Trends in Survival and Incidence of Bronchopulmonary Dysplasia in Extremely Preterm Infants at 23–26 Weeks Gestation

Bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants that requires prolonged ventilator and oxygen therapy, is a serious complication of preterm birth (1, 2). BPD remains a major cause of mortality and lifelong morbidity in premature infants because only few therapeutic measures are available to prevent or ameliorate this common and serious disorder (3, 4). The most severely affected infants were the most premature, particularly infants born at 23–26 weeks gestation. Recent advances in neonatal intensive care medicine have resulted in improved survival of infants born as early as 23–24 weeks gestation and therefore, the actual number of extremely premature infants at high risk for developing BPD might be increasing. Consequently, improved survival of extremely preterm infants might be closely linked to increasing rates of BPD (5, 6). However, other researchers have reported stable, or even reduced, BPD incidences (7, 8, 9). Overall, the role of improved survival in the development of BPD remains largely controversial, and further studies are necessary to clarify this.

Recently, we have noted markedly improved survival rates with improvements in perinatal and neonatal intensive care in extremely preterm infants, especially those born at 23–24 weeks gestation (10, 11, 12). Therefore, in the present study, we investigated whether improved survival was associated with the altered incidence of BPD, and if applicable, the clinical factors responsible for this alteration.

The medical records of 350 preterm infants at 23–26 weeks gestation who were born and admitted to the neonatal intensive care unit (NICU) at Samsung Medical Center from January 1, 2000 to December 31, 2005 (period I, n = 137) and January 1, 2006 to December, 2010 (period II, n = 213) were retrospectively reviewed. The study periods were divided according to the survival rate, and infants were stratified into the 23–24 and 25–26 weeks gestation subgroups.

Maternal and neonatal characteristics, mortality and various major morbidity rates until discharge were assessed in the 23–24 and 25–26 weeks gestation subgroups during the study periods. The survival rate was assessed until discharge from the NICU. The traditional definition of BPD, oxygen use at postmenstrual age of 36 weeks (13), was used in this study; this was equivalent to moderate to severe BPD as determined by using the National Institutes of Health Workshop severity-based diagnostic criteria (14). In the present study, we evaluated the incidence of BPD in association with the survival rates of patients; BPD was assessed only in the survivors until NICU discharge. Subgroup analyses for infants at 23–24 and 25–26 weeks gestation were performed throughout the study periods. To identify the responsible associated factors for the changes in total mortality and BPD incidence in the survivors according to period, univariate and subsequent multivariate analyses were conducted with various clinical factors. The following variables were analyzed for the analysis of clinical factors: period, gestational age (GA), birth weight, male, appropriate for gestational age (AGA), Apgar score at 5 min, histologic chorioamnionitis, pregnancy-induced hypertension (PIH), antenatal and postnatal steroid therapy, respiratory distress syndrome (RDS), patent ductus arteriosus (PDA) at week 1, intraventricular hemorrhage (IVH) grade ≥ 3 (15), necrotizing enterocolitis (NEC) stage ≥ 2b (16), retinopathy of prematurity (ROP) stage ≥ 3 (17), neonatal sepsis, duration of total parenteral nutrition (TPN), intubation, continuous positive airway pressure (CPAP), and supplemental oxygen therapy (11). GA was determined by the last maternal menstrual period and modified Ballard test. AGA was defined as a birth weight between the 90th and 10th percentiles. RDS was defined as requiring surfactant and ventilator treatment or clinical features of RDS within the first 24 hours or birth. Neonatal sepsis was defined as a positive blood culture in symptomatic infants with antibiotic treatment.

In the present study, the survival rate in extremely preterm infants at 23–26 weeks gestation was significantly improved during period II compared to that in period I, which was mostly attributable to improved survival in infants born at 23–24 weeks gestation. This improved survival of extremely preterm infants was not associated with increased incidence of BPD at 23–24 weeks gestation. Furthermore, the incidence of BPD in survivor infants at 25–26 weeks gestation was significantly decreased during period II compared to period I. Possible factors responsible for these changes include higher antenatal steroid use and improved 5-min Apgar scores, which were associated with improved survival in infants at 23–24 weeks gestation. In addition, earlier extubation, less oxygen supplementation, and increased less invasive nasal CPAP use were associated with reduced BPD incidence, especially in infants at 25–26 gestation.

The association between the increased survival of preterm infants and BPD remains a controversy. A lower GA at delivery, especially ≤ 26 weeks gestation, which results in extreme structural and biochemical lung immaturity, is the most powerful risk factor for the development of BPD (18, 19, 20). Increased survival of extremely premature infants might increase the actual number of premature infants at risk for BPD (5, 21, 22, 23). However, increased survival of extremely preterm infants at 23–24 weeks gestation was associated with reduced incidence of BPD in infants at 25–26 weeks gestation at our NICU setting. Botet et al. (1) reported that there was no increase in the survival of extremely low birth weight infants; however, the survival of infants without BPD increased from 58.5% in 1997–2000 to 75% in 2006–2009. According to these findings, better perinatal and neonatal intensive care for improving survival of extremely preterm infants also simultaneously reduces the incidence of BPD in these infants (24, 25). Currently, few effective treatments are available for treating BPD. However, marked variation in the BPD incidence rates among medical centers and some reported success in reducing the BPD incidence rate within individual hospitals through quality improvement efforts suggest that identification and implementation of specific neonatal intensive care practices could modify the incidence of BPD (26, 27, 28, 29). In the present study, early CPAP after having early extubation and reducing supplemental oxygen use were independent effective strategies identified for reducing the incidence of BPD. Intubation and ventilation could induce volutrauma and barotrauma, and the use of less invasive CPAP could allow continuous alveolar growth, which might consequently reduce lung damage (30). Other possible risk or preventive factors for BPD, including birth weight, nosocomial sepsis, PDA, postnatal steroid use, and nutrition (31, 32) were not significantly associated with the development of BPD in the present study. Collectively, these findings suggest that although the ‘magic bullet’ for preventing and/or treating BPD might not exist, the implementation of combined clinical practices, including reduced oxygen exposure, early extubation and less invasive CPAP, might be an effective strategy for reducing BPD among extremely preterm infants (33).

This study had several limitations, including its retrospective nature and the relatively small sample size of infants born at 23–24 weeks gestation during period I. In addition, although “period” was included as an independent factor for multivariate analysis for the effect, unknown confounders might not be controlled in this retrospective study. Another limitation was that the results were obtained from a single institution and therefore, our findings might not be generalizable to another NICU. However, a strength of this study was the relatively large sample size of infants at 23–26 weeks gestation (n = 350) with similar baseline characteristics who were born at a single institution. Furthermore, possible factors responsible for these outcome changes were confirmed using both period comparison and risk factor analysis in the present study. In period II, increased antenatal steroid use and higher 5-min Apgar scores, which were confirmed as associated factors for improved survival were demonstrated in infants at 23–24 weeks gestation; these infants had significantly improved survival rates compared to those in period I. Earlier extubation and less oxygen supplement with increased nasal CPAP use, which were associated factors confirmed to be responsible for protecting against BPD, were also demonstrated in period II in the 25–26 weeks gestation subgroup; the BPD incidence was significantly lower compared to period I in these infants.

In conclusion, infants born at 23–26 weeks gestation had improved survival rates, which was mostly attributable to improved survival of infants born at 23–24 weeks gestation. Simultaneously, the incidence of BPD in survivors was reduced in infants born at 23–26 weeks gestation, which was mostly attributable to decreased BPD incidence in infants born at 25–26 weeks gestation. In this study, improved survival of extremely preterm infants born at 23–24 weeks gestation may be associated with reduced incidence of significant BPD in survivor infants born at 25–26 weeks gestation. These findings are in agreement with those of other studies in which the quality of life was improved in extremely preterm infants. The development of perinatal and neonatal care improved the survival of immature preterm infants and simultaneously decreased morbidities in mature preterm infants (34, 35). Collectively, aggressive perinatal and improved neonatal care can simultaneously lead to improved survival and decreased BPD incidence in extremely premature infants.