Contributions of the NICHD Neonatal Research Network to the Diagnosis, Prevention, and Treatment of Bronchopulmonary Dysplasia

Abstract

Despite improvements in the care and outcomes of infants born extremely preterm, bronchopulmonary dysplasia (BPD) remains a common and frustrating complication of prematurity. This review summarizes the BPD-focused research conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN). To improve disease classification and outcome prediction, the NRN developed new data-driven diagnostic criteria for BPD and web-based tools that allow clinicians and investigators to reliably estimate BPD risk in preterm infants. Randomized trials of intramuscular vitamin A and prophylactic nasal continuous positive airway pressure conducted by the NRN have contributed to our current use of these therapies as evidence-based approaches to reduce BPD risk. A recent large, randomized trial of hydrocortisone administered beginning between the 2^nd and 4^th postnatal weeks provided strong evidence that this therapy promotes successful extubation but does not lower BPD rates. Ongoing studies within the NRN will address important, unanswered questions on the risks and benefits of intratracheal surfactant/corticosteroid combinations and treatment versus expectant management of the patent ductus arteriosus to prevent BPD.

Introduction

Bronchopulmonary dysplasia (BPD) is among the most common and consequential complications of prematurity. BPD affects approximately half of infants born less than 28 weeks’ gestation and is a leading pediatric cause of death and long-term respiratory and neurodevelopmental disability.^1–4 Despite the availability of several therapies shown in randomized controlled trials or meta-analyses to reduce the risk of developing BPD, rates of BPD appear to have increased over the past 2–3 decades.^{2, 5} Improved survival of vulnerable preterm infants may contribute to the increasing proportion of infants who developed BPD. However, other common major neonatal morbidities such as retinopathy of prematurity (ROP), necrotizing enterocolitis, and late onset sepsis have declined in incidence.^{2, 5, 6} These divergent trends underscore the challenge of preventing BPD in extremely preterm infants.

This review summarizes the work performed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) that has focused on measuring and improving respiratory outcomes among very preterm infants. Advancements in the diagnosis of BPD, characterization of BPD epidemiology, and evaluation of therapies and care strategies that target BPD prevention or treatment are discussed. Research conducted since the inception of the NRN in 1986 is reviewed, with emphasis on studies reported since 2016, the year a previous review of NRN studies on BPD was published.⁷

Diagnosis and Prediction of BPD: Refinements to the Diagnostic Criteria for BPD

Since Northway and colleagues first described the clinical, radiographic, and histological features of BPD that developed in some moderate and late preterm infants treated for severe respiratory distress syndrome in the 1960s, neonatal intensive care and outcomes in preterm infants have improved.⁸ In response to these changes, investigators have periodically proposed new diagnostic criteria for BPD to correspond with contemporary respiratory care practices, to better categorize BPD presence and severity, and to improve prediction of childhood respiratory and developmental outcomes. Studies conducted by the NRN have played a critical role in the evolution and evaluation of the diagnostic criteria for BPD.

Dating to the late 1970s, clinicians and investigators have most commonly defined BPD as the use of oxygen therapy at 28 days’ postnatal age (no longer the preferred definition) or at 36 weeks’ post-menstrual age (PMA) (the most common current approach).^9–11 A limitation of these diagnostic criteria is the inability to distinguish between “use” versus “need” of supplemental oxygen. In 2003, Walsh et al. proposed a “physiologic” definition of BPD.¹² This definition uses an oxygen reduction challenge in preterm infants who are receiving ≤30% supplemental oxygen without positive airway pressure to identify infants who are able to maintain oxygen saturation (SpO₂) levels ≥88% for 60 minutes without oxygen therapy at 36±1 week PMA.¹² Infants who successfully pass the oxygen reduction challenge are classified as not having BPD.¹² In 2004, a study from the NRN demonstrated that a slightly modified oxygen reduction test (defining BPD as the inability to maintain SpO₂ ≥90% for 30 minutes after stepwise weaning from supplemental oxygen), as compared to clinician-selected oxygen supplementation, reduced the diagnosis of BPD and decreased inter-center variability in BPD rates.¹³ Despite these benefits, the physiologic definition of BPD has not been consistently used in research or clinical practice.¹⁴ Two subsequent NRN studies also suggested that application of the physiologic definition may not improve prediction of respiratory morbidity or neurodevelopmental disability at 2 years’ corrected age among infants who qualify for testing.^15,16

