Rationale: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.
Objectives: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.
Methods: We assessed infants of 23–30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000–2004.
Measurements and Main Results: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2, and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.
Conclusions: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.
Bronchopulmonary dysplasia is the most common serious pulmonary morbidity in premature infants. Although accurate predictive models of bronchopulmonary dysplasia risk are sometimes used in research, none are currently used in common clinical practice for a variety of reasons.
In this study, we identified the change in the relative contributions of a variety of risk factors to the prediction of bronchopulmonary dysplasia with advancing postnatal age. This tool may help identify patients most likely to benefit from postnatal treatment and assist in the design of clinical trials to assess the efficacy of preventive therapies in high-risk populations.
An additional problem with previously reported analyses is a lack of detail regarding the change in BPD risk with advancing postnatal age (5–14). Traditionally, researchers identified risk factors for BPD by categorizing premature infants as having or not having BPD at 28 postnatal days or 36 weeks postmenstrual age, and then examining all factors that influenced risk up to the time of diagnosis. Subsequent multivariable models included risk factors identifiable at birth, and exposures up to the time of diagnosis of BPD. Using this approach, risk factors for BPD include lower birth weight, lower gestational age, male sex, patent ductus arteriosus (PDA), sepsis, and mechanical ventilation, among many others (16–19). These models typically do not include postnatal age and therefore cannot quantify the variable contribution of neonatal exposures over time. Including postnatal age facilitates the development and evaluation of potentially time-sensitive preventive or therapeutic strategies to modify BPD risk.
Our objectives were to identify risk factors for BPD (defined according to the National Institute of Child Health and Human Development consensus definition of no, mild, moderate, and severe BPD [20, 21]) and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based “BPD estimator” using readily available clinical information that accurately predicts the risk of BPD or death. Some of the results of these studies have been previously reported in the form of abstracts at the Pediatric Academic Societies Meetings (22–24).
We performed a secondary analysis of data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Benchmarking Trial. This study enrolled infants from 17 centers admitted from 2000–2004 in a cluster-randomized, controlled trial to test whether neonatal intensive care units trained in benchmarking and multimodal quality improvement techniques could improve survival without BPD compared with centers with usual practice (25). All sites' institutional review boards approved the study. To be eligible for the Benchmarking Trial, infants needed to survive more than 12 hours and have a birth weight of 401–1,250 g. For this secondary analysis, infants less than 23 weeks of age were not included because they all developed BPD, and infants greater than 30 weeks of age were not included because less than 1% of these infants developed BPD.
In the Benchmarking Trial, trained research coordinators using standardized definitions collected data before discharge, including gestational age, birth weight, race and ethnicity, and sex at birth; respiratory support and FiO2 were recorded on specified postnatal days (26). Gestational age (completed weeks of age) was determined by the best obstetric estimate using the last menstrual period or early ultrasonographic examination, except in unusual circumstances when only an estimate by the pediatrician (27) was available.
Race and ethnic group were assigned by maternal report. The FiO2 and respiratory support were recorded every 6 hours starting at 0600 hour on each of the Postnatal Days 1, 3, and 7, and then once on Days 14, 21, and 28. Mean FiO2 was used on Days 1, 3, and 7 when more than one FiO2 was recorded. We assigned the respiratory support as none, nasal cannula, nasal continuous positive airway pressure (NCPAP), conventional mechanical ventilation (either synchronized or nonsynchronized intermittent mandatory ventilation), or high-frequency ventilation every 6 hours on Days 1, 3, 7, 14, 21, and 28. Infants who never received mechanical ventilation (i.e., NCPAP only) were included in the data. If an infant had more than one respiratory support recorded, we used the “highest” form of ventilation for that day (e.g., if an infant received both conventional mechanical ventilation and NCPAP, the infant was coded as having received conventional mechanical ventilation on that day). Five infants who received oxygen via hood were included in the nasal cannula group. We did not assess the type (e.g., continuous flow vs. variable flow) or manufacturer of any positive–pressure device, including mechanical or high-frequency ventilation. The nasal cannula flow rate was not recorded.
We examined the use of postnatal corticosteroids (15) and the diagnoses of necrotizing enterocolitis (NEC) (28, 29) and sepsis (30), and therapy for PDA (31) by postnatal day using standardized Neonatal Research Network definitions. The date of surgical ligation of the PDA was unavailable.
BPD was defined as a categorical variable (none, mild, moderate, or severe) among survivors by modifying the National Institutes of Health consensus definition of BPD (20, 21) to include infants transferred before 36 weeks and by defining the need for oxygen at 36 weeks using a physiologic challenge (32). BPD was defined as follows: no BPD as not receiving supplemental oxygen (O2) for 28 days or at 36 weeks; mild BPD as receiving O2 for greater than or equal to 28 days but not at 36 weeks; moderate BPD as receiving O2 for greater than or equal to 28 days plus treatment with less than 30% O2 at 36 weeks; and severe BPD as receiving O2 for greater than or equal to 28 days plus greater than or equal to 30% O2 or positive pressure at 36 weeks. For infants transferred between 28 days and 36 weeks, we defined BPD using the O2 therapy at the time of transfer. For infants who were discharged or transferred less than 28 postnatal days for whom 28-day data were unavailable, we defined no BPD as not receiving O2, mild BPD as receiving FiO2 0.21–0.30, moderate BPD as receiving FiO2 0.31–0.5, and severe BPD as FiO2 greater than 0.5 at the time of transfer.
A set of a priori risk factors was considered for inclusion in each postnatal day model based on their known association with the outcomes of BPD or death and availability in clinical records. Those selected for potential inclusion in the models included gestational age, birth weight, race and ethnicity, sex, respiratory support, FiO2, treatment for PDA, sepsis, NEC, postnatal corticosteroids, and center (16–19). We examined each risk factor in each category of BPD or death, first using unadjusted analysis and then in multivariable analysis.
A series of multinomial logistic regressions were performed using SAS software version 9.2 (SAS Institute Inc., Cary, NC), simultaneously modeling level of BPD or death as a function of the previously mentioned risk factors to develop predictive models for severity of BPD or death. Models were developed separately for each of six time periods: Postnatal Days 1 (day of birth), 3, 7, 14, 21, and 28. Infants were included in the model if they survived through the day of prediction (e.g., infants in the Postnatal Day 7 model had to survive to that day).
Final model selection was based less on statistical significance and more on how a predictor enhanced the predictive ability of the model. Each covariate was entered into the model using stepwise forward selection. Six risk factors were included in the final model: (1) gestational age, (2) birth weight, (3) race and ethnicity, (4) sex, (5) respiratory support, and (6) FiO2. Other variables, such as sepsis, NEC (either medical or surgical), treatment for PDA (a substitute for diagnosis of PDA because this variable was not in the dataset), and postnatal corticosteroids, did not enhance the predictive ability of the models beyond that achieved by the previously mentioned six factors and thus were not further evaluated. Because of the need to develop a predictive model that can be widely used, we could not include clinical center as a factor in the models. We tested for the effect of adding center to the models and found that the predictive ability of the models increased only marginally: the C statistic increased by 0.9%–1.3% for models that included center.
Predictive performance of our models was assessed using a C statistic, which corresponds to the area under the receiver–operating characteristic curve, which is suitable for multinomial outcomes, such as our five-level outcome. Internal validation was accomplished by dividing the cohort into two parts: two-thirds of the infants were randomly selected from each site as the model development cohort, and the remaining third were used as an internal model validation cohort. External validation was accomplished by applying the development models on two different cohorts of infants and comparing the results. One cohort included infants in the recently reported Neonatal Research Network Surfactant Positive Airway Pressure and Pulse Oximetry Trial in Extremely Low-birth-weight Infants (SUPPORT) trial who were at the same centers as the Benchmarking Trial, and the other cohort included infants in the Benchmarking Trial who were at the same gestational age and center as those in SUPPORT (33, 34).
We identified 4,095 infants with Benchmarking Trial data: 3,636 (88.8%) infants were eligible for this study; 68 infants were excluded because of death at less than or equal to 12 hours. Ten infants at less than 23 weeks (100% developed BPD) and 381 infants at more than 30 weeks gestation (<1% developed BPD) were also excluded. There were seven infants for whom an outcome was not determined.
The mean birth weight for the cohort was 897 ± 203 g, the mean gestational age was 26.7 ± 1.9 weeks, the mean maternal age was 27.2 ± 6.5 years, 51% were male, and 13% received postnatal corticosteroids (Table 1). In addition, 85% received antenatal steroids, and 81% received surfactant.
|Number of subjects with outcome||1,218||757||714||472||468||3,629|
|Birth weight, g, mean ± SD||1,042 ± 149||891 ± 174||839 ± 180||788 ± 177||727 ± 173||897 ± 203|
|Gestational age, wks, mean ± SD||28.2 ± 1.4||26.4 ± 1.4||26.2 ± 1.6||25.8 ± 1.7||25.1 ± 1.7||26.7 ± 1.9|
|Race: black not Hispanic, %||42.5||38.3||34.5||38.6||45.1||39.9|
|Ethnicity: Hispanic, %||18.1||18.8||15.4||15.7||18||17.4|
|Patent ductus arteriosus, n (%)||301 (25)||346 (46)||388 (54)||278 (59)||230 (49)||1,543 (43)|
|Indomethacin, n (%)||228 (19)||296 (39)||330 (46)||228 (48)||172 (37)||1,254 (35)|
|Ligation, n (%)||22 (2)||73 (10)||146 (20)||141 (30)||37 (8)||419 (12)|
|Early onset sepsis ≤ 72 h, n (%)||13 (1)||14 (2)||13 (2)||10 (2)||25 (5)||75 (2)|
|Late-onset sepsis >72 h, n (%)||211 (17)||243 (32)||276 (39)||270 (57)||164 (35)||1,164 (32)|
|Medical, n (%)||46 (4)||49 (6)||29 (4)||33 (7)||18 (4)||175 (5)|
|Surgical, n (%)||19 (2)||25 (3)||20 (3)||35 (7)||73 (16)||172 (5)|
|Postnatal corticosteroids, n (%)||9 (1)||62 (8)||154 (22)||222 (47)||32 (7)||479 (13)|
When examining categories of BPD, increasing severity of BPD was inversely proportional to gestational age and birth weight (Table 1). As the severity of BPD increased, the percentage of male infants increased. Infants with increasing severity of BPD were also more likely to have other morbidities of prematurity, such as PDA, sepsis, and surgical NEC (Table 1). A higher proportion of infants receiving mechanical ventilation, either conventional or high-frequency, compared with NCPAP, nasal cannula, or no support at each postnatal day developed severe BPD (Table 2). At each time point studied, FiO2 was higher with increasing severity of BPD and death. We present the adjusted odds ratios for each of the risk factors by postnatal day for all outcomes in Appendix 1.
