Journal of Perinatology (2015), 1–7 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp
ORIGINAL ARTICLE
Does chronic oxygen dependency in preterm infants with bronchopulmonary dysplasia at NICU discharge predict respiratory outcomes at 3 years of age? A Lodha1,2,3,4, K Ediger1, Y Rabi1,2,3, S Lodha1, S Tang3, A Bhandari5, R Sauve1,2,3 and V Bhandari6 OBJECTIVE: To determine whether chronic oxygen dependency at the time of discharge from the neonatal intensive care unit (NICU) in infants with bronchopulmonary dysplasia (BPD) predicts respiratory outcomes at 3 years. STUDY DESIGN: Preterm infants ⩽ 1250 g without BPD, BPD and BPD with chronic oxygen dependency were identified from the Southern Alberta Perinatal Follow-up clinic database (1995–2007). Respiratory outcomes at 4, 8, 18 and 36 months corrected age following NICU discharge were examined. Univariate analyses were done. RESULTS: Out of 1563 infants admitted to the NICU, 1212 survived. Complete follow-up data at 36 months were available for 1030 (85%) children. Children with BPD with or without chronic oxygen dependency had significantly (P o 0.001) lower birth weights and gestational ages, and greater post-natal steroid use, compared with those with no BPD. At 4, 8 and 18 months follow-up, the use of respiratory medications and supplemental oxygen were both significantly higher in the BPD infants with chronic oxygen dependency group compared with the no-BPD group and BPD group. At 36 months, children in the BPD with chronic oxygen dependency group were more likely to use respiratory medications and supplemental oxygen vs the no-BPD or the BPD groups. At 4, 8 and 36 months of age, more children in the BPD with chronic oxygen dependency group had post-neonatal chronic lung disease (PNCLD) than children in the other groups, but at 36 months the difference was significant only for the BPD with chronic oxygen dependency vs no-BPD group (P o 0.001). CONCLUSIONS: At 36 months, children diagnosed with BPD with chronic oxygen dependency at NICU discharge were more likely to need respiratory medications and supplemental oxygen in the previous 12 months, as compared with no-BPD or BPD groups. They were also more likely to require frequent physician visits and have PNCLD at 3 years, as compared with the no-BPD group. Journal of Perinatology advance online publication, 26 February 2015; doi:10.1038/jp.2015.7
INTRODUCTION Bronchopulmonary dysplasia (BPD) is a serious pulmonary condition and a common cause of mortality and morbidity among very preterm infants. Reported incidence rates of BPD varies widely, based on various factors such as definition used and site of care.1 A common description defines BPD based on oxygen dependency or respiratory support at 36 weeks post-menstrual age (PMA).2 BPD is a multifactorial disease: a number of prenatal, perinatal and post-natal factors are thought to influence the pathogenesis, severity and outcomes of infants with BPD. Contributing factors include in utero environment, genetics, prematurity, oxygen administration, surfactant deficiency and ventilation, infection/inflammation, patent ductus arteriosus and fluid status.3 Despite the large burden of disease presented by BPD, little is known about the pathogenic mechanisms underlying the clinical picture seen in BPD survivors. BPD is known to have a long-term impact on both lung growth and function. It has been reported 1
that survivors of BPD tend to have persistent airflow limitation,4 decreased exercise capacity5 and may have a steeper decline of lung function with aging.6 The primary objective of this study was to determine the relationship between no BPD, BPD and BPD with chronic oxygen dependency and 3-year respiratory outcomes. The secondary outcome was to determine the respiratory outcomes at 4, 8 and 18 months. METHODS In a longitudinal cohort study, premature infants born between January 1995 and December 2007 with a birth weight (BW) ⩽ 1250 g and admitted to the neonatal intensive care unit (NICU; a tertiary center serving southern Alberta, Canada) were eligible for inclusion in the study. The infants were followed from NICU discharge to 3 years of age at a regional neonatal follow-up clinic. Exclusion criteria for the study were deaths, major congenital malformations or chromosomal disorders. This study was approved by the University of Calgary institutional ethics review board and informed consent was obtained from all participants. The cohort data used
Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada; 2Department of Pediatrics, Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada; Department of Pediatrics, Alberta Health Services, Calgary, Alberta, Canada; 4Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; 5 Department of Pediatric Pulmonology, Connecticut Children's Medical Center, Hartford, CT, USA and 6Department of Pediatrics, Yale University, New Haven, CT, USA. Correspondence: Dr V Bhandari, Yale University School of Medicine, Yale Child Health Research Center, Room Number: 219, PO Box 208081, 464 Congress Avenue, New Haven, CT 06520, USA. E-mail: [email protected] Received 16 September 2014; revised 19 January 2015; accepted 20 January 2015 3
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
2 Table 1.
Discharge criteria of infants from the NICU
Criteria a. Corrected gestational age 434 weeks b. Able to maintain body temperature (436.4 °C) in an open crib c. Competent suckle feeding (breast or bottle) without cardiorespiratory compromise and gaining weight d. Physiologically mature e. Stable cardiorespiratory function f. No apnea of prematurity g. No active medical problems h. Receipt of appropriate immunizations i. Appropriate metabolic screening and car seat testing performed j. Family readiness Abbreviation: NICU, neonatal intensive care unit.
for this analysis was part of a larger study on 3-year neurodevelopmental outcomes of infants with BPD.7 Upon NICU discharge, standardized demographic, perinatal and neonatal data were obtained from infant charts and entered into a computerized database by a trained research assistant. Specific discharge criteria are presented in Table 1. According to these criteria, for an infant to be discharged home on supplemental oxygen with no ‘active’ medical problem, they should have no acute life threatening illness, they should not be requiring continuous cardiorespiratory monitoring or nursing care and pulse oximetry results showing SpO2 ⩽ 89% in room air had to be obtained 48 h before discharge home. At discharge, infants were categorized as having no BPD, BPD (defined as O2 dependency and/or respiratory support at 36 weeks PMA) or BPD with chronic oxygen dependency (defined as oxygen requirement at 36 weeks PMA and at the time of discharge home).2 The infants were then routinely followed prospectively by the perinatal follow-up clinic, where their respiratory outcome data were obtained at 4, 8, 18 and 36 months. These data included information obtained from parents’ and pediatrician follow-up reports. All outcome measures were defined as outlined below, and these definitions remained constant throughout the study period. Chorioamnionitis was diagnosed based on clinical criteria (maternal fever ⩾ 38.4 °C within 24 h before birth and uterine tenderness ± leukocytosis of 415 000 per mm3) or evidence of chorioamnionitis on placental histopathological examination. This was diagnosed by noting the presence of histological markers suggestive of maternal inflammation including neutrophilic infiltration of subchorionic space (subchorionitis), chorionic plate (chorionitis) or free placental membranes (chorioamnionitis). Gestational age (GA) was defined as estimated by obstetric history, examination and prenatal ultrasound.8 Infants were considered small for GA (SGA) if their BW was less than the 10th percentile for the given GA. Respiratory distress syndrome was diagnosed based on the clinical examination, chest X-ray findings, the need for surfactant administration and mechanical ventilation for few hours, as per the Canadian Neonatal Network guidelines.9 Total duration of oxygen was defined as the total number of days the infant received supplemental oxygen. Duration of mechanical ventilation was defined by the total number of days the infant was mechanically ventilated for any part of the day. The duration of respiratory support included mechanical ventilation and non-invasive respiratory support. Patent ductus arteriosus was diagnosed clinically or by echocardiography. Diagnosis and severity of intraventricular hemorrhage (IVH) were classified according to the criteria of Papile et al.10 from the most severe finding on head ultrasonography performed at any time during the patient’s admission. Necrotizing enterocolitis was classified according to modified Bell’s criteria (stage ⩾ 2) and was classified as medical or surgical based on this staging.8 Retinopathy of prematurity was classified according to the international classification.11 The total number of days the infant stayed in the NICU from birth to discharge determined the total length of stay (LOS). Post-neonatal chronic lung disease (PNCLD) was defined as the presence of one of the following criteria in the previous 12 months before reaching 3 years of age: current oxygen therapy, ongoing therapy with respiratory medications for 44 months duration, ⩾ 2 courses of antibiotics per year for respiratory indications, oral steroids for respiratory indications and/or evidence of abnormal respiratory signs (for e.g., rales) on clinical Journal of Perinatology (2015), 1 – 7
Total number of eligible newborns, Birth weight ≤ 1250 grams, Born between January 1995-December 2007 N = 1563
Deaths n = 216 Total number of infants discharged from NICU N = 1347 (86%)
Excluded: Total n = 135 Congenital anomalies (n = 37) Transfer to other hospitals (n = 83) Died prior to 36 months PMA (n = 15)
Total number of infants eligible for the study N = 1212 (90%)
Complete follow-up at 36 months PMA N = 1030 (85%)
No BPD
BPD
N = 442
N = 144
BPD with chronic O2 dependency N = 444
Figure 1. Flow diagram of our study population. BPD, bronchopulmonary dysplasia; NICU, neonatal intensive care unit; PMA, postmenstrual age.