In 2001, attendees of a workshop on BPD sponsored by the U.S. National Institutes of Health (NIH) and the Office of Rare Diseases published the first diagnostic criteria to categorize BPD severity.¹⁷ These criteria define BPD in very preterm infants as the use of oxygen therapy for at least 28 days between birth and 36 weeks’ PMA and categorize BPD severity as mild, moderate, or severe according to the amount of supplemental oxygen and the mode of respiratory support administered at 36 weeks’ PMA.¹⁷ Using data from the NRN Generic Database, a registry of very low birth weight infants, Ehrenkranz et al. reported, in 2005, the first study to validate this consensus definition.¹⁸ The investigators showed that increasing severity of BPD was associated with greater risk of neurodevelopmental impairment (NDI), re-hospitalization for pulmonary reasons, and use of respiratory medications through 18–22 months’ corrected age.¹⁸

Continued evolution of neonatal respiratory care over the past 2 decades and concerns that existing diagnostic criteria may not optimally predict adverse childhood outcomes across the BPD severity spectrum prompted NRN investigators to evaluate alternative definitions of BPD.³ Using a data-driven approach, NRN members evaluated the prognostic accuracy of 18 different potential definitions of BPD for predicting late death or serious respiratory morbidity and late death or moderate to severe NDI at 18–26 months corrected age.³ This analysis, published in 2019, found that the diagnostic criteria for BPD that best predicted both composite outcomes categorized BPD severity based on the mode of respiratory support administered at 36 weeks PMA (Table 1).³ Consideration of oxygen therapy for ≥28 days prior to 36 weeks PMA or treatment with <30% vs. ≥30% supplemental oxygen at 36 weeks PMA did not improve prognostic accuracy.³ This new definition was a better predictor of adverse 2-year outcomes than the 2001 NIH consensus definition and the one proposed in 2018 by an NICHD-sponsored workshop on BPD.³ Recent external studies have confirmed the diagnostic utility of this new, evidence-based definition.^{1, 19–21}

Table 1.

2019 NICHD Neonatal Research Network Diagnostic Criteria for BPD

BPD severity	Mode of respiratory support administered at 36 weeks PMA*
No BPD	Room air (no support)
Grade 1 BPD	Nasal cannula ≤2L/mm
Grade 2 BPD	Nasal cannula >2L/min, nCPAP, or NIPPV
Grade 3 BPD	Invasive mechanical ventilation

^*BPD presence and severity classified at 36 weeks PMA, irrespective of the prior duration or current level of oxygen therapy nCPAP, nasal continuous positive airway pressure; NIPPV, nasal intermittent positive pressure ventilation

Prediction of BPD Development

Accurate estimation of the risk of developing BPD during the neonatal period is useful for counseling families, predicting the likelihood of therapeutic benefit or harm for individual patients, and selecting participants for enrollment into randomized trials. In 2011, the NRN published a validated prediction tool that estimates probabilities of death prior to 36 weeks PMA or BPD severity categorized according to the 2001 NIH consensus definition.²² This tool, available online (https://neonatal.rti.org/index.cfm?fuseaction=BPDCalculator.start), estimates the risk of death or BPD on postnatal days 1, 3, 7, 14, 21, and 28 using 6 readily available demographic and respiratory support characteristics.²² In 2022, investigators from the NRN developed a new BPD risk estimator using the 2019 NRN BPD definition.²³ This analysis used clinical data from 9181 infants born <29 weeks gestation to estimate BPD risk on postnatal days 1, 3, 7, 14, and 28.²³ The study identified 5 variables that were significantly associated with the risk of developing BPD at each time point: birth weight, gestational age, sex, mode of respiratory support, and fraction of inspired oxygen.²³ In addition, inclusion of antenatal corticosteroid therapy improved estimation of BPD risk on postnatal day 1, and inclusion of a prior history of surgical necrotizing enterocolitis improved estimation on postnatal days 14 and 28.²³ This tool provides a new resource for clinicians and investigators to estimate BPD risk using contemporary diagnostic criteria for BPD.

Prediction models that rely on clinical variables facilitate risk estimation across a range of clinical settings. However, these models may also be subject to bias owing to variability in provider or center-level practice patterns. Valid biologic and genetic markers may improve objective prediction of BPD risk and further elucidate mechanisms of BPD pathobiology. The NRN conducted two studies that targeted this objective.^{24, 25} Using blood samples from 1067 extremely preterm infants, the NRN’s cytokines study showed that higher concentrations of interleukins 1β, 6, 8, 10 and interferon γ and lower concentrations of interleukin 17, “regulated on activation, normal T cell expressed and secreted” (RANTES), and tumor necrosis factor β were associated with increased risk of death or BPD at 36 weeks PMA.²⁴ This cytokine pattern suggests that death or BPD may be associated with impairment in the transition from the neutrophil-mediated innate immune response to the T lymphocyte-mediated adaptive immune response. However, the cytokine data provided only modest prognostic utility when added to a multivariable prediction model that included demographic and clinical information.²⁴ The strongest predictors of death or BPD were male sex, treatment with invasive mechanical ventilation, and NRN center, suggesting that the biological effects of these clinical variables outweighed those of specific immunological profiles.²⁴

From banked DNA of 751 participants in the NRN cytokine study, investigators performed a subsequent genome-wide association study (GWAS) on 1.2 million genotyped single nucleotide polymorphisms (SNPs) and 7 million imputed SNPs.²⁵ This analysis did not identify any single variants that were associated with genome-wide significance of BPD.²⁵ Three pathways (out of >7500), all of which are involved in lung development and repair, were significantly associated with the outcomes of BPD or death, severe BPD or death, and severe BPD among survivors.²⁵ One hundred and five pathways were associated with severe BPD and death or BPD.²⁵ These findings add to the growing body of literature which implicate multiple, heterogenous mechanisms in the development of severe BPD, and suggest some may initiate at the genetic level.³⁶

Long-term Health Consequences Associated with BPD

BPD is a strong predictor of multiple enduring adverse health outcomes, including chronic cardiopulmonary impairments, growth failure, neurodevelopmental disability, and post-neonatal mortality.^{3, 18, 26, 27} Using NRN data from 22,248 liveborn infants delivered at <29 weeks gestation between 2000–2011, Patel et al. found that BPD was the most ascribed reason for in-hospital mortality after 60 days’ postnatal age and that 53% of all in-hospital deaths were attributed to a pulmonary etiology (BPD or respiratory distress syndrome).²⁸ A separate analysis of NRN data showed that rates of death during the first 2 years after birth were over 2-fold higher among very preterm infants with BPD than those without BPD, and that as many as 20% of very preterm infants diagnosed with grade 3 BPD died before age 2 years.³

Among survivors, BPD is associated with increased rates of health care utilization and complaints of adverse respiratory health. In a follow-up study of participants in the NRN Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT), the parents of extremely preterm infants diagnosed with BPD, compared to those without BPD, more frequently reported physician-assigned diagnoses of bronchiolitis, reactive airway disease, or pneumonia in their children at 2-years of age.²⁹ NRN data show that rates of hospital readmission, home oxygen therapy, post-discharge respiratory medication use, feeding tube use, and drug therapy for gastroesophageal reflux are more common among children with a history of BPD and increase in frequency with greater BPD severity (Figure 1).³

Figure 1.

Rates of health care utilization at 18–26 months’ corrected age, stratified by BPD severity, among 2677 very preterm infants in the NRN Generic Database and Follow-up Registry. Adapted from Jensen et al.³

In 2005, Ehrenkranz et al. demonstrated a clear association between BPD severity and incidence of NDI at 18–22 months’ corrected age in infants born with birth weights ≤1,000g.¹⁸ A similar association was noted when the 2019 NRN severity graded definition of BPD was applied to a recent cohort of infants cared for at NRN centers.³ Among infants diagnosed with BPD, data from 2 NRN studies show that longer duration of exposure to supplemental respiratory support after 36 weeks PMA is associated with further increases in the risks of death or NDI.^{30, 31} Lastly, higher BPD severity grade is associated with increased risk of withdrawal behaviors and pervasive developmental problems.³² Importantly, NRN data indicate that abnormalities in cognitive, language, and motor skills may mediate the effect of BPD on behavioral problems.³² These findings suggest that interventions that reduce BPD frequency and severity may also improve neurodevelopmental outcomes and childhood behavior profiles.

Despite the well-established relationship between BPD and poor respiratory and developmental outcomes, there is uncertainty as to how BPD may affect functional respiratory and physical abilities in childhood and adult years. A better understanding of these outcomes will improve family counseling and help develop robust, data-driven respiratory outcomes for use in future studies. To provide this important data, the ongoing NRN is following participants enrolled in the Hydrocortisone for BPD trial (NCT01353313) (see section on systemic corticosteroids for the primary trial results) to assess functional developmental and respiratory outcomes through 5–6 years corrected age. The results of this research are expected in 2025.

Investigation of Therapies to Prevent BPD: Systemic Corticosteroids

The use of systemic corticosteroids to prevent or treat BPD is among the most controversial topics in neonatology.^{33, 34} Demonstration that pulmonary and systemic inflammation contribute to the pathobiology of BPD make systemic corticosteroids, with their potent anti-inflammatory properties, an appealing therapy.^{35, 36} However, the observation that some corticosteroid treatment regimens predispose infants to long-term neurologic deficits, despite short-term respiratory benefits, represents a cautionary tale that emphasizes the importance of long-term outcome monitoring in neonatal trials.^{34, 37} During the past 35 years, randomized trials and observational studies conducted by the NRN have contributed to our current understanding of the benefits and harms of various corticosteroid medications and dosing strategies used to prevent BPD.