|Maximum N = 1,218||Maximum N = 757||Maximum N = 714||Maximum N = 472||Maximum N = 468|
|Nasal cannula, %||74||18||5||3||0|
|No ventilation, %||85||8||3||0||5|
|Mean FiO2, %||38||39||42||46||53|
|Nasal cannula, %||63||22||8||4||3|
|No ventilation, %||87||6||3||2||3|
|Mean FiO2, %||35||37||37||38||47|
|Nasal cannula, %||56||24||12||6||2|
|No ventilation, %||86||7||4||1||2|
|Mean FiO2, %||41||37||36||37||44|
|Nasal cannula, %||47||32||17||3||2|
|No ventilation, %||93||3||2||2||2|
|Mean FiO2, %||44||42||43||46||54|
|Nasal cannula, %||43||34||17||5||2|
|No ventilation, %||97||1||1||1||1|
|Mean FiO2, %||41||42||44||47||55|
|Nasal cannula, %||32||41||21||5||1|
|No ventilation, %||97||1||1||1||1|
|Mean FiO2, %||36||41||44||47||54|
The six covariates in the final models were (1) gestational age; (2) birth weight; (3) race and ethnicity; (4) sex; (5) respiratory support (none, nasal cannula, NCPAP, conventional mechanical ventilation, or high-frequency ventilation); and (6) FiO2. These six covariates were independently strongly associated with outcome and collectively predicted outcome well. Using the six risk-factor model, the C statistic for the Postnatal Day 1 model was 0.793. Models for subsequent days had a steadily increasing C statistic, reaching a maximum of 0.854 on Postnatal Day 28 (Table 3). The factor that contributed most to model prediction changed depending on the postnatal day (Table 3). Gestational age best improved prediction of the outcome on Postnatal Days 1 (C statistic = 0.750) and 3 (C statistic = 0.745). On Postnatal Days 7, 14, 21, and 28, type of respiratory support increasingly improved outcome prediction (from a C statistic of 0.771–0.823) more than any of the other factors.
|Variable||C Statistic||Variable||C Statistic||Variable||C Statistic|
|Gestational age||0.750||Gestational age||0.745||Respiratory support||0.771|
|Birth weight||0.772||Respiratory support||0.787||Gestational age||0.806|
|FiO2||0.784||Birth weight||0.798||Birth weight||0.814|
|Race and ethnicity||0.791||Male sex||0.807||Race and ethnicity||0.817|
|Male sex||0.793||Race and ethnicity||0.807||Male sex||0.818|
|Day 14||Day 21||Day 28|
|Variable||C Statistic||Variable||C Statistic||Variable||C Statistic|
|Respiratory support||0.795||Respiratory support||0.802||Respiratory support||0.823|
|Gestational age||0.825||Gestational age||0.833||Birth weight||0.851|
|FiO2||0.826||Birth weight||0.835||Race and ethnicity||0.853|
|Race and ethnicity||0.826||Race and ethnicity||0.835||Gestational age||0.853|
|Male sex||0.827||Male sex||0.836||Male sex||0.854|
C statistics derived by fitting these models to the internal validation cohort were similar (Table 4). In addition, we identified 1,055 infants in the Benchmarking Trial and 722 infants in SUPPORT between 23 and 27 weeks' gestation and at the same centers. We applied the Postnatal Day 1, 3, 7, and 14 development models to both cohorts of infants and found that the C statistic was always within 2% (Table 4). FiO2 data after Day 14 were unavailable in SUPPORT.
|Benchmarking: Development(n = 2,415)||Benchmarking: Validation(n = 1,214)||Benchmarking*(n = 1,055)||SUPPORT(n = 722)|
|Gestational age, wk ± SD||26.7 ± 1.9||26.8 ± 1.9||25.7 ± 1.1||25.7 ± 1.1|
|Birth weight, g ± SD||894 ± 203||903 ± 202||830 ± 175||842 ± 168|
|Antenatal steroids, %||85||85||87||96|
|Outcome at 36 wks PMA, %|
|Models: C statistic|
A prediction tool was developed that provides individual predicted estimates of BPD risk or death at each of six postnatal days. The model requires birth weight, gestational age, sex, race and ethnicity, respiratory support, and FiO2 as inputs. Table 5 presents two examples of BPD risk or death for two hypothetical infants. A Web-based version of this tool is available at https://neonatal.rti.org/.
