Abstract
OBJECTIVES:
To describe the characteristics of bronchopulmonary dysplasia (BPD) and respiratory distress syndrome subjects, along with the trends in severity and mortality associated with BPD over the past three decades.
METHODS:
Retrospective study of BPD and respiratory distress syndrome subjects born between 1980 and 2008, and admitted to Montreal Children’s Hospital (Montreal, Quebec). Data were abstracted from hospital records.
RESULTS:
Gestational age and birth weight were correlated with the occurrence of BPD with each additional week of gestation and 100 g in birth weight being associated with an OR of developing BPD of 0.77 and 0.89, respectively. BPD severity was associated with male sex, Apgar score and the occurrence of neonatal pneumonia. Significant trends were observed for lower mortality despite lower gestational age and birth weight, greater maternal age and multiple gestations.
CONCLUSION:
Mortality from BPD has improved over the past three decades despite significant trends toward more pronounced prematurity and lower birth weights.
Keywords: Bronchopulmonary dysplasia, Infant respiratory distress syndrome, Preterm birth
Abstract
OBJECTIF :
Décrire les caractéristiques des sujets atteints de la dysplasie bronchopulmonaire (DBP) et du syndrome de détresse respiratoire, de même que les tendances quant à la gravité de la DBP et à la mortalité s’y rapportant depuis 30 ans.
MÉTHODOLOGIE :
Les chercheurs ont mené une étude rétrospective des sujets atteints de la DBP et du syndrome de détresse respiratoire nés entre 1980 et 2008 et hospitalisés à L’Hôpital de Montréal pour enfants, au Québec. Ils ont tiré les données des dossiers hospitaliers.
RÉSULTATS :
Les chercheurs ont corrélé l’âge gestationnel et le poids de naissance avec l’occurrence de DBP, chaque nouvelle semaine de grossesse et nouvelle tranche de 100 g de poids de naissance s’associant à un RRR de DBP de 0,77 et de 0,89, respectivement. La gravité de la DBP s’associait au sexe masculin, à l’indice d’Apgar et à l’occurrence d’une pneumonie néonatale. Les chercheurs ont observé des tendances importantes de diminution de la mortalité malgré un âge gestationnel et un poids de naissance moins élevés, l’âge plus avancé des mères et des gestations multiples.
CONCLUSION :
La mortalité liée à la DBP a diminué depuis 30 ans, malgré des tendances importantes vers une prématurité plus prononcée et un plus petit poids à la naissance.
Preterm birth has been an under-recognized global health issue, partly because of scarce data on the extent of the problem. In 2005, it was estimated that 13 million preterm babies were born worldwide, with North America’s rates of prematurity being second only to Africa (1). The number of babies born prematurely, defined as a gestational age <37 weeks, is also increasing. In Canada and the United States, rates have risen by approximately 35% in the past 25 years. This progression is believed to be due in part to the increasing use of assisted reproduction and advancing maternal age at first delivery (1). In the Western world, preterm birth has become an important cause of infant mortality. Worldwide, more than one million infants die annually from complications of prematurity. Survivors suffer more frequently from cerebral palsy, chronic lung disease, blindness and hearing loss (1), all of which places a substantial burden on the health care system.
Infant respiratory distress syndrome (RDS) is the most common respiratory disorder affecting preterm infants. It begins shortly after birth and manifests itself through tachypnea, hypoxia, increased work of breathing and a characteristic chest radiograph. The primary abnormality in RDS is surfactant deficiency caused by lung immaturity. Frequently, infants with RDS may develop respiratory failure requiring supplemental oxygen and mechanical ventilation. This more severe form of RDS is considered to be a risk factor for bronchopulmonary dysplasia (BPD) (2–4). RDS occurs in approximately 7% of all preterm infants, with an incidence that increases with decreasing gestational age (5). The incidence may reach up to 93% in extremely preterm infants, defined as a gestational age <28 weeks (6). Despite advances in care, RDS remains the single most common cause of death in the first month of life in the developed world (5).
BPD is a chronic lung disease, which most commonly occurs in preterm, low birth weight infants who require mechanical ventilation and oxygen therapy, although it can also occur in infants born at term who require aggressive ventilatory support for severe, acute lung disease (7–9). It can be considered a disorder of lung development, characterized by disruption in the septation of the alveoli and alveolar hypoplasia leading to fewer, larger alveoli and, therefore, a decreased surface area available for gas exchange. The overall incidence of BPD at birth is believed to have remained constant over the past three decades (10), but its pathophysiology and presentation have been modulated by changes in clinical practice, such as lung protective ventilation strategies, antenatal glucocorticosteroids and surfactant therapy (2,11,12). There used to be a striking lack of uniformity in the diagnostic criteria for BPD among clinicians and in the medical literature (13). The first proposed criteria to define BPD included a continued oxygen dependency beyond the first 28 days, in addition to compatible clinical and radiological changes (8). These criteria were appropriate for the classic presentation of BPD but, with time, were believed to lack sensitivity and specificity in identifying the ‘new’ BPD cases seen in smaller and more premature infants. To improve the definition, it was proposed to use the need for supplemental oxygen at 36 weeks’ postmenstrual age as a better, more adequate criterion for BPD (14). This definition was viewed as more specific for identifying infants with more severe lung disease and, therefore, better at predicting long-term outcomes (15,16). The definition and severity of BPD were further refined at a National Institutes of Health (NIH) workshop in 2000 where a uniform definition was proposed, which used the need for ≥28 days of supplemental oxygen and a severity assessment date at 36 weeks’ postmenstrual age (17).
Despite notable advances in prenatal and neonatal care, RDS and BPD remain important complications of preterm births, frequently resulting in mortality as well as short- and long-term morbidities. The present study aimed to describe the characteristics of BPD and RDS subjects, along with the trends in severity and mortality of BPD over the past three decades in a tertiary paediatric hospital in Quebec.
METHODS
Subjects
The study population included all preterm infants, defined as a gestational age of <37 weeks, who were admitted between January 1, 1980 and December 31, 1992 and January 1, 1995 and December 31, 2008, and carried a discharge diagnosis of either RDS or BPD at the Montreal Children’s Hospital (Montreal, Quebec). All subjects included in the BPD group had their diagnoses of BPD confirmed using the NIH consensus definition (17). The Montreal Children’s Hospital is a tertiary paediatric hospital with specialized neonatal care that serves as a referral centre for the province of Quebec. All study subjects were transferred to this institution following a premature birth. Data were abstracted from hospital records, using a standardized data collection sheet. Information collected included demographic data, maternal, prenatal, delivery and main neonatal outcomes. Less than 2% of the data on gestational age or birth weight and only 8.4% of the criteria needed to establish BPD severity according to the NIH-consensus definition (17) were missing. Subjects admitted in 1993 and 1994 were not included in the chart review because a clinical trial involving artificial pulmonary surfactant was being conducted and could have affected the primary end points analyzed in the current study. The study was approved by the research ethics board of the McGill University Health Centre (Montreal, Quebec).
Definitions
BPD is a chronic lung disorder common among premature infants. Only subjects who fit the NIH consensus definition were included in the BPD group (17,18). BPD severity was graded based on an assessment performed at 36 weeks’ postmenstrual age (or 56 days of life if born after 32 weeks). Mild disease was defined as breathing room air, moderate disease as requiring supplemental oxygen, with a fraction of inspired oxygen <0.30, and severe disease was defined as requiring supplemental oxygen with a fraction of inspired oxygen ≥0.30, or requiring positive pressure ventilation. Infants with BPD who died of respiratory causes before the assessment date were considered to have severe disease.
Neonatal pneumonia was defined as the presence of pneumonia confirmed by chest radiograph that occurred in the first 28 days of life (19). Due to the interest in BPD severity, the episode of pneumonia had to occur before the assessment date for establishing the diagnosis of BPD.
Because clinical factors associated with pulmonary complications were of interest in the present study, only pneumothoraces that occurred within the first 48 h of life and confirmed by chest radiograph were tabulated to minimize the confounding effect of mechanical ventilation on the incidence of pneumothorax.
Statistical analyses
To assess neonatal, maternal and perinatal characteristics associated with development of RDS or BPD, all preterm infants were grouped into two categories: preterm with RDS and no subsequent diagnosis of BPD; and preterm with BPD (with or without preceding RDS). Differences between groups were tested using one-way ANOVA or Student’s t tests for continuous variables (eg, birth weight, gestational age, Apgar score, length of stay and maternal age), and Mantel-Haenszel χ2 tests (20) for ordinal variables. Risk factors associated with the occurrence and the severity of BPD were examined using univariate and multivariate logistic regression on maternal and neonatal variables and on clinical variables present in the first 28 days of life. For multivariable analyses, variables that were significantly associated with the outcome in univariate analyses were initially included, using a cut-off for significance set at P≤0.05 (20,21). To assess factors associated with severity of BPD, infants with BPD were categorized as mild, moderate or severe, using the NIH consensus criteria. To allow for the analyses of trends from 1980 to 2008, Poisson regression models were used to calculate P and coefficients of determination (R2) were calculated for continuous variables and categorical variables, respectively, using mean values and rate of events for each given birth year. Statistical analyses were conducted using SAS version 9.2 (SAS Institute Inc, USA).
RESULTS
During the study period, 2233 preterm subjects with respiratory complications consisting of either RDS or BPD were discharged from the Montreal Children’s Hospital. Characteristics of the study population are listed in Table 1. Male infants outnumbered their female counterparts in each of the two groups, and mean gestational age and birth weight were significantly lower in the BPD subjects compared with the RDS group. This was further reflected in the discrepancy observed in the prevalence of prematurity-related complications, such as apnea of prematurity, patent ductus arteriosus and necrotizing enterocolitis between the BPD and RDS groups. Table 2 illustrates the changes observed over time with regard to the use of antenatal steroids, pulmonary surfactant and mechanical ventilation in BPD subjects.
TABLE 1.
Characteristics of the study subjects
| RDS subjects without subsequent BPD | BPD subjects | P | |
|---|---|---|---|
| Perinatal characteristics | |||
| Total cases | 1427 (63.9) | 806 (36.1) | – |
| Birth weight, kg, mean ± SD | 2.10±0.73 | 1.02±0.46 | <0.0001 |
| Gestational age, days, mean ± SD | 233.2±23.1 | 191.3±20.6 | <0.0001 |
| Male sex | 908 (63.6) | 476 (59.1) | 0.03 |
| One-minute Apgar score, mean ± SD | 6.1±2.6 | 4.3±2.3 | <0.0001 |
| Length of hospital stay, days, median | 13.6 | 115.9 | <0.0001 |
| Maternal or antenatal characteristics | |||
| Maternal age, years, mean ± SD | 27.3±5.6 | 28.8±6.2 | 0.09 |
| Twin or multiple births | 197 (13.8) | 176 (21.4) | <0.0001 |
| Delivery by Caesarean section | 570 (39.8) | 377 (46.6) | 0.001 |
| Other diagnoses associated with preterm births | |||
| Neonatal pneumonia | 226 (15.8) | 306 (37.8) | <0.0001 |
| Patent ductus arteriosus | 218 (15.2) | 521 (64.5) | <0.0001 |
| Apnea of prematurity | 334(23.3) | 395 (48.8) | <0.0001 |
| Pneumothorax | 164 (11.5) | 118 (14.6) | 0.03 |
| Necrotizing enterocolitis | 100 (6.9) | 149 (18.4) | <0.0001 |
Data expressed as n (%) unless otherwise indicated. BPD Bronchopulmonary dysplasia; RDS Infant respiratory distress syndrome
TABLE 2.