examination or any hospitalizations for respiratory illness. Perinatal and neonatal data were defined according to the Canadian Neonatal Network standards.9
Statistical analysis The infant and maternal characteristics of the cohort were compared across the three groups using Pearson χ2 or Fisher’s exact test for categorical variables. To compare pairwise differences between groups (no BPD vs BPD, no BPD vs BPD with chronic oxygen dependency and BPD vs BPD with chronic oxygen dependency), confidence intervals for the pairwise differences in proportion were calculated and the Bonferroni correction was applied. Confidence intervals were reported at the (1– 0.05/3) % level. All results were generated using SAS 9.3 (SAS Institute, Cary, NC, USA). © 2015 Nature America, Inc.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
RESULTS A flow diagram of our study population is presented in Figure 1. A total of 1563 infants with a BW ⩽ 1250 g were eligible for inclusion. After excluding infants who had major congenital or chromosomal abnormalities, or who died before 36 months, a total of 1212 (90%) infants remained in the study cohort. Of these, 1030 (85%) infants were available for complete follow-up at 36 months. These infants had been divided into three groups based on oxygen dependency status at NICU discharge: no BPD (442 infants; 43%), BPD (144 infants; 14%) or BPD with chronic oxygen dependency (444 infants, 43%). Rates of follow-up were similar across the three groups. Children lost to follow-up at 36 months (n = 182) were not significantly different than those who underwent follow-up in terms of BW (median 983 g vs 950 g, P = 0.101) or GA (median 28 weeks vs 27 weeks, P = 0.096). Children lost to follow-up were more likely to have a shorter duration of respiratory support (median 6 days vs 13 days, P = 0.031) and shorter periods of hospitalization (median 71 days vs 75 days, P = 0.019). Maternal and infant characteristics of the study cohort are presented in Table 2. Overall, maternal Caucasian race was significantly more common in the BPD groups; in contrast, the use of maternal antihypertensive medications and rate of Cesarean sections were significantly more common in the no-BPD group. Infants without BPD were discharged from hospital at a median of 37 weeks PMA, which is significantly earlier than infants with BPD, who were discharged at a median PMA age of 39 weeks (P o 0.001). Overall, infants with BPD and BPD with chronic oxygen dependency had significantly lower BW and GA (P o 0.001), less likely to be SGA (P = 0.019), more likely to be male, with an increased incidence of respiratory distress syndrome, patent ductus arteriosus, confirmed sepsis, severe IVH and retinopathy of prematurity stage II and greater or plus disease or laser treatment (all Po 0.001), as well as necrotizing enterocolitis (P = 0.037; Table 2). A comparison of health resource utilization between the three groups while in the NICU is presented in Table 3. Children in the BPD with chronic oxygen dependency group were more likely to have had more blood transfusion, a longer duration of respiratory support (inclusive of mechanical ventilation and non-invasive respiratory support) and oxygen requirement (P o 0.001). Use of post-natal steroids and diuretics were also higher (P o 0.001) in those infants with BPD and BPD with chronic oxygen dependency. Length of hospital stay was longer in infants with BPD, regardless of chronic need for oxygen (P o0.001; Table 3). One of the 15 deaths occurred before 36 weeks PMA, thus we could not determine BPD status on one child. The remaining 14 children (436 weeks PMA) died after discharge from the hospital; 5 were in the no-BPD group, 1 in the BPD group and 8 in the BPD with chronic oxygen dependency group. Respiratory outcomes at 4, 8 and 18 months are shown in Table 4A. At 4, 8 and 18 months follow-up, the use of respiratory medications and supplemental oxygen since discharge, last clinic visit or in the past 12 months was significantly more common in the BPD with chronic O2 dependency group than in the no-BPD group and the BPD group (Table 4A). In addition, at 4 and 8 months follow-up, the diagnosis of PNCLD was significantly more common in the BPD with chronic O2 dependency group compared with the no-BPD group and the BPD group. A total of 14 children died after discharge from the hospital. Including or excluding these infants did not make a significant impact on the incidence of PNCLD at any follow-up age. The proportion of children with frequent physician visits in the 4–8-month time period was significantly higher for the BPD and the BPD with chronic O2 dependency groups than for the no-BPD group (Table 4A). At the 18-month follow-up, frequent physician visits in the past year were more common in the BPD with chronic O2 © 2015 Nature America, Inc.
3 dependency group compared with the other two groups (Table 4A). Respiratory outcomes at 36 months PMA are presented in Table 4B. At the 36 months follow-up, the use of respiratory medications and supplemental oxygen in the past year was significantly more common in the BPD with chronic O2 dependency group as compared with the BPD group and the no-BPD group (Table 4B). Frequent physician visits and the diagnosis of PNCLD were significantly more commonly seen in the BPD with chronic O2 dependency group compared with the no-BPD group, but were not significantly different between the BPD with chronic O2 dependency group and the BPD group (Table 4B). DISCUSSION Our study revealed that at 36 months PMA, preterm infants with BPD with chronic oxygen dependency had greater respiratory morbidity as compared with the BPD or no-BPD groups. BPD with chronic oxygen dependency infants were more likely to need respiratory medications (post-natal steroids and diuretics) and supplemental oxygen in the previous 12 months, as compared with the no-BPD or BPD groups. We also observed a higher incidence of PNCLD and frequent physician visits as compared with the no-BPD group. At 4, 8 and 18 months follow-up, the use of respiratory medications and supplemental oxygen were both significantly higher in the BPD with chronic oxygen dependency infants, compared with the no-BPD group and the BPD group. Forty-three percent of infants had BPD with chronic oxygen dependency. This is possibly owing to the facts that Calgary is 1100 m (3600 ft) above sea level and our clinical practice.12 The continuing morbidity associated with BPD has been attributed to the increased survival rates for very low BW and younger preterm infants.13 In our study, infants with BPD with chronic oxygen dependency were more likely to have been prescribed post-natal steroids than infants with no BPD or BPD, and more diuretics compared with no BPD. They were also more likely to have required a longer duration of mechanical ventilation than infants with no BPD or BPD, with an increased LOS in hospital, compared with no BPD. This finding was consistent with other reports from the literature, suggesting that BPD,14 chronic oxygen dependency and factors (extreme prematurity, SGA15,16) that increase the likelihood of BPD can lead to increased resource utilization and health care costs.15,17 The severity of CLD also varies among affected infants. Some infants discharged home on oxygen require short-term treatment and subsequently improve. However, there is another group of infants with CLD who fall into a category whom we have termed PNCLD. These infants require oxygen for a longer period, have more severe disease and greater respiratory morbidity. The Heron et al.18 study revealed that 25% premature infants had severe CLD at the age of 1 year. We speculate that these infants possibly had PNCLD. In the Ehrenkranz et al.19 study, BPD was classified into three types based on the National Institutes of Health (NIH) consensus definition (mild, moderate and severe) and infants who received inspiratory oxygen by nasal cannula at 36 weeks’ PMA were considered to have moderate BPD, as the effective inspiratory oxygen concentration was not collected. In the earlier study,19 infants born between 1995 and 1999 were enrolled, whereas our study has included babies born between 1995 and 2007. So, although the earlier study19 is probably more reflective of the ‘old’ BPD population, our study does include infants with ‘new’ BPD.13,20–22 In our study, the median LOS of BPD infants and BPD with chronic oxygen dependency infants were 92– 93 days in contrast to mean LOS of moderate BPD and severe BPD of 99 and 127 days in the earlier study.19 This was probably an underestimate, as the earlier study did not have LOS data on infants who had been transferred to other hospitals.19 In our study, 20–32% infants with BPD required post-natal steroids in contrast to the Ehrenkranz et al.19 study where 62–76% Journal of Perinatology (2015), 1 – 7
Journal of Perinatology (2015), 1 – 7 252 41 274 121 378 101 303 94 247
(60.9) (33, 56) (70.8) (28.3) (86.7) (23.2) (68.7) (22.3) (57.2)
79 46 93 39 116 14 94 37 84
(57.3) (33, 57) (79.5) (27.7) (82.9) (10.3) (65.3) (27.4) (60.4)
BPD (n = 144)
(690, 1000) (25, 28) (37, 41) (15.9) (71.4) (88.1) (57.7) (87.1) (69.3) (25.0) (12.2) (9.2) (1.6) (52.5)
317 391 256 386 307 110 54 41 7 223
(59.8) (33, 57) (77.6) (23.8) (83.8) (17.3) (55.5) (21.5) (60.5)
820 26 39 70
253 44 280 102 366 75 246 93 262
BPD with chronic oxygen dependency (n = 444)
0.121 0.496 o0.001 o0.001 o0.001 o0.001 0.037 o0.001 0.196 o0.001
o0.001 o0.001 o0.001 0.019
0.753 0.227 0.047 0.302 0.367 0.002 o0.001 0.354 0.572
P-valuea
(−0.03 (−0.04 (−0.13 (−0.44 (−0.46 (−0.27 (−0.16 (−0.11 (−0.06 (−0.38
to to to to to to to to to to
0.19) 0.11) 0.10) − 0.26) − 0.24) − 0.08) 0.01) 0.002) 0.02) − 0.17)
(90 to 180) (1 to 2) (−4 to − 2) (0.01 to 0.17)
(−0.08 to 0.15) (−6 to 1) (−0.19 to 0.02) (−0.10 to 0.11) (−0.05 to 0.12) (0.05 to 0.21) (−0.07 to 0.14) (−0.15 to 0.05) (−0.15 to 0.08)
No BPD vs BPD
(−0.08 (−0.04 (−0.20 (−0.43 (−0.50 (−0.21 (−0.08 (−0.11 (−0.02 (−0.47
to to to to to to to to to to
0.06) 0.07) − 0.04) − 0.30) − 0.36) − 0.09) 0.02) − 0.03) 0.03) − 0.32)
(180 to 245) (2 to 3) (−3 to − 2) (−0.01 to 0.12)
(−0.09 to 0.07) (−4 to 1) (−0.14 to 0.01) (−0.03 to 0.12) (−0.03 to 0.09) (−0.01 to 0.12) (0.05 to 0.21) (−0.06 to 0.08) (−0.11 to 0.05)
No BPD vs BPD with chronic oxygen dependency
to 4) to to to to to to to
0.12) 0.14) 0.08) 0.01) 0.21) 0.16) 0.11)
0.09)
(−0.20 (−0.10 (−0.22 (−0.10 (−0.19 (−0.08 (−0.04 (−0.08 (−0.02 (−0.23
to to to to to to to to to to
0.02) 0.06) 0.01) 0.06) 0.04) 0.12) 0.13) 0.05) 0.07) − 0.003)
(20 to 120) (0 to 1) (0 to 1) (−0.11 to 0.04)
(−0.14 (−3 to (−0.08 (−0.06 (−0.10 (−0.15 (−0.01 (−0.04 (−0.11
BPD vs BPD with chronic oxygen dependency
Confidence intervals for pairwise differencesb
Abbreviations: BPD, bronchopulmonary dysplasia; IQR, interquartile range; no., number. aKruskal–Wallis test for continuous variables; Pearson χ2-test for categorical variables. bBonferroni correction applied to adjust for the three pairwise comparisons, thus confidence intervals are reported at the (1–0.05/3)% level.
