MANUSCRIPT CITATION 

Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, Kirpalani H, Laughon MM, Poindexter BB, Duncan AF, Yoder BA, Eichenwald EC, DeMauro SB.et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants: An Evidence-Based Approach. Am J Respir Crit Care Med. 2019 Sep 15;200(6):751-759. doi: 10.1164/rccm.201812-2348OC. PMID:30995069

REVIEWED BY

Lakshmi Katakam, MD, MPH
Associate Professor, Neonatology
Medical Director of NICU
Texas Children’s Hospital, Baylor College of Medicine

Suresh Gautham, MD
Section Head and Service Chief, Neonatology
Texas Children’s Hospital, Baylor College of Medicine

TYPE OF INVESTIGATION 

Diagnosis

QUESTION

In preterm infants less than 32 weeks gestation at birth, does a definition of Bronchopulmonary Dysplasia (BPD) that takes into account the type of respiratory support at 36 weeks PMA, compared to a definition that only includes supplemental oxygen at 36 weeks PMA, better predict respiratory and neurodevelopmental outcomes at 18-26 months corrected age?

METHODS

• Design: Retrospective, multicenter cohort study
• Allocation: N/A
• Blinding: N/A
• Setting and time period: Data on infants from NICHD Neonatal Research Network centers between April 1, 2011 and April 1, 2015 were evaluated
• Follow-up period: 18-26 months corrected age
• Subjects:
  • Inclusion Criteria:
    • Born at < 32 weeks gestation
    • Infants born at 18 network centers
    • Survival to 36 weeks PMA AND either:
      • Completed 18-26 month follow up or
      • Died prior to anticipated follow-up
  • Exclusion Criteria:
    • Severe congenital malformations or syndromes
    • Those who were missing key study data
• Intervention: N/A
• Outcomes:
  • Primary outcome: composite of death between 36 weeks PMA and 18-26 month follow-up (late death) or serious respiratory morbidity, defined as at least one of the following:
    1. Tracheostomy placed any time prior to follow-up
    2. Continued hospitalization for respiratory reasons at or beyond 50 weeks PMA
    3. Use of supplemental oxygen, respiratory support, or respiratory monitoring (e.g. pulse oximeter, apnea monitor) at follow-up
    4. ≥ 2 re-hospitalizations for respiratory reasons prior to follow-up
  • Secondary outcomes:
    1. Composite of late death or moderate to severe neurodevelopmental impairment at 18-26 months corrected age.
       • Assessed by neurologic examination and
       • Defined as a Bayley Scales of Infant and Toddler Development, 3^rd edition cognitive or motor composite score <85, a Gross Motor Function Classification System Level ≥2, bilateral blindness, and/or severe hearing impairment that cannot be corrected with amplification.
    2. Growth restriction
    3. Measures of healthcare utilization
• Analysis and Sample Size:
  • 18 pre-specified definitions of BPD were tested to determine the strength of association between each definition and the two composite study outcomes
  • Regression models were adjusted for gestational age, birthweight, sex, small for gestational age, race/ethnicity, treatment with antenatal corticosteroids, treatment with magnesium, maternal education, insurance type, primary caretaker marital status, and study center.
  • A concordance statistic was calculated for each regression model quantifying each model’s predictive accuracy
    1. How well does each definition discriminate between babies who did and did not develop the study outcome
  • A priori specifications:
    1. Model with highest concordance statistic for primary outcome will be considered the optimal diagnostic criteria for BPD
    2. Accuracy of predicting secondary outcome will be used to resolve any equivalent results for the primary outcome
  • 3,419 infants were screened
    • 742 excluded (lost to follow-up or missing study data)
    • 2677 infants were included in this analysis
• Patient follow-up: 78% of screened subjects were included in analysis

MAIN RESULTS

Among the 2677 infants analyzed, the mean birthweight is 765 grams and mean gestational age is 25.2 weeks, with 89% of study cohort being under 27 weeks. Corrected age at follow up is 18-22 months for 28% of the cohort and 22-26 months for remainder (72%) of the cohort. Antenatal corticosteroid rate in the cohort is high at 90% and incidence of maternal education less than high school is 19%.

Primary Outcome

The primary outcome of late death or serious respiratory morbidity occurred in 26% of the study cohort.

Secondary Outcomes

The secondary outcome of late death or moderate to severe NDI occurred in 49% of the study cohort.

Optimal BPD definition

Of the 18 definitions tested, the optimal definition (one with the highest predictive accuracy for primary outcome) categorized BPD severity according to the mode of respiratory support administered at 36 weeks’ PMA, regardless of the prior duration or current level of oxygen therapy. More specifically, this definition classifies infants breathing in room air at 36 weeks’ PMA as not having BPD and disease severity among the remaining infants is classified as grade 1 for nasal cannula flow rates ≤2 L/min; grade 2 for nasal cannula flow rates > 2L/min or noninvasive positive airway pressure; and grade 3 for invasive mechanical ventilation. Using this definition, 29% of the study cohort would be classified as not having BPD, 39% as having Grade 1, 23% as having Grade 2, and 9% as having Grade 3 BPD.

The definition most similar to the 2001 NIH consensus definition was among the least accurate predictors of both study outcomes. The optimal definition performed better than the 2001 and 2018 NICHD consensus definitions of BPD (P<0.001 and P≤0.002 respectively). It also demonstrated good discriminatory power and correctly predicted the presence or absence of late death or serious respiratory morbidity in over 80% of study infants.

CONCLUSION

In preterm infants born at gestational age less than 32 weeks, the definition of BPD that best predicts late death or serious respiratory morbidity (with highest predictive accuracy) is also the definition that best predicts late death or moderate to severe neurodevelopmental impairment.  This optimal definition of BPD takes into consideration mode of respiratory support at 36 weeks PMA and does not rely on supplemental oxygen requirement.

COMMENTARY

Bronchopulmonary Dysplasia is an important morbidity in preterm infants that results from altered course of lung development and disruption in the balance between lung injury and repair mechanisms. Despite its complexity, the disease has been defined simply by the type of treatments used to address its symptoms rather than the intricate pathophysiology.

BPD was initially described by Northway in 1967 and the definition has since been modified in 1978, 1988, 2001, and 2018. Currently, the definition that is commonly used for research purposes is the NICHD definition from 2001 which classifies infants requiring at least 28 days of oxygen as having BPD and categorizes the severity of disease based on respiratory support at 36 weeks PMA(1). On the other hand, the definition that many units use to track their outcomes over time is oxygen requirement at 36 weeks PMA.

The Neonatology community has recognized the some important limitations of these prevailing definitions (2-4):

• • Lack of standardization of target saturations results in variability in BPD rates.
  • Optimal timing for assessment is unclear and later time points of assessment, 40 weeks PMA, may be better predictors of long-term outcomes.
  • Oxygen requirement is influenced by factors such as altitude, presence of comorbidities, and medications.
  • Definition does not capture the infants dying from severe lung disease prior to 36 weeks PMA.

In this study, Jensen et al. took an evidence based approach to evaluate 18 potential definitions of BPD and compared their ability to predict important long term pulmonary and neurodevelopmental outcomes. Surprisingly, the definition that doesn’t take into account oxygen requirement at the time of assessment is the one that fared well with the highest predictive accuracy. Infants with BPD can have multiple clinical phenotypes and varying degrees of dysfunction related to the airway, lung parenchyma, and pulmonary vasculature (5-7).  With this new recognition that dependency on respiratory support rather than dependency on oxygen better predicts important long-term outcomes, it makes us speculate if certain phenotypes of BPD are more likely to contribute to the disease burden than others. For example, in a recent observational study of 73 infants with severe BPD, 32% had three phenotypes of the disease (parenchymal disease, pulmonary hypertension and large airway disease) and having more phenotypes was associated with increase in risk of composite outcome of death, tracheostomy, or pulmonary vasodilator therapy (5).

Eliminating oxygen requirement as a component certainly simplifies the definition and helps overcome limitations related to target saturations.  However, this new definition did not accurately predict late death or serious respiratory morbidity in 20% of infants. Investigators were also not able to compare performance of this definition at gestational ages other than 36 weeks. Furthermore, this new definition is not able to take into account mortality secondary to lung disease that occurs prior to 36 weeks PMA, limiting its applicability for the younger preterm infants who never reach 36 weeks PMA. However, this definition outperformed and more accurately predicted study outcomes when compared to the 2001 NIH consensus definition and the modified 2018 definition.

When it comes to picking an ideal definition for BPD, Bancalari et al suggested that “the definition of BPD has different meanings for different stakeholders…for clinicians and researchers, a definition with some correlation with long-term outcome is important. On the other hand, for a parent…survival and the effect on long-term respiratory health is paramount.”(2) It is important to see if this definition will be accepted by the various stakeholders and whether the predictive accuracy is reproducible in other cohorts of preterm infants.

REFERENCES

1. Hines D, Modi N, Lee SK, Isayama T, Sjors G, Gagliardi L, et al. Scoping review shows wide variation in the definitions of bronchopulmonary dysplasia in preterm infants and calls for a consensus. Acta paediatrica. 2017;106(3):366-74.
2. Bancalari E, Jain D. Bronchopulmonary Dysplasia: Can We Agree on a Definition? American journal of perinatology. 2018;35(6):537-40.
3. Ibrahim J, Bhandari V. The definition of bronchopulmonary dysplasia: an evolving dilemma. Pediatric research. 2018;84(5):586-8.
4. Stoecklin B, Simpson SJ, Pillow JJ. Bronchopulmonary dysplasia: Rationale for a pathophysiological rather than treatment based approach to diagnosis. Paediatric respiratory reviews. 2018.
5. Wu KY, Jensen EA, White AM, Wang Y, Biko DM, Nilan K, et al. Characterization of Disease Phenotype in Very Preterm Infants with Severe Bronchopulmonary Dysplasia. American journal of respiratory and critical care medicine. 2020;201(11):1398-406.
6. Shepherd EG, Clouse BJ, Hasenstab KA, Sitaram S, Malleske DT, Nelin LD, et al. Infant Pulmonary Function Testing and Phenotypes in Severe Bronchopulmonary Dysplasia. Pediatrics. 2018;141(5).
7. Bamat NA, Zhang H, McKenna KJ, Morris H, Stoller JZ, Gibbs K. The Clinical Evaluation of Severe Bronchopulmonary Dysplasia. NeoReviews. 2020;21(7):e442-e53.