EF, Hintz SR, Hansen NI, et al. Mortality, in-hospital morbidity, care practices, and 2-year outcomes for extremely preterm infants in the US, 2013–2018. JAMA. 2022;327(3):248–263. doi:10.1001/jama.2021.23580

 PubMed Web of Science ®Google Scholar

Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723–1729. doi:10.1164/ajrccm.163.7.2011060

 PubMedGoogle Scholar

Nakashima T, Inoue H, Sakemi Y, et al. Trends in bronchopulmonary dysplasia among extremely preterm infants in Japan, 2003–2016. J Pediatr. 2021;230:119–125.e7. doi:10.1016/j.jpeds.2020.11.041

 PubMed Web of Science ®Google Scholar

Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics. 1988;82(4):527–532. doi:10.1542/peds.82.4.527

 PubMed Web of Science ®Google Scholar

Lee SM, Sie L, Liu J, Profit J, Lee HC. Evaluation of trends in bronchopulmonary dysplasia and respiratory support practice for very low birth weight infants: a population-based cohort study. J Pediatr. 2022;243:47–52.e2. doi:10.1016/j.jpeds.2021.11.049

 PubMed Web of Science ®Google Scholar

Walsh MC, Yao Q, Gettner P, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics. 2004;114(5):1305–1311. doi:10.1542/peds.2004-0204

 PubMed Web of Science ®Google Scholar

Bührer C, Heller G, Thome UH. Population-based outcome data of extremely preterm infants in Germany during 2010–2017. Neonatology. 2022;119(3):370–376. doi:10.1159/000524455

 PubMed Web of Science ®Google Scholar

Isayama T, Lee SK, Yang J, et al. Revisiting the definition of bronchopulmonary dysplasia: effect of changing panoply of respiratory support for preterm neonates. JAMA Pediatr. 2017;171(3):271–279. doi:10.1001/jamapediatrics.2016.4141

 PubMed Web of Science ®Google Scholar

Chung J, Iyengar A, Santry L, Swanson E, Davis JM, Volpe MV. Changes in respiratory management and the impact on bronchopulmonary dysplasia. Pediatr Pulmonol. 2022;57(10):2327–2334. doi:10.1002/ppul.26035

 PubMed Web of Science ®Google Scholar

Adler-Haltovsky T, Gileles-Hillel A, Erlichman I, Eventov-Friedman S. Changes in ventilation modes in the last decade and their impact on the prevalence of bronchopulmonary dysplasia in preterm infants. Pediatr Pulmonol. 2023;58(7):1959–1966. doi:10.1002/ppul.26418

 PubMed Web of Science ®Google Scholar

Greenberg RG, McDonald SA, Laughon MM, et al. Online clinical tool to estimate risk of bronchopulmonary dysplasia in extremely preterm infants. Arch Dis Child Fetal Neonatal Ed. 2022;107(6):638–643. doi:10.1136/archdischild-2021-323573

 Web of Science ®Google Scholar

Jensen EA, Edwards EM, Greenberg LT, Soll RF, Ehret DEY, Horbar JD. Severity of bronchopulmonary dysplasia among very preterm infants in the United States. Pediatrics. 2021;148(1). doi:10.1542/peds.2020-030007

 PubMed Web of Science ®Google Scholar

Geetha O, Rajadurai VS, Anand AJ, et al. New BPD-prevalence and risk factors for bronchopulmonary dysplasia/mortality in extremely low gestational age infants ≤28 weeks. J Perinatol. 2021;41(8):1943–1950. doi:10.1038/s41372-021-01095-6

 PubMed Web of Science ®Google Scholar

Sucasas Alonso A, Pértega Diaz S, Sáez Soto R, Avila-Alvarez A. Epidemiology and risk factors for bronchopulmonary dysplasia in preterm infants born at or less than 32 weeks of gestation. An Pediatr. 2022;96(3):242–251. doi:10.1016/j.anpede.2021.03.006

 Google Scholar

Ramos-Navarro C, Maderuelo-Rodríguez E, Concheiro-Guisán A, et al. Risk factors and bronchopulmonary dysplasia severity: data from the Spanish Bronchopulmonary Dysplasia Research Network. Eur J Pediatr. 2022;181(2):789–799. doi:10.1007/s00431-021-04248-z

 PubMed Web of Science ®Google Scholar

He W, Zhang L, Feng R, et al. Risk factors and machine learning prediction models for bronchopulmonary dysplasia severity in the Chinese population. World J Pediatr. 2023;19(6):568–576. doi:10.1007/s12519-022-00635-0

 PubMed Web of Science ®Google Scholar

Oei JL, Vento M, Rabi Y, et al. Higher or lower oxygen for delivery room resuscitation of preterm infants below 28 completed weeks gestation: a meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2017;102(1):F24–F30. doi:10.1136/archdischild-2016-310435

