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Changes in the Incidence of Bronchopulmonary Dysplasia among Preterm Infants in a Single Center over 10 Years

Purpose: Bronchopulmonary dysplasia (BPD) is one of the most fatal respiratory morbidities in preterm infants, causing adverse respiratory and neurodevelopmental outcomes. Despite advances in neonatal ventilator care, the incidence of BPD has been static or even increased. The purpose of this study was to evaluate the incidence of BPD in a single center over 10 years. Methods: Preterm infants with gestational age (GA) <30 weeks who were admitted to Inje University Busan Paik Hospital from January 2009 to December 2018 and sur vived 28 days or more were enrolled. The incidence of BPD according to year and GA and the risk factors of BPD were evaluated. Results: Among 629 infants, 521 infants who survived 28 days or more were enrolled (BPD group, n=252; non-BPD group, n=269). The incidence of BPD was 48.4%, with moderate to severe BPD accounting for 13.9%. In preterm infants with GA ≤25, 26 to 27, and 28 to 29 weeks, the incidences of BPD were 57.5%, 51.5%, and 14.6%, respectively, with moderate to severe BPD accounting for 23.8%, 10.5%, and 3.7%, respectively. The incidence of BPD decreased from 68% in 2009 to 34.3% in 2014. Subsequently, it increased. Surfactant re-dosing and patent ductus arteriosus were more frequent in the BPD group than in the non-BPD group. Conclusion: BPD did not decrease over the previous 10 years despite advances in neonatal care.


INTRODUCTION
Bronchopulmonary dysplasia (BPD) is one of the most fatal respiratory morbidities in preterm infants. BPD was first coined by Northway et al. 1) in 1967 as a chronic lung injury in preterm infants treated with oxygen and mechanical ventilation. Despite advances in neonatal ventilator care with reduced intubation and ventilation, increased early nasal continuous positive airway pressure (CPAP), and increased high flow nasal cannula (HFNC), the incidence of BPD has remained the same or even increas ed. This might be due in part to active resuscitation with improved survival of extremely low birth weight infants (ELBWIs, birth weight <1,000 g) and extreme preterm infants at greatest risk of BPD 2) . The incidence of BPD (defined as oxygen require ment at 36 weeks of postmenstrual age [PMA]) in preterm infants with gestational age (GA) <29 weeks increased from 32% in 1993 to 45% in 2000 3) , but it was seen to be static from 2008 to 2014 in another study 4) . The incidence of BPD among preterm infants with birth weight <1,250 g increased from 34% in 2001-2004 to 39% in 2006 5) , and was 19% in very low birth weight infants (birth weight <1,500 g) and 30% in ELBWIs in another study 6) . BPD defined as oxygen dependency for ≥28 days of life was reported in up to 58% of preterm infants with GA <30 weeks in 2000 to 2013 7) . Although the incidence of BPD differs according to cen ters, it shows an increasing trend.
BPD is related to increased mortality, cardiovascular impairment, poor growth, long-term respiratory impairment, and poor neurodevelopmental outcome 8) . Some preterm infants with severe BPD require supplemental oxygen or respiratory support for months or years. The increased number of infants with these comorbidities of BPD is an emerging social issue. Thus, it is important to reduce the incidence of BPD to improve outcomes of preterm infants.
The incidence of BPD in a single center over a long period can be used to evaluate the quality of neonatal care in a neonatal intensive care unit (NICU). Hence, the objective of this study was to evaluate the incidence of BPD by year in a single center over 10 years. The incidence of BPD according to GA was evaluated. Maternal and infant risk factors of BPD were also evaluated to suggest ways to reduce BPD in preterm infants.

Demographic factors
A total of 629 preterm infants under 30 weeks of GA were admitted. Six preterm infants with chromosomal abnormalities or major congenital malformations were excluded (one case of double outlet right ventricle with pulmonary stenosis; one case of lethal atelosteogenesis type 1; two cases of Edwards syndrome; two cases of multiple anomalies). After excluding 108 infants who were dead before 28 days, 521 preterm infants who survived 28 days or more days were enrolled (BPD group, n=252; non-BPD group, n=269). GA and birth weight were smaller in the BPD group than in the non-BPD group (26.3±1.7 weeks vs. 28.5±1.2 weeks, P<0.001; 846.4±209.7 g vs. 1,202.4±255.0 g, P=0.013, respectively). The gen der ratio or Apgar score at 1 minute was not significantly different between the two groups. However, the Apgar score at 5 minutes was lower in the BPD group than in the non-BPD group (6.4±1.2 vs. 7.1±1.0, P<0.001). Maternal PIH, antenatal steroid therapy, or chorioamnionitis was not significantly differ ent between the two groups. GDM was more frequent in the non-BPD group ( Table 1).

Outcomes
Most patients had RDS, and surfactant re-dosing was more frequent in the BPD group than in the non-BPD group (19% vs.  Table 2).

Incidence of BPD according to year
Mortality, BPD, and moderate to severe BPD did not decrease according to year. A total of 131 infants died (108 infants died <28 days and 23 infants died ≥28 days). Thus, the overall mortality rate of preterm infants with GA less than 30 weeks was 20.8%. The mortality rate was the lowest in 2012 (9.2%). The mortality rate was lower in 2017 compared to 2016. The overall incidence of BPD was 48.4%. The incidence of moderate to severe BPD was 13.9%. The However, there was no statistically significant trend between the incidence of BPD and mortality rate of preterm infants with GA ≤25 weeks. The incidence of moderate to severe BPD decreased in 2014 (7.8%) but increased in 2016 (25%) (Figure 1).    36 weeks of PMA are more likely to be neurodevelopmentally impaired at 2 years of age than those with mild to moderate BPD 7) .

Incidence of BPD according to GA
Various drugs have been used to treat BPD over the past 20 years.
However, only a few drugs have shown to be effective 14,15) . Currently, there is no drug approved by the U.S. Food and Drug Administration (FDA) to prevent BPD 16) . Aggressive surfactant instillation has been used to reduce BPD. Surfactants have been administered as prophylactic therapy in preterm infants with GA <30 weeks or with a birth weight ≤1,250 g in Korea since January 2011 17) . Less invasive ventilators 18,19) , less invasive surfactant admini stration 20) , and even surfactant administra tion without intubation 21) have been tried to reduce BPD. Despite a variety of efforts as previously mentioned, the incidence of BPD has not decreased.
The definition of BPD was revised several times after its first description by Northway et al. 1) in 1967. Shennan et al. 22) have suggested that oxygen requirement at 36 weeks of PMA is more predictive of an adverse respiratory outcome than oxygen requirement for ≥28 days of life. The definition of BPD was revised in 2000 10) at a workshop organized by NICHD on the basis of respiratory status at 36 weeks of PMA. This has become the most widely used definition for BPD 10) . The physiologic definition of BPD is also used in infants at 36 weeks of PMA with an oxygen reduction test to confirm oxygen requirement 23) .
The incidence of BPD differs according to different centers.
Inter-center differences may be caused by different definitions

DISCUSSION
BPD is associated with adverse respiratory outcomes and poor neurodevelopmental outcomes in preterm infants [11][12][13] . In particular, infants with severe BPD who need respiratory support at used for BPD in each center. The overall incidence of BPD was 48.4%, with moderate to severe BPD accounting for 13.9% in this study from 2009 to 2018. A similar result was reported by ano ther study that the incidence of BPD was 42%, with moderate to severe BPD at 19% 24) . According to a nationwide survey from 52 NICUs in Korea in 2012 25) , the incidence of BPD was 28% and that of moderate to severe BPD was 16% in infants with GA <32 weeks. This incidence of BPD was lower than in the present study. However, the GA of the enrolled preterm infants was younger in the present study (GA <30 weeks vs. GA <32 weeks). In another nationwide study from 55 NICUs in Korea in 2015 26) , the incidence of moderate to severe BPD increased to 33% in preterm infants with GA <32 weeks. This incidence of BPD was higher than in the present study. The incidence of BPD in pre term infants with GA <30 weeks from 2000 to 2013 was 58% as reported by Malavolti et al. 7) , which was higher than that in the present study. In a large neonatal network dataset, the incidence of BPD defined as oxy- The strength of this study is that it was a single center study.
There were no inter-center differences in the definition for BPD.
In addition, the same diagnostic criteria for BPD were used. There were no differences according to caregivers' practice styles, such as weaning of ventilators, oxygen, or targeted oxygen sa turation.
Since uniform diagnostic criteria for BPD and uni form care prac tice were used, the real incidence of BPD could be evaluated.
However, this study also has limitations. The NICU was closed for a period of time without a neonatologist. This might have affected the number of admissions and the outcomes of preterm infants, especially extreme preterm infants at the limit of viability. The physiologic definition of BPD, which could reduce the variation and incidence of BPD, was not used in this study. As such, there are chances of overestimation and reporting inaccurate incidences of BPD.
In conclusion, the incidence of BPD did not decrease over a ten-year period despite advances in neonatal care. the incidence of BPD decreased from 2009 to 2014, but then increased. The overall incidence of BPD was 48.4%, with moderate to severe BPD ac counting for 13.9%.

Ethical statement
The study protocol was reviewed and approved by the Institu-

Conflicts of interest
No potential conflict of interest relevant to this article was reported.

Author contributions
Conception or design: G.W.J.
Acquisition, analysis, or interpretation of data: G.W.J.
Drafting the work or revising: G.W.J.
Final approval of the manuscript: G.W.J.