Comparisons of bronchopulmonary dysplasia (BDP) subjects, between the time periods from 1980 to 1992 and 1995 to 2008
| BPD subjects born between 1980 and 1992 | BPD subjects born between 1995 and 2008 | P | |
|---|---|---|---|
| Total cases, n | 322 | 484 | – |
| Male sex | 190 (59.0) | 288 (59.5) | 0.85 |
| Gestational age, days, mean ± SD | 196.41±22.3 | 188.01±18.64 | <0.0001 |
| Birth weight, kg, mean ± SD | 1.13±0.52 | 0.95±0.41 | <0.0001 |
| One minute Apgar score, mean ± SD | 4.05±2.35 | 4.47±2.29 | 0.02 |
| Mortality | 53 (16.5) | 62 (12.8) | 0.02 |
| Use of antenatal steroids | 95 (29.5) | 306 (63.2) | <0.0001 |
| Use of pulmonary surfactant for treatment of RDS | 29 (9.0) | 316 (65.3) | <0.0001 |
| Invasive mechanical ventilation | |||
| Use of mechanical ventilation | 302 (93.8) | 472 (97.5) | 0.42 |
| Maximal pressure, cmH2O, mean ± SD | 21.86±7.64 | 17.02±4.34 | <0.0001 |
| PEEP, cmH2O, mean ± SD | 4.37±1.7 | 4.86±0.85 | <0.0001 |
| Maximal FiO2, mean ± SD | 0.84±0.23 | 0.90±0.19 | 0.03 |
| Duration of mechanical ventilation, days, median | 42 | 43 | 0.17 |
| Noninvasive positive pressure ventilation (NIV) | |||
| Use of NIV | 123 (38.2) | 348 (71.9) | <0.0001 |
| De novo* NIV | 12 (3.7) | 60 (12.4) | <0.0001 |
| Maximal pressure, cmH2O, mean ± SD | 4.81±1.4 | 8.0±1.0 | 0.0002 |
| Duration of NIV, days, median | 4.0 | 4.5 | 0.10 |
| Supplemental O2 therapy following mechanical ventilation | |||
| Use of O2 | 245 (76.1) | 413 (85.3) | 0.005 |
| Duration of O2 supplementation, days, median | 55 | 42 | 0.49 |
| Discharged home on supplemental O2 | 63 (19.6) | 120 (24.8) | <0.0001 |
Data presented as n (%) unless otherwise indicated.
de novo NIV is defined as the need for NIV without previous need for invasive mechanical ventilation. FiO2 Fraction of inspired oxygen; PEEP Positive end-expiratory pressure; RDS Infant respiratory distress syndrome
Table 3 illustrates the unadjusted and adjusted ORs for the development of BPD following a preterm birth complicated by RDS. Gestational age and birth weight were significantly associated with the occurrence of BPD, with each additional week of gestation and each additional 100 g in birth weight associated with ORs of developing BPD of 0.77 and 0.89, respectively. Male sex, maternal age, multiple gestation, delivery by Caesarean section and the administration of pulmonary surfactant for the treatment of RDS did not remain significantly associated with the development of BPD after adjustments (for sex, gestational age, birth weight, maternal age, patent ductus arteriosus, neonatal pneumonia, pneumothorax within the first 48 h, Apgar scores, type of delivery, multiple gestation and year of birth). The presence of a patent ductus arteriosus, the occurrence of a pneumothorax within 48 h of birth and neonatal pneumonia were associated with the development of BPD.
TABLE 3.
Association of perinatal and maternal factors with the occurrence of bronchopulmonary dysplasia (BDP) after a premature birth complicated by respiratory distress syndrome (RDS)
| OR for BPD | Adjusted* OR for BPD | |
|---|---|---|
| Male sex | 1.21 (1.02–1.45) | n/s |
| Gestational age | 0.62/week (0.60–0.64) | 0.77/week (0.71–0.984) |
| Birth weight | 0.76/100 g (0.74–0.78) | 0.89/100 g (0.86–0.94) |
| Maternal age | 1.04/year (1.03–1.06) | n/s |
| Multiple gestation | 1.69 (1.39–2.06) | n/s |
| Pneumothorax | 1.32 (1.03–1.71) | 1.92 (1.15–3.23) |
| Patent ductus arteriosus | 10.1 (8.26–12.35) | 3.36 (2.38–4.74) |
| Neonatal pneumonia | 3.25 (2.65–3.97) | 2.07 (1.42–3.03) |
| Apgar score at one minute | 0.76/point (0.73–0.79) | 0.84/point (0.76–0.932) |
| Use of pulmonary surfactants for treatment of RDS | 0.29 (0.24–0.35) | n/s |
| Delivery by Caesarean section | 1.3 (1.1–1.6) | n/s |
Data presented as OR (95% CI).
Adjusted for sex, gestational age, birth weight, maternal age, presence of patent ductus arteriosus, occurrence of neonatal pneumonia and/or pneumothorax within the first 48 h of birth, Apgar scores at one and five minutes, mean of delivery, multiple gestation and year of birth. n/s Not significant; RDS Infant respiratory distress syndrome
Once it occurred, the severity of BPD was associated with male sex, the Apgar score at one minute and the occurrence of neonatal pneumonia in the first 28 days of life (Table 4). Each additional 100 g in birth weight was associated with an OR of 0.88 for a more severe form of BPD. The use of pulmonary surfactant for the treatment of RDS, the type of delivery and the extent of the prematurity did not influence the severity of BPD once adjusted.
TABLE 4.
Association of perinatal and maternal factors with the severity of bronchopulmonary dysplasia (BPD)
| OR for more severe BPD | Adjusted* OR for more severe BPD | |
|---|---|---|
| Birth weight | 0.96/100 g (0.94–0.99) | 0.88/100g (0.84–0.93) |
| Gestational age | 0.99/week (0.95–1.04) | – |
| Multiple gestation | 0.87 (0.67–1.14) | – |
| Maternal age | 0.99/year (0.97–1.02) | – |
| Apgar score at one minute | 0.87/point (0.82–0.93) | 0.87/point (0.79–0.96) |
| Male sex | 1.36 (1.03–1.78) | 1.51 (1.14–2.0) |
| Patent ductus arteriosus | 1.04 (0.79–1.38) | – |
| Pneumothorax | 1.54 (1.06–2.24) | n/s |
| Neonatal pneumonia | 1.66 (1.26–2.20) | 1.49 (1.11–2.01) |
| Use of pulmonary surfactant for treatment of RDS | 1.10 (0.83–1.43) | – |
| Delivery by Caesarean section | 1.11 (0.84–1.48) | – |
Data presented as OR (95% CI).
Adjusted for sex, gestational age, birth weight, occurrence of neonatal pneumonia and/or pneumothorax within the first 48 h of birth, Apgar scores at one and five minutes, pulmonary surfactant administration and year of birth. n/s= Not significant; RDS Infant respiratory distress syndrome
Figure 1 shows the trends in gestational age, birth weight, maternal age and multiple gestations in BPD and RDS subjects over the past three decades. It shows a significant progression in the proportion of multiple gestations in mothers of BPD subjects (P=0.02), along with an increase in maternal age of both RDS (P<0.0001) and BPD (P<0.0001) subjects over the years. More pronounced prematurity (P<0.0001) and lower birth weights (P=0.012) were also observed in BPD subjects, a finding not observed in the RDS group. Despite the overall increase in the number of BPD cases observed, the proportion of mild, moderate and severe BPD did not change over time, but a tendency to lower mortality before hospital discharge was observed in BPD subjects (R2=0.2094) (Figure 2). This trend for a lower mortality was statistically significant (P=0.03).
Figure 1).
