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Validation of the National Institutes of Health Consensus Definition of Bronchopulmonary Dysplasia

Richard A. Ehrenkranz, MD^*, Michele C. Walsh, MD, Betty R. Vohr, MD, Alan H. Jobe, MD, PhD^||, Linda L. Wright, MD^¶, Avroy A. Fanaroff, MB, BCh, Lisa A. Wrage, MPH^#, Kenneth Poole, PhD^# for the National Institutes of Child Health and Human Development Neonatal Research Network

^* Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio
Department of Pediatrics, Brown University, Providence, Rhode Island
^|| Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
^¶ National Institute of Child Health and Human Development, Bethesda, Maryland
^# RTI International, Research Triangle Park, North Carolina

	ABSTRACT

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Objective. A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants <32 weeks’ gestational age (GA). Mild BPD was defined as a need for supplemental oxygen (O₂) for 28 days but not at 36 weeks’ postmenstrual age (PMA) or discharge, moderate BPD as O₂ for 28 days plus treatment with <30% O₂ at 36 weeks’ PMA, and severe BPD as O₂ for 28 days plus 30% O₂ and/or positive pressure at 36 weeks’ PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD.

Methods. Data from 4866 infants (birth weight 1000 g, GA <32 weeks, alive at 36 weeks’ PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between January 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months’ corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medications, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevelopmental abnormalities) were compared among infants who were identified with BPD defined as O₂ for 28 days (28 days definition), as O₂ at 36 weeks’ PMA (36 weeks’ definition), and with the consensus definition of BPD.

Results. A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months’ corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up.

Conclusion. The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions.

Key Words: bronchopulmonary dysplasia • chronic lung disease • extremely preterm infants • neurodevelopmental

Abbreviations: BPD, bronchopulmonary dysplasia • CLD, chronic lung disease • PMA, postmenstrual age • VLBW, very low birth weight • GA, gestational age • ELBW, extremely low birth weight • NICHD, National Institute of Child Health and Human Development • CPAP, continuous positive airway pressure • RSV, respiratory syncytial virus • CP, cerebral palsy

Several definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease (CLD), have been used since 1967, when Northway et al¹ first described the clinical, radiologic, and pathologic changes seen in infants who had severe respiratory distress syndrome and had been treated with prolonged mechanical ventilation and high inspiratory oxygen levels. The term BPD had been applied to that condition so as to emphasize that all of the tissues of the lung, airways, and parenchyma were involved in the pathologic process.

During the late 1970s and early 1980s, the radiologic stages of worsening BPD that were described in the initial description were rarely seen, and a number of investigators defined BPD by clinical characteristics that were present at 1 month of age in association with an abnormal or "characteristic" chest radiograph.^2–4 In 1988, Shennan et al⁵ suggested that the need for or treatment with oxygen at 36 weeks’ postmenstrual age (PMA) was a better predictor of abnormal pulmonary outcome in infancy for very low birth weight (VLBW; birth weight 1500 g) infants <32 weeks’ gestational age (GA) than the need for or treatment with oxygen at 1 month of age. The term "chronic lung disease" was used to describe those infants.

BPD/CLD continues to be a major cause of mortality and long-term morbidity in VLBW, especially extremely low birth weight (ELBW; birth weight 1000 g) infants. The definitions of BPD/CLD have become less precise as survival of ELBW infants has increased, and the terms are now often used interchangeably. Most current diagnostic criteria are based solely on treatment with supplemental oxygen therapy at 36 weeks’ PMA and do not require or specify chest radiographic abnormalities.

The definition of BPD/CLD in preterm infants was reviewed at a June 2000 National Institute of Child Health and Human Development (NICHD)/National Heart, Lung, and Blood Institute Workshop, "From BPD to CLD: Emergence of a New Disease."⁶ A consensus of workshop participants chose to refer to the condition as BPD because "it is clearly distinct from the multiple chronic lung diseases of later life." In addition, a consensus, severity-based definition of BPD was proposed (Table 1). One of the aims of the consensus BPD definition was to acknowledge that infants who had been treated with oxygen for >28 days but no longer required oxygen at 36 weeks’ PMA might have residual lung disease. Although not specified in the consensus BPD definition, it was recommended that a physiologic test confirming the need for supplemental oxygen be performed.⁷ Furthermore, specific radiographic findings were not required as part of the workshop definition because these findings had not been found to increase diagnostic sensitivity or specificity.^8,9 The primary objective of this project was to determine the predictive validity of the proposed severity-based diagnostic criteria for BPD on pulmonary, neurodevelopmental, and growth outcomes at 18 to 22 months’ corrected age.

	METHODS

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NICU data were abstracted from the infants’ charts by trained research nurses using previously described definitions.^10–12 After discharge, families were invited to participate in the NICHD Neonatal Research Network ELBW Follow-up Program for a comprehensive assessment at 18 to 22 months’ corrected age. The follow-up assessment has been described in detail; it is performed by certified examiners and included a standardized neurologic examination, Bayley Scales of Infant Development II-R (Mental Scale, Motor Scale, and Behavioral Rating Scale), structured parent interviews about medical and social history and functional performance, and anthropometric measurements.¹³ Anthropometric measures were compared with the 2000 Centers for Disease Control and Prevention growth curves¹⁴ after adjustment for gender and age at the time of the follow-up assessment.

For the purpose of this report, the incidence of selected follow-up outcomes was compared among infants who were identified with BPD defined variously as (1) supplemental oxygen therapy for all 28 days of the first 28 days of life (28-days definition), (2) supplemental oxygen for all 28 days of the first 28 days of life and an abnormal chest radiograph consistent with parenchymal lung disease (28 days–CXR definition), (3) receipt of supplemental oxygen at 36 weeks’ PMA (36-weeks definition), (4) receipt of supplemental oxygen at 36 weeks’ PMA and an abnormal chest radiograph consistent with parenchymal lung disease (36 weeks–CXR definition), and (5) by the consensus BPD definition (Table 1). Although the diagnostic criteria outlined in the consensus BPD definition specified that a day of treatment with supplemental oxygen meant that the infant received >21% oxygen for >12 hours on that day and that a physiologic assessment be used to confirm oxygen dependence at 36 weeks’ PMA,⁷ that information was not available in the Network VLBW Registry. Respiratory support and supplemental inspired oxygen therapy were administered at the discretion of the infant’s clinical team. Data describing the mode of respiratory support (ventilator, nasal continuous positive airway pressure [CPAP], oxyhood, or nasal cannula) and the highest measured concentration of oxygen received on day 28 of life and at 36 weeks’ PMA or discharge were recorded by trained neonatal research nurses. In addition, the total duration of different modes of respiratory support and of supplemental oxygen therapy were recorded. Therefore, the analyses described in this report were based on therapies received. Furthermore, because data to permit calculation of the effective inspiratory oxygen concentration had not been collected, an infant who was receiving nasal cannula oxygen at 36 weeks’ PMA was considered to have moderate BPD, whereas an infant who was receiving 30% oxygen via an oxyhood and/or positive pressure from a mechanical ventilator or nasal CPAP at 36 weeks’ PMA was considered to have severe BPD. The decision about whether respiratory syncytial virus (RSV) prophylaxis was prescribed was made by each infant’s primary care provider. Abnormal pulmonary outcomes at 18 to 22 months’ corrected age included the incidence of treatment with diuretics or bronchodilators (referred to as pulmonary medications) and rehospitalization for pulmonary causes between discharge and the 18- to 22-months’ corrected age follow-up visit. Neurodevelopmental impairment was defined as the presence of any of the following: cerebral palsy (CP), Bayley Mental Developmental Index <70, Bayley Psychomotor Developmental Index <70, deaf/hearing loss requiring amplification in both ears, or bilaterally blind.

Infants (n = 672) who were transferred to another hospital before discharge home were categorized similarly to infants who were discharged directly home. Of the 473 infants who were transferred before 36 weeks’ PMA, 271 were still being treated with oxygen and/or respiratory support at the time of transfer; for this analysis, they were classified according to their therapies at transfer. Because transfer to another hospital occurred after 36 weeks’ PMA for the remaining 199 infants, sufficient data were available to determine whether BPD developed and, if so, which definitions were met. Length of stay was defined as the number of days to discharge or transfer from a network participating center. However, the accuracy of that analysis is limited because the number of days spent by transferred infants in the other hospital or chronic care facility was not included in the data set.

Statistical Analyses
² tests, odds ratios, Mantel-Haenszel ² tests and analysis of variance were used to examine the relationship among BPD diagnostic category, maternal and neonatal characteristics, and outcomes in the NICU and at 18 to 22 months’ corrected age. P < .05 was considered significant. Analyses were completed at RTI International (Research Triangle Park, NC) using SAS Software.

	RESULTS

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The proportion of the study population (n = 4866) that was classified as having BPD according to the 5 BPD definitions and among the 3848 infants who were seen at follow-up is displayed in Table 2. The addition of information about the presence of an abnormal chest radiograph to the 28-days definition and 36-weeks definition of BPD did not improve significantly the ability of those definitions to predict abnormal pulmonary outcomes. As expected, fewer infants met the 36-weeks definition than the 28-days definition, because many infants who needed oxygen during the first 28 days of life no longer needed it at 36 weeks’ PMA. Furthermore, the 28-days definition identified a similar proportion of infants with BPD as the combined mild, moderate, and severe categories of the consensus BPD definition, whereas the 36-weeks definition identified a similar proportion of infants as the combined moderate and severe categories of consensus definition.

	DISCUSSION

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During the past 35 years, the diagnostic criteria used to define BPD have also changed. In addition, a number of investigators have attempted to describe scoring systems for predicting the risk or severity of BPD,^15–17 to identify risk factors that are associated with the development of BPD,^18,19 or to identify diagnostic criteria that predicted abnormal pulmonary and functional outcomes.^20–23 Older studies have tended to define BPD as treatment with supplemental oxygen for longer than 28 to 30 days,^15–18 whereas more recent studies have defined BPD as treatment with supplemental oxygen at 36 weeks’ PMA.^19–23 However, studies^20–23 that have described the relationship between the duration of oxygen therapy, especially supplemental oxygen therapy at 36 weeks’ PMA, and pulmonary outcomes such as treatment with pulmonary medications (bronchodilators and/or steroids) and rehospitalization for respiratory causes have reported variable findings. Palta et al²⁰ reported that the presence of radiographic evidence of moderate to severe BPD (as defined by a radiographic scoring system) was more predictive of the need for pulmonary medications up to 2 years of age and for rehospitalization for respiratory causes up to 5 years of age than treatment with oxygen at 36 weeks’ PMA. Davis et al²² reported that the duration of oxygen therapy, including need for or treatment with supplemental oxygen at 36 weeks’ PMA, was found to be a poor surrogate for long-term pulmonary abnormalities, whereas Gregoire et al²¹ observed an association with longer hospital stays during readmissions for respiratory problems but not with the number of rehospitalizations, and Smith et al²³ noted an increased rate of rehospitalization. We observed an increasing incidence of adverse pulmonary outcomes as the severity of BPD, defined by the consensus definition, worsened from mild to severe but did not find that the presence of an abnormal chest radiograph improved the ability of the 28-days or 36-weeks definitions of BPD in predicting adverse pulmonary outcomes (Table 2). In addition, consistent with reports that healthy preterm infants have abnormal lung function at term PMA²⁴ and altered airway development during infancy,²⁵ making them prone to airway problems during early childhood, we observed a substantial rate of adverse pulmonary outcomes in the infants who did not meet any of the definitions of BPD (Table 2).

Although some investigators have suggested that BPD is not independently associated with poor neurodevelopmental outcome,^26,27 most^13,28–32 have reported that BPD was a significant risk factor for the development of CP and poor functional outcomes. Vohr et al,¹³ reporting for the NICHD Neonatal Research Network, previously described logistic regression analyses in which both BPD and postnatal steroids for pulmonary disease were significant risk factors associated with the likelihood of neurodevelopmental impairment in ELBW survivors at 18 to 22 months’ corrected age. Evaluating children at 8 years of age, Short et al³¹ demonstrated that compared with VLBW infants without BPD and with term infants, VLBW infants with BPD were more likely to receive special education services and to have difficulties with motor and cognitive skills. After controlling for birth weight and neurologic complications, these outcomes were found to be significantly related to the severity of BPD and the duration of supplemental oxygen.³⁰ Although Davis et al²² reported that BPD defined by duration of oxygen therapy had limited accuracy in predicting long-term neurosensory outcomes, the study by Gregoire et al²¹ found that oxygen dependence at 36 weeks’ PMA by infants of 24 to 28 weeks’ GA predicted developmental delay at 18 months of age; of note, infants who needed oxygen at 28 days and not at 36 weeks’ PMA had similar developmental outcomes to infants who needed oxygen for <28 days. One report³² indicated that >75% of ELBW infants who remain ventilator dependent beyond 60 days of life have abnormal long-term neurodevelopment and that 25% will die before hospital discharge. Furthermore, postnatal corticosteroid therapy for prevention or treatment of BPD has been increasingly incriminated as a factor that contributes to the development of CP.^33–38 Our study found that the incidence of postnatal corticosteroid use (Table 4) and of neurodevelopmental impairment and head circumference growth (Table 5) corresponded to the severity of BPD defined by the consensus definition.

With increasing survival of ELBW infants, a definition of BPD based on the duration of oxygen therapy or treatment with supplemental oxygen at 36 weeks’ PMA may no longer accurately identify all infants with BPD.^6,22,39 Methods for assessing the need for supplemental oxygen are not standardized between NICUs and among physicians; thus, the incidence of BPD varies with clinical practice, rather than being determined by an objective physiologic test.^6,7,20,39 Because the development of BPD as defined by the treatment with supplemental oxygen at 36 weeks’ PMA has been the primary outcome for many multicenter, intervention, randomized, controlled trials (eg,^40–44), practice variation might reduce the likelihood that a therapeutic intervention would be found efficacious³⁸ and account for some of the variability in the relationship between the need for oxygen at 36 weeks’ PMA and pulmonary and neurodevelopmental outcomes.^{21,22,26–31}

In addition, infants who are <32 weeks’ GA, treated with supplemental oxygen for >28 days but not at 36 weeks’ PMA, or are receiving room air via nasal CPAP at 36 weeks’ PMA may not be counted as having BPD by some clinicians, although they may have an abnormal chest radiograph, are being treated with diuretics or bronchodilators for pulmonary disease, and will receive RSV prophylaxis. Because neonatal ventilation and oxygen exposure have been shown to be risk factors for bronchial hyperresponsiveness and asthma,⁴⁵ children with a history of mild BPD may have a greater risk than children with a history of oxygen therapy for <28 days and thus warrant closer follow-up. This limitation of a definition of BPD based on the duration or treatment with supplemental oxygen has been acknowledged by others.^6,7,20,22,39

This study restricted its analysis to infants who were 1000 g birth weight and <32 weeks’ GA, although the consensus definition was developed for all infants who are <32 weeks’ gestation. In addition, as noted above, accurate classification of study infants by the consensus BPD definition was limited by the lack of an objective physiologic test confirming oxygen dependence. Walsh et al⁷ recently reported that a physiologic assessment that was based on an oxygen reduction challenge at 36 weeks’ PMA led to a 10% reduction in the number of infants who received a diagnosis of BPD defined as oxygen treatment at 36 weeks’ PMA. Reports by the NICHD Neonatal Research Network^10–12 listing the incidence of treatment with supplemental oxygen at 36 weeks’ PMA and of the use of postnatal corticosteroids display wide center-to-center differences, reflecting known practice variations related to criteria for oxygen treatment and the target range for pulse oximetry. Nonetheless, although such a physiologic assessment might alter the percentages of mild and moderate BPD within this study cohort, the overall incidence would not be expected to change greatly.

By identifying infants with mild to severe BPD, the severity-based diagnostic criteria correspond with the spectrum of pulmonary and neurodevelopmental outcomes observed in surviving ELBW infants with BPD. As severity increased, length of hospital stay increased and the use of postnatal steroids for pulmonary disease increased. In contrast to the 28-days and 36-weeks definitions that identified similar percentages of infants with abnormal pulmonary outcomes (Table 2), the incidence of adverse pulmonary (Table 2) and neurodevelopmental outcomes (Table 5) corresponded to the severity of BPD defined by the consensus BPD definition. However, similar to the administration of oxygen therapy, the decision to treat infants with pulmonary medications during the first 1 to 2 years of life and to rehospitalize for respiratory causes was determined by the clinical team, and wide practice variations exist.

The consensus definition, as modified for the current study, refines current practice-based definitions by grading severity. Because the definition can be applied easily to widely available clinical information, it is well suited to investigations that use a retrospective design, such as epidemiologic studies focused on pulmonary function outcomes during infancy or childhood. By including the recommended physiologic assessment of oxygen dependence at 36 weeks’ PMA with the severity-based diagnostic criteria, an objective outcome that is suitable for prospective cohort studies and randomized controlled trials can be defined.

Two recent reports support our contention about the usefulness of the severity-based diagnostic criteria for BPD. In a retrospective study, Sahni et al⁴⁶ reported that our system for grading the severity of BPD offered a better description of an infant’s underlying pulmonary disease and correlated with growth, length of hospital stay, and overall severity of illness. Hjalmarson and Sandberg⁴⁷ performed pulmonary function tests at term PMA on preterm infants who had BPD classified with these severity-based criteria and found that the magnitude of functional impairments was related to the clinical severity of BPD.

We conclude, therefore, that these severity-based diagnostic criteria for BPD reflect the continuum of lung injury and repair present in BPD and identify a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions. We believe that these criteria will be useful to clinicians in their NICU practice and to clinical investigators who evaluate therapeutic intervention strategies in randomized, controlled trials. We also believe that they should permit comparisons between different NICUs and facilitate benchmarking and epidemiologic studies.

	ACKNOWLEDGMENTS

 
Participants in the NICHD Neonatal Research Network (1995–1999): Chairman, Alan H. Jobe, MD, PhD; University of Alabama (U10 HD34216): Waldemar A. Carlo, MD, Kathy Nelson, MD, Monica V. Collins, RN; Case Western Reserve University (U10 HD21364): Avroy A. Fanaroff, MB, BCh, Maureen Hack, MD, Nancy Newman, RN, Harriet Friedman, MA; University of Cincinnati (U10 HD27853, M01 RR 08084): Edward F. Donovan, MD, Jean J. Steichen, MD, Cathy Grisby, RN, Tari Gratton, RN; Emory University (U10 HD27851): Barbara J. Stoll, MD, Neal Simon, MD, Ellen Hale, RN; RTI International (U01 HD36790): W. Kenneth Poole, PhD, Betty Hastings; Indiana University (U10 HD27856, M01 RR 00750): James A. Lemons, MD, Anna Dusick, MD, Diane Appel, RN (NC), Julie Ahlrichs, RN; University of Miami (U10 HD21397): Charles R. Bauer, MD, Amy Mur Worth, RN, Wendy Griffin, RN; NICHD: Linda L. Wright, MD, Elizabeth McClure, Med; University of New Mexico (U10 HD27881, M01 RR 00997): Lu-Ann Papile, MD, Conra Backstom, RN, Jeanne Lowe, PhD, Barbara Woodward, MPH, OTR/L; Stanford University (U10 HD27880, M01 RR 00070): David K. Stevenson, MD, Barry E. Fleisher, MD, Bethany Ball, CCRC; University of Tennessee, Memphis (U10 HD21415): Sheldon B. Korones, MD, Henrietta Bada, MD, Tina Hudson, RN; University of Texas Southwestern Medical Center (U10 HD21373): Jon E. Tyson, MD, MPH, Sue Broyles, MD, Susan Madison, RN, Jackie Hickman, RN; Wayne State University (U10 HD21385): Seetha Shankaran, MD, Geraldine Muran, RN, Rebecca Bara, RN; Yale University (U10 HD27871, M01 RR 06022): Richard A. Ehrenkranz, MD, Linda Mayes, MD, Patricia Gettner, RN, Elaine Romano, MSN; Brigham and Women’s Hospital (U10 HD34167, M01 RR 02635, M01 RR 02172, M01 RR 01032): Ann R. Stark, MD, Kerri Fournier, RN, Stacy Dow, RN; Brown University (U10 HD27904): William Oh, MD, Betty Vohr, MD, Angelita Hensman, RNC, Terri Leach, MEd.

	FOOTNOTES

 
Accepted Apr 21, 2005.

Address correspondence to Richard A. Ehrenkranz, MD, Department of Pediatrics, Yale University School of Medicine, 333 Cedar St, PO Box 208064, New Haven, CT 06520-8064. E-mail: richard.ehrenkranz{at}yale.edu

Presented in part at the annual meeting of the Pediatric Academic Societies; April 28–May 1, 2001; Baltimore, MD.

No conflict of interest declared.

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