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Comparison of definitions of bronchopulmonary dysplasia to reflect the long-term outcomes of extremely preterm infants

Survivors of neonatal bronchopulmonary dysplasia (BPD) have persistent respiratory, neurodevelopmental, and growth impairment over the first few years of life and later childhood, which represents an emerging burden for health systems. Therefore, there is an increasing need for a new definition and grading system of BPD that predicts long-term outcomes of high-risk infants who need timely and proper intervention to improve outcomes. We compared new definitions of BPD (National Institute of Child Health and Human Development [NICHD] 2018 and Neonatal Research Network [NRN] 2019) to the original NICHD 2001 definition at 3 years of age using a nationwide cohort of extreme preterm infants. New definitions and severity grading were clearly related to respiratory, neurodevelopmental, and growth impairments at 3 years of age and at 18–24 months corrected age (CA), whereas the original NICHD 2001 definition was not. Furthermore, the negative effect of BPD on growth was ameliorated at 3 years of age compared to 18–24 months CA. However, the negative effect of BPD in neonates on the respiratory system and neurodevelopment persisted at 3 years of age. These new definitions should be adopted to identify high-risk infants and improve long-term outcomes by exact diagnosis and BPD severity classification.


Characteristics of the patients. A total of 2380 EPIs who survived and registered to Korean Neonatal
Network (KNN) were enrolled. The mean gestational age was 25.8 ± 1.2 weeks, and the mean birth weight was 882.0 ± 194.2 g. Overall, male neonates made up 53.5% of patients, and 6.2% of the patients were small for gestational age (SGA). Maternal gestational diabetes mellitus (GDM) and pregnancy induced hypertension (PIH) were observed in 6.9% and 8.9% of cases, respectively. Apgar scores at 1 and 5 min were 4 (3-5) and 7 (5-7), respectively. Follow-up rate at follow-up 1 (CA of 18-24 months) and 2 (3 years of age) were 69.4 and 43.1%, respectively ( Table 1). The characteristics of EPIs who completed follow-up and those who were lost-to-followup are shown in Supplementary Table 1. EPIs who completed follow-up had lower birth weight, younger gestational age, higher rates of SGA and maternal chorioamnionitis, and higher level of maternal education than those who were lost-to-follow-up. Table 1. Characteristics of the patients who were registered in the Korean Neonatal Network. Values are expressed as mean ± standard deviation or number (%). IQR, interquartile range; GDM, gestational diabetes mellitus; PIH, pregnancy induced hypertension.

Total N = 2380
Neurodevelopmental impairments. A total of 22, 24, and 6% of infants had mental developmental delay, motor developmental delay, and social developmental delay at follow-up 1. Overall, 23, 27, and 13% of infants had mental developmental delay, motor developmental delay, and social developmental delay, respectively, at follow-up 2. Neurodevelopmental impairments at follow-up 1 and 2 were 33, and 36%, respectively (Table 3).
By definition A, the risk for neurodevelopmental impairments in infants with BPD did not increase compared to the risk in infants without BPD at follow-up 1. Infants with grade 3 BPD had 2.69 times (95% CI 1.11, 6.52) higher risk for neurodevelopmental impairments compared to infants without BPD at follow-up 2.
By definition B, neurodevelopmental impairments increased from 24% among infants without BPD to 47% among those with grade 3 BPD at follow-up 1, while neurodevelopmental impairments were 27%, and 53% among infants without BPD and those with grade 3 BPD, respectively, at follow-up 2. Infants with grade 2 and 3 BPD had 1.99 times (95% CI 1.37, 2.88) and 1.96 times (95% CI 1.36, 2.82) higher risk for neurodevelopmental Table 2. Respiratory morbidities at a corrected age of 18-24 months and at 3 years of age according to the severity of bronchopulmonary dysplasia per each definition. AOR adjusted odds ratio; CI, confidence interval. ORs were adjusted for antenatal steroids therapy, surfactant use, gestational age, small for gestational age, intraventricular hemorrhage (≥ grade 3), periventricular leukomalacia, necrotizing enterocolitis (≥ stage 2), retinopathy of prematurity (requiring surgery), and sepsis using multivariable logistic regression. Respiratory morbidities were defined as (1) death due to respiratory causes from 36 weeks' postmenstrual age prior to follow-up 1 or between follow-ups 1 and 2; (2) (2) more than two readmissions due to respiratory causes between discharge from the neonatal intensive care unit and follow-up 1 or between follow-ups 1 and 2; or (3) the requirement of oxygen, mechanical ventilation, or tracheostomy at follow-up 1 or 2. Follow-up 1, follow-up at a corrected age of 18-24 months; follow-up 2, follow-up at 3 years of age. By definition C, neurodevelopmental impairments increased from 24% among infants without BPD to 57% among those with grade 3 BPD at follow-up 1, while neurodevelopmental impairments were 27% and 60% among infants without BPD and those with grade 3 BPD, respectively, at follow-up 2. The risk of neurodevelopmental impairments increased according to the severity of BPD at follow-ups 1 and 2 (P for trend < 0.001). Infants with grade 2 and 3 BPD had 1.73 times (95% CI 1.27, 2.35) and 2.74 times (95% CI 1.72, 4.34) higher risk for neurodevelopmental impairments, respectively, compared to infants without BPD at follow-up 1. Infants with grade 2 and 3 BPD had 1.76 times (95% CI 1.18, 2.62) and 2.38 times (95% CI 1.30, 4.35) higher risk for neurodevelopmental impairments compared to infants without BPD at follow-up 2, respectively (Table 3).
By definition A, infants with grade 3 BPD had 2.70 times (95% CI 1.43, 5.11) higher risk for growth restrictions than infants without BPD at follow-up 1. However, there was not increased risk for growth restrictions in infants with BPD compared to infants without BPD at follow-up 2 ( Table 4).
By definition B, growth restrictions increased from 28% among infants without BPD to 54% among those with grade 3 BPD at follow-up 1, which were decreased to 5 and 19% among infants without BPD and among those with grade 3 BPD, respectively, at follow-up 2. The risk of growth restrictions increased according to the severity of BPD at follow-ups 1 and 2 (P for trend < 0.001). Infants with grade 1, 2 and 3 BPD had 1.47 (95% CI 1.09, 1.97), 1.68 (95% CI 1.20, 2.35), and 2.21 (95% CI 1.59, 3.07) times higher risk for growth restrictions compared to infants without BPD at follow-up 1, respectively. Infants with grade 2 and 3 BPD had 3.13 times (95% CI 1.60, 6.13) and 3.85 times (95% CI 1.99, 7.45) higher risk for growth restrictions compared to infants without BPD at follow-up 2, respectively.
By definition C, growth restrictions increased from 28% among infants without BPD to 61% among those with grade 3 BPD at follow-up 1, which were decreased to 5 and 30% among infants without BPD and among those with grade 3 BPD, respectively, at follow-up 2. The risk of growth restrictions increased according to the severity of BPD at follow-ups 1 and 2 (P for trend < 0.001). Infants with grade 2 and 3 BPD had 1.77 times (95% CI 1.34, 2.33) and 2.82 times (95% CI 1.85, 4.30) higher risk for growth restrictions, respectively, compared to infants without BPD at follow-up 1. Infants with grade 2 and 3 BPD had 2.59 times (95% CI 1.41, 4.78) and 6.47 times (95% CI 3.12, 13.42) higher risk for growth restrictions, respectively, compared to infants without BPD at follow-up 2, respectively.
Association of the severity of BPD and the risk of long-term outcomes over time. To account for repeated measures and missing data, we reanalyzed the data with generalized estimating equation (GEE) models. Infants with BPD did not have higher risk of respiratory morbidities in all BPD severities by definition A (Table 5). By definition B and C, infants with grade 3 BPD had 2.61 times (95% CI 1.26, 5.41) and 3.10 times (95% CI 1.23, 7.77) higher risk for respiratory morbidities, respectively, compared to infants without BPD. By Table 3. Neurodevelopmental impairments at a corrected age of 18-24 months and at 3 years of age according to the severity of bronchopulmonary dysplasia per each definition. AOR adjusted odds ratio; CI confidence interval. ORs were adjusted for gestational age, small for gestational age, intraventricular hemorrhage (≥ grade 3), periventricular leukomalacia, necrotizing enterocolitis (≥ stage 2), retinopathy of prematurity (requiring surgery), and sepsis using multivariable logistic regression. Neurodevelopmental impairment was defined as mental developmental delay, motor developmental delay, or social developmental delay.   Table 5. Association of the severity of bronchopulmonary dysplasia and the risk of long-term outcomes over time per each definition. AOR adjusted odds ratio; CI confidence interval. ORs were adjusted for gestational age, small for gestational age, intraventricular hemorrhage (≥ grade 3), periventricular leukomalacia, necrotizing enterocolitis (≥ stage 2), retinopathy of prematurity (requiring surgery), and sepsis. A generalized estimating equation (GEE) method was applied to find the association between the severity of bronchopulmonary dysplasia and the risk of long-term outcomes over time per each definition.  Table 5).

Discussion
In this study, infants with BPD by definition A (NICHD 2001 definition) did not show higher risk for long-term respiratory, neurodevelopmental, and growth outcomes. However, infants with BPD by definition B (modified NICHD 2018 definition) and C (modified NRN 2019 definition) showed increased risk for poor long-term respiratory, neurodevelopmental, and growth outcomes at 3 years of age as well as at CA of 18-24 months according to the severity of BPD. In Korea, 65.7% (2153/3277) of EPIs with a gestational age of 23 to 27 weeks born between 2014 and 2017 died before 36 weeks' PMA or developed BPD (by definition B/C) in the present study. In 2018, reports from the United States showed that 51% of infants born at a gestational age of 22-29 weeks died before 36 weeks' PMA or developed BPD 14 . This means clearly that BPD is a big burden for the society and health systems.
To improve long-term outcomes of EPIs with BPD who have high risks of respiratory, neurodevelopmental, and growth impairments, the definition of BPD has evolved to predict high-risk infants who require early interventions.
The most widely used definition is the one proposed by the NICHD workshop in 2001 10 . This definition was proposed more than 20 years ago when survival rates of EPIs were extremely low. Nowadays, together with the markedly improved survival, the surviving EPIs require oxygen for a long duration, sometimes more than 28 days. These EPIs were diagnosed at least with "mild BPD" according to the NICHD 2001 definition. However, long-term outcomes of infants with "mild BPD, " according to this definition, were comparable to those of infants without BPD. Therefore, we did not need to classify these infants as having BPD. Furthermore, infants with a high-flow nasal cannula or recently developed respiratory support cannot be classified according to the NICHD 2001 definition. Thus, this definition is no longer useful for EPIs. Furthermore, the new definition proposed in the NICHD workshop in 2016 13 had better predictive ability at CA of 20-24 months 15 , that also had higher specificity and better positive predictive value at CA of 18-24 months 16 than the NICHD 2001 definition. The NICHD 2018 definition diagnose BPD on respiratory support and oxygen concentration at 36 weeks' PMA without requiring oxygen for the first 28 days of life. However, this definition is not easy to use and somewhat complicated ( Table 6). The NICHD NRN proposed definition in 2019 1 only depends on respiratory support at 36 weeks' PMA, which depends on neither oxygen concentration at 36 weeks' PMA nor oxygen requirement for the first 28 days of life. This definition is easy to apply, and can predict late death or long-term respiratory morbidities (predictive  19,20 . This result also implies that dependency on IV at 36 weeks' PMA (grade 3 BPD by NRN 2019 definition) is the most important prognostic factor for mortality and outcomes. Adult survivors of neonatal BPD show greater deficits in executive functioning related to problem solving, awareness of behavior, and organization of environment compared to preterm infants without BPD or term infants 21 . Though neurodevelopmental, respiratory, or growth impairments in BPD survivors extend into adulthood in those with great deficits, there are few studies that compare long-term morbidities at certain time points, such as at a CA of 18-24 months and 3 years of age like our present study.
Long-term motor developmental impairment both at 18-24 months of CA and at 3 years was found in EPIs with grade 3 BPD according to definitions B and C in the present study. Further, BPD was strongly associated with the increased risk of developmental delay at a CA of 24 months 22 . Also, 31.3% of preterm infants with BPD born at gestational age < 29 weeks had neurodevelopmental impairment at CA 2 years 23 . Together with longterm motor developmental impairment, severe BPD increased the risk of early motor developmental delay at CA of 3 and 6 months 24 . Hence, early precise diagnosis of BPD and identification of high-risk infants to facilitate earlier intervention is crucial to improve long-term outcomes. Neurodevelopmental impairments became more severe according to the progressive severity of BPD, which were aggravated at a CA of 5 years compared to a CA of 2 years by Katz et al. 25 . However, in the present study, the risk of neurodevelopmental impairments was not increased according to time, namely from a CA of 18-24 months to 3 years of age.
Respiratory morbidities were not improved at 3 years of age compared to a CA of 18-24 months in the present study. A total of 39% of EPIs with BPD readmitted because of pulmonary complications of BPD in the present study before reaching a CA of 18-24 months. Similarly, 49% of preterm infants with BPD were readmitted due to respiratory cause for the first year of life 26 . Furthermore, pulmonary dysfunction, exercise intolerance, or wheezing can persist in survivors of neonatal BPD during early childhood even in young adulthood due to the injury on respiratory system occurred during the neonatal period, though BPD tends to improve with lung development after birth 26,27 . This is why the risk of respiratory morbidities was not decreased at 3 years of age compared to at a CA of 18-24 months in the present study.
Growth restrictions were improved at 3 years of age compared to at a CA of 18-24 months in the present study. Growth restriction at a CA of 18-24 months in grade 3 BPD by definition B and C were 54 and 61%, which was decreased to 19 and 30% at 3 years of age, respectively. This might be explained by the aggressive nutritional strategies for infants with BPD 28 . EPIs with BPD usually have postnatal growth restriction, because of high metabolic demands with poor nutritional reserves. However, Dassios et al. reported that through the use of aggressive nutritional strategies, short-term outcomes of weight and head circumference growth in infants with BPD at 36 weeks' PMA had overcome those of infants without BPD 28 .
This study has some limitations. First, because of the multi-center nature of this registry, each hospital uses different modalities to evaluate neurodevelopment, so inter-hospital variability or inter-test variability was inevitable. Furthermore, we developed the composite data to minimize these variability and selection bias. We developed the composite scores on motor, mental, and social domain using each item in Bayley Scales of Infant Development (BSID) II, BSID III, Korean Developmental Screening Test for Infants and Children (K-DST) 29 , or Korean Ages & Stages Questionnaires (K-ASQ) 30 described in the section of method 2 . Second, modifications of the NICHD 2018 definition and the NRN 2019 definition to definitions B and C were inevitable, because the KNN pre-set registry data were used. The comparison between definition B, C, NICHD 2018, and NRN 2019 definition is presented in Table 6. Third, in the present study, the number of emergency room visits due to respiratory causes was not included in the respiratory morbidities, and an abnormal pulmonary function test was also not included because the KNN data did not comprise these types of data.
However, a strength of this study is the exact comparison of long-term respiratory, neurodevelopmental, and growth outcomes in EPIs with BPD in a nationwide prospective cohort at certain time points (at a CA of 18-24 months and at 3 years of age). There are few studies comparing long-term morbidities of such infants at certain time points. Our previous study 2 concluded that the recently suggested BPD definitions better reflected long-term morbidities at a CA of 18-24 months than the original NICHD 2001 definition. The present study also confirmed this result at 3 years of age, in addition to a CA of 18-24 months. BPD survivors have persistent long-term morbidities during the first few years of life; therefore, there is a need to evaluate more long-term morbidities. Further, we aimed to determine whether long-term morbidities were overcome over time from CA of 18-24 months to 3 years of age. The rates of respiratory morbidities and growth restrictions at a CA of 18-24 months were 11 and 38%, respectively, which decreased to 7 and 10%, respectively, at 3 years of age, although without statistical comparison. In our previous study 2 , EPIs were enrolled between January 1, 2013 and December 31, 2015, while the present study enrolled more EPIs born between January 1, 2014 and December 31, 2017. Overlapping of some EPIs was unavoidable. Similar to a previous study with KNN data 31 , EPIs with lower birth weight, younger gestational age, SGA, and maternal chorioamnionitis were followed-up in the present study. It appears that there was at least no bias to exclude more severe EPIs in the present study performed with those who completed follow-up. www.nature.com/scientificreports/ In conclusion, respiratory, neurodevelopmental, and growth impairments at 3 years of age as well as at a CA of 18-24 months were clearly associated with the increased severity of BPD according to the new definitions (definition B and C) not by the original NICHD 2001 definition. This negative effect of BPD on growth tends to be ameliorated with the growth of the infants. However, the negative effect of BPD occurred in neonatal period on respiratory system and neurodevelopment persisted at 3 years of age. So, these new definitions should be adopted to identify high-risk infants who require timely and proper intervention to improve long-term outcomes by exact diagnosis and classification of the severity of BPD.

Methods
This prospective, nationwide, large cohort study included preterm infants in the 70 participating centers, covering > 80% of very low birth weight infants (VLBWIs) in Korea since KNN was launched in 2013 32 . A total of 3277 EPIs born at a gestational age of 23-27 weeks between January 1, 2014 and December 31, 2017 were registered to KNN, and 897 of them who died before being diagnosed with BPD at 36 weeks PMA or due to congenital anomalies were excluded. The 2380 EPIs who survived were enrolled, and among them, 1508 were followed up at a CA of 18-24 months (follow-up 1), and 938 were followed up at 3 years of age (follow-up 2). The baseline characteristics of the EPIs registered in the KNN were analyzed. Furthermore, the characteristics of EPIs who completed follow-up were compared with those of EPIs who were lost-to-follow-up. We evaluated long-term outcomes, namely, respiratory morbidities, neurodevelopmental impairment, and growth restriction both at follow-up 1 and 2.
BPD was assessed at 36 weeks' PMA, which was classified to no, grade 1, 2, and 3 BPD according to severity by each definition (Table 6) (Table 6). Definition C is the modified NRN 2019 definition 1 . Grade 1 BPD breathes oxygen using a nasal cannula at < 2 L/min. Grade 2 BPD breathe with NIV (including nasal cannula oxygen at ≥ 2 L/min). Grade 3 BPD needs IV. The only difference between definitions C and NRN 2019 is that NIV includes nasal cannula oxygen ≥ 2 L/min in the KNN registry, whereas, it includes nasal cannula oxygen > 2 L/min in the NRN 2019 definition (Table 6).
Respiratory morbidities were defined as (1) death due to respiratory causes from 36 weeks' PMA prior to follow-up 1 or between follow-ups 1 and 2; (2) more than two readmissions due to respiratory causes between discharge from the NICU and follow-up 1 or between follow-ups 1 and 2; or (3) the requirement of oxygen, mechanical ventilation, or tracheostomy at follow-up 1 or 2.
Neurodevelopmental impairment was defined as mental developmental delay, motor developmental delay, or social developmental delay. Mental developmental delay was defined as (1) a mental developmental index (MDI) < 70 on the BSID II; (2) cognitive or language < 70 on the BSID III; (3) cognition, language, or self-help score that is less than the cut-off value on the K-DST; or (4) communication or problem-solving score that is less than the cut-off value on the K-ASQ. Motor developmental delay was defined as (1) a psychomotor developmental index (PDI) < 70 on the BSID II; (2) motor < 70 on the BSID III; (3) gross motor or fine motor score that is less than the cut-off value on K-DST or K-ASQ; or (4) cerebral palsy defined as Gross Motor Functional Classification System ≥ 2 33 . Social developmental delay was defined as (1) a sociality less than the cut-off value on the K-DST; or (2) a personal-social score less than the cut-off value on the K-ASQ.
Growth restriction was defined as z-scores < − 1.28 (equivalent to < 10th percentile) of weight, height, or head circumference according to the CA by the 2006 World Health Organization (WHO) Child Growth Standards, meaning failure of catch-up growth 34 .
Statistical analysis. Continuous variables were compared using the t-test or Mann-Whitney U test, and categorical variables were compared using the chi-square test or Fisher's exact test, as appropriate. Continuous variables are presented as mean ± standard deviation (SD) and categorical variables are presented as number (percentage). Apgar scores are presented as median (interquartile range [IQR]).
ORs compared to no BPD according to various BPD severity per each definition using multivariable logistic regression were analyzed. ORs for neurodevelopmental impairment and growth restriction were adjusted for gestational age, SGA, intraventricular hemorrhage (≥ grade 3), periventricular leukomalacia, necrotizing enterocolitis (≥ stage 2), retinopathy of prematurity (requiring surgery), and sepsis, which might affect longterm neurodevelopmental and growth outcomes 2 . ORs for respiratory morbidities were adjusted for antenatal steroids therapy, surfactant use, gestational age, SGA, intraventricular hemorrhage (≥ grade 3), periventricular leukomalacia, necrotizing enterocolitis (≥ stage 2), retinopathy of prematurity (requiring surgery), and sepsis, which might affect long-term respiratory outcomes. The long-term outcomes were considered as binary dependent variables, and the BPD definition was considered as a categorical independent variable in each model. A