Following publication of several small trials conducted in the 1980s showing short-term respiratory benefit with prolonged, high-dose courses of dexamethasone (0.5mg/kg/day starting dose, treatment duration up to 42 days), the NRN conducted two trials in the 1990s that evaluated different dexamethasone treatment regimens.^38–42 The first, published in 1998, compared 14-day courses of dexamethasone (0.5mg/kg/day starting dose) initiated at either 2 weeks or 4 weeks of age in 371 ventilator-dependent infants born with birth weights <1500g.⁴¹ There were no differences in the timing of successful extubation or the incidence of BPD between the two groups, but treatment beginning at 2 weeks rather than 4 weeks postnatal age was associated with increased risk of infection and hyperglycemia.⁴¹ The second trial, published in 2001, was conducted following the observation that high dose dexamethasone (0.5–0.6mg/kg/day), initiated as early as 48 hours after birth, predisposed to adverse effects.^42–44 In response, Stark and colleagues tested the safety and efficacy of a lower dose of dexamethasone (0.15mg/kg/day starting dose) initiated within 24 hours after birth and tapered over 10 days in ventilated infants with birth weights of 501 to 1,000g.⁴² This trial was stopped after enrollment of 220 infants (21% of the target sample size of 1,064) owing to an unexpected increase in the risk of spontaneous gastrointestinal perforation in the dexamethasone treated participants.⁴² Based on the results of these two studies and other trial data, a near moratorium was placed on clinical use and investigation of corticosteroids for BPD in the early 2000s.^{45, 46}

During the subsequent decade, however, new observations prompted reconsideration of the potential risks and benefits of corticosteroid therapy. Reductions in the use of dexamethasone were accompanied by a possible increase in the incidence of BPD without clear improvements in neurodevelopmental outcomes.^{47, 48} Moreover, a series of meta-analyses suggested a risk/benefit balance that favored corticosteroids for neurodevelopmental outcomes in very preterm infants at high risk of BPD.^49–52 These publications led several pediatric governing bodies to recommend that clinicians may consider low-dose corticosteroid therapy in very preterm infants receiving invasive mechanical ventilation after 1 to 2 weeks postnatal age.^53–55

Recent observational studies conducted by the NRN provide additional insights into the risks and benefits of corticosteroid therapy to prevent BPD. Harmon et al assessed the risks of death, severe BPD, and neurodevelopmental impairment associated with the postnatal age at systemic corticosteroid therapy in 951 infants born <27 weeks GA.⁵⁶ The investigators found that initiation of corticosteroids after 7 weeks postnatal age, compared to at 4 weeks postnatal age, was associated with an increased risk of severe BPD and a possible increased risk of moderate to severe NDI.⁵⁶ These data suggest corticosteroids may confer greater benefit when initiated prior to rather than after 50 days’ postnatal age. To further evaluate the risk/benefit balance of postnatal corticosteroids, an NRN propensity score-matched cohort study of 964 extremely preterm infants assessed whether the estimated pre-treatment probability of death or grade 2–3 BPD modified the association between corticosteroid therapy and death or NDI.⁵⁷ The results of this analysis showed that postnatal corticosteroids were associated with a possible increased risk of death or NDI in infants with a pre-treatment probability of death or grade 2–3 BPD <44%, but a decreased risk of death or NDI in infants with a pre-treatment probability of death or grade 2–3 BPD >61%.⁵⁷ Similar results were observed for the composite outcome of death or cerebral palsy (CP), agreeing with an older meta-regression performed by Doyle et al.^{52, 57}

Lastly, the NRN recently completed the Hydrocortisone for BPD trial.⁵⁸ This study was designed around the framework that hydrocortisone may confer the promising anti-inflammatory properties of glucocorticoids while avoiding the adverse effects of dexamethasone.⁵⁸ The trial enrolled 800 infants receiving invasive mechanical ventilation who were born <30 weeks gestational age and had been intubated for >7 days.⁵⁸ Study participants were randomly assigned to receive hydrocortisone beginning between 2 to 4 weeks postnatal age (starting dose of 4mg/kg/day then tapered over 10-day treatment period) or placebo.⁵⁸ The primary trial outcomes were survival without BPD at 36 weeks PMA and survival without moderate to severe NDI at 22–26 months’ corrected age.⁵⁸ Rates of both outcomes were similar between the treatment groups.⁵⁸ Evaluation of multiple secondary trial outcomes demonstrated that hydrocortisone increased rates of successful extubation by the end of the treatment period (45% vs. 34%; RR 1.54, 95% CI 1.23–1.92) and reduced the duration of invasive ventilation before 36 weeks PMA (median 37 vs. 40 days), but it did not affect BPD severity.⁵⁸ Hydrocortisone was not associated with significant adverse events, indicating it is a reasonable treatment option to promote extubation, but not to reduce BPD risk.⁵⁸

Intramuscular Vitamin A

Studies conducted in the 1980s observed lower plasma vitamin A levels in preterm infants who developed BPD.^59–61 To evaluate the potential benefits of vitamin A supplementation, the NRN conducted a multicenter randomized trial in 1996–1997 comparing intramuscular (IM) injections of vitamin A (5000 international units 3 times per week) during the first 4 postnatal weeks to sham treatments in infants with birth weights of 401 to 1000g.⁶² Vitamin A reduced the rates of the primary composite outcome of death or BPD (55% vs. 62%; RR 0.89, 95% CI 0.80–0.98) and the secondary outcome of BPD among survivors (47% vs. 56%; RR 0.85, 95% CI 0.73–0.98).⁶² Follow-up data at 18–22 month’s corrected age showed no evidence of an effect of Vitamin A on death or NDI.⁶³ A 2016 Cochrane meta-analysis confirmed that IM vitamin A reduced the risk of BPD among survivors but it did not reduce the composite outcome of death or BPD.⁶⁴

A recent post-hoc reanalysis of NRN vitamin A trial data found possible heterogeneity of treatment effects.⁶⁵ This analysis suggested that the benefit of IM vitamin A for prevention of death or BPD was greatest for infants at lowest risk of death or BPD.⁶⁵ This intriguing finding should be viewed as hypothesis generating only.

Respiratory support strategies and oxygen therapy

Invasive mechanical ventilation and supplemental oxygen are two potentially life-saving therapies used in extremely preterm infants with respiratory failure. However, both have been implicated as contributors to the development of BPD, and efforts to safely minimize their exposure are prominent areas of neonatal research.^{36, 66} The NRN has conducted several studies that helped inform evidence-based approaches to respiratory support and oxygen administration in extremely preterm infants.

Non-invasive continuous positive airway pressure

Although early intubation and surfactant administration became a dominant approach to the care very preterm infants in the 1990s, randomized trials failed to demonstrate a reduction in the risk of BPD at 36 weeks PMA with surfactant therapy.⁶⁷ Moreover, some observational data published as early as the 1980s suggested that aggressive use of non-invasive continuous positive airway pressure (CPAP) with intubation reserved for infants who fail non-invasive support may safely reduce rates of BPD.^{68, 69} This question was addressed by 4 randomized trials published between 2008 and 2011.^70–73 The largest was the SUPPORT trial.⁷⁰ This 2-by-2 factorial design randomized trial assessed two different respiratory care strategies: (1) treatment with CPAP versus endotracheal intubation and surfactant administration immediately after birth; and (2) targeting a higher versus lower SpO₂ range (91–95% vs 85–89%) (see oxygen saturation targeting for further details of this comparison).^{70, 74} SUPPORT enrolled 1,316 infants born with gestational ages of 24 to 27 weeks between 2005–2009.^{70, 74}

The primary outcome for the CPAP vs. intubation/surfactant arm was death or BPD at 36 weeks PMA, and no difference was found.⁷⁰ However, infants who received CPAP less frequently received subsequent intubation or postnatal corticosteroids, and received fewer days of invasive mechanical ventilation.⁷⁰ In a meta-analysis of SUPPORT and the 3 other CPAP trials, the pooled data demonstrated a reduction in the composite risk of death or BPD with early CPAP (relative risk 0.90, 95% CI 0.83–0.98).^{75, 76} BPD among survivors was not statistically different, but the point estimate favored CPAP (RR 0.91, 95% CI 0.81–1.01).⁷⁵ Follow-up data from SUPPORT showed that rates of most respiratory outcomes were similar between the study groups, but that CPAP-treated infants had significantly fewer episodes of wheezing and emergency visits for breathing problems in early childhood.²⁹ Collectively, these trial data demonstrate that routine use of early CPAP is safe and provides modest improvement in respiratory outcomes.

The optimal timing and strategy for weaning CPAP therapy remains unclear. Small randomized trials suggest immediate rather than gradual weaning off CPAP results in similar or even lower rates of BPD.^77–80 A retrospective observational study of 6,268 infants born less than 29 weeks gestation from the NRN examined whether the duration of non-invasive respiratory support was associated with differences in the risk of death or BPD at 36 weeks PMA.⁸¹ The study employed two robust analytical techniques, an instrumental variable approach and generalized propensity score matching.⁸¹ These two analyses yielded conflicting and ultimately inconclusive results.⁸¹ This finding underscores the difficulty of evaluating the risks and benefits of respiratory support modalities in observational studies owing to the frequent presence of unmeasurable confounding. Appropriately powered randomized trials are likely necessary to establish evidence-based weaning strategies for CPAP therapy.

Oxygen saturation targeting

During the past 80 years, the care of preterm infants has oscillated between periods of liberal and restrictive oxygen supplementation as clinicians and researchers identified the consequences of both excessive and insufficient oxygen supplementation.^{82, 83} In an effort to resolve this uncertainty, the Neonatal Oxygen Prospective Meta-analysis (NeOProM) Collaboration was formed in 2003 by investigators from 5 separate randomized controlled trials, including SUPPORT.⁸⁴ All 5 trials randomized participants to a target SpO₂ range of 85–89% versus 91–95% within 24 hours after birth.⁸⁵ The primary outcome for this comparison in SUPPORT was death prior to hospital discharge or severe ROP.⁷⁴ Secondary outcomes included death or BPD at 36 weeks PMA and NDI at 18–22 months’ corrected age.^{66, 74} The rates of the composite outcome of death or severe ROP did not differ significantly between the treatment groups.⁷⁴ However, death before discharge was more common in the group with lower SpO₂ targets (19.9% vs. 16.2%; RR 1.27, 95% CI 1.01–1.60), while severe ROP among survivors was less common in this study arm (8.6% vs. 17.9%; RR 0.52, 95% CI 0.37–0.73).⁷⁴ Rates of death or BPD and BPD among survivors, defined using the physiologic definition at 36 weeks PMA, were similar between the treatment groups.⁷⁴

In 2018, the NeOProM Collaboration combined the data from all 5 randomized trials into an individual participant data (IPD) meta-analysis.⁸⁵ Similar to SUPPORT, the IPD meta-analysis demonstrated increased mortality but decreased severe ROP in the lower SpO₂ target group.⁸⁵ In addition, severe necrotizing enterocolitis was more common among infants randomized to the lower saturation range.⁸⁵ Rates of the primary outcome of death or neurodevelopmental disability at 2 years’ corrected age were similar between the groups.⁸⁵ Oxygen therapy at 36 weeks PMA was more common among infants randomized to higher versus lower SpO₂ targets.⁸⁵ However, this outcome was reported using the clinical rather than physiologic definition of BPD and may therefore be a consequence of targeting higher SpO₂ values rather than a true treatment advantage of lower SpO₂ goals.⁸⁵

The findings of SUPPORT and the NeOProM Collaboration prompted many institutions to revise their SpO₂ goals and/or oximeter alarm settings, generally favoring narrower SpO₂ target ranges between 88–90% and 95–96%.^86–88 A 2016 NRN study found that among 19 hospitals with continuous participation in the NRN between 2006 and 2014, 10 changed their SpO₂ alarm settings, transitioning from a median range of 85%−96% to 89%−95%.⁸⁶ Among the hospitals that did not enact a policy change, the median lower and upper SpO₂ alarm limits were 88% and 95%.⁸⁶ Evaluation of 7,494 extremely preterm infants cared for in these hospitals during the study period did not identify a significant association between a change in SpO₂ alarm policy and the risks of mortality, severe ROP, or necrotizing enterocolitis.⁸⁶ For infants in hospitals with an SpO₂ alarm policy change, the adjusted odds of BPD were significantly greater in the years following than preceding the policy change.⁸⁶ There were no temporal differences in the adjusted odds of BPD among infants cared for in hospitals that did not change alarm policies.⁸⁶ Outside of the NRN, some investigators have observed differences in morbidity rates following changes to SpO₂ target policies, but others have not.^{87, 88}

Treatment of the Patent Ductus Arteriosus

The optimal management of a patent ductus arteriosus (PDA) in very preterm infants remains uncertain. Observational studies from the NRN and other data sources demonstrate a strong association between the presence of a PDA in very preterm infants and the subsequent development of BPD, but no causal link has been established.^89–94 Past and ongoing studies from the NRN seek to better understand the pathophysiology of the PDA and the potential risks and benefits of its treatment. An NRN analysis of genetic variants associated with the development of a PDA studied 1,634 SNPs from candidate genes in 1,013 extremely preterm infants.⁹⁵ SNPs in several genes known to encode proteins found in murine ductal tissue or relevant to diseases that include PDA as a presenting finding were associated with a PDA in the NRN cohort, suggesting the possibility of genetic susceptibility for PDA in extremely preterm infants.⁹⁵

Two observational studies from the NRN evaluated outcomes associated with different pharmacological treatments for a PDA. Motivated by a possible small increase in the risk of BPD among infants assigned to receive indomethacin in the Trial of Indomethacin Prophylaxis in Preterms, NRN members evaluated the association between prophylactic indomethacin in extremely preterm infants and the risks of death or BPD.^{96, 97} After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD or death or BPD.⁹⁷ However, a potential, but non-significant reduction in the odds of death was observed (OR 0.80, 95% CI 0.64–1.01).⁹⁷ When these data were combined with an additional observational study into a meta-analysis (total n=11,289), prophylactic indomethacin was associated with a reduced risk-adjusted odds of death (OR 0.81, 95% CI 0.66–0.89).⁹⁸ These findings raise the hypothesis of a beneficial effect of prophylactic indomethacin on mortality, but testing in a future randomized trial is required before practice is changed.

Following a chance observation that acetaminophen may promote ductal closure, this medication has gained prominence as an alternative treatment for the PDA.^99–101 However, the risks and benefits of acetaminophen in extremely preterm infants are unclear and pre-clinical models suggest the developing lung may be susceptible to acetaminophen-induced injury.¹⁰² To evaluate this hypothesis, a recent NRN study compared the risks of death and respiratory morbidity associated with acetaminophen (n=627) versus alternative medications (n=1,294) used for treatment of a PDA.¹⁰³ Acetaminophen was not associated with increased risks of respiratory morbidity, but the risk of death prior to discharge approached significance (adjusted RR 1.36, 95% CI .98–1.88).¹⁰³ In pre-specified subgroup analyses, acetaminophen exposure was associated with increased risk of death or home oxygen therapy in infants born with gestational ages ≥26 weeks and with increased mortality among infants who received single drug therapy for a PDA.¹⁰³ These findings reinforce the need to properly evaluate the safety of acetaminophen therapy for PDA closure.

Other strategies

Wide inter-center differences in the incidence of BPD have been reported since the 1980s and continue to persist in contemporary practice (Figure 2).^{7, 104} In 2007, the NRN published a cluster randomized “benchmarking” trial that evaluated a bundled quality improvement (QI) initiative to reduce BPD rates in 14 centers randomized to intervention (QI bundle) or control (routine practice) arms.¹⁰⁵ The bundle interventions were selected to mimic practices used in NRN centers with the lowest BPD rates: prophylactic surfactant administration, permissive hypercapnia, limitation of tidal volumes during mechanical ventilation, fluid restriction, and liberal use of CPAP versus invasive ventilation.¹⁰⁵ Unfortunately, survival without BPD did not improve in either arm.¹⁰⁵ This result differs from some non-randomized QI studies, which showed reductions in BPD using similar interventions, highlighting the variation in findings that can occur between observational studies and randomized trials.^{106, 107}

Figure 2.

Rates of death prior to 36 weeks PMA and of BPD stratified by severity grade among 9758 live born infants with gestational ages <29 weeks who were cared for at 1 of 15 NRN centers between 2016 and 2021. Data obtained from the NRN Generic Database.

Myo-inositol is a nutritionally derived compound that plays an essential role in multiple biological processes, including maintenance of cell membrane integrity, mediation of osmoregulation, and synthesis and maturation of surfactant phospholipids. Accumulation of data from small trials suggested that myo-inositol reduced death, pneumothorax, severe intraventricular hemorrhage, and ROP in preterm infants with respiratory distress syndrome.¹⁰⁸ An NRN multicenter RCT investigated myo-inositol supplementation for prevention of death or ROP and other secondary outcomes, including BPD.¹⁰⁹ The trial was stopped after enrolling 638 of a planned 1,760 infants owing to a significantly higher mortality rate in the myo-inositol group (18% vs. 11%; RR 1.66, 95% CI 1.14–2.43).¹⁰⁹ Rates of BPD were similar between the myo-inositol and placebo groups.¹⁰⁹ Informed by these data, current recommendations indicate myo-inositol should not be routinely used in preterm infants and that further trials in neonates should not be conducted.¹⁰⁸

Treatment of Infants Diagnosed with BPD

Preterm infants who develop the most severe forms of BPD often require prolonged treatment with supplemental oxygen and/or positive airway pressure. NRN investigators have examined the risks and benefits associated with respiratory interventions used to support infants with established BPD.^{110, 111} In a propensity score matched analysis of 2,078 extremely preterm infants, DeMauro et al. found that infants discharged on oxygen therapy, compared to similar controls discharged in room air, exhibited modestly better growth but were more likely to be rehospitalized for respiratory illnesses and to use respiratory medications at 18–26 months’ corrected age.¹¹⁰ Rates of NDI were high (>50% exhibited moderate to severe developmental disability) but similar between the groups.¹¹⁰ In a separate analysis, DeMauro et al. evaluated the association between tracheostomy and death or NDI at 18–22 months’ corrected age in a cohort of 8683 extremely preterm infants, including 304 with tracheostomies.¹¹¹ The odds of death or NDI were higher among infants with tracheostomy (83% vs. 40%, adjusted OR 3.3, 95% CI 2.4–4.6).¹¹¹ However, tracheostomy placement before, rather than after, 120 days postnatal age (equivalent to a median PMA of approximately 42 weeks) was associated with lower odds of death or NDI (adjusted OR 0.5, 95% CI 0.3–0.9).¹¹¹ This latter finding suggests that among infants who are highly likely to receive tracheostomy, earlier rather than later placement may confer long-term developmental benefit. The high incidence of developmental disability observed in these two studies reinforce the need for randomized trials that will identify best practices in the care of extremely preterm infants with BPD.^{110, 111}

Ongoing Studies Focused on BPD

The lack of improvements in BPD rates despite the availability of several therapies shown in randomized trials to reduce BPD risk mandate continued investigation of novel interventions that may reduce respiratory morbidity and improve long-term pulmonary and developmental outcomes in very preterm infants. Several active randomized trials within the NRN are investigating drug therapies or treatment strategies that target BPD prevention and other clinically important respiratory outcomes (Table 2).

Table 2.

Ongoing respiratory-focused randomized controlled trials conducted by the NICHD Neonatal Research Network

Inclusion criteria	Exclusion criteria	Intervention	Control	Primary Outcome	Estimated enrollment	Estimated completion year
Budesonide in Babies (BIB) trial (NCT04545866)
GA 22 0/7 to 28 6/7wk or BW 401–1000g Clinical decision to give surfactant ≤48hr postnatal age at enrollment	Terminal illnesses or care redirection Prior surfactant therapy Maternal indomethacin use ≤24hr prior to delivery Planned or administered infant indomethacin therapy between birth and 7d of the final study drug dose Congenital infection Permanent neuromuscular disorder	Intratracheal budesonide (0.25mg/kg in 1mL/kg) + poractant alpha (2.5mL/kg)	Poractant alpha (2.5mL/kg)	Death or physiologic BPD at 36 weeks PMA	1160	2025
Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial (NCT03340727)
GA 29 0/7 to 33 6/7wk ≤35 6/7wk PMA at randomization Receiving caffeine with plan to discontinue treatment or discontinued caffeine therapy ≤72hr prior to randomization ≥120mL/kg/day oral or tube feedings	Receiving supplemental respiratory support Infants with conditions that necessitate use of a home apnea monitor Parental request for apnea monitor Complex congenital heart disease Neuromuscular condition that affects respiration Major congenital malformation or genetic disorder	Oral caffeine citrate (10mg/kg once per day)	Placebo	Length of hospitalization from randomization until 48wk PMA	800	2023
Management of the Patent Ductus Arteriosus (PDA) Trial (NCT03456336)
GA 22 0/7 to 28 6/7 48hr to 21d postnatal age PDA diagnosed by echocardiogram plus pre-defined clinical criteria	Cardiopulmonary compromise Complex congenital heart disease Known pulmonary malformation Conditions that, in the opinion of the investigator, would preclude enrollment	Active treatment of the PDA (treatment with indomethacin or ibuprofen based on center preference)	Expectant management (indomethacin or ibuprofen only if cardiopulmonary compromise occurs)	Death or physiologic BPD at 36 weeks PMA	1116	2023

Conclusion

Since its inception over 35 years ago, the Neonatal Research Network has made substantial scientific contributions that increased knowledge of the pathobiology and classification of BPD and the safety and efficacy of therapies used to prevent or treat BPD. New, evidence-based diagnostic criteria for BPD and early prediction tools developed by the NRN hold promise to improve family counseling, risk stratification, and outcome assessments in randomized trials and observational studies. Ongoing studies within the NRN will provide important data on childhood functional outcomes in survivors with BPD, the use of intratracheal surfactant/corticosteroid combinations to prevent BPD, and the potential risks and benefits of treatment versus expectant management of the PDA.

Abbreviations

BPD

Bronchopulmonary dysplasia

CI

Confidence interval

CP

Cerebral palsy

CPAP

Continuous positive airway pressure

GWAS

Genome-wide association study

IM

Intramuscular

IPD

Individual participant data

nCPAP

Nasal continuous positive airway pressure

NDI

Neurodevelopmental impairment

NeOProM

Neonatal Oxygen Prospective Meta-analysis

NICHD

Eunice Kennedy Shriver National Institute of Child Health and Human Development

NIH

National Institutes of Health

NIPPV

Nasal intermittent positive pressure ventilation

NRN

Neonatal Research Network

OR

Odds ratio

PDA

Patent ductus arteriosus

PMA

Post-menstrual age

QI

Quality improvement

RANTES

Regulated on activation, normal T cell expressed and secreted

ROP

Retinopathy of prematurity

RR

Relative risk

SNP

Single nucleotide polymorphism

SpO2

Oxygen saturation

SUPPORT

Surfactant Positive Airway Pressure and Pulse Oximetry Trial