Infants Birth weight (grams), median (IQR) 1070 (930, 1180) 885 (750, 1060) Gestational age (weeks), median (IQR) 29 (27, 30) 27 (26, 28) Gestational age at discharge (weeks), median (IQR) 37 (35, 38) 40 (38, 41) Small for gestational age (o 10th percentile), 95 (21.5) 18 (12.5) no. (%) Singleton, no. (%) 311 (70.4) 90 (62.5) Inborn, no. (%) 396 (89.6) 124 (86.1) Male sex, no. (%) 201 (45.5) 68 (47.2) Respiratory distress syndrome, no. (%) 224 (50.7) 123 (85.4) Patent ductus arteriosus, no. (%) 117 (26.5) 89 (61.8) Confirmed sepsis, no. (%) 42 (9.7) 39 (27.3) Necrotizing enterocolitis, no. (%) 40 (9.1) 24 (16.7) Intraventricular hemorrhage grade ⩾ III, no. (%) 10 (2.3) 11 (7.7) Periventricular leukomalacia, no. (%) 10 (2.3) 6 (4.2) Retinopathy of prematurity stage ⩾ II or plus 51 (13.0) 56 (40.6) disease or laser treatment, no. (%)
Maternal Maternal education more than high school, no. (%) Blishen score, median (IQR) Maternal race Caucasian, no. (%) Smoking during pregnancy, no. (%) Antenatal corticosteroids, no. (%) Maternal antihypertensive medications, no. (%) Cesarean section, no. (%) Chorioamnionitis, no. (%) Maternal antibiotics, no. (%)
No BPD (n = 442)
Maternal and infants’ characteristics of the follow-up cohort
Characteristic
Table 2.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
4
© 2015 Nature America, Inc.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
5 Table 3.
Comparison of resource utilization between preterm infants with no BPD, BPD and BPD with chronic oxygen dependency
Variable Total blood transfusions (times), median (IQR) Duration of oxygen requirement (days), median (IQR) a Duration of respiratory support (days), median (IQR) NCPAP, n (%) Mechanical ventilation, n (%) Postnatal steroids, n (%) Diuretics, n (%) Length of stay (days), median (IQR)
No BPD (N = 442) 0 6 1 170 250 91 139 56
(0, 1) (2, 37) (0, 6) (38.5) (56.6) (4.8) (31.6) (43, 71)
BPD (N = 144) 3 78 21 107 133 29 114 93
(1, 4) (62, 93) (8, 39) (74.3) (92.4) (20.3) (79.7) (76, 103)
BPD with chronic oxygen dependency (N = 444) 4 209 36 368 424 144 384 92
(2, 6) (153, 277) (18, 52) (82.9) (95.5) (32.5) (86.5) (74, 109)
P-value o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001
Abbreviations: BPD, bronchopulmonary dysplasia; IQR, interquartile range; NCPAP, nasal continuous positive airway pressure. aRespiratory support includes mechanical ventilation and non-invasive respiratory support.
infants with moderate to severe BPD required post-natal steroids. The earlier study reported pulmonary and neurodevelopmental outcomes only till 18–22 months; our study has extended that observation and report respiratory outcomes at 36 months corrected age. In the previous study,19 the number of infants discharged home on oxygen varied from 57.8 to 62.1% in the moderate to severe BPD group compared with 43% infants discharged home on oxygen in our study. In our study, 79.7–86.5% infants with BPD and BPD with chronic oxygen dependency required diuretics. No information was provided about the use of diuretics in the earlier study.19 In our study, 83 (6.2%) infants who were transferred to other peripheral hospitals were excluded from analyses owing to the absence of information regarding their BPD status and follow-up data. In the earlier study, although it had a larger sample size, had more than double (672 infants; 13.8%) our rate of infants who were transferred to another hospital before discharge home but were categorized similarly to the infants who were discharged directly home. This may potentially overestimate the BPD rate and impact the results. Our study has reported sequential longitudinal follow-up of BPD infants at 4, 8, 18 and 36 months, the number of doctor’s visits, the use of antibiotics, oxygen use and PNCLD status compared with the earlier study that had information only at 18–22 months follow-up.19 Our findings are consistent with the previously reported literature that suggest that children with BPD have greater respiratory morbidity.23–25 Although their increased rate of hospitalization abates as they age, these children continue to have frequent respiratory symptoms and persistent small airway disease.23–25 Our study also found that infants with BPD with chronic oxygen dependency were more likely to require respiratory medications and oxygen use at 4, 8 and 18 months. As expected, infants with BPD with chronic oxygen dependency needed more respiratory support compared with infants with BPD. The use of respiratory medications in BPD infants varied from 24 to 40% at 18 months corrected age, which is consistent with the earlier study.19 In the study by Ehrenkranz et al.,19 the rehospitalization rate of moderate to severe BPD was 33.5–39.4% in contrast to our study where this rate was 2% at 18 months. There is limited information known about the respiratory outcomes of preterm infants with BPD or BPD with chronic oxygen dependency at 3 years of age. Hennessey et al. followed infants with BPD for 6 years, reassessing respiratory outcomes at 30 months and 6 years of age using parental questionnaire and peak expiratory flow measurements. They found that the group with BPD was more likely to have respiratory symptoms and need for respiratory medications than those without BPD.26 Similarly, our study also showed that preterm infants with BPD with chronic oxygen dependency were more likely to need respiratory medications, suggesting an increased pulmonary morbidity. The EPICure study27 further corroborates these findings, suggesting that survivors of BPD are more likely to have abnormal baseline © 2015 Nature America, Inc.
spirometry into childhood and are more likely than control agematched peers to have a diagnosis of asthma at age 11. At our center, we did not have the ability to measure infant pulmonary function tests at the age of 3 years. Hence, we are unable to comment whether our cohort had abnormal pulmonary function, as suggested by the greater need for respiratory medications. Hennesey et al.26 reported increased rates of hospitalization in oxygen-dependent BPD at age 30 months and 6 years, when comparing BPD with no-BPD infants, but did not specifically report data on infants with BPD vs those with O2-dependent BPD at NICU discharge. We found a large percentage of infants were discharged home on oxygen, perhaps to facilitate an earlier transition to home. We noted that when assessed at 36 months PMA, overall, children with BPD with chronic oxygen dependency at NICU discharge more often needed respiratory medications and supplemental oxygen than those with no BPD or BPD. They were also more likely to have PNCLD at 3 years than those with no BPD. BPD with chronic oxygen dependency may lead to an increased use of health resources in the NICU and after discharge.28,29 The rate of rehospitalization of premature infants with BPD has been reported to 15% in first year and 25–40% in the second year of life.19,30 However, in our study, rehospitalization rate (41 admission) was low compared with the earlier study19 and there were similar rates of readmission at 4, 8 and 18 months of age, among the three groups of infants. (Table 4A). Infants in the BPD with chronic oxygen dependency group needed more respiratory medications and supplemental oxygen use since discharge, last clinic visit or in the last year at 4, 8 and 18 months of age, respectively. This finding signifies that infants with BPD with chronic oxygen dependency do require close follow-up with their family physicians or pediatrician to avoid respiratory morbidities and readmission in the hospital, as well as parental anxiety, owing to respiratory problems. To our knowledge, our study is the largest single-center, longitudinal cohort study that followed infants prospectively from NICU discharge to determine the impact of chronic oxygen dependency on long-term respiratory outcomes. However, this study has some limitations. The NICHD’s new definitions of BPD related to fraction of inspired oxygen at various time points could not be applied retrospectively. We used a definition that was consistent with that used by the majority of Canadian Neonatal Network centers. During our study period of 1997–2007, significant changes occurred in the medical management of infants in the NICU. These included changes in ventilation practices, with most centers moving towards increased use of nasal continuous positive airway pressure and non-invasive positive pressure ventilation, patient triggered ventilation and high-frequency oscillation. There was also increased use of antenatal steroids, early parental nutrition and use of caffeine before extubation. There was also a move to a more restrictive use of blood transfusions and post-natal steroids. Since 2001, however, our Journal of Perinatology (2015), 1 – 7
Journal of Perinatology (2015), 1 – 7 n = 138/144 2 (1%) 21 (15%) 24 (18%) 10 (7%) 19/135 (14%) n = 142/144 43/125 (34%) 4 (3%) 36 (25%) 27 (19%) 9 (6%) 13/140 (9%) n = 142/144 37/129 (29%) 3 (2%) 46 (33%) 34 (24%) 2 (1%)
n = 424/442 6 (1%) 63 (15%) 76 (18%) 19 (4%) 28/415 (7%) n = 405/442 72/361 (20%) 3 (1%) 102 (25%) 61 (15%) 10 (2%) 22/390 (6%) n = 433/442 103/317 (28%) 2 (0.5%) 148 (35%) 100 (23%) 4 (1%)
4 months 41 Hospitalization for LRTI since discharge, no. (%) Antibiotic use since discharge,c no. (%) Respiratory medications since discharge, no. (%) Oxygen use since discharge, no. (%) PNCLD at 4 m months, no. (%)
8 months 43 Doctor visits between 4–8 months visit, no. (%) 41 Hospitalization for LRTI between 4–8 months, no. (%) Antibiotic use between 4–8 months,c no. (%) Respiratory medications between 4–8 months, no. (%) Oxygen use between 4–8 months, no. (%) PNCLD at 8 months, no. (%)
18 months 43 Doctor visits during past year, no. (%) 41 Hospitalization for LRTI during past year, no. (%) Antibiotic use in the past 12 months,c no. (%) Respiratory medications in the past 12 months, no. (%) Oxygen use in the past 12 months, no. (%)
n = 437/444 150/362 (41%) 10 (2%) 158 (37%) 174 (40%) 71 (16%)
n = 427/444 132/361 (37%) 11 (3%) 109 (26%) 145 (34%) 189 (44%) 128/413 (31%)
n = 432/444 13 (3%) 74 (17%) 126 (29%) 422 (98%) 222/419 (53%)
BPD with chronic oxygen dependency (n = 444)
o0.001 0.066 0.651 o0.001 o0.001
o0.001 0.095 0.994 o0.001 o0.001 o0.001
0.224 0.657 o0.001 o0.001 o0.001
P-valuea
(−0.12 (−0.05 (−0.09 (−0.11 (−0.03
to to to to to
0.10) 0.01) 0.13) 0.09) 0.02)
(−0.26 to − 0.03) (−0.06 to 0.01) (−0.10 to 0.10) (−0.13 to 0.05) (−0.09 to 0.01) (−0.10 to 0.03)
(−0.03 to 0.03) (−0.09 to 0.08) (−0.09 to 0.09) (−0.09 to 0.03) (−0.15 to 0.004)
No BPD vs BPD
(−0.22 to − 0.05) (−0.04 to 0.001) (−0.10 to 0.06) (−0.24 to − 0.10) (−0.20 to − 0.11)
(−0.25 to − 0.09) (−0.04 to 0.003) (−0.08 to 0.07) (−0.26 to − 0.12) (−0.48 to − 0.36) (−0.31 to − 0.19)
(−0.04 to 0.01) (−0.08 to 0.04) (−0.18 to − 0.04) (−0.96 to − 0.90) (−0.53 to − 0.40)
No BPD vs BPD with chronic oxygen dependency
Confidence intervals for pairwise differencesb
(−0.24 to − 0.01) (−0.04 to 0.03) (−0.15 to 0.07) (−0.26 to − 0.06) (−0.20 to − 0.10)
(−0.14 to 0.10) (−0.04 to 0.04) (−0.10 to 0.10) (−0.25 to − 0.05) (−0.46 to − 0.30) (−0.30 to − 0.14)
(−0.05 to 0.02) (−0.10 to 0.07) (−0.21 to − 0.02) (−0.96 to − 0.85) (−0.48 to − 0.30)
BPD vs BPD with chronic oxygen dependency
55 (39.3) 40 (28.6) 1 (0.7) 16 (11.4)
143 (33.3) 86 (20.0) 5 (0.9) 24 (5.8)
41 (9.5) 76 (18.2)
171 (39.7) 181 (42.0)
114 (31.4) 7 (1.6)
BPD with chronic oxygen dependency (n = 439/444)
(−0.14 to 0.01) (−0.29 to − 0.15) (−0.12 to − 0.05) (−0.18 to − 0.07)
0.121 (−0.17 to 0.05) o0.001 (−0.19 to 0.02) o0.001 (−0.02 to 0.02) o0.001 (−0.13 to 0.01)
(−0.17 to − 0.02) (−0.03 to 0.01)
(−0.13 to − 0.05) (−0.15 to 0.01)
(−0.12 to 0.11) (−0.24 to − 0.03)
(−0.14 to 0.09) (−0.03 to − 0.002)
BPD vs BPD with chronic oxygen dependency
Confidence intervals for pairwise differencesb No BPD vs BPD No BPD vs BPD with Chronic oxygen dependency 0.012 (−0.18 to 0.04) 0.282 (−0.002 to 0.02)
P-valuea
Abbreviations: BPD, bronchopulmonary dysplasia, LRTI, lower respiratory tract infection; no., number; PNCLD, post-neonatal chronic lung disease. aPearson χ2-test or Fisher’s exact test. bBonferroni correction applied to adjust for the three pairwise comparisons, thus confidence intervals are reported at the (1–0.05/3)% level. cExcludes prophylactic use of antibiotics.