 PubMed Web of Science ®Google Scholar

Askie LM, Darlow BA, Davis PG, et al. Effects of targeting lower versus higher arterial oxygen saturations on death or disability in preterm infants. Cochrane Database Syst Rev. 2017;4:CD011190. doi:10.1002/14651858.CD011190.pub2

 PubMed Web of Science ®Google Scholar

Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2012;11(11):CD001456. doi:10.1002/14651858.CD001456.pub2

 PubMed Web of Science ®Google Scholar

Bhandari V, Black R, Gandhi B, et al. RDS-NExT workshop: consensus statements for the use of surfactant in preterm neonates with RDS. J Perinatol. 2023;43(8):982–990. doi:10.1038/s41372-023-01690-9

 PubMed Web of Science ®Google Scholar

Lemyre B, Deguise MO, Benson P, Kirpalani H, Ekhaguere OA, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev. 2023;7(7):CD005384. doi:10.1002/14651858.CD005384.pub3

 PubMedGoogle Scholar

Klingenberg C, Wheeler KI, McCallion N, Morley CJ, Davis PG. Volume-targeted versus pressure-limited ventilation in neonates. Cochrane Database Syst Rev. 2017;10(10):CD003666. doi:10.1002/14651858.CD003666.pub4

 PubMedGoogle Scholar

Cools F, Offringa M, Askie LM. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev. 2015;3:CD000104. doi:10.1002/14651858.CD000104.pub4

 Google Scholar

Kamlin C, Davis PG. Long versus short inspiratory times in neonates receiving mechanical ventilation. Cochrane Database Syst Rev. 2004;4:CD004503. doi:10.1002/14651858.CD004503.pub2

 Google Scholar

Ambalavanan N, Carlo WA. Ventilatory strategies in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol. 2006;30(4):192–199. doi:10.1053/j.semperi.2006.05.006

 PubMed Web of Science ®Google Scholar

Thome UH, Ambalavanan N. Permissive hypercapnia to decrease lung injury in ventilated preterm neonates. Semin Fetal Neonatal Med. 2009;14(1):21–27. doi:10.1016/j.siny.2008.08.005

 PubMed Web of Science ®Google Scholar

Thome UH, Genzel-Boroviczeny O, Bohnhorst B, et al. Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial. Lancet Respir Med. 2015;3(7):534–543. doi:10.1016/S2213-2600(15)00204-0

 PubMed Web of Science ®Google Scholar

Bhandari V. Nasal intermittent positive pressure ventilation in the newborn: review of literature and evidence-based guidelines. J Perinatol. 2010;30(8):505–512. doi:10.1038/jp.2009.165

 PubMed Web of Science ®Google Scholar

Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354(20):2112–2121. doi:10.1056/NEJMoa054065

 PubMed Web of Science ®Google Scholar

Davis PG, Schmidt B, Roberts RS, et al. Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. J Pediatr. 2010;156(3):382–387. doi:10.1016/j.jpeds.2009.09.069

 PubMed Web of Science ®Google Scholar

Doyle LW, Schmidt B, Anderson PJ, et al. Reduction in developmental coordination disorder with neonatal caffeine therapy. J Pediatr. 2014;165(2):356–359.e2. doi:10.1016/j.jpeds.2014.04.016

 PubMed Web of Science ®Google Scholar

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev. 2010;12:CD000139. doi:10.1002/14651858.CD000139.pub2

 Google Scholar

Yeh TF, Chen CM, Wu SY, et al. Intratracheal administration of budesonide/surfactant to prevent bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2016;193(1):86–95. doi:10.1164/rccm.201505-0861OC

 PubMed Web of Science ®Google Scholar

Tyson JE, Wright LL, Oh W, et al. Vitamin A supplementation for extremely-low-birth-weight infants. National institute of child health and human development neonatal research network. N Engl J Med. 1999;340(25):1962–1968. doi:10.1056/NEJM199906243402505

 PubMed Web of Science ®Google Scholar

Ambalavanan N, Tyson JE, Kennedy KA, et al. Vitamin A supplementation for extremely low birth weight infants: outcome at 18 to 22 months. Pediatrics. 2005;115(3):e249–54. doi:10.1542/peds.2004-1812

 PubMed Web of Science ®Google Scholar

Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021;10(10):CD001146. doi:10.1002/14651858.CD001146.pub6

 PubMedGoogle Scholar

Letouzey M, Lorthe E, Marchand-Martin L, et al. Early antibiotic exposure and adverse outcomes in very preterm infants at low risk of early-onset sepsis: the EPIPAGE-2 cohort study. J Pediatr. 2022;243:91–98.e4. doi:10.1016/j.jpeds.2021.11.075