25-wk gestational age, 700-g birth weight, white, male
|Probability of Outcome|
|Day||Respiratory support and FiO2||Death||Severe BPD||Moderate BPD||Mild BPD||No BPD|
|1||HFV and FiO2 = 50%||0.31||0.17||0.31||0.20||0.01|
|3||HFV and FiO2 = 100%||0.52||0.17||0.19||0.12||0.00|
|7||HFV and FiO2 = 100%||0.42||0.20||0.28||0.10||0.00|
|14||CMV and FiO2 = 50%||0.07||0.28||0.36||0.27||0.02|
|21||NCPAP and FiO2 = 50%||0.02||0.19||0.36||0.39||0.04|
|28||Nasal cannula and FiO2 = 50%||0.01||0.06||0.28||0.57||0.07|
|28-wk gestational age, 1,000-g birth weight, black, female|
|Probability of Outcome|
|Day||Respiratory support and FiO2||Death||Severe BPD||Moderate BPD||Mild BPD||No BPD|
|1||CMV and FiO2 = 70%||0.06||0.09||0.15||0.23||0.47|
|3||CMV and FiO2 = 35%||0.05||0.09||0.22||0.30||0.34|
|7||Nasal cannula and FiO2 = 50%||0.01||0.04||0.09||0.21||0.65|
|14||No ventilation and room air||0.02||0.01||0.01||0.03||0.93|
|21||No ventilation and room air||0.01||0.01||0.01||0.01||0.96|
|28||No ventilation and room air||0.01||0.00||0.00||0.01||0.97|
Our large, multicenter study identified the change in the relative contributions of a variety of risk factors to the prediction of BPD with advancing postnatal age. This knowledge is important because the benefits of postnatal treatment strategies might depend on baseline BPD risk. For example, the benefits of postnatal steroids for the prevention of BPD seem to outweigh the risks only in populations of premature infants at high risk of BPD. A meta-regression analysis of randomized, controlled trials of BPD demonstrated that, as the BPD risk increased above 65% in the control groups, postnatal steroid use was associated with a decrease in the risk of mortality or cerebral palsy; at lower baseline risk, treatment was associated with increased risk of mortality or cerebral palsy (35). In infants with more severe lung disease, corticosteroids seemed to reduce risk of adverse neurodevelopmental outcome (15). In addition, steroids seem to be of greatest benefit if used after the first postnatal week (36, 37). Our models provide a precise and objective estimate of BPD risk at various postnatal ages, which is essential information for conducting trials to determine if preventive therapies, such as postnatal corticosteroids or inhaled nitric oxide, are beneficial in high-risk populations. These models might serve as a foundation for researchers to assess long-term respiratory risk including the development of asthma, long-term pulmonary function test status, and potential development of emphysema in adult life.
Previously identified risk factors for BPD include birth weight, gestational age, male sex, oxygen therapy at 24 hours, mechanical ventilation at 48 hours, and duration of assisted ventilation (16–19). These factors, measured in greater detail and at different time points, were included in our model. We added the contribution of these factors relative to each other and their relative importance at different postnatal ages. For example, although oxygen exposure is a risk factor, its independent contribution to prediction of BPD risk is small relative to gestational age on Postnatal Day 1 and to respiratory support thereafter. Risk factors that were found to be significant in previous studies but that we did not include in our final models include PDA, NEC, sepsis, and postnatal corticosteroids (16–19). None of these factors improved prediction of the risk of BPD after adjustment for the six critical risk factors.
Previous BPD prediction scoring systems have been described, but none has been widely adopted. Some have satisfactory sensitivity and specificity but use oxygen therapy at 28 postnatal days as a definition of BPD, which is now outdated (5–7). Some include radiographs as part of the scoring system, which introduces subjectivity and reduces generalizability (8–11). Other problems limiting the use of these models are the inclusion of ventilated infants only, the lack of categorization of BPD by severity, the exclusion of infants who die, and underuse of antenatal corticosteroids and surfactant therapy (8–13, 38, 39). Most importantly, none examined models by postnatal day through the first 28 postnatal days. In addition, we internally and externally validated our models; our models were able successfully to classify infants in the internal validation sample into the correct level of BPD or death in more than 8 out of 10 cases. The models performed similarly in subjects in the SUPPORT trial who were born between 2004 and 2009. The C statistic is lower for both the subset of subjects in the reduced Benchmarking group and SUPPORT group because the excluded subjects had higher and lower gestational ages, and outcome is more accurately predicted at the extreme values (i.e., subjects with higher gestational age have better outcomes, with more accuracy; subjects with lower gestational age have worse outcomes, again with more accuracy).
We developed an on-line application of the prediction models. Caution should be exercised when using the on-line estimator to identify BPD risk in populations in which the demography or care practices differ markedly from our cohort. Our models and the on-line application were based on data from Level III neonatal intensive care units at large, mostly urban academic medical centers. Because our BPD definitions depended in part on various respiratory therapies, center-specific use of these therapies might influence the prediction models. For example, we speculate that high-frequency ventilation was most likely used in our study centers as a “rescue” therapy for infants with profound respiratory failure or pulmonary interstitial emphysema (40), and therefore BPD risks were higher among infants exposed to high-frequency ventilation. In centers where high-frequency ventilation is used as a primary therapy, BPD risk might be overestimated using our model (41).
In conclusion, we found that gestational age conveyed the most predictive information for BPD risk on Postnatal Days 1 and 3, and respiratory support on Days 7, 14, 21, and 28. The BPD estimator will provide prognostic information for families and clinicians, and will assist in identifying the optimal candidates for enrollment in clinical trials to prevent BPD.
The authors are indebted to their medical and nursing colleagues and the infants and their parents who agreed to take part in this study. Study concept and design: Matthew Laughon, Carl Bose, Brian Smith, Michael Cotten, Namasivayam Ambalavanan, Bradley Yoder, Waldemar Carlo, Kathleen Kennedy, Krisa Van Meurs, Richard Ehrenkranz, Marie Gantz, and Deanne Wilson-Costello. Acquisition of data: Barbara Stoll, Richard Ehrenkranz, Waldemar Carlo, Rosemary Higgins, Seetha Shankaran, Deanne Wilson-Costello, Roger Faix, Bradley Yoder, Krisa Van Meurs, Kurt Schibler, Susan Buchter, Neil Finer, Richard Ehrenkranz, Abhik Das, Marie Gantz, Nancy Newman, and Michael Cotten. Analysis and interpretation of data: Matthew Laughon, Carl Bose, P. Brian Smith, Alexis Davis, Namasivayam Ambalavanan, Barbara Stoll, Abbot Laptook, Bradley Yoder, Roger Faix, Waldemar Carlo, Rosemary Higgins, Abhik Das, Krisa Van Meurs, Kathleen Kennedy, Michael Cotten, and Deanne Wilson-Costello. Drafting of the manuscript: Matthew Laughon, Carl Bose, Waldemar Carlo, Alexis Davis, and Michael Cotten. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: Matthew Laughon, John Langer, Michele Walsh, P. Brian Smith, Waldemar Carlo, Marie Gantz, and Abhik Das. Obtained funding: Barbara Stoll, Waldemar Carlo, Seetha Shankaran, Michele Walsh, Krisa Van Meurs, Waldemar Carlo, Neil Finer, Rosemary Higgins, Abhik Das, Roger Faix, and Michael Cotten. Administrative, technical, or material support: Matthew Laughon, Barbara Stoll, Richard Ehrenkranz, Waldemar Carlo, Rosemary Higgins, Abhik Das, Kurt Schibler, and Neil Finer. Study supervision: Matthew Laughon, Carl Bose, Abbot Laptook, Bradley Yoder, Waldemar Carlo, Rosemary Higgins, Abhik Das, Roger Faix, Deanne Wilson-Costello, Susan Buchter, and Michael Cotton.
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