35 (28.7) 0 (0.0)
BPD (n = 142/144)
82 (21.9) 4 (0.9)
No BPD (n = 439/442)
Respiratory outcomes at 36 months corrected age
43 Doctor visits during past year, no. (%) 41 Hospitalization for LRTI during past year, no. (%) Antibiotic use in the past 12 months,c no. (%) Respiratory medications in the past 12 months, no. (%) Oxygen use in the past 12 months, no. (%) PNCLD at 3 years, no. (%)
Table 4B.
Abbreviations: BPD, bronchopulmonary dysplasia, LRTI, lower respiratory tract infection; no., number; PNCLD, post-neonatal chronic lung disease. Note: Doctor visits at 4 months not reported due to 40% missing data; PNCLD data at 18 months not available as not seen by physician at that time point. aPearson χ2 test or Fisher’s exact test. bBonferroni correction applied to adjust for the three pairwise comparisons, thus confidence intervals are reported at the (1–0.05/3)% level. cExcludes prophylactic use of antibiotics.
BPD (n = 144)
Respiratory outcomes at 4, 8 and 18 months corrected age No BPD (n = 442)
Table 4A.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
6
© 2015 Nature America, Inc.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
7 criteria for discharge home on oxygen have remained unchanged. We did not have data about respiratory syncytial virus prophylaxis and cannot comment on the temporal sequence of changes in clinical practice that could potentially have impacted on our results owing to the fact that some of these changes in practice were overlapping with birth years and may have taken variable duration to be completely adopted by the attending physicians. The impact of our loss to follow-up is unknown, although we believe that as the infants lost to follow-up were not significantly different in patient demographics, our results would not be affected in a significant manner. Generalizability of our results may be most useful to centers located at high altitude and less applicable to units located at sea level. In conclusion, in a longitudinal follow-up study, use of respiratory medications and supplemental oxygen were both significantly higher in the BPD with chronic oxygen dependency infants, compared with the no-BPD group and the BPD group, at 4, 8 and 18 months. Similarly, at 36 months, children diagnosed with BPD with chronic oxygen dependency were more likely to need respiratory medications and supplemental oxygen as compared with the no-BPD or BPD groups. They were also more likely to require frequent physician visits and have PNCLD at 3 years, compared with those with no BPD. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Vohr BR, Wright LL, Dusick AM, Perritt R, Poole WK, Tyson JE et al. Center differences and outcomes of extremely low birth weight infants. Pediatrics 2004; 113: 781–789. 2 Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82: 527–532. 3 Chess PR, D'Angio CT, Pryhuber GS, Maniscalco WM. Pathogenesis of bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 171–178. 4 Koumbourlis AC, Motoyama EK, Mutich RL, Mallory GB, Walczak SA, Fertal K. Longitudinal follow-up of lung function from childhood to adolescence in prematurely born patients with neonatal chronic lung disease. Pediatr Pulmonol 1996; 21: 28–34. 5 Smith LJ, van Asperen PP, McKay KO, Selvadurai H, Fitzgerald DA. Reduced exercise capacity in children born very preterm. Pediatrics 2008; 122: e287–e293. 6 Carraro S, Filippone M, Da Dalt L, Ferraro V, Maretti M, Bressan S et al. Bronchopulmonary dysplasia: the earliest and perhaps the longest lasting obstructive lung disease in humans. Early Hum Dev 2013; 89(Suppl 3): S3–S5. 7 Lodha A, Sauve R, Bhandari V, Tang S, Christianson H, Bhandari A et al. Need for supplemental oxygen at discharge in infants with bronchopulmonary dysplasia is not associated with worse neurodevelopmental outcomes at 3 years corrected age. PLoS One 2014; 9: e90843. 8 Lodha A, Zhu Q, Lee SK, Shah PS. Canadian Neonatal Network Neonatal outcomes of preterm infants in breech presentation according to mode of birth in Canadian NICUs. Postgrad Med J 2011; 87: 175–179.
© 2015 Nature America, Inc.
9 CNN (2014). The Canadian Neonatal Network annual report 2013 [online]. Available at http://www.canadianneonatalnetwork.org/portal/. 10 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: 529–534. 11 An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. Pediatrics 1984; 74: 127–133. 12 Lee SK, Ye XY, Singhal N, De La Rue S, Lodha A, Shah PS. Higher altitude and risk of bronchopulmonary dysplasia among preterm infants. Am J Perinatol 2012; 30: 601–606. 13 Bhandari A, McGrath-Morrow S. Long-term pulmonary outcomes of patients with bronchopulmonary dysplasia. Semin Perinatol 2013; 37: 132–137. 14 Tapia JL, Agost D, Alegria A, Standen J, Escobar M, Grandi C et al. Bronchopulmonary dysplasia: incidence, risk factors and resource utilization in a population of South American very low birth weight infants. J Pediatr (Rio J) 2006; 82: 15–20. 15 Johnson TJ, Patel AL, Jegier BJ, Engstrom JL, Meier PP. Cost of morbidities in very low birth weight infants. J Pediatr 2013; 162: 243–249 e241. 16 Qiu X, Lodha A, Shah PS, Sankaran K, Seshia MM, Yee W et al. Neonatal outcomes of small for gestational age preterm infants in Canada. Am J Perinatol 2012; 29: 87–94. 17 Stroustrup A, Trasande L. Epidemiological characteristics and resource use in neonates with bronchopulmonary dysplasia: 1993-2006. Pediatrics 2010; 126: 291–297. 18 Heron M, Sutton PD, Xu J, Ventura SJ, Strobino DM, Guyer B. Annual summary of vital statistics: 2007. Pediatrics 2010; 125: 4–15. 19 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116: 1353–1360. 20 Bhandari A, Bhandari V. Pitfalls, problems, and progress in bronchopulmonary dysplasia. Pediatrics 2009; 123: 1562–1573. 21 Gien J, Kinsella JP. Pathogenesis and treatment of bronchopulmonary dysplasia. Curr Opin Pediatr 2011; 23: 305–313. 22 Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet 2006; 367: 1421–1431. 23 Doyle LW, Casalaz D. Victorian Infant Collaborative Study Group Outcome at 14 years of extremely low birthweight infants: a regional study. Arch Dis Child Fetal Neonatal Ed 2001; 85: F159–F164. 24 Lista G, Castoldi F, Bianchi S, Lupo E, Cavigioli F, Farolfi A et al. Lung function and respiratory health at school age in ventilated very low birth weight infants. Indian J Pediatr 2014; 81: 275–278. 25 Anand D, Stevenson CJ, West CR, Pharoah PO. Lung function and respiratory health in adolescents of very low birth weight. Arch Dis Child 2003; 88: 135–138. 26 Hennessy EM, Bracewell MA, Wood N, Wolke D, Costeloe K, Gibson A et al. Respiratory health in pre-school and school age children following extremely preterm birth. Arch Dis Child 2008; 93: 1037–1043. 27 Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V et al. Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am J Respir Crit Care Med 2010; 182: 237–245. 28 Greenough A, Alexander J, Boorman J, Chetcuti PA, Cliff I, Lenney W et al. Respiratory morbidity, healthcare utilisation and cost of care at school age related to home oxygen status. Eur J Pediatr 2011; 170: 969–975. 29 Landry JS, Croitoru D, Jin Y, Schwartzman K, Benedetti A, Menzies D. Health care utilization by preterm infants with respiratory complications in Quebec. Can Respir J 2012; 19: 255–260. 30 Underwood MA, Danielsen B, Gilbert WM. Cost, causes and rates of rehospitalization of preterm infants. J Perinatol 2007; 27: 614–619.
Journal of Perinatology (2015), 1 – 7
ORIGINAL ARTICLE
Does chronic oxygen dependency in preterm infants with bronchopulmonary dysplasia at NICU discharge predict respiratory outcomes at 3 years of age? A Lodha1,2,3,4, K Ediger1, Y Rabi1,2,3, S Lodha1, S Tang3, A Bhandari5, R Sauve1,2,3 and V Bhandari6 OBJECTIVE: To determine whether chronic oxygen dependency at the time of discharge from the neonatal intensive care unit (NICU) in infants with bronchopulmonary dysplasia (BPD) predicts respiratory outcomes at 3 years. STUDY DESIGN: Preterm infants ⩽ 1250 g without BPD, BPD and BPD with chronic oxygen dependency were identified from the Southern Alberta Perinatal Follow-up clinic database (1995–2007). Respiratory outcomes at 4, 8, 18 and 36 months corrected age following NICU discharge were examined. Univariate analyses were done. RESULTS: Out of 1563 infants admitted to the NICU, 1212 survived. Complete follow-up data at 36 months were available for 1030 (85%) children. Children with BPD with or without chronic oxygen dependency had significantly (P o 0.001) lower birth weights and gestational ages, and greater post-natal steroid use, compared with those with no BPD. At 4, 8 and 18 months follow-up, the use of respiratory medications and supplemental oxygen were both significantly higher in the BPD infants with chronic oxygen dependency group compared with the no-BPD group and BPD group. At 36 months, children in the BPD with chronic oxygen dependency group were more likely to use respiratory medications and supplemental oxygen vs the no-BPD or the BPD groups. At 4, 8 and 36 months of age, more children in the BPD with chronic oxygen dependency group had post-neonatal chronic lung disease (PNCLD) than children in the other groups, but at 36 months the difference was significant only for the BPD with chronic oxygen dependency vs no-BPD group (P o 0.001). CONCLUSIONS: At 36 months, children diagnosed with BPD with chronic oxygen dependency at NICU discharge were more likely to need respiratory medications and supplemental oxygen in the previous 12 months, as compared with no-BPD or BPD groups. They were also more likely to require frequent physician visits and have PNCLD at 3 years, as compared with the no-BPD group. Journal of Perinatology advance online publication, 26 February 2015; doi:10.1038/jp.2015.7
INTRODUCTION Bronchopulmonary dysplasia (BPD) is a serious pulmonary condition and a common cause of mortality and morbidity among very preterm infants. Reported incidence rates of BPD varies widely, based on various factors such as definition used and site of care.1 A common description defines BPD based on oxygen dependency or respiratory support at 36 weeks post-menstrual age (PMA).2 BPD is a multifactorial disease: a number of prenatal, perinatal and post-natal factors are thought to influence the pathogenesis, severity and outcomes of infants with BPD. Contributing factors include in utero environment, genetics, prematurity, oxygen administration, surfactant deficiency and ventilation, infection/inflammation, patent ductus arteriosus and fluid status.3 Despite the large burden of disease presented by BPD, little is known about the pathogenic mechanisms underlying the clinical picture seen in BPD survivors. BPD is known to have a long-term impact on both lung growth and function. It has been reported 1
that survivors of BPD tend to have persistent airflow limitation,4 decreased exercise capacity5 and may have a steeper decline of lung function with aging.6 The primary objective of this study was to determine the relationship between no BPD, BPD and BPD with chronic oxygen dependency and 3-year respiratory outcomes. The secondary outcome was to determine the respiratory outcomes at 4, 8 and 18 months. METHODS In a longitudinal cohort study, premature infants born between January 1995 and December 2007 with a birth weight (BW) ⩽ 1250 g and admitted to the neonatal intensive care unit (NICU; a tertiary center serving southern Alberta, Canada) were eligible for inclusion in the study. The infants were followed from NICU discharge to 3 years of age at a regional neonatal follow-up clinic. Exclusion criteria for the study were deaths, major congenital malformations or chromosomal disorders. This study was approved by the University of Calgary institutional ethics review board and informed consent was obtained from all participants. The cohort data used
Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada; 2Department of Pediatrics, Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada; Department of Pediatrics, Alberta Health Services, Calgary, Alberta, Canada; 4Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; 5 Department of Pediatric Pulmonology, Connecticut Children's Medical Center, Hartford, CT, USA and 6Department of Pediatrics, Yale University, New Haven, CT, USA. Correspondence: Dr V Bhandari, Yale University School of Medicine, Yale Child Health Research Center, Room Number: 219, PO Box 208081, 464 Congress Avenue, New Haven, CT 06520, USA. E-mail: [email protected] Received 16 September 2014; revised 19 January 2015; accepted 20 January 2015 3
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
2 Table 1.
Discharge criteria of infants from the NICU
Criteria a. Corrected gestational age 434 weeks b. Able to maintain body temperature (436.4 °C) in an open crib c. Competent suckle feeding (breast or bottle) without cardiorespiratory compromise and gaining weight d. Physiologically mature e. Stable cardiorespiratory function f. No apnea of prematurity g. No active medical problems h. Receipt of appropriate immunizations i. Appropriate metabolic screening and car seat testing performed j. Family readiness Abbreviation: NICU, neonatal intensive care unit.
for this analysis was part of a larger study on 3-year neurodevelopmental outcomes of infants with BPD.7 Upon NICU discharge, standardized demographic, perinatal and neonatal data were obtained from infant charts and entered into a computerized database by a trained research assistant. Specific discharge criteria are presented in Table 1. According to these criteria, for an infant to be discharged home on supplemental oxygen with no ‘active’ medical problem, they should have no acute life threatening illness, they should not be requiring continuous cardiorespiratory monitoring or nursing care and pulse oximetry results showing SpO2 ⩽ 89% in room air had to be obtained 48 h before discharge home. At discharge, infants were categorized as having no BPD, BPD (defined as O2 dependency and/or respiratory support at 36 weeks PMA) or BPD with chronic oxygen dependency (defined as oxygen requirement at 36 weeks PMA and at the time of discharge home).2 The infants were then routinely followed prospectively by the perinatal follow-up clinic, where their respiratory outcome data were obtained at 4, 8, 18 and 36 months. These data included information obtained from parents’ and pediatrician follow-up reports. All outcome measures were defined as outlined below, and these definitions remained constant throughout the study period. Chorioamnionitis was diagnosed based on clinical criteria (maternal fever ⩾ 38.4 °C within 24 h before birth and uterine tenderness ± leukocytosis of 415 000 per mm3) or evidence of chorioamnionitis on placental histopathological examination. This was diagnosed by noting the presence of histological markers suggestive of maternal inflammation including neutrophilic infiltration of subchorionic space (subchorionitis), chorionic plate (chorionitis) or free placental membranes (chorioamnionitis). Gestational age (GA) was defined as estimated by obstetric history, examination and prenatal ultrasound.8 Infants were considered small for GA (SGA) if their BW was less than the 10th percentile for the given GA. Respiratory distress syndrome was diagnosed based on the clinical examination, chest X-ray findings, the need for surfactant administration and mechanical ventilation for few hours, as per the Canadian Neonatal Network guidelines.9 Total duration of oxygen was defined as the total number of days the infant received supplemental oxygen. Duration of mechanical ventilation was defined by the total number of days the infant was mechanically ventilated for any part of the day. The duration of respiratory support included mechanical ventilation and non-invasive respiratory support. Patent ductus arteriosus was diagnosed clinically or by echocardiography. Diagnosis and severity of intraventricular hemorrhage (IVH) were classified according to the criteria of Papile et al.10 from the most severe finding on head ultrasonography performed at any time during the patient’s admission. Necrotizing enterocolitis was classified according to modified Bell’s criteria (stage ⩾ 2) and was classified as medical or surgical based on this staging.8 Retinopathy of prematurity was classified according to the international classification.11 The total number of days the infant stayed in the NICU from birth to discharge determined the total length of stay (LOS). Post-neonatal chronic lung disease (PNCLD) was defined as the presence of one of the following criteria in the previous 12 months before reaching 3 years of age: current oxygen therapy, ongoing therapy with respiratory medications for 44 months duration, ⩾ 2 courses of antibiotics per year for respiratory indications, oral steroids for respiratory indications and/or evidence of abnormal respiratory signs (for e.g., rales) on clinical Journal of Perinatology (2015), 1 – 7
Total number of eligible newborns, Birth weight ≤ 1250 grams, Born between January 1995-December 2007 N = 1563
Deaths n = 216 Total number of infants discharged from NICU N = 1347 (86%)
Excluded: Total n = 135 Congenital anomalies (n = 37) Transfer to other hospitals (n = 83) Died prior to 36 months PMA (n = 15)
Total number of infants eligible for the study N = 1212 (90%)
Complete follow-up at 36 months PMA N = 1030 (85%)
No BPD
BPD
N = 442
N = 144
BPD with chronic O2 dependency N = 444
Figure 1. Flow diagram of our study population. BPD, bronchopulmonary dysplasia; NICU, neonatal intensive care unit; PMA, postmenstrual age.
examination or any hospitalizations for respiratory illness. Perinatal and neonatal data were defined according to the Canadian Neonatal Network standards.9
Statistical analysis The infant and maternal characteristics of the cohort were compared across the three groups using Pearson χ2 or Fisher’s exact test for categorical variables. To compare pairwise differences between groups (no BPD vs BPD, no BPD vs BPD with chronic oxygen dependency and BPD vs BPD with chronic oxygen dependency), confidence intervals for the pairwise differences in proportion were calculated and the Bonferroni correction was applied. Confidence intervals were reported at the (1– 0.05/3) % level. All results were generated using SAS 9.3 (SAS Institute, Cary, NC, USA). © 2015 Nature America, Inc.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
RESULTS A flow diagram of our study population is presented in Figure 1. A total of 1563 infants with a BW ⩽ 1250 g were eligible for inclusion. After excluding infants who had major congenital or chromosomal abnormalities, or who died before 36 months, a total of 1212 (90%) infants remained in the study cohort. Of these, 1030 (85%) infants were available for complete follow-up at 36 months. These infants had been divided into three groups based on oxygen dependency status at NICU discharge: no BPD (442 infants; 43%), BPD (144 infants; 14%) or BPD with chronic oxygen dependency (444 infants, 43%). Rates of follow-up were similar across the three groups. Children lost to follow-up at 36 months (n = 182) were not significantly different than those who underwent follow-up in terms of BW (median 983 g vs 950 g, P = 0.101) or GA (median 28 weeks vs 27 weeks, P = 0.096). Children lost to follow-up were more likely to have a shorter duration of respiratory support (median 6 days vs 13 days, P = 0.031) and shorter periods of hospitalization (median 71 days vs 75 days, P = 0.019). Maternal and infant characteristics of the study cohort are presented in Table 2. Overall, maternal Caucasian race was significantly more common in the BPD groups; in contrast, the use of maternal antihypertensive medications and rate of Cesarean sections were significantly more common in the no-BPD group. Infants without BPD were discharged from hospital at a median of 37 weeks PMA, which is significantly earlier than infants with BPD, who were discharged at a median PMA age of 39 weeks (P o 0.001). Overall, infants with BPD and BPD with chronic oxygen dependency had significantly lower BW and GA (P o 0.001), less likely to be SGA (P = 0.019), more likely to be male, with an increased incidence of respiratory distress syndrome, patent ductus arteriosus, confirmed sepsis, severe IVH and retinopathy of prematurity stage II and greater or plus disease or laser treatment (all Po 0.001), as well as necrotizing enterocolitis (P = 0.037; Table 2). A comparison of health resource utilization between the three groups while in the NICU is presented in Table 3. Children in the BPD with chronic oxygen dependency group were more likely to have had more blood transfusion, a longer duration of respiratory support (inclusive of mechanical ventilation and non-invasive respiratory support) and oxygen requirement (P o 0.001). Use of post-natal steroids and diuretics were also higher (P o 0.001) in those infants with BPD and BPD with chronic oxygen dependency. Length of hospital stay was longer in infants with BPD, regardless of chronic need for oxygen (P o0.001; Table 3). One of the 15 deaths occurred before 36 weeks PMA, thus we could not determine BPD status on one child. The remaining 14 children (436 weeks PMA) died after discharge from the hospital; 5 were in the no-BPD group, 1 in the BPD group and 8 in the BPD with chronic oxygen dependency group. Respiratory outcomes at 4, 8 and 18 months are shown in Table 4A. At 4, 8 and 18 months follow-up, the use of respiratory medications and supplemental oxygen since discharge, last clinic visit or in the past 12 months was significantly more common in the BPD with chronic O2 dependency group than in the no-BPD group and the BPD group (Table 4A). In addition, at 4 and 8 months follow-up, the diagnosis of PNCLD was significantly more common in the BPD with chronic O2 dependency group compared with the no-BPD group and the BPD group. A total of 14 children died after discharge from the hospital. Including or excluding these infants did not make a significant impact on the incidence of PNCLD at any follow-up age. The proportion of children with frequent physician visits in the 4–8-month time period was significantly higher for the BPD and the BPD with chronic O2 dependency groups than for the no-BPD group (Table 4A). At the 18-month follow-up, frequent physician visits in the past year were more common in the BPD with chronic O2 © 2015 Nature America, Inc.
3 dependency group compared with the other two groups (Table 4A). Respiratory outcomes at 36 months PMA are presented in Table 4B. At the 36 months follow-up, the use of respiratory medications and supplemental oxygen in the past year was significantly more common in the BPD with chronic O2 dependency group as compared with the BPD group and the no-BPD group (Table 4B). Frequent physician visits and the diagnosis of PNCLD were significantly more commonly seen in the BPD with chronic O2 dependency group compared with the no-BPD group, but were not significantly different between the BPD with chronic O2 dependency group and the BPD group (Table 4B). DISCUSSION Our study revealed that at 36 months PMA, preterm infants with BPD with chronic oxygen dependency had greater respiratory morbidity as compared with the BPD or no-BPD groups. BPD with chronic oxygen dependency infants were more likely to need respiratory medications (post-natal steroids and diuretics) and supplemental oxygen in the previous 12 months, as compared with the no-BPD or BPD groups. We also observed a higher incidence of PNCLD and frequent physician visits as compared with the no-BPD group. At 4, 8 and 18 months follow-up, the use of respiratory medications and supplemental oxygen were both significantly higher in the BPD with chronic oxygen dependency infants, compared with the no-BPD group and the BPD group. Forty-three percent of infants had BPD with chronic oxygen dependency. This is possibly owing to the facts that Calgary is 1100 m (3600 ft) above sea level and our clinical practice.12 The continuing morbidity associated with BPD has been attributed to the increased survival rates for very low BW and younger preterm infants.13 In our study, infants with BPD with chronic oxygen dependency were more likely to have been prescribed post-natal steroids than infants with no BPD or BPD, and more diuretics compared with no BPD. They were also more likely to have required a longer duration of mechanical ventilation than infants with no BPD or BPD, with an increased LOS in hospital, compared with no BPD. This finding was consistent with other reports from the literature, suggesting that BPD,14 chronic oxygen dependency and factors (extreme prematurity, SGA15,16) that increase the likelihood of BPD can lead to increased resource utilization and health care costs.15,17 The severity of CLD also varies among affected infants. Some infants discharged home on oxygen require short-term treatment and subsequently improve. However, there is another group of infants with CLD who fall into a category whom we have termed PNCLD. These infants require oxygen for a longer period, have more severe disease and greater respiratory morbidity. The Heron et al.18 study revealed that 25% premature infants had severe CLD at the age of 1 year. We speculate that these infants possibly had PNCLD. In the Ehrenkranz et al.19 study, BPD was classified into three types based on the National Institutes of Health (NIH) consensus definition (mild, moderate and severe) and infants who received inspiratory oxygen by nasal cannula at 36 weeks’ PMA were considered to have moderate BPD, as the effective inspiratory oxygen concentration was not collected. In the earlier study,19 infants born between 1995 and 1999 were enrolled, whereas our study has included babies born between 1995 and 2007. So, although the earlier study19 is probably more reflective of the ‘old’ BPD population, our study does include infants with ‘new’ BPD.13,20–22 In our study, the median LOS of BPD infants and BPD with chronic oxygen dependency infants were 92– 93 days in contrast to mean LOS of moderate BPD and severe BPD of 99 and 127 days in the earlier study.19 This was probably an underestimate, as the earlier study did not have LOS data on infants who had been transferred to other hospitals.19 In our study, 20–32% infants with BPD required post-natal steroids in contrast to the Ehrenkranz et al.19 study where 62–76% Journal of Perinatology (2015), 1 – 7
Journal of Perinatology (2015), 1 – 7 252 41 274 121 378 101 303 94 247
(60.9) (33, 56) (70.8) (28.3) (86.7) (23.2) (68.7) (22.3) (57.2)
79 46 93 39 116 14 94 37 84
(57.3) (33, 57) (79.5) (27.7) (82.9) (10.3) (65.3) (27.4) (60.4)
BPD (n = 144)
(690, 1000) (25, 28) (37, 41) (15.9) (71.4) (88.1) (57.7) (87.1) (69.3) (25.0) (12.2) (9.2) (1.6) (52.5)
317 391 256 386 307 110 54 41 7 223
(59.8) (33, 57) (77.6) (23.8) (83.8) (17.3) (55.5) (21.5) (60.5)
820 26 39 70
253 44 280 102 366 75 246 93 262
BPD with chronic oxygen dependency (n = 444)
0.121 0.496 o0.001 o0.001 o0.001 o0.001 0.037 o0.001 0.196 o0.001
o0.001 o0.001 o0.001 0.019
0.753 0.227 0.047 0.302 0.367 0.002 o0.001 0.354 0.572
P-valuea
(−0.03 (−0.04 (−0.13 (−0.44 (−0.46 (−0.27 (−0.16 (−0.11 (−0.06 (−0.38
to to to to to to to to to to
0.19) 0.11) 0.10) − 0.26) − 0.24) − 0.08) 0.01) 0.002) 0.02) − 0.17)
(90 to 180) (1 to 2) (−4 to − 2) (0.01 to 0.17)
(−0.08 to 0.15) (−6 to 1) (−0.19 to 0.02) (−0.10 to 0.11) (−0.05 to 0.12) (0.05 to 0.21) (−0.07 to 0.14) (−0.15 to 0.05) (−0.15 to 0.08)
No BPD vs BPD
(−0.08 (−0.04 (−0.20 (−0.43 (−0.50 (−0.21 (−0.08 (−0.11 (−0.02 (−0.47
to to to to to to to to to to
0.06) 0.07) − 0.04) − 0.30) − 0.36) − 0.09) 0.02) − 0.03) 0.03) − 0.32)
(180 to 245) (2 to 3) (−3 to − 2) (−0.01 to 0.12)
(−0.09 to 0.07) (−4 to 1) (−0.14 to 0.01) (−0.03 to 0.12) (−0.03 to 0.09) (−0.01 to 0.12) (0.05 to 0.21) (−0.06 to 0.08) (−0.11 to 0.05)
No BPD vs BPD with chronic oxygen dependency
to 4) to to to to to to to
0.12) 0.14) 0.08) 0.01) 0.21) 0.16) 0.11)
0.09)
(−0.20 (−0.10 (−0.22 (−0.10 (−0.19 (−0.08 (−0.04 (−0.08 (−0.02 (−0.23
to to to to to to to to to to
0.02) 0.06) 0.01) 0.06) 0.04) 0.12) 0.13) 0.05) 0.07) − 0.003)
(20 to 120) (0 to 1) (0 to 1) (−0.11 to 0.04)
(−0.14 (−3 to (−0.08 (−0.06 (−0.10 (−0.15 (−0.01 (−0.04 (−0.11
BPD vs BPD with chronic oxygen dependency
Confidence intervals for pairwise differencesb
Abbreviations: BPD, bronchopulmonary dysplasia; IQR, interquartile range; no., number. aKruskal–Wallis test for continuous variables; Pearson χ2-test for categorical variables. bBonferroni correction applied to adjust for the three pairwise comparisons, thus confidence intervals are reported at the (1–0.05/3)% level.
Infants Birth weight (grams), median (IQR) 1070 (930, 1180) 885 (750, 1060) Gestational age (weeks), median (IQR) 29 (27, 30) 27 (26, 28) Gestational age at discharge (weeks), median (IQR) 37 (35, 38) 40 (38, 41) Small for gestational age (o 10th percentile), 95 (21.5) 18 (12.5) no. (%) Singleton, no. (%) 311 (70.4) 90 (62.5) Inborn, no. (%) 396 (89.6) 124 (86.1) Male sex, no. (%) 201 (45.5) 68 (47.2) Respiratory distress syndrome, no. (%) 224 (50.7) 123 (85.4) Patent ductus arteriosus, no. (%) 117 (26.5) 89 (61.8) Confirmed sepsis, no. (%) 42 (9.7) 39 (27.3) Necrotizing enterocolitis, no. (%) 40 (9.1) 24 (16.7) Intraventricular hemorrhage grade ⩾ III, no. (%) 10 (2.3) 11 (7.7) Periventricular leukomalacia, no. (%) 10 (2.3) 6 (4.2) Retinopathy of prematurity stage ⩾ II or plus 51 (13.0) 56 (40.6) disease or laser treatment, no. (%)
Maternal Maternal education more than high school, no. (%) Blishen score, median (IQR) Maternal race Caucasian, no. (%) Smoking during pregnancy, no. (%) Antenatal corticosteroids, no. (%) Maternal antihypertensive medications, no. (%) Cesarean section, no. (%) Chorioamnionitis, no. (%) Maternal antibiotics, no. (%)
No BPD (n = 442)
Maternal and infants’ characteristics of the follow-up cohort
Characteristic
Table 2.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
4
© 2015 Nature America, Inc.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
5 Table 3.
Comparison of resource utilization between preterm infants with no BPD, BPD and BPD with chronic oxygen dependency
Variable Total blood transfusions (times), median (IQR) Duration of oxygen requirement (days), median (IQR) a Duration of respiratory support (days), median (IQR) NCPAP, n (%) Mechanical ventilation, n (%) Postnatal steroids, n (%) Diuretics, n (%) Length of stay (days), median (IQR)
No BPD (N = 442) 0 6 1 170 250 91 139 56
(0, 1) (2, 37) (0, 6) (38.5) (56.6) (4.8) (31.6) (43, 71)
BPD (N = 144) 3 78 21 107 133 29 114 93
(1, 4) (62, 93) (8, 39) (74.3) (92.4) (20.3) (79.7) (76, 103)
BPD with chronic oxygen dependency (N = 444) 4 209 36 368 424 144 384 92
(2, 6) (153, 277) (18, 52) (82.9) (95.5) (32.5) (86.5) (74, 109)
P-value o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001
Abbreviations: BPD, bronchopulmonary dysplasia; IQR, interquartile range; NCPAP, nasal continuous positive airway pressure. aRespiratory support includes mechanical ventilation and non-invasive respiratory support.
infants with moderate to severe BPD required post-natal steroids. The earlier study reported pulmonary and neurodevelopmental outcomes only till 18–22 months; our study has extended that observation and report respiratory outcomes at 36 months corrected age. In the previous study,19 the number of infants discharged home on oxygen varied from 57.8 to 62.1% in the moderate to severe BPD group compared with 43% infants discharged home on oxygen in our study. In our study, 79.7–86.5% infants with BPD and BPD with chronic oxygen dependency required diuretics. No information was provided about the use of diuretics in the earlier study.19 In our study, 83 (6.2%) infants who were transferred to other peripheral hospitals were excluded from analyses owing to the absence of information regarding their BPD status and follow-up data. In the earlier study, although it had a larger sample size, had more than double (672 infants; 13.8%) our rate of infants who were transferred to another hospital before discharge home but were categorized similarly to the infants who were discharged directly home. This may potentially overestimate the BPD rate and impact the results. Our study has reported sequential longitudinal follow-up of BPD infants at 4, 8, 18 and 36 months, the number of doctor’s visits, the use of antibiotics, oxygen use and PNCLD status compared with the earlier study that had information only at 18–22 months follow-up.19 Our findings are consistent with the previously reported literature that suggest that children with BPD have greater respiratory morbidity.23–25 Although their increased rate of hospitalization abates as they age, these children continue to have frequent respiratory symptoms and persistent small airway disease.23–25 Our study also found that infants with BPD with chronic oxygen dependency were more likely to require respiratory medications and oxygen use at 4, 8 and 18 months. As expected, infants with BPD with chronic oxygen dependency needed more respiratory support compared with infants with BPD. The use of respiratory medications in BPD infants varied from 24 to 40% at 18 months corrected age, which is consistent with the earlier study.19 In the study by Ehrenkranz et al.,19 the rehospitalization rate of moderate to severe BPD was 33.5–39.4% in contrast to our study where this rate was 2% at 18 months. There is limited information known about the respiratory outcomes of preterm infants with BPD or BPD with chronic oxygen dependency at 3 years of age. Hennessey et al. followed infants with BPD for 6 years, reassessing respiratory outcomes at 30 months and 6 years of age using parental questionnaire and peak expiratory flow measurements. They found that the group with BPD was more likely to have respiratory symptoms and need for respiratory medications than those without BPD.26 Similarly, our study also showed that preterm infants with BPD with chronic oxygen dependency were more likely to need respiratory medications, suggesting an increased pulmonary morbidity. The EPICure study27 further corroborates these findings, suggesting that survivors of BPD are more likely to have abnormal baseline © 2015 Nature America, Inc.
spirometry into childhood and are more likely than control agematched peers to have a diagnosis of asthma at age 11. At our center, we did not have the ability to measure infant pulmonary function tests at the age of 3 years. Hence, we are unable to comment whether our cohort had abnormal pulmonary function, as suggested by the greater need for respiratory medications. Hennesey et al.26 reported increased rates of hospitalization in oxygen-dependent BPD at age 30 months and 6 years, when comparing BPD with no-BPD infants, but did not specifically report data on infants with BPD vs those with O2-dependent BPD at NICU discharge. We found a large percentage of infants were discharged home on oxygen, perhaps to facilitate an earlier transition to home. We noted that when assessed at 36 months PMA, overall, children with BPD with chronic oxygen dependency at NICU discharge more often needed respiratory medications and supplemental oxygen than those with no BPD or BPD. They were also more likely to have PNCLD at 3 years than those with no BPD. BPD with chronic oxygen dependency may lead to an increased use of health resources in the NICU and after discharge.28,29 The rate of rehospitalization of premature infants with BPD has been reported to 15% in first year and 25–40% in the second year of life.19,30 However, in our study, rehospitalization rate (41 admission) was low compared with the earlier study19 and there were similar rates of readmission at 4, 8 and 18 months of age, among the three groups of infants. (Table 4A). Infants in the BPD with chronic oxygen dependency group needed more respiratory medications and supplemental oxygen use since discharge, last clinic visit or in the last year at 4, 8 and 18 months of age, respectively. This finding signifies that infants with BPD with chronic oxygen dependency do require close follow-up with their family physicians or pediatrician to avoid respiratory morbidities and readmission in the hospital, as well as parental anxiety, owing to respiratory problems. To our knowledge, our study is the largest single-center, longitudinal cohort study that followed infants prospectively from NICU discharge to determine the impact of chronic oxygen dependency on long-term respiratory outcomes. However, this study has some limitations. The NICHD’s new definitions of BPD related to fraction of inspired oxygen at various time points could not be applied retrospectively. We used a definition that was consistent with that used by the majority of Canadian Neonatal Network centers. During our study period of 1997–2007, significant changes occurred in the medical management of infants in the NICU. These included changes in ventilation practices, with most centers moving towards increased use of nasal continuous positive airway pressure and non-invasive positive pressure ventilation, patient triggered ventilation and high-frequency oscillation. There was also increased use of antenatal steroids, early parental nutrition and use of caffeine before extubation. There was also a move to a more restrictive use of blood transfusions and post-natal steroids. Since 2001, however, our Journal of Perinatology (2015), 1 – 7
Journal of Perinatology (2015), 1 – 7 n = 138/144 2 (1%) 21 (15%) 24 (18%) 10 (7%) 19/135 (14%) n = 142/144 43/125 (34%) 4 (3%) 36 (25%) 27 (19%) 9 (6%) 13/140 (9%) n = 142/144 37/129 (29%) 3 (2%) 46 (33%) 34 (24%) 2 (1%)
n = 424/442 6 (1%) 63 (15%) 76 (18%) 19 (4%) 28/415 (7%) n = 405/442 72/361 (20%) 3 (1%) 102 (25%) 61 (15%) 10 (2%) 22/390 (6%) n = 433/442 103/317 (28%) 2 (0.5%) 148 (35%) 100 (23%) 4 (1%)
4 months 41 Hospitalization for LRTI since discharge, no. (%) Antibiotic use since discharge,c no. (%) Respiratory medications since discharge, no. (%) Oxygen use since discharge, no. (%) PNCLD at 4 m months, no. (%)
8 months 43 Doctor visits between 4–8 months visit, no. (%) 41 Hospitalization for LRTI between 4–8 months, no. (%) Antibiotic use between 4–8 months,c no. (%) Respiratory medications between 4–8 months, no. (%) Oxygen use between 4–8 months, no. (%) PNCLD at 8 months, no. (%)
18 months 43 Doctor visits during past year, no. (%) 41 Hospitalization for LRTI during past year, no. (%) Antibiotic use in the past 12 months,c no. (%) Respiratory medications in the past 12 months, no. (%) Oxygen use in the past 12 months, no. (%)
n = 437/444 150/362 (41%) 10 (2%) 158 (37%) 174 (40%) 71 (16%)
n = 427/444 132/361 (37%) 11 (3%) 109 (26%) 145 (34%) 189 (44%) 128/413 (31%)
n = 432/444 13 (3%) 74 (17%) 126 (29%) 422 (98%) 222/419 (53%)
BPD with chronic oxygen dependency (n = 444)
o0.001 0.066 0.651 o0.001 o0.001
o0.001 0.095 0.994 o0.001 o0.001 o0.001
0.224 0.657 o0.001 o0.001 o0.001
P-valuea
(−0.12 (−0.05 (−0.09 (−0.11 (−0.03
to to to to to
0.10) 0.01) 0.13) 0.09) 0.02)
(−0.26 to − 0.03) (−0.06 to 0.01) (−0.10 to 0.10) (−0.13 to 0.05) (−0.09 to 0.01) (−0.10 to 0.03)
(−0.03 to 0.03) (−0.09 to 0.08) (−0.09 to 0.09) (−0.09 to 0.03) (−0.15 to 0.004)
No BPD vs BPD
(−0.22 to − 0.05) (−0.04 to 0.001) (−0.10 to 0.06) (−0.24 to − 0.10) (−0.20 to − 0.11)
(−0.25 to − 0.09) (−0.04 to 0.003) (−0.08 to 0.07) (−0.26 to − 0.12) (−0.48 to − 0.36) (−0.31 to − 0.19)
(−0.04 to 0.01) (−0.08 to 0.04) (−0.18 to − 0.04) (−0.96 to − 0.90) (−0.53 to − 0.40)
No BPD vs BPD with chronic oxygen dependency
Confidence intervals for pairwise differencesb
(−0.24 to − 0.01) (−0.04 to 0.03) (−0.15 to 0.07) (−0.26 to − 0.06) (−0.20 to − 0.10)
(−0.14 to 0.10) (−0.04 to 0.04) (−0.10 to 0.10) (−0.25 to − 0.05) (−0.46 to − 0.30) (−0.30 to − 0.14)
(−0.05 to 0.02) (−0.10 to 0.07) (−0.21 to − 0.02) (−0.96 to − 0.85) (−0.48 to − 0.30)
BPD vs BPD with chronic oxygen dependency
55 (39.3) 40 (28.6) 1 (0.7) 16 (11.4)
143 (33.3) 86 (20.0) 5 (0.9) 24 (5.8)
41 (9.5) 76 (18.2)
171 (39.7) 181 (42.0)
114 (31.4) 7 (1.6)
BPD with chronic oxygen dependency (n = 439/444)
(−0.14 to 0.01) (−0.29 to − 0.15) (−0.12 to − 0.05) (−0.18 to − 0.07)
0.121 (−0.17 to 0.05) o0.001 (−0.19 to 0.02) o0.001 (−0.02 to 0.02) o0.001 (−0.13 to 0.01)
(−0.17 to − 0.02) (−0.03 to 0.01)
(−0.13 to − 0.05) (−0.15 to 0.01)
(−0.12 to 0.11) (−0.24 to − 0.03)
(−0.14 to 0.09) (−0.03 to − 0.002)
BPD vs BPD with chronic oxygen dependency
Confidence intervals for pairwise differencesb No BPD vs BPD No BPD vs BPD with Chronic oxygen dependency 0.012 (−0.18 to 0.04) 0.282 (−0.002 to 0.02)
P-valuea
Abbreviations: BPD, bronchopulmonary dysplasia, LRTI, lower respiratory tract infection; no., number; PNCLD, post-neonatal chronic lung disease. aPearson χ2-test or Fisher’s exact test. bBonferroni correction applied to adjust for the three pairwise comparisons, thus confidence intervals are reported at the (1–0.05/3)% level. cExcludes prophylactic use of antibiotics.
35 (28.7) 0 (0.0)
BPD (n = 142/144)
82 (21.9) 4 (0.9)
No BPD (n = 439/442)
Respiratory outcomes at 36 months corrected age
43 Doctor visits during past year, no. (%) 41 Hospitalization for LRTI during past year, no. (%) Antibiotic use in the past 12 months,c no. (%) Respiratory medications in the past 12 months, no. (%) Oxygen use in the past 12 months, no. (%) PNCLD at 3 years, no. (%)
Table 4B.
Abbreviations: BPD, bronchopulmonary dysplasia, LRTI, lower respiratory tract infection; no., number; PNCLD, post-neonatal chronic lung disease. Note: Doctor visits at 4 months not reported due to 40% missing data; PNCLD data at 18 months not available as not seen by physician at that time point. aPearson χ2 test or Fisher’s exact test. bBonferroni correction applied to adjust for the three pairwise comparisons, thus confidence intervals are reported at the (1–0.05/3)% level. cExcludes prophylactic use of antibiotics.
BPD (n = 144)
Respiratory outcomes at 4, 8 and 18 months corrected age No BPD (n = 442)
Table 4A.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
6
© 2015 Nature America, Inc.
Outcomes of BPD with O2 dependency at 3 years A Lodha et al
7 criteria for discharge home on oxygen have remained unchanged. We did not have data about respiratory syncytial virus prophylaxis and cannot comment on the temporal sequence of changes in clinical practice that could potentially have impacted on our results owing to the fact that some of these changes in practice were overlapping with birth years and may have taken variable duration to be completely adopted by the attending physicians. The impact of our loss to follow-up is unknown, although we believe that as the infants lost to follow-up were not significantly different in patient demographics, our results would not be affected in a significant manner. Generalizability of our results may be most useful to centers located at high altitude and less applicable to units located at sea level. In conclusion, in a longitudinal follow-up study, use of respiratory medications and supplemental oxygen were both significantly higher in the BPD with chronic oxygen dependency infants, compared with the no-BPD group and the BPD group, at 4, 8 and 18 months. Similarly, at 36 months, children diagnosed with BPD with chronic oxygen dependency were more likely to need respiratory medications and supplemental oxygen as compared with the no-BPD or BPD groups. They were also more likely to require frequent physician visits and have PNCLD at 3 years, compared with those with no BPD. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Vohr BR, Wright LL, Dusick AM, Perritt R, Poole WK, Tyson JE et al. Center differences and outcomes of extremely low birth weight infants. Pediatrics 2004; 113: 781–789. 2 Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82: 527–532. 3 Chess PR, D'Angio CT, Pryhuber GS, Maniscalco WM. Pathogenesis of bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 171–178. 4 Koumbourlis AC, Motoyama EK, Mutich RL, Mallory GB, Walczak SA, Fertal K. Longitudinal follow-up of lung function from childhood to adolescence in prematurely born patients with neonatal chronic lung disease. Pediatr Pulmonol 1996; 21: 28–34. 5 Smith LJ, van Asperen PP, McKay KO, Selvadurai H, Fitzgerald DA. Reduced exercise capacity in children born very preterm. Pediatrics 2008; 122: e287–e293. 6 Carraro S, Filippone M, Da Dalt L, Ferraro V, Maretti M, Bressan S et al. Bronchopulmonary dysplasia: the earliest and perhaps the longest lasting obstructive lung disease in humans. Early Hum Dev 2013; 89(Suppl 3): S3–S5. 7 Lodha A, Sauve R, Bhandari V, Tang S, Christianson H, Bhandari A et al. Need for supplemental oxygen at discharge in infants with bronchopulmonary dysplasia is not associated with worse neurodevelopmental outcomes at 3 years corrected age. PLoS One 2014; 9: e90843. 8 Lodha A, Zhu Q, Lee SK, Shah PS. Canadian Neonatal Network Neonatal outcomes of preterm infants in breech presentation according to mode of birth in Canadian NICUs. Postgrad Med J 2011; 87: 175–179.
© 2015 Nature America, Inc.
9 CNN (2014). The Canadian Neonatal Network annual report 2013 [online]. Available at http://www.canadianneonatalnetwork.org/portal/. 10 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: 529–534. 11 An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. Pediatrics 1984; 74: 127–133. 12 Lee SK, Ye XY, Singhal N, De La Rue S, Lodha A, Shah PS. Higher altitude and risk of bronchopulmonary dysplasia among preterm infants. Am J Perinatol 2012; 30: 601–606. 13 Bhandari A, McGrath-Morrow S. Long-term pulmonary outcomes of patients with bronchopulmonary dysplasia. Semin Perinatol 2013; 37: 132–137. 14 Tapia JL, Agost D, Alegria A, Standen J, Escobar M, Grandi C et al. Bronchopulmonary dysplasia: incidence, risk factors and resource utilization in a population of South American very low birth weight infants. J Pediatr (Rio J) 2006; 82: 15–20. 15 Johnson TJ, Patel AL, Jegier BJ, Engstrom JL, Meier PP. Cost of morbidities in very low birth weight infants. J Pediatr 2013; 162: 243–249 e241. 16 Qiu X, Lodha A, Shah PS, Sankaran K, Seshia MM, Yee W et al. Neonatal outcomes of small for gestational age preterm infants in Canada. Am J Perinatol 2012; 29: 87–94. 17 Stroustrup A, Trasande L. Epidemiological characteristics and resource use in neonates with bronchopulmonary dysplasia: 1993-2006. Pediatrics 2010; 126: 291–297. 18 Heron M, Sutton PD, Xu J, Ventura SJ, Strobino DM, Guyer B. Annual summary of vital statistics: 2007. Pediatrics 2010; 125: 4–15. 19 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116: 1353–1360. 20 Bhandari A, Bhandari V. Pitfalls, problems, and progress in bronchopulmonary dysplasia. Pediatrics 2009; 123: 1562–1573. 21 Gien J, Kinsella JP. Pathogenesis and treatment of bronchopulmonary dysplasia. Curr Opin Pediatr 2011; 23: 305–313. 22 Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet 2006; 367: 1421–1431. 23 Doyle LW, Casalaz D. Victorian Infant Collaborative Study Group Outcome at 14 years of extremely low birthweight infants: a regional study. Arch Dis Child Fetal Neonatal Ed 2001; 85: F159–F164. 24 Lista G, Castoldi F, Bianchi S, Lupo E, Cavigioli F, Farolfi A et al. Lung function and respiratory health at school age in ventilated very low birth weight infants. Indian J Pediatr 2014; 81: 275–278. 25 Anand D, Stevenson CJ, West CR, Pharoah PO. Lung function and respiratory health in adolescents of very low birth weight. Arch Dis Child 2003; 88: 135–138. 26 Hennessy EM, Bracewell MA, Wood N, Wolke D, Costeloe K, Gibson A et al. Respiratory health in pre-school and school age children following extremely preterm birth. Arch Dis Child 2008; 93: 1037–1043. 27 Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V et al. Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am J Respir Crit Care Med 2010; 182: 237–245. 28 Greenough A, Alexander J, Boorman J, Chetcuti PA, Cliff I, Lenney W et al. Respiratory morbidity, healthcare utilisation and cost of care at school age related to home oxygen status. Eur J Pediatr 2011; 170: 969–975. 29 Landry JS, Croitoru D, Jin Y, Schwartzman K, Benedetti A, Menzies D. Health care utilization by preterm infants with respiratory complications in Quebec. Can Respir J 2012; 19: 255–260. 30 Underwood MA, Danielsen B, Gilbert WM. Cost, causes and rates of rehospitalization of preterm infants. J Perinatol 2007; 27: 614–619.
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