Trends in multiple gestation, maternal age, gestational age and birth weight in bronchopulmonary dysplasia (BDP) and respiratory distress syndrome (RDS) subjects over the past three decades
Figure 2).
Trends in bronchopulmonary dysplasia (BPD) severity and mortality among preterm infants with respiratory distress syndrome (RDS) over the past three decades
DISCUSSION
The study population was comparable with previously published preterm cohorts with regard to clinical characteristics (22,23). The finding of male sex being a risk factor for respiratory complications following a preterm birth was also previously reported (24), but its association with subsequent disease severity, once adjusted for gestational age and birth weight, had not been shown previously (25).
Based on previous studies, pulmonary surfactant replacement therapy was not believed to have altered the incidence of BPD since its routine introduction into clinical practice (26–28). Similar findings were revealed in the present study, where no influence on either the occurrence of BPD or its subsequent severity was demonstrated with the introduction of the routine use of pulmonary surfactant, although this may simply reflect the phenomenon that very preterm infants who may not have survived without surfactant replacement therapy are now surviving, only to subsequently develop BPD.
Over the past 20 years, Canada has witnessed a substantial increase in the proportion of first births occurring among women older than 35 years of age. In 1987, this demographic represented only 4% of such births; however, by 2005, the rate had nearly tripled to 11% (29,30). Preterm birth and low birth weight have been clearly associated with increased maternal age (31). This trend was also shown in the present study, but it is reassuring to observe that the increase in maternal age, despite being associated with more frequent preterm birth, does not have an additional impact on the occurrence of BPD or its subsequent severity, when accounting for gestational age and birth weight. A similar observation was seen with multiple gestation which, while being a risk factor for preterm birth, does not further increase the odds for BDP once adjusted for the degree of prematurity and birth weight. Maternal age has also been associated with improved odds of surviving without major morbidity (increased by 5% as maternal age increased by five years), and improved mortality (8% as maternal age increased by five years) (32).
The trend analyses of the data clearly shows a progression in the degree of prematurity and a progression in lower birth weight being observed in infants born over the past 30 years. This is counterbalanced by the observation of a decrease in the mortality in this cohort, despite a low correlation coefficient resulting from high variations and inhomogeneity of the data. This improvement in mortality had been previously documented in BPD subjects born in 1996 and 2007 (unadjusted OR 0.68 [0.50 to 0.98]), but after adjustment, no improvement in the mortality or the severity of the disease was observed (33).
One limitation of the present study was the missing data for infants born between 1993 and 1994. We wanted to avoid sampling this period because of changes in clinical practice with the introduction of widespread use of pulmonary surfactant as part of clinical trials during this period of time. This only constitutes a small proportion of the total duration of sampling and likely does not result in any significant bias. Sampling from a single referral centre where sicker infants are transferred for subspecialty care could have also introduced a bias toward a sicker population of preterm infants. This was not reflected in the decreased mortality rate or in the stability of BPD severity over the years but could have resulted in an underestimation of the real improvement in survival rate following a preterm birth complicated by BPD. Missing data from the medical charts reviewed and the retrospective design of the study are also among the limitations of the present study and may have affected our observations, although the rate of missing data was low and considered to be acceptable and not likely to be the source of a major bias. The design of the study did not allow the detection of a change in the referring pattern of preterm infants to a tertiary centre.
CONCLUSION
The mortality rate of infants with BPD has improved over the past three decades despite a significant trend toward more pronounced prematurity, lower birth weights, more advanced maternal age and multiple gestation. Despite these factors and the introduction of routine use of pulmonary surfactant, the proportion of the various levels of BPD severity, from mild, moderate to severe, has remained unchanged.
Acknowledgments
The authors acknowledge the help and support of Tony Sonnylal, medical archivist at the Montreal Children’s Hospital, and Linda M Karpowicz for critical revisions of the manuscript. This research was funded by a grant from the Réseau en santé respiratoire – Fonds de la recherche en santé du Québec.
REFERENCES
- 1.March of Dimes White paper on preterm birth, the global and regional toll. White Plains: March of Dimes Foundation; 2009. [Google Scholar]
- 2.Bancalari E, Claure N, Sosenko IR. Bronchopulmonary dysplasia: Changes in pathogenesis, epidemiology and definition. Semin Neonatol. 2003;8:63–71. doi: 10.1016/s1084-2756(02)00192-6. [DOI] [PubMed] [Google Scholar]
- 3.Chess PR, D’Angio CT, Pryhuber GS, Maniscalco WM. Pathogenesis of bronchopulmonary dysplasia. Semin Perinatol. 2006;30:171–8. doi: 10.1053/j.semperi.2006.05.003. [DOI] [PubMed] [Google Scholar]
- 4.Aly H. Respiratory disorders in the newborn: Identification and diagnosis. Pediatr Rev. 2004;25:201–8. doi: 10.1542/pir.25-6-201. [DOI] [PubMed] [Google Scholar]
- 5.Hermansen CL, Lorah KN. Respiratory distress in the newborn. Am Fam Physician. 2007;76:987–94. [PubMed] [Google Scholar]
- 6.McElrath TF, Colon I, Hecht J, Tanasijevic MJ, Norwitz ER. Neonatal respiratory distress syndrome as a function of gestational age and an assay for surfactant-to-albumin ratio. Obstet Gynecol. 2004;103:463–8. doi: 10.1097/01.AOG.0000113622.82144.73. [DOI] [PubMed] [Google Scholar]
- 7.Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet. 2006;367:1421–31. doi: 10.1016/S0140-6736(06)68615-7. [DOI] [PubMed] [Google Scholar]
- 8.Bancalari E, Abdenour GE, Feller R, Gannon J. Bronchopulmonary dysplasia: Clinical presentation. J Pediatr. 1979;95:819–23. doi: 10.1016/s0022-3476(79)80442-4. [DOI] [PubMed] [Google Scholar]
- 9.Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med. 2007;357:1946–55. doi: 10.1056/NEJMra067279. [DOI] [PubMed] [Google Scholar]
- 10.Smith VC, Zupancic JA, McCormick MC, et al. Trends in severe bronchopulmonary dysplasia rates between 1994 and 2002. J Pediatr. 2005;146:469–73. doi: 10.1016/j.jpeds.2004.12.023. [DOI] [PubMed] [Google Scholar]
- 11.Manktelow BN, Draper ES, Annamalai S, Field D. Factors affecting the incidence of chronic lung disease of prematurity in 1987, 1992, and 1997. Arch Dis Child Fetal Neonatal Ed. 2001;85:F33–5. doi: 10.1136/fn.85.1.F33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Baraldi E, Carraro S, Filippone M. Bronchopulmonary dysplasia: Definitions and long-term respiratory outcome. Early Hum Dev. 2009;85(10 Suppl):S1–3. doi: 10.1016/j.earlhumdev.2009.08.002. [DOI] [PubMed] [Google Scholar]
- 13.Roussy JP, Aubin MJ, Brunette I, Lachaine J. Cost of corneal transplantation for the Quebec health care system. Can J Ophthalmol. 2009;44:36–41. doi: 10.3129/i08-180. [DOI] [PubMed] [Google Scholar]
- 14.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;82:527–32. [PubMed] [Google Scholar]
- 15.Silber JH, Lorch SA, Rosenbaum PR, et al. Time to send the preemie home? Additional maturity at discharge and subsequent health care costs and outcomes. Health Serv Res. 2009;44:444–63. doi: 10.1111/j.1475-6773.2008.00938.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Landry JS, Chan T, Lands L, Menzies D. Long-term impact of bronchopulmonary dysplasia on pulmonary function. Can Respir J. 2011;18:265–70. doi: 10.1155/2011/547948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163:1723–9. doi: 10.1164/ajrccm.163.7.2011060. [DOI] [PubMed] [Google Scholar]
- 18.Lavoie PM, Pham C, Jang KL. Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the national institutes of health. Pediatrics. 2008;122:479–85. doi: 10.1542/peds.2007-2313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Davanzo R, Ronfani L, Brovedani P, Demarini S. Breast feeding very-low-birthweight infants at discharge: A multicentre study using WHO definitions. Paediatr Perinat Epidemiol. 2009;23:591–6. doi: 10.1111/j.1365-3016.2009.01068.x. [DOI] [PubMed] [Google Scholar]
- 20.Armitage PBG, Matthews JNS. Statistical methods in medical research. 4th edn. Malden: Blackwell Science; 2005. [Google Scholar]
- 21.SAS annotated output: Multinomial logistic regression <www.ats.ucla.edu/stat/SAS/output/SAS_mlogit.htm> (Accessed November 23, 2012) [Google Scholar]
- 22.Joseph K. The natural history of pregnancy: Diseases of early and late gestation. Bjog. 2011;118:1617–29. doi: 10.1111/j.1471-0528.2011.03128.x. [DOI] [PubMed] [Google Scholar]
- 23.Bardin C, Zelkowitz P, Papageorgiou A. Outcome of small-for-gestational age and appropriate-for-gestational age infants born before 27 weeks of gestation. Pediatrics. 1997;100:E4. doi: 10.1542/peds.100.2.e4. [DOI] [PubMed] [Google Scholar]
- 24.Binet ME, Bujold E, Lefebvre F, Tremblay Y, Piedboeuf B. Role of gender in morbidity and mortality of extremely premature neonates. Am J Perinatol. 2012;29:159–66. doi: 10.1055/s-0031-1284225. [DOI] [PubMed] [Google Scholar]
- 25.Landry JS, Menzies D. Occurrence and severity of bronchopulmonary dysplasia and respiratory distress syndrome after a preterm birth. Paediatr Child Health. 2011;16:399–403. doi: 10.1093/pch/16.7.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Donn SM, Dalton J. Surfactant replacement therapy in the neonate: Beyond respiratory distress syndrome. Respir Care. 2009;54:1203–8. [PubMed] [Google Scholar]
- 27.Pinkerton KE, Ikegami M, Dillard LM, Jobe AH. Surfactant treatment effects on lung structure and type II cells of preterm ventilated lambs. Biol Neonate. 2000;77:243–52. doi: 10.1159/000014223. [DOI] [PubMed] [Google Scholar]
- 28.Rush MG, Hazinski TA. Current therapy of bronchopulmonary dysplasia. Clin Perinatol. 1992;19:563–90. [PubMed] [Google Scholar]
- 29.Broekmans FJ, Knauff EA, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: Current knowledge and future trends. Trends Endocrinol Metab. 2007;18:58–65. doi: 10.1016/j.tem.2007.01.004. [DOI] [PubMed] [Google Scholar]
- 30.Bushnik TGR. The children of older first-time mothers in Canada: Their health and development. Child and Youth Research paper series 2008. < www.statcan.gc.ca/pub/89-599-m/89-599-m2008005-eng.pdf> (Accessed November 23, 2012).
- 31.Astolfi P, Zonta LA. Delayed maternity and risk at delivery. Paediatr Perinat Epidemiol. 2002;16:67–72. doi: 10.1046/j.1365-3016.2002.00375.x. [DOI] [PubMed] [Google Scholar]
- 32.Kanungo J, James A, McMillan D, et al. Advanced maternal age and the outcomes of preterm neonates: A social paradox? Obstet Gynecol. 2011;118:872–7. doi: 10.1097/AOG.0b013e31822add60. [DOI] [PubMed] [Google Scholar]
- 33.Shah PS, Sankaran K, Aziz K, et al. Outcomes of preterm infants <29 weeks gestation over 10-year period in Canada: A cause for concern? J Perinatol. 2012;32:132–8. doi: 10.1038/jp.2011.68. [DOI] [PubMed] [Google Scholar]