Improving Understanding of Bronchopulmonary Dysplasia to Optimize Childhood Outcomes

Preterm infants with bronchopulmonary dysplasia (BPD), particularly those who require prolonged mechanical ventilation during the neonatal period, are at high risk for poor medical and developmental outcomes throughout childhood. Today, about half of extremely preterm infants who survive to 36 weeks post-menstrual age (PMA) have BPD. Infants with BPD have increased risk for poor respiratory health, developmental delay, and cerebral palsy. As children with BPD mature beyond infancy, they continue to demonstrate important developmental sequelae. BPD is associated with approximately one-standard deviation decrease in childhood intelligence and significantly increased risk for cerebral palsy. In addition, children and adolescents with BPD have poorer performance than other children across multiple domains, including academic skills, visual-motor integration, executive function, motor coordination, and social function.

Our team of investigators in the Children’s Hospital of Philadelphia Chronic Lung Disease Program, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, developed a treatment-based classification of BPD disease severity. This new definition of BPD is based on the level of respiratory support at 36 weeks PMA, regardless of oxygen administration. This definition has high predictive accuracy for both death or serious respiratory morbidity and death or moderate to severe neurodevelopmental impairment at 18-26 months corrected age. A higher grade of BPD is associated with more severe developmental impairment.

Impact of strategies to prevent or treat BPD

Over the past several decades, many therapies and care strategies—including prenatal therapies, immediate postnatal medications, and respiratory strategies to prevent BPD and later approaches to treat or decrease severity of BPD—have been rigorously evaluated and introduced into the bedside armamentarium. The hope is that by preventing or treating BPD, these strategies will also improve longer-term outcomes.

The key perinatal strategy to prevent BPD is administration of antenatal corticosteroids, which reduce mortality, respiratory distress syndrome, and several other important neonatal morbidities. Unfortunately, however, antenatal steroid treatment does not reduce the incidence of BPD or improve the developmental outcomes of survivors. In the immediate postnatal period, noninvasive respiratory support as an alternative to routine intubation in the delivery room, early surfactant treatment of intubated infants, and vitamin A all lead to reductions in the combined endpoint of death or BPD in very preterm infants. However, none of these approaches has been demonstrated to improve developmental outcomes at 2 years.

The impact of postnatal corticosteroids on both BPD and longer-term developmental outcomes is uncertain due to heterogeneity in existing research as well as in clinical practice, including the type of steroid used, timing of administration, dosing regimen, route of administration, and baseline risk for adverse outcomes in the treated children. When given during the second week or beyond, this therapy may reduce risk for adverse developmental sequelae. However, much remains to be learned about how to best use postnatal steroids to reduce BPD while protecting neurodevelopment. Lastly, inhaled steroids have also been studied both for prevention and treatment of BPD. When initiated in the first 2 weeks of life, inhaled steroids reduce BPD but may increase mortality without clear developmental benefits or harms. Later initiation of inhaled steroids does not reduce BPD and longer-term impacts are unknown.

In the neonatal intensive care unit, caffeine is standard of care for infants at risk for apnea. Caffeine is the only neonatal intervention that has been clearly proven to reduce BPD and provide lasting developmental benefits, with particular benefit for motor outcomes. Importantly, at least half of the improvement in motor impairment that is observed until 11 years in children treated with caffeine is attributed directly to shorter duration of mechanical ventilation.

As BPD progresses, it becomes increasingly difficult to differentiate the impact of the lung disease itself from the impact of therapies to manage or treat the lung disease. The relative risks and benefits of available therapies must be weighed against one another to determine the best care plan for each individual infant.

Next steps for BPD research and clinical care

New strategies for prevention and treatment of BPD are always being evaluated. For example, budesonide instilled with surfactant is likely to significantly reduce BPD, and effects on longer term outcomes are currently under investigation. State-of-the-art approaches, such as the artificial placenta, stem cell therapies, and liquid ventilation, all have the potential to alter the landscape of BPD epidemiology and, hopefully, the subsequent adverse sequelae of BPD.

After discharge, intensive developmental interventions and comprehensive multidisciplinary care are essential for improving medical and neurodevelopmental outcomes for this high-risk population. Yet much remains to be learned about how best to support infants with BPD and their families throughout childhood, in order to help them obtain their maximum developmental potential and reduce childhood functional impairments.

References

Jensen EA, Dysart K, Gantz MG, et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. An evidence-based approach. Am J Respir Crit Care Med. 2019;200(6):751-759.

DeMauro SB, D’Agostino JA, Bann C, et al. Developmental outcomes of very preterm infants with tracheostomies. J Pediatr. 2014;164(6):1303-1310.e2.

Schmidt B, Roberts RS, Anderson PJ, et al. Academic performance, motor function, and behavior 11 years after neonatal caffeine citrate therapy for apnea of prematurity: An 11-year follow-up of the CAP randomized clinical trial. JAMA Pediatr. 2017;171(6):564-572.

Sriram S, Schreiber MD, Msall ME, et al. Cognitive development and quality of life associated with BPD in 10-year-olds born preterm. Pediatrics. 2018;141(6).

Gou X, Yang L, Pan L, Xiao D. Association between bronchopulmonary dysplasia and cerebral palsy in children: A meta-analysis. BMJ Open. 2018;8(9):e020735.

To access our Inpatient and ICU Clinical Pathway for Pulmonary Hypertension (PH) Screenings in Patients with Bronchopulmonary Dysplasia (BPD) visit www.chop.edu/bpdpathwayph.