What Are Risk Factors for Bronchopulmonary Dysplasia?

Patient Presentation
A 10 week-old male came to clinic for his first well-child visit after being discharged from the neonatal intensive care setting.

The past medical history showed an infant born prematurely at 28 weeks gestation and 965 grams (10%) to a G2P2 female who presented to a local emergency room in active labor. He was transported to a regional children’s hospital and his hospitalization had been complicated by mechanical ventilation for 3 weeks, medical closure of his patent ductus arteriosus, poor initial weight gain and presumed sepsis that occurred early in his treatment. For the past 3 weeks he had been on 1.5 liters of oxygen by nasal cannula without apnea and bradycardia, was slow but consistently eating 24 kcal formula with consistent weight gain. From a health maintenance standpoint, he did not have retinopathy of prematurity, he had received his first vaccines and first dose of palivizumab to prevent respiratory syncytial virus infections. The family was living in a local charity’s long-term accommodation facility for the first 2 weeks after discharge, so this visit was for temporary outpatient care until they returned to their own home. Once home, a visiting nurse was scheduled for the first month to monitor him and support his family, along with establishing care with his own doctor.

The pertinent physical exam showed a small infant with a weight of 2410 gram (5%) which was up 15 grams/day for 2 days with a nasal cannula in place. His saturation was 91-94% in clinic. He was proportional in his other growth parameters. His physical examination was non-contributory.

The diagnosis of a premature infant was made. The family was to continue his routine care and was to followup in 1 week and when he returned he was gaining 11 grams/day with a stable physical examination. He was to followup with neonatology the next week before returning home. He also already had another neonatology appointment 2 months later to follow his weight, his bronchopulmonary dysplasia and weaning off of oxygen and developmental status.

Bronchopulmonary dysplasia (BPD) was first described in 1967 by Northway et.al. At that time it was described as “relatively mature preterm infants with severe respiratory failure to survive their initial respiratory distress syndrome after receiving aggressive respiratory support with high oxygen and positive pressure ventilation. Their clinical course was characterized by severe chronic respiratory failure with a radiographic picture showing areas of hyperinflation alternating with adjacent increased densities.” This is often referred to as “Old BPD.”

Over time more has been learned and improvements in care of preterm and term infants has occurred. “New BPD” occurs in younger preterm infants but they are treated with antenatal steroids, surfactant and gentler methods of mechanical ventilation. Pathologically the lung has less emphysema, fibrosis, smooth muscle hypertrophy and epithelial metaplasia. There are various specific definitions especially for BPD severity, but basically it is defined as the need for chronic supplemental oxygen. Usually this is for more than 28 days and the need for oxygen at 36 weeks corrected gestation. In extremely low birth weight premature infants (<28 weeks gestation) about 40% develop BPD.

The lung embryologically undergoes changes that are characterized as increased branching of the airway tubules, differentiation of the airway cells, and thinning of the cellular walls of the lung. Many preterm infants are born at the canalicular stage at 16-26 weeks gestation that has acinar tubules, and at 26-36 weeks gestation in the saccular stage with terminal saccules. The alveolar stage occurs from then on. Simplistically, the lung at the canalicular and saccular stages has relatively few branches, there is “thick” tissue where air exchange/diffusion occurs, and the lung doesn’t make as much surfactant to help keep the tubular structures patent. So simplistically the lung has less surface area for air exchange, it is harder for the air exchange/diffusion to occur, and the tubular structures can easily close down and not allow air to flow through the lung. These problems along with others make it difficult for the preterm infant to have successful respiration and ventilation such as immature bones and muscles of the chest wall and diaphragm which are needed to exert the pressures required to move a relatively stiff lung. Premature infants also have an immature central nervous system trying to regulate respiration.

Trying to treat a premature infant is a real balancing act. Neonatologists are trying to balance the ongoing needs of the premature infant which constantly are physiologically changing even moment to moment, in an infant who is still rapidly developing all organ systems but which are all immature, using equipment and methods in tiny body spaces, and with incomplete medical knowledge regarding physiology where optimal levels of many treatments still are not conclusively known. The neonatologist must try to balance the specific immediate needs with the potential for increasing other problems in the future.

The most efficacious treatment has not been determined with strategies for BPD prevention centering on use of antenatal steroids to accelerate lung development of the fetus and use of exogenous surfactant to aid lung tubule patency and improve mechanics. Additionally, minimizing the respiratory support needed by using noninvasive respiratory support measures such high flow nasal cannula or intermittent positive pressure ventilation is very important for BPD prevention. Using these measures for the least amount of time necessary and the least pressures decreases BPD. However, stiff lungs make it difficult to ventilate a premature infant to allow for adequate air exchange and oxygenation to occur.

Oxygen therapy really highlights the delicate balancing act of managing competing priorities. Oxygen therapy needs to keep the oxygen levels up to minimize hypoxia and potential brain damage, but it is also directly toxic to the lungs. Therefore using the minimal supplemental oxygen needed is important but also the “best” oxygen levels aren’t totally elucidated. Different oxygen levels are also associated with other problems such as mortality, necrotizing enterocolitis, and retinopathy of prematurity and have to be balanced.

Optimizing premature infant nutrition also helps prevent BPD. However it can be difficult to provide adequate calorie and nutrient needs because the gastrointestinal system itself is immature and parenteral nutrition has risks of infection, extravasation and the pragmatic problems of obtaining and maintaining parenteral access.

Other treatments that may have some beneficial effects are caffeine and Vitamin A. Diuretics are also commonly used to treat fluid retention and pulmonary edema that may be associated with BPD.

Learning Point

Risk factors for BPD include:

  • Gestational age which is inversely proportional to the risk of BPD
  • Birth weight, which is also inversely proportional to the risk of BPD
  • Oxygen therapy – higher concentrations have higher risks
  • Mechanical ventilation trauma – more invasive measures, for longer periods with higher pressures have higher risks of BPD
  • Antenatal factors – maternal smoking, hypertension, lower socioeconomics factors
  • Genetics
  • Male gender
  • White race
  • Inflammation – trauma, infection (systemic or pulmonary)
  • Colonization or microbiome – possibly
  • Patent ductus arteriosus – possibly
  • Transfusion – possibly

Note that not all of these risk factors have clearly indicated causality in studies. They may only be associated with BPD.

Questions for Further Discussion
1. What are the relationships to BPD of respiratory distress syndrome and hyaline membrane disease?
2. What makes oxygen so potentially toxic to living tissue?
3. What are the long term potential problems with BPD?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Bronchial Disorders and Premature Babies.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Hwang JS, Rehan VK. Recent Advances in Bronchopulmonary Dysplasia: Pathophysiology, Prevention, and Treatment. Lung. 2018;196(2):129-138. doi:10.1007/s00408-018-0084-z

Bancalari E, Jain D. Bronchopulmonary Dysplasia: 50 Years after the Original Description. Neonatology. 2019;115(4):384-391. doi:10.1159/000497422

Tracy MK, Berkelhamer SK. Bronchopulmonary Dysplasia and Pulmonary Outcomes of Prematurity. Pediatr Ann. 2019;48(4):e148-e153. doi:10.3928/19382359-20190325-03

Thebaud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers. 2019;5(1):78. doi:10.1038/s41572-019-0127-7

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa