Bronchopulmonary dysplasia appropriateness as a surrogate marker for long-term pulmonary outcomes: A Systematic review

Abstract

BACKGROUND:

Bronchopulmonary dysplasia (BPD) is used to clinically describe the severity of lung disease and to serve as a common surrogate endpoint for long-term pulmonary morbidity in clinical trials, but its performance as a surrogate end-point warrants evaluation. Our objective was to assess real-world performance of BPD as a surrogate marker for long-term pulmonary outcomes.

METHODS:

We performed a systematic review of large, multi-centered, blinded, randomized control trials to evaluate the use of BPD as a surrogate marker for long-term pulmonary outcomes. Long-term pulmonary outcomes occurred within two years and included measures of hospital utilization, respiratory illness, respiratory medication, and mortality. Direction and magnitude of effect were evaluated using number needed to treat analysis.

RESULTS:

Five studies were included in our review. Studies varied in definition of BPD and in long-term outcomes measured. Only one study found a significant, consistent risk reduction in both BPD and any long-term pulmonary outcome. Two studies found significant reductions in long-term pulmonary outcomes with a non-significant reduction in BPD.

CONCLUSIONS:

BPD is an imperfect surrogate marker for long-term pulmonary outcomes. It did not consistently predict the magnitude or direction of the effect of an intervention on longer-term pulmonary outcomes. Furthermore, there was significant variation in the definitions of BPD and in the long-term pulmonary outcomes used. There is a need for future work to identify more predictive surrogate markers and a need for better standardization of assessments of long-term pulmonary outcomes.

Keywords

Bronchopulmonary dysplasia chronic lung disease clinical trials

1 Introduction

Bronchopulmonary dysplasia (BPD) was first described in 1967 by Northway and colleagues as a group of clinical, radiological, and pathologic findings in infants with chronic lung disease [1]. The lungs of these preterm infants were acutely injured leading to inflammation, fibrosis, and smooth muscle hypertrophy. Since that time, the definition of BPD has evolved to reflect the changing patient population and pathology of the disease [2 –7]. In 1988, Sheehan et al proposed a new definition for BPD of oxygen dependence at 36 weeks post menstrual age (PMA), which could serve as a useful predictor of abnormal pulmonary outcomes in the first two years of life. They believed that this definition more accurately portrayed the increasing incidence in earlier gestation infants and better reflected long-term pulmonary outcomes when compared to the previously used definition of oxygen use at 28 days [3]. Given the lack of uniformity in the administration of supplemental oxygen, efforts have been made to standardize the definition of BPD. Subsequently, Walsh et al. proposed a physiological definition designed to account for discrepancies in oxygen administration across institutions, and the National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute and the Office of Rare Diseases proposed a new severity-based definition of BPD [8, 9]. Currently, the diagnosis of BPD is used to clinically describe the severity of lung disease and continues to serve as a common surrogate endpoint for long-term pulmonary morbidity in clinical trials, but its performance as a surrogate end-point for trials warrants evaluation.

The National Institutes of Health put forth a preferred definition of a surrogate endpoint as “a biomarker that is intended to substitute for a clinical endpoint” [10]. According to the US Institute of Medicine of the National Academies, evaluating biomarkers consists of three steps: 1) analytical validation, to ensure that biomarker tests are reliable, reproducible, and adequately sensitive and specific; 2) qualification, to ensure the biomarker is associated with the clinical outcome of concern; 3) utilization analysis, to determine that the biomarker is appropriate for the proposed use [11]. A proper surrogate marker should go beyond correlation by accurately predicting a clinical endpoint with high positive and negative predictive values [12].

Recently, it has been suggested that BPD is an inappropriate surrogate marker [13 –15]. Critics point to the evolution of the basis of the term to a clinical, functional definition (i.e. the need for oxygen) rather than one based on histopathology, as well as a lack of evidence supporting its use as a sufficiently predictive surrogate marker for long-term outcomes. Therefore, we have performed a systematic review designed to assess real-world performance of BPD in clinical trials as a surrogate marker for long-term pulmonary outcomes.

2 Methods

We conducted a PubMed search using the search terms “bronchopulmonary dysplasia” or “chronic lung disease,” “premature,” and “infant.” Search limitations included randomized control trials and clinical trials, English language, human subjects, age group “birth to 23 months,” and publication dates from January 2000 to May 2015 with full-text available on-line. Study enrollment was limited to at least 200 subjects.

We included only published articles in the systematic review. Study design was limited to multi-center, blinded, randomized control trials. Cohort studies, case-control studies, abstracts, case series, and review articles were excluded from analysis. Controls consisted of a separate group of randomly assigned patients receiving either alternative treatment or placebo.

To be included in the review, papers were required to have used bronchopulmonary dysplasia or chronic lung disease as a primary outcome. We included studies using any definition of BPD including the traditional definition (any oxygen requirement at 36 weeks PMA), physiological definition (ventilator support, >30% oxygen, or oxygen saturation under 88% on room air with a step-wise reduction in oxygen if receiving under 30% oxygen at 36 weeks PMA), as well as study definitions. Studies were required to include long-term respiratory outcomes or have a follow up study with long-term pulmonary outcomes. Long-term pulmonary outcomes evaluated included healthcare utilization (e.g. physician visits, admissions to hospital), respiratory illness (e.g. asthma, wheezing), use of respiratory medications (e.g. bronchodilators, inhaled or systemic steroids, diuretics), use of oxygen post discharge, and mortality. Evaluated outcomes occurred within the first two years of life.

Follow-up studies that included long-term pulmonary outcomes were searched for and included for studies that met initial search criteria but lacked long-term outcome data.

Studies were identified by one author (BKC) and reviewed for eligibility by two co-authors (AMH, ANT).

3 Results

The PubMed search returned 361 articles. After review, five studies met inclusion criteria [16 –24]. All studies were multi-center, blinded, randomized control trials with study size ranging from 209 to 1,316. Follow-up rates ranged from 69.8% to 93.5% . All studies reported summary statistics. Two studies were sufficiently powered to evaluate for BPD and long-term outcomes, [18 , 23] while the remaining studies were powered for BPD but not long-term outcomes.

3.1 Patient population

The studies differed in their patient populations (Table 1). Four of the five studies had a mean or median gestational age between 25–27 weeks and birth weights between 750–900 g. The DINO trial enrolled neonates with a mean gestational age (GA) of 30 weeks and a mean birth weight (BW) over 1300 g. Four of the five studies excluded infants with major congenital abnormalities or severe co-morbidities [16–19 , 22]. Three of the five studies had an eligibility requirement of receipt of respiratory intervention (e.g. supplemental oxygen, mechanical ventilation) [17–19 , 22]. Two studies [17 , 22] compared inhaled nitric oxide (iNO) to placebo, one study [18] compared intra-tracheal recombinant human CuZn superoxide dismutase (r-h CuZnSOD) to placebo, one study [16] compared high docosahexaenoic acid (DHA) diet to standard DHA diet, and one study [20, 23] compared continuous positive airway pressure (CPAP) to surfactant and mechanical ventilation as well as low target oxygen saturation (85–89%) to high target oxygen saturation (91–95%).

Table 1
Summary of studies meeting inclusion criteria

Study N Population Design Intervention BPD definition Long-term Respiratory Outcomes

Docosahexaenoic acid for the improvement of neurodevelopmental outcome in preterm infants (DINO) [16, 24] 657 (614) GA < 33 wks; approached within 5 days of enteral feeding commencement; stratified by BW, center, sex 5 centers; structured parent interview at 12 and 18 months High DHA diet vs standard DHA diet 1. Traditional definition Any hospitalization Asthma at 12 or 18 months

Nitric oxide (to prevent) chronic lung disease (NO CLD) [17, 21] 582 (455) GA < 32 wks; BW 500–1250 g; receiving mechanical ventilation for lung disease between 7–21 days of age; stratified by BW, center 21 centers; standardized follow-up interviews at 12 months, assessment in neonatal follow-up clinics at 12±3 months iNO vs placebo 1. Physiological definition Any hospitalization
Respiratory hospitalization
Wheezing or whistling in the chest
Bronchodilator use
Inhaled steroid use
Systemic steroid use
Diuretic use
Any/home O₂
O₂ at follow-up

Superoxide dismutase (SOD) [18] 302 GA≥24 wks; BW 600–1200 g; <24 h of age; clinical and radiographic evidence of RDS; treatment with supplemental O₂, mechanical ventilation, exogenous surfactant; stratified by BW, center 15 centers; follow-up assessment and health assessment questionnaire at 1 year r-h CuZnSOD vs placebo 1. Oxygen requirement at 28d of life with chest radiograph with quantitative Edwards score≥3;
2. Traditional definition; 3. Oxygen requirement at 28d Any hospitalization
Any ER visit
Respiratory illness requiring asthma meds

Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT) [20, 23] 1316 (918) GA 24–27.6 wks; stratified by BW, center 20 centers; structured questionnaire at discharge, 6, 12, 18–22 months CPAP vs intubation/ surfactant; low target O₂ sat vs high target O₂ sat 1. Physiological definition
2. Traditional definition Any hospitalization
Respiratory hospitalization
Respiratory ER/physician visit
Wheezing or whistling in the chest
Cough
Asthma/RAD/BPD
Bronchiolitis, bronchitis, pneumonia
Nebulizer use
Inhaled steroid use
Systemic steroid use
Diuretic use
Any/home O₂

Early iNO [19, 22] 793 (652) GA≤34 wks; BW 500–1250 g; birth within 48 hours; respiratory failure requiring endotracheal intubation and mechanical ventilation; stratified by BW, center 16 centers; telephone interviews at 3, 6, 9, 12, and 18 months chronological age iNO vs placebo 1. Traditional definition plus abnormal findings on chest radiograph Any hospitalization
Any ER visit
ICU readmission
MV during readmission
Any/home O₂
O₂ at follow-up

Study	N	Population	Design	Intervention	BPD definition	Long-term Respiratory Outcomes
Docosahexaenoic acid for the improvement of neurodevelopmental outcome in preterm infants (DINO) [16, 24]	657 (614)	GA < 33 wks; approached within 5 days of enteral feeding commencement; stratified by BW, center, sex	5 centers; structured parent interview at 12 and 18 months	High DHA diet vs standard DHA diet	1. Traditional definition	Any hospitalization Asthma at 12 or 18 months
Nitric oxide (to prevent) chronic lung disease (NO CLD) [17, 21]	582 (455)	GA < 32 wks; BW 500–1250 g; receiving mechanical ventilation for lung disease between 7–21 days of age; stratified by BW, center	21 centers; standardized follow-up interviews at 12 months, assessment in neonatal follow-up clinics at 12±3 months	iNO vs placebo	1. Physiological definition	Any hospitalization Respiratory hospitalization Wheezing or whistling in the chest Bronchodilator use Inhaled steroid use Systemic steroid use Diuretic use Any/home O₂ O₂ at follow-up
Superoxide dismutase (SOD) [18]	302	GA≥24 wks; BW 600–1200 g; <24 h of age; clinical and radiographic evidence of RDS; treatment with supplemental O₂, mechanical ventilation, exogenous surfactant; stratified by BW, center	15 centers; follow-up assessment and health assessment questionnaire at 1 year	r-h CuZnSOD vs placebo	1. Oxygen requirement at 28d of life with chest radiograph with quantitative Edwards score≥3; 2. Traditional definition; 3. Oxygen requirement at 28d	Any hospitalization Any ER visit Respiratory illness requiring asthma meds
Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT) [20, 23]	1316 (918)	GA 24–27.6 wks; stratified by BW, center	20 centers; structured questionnaire at discharge, 6, 12, 18–22 months	CPAP vs intubation/ surfactant; low target O₂ sat vs high target O₂ sat	1. Physiological definition 2. Traditional definition	Any hospitalization Respiratory hospitalization Respiratory ER/physician visit Wheezing or whistling in the chest Cough Asthma/RAD/BPD Bronchiolitis, bronchitis, pneumonia Nebulizer use Inhaled steroid use Systemic steroid use Diuretic use Any/home O₂
Early iNO [19, 22]	793 (652)	GA≤34 wks; BW 500–1250 g; birth within 48 hours; respiratory failure requiring endotracheal intubation and mechanical ventilation; stratified by BW, center	16 centers; telephone interviews at 3, 6, 9, 12, and 18 months chronological age	iNO vs placebo	1. Traditional definition plus abnormal findings on chest radiograph	Any hospitalization Any ER visit ICU readmission MV during readmission Any/home O₂ O₂ at follow-up

BW, birth weight; DHA, docosahexaenoic acid; ER, emergency room; GA, gestational age; ICU, intensive care unit; iNO, inhaled nitric oxide; PMA, post-menstrual age; RAD, reactive airway disease; RDS, respiratory distress syndrome.

Duration of study follow-up ranged from 12 months to 18–22 months, with two studies [17, 18`] ending at 12 months, two studies [16, 22] ending at 18 months, and one study [23] ending at 18–22 months. All studies conducted parent or primary caregiver interviews at 12 months of age. The studies otherwise varied in frequency of follow-up. Two studies also conducted in-person assessments of study participants.

3.2 BPD results

All studies evaluated rate of BPD in the initial study and/or secondary analysis. The studies used various definitions for defining BPD with two studies [18 , 23] evaluating multiple definitions of BPD (Table 1). Although the observed rate of BPD was lower in the intervention group than the control group for all five studies, statistical significance was only achieved in the NO CLD trial (Table 2).

Table 2
BPD and long-term respiratory outcomes

Outcome DINO^a NO CLD^b SOD^c Support^b Early iNO^c

CPAP Saturation

BPD @ 36 weeks Rate (%) 18.8 v 25.1 50.7 v 56.9 36 v 37 39.2 v 40.6 37.4 v 40.0^d 65.0 v 68.0

NNT 15.9 16.1 100 71.4 38.5 33.3

RR 0.77 (0.59–1.02) RB: 1.23^e (1.01–1.51) –– 0.99 (0.87–1.14) Not sig 0.96 (0.86–1.09)

Any hospitalization NNT 76.9 25.6 33.3 27.8 37.0 –34.5

RR 0.98 (0.85–1.14) OR: 0.83 (0.57–1.21) — 0.87 (0.66–1.16) 0.90 (0.68–1.20) —

Respiratory hospitalization NNT — –142.9 — 25.0 –200 —

RR — OR: 1.03 (0.65–1.62) — 0.82 (0.61–1.11) 1.04 (0.77–1.40) —

ER/physician visit NNT — — 16.7 20.4 ∞ –17.9

RR — — — 0.73 (0.53–1.00) 0.98 (0.72–1.34) —

ICU readmission NNT — — — — — –66.7

RR — — — — — —

Mechanical ventilation during readmission NNT — — — — — –33.3

RR — — — — — —

Wheezing or whistling in the chest NNT — 14.7 — 50 27.8 —

RR — OR: 0.70 (0.48–1.03) — 0.86 (0.64–1.15) 0.85 (0.64–1.13) —

Wheezing or whistling in the chest > 2x in 1 week NNT — — — 200 41.7 —

RR — — — 0.90 (0.68–1.19) 0.92 (0.70–1.22) —

Wheezing or whistling in the chest apart from colds NNT — — — 13.2 12.7 —

RR — — — 0.68 (0.50–0.92) 0.67 (0.49–0.91) —

Cough >3 days without cold NNT — — — 18.9 333.3 —

RR — — — 0.81 (0.60–1.10) 1.01 (0.75–1.37) —

Wheezing or whistling in the chest > 2x in 1 week or cough > 3 days without cold NNT — — — 111.1 37.0 —

RR — — — 0.95 (0.70–1.29) 0.87 (0.65–1.18) —

Asthma NNT 83.3 — — — — —

RR 0.95 (0.66–1.36) — — — — —

Asthma, RAD, BPD exacerbation or flare-up NNT — — — 21.7 90.9 —

RR — — — 0.81 (0.60–1.09) 1.01 (0.75–1.37) —

Bronchiolitis, bronchitis or pneumonia NNT — — — 20.8 71.4 —

RR — — — 0.81 (0.61–1.09) 0.96 (0.72–1.28) —

Respiratory illness requiring asthma medication NNT — — 7.7 — — —

RR — — — — — —

Bronchodilators/nebulizer NNT — 6.3 (4.0–15.6) — –90.9 45.5 —

RR — OR: 0.53 (0.36–0.78) — 1.11 (0.67–1.84) 0.73 (0.44–1.22) —

Inhaled steroids NNT — 7.5 (4.6–19.6) — –62.5 76.9 —

RR — OR: 0.50 (0.32–0.77) — 1.10 (0.80–1.50) 0.97 (0.71–1.32) —

Systemic steroids NNT — 14.1 (7.3–250.0) — –62.5 –76.9 —

RR — OR: 0.56 (0.32–0.97) — 1.22 (0.77–1.95) 1.13 (0.71–1.80) —

Diuretics NNT — 9.0 (5.2–33.3) — 52.6 –47.6 —

RR — OR: 0.54 (0.34–0.85) — 0.68 (0.39–1.20) 1.50 (0.85–2.64) —

Any/home oxygen use NNT — 9.4 (5.0–76.9) — 23.3 –24.4 ∞

RR — OR: 0.65 (0.44–0.95) — 0.80 (0.56–1.15) 1.31 (0.92–1.88) —

Oxygen use at follow-up NNT — 15.9 (9.4–52.6) — — — –66.7

RR — OR: 0.30 (0.13–0.73) — — — —

Outcome	DINO^a	NO CLD^b	SOD^c	Support^b	Early iNO^c
BPD @ 36 weeks	Rate (%)	18.8 v 25.1	50.7 v 56.9	36 v 37	39.2 v 40.6	37.4 v 40.0^d	65.0 v 68.0
	NNT	15.9	16.1	100	71.4	38.5	33.3
	RR	0.77 (0.59–1.02)	RB: 1.23^e (1.01–1.51)	––	0.99 (0.87–1.14)	Not sig	0.96 (0.86–1.09)
Any hospitalization	NNT	76.9	25.6	33.3	27.8	37.0	–34.5
	RR	0.98 (0.85–1.14)	OR: 0.83 (0.57–1.21)	—	0.87 (0.66–1.16)	0.90 (0.68–1.20)	—
Respiratory hospitalization	NNT	—	–142.9	—	25.0	–200	—
	RR	—	OR: 1.03 (0.65–1.62)	—	0.82 (0.61–1.11)	1.04 (0.77–1.40)	—
ER/physician visit	NNT	—	—	16.7	20.4	∞	–17.9
	RR	—	—	—	0.73 (0.53–1.00)	0.98 (0.72–1.34)	—
ICU readmission	NNT	—	—	—	—	—	–66.7
	RR	—	—	—	—	—	—
Mechanical ventilation during readmission	NNT	—	—	—	—	—	–33.3
	RR	—	—	—	—	—	—
Wheezing or whistling in the chest	NNT	—	14.7	—	50	27.8	—
	RR	—	OR: 0.70 (0.48–1.03)	—	0.86 (0.64–1.15)	0.85 (0.64–1.13)	—
Wheezing or whistling in the chest > 2x in 1 week	NNT	—	—	—	200	41.7	—
	RR	—	—	—	0.90 (0.68–1.19)	0.92 (0.70–1.22)	—
Wheezing or whistling in the chest apart from colds	NNT	—	—	—	13.2	12.7	—
	RR	—	—	—	0.68 (0.50–0.92)	0.67 (0.49–0.91)	—
Cough >3 days without cold	NNT	—	—	—	18.9	333.3	—
	RR	—	—	—	0.81 (0.60–1.10)	1.01 (0.75–1.37)	—
Wheezing or whistling in the chest > 2x in 1 week or cough > 3 days without cold	NNT	—	—	—	111.1	37.0	—
	RR	—	—	—	0.95 (0.70–1.29)	0.87 (0.65–1.18)	—
Asthma	NNT	83.3	—	—	—	—	—
	RR	0.95 (0.66–1.36)	—	—	—	—	—
Asthma, RAD, BPD exacerbation or flare-up	NNT	—	—	—	21.7	90.9	—
	RR	—	—	—	0.81 (0.60–1.09)	1.01 (0.75–1.37)	—
Bronchiolitis, bronchitis or pneumonia	NNT	—	—	—	20.8	71.4	—
	RR	—	—	—	0.81 (0.61–1.09)	0.96 (0.72–1.28)	—
Respiratory illness requiring asthma medication	NNT	—	—	7.7	—	—	—
	RR	—	—	—	—	—	—
Bronchodilators/nebulizer	NNT	—	6.3 (4.0–15.6)	—	–90.9	45.5	—
	RR	—	OR: 0.53 (0.36–0.78)	—	1.11 (0.67–1.84)	0.73 (0.44–1.22)	—
Inhaled steroids	NNT	—	7.5 (4.6–19.6)	—	–62.5	76.9	—
	RR	—	OR: 0.50 (0.32–0.77)	—	1.10 (0.80–1.50)	0.97 (0.71–1.32)	—
Systemic steroids	NNT	—	14.1 (7.3–250.0)	—	–62.5	–76.9	—
	RR	—	OR: 0.56 (0.32–0.97)	—	1.22 (0.77–1.95)	1.13 (0.71–1.80)	—
Diuretics	NNT	—	9.0 (5.2–33.3)	—	52.6	–47.6	—
	RR	—	OR: 0.54 (0.34–0.85)	—	0.68 (0.39–1.20)	1.50 (0.85–2.64)	—
Any/home oxygen use	NNT	—	9.4 (5.0–76.9)	—	23.3	–24.4	∞
	RR	—	OR: 0.65 (0.44–0.95)	—	0.80 (0.56–1.15)	1.31 (0.92–1.88)	—
Oxygen use at follow-up	NNT	—	15.9 (9.4–52.6)	—	—	—	–66.7
	RR	—	OR: 0.30 (0.13–0.73)	—	—	—	—

BPD, bronchopulmonary dysplasia; ER, emergency room; ICU, intensive care unit; NNT, number needed to treat; OR, odds ratio; RAD, reactive airway disease; RB, risk benefit; RR, relative risk. Significant data in bold. ^aTraditional definition of BPD at 36 weeks. ^bPhysiological definition of BPD at 36 weeks. ^cTraditional definition of BPD at 36 weeks with abnormal findings on chest radiograph. ^dData from follow-up study. ^eRisk benefit for survival without chronic lung disease.

In stratified analyses, the DINO trial found a significant difference in rate of BPD between intervention groups among those with BW < 1250 g (p: 0.04) and male gender (0.03); however, there were no significant differences between genders (p: 0.20) and BWs (p: 0.84). The Early iNO trial also found a significant difference in rates of BPD for infants with BW 1000–1250 g (p: 0.001). The SUPPORT trial found a significant difference in rate of BPD by the traditional definition with secondary randomization between target oxygen saturation (p: < 0.01).

3.3 Long-term respiratory outcomes

All studies included utilization of healthcare services as a secondary outcome (e.g. hospitalizations, emergency room (ER)/physician visits) (Table 1). Three studies reported respiratory illness (e.g. asthma, signs and symptoms of asthma) as a secondary outcome [16 , 23]. Four studies used requirement for respiratory medications (e.g. bronchodilators, steroids, diuretics, oxygen) [17 , 23]. One study used infant mortality at one year as a secondary outcome [22].

3.4 Relationship of BPD and long-term respiratory outcomes between intervention groups

3.4.1 Healthcare utilization

Long-term measures of healthcare utilization included any hospitalizations, respiratory hospitalizations, ER/physician visits, intensive care unit (ICU) readmissions, and mechanical ventilation during readmission. When comparing the impact of the treatment on BPD and post-neonatal intensive care unit (NICU) healthcare utilization, expressed in terms of number needed to treat, two studies [16, 18] showed consistent direction of risk difference, two studies [17, 23] showed mixed direction of risk difference, and one study [22] showed inconsistent direction of risk difference between rates of BPD and rates of healthcare utilization outcomes (Table 2). All studies evaluated the rate of any hospitalization. With the exception of the Early iNO trial, the remaining studies showed non-significant reductions in rates of any hospitalization. The Early iNO trial showed a non-significant increase in the rates of any hospitalization. Both trials evaluating the rates of respiratory hospitalizations showed non-significant changes between the intervention and control groups. The NO CLD trial and the oxygen saturation study arm of the SUPPORT trial showed increases in respiratory hospitalizations that were inconsistent with the reductions seen in BPD. The CPAP study arm of the SUPPORT trial showed a consistent reduction in respiratory hospitalizations. The three studies that evaluated ER/physician visits found mixed directions of effect when compared to rates of BPD. The only significant change was seen in the CPAP study arm of the SUPPORT trial which observed a decrease in the rate of ER/physician visits despite a non-significant decrease in the rate of BPD. Non-significant reductions in the rates of ER/physician visits were seen in the oxygen saturation study arm of the SUPPORT trial and the SOD trial. The Early iNO trial found a non-significant increase in ER/physician visits that was inconsistent with the reduction in BPD. They also found inconsistent, non-significant increases in ICU readmissions and mechanical ventilation during readmission.

3.4.2 Respiratory illness

Long-term measures of respiratory illness included asthma or asthma-like symptoms, cough, and other respiratory illnesses such as pneumonia. Of the three studies that evaluated for asthma or asthma-like symptoms, one study [16] used asthma only, one study [17] used wheezing or whistling in the chest only, and one study [23] used asthma, asthma-like symptoms, and other respiratory illness such as reactive airway disease and bronchiolitis as secondary outcomes. All measures of respiratory illness showed consistent risk reduction with BPD; however, the only significant reduction was seen in the SUPPORT trial when evaluating wheezing or whistling in the chest apart from colds (Table 2). The magnitude of the number needed to treat (NNT) relative to the NNT of BPD varied by study. The DINO trial had a risk difference less than that of BPD, the NO CLD study had a risk difference greater than that of BPD, while the SUPPORT trial had risk differences both less than and greater than that of BPD.

3.4.3 Respiratory medication

Long-term measures in the four studies evaluating respiratory medication use included respiratory illness requiring asthma medications, inhaled steroids, systemic steroids, diuretics, and home and follow-up oxygen use [17 , 23]. Of these four trials, two showed consistent, significant decreases in the rates of respiratory medications (Table 2). The NO CLD trial showed a significant, consistent risk reduction between rates of BPD and use of all respiratory medications with reductions greater than the reduction seen in BPD. The SOD trial showed a significant, consistent risk reduction in respiratory illness requiring asthma medications with a greater reduction than that for BPD. The SUPPORT trial found mixed, non-significant direction of risk differences in both study arms. The Early iNO trial showed an inconsistent, non-significant risk increase in follow-up oxygen use with no difference in any/home oxygen use.

3.4.4 Mortality

Only the Early iNO trial used infant mortality as a long-term secondary outcome. This study showed a consistent, non-significant risk reduction in mortality at 1 year corrected age (NNT: 21.2).

3.4.5 Results stratified by BPD

Only the SUPPORT trial stratified results by BPD. They found significant increases in the rate of long-term respiratory outcomes in those with BPD for all measures of healthcare utilization, all measures of respiratory illness except cough for more than 3 days without a cold, and all measures of respiratory medications except use of systemic steroids and nebulized medications (p < 0.05). No significant differences were seen in those three measures.

3.4.6 Summary of significant results

A consistent relationship between BPD and subsequent markers of respiratory morbidity was not seen in the trials studied (Table 3). Only the NO CLD trial found a significant decrease in rates of BPD. This study also saw significant decreases in the use of respiratory medications including oxygen, but in no other outcome measures. The SOD study also found a significant decrease in respiratory illness requiring asthma medications, but failed to find a significant decrease in BPD. Similarly, the SUPPORT study failed to find a significant decrease in BPD, but did see significant decreases in measures of healthcare utilization and respiratory illness.

Table 3
Summary of significant interactions of bpd and long-term respiratory outcomes

Study BPD HU RI RM Oxygen Mortality

DINO — — — — — —

NO CLD ↓ — — ↓ ↓ —

SOD — — — ↓ — —

Support CPAP — ↓ ↓ — — —

Support SAT — — ↓ — —

Early iNO — — — — — —

Study	BPD	HU	RI	RM	Oxygen	Mortality
DINO	—	—	—	—	—	—
NO CLD	↓	—	—	↓	↓	—
SOD	—	—	—	↓	—	—
Support CPAP	—	↓	↓	—	—	—
Support SAT	—	—	↓	—	—
Early iNO	—	—	—	—	—	—

4 Discussion

We performed a systematic review designed to evaluate interventional effects on BPD and long-term pulmonary outcomes to see if BPD is performing as a consistent surrogate marker of later respiratory morbidity in neonates in large, multi-center, randomized control trials. The results of this review indicate that BPD has not performed as a strong surrogate marker for long-term pulmonary outcomes. It did not consistently predict the magnitude or direction of the effect of an intervention on longer-term pulmonary outcomes.

In the trials reviewed, BPD may have identified infants at higher risk for respiratory disease overall, but was not highly predictive of requirement for medication and/or treatment. Only the NO CLD trial found a consistent, significant decrease between BPD and any measure of long-term pulmonary outcomes. Of those outcomes, only a decrease in respiratory medications including oxygen was significant. Moreover, while that study found consistent reductions in the need for respiratory medications, the reduction exceeded that of BPD. The SOD trial found a similar magnitude of reduction in the need for respiratory medications, albeit without a significant decrease in rates of BPD.

Taken together, studies varied both in the definition of BPD, as well as the in the long-term respiratory outcomes evaluated. The variation in the definition of BPD creates differing populations of patients under the term BPD, making it difficult to evaluate its use as a surrogate marker for long-term pulmonary outcomes. Similarly, there is not one marker for long-term pulmonary outcomes. While many of the studies used similar themes to evaluate long-term pulmonary outcomes, the definitions of the outcomes measures used varied significantly. For example, multiples studies evaluated asthma and asthma-like symptoms; however, where one study used “asthma” as an outcome measure [16], a second study used multiple wheezing episodes to evaluate asthma [23]. There is a need for both validated questionnaires to assess clinically relevant symptoms, as well as physiologic measurements to complement such. The lack of standardization in assessment of long-term pulmonary outcomes is a design issue for randomized controlled trials in the field, just as the variety of BPD definitions is. Outcomes for extremely preterm birth infants provide information that is critical for future clinical and policy decisions, and a failure to develop appropriate outcome measures can have far-reaching effects [25]. Steps are currently underway to standardize the definitions of pulmonary outcome assessments in preterm infants, and several studies of pulmonary outcomes in infants have collaborated to standardize wheezing assessments (NCT01601847, NCT00920621) [26, 27].

The findings of this review are consistent with previous findings stating that BPD is an imperfect surrogate marker for long-term pulmonary outcomes [13 –15]. Future steps can be undertaken to try to identify other surrogate markers that more accurately predict long-term pulmonary outcomes. Certainly, work has already been done to better characterize extremely pre-term infants with biological, physiological, and clinical data to then provide surrogate markers to predict respiratory morbidity [14, 28].

Limitations of our review include only five studies that met our inclusion criteria. However, this also underscores the paucity of studies directly measuring long-term pulmonary outcomes. The included studies employed diverse methodologies with a lack of standardized definitions of BPD and long-term pulmonary outcomes. As such, it is not only difficult to directly compare rates of BPD between studies, but also how rates of BPD amongst the study populations compare to respiratory clinical endpoints. A further limitation of our study is the focus only on randomized control trials. Other study designs, including longitudinal cohort studies, have documented BPD in the neonatal period and long-term outcomes beyond two years, and analogous study design issues with regards to the functioning of BDP as a surrogate outcome and validation and standardization of ascertainment of long-term pulmonary outcomes. Finally, there was a lack of power for long-term pulmonary outcomes in the trials themselves, so we have reported not only significance levels but also direction and magnitude of effects.

Overall, BPD appears to be an imperfect surrogate marker for long-term pulmonary outcomes at two years of age. Interventions in large, multi-center, randomized control trials showed inconsistent directionality and magnitude of effect between rates of BPD and long-term pulmonary outcomes. Moreover, there is still variation in the definition of BPD used for diagnosis and in the specific long-term pulmonary outcomes used to evaluate infant morbidity. Our aim was to assess real-life performance of BPD in randomized controlled trials; however, a lack of standardization in both the definition of BPD and in pulmonary outcome measures complicates the design of the study and this assessment. Further studies may benefit from using individual patient data analyses in working to identify a more predictive surrogate marker and more standardized assessments of long-term pulmonary outcomes.

Disclosure statements

The authors have no competing financial interests or other conflicts of interest to disclose. The authors received no honorarium, grant or other form of payment to produce the manuscript.

References

Northway

, Rosan

, Porter

. Pulmonary disease following respirator therapy of hyaline-membrane disease: Bronchopulmonary dysplasia. N Engl J Med. 1967;278:357–68.

Tooley

. Epidemiology of Bronchopulmonary dysplasia. J Pediatr. 1979;95(5, part 2):851–5.

Shennan

, Dunn

, Ohlsson

, et al. Abnormal pulmonary outcomes in premature infants: Prediction from oxygen requirement in the neonatal period. Pediatrics. 1988;82(4):527–32.

Jobe

. The new BPD: An arrest of lung development. Pediatr Res. 1999;46(6):641–3.

Hislop

, Wigglesworth

, Desai

. Alveolar development in the human fetus and infant. Early Hum Dev. 1986;13:1–11.

Husain

, Siddiqui

, Stocker

. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol. 1998;7(710-717).

Thibeault

, Mabry

, Ekekezie

, Truog

. Lung elastic tissue maturation and perturbations during the evolution of chronic lung disease. Pediatrics. 2000;106(6):1452–9.

Jobe

, Bancalari

. Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2001;163:1723–9.

Walsh

, Wilson-Costello

, Zadell

, Newman

. Safety, reliability, and validity of a physiological definition of bronchopulmonary dysplasia. J Perinatol. 2003;23:451–6.

10.

Biomarkers definitions working group biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.

11.

Institute of Medicine. Evaluation of biomarkers and surrogate endpoints in chronic disease. Micheel

, Ball

, editors. Washington D.C.: The National Academies Press; 2010.

12.

Baker

, Kramer

. A perfect correlate does not a surrogate make. BMC Med Res Methodol. 2003;5:1–5.

13.

Lefkowitz

, Rosenberg

. Bronchopulmonary dysplasia: Pathway from disease to long-term outcome. J Perinatol. 2008;28(12):837–40.

14.

Maitre

, Ballard

, Ellenberg

, et al. Respiratory consequences of prematurity: Evolution of a diagnosis and development of a comprehensive approach. J Perinatol. 2015;35(5):313–21.

15.

Davis

, Thorpe

, Roberts

, et al. Evaluating “Old” Definitions for the “New” bronchopulmonary dysplasia. J Pediatr. 2002;140(5):555–60.

16.

Manley

, Makrides

, Collins

, et al. High-dose docosahexaenoic acid supplementation of preterm infants: Respiratory and allergy outcomes. Pediatrics. 2011;128(1):e71–7.

17.

Hibbs

, Walsh

, Martin

, et al. One-year respiratory outcomes of preterm infants enrolled in the nitric oxide (to prevent) chronic lung disease Trial. J Pediatr. 2008;153(4):525–9.

18.

Davis

, Parad

, Michele

, et al. Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics. 2003;111(3):469–76.

19.

Kinsella

, Cutter

, Walsh

, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–64.

20.

Finer

, Carlo

, Walsh

, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010;362(21):1970–9.

21.

Ballard

, Truog

, Cnaan

, et al. Inhaled Nitric Oxide in Preterm Infants Undergoing Mechanical Ventilation. N Engl J Med. 2006;355(4):343–53.

22.

Watson

, Clermont

, Kinsella

, et al. Clinical and Economic Effects of iNO in Premature Newborns with Respiratory Failure at 1 year. Pediatrics. 2009;124(5):1333–43.

23.

Stevens

, Finer

, Carlo

, et al. Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial (SUPPORT). J Pediatr. 2014;165(2):240–249.

24.

Makrides

, Gibson

, Mcphee

, et al. Neurodevelopmental Outcomes of Preterm Infatns Fed High-Dose Docosahexaenoic Acid. JAMA. 2009;301(2):175–82.

25.

Rysavy

, Marlow

, Doyle

, et al. Reporting outcomes of extremely preterm births. Pediatrics. 2016;138(3).

26.

Boggs

, Minich

, Hibbs

. Performance of commmonly used respiratory questionnaire items in a cohort of infants born preterm. Open J Pediatr. 2013;3(3):260–5.

27.

Litonjua

, Lange

, Carey

, et al. The Vitamin D Antenatal Asthma Reduction Trial (VDAART): Rationale, design, and methods of a randomized, controlled trial of vitamin D supplementation in pregnancy for the primary prevention of asthma and allergies in children. Contemp Clin Trials. 2014;38(1):37–50.

28.

Pryhuber

, Maitre

, Ballard

, et al. Prematurity and respiratory outcomes program (PROP): Study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States. BMC Pediatr. 2015;15(37):1–14.