 PubMed Web of Science ®Google Scholar

Starr MC, Griffin R, Gist KM, et al. Association of fluid balance with short- and long-term respiratory outcomes in extremely premature neonates: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2022;5(12):e2248826. doi:10.1001/jamanetworkopen.2022.48826

 PubMed Web of Science ®Google Scholar

Uberos J, Jimenez-Montilla S, Molina-Oya M, García-Serrano JL. Early energy restriction in premature infants and bronchopulmonary dysplasia: a cohort study. Br J Nutr. 2020;123(9):1024–1031. doi:10.1017/S0007114520000240

 PubMed Web of Science ®Google Scholar

Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feeding of extremely premature infants. Pediatrics. 2005;116(2):400–406. doi:10.1542/peds.2004-1974

 PubMed Web of Science ®Google Scholar

Uberos-Fernández J, Ruiz-López A, Carrasco-Solis M, Fernandez-Marín E, Garcia-Cuesta A, Campos-Martínez A. Extrauterine growth restriction and low energy intake during the early neonatal period of very low birth weight infants are associated with decreased lung function in childhood. Br J Nutr. 2023;1–9. doi:10.1017/S0007114523001332

 Web of Science ®Google Scholar

Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB, Investigators DS. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics. 2006;117(1):75–83. doi:10.1542/peds.2004-2843

 PubMed Web of Science ®Google Scholar

Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Late (≥ 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021;11(11):CD001145. doi:10.1002/14651858.CD001145.pub5

 PubMedGoogle Scholar

Jensen EA, Wiener LE, Rysavy MA, et al. Assessment of corticosteroid therapy and death or disability according to pretreatment risk of death or bronchopulmonary dysplasia in extremely preterm infants. JAMA Netw Open. 2023;6(5):e2312277. doi:10.1001/jamanetworkopen.2023.12277

 PubMed Web of Science ®Google Scholar

Dumpa V, Avulakunta I, Bhandari V. Respiratory management in the premature neonate. Expert Rev Respir Med. 2023;17(2):155–170. doi:10.1080/17476348.2023.2183843

 PubMed Web of Science ®Google Scholar

Lam R, Schilling D, Scottoline B, et al. The effect of extended continuous positive airway pressure on changes in lung volumes in stable premature infants: a randomized controlled trial. J Pediatr. 2020;217:66–72.e1. doi:10.1016/j.jpeds.2019.07.074

 PubMed Web of Science ®Google Scholar

Stewart A, Brion LP, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for preterm infants with (or developing) chronic lung disease. Cochrane Database Syst Rev. 2011;9:CD001817. doi:10.1002/14651858.CD001817.pub2

 Google Scholar

Hou S, Yu Y, Wu Y, et al. Association between antibiotic overexposure and adverse outcomes in very-low-birth-weight infants without culture-proven sepsis or necrotizing enterocolitis: a multicenter prospective study. Indian J Pediatr. 2022;89(8):785–792. doi:10.1007/s12098-021-04023-w

 PubMed Web of Science ®Google Scholar

Hansmann G, Koestenberger M, Alastalo TP, et al. 2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: the European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT. J Heart Lung Transplant. 2019;38(9):879–901. doi:10.1016/j.healun.2019.06.022

 PubMed Web of Science ®Google Scholar

Duijts L, van Meel ER, Moschino L, et al. European respiratory society guideline on long-term management of children with bronchopulmonary dysplasia. Eur Respir J. 2020;55(1):1900788. doi:10.1183/13993003.00788-2019

 PubMed Web of Science ®Google Scholar

Bhandari A, Schramm CM, Kimble C, Pappagallo M, Hussain N. Effect of a short course of prednisolone in infants with oxygen-dependent bronchopulmonary dysplasia. Pediatrics. 2008;121(2):e344–9. doi:10.1542/peds.2006-3668

 PubMed Web of Science ®Google Scholar

Miller AN, Moise AA, Cottrell L, Loomis K, Polak M, Gest A. Linear growth is associated with successful respiratory support weaning in infants with bronchopulmonary dysplasia. J Perinatol. 2022;42(4):544–545. doi:10.1038/s41372-022-01322-8

 PubMed Web of Science ®Google Scholar

Miller AN, Curtiss J, Taylor SN, Backes CH, Kielt MJ. A review and guide to nutritional care of the infant with established bronchopulmonary dysplasia. J Perinatol. 2023;43(3):402–410. doi:10.1038/s41372-022-01578-0

 PubMed Web of Science ®Google Scholar

Narayan O, Bentley A, Mowbray K, et al. Updated cost-effectiveness analysis of palivizumab (Synagis) for the prophylaxis of respiratory syncytial virus in infant populations in the UK. J Med Econ. 2020:1–13. doi:10.1080/13696998.2020.1836923

 PubMed Web of Science ®Google Scholar

Gilfillan M, Bhandari A, Bhandari V. Diagnosis and management of bronchopulmonary dysplasia. BMJ. 2021;375:n1974. doi:10.1136/bmj.n1974

 PubMedGoogle Scholar

Ratliff-Crain D, Wallingford B, Jorgenson L. Using a bundle approach to prevent bronchopulmonary dysplasia in very premature infants. Adv Neonatal Care. 2022;22(4):300–308. doi:10.1097/ANC.0000000000000920

 PubMed Web of Science ®Google Scholar

Villosis MFB, Barseghyan K, Ambat MT, Rezaie KK, Braun D. Rates of bronchopulmonary dysplasia following implementation of a novel prevention bundle. JAMA Netw Open. 2021;4(6):e2114140. doi:10.1001/jamanetworkopen.2021.14140

 PubMed Web of Science ®Google Scholar

White H, Merritt K, Martin K, Lauer E, Rhein L. Respiratory support strategies in the prevention of bronchopulmonary dysplasia: a single center quality improvement initiative. Front Pediatr. 2022;10:1012655. doi:10.3389/fped.2022.1012655

 PubMed Web of Science ®Google Scholar

McEvoy CT, Schilling D, Clay N, et al. Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial. JAMA. 2014;311(20):2074–2082. doi:10.1001/jama.2014.5217

 PubMed Web of Science ®Google Scholar

McEvoy CT, Shorey-Kendrick LE, Milner K, et al. Vitamin C to pregnant smokers persistently improves infant airway function to 12 Months of age: a randomised trial. Eur Respir J. 2020;56(6):1902208. doi:10.1183/13993003.02208-2019

 Web of Science ®Google Scholar

Shorey-Kendrick LE, McEvoy CT, O’Sullivan SM, et al. Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes. Clin Epigenetics. 2021;13(1):177. doi:10.1186/s13148-021-01161-y

 PubMed Web of Science ®Google Scholar

Buhimschi CS, Bahtiyar MO, Zhao G, et al. Antenatal N-acetylcysteine to improve outcomes of premature infants with intra-amniotic infection and inflammation (triple I): randomized clinical trial. Pediatr Res. 2021;89(1): 175–184. doi:10.1038/s41390-020-01106-w

 PubMed Web of Science ®Google Scholar

McEvoy CT, Ballard PL, Ward RM, et al. Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE). Pediatr Res. 2020;88(4):629–636. doi:10.1038/s41390-020-0792-y

 PubMed Web of Science ®Google Scholar

Hillman NH, Kemp MW, Fee E, et al. Budesonide with surfactant decreases systemic responses in mechanically ventilated preterm lambs exposed to fetal intra-amniotic lipopolysaccharide. Pediatr Res. 2021;90(2):328–334. doi:10.1038/s41390-020-01267-8

 PubMed Web of Science ®Google Scholar

Hillman NH, Kothe TB, Schmidt AF, et al. Surfactant plus budesonide decreases lung and systemic responses to injurious ventilation in preterm sheep. Am J Physiol Lung Cell Mol Physiol. 2020;318(1):L41–L48. doi:10.1152/ajplung.00203.2019

 PubMed Web of Science ®Google Scholar

Kothe TB, Royse E, Kemp MW, et al. Effects of budesonide and surfactant in preterm fetal sheep. Am J Physiol Lung Cell Mol Physiol. 2018;315(2):L193–L201. doi:10.1152/ajplung.00528.2017

 PubMed Web of Science ®Google Scholar

Ley D, Hallberg B, Hansen-Pupp I, et al. rhIGF-1/rhIGFBP-3 in preterm infants: a phase 2 randomized controlled trial. J Pediatr. 2019;206:56–65.e8. doi:10.1016/j.jpeds.2018.10.033

 PubMed Web of Science ®Google Scholar

Seedorf G, Kim C, Wallace B, et al. rhIGF-1/BP3 preserves lung growth and prevents pulmonary hypertension in experimental bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2020;201(9):1120–1134. doi:10.1164/rccm.201910-1975OC

 PubMed Web of Science ®Google Scholar

Ahn SY, Chang YS, Lee MH, et al. Stem cells for bronchopulmonary dysplasia in preterm infants: a randomized controlled phase II trial. Stem Cells Transl Med. 2021;10(8):1129–1137. doi:10.1002/sctm.20-0330

 PubMed Web of Science ®Google Scholar

Omar SA, Abdul-Hafez A, Ibrahim S, et al. Stem-cell therapy for bronchopulmonary dysplasia (BPD) in newborns. Cells. 2022;11(8):1275. doi:10.3390/cells11081275

 PubMed Web of Science ®Google Scholar

Wu S, Benny M, Duara J, et al. Extracellular vesicles: pathogenic messengers and potential therapy for neonatal lung diseases. Front Pediatr. 2023;11:1205882. doi:10.3389/fped.2023.1205882

 PubMed Web of Science ®Google Scholar