I just published a “different view” article addressing the question in the title, with a group of expert collaborators, Mai Luu who is our follow up doc in Montreal, and helps to run the Canadian Neonatal Follow-Up Network (CNFUN), Paige Church, who organizes the neonatal follow-up in Toronto, and Peter Davis, who needs no introduction.
Barrington KJ, et al. Respiratory outcomes in preterm babies, is bronchopulmonary dysplasia important? Acta Paediatr. 2022.
I was stimulated to write the article when reviewing publications about postnatal steroid use, we were trying to develop a common approach for our NICU, and be as evidence-based as possible. During the process I realised, what I guess I already knew, that there is no evidence from any of the trials that long term pulmonary health is improved by steroid use. Even though there are many trials showing a reduction in BPD. Regardless of how it is defined; all the various definitions of BPD are based on abnormal oxygenation, either at 28 days of life or at 36 weeks PMA, sometimes requiring x-ray changes. Our contention in the article is that such short term changes in gas exchange do not correlate very strongly with long term respiratory morbidity. In addition, it probably isn’t very important to families if a baby is on oxygen at 36 weeks PMA, if they go home with little support and few respiratory signs, and have minor respiratory problems in the first year or so of life.
You may remember that BPD was first described, and named, by Bill Northway (a radiologist) and colleagues in a seminal paper in the NEJM (Northway WH, Jr., et al. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276(7):357-68.) which you can find easily on-line, along with the description of stages (which we rarely use now) and pathology specimens. This was entirely a clinical description of a new phenomenon among babies who had been supported with the new innovation, assisted mechanical ventilation! PEEP was not yet in use, so babies were being ventilated as a last resort to prevent death, using high peak pressures and zero PEEP, and oxygen concentrations were kept extremely high for long periods, as it wasn’t possible to measure oxygenation continuously, or even very frequently, because arterial blood gas results took a while.
The various newer definitions of BPD, have usually been developed because it was realized that many babies who satisfy the contemporary definition (initially, persistent oxygen needs up to a completely arbitrary 28 days of life) had little long term respiratory difficulty. Andy Shennan and colleagues in Toronto (including Michael Dunn, who must have been very young at the time) compared long term outcomes to the neonatal evolution of lung disease, and realized that adverse long term outcomes were much better predicted by oxygen need at 36 weeks Post-Menstrual Age. In other words they were acknowledging from the start that it is the long term respiratory morbidity that is important, and that the definition of BPD is important as an interim, surrogate, outcome. What they used as their long term outcome of interest is any one the following up to 2 years of age: death not due to congenital anomaly; O2 at 40 weeks PMA; respiratory surgery; 2 or more respiratory re-hospitalisations; recurrent wheezing requiring medication; or, X-ray changes or persistent wheezing/retractions/tachypnoea with growth failure, hypotonia, neurological impairment or developmental delay. Which, interestingly, includes neurodevelopmental outcomes in the respiratory morbidity definition. Among the group of babies they studied, the prevalence of that outcome was just under 20%, and the PPV for such an outcome, of needing oxygen at 36 weeks, was 63% with a NPV of 90%.
Other proposed definitions of BPD have also used different aspects of long term respiratory morbidity as their standard for evaluating their definition. The NICHD definition, which introduced grades of BPD, looked at re-hospitalisations in one analysis, and chronic respiratory medication use in another. They showed that having moderate or severe BPD was, statistically speaking, a predictor of both re-hospitalisation and chronic respiratory medication use, but if you look at the data, the PPV for either of those outcomes was only about 40%, and the NPV about 70%. In other words, many babies without BPD have chronic respiratory morbidity, and many babies with BPD, even those with severe BPD, do not, at least using these very broad simplistic descriptions of respiratory morbidity.
I think that our reliance on “BPD” as an outcome could well be having serious adverse impacts on our ability to improve long-term respiratory function among preterm infants.
If we take one example, the SUPPORT trial, the primary outcome of “death or BPD” was just about identical between groups (48% vs 51%) and BPD alone was 39% vs 41%. In marked contrast, all the long term respiratory outcomes, mostly things which probably matter to infants and their families, were better in the CPAP group. The CPAP babies had “fewer episodes of wheezing without a cold (28.9% vs 36.5%; P < .05), respiratory illnesses diagnosed by a doctor (47.7% vs 55.2%; P < .05), and physician or emergency room visits for breathing problems (68.0% vs 72.9%; P < .05) by 18-22 months CA”. Respiratory re-hospitalisations were also less frequent, 43% vs 50%.
According to these outcomes, CPAP is clearly preferable to immediate intubation for surfactant, even though BPD is not improved. In contrast, many studies of postnatal steroids (Yeh et al, Kothadia et al, UK dexamethasone trial….) have shown less BPD, but all those that have published long-term respiratory morbidity data show no benefit of postnatal steroids. My explanation of that is that steroids reduce inflammation and, as a result, improve gas exchange for a period, but they also have adverse effects on pulmonary growth and development. Of course, many of the steroid trials are relatively unreliable for long term outcomes because of high rates of treatment of controls with steroids, but that does hold true for the trials with low rates of control steroid administration (Such as Yeh et al and Kothadia et al). If we focus on improving long-term respiratory morbidity, then there is little indication for postnatal steroids, infants at risk of dying from their lung disease may be saved by postnatal steroids, but giving steroids to reduce FiO2 or to assist in extubation might be successful for those outcomes, but probably won’t improve pulmonary outcomes in the long term.
We should think of BPD as a short term, interim, surrogate outcome, a way of classifying infants and evaluating lung injury in the short term, but with poor predictive value for respiratory morbidity in the longer term. Much like brain injury, and neurological and developmental outcomes compared to head ultrasound findings; we know that head ultrasound abnormalities are statistically related to longer term neurodevelopmental outcomes, but in order to decide which therapies are likely to improve outcomes we do not rely on ultrasound findings, or even MRI, objective evaluation of longer term function is far more important. We cannot, of course, decide after the fact for each individual trial what long term outcomes are valuable, that would lead to a major risk of bias, and post hoc selection of features of respiratory morbidity which are consistent with one’s prejudices. What long term respiratory morbidities should we evaluate?
When I looked at what features of long term respiratory morbidity have been reported in various trials, it is extremely variable, in addition to the factors already discussed, as outcomes in the Shennan et al paper, and in the NICHD definition of BPD paper, and in the respiratory outcomes of SUPPORT, other articles have presented chronic use of inhaled respiratory medications, post-discharge use of systemic or inhaled respiratory medications, emergency room visits, more than 2 re-hospitalisations, cough without other signs of Upper Respiratory Infection, still requiring oxygen at 2 years after discharge, tracheostomy, and so on. Feeding difficulties, and many other outcomes which are important to families according to recent publications, were never reported.
In the article we plead for the development of long-term respiratory morbidity measures which reflect morbidity of importance to babies and families, and the use of such outcomes as the primary measure of efficacy of neonatal respiratory interventions. There have been one or two attempts to create a definition; one definition from the prematurity and respiratory outcomes study created the following definition “one of the following, hospitalization for respiratory indication, home respiratory support, respiratory medication administration, or respiratory symptoms, being present on at least two of the four 3-monthly questionnaires completed by families during the first year of life”. As far as I can tell the definition was arbitrarily created by the investigators; it was used as a dichotomous outcome. PROP showed a statistically significant association between a diagnosis of BPD and the presence of their outcome, that they called Post-Prematurity Respiratory Disease, PRD. But the predictive ability of a diagnosis of BPD or of severe BPD was poor. PPV of BPD for PRD was only 50%, and the NPV was only 30%. The PPV of severe BPD for PRD was only 37%, and the NPV was 83%.
Again, in other words, many babies with a diagnosis of BPD did not have PRD, and many babies without a diagnosis of BPD, nevertheless had this degree of post-discharge respiratory morbidity.
A more complete definition, which gives a score on an ordinal scale has been developed in the Netherlands for children aged 4 to 8 years, (Meijer-Schaap L, et al. Development and construct validation of a parent-proxy quality of life instrument in children with bronchopulmonary dysplasia aged 4-8 years old. Qual Life Res. 2019;28(2):523-33) it includes 33 items, in 5 domains, respiratory symptoms, school functioning, growth and nutrition, exercise and locomotion, and emotional functioning and health care concerns. It has the great advantage of being developed from items proposed by a multidisciplinary group including parents.
There is a real need for a respiratory outcomes scale developed for use in the first couple of years of life, it should be an ordinal scale, reflecting the range of respiratory morbidities among former very preterm infants, it should be simple to administer, and, most importantly, include items that parents report having an impact on the family.
Dr. Barrington’s analysis and views on Bronchopulmonary Dysplasia are refreshing and spot on. While the vast majority of infants with a diagnosis of BPD can engage in normal physical activities requiring strenouis excercise, some are unable to do so, as with some term infants. While senior neonatologists recall horrific cases of profound respiratory failure leading to death in earlier years, current therapies (and there are many) have permitted lung growth and physical resliency. While among young adults with BPD as infants in the 1980s had some impairments in lung function, nearly all could live a « normal life. » What studies using BPD as an end point (and most frequently BPD or Death) failed to consider was as with other comorbid conditons of prematurity BPD had a variable course once an infant was discharged. RSV could be devastating, and may still be, among some infants, but also eposure to second hand tobacco smoke, air pollution, « vulnerable child syndrome » among some parents treating their children as delicate china perhaps affected lung function far more than early arrested lung development from both prematurity, respiratory distress syndomre, invasive ventilation, and neonatal infections. The mutliple and evolving definitioins fo BPD, including the NIH severity scores, may have been helpful, but did not impact early approaches to therapy. Exogenouis surfactant even with added steroids permitted more ELBW infants to survive with some impariment in lung growth, but the trade off of some « chronic lung diease » versus a dead baby has withstood the test of time, multiple systematic reviews, and has been a major advance in Neonatology. Developing molecular tools to enhance lung grwoth, prevent oxidative damage or the effects of barotrauma by using non-invasive ventilation including HFV will permit more infannt as children to be active physically. Neonatologists have focused on treating only the infant, when additional focus on encourgaging a healthier environment in which the lungs continue to grow (great nutrition, avoidance of second hand smoke expsure, childhood immunizations including treatment to reduce RSV infections, and a healier environment) are perhaps more important for the « Nature of Things » in normal child develpment. T. Allen Merritt, M.D, MHD