What are the causes and risk factors for bronchopulmonary dysplasia in premature infants?

Causes and Risk Factors for Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia is caused by a multifactorial injury to the immature premature lung, with prematurity itself being the primary risk factor, compounded by oxygen toxicity, mechanical ventilation-induced barotrauma/volutrauma, infection, and patent ductus arteriosus. 1

Primary Causative Factors

Prematurity and Lung Immaturity

• Extreme prematurity (birth <30 weeks gestation and <1000g birth weight) is the single most important risk factor, with approximately 30% of infants <1000g developing BPD 1, 2
• Very preterm infants born before 30 weeks have interrupted alveolar development, leading to the characteristic alveolar simplification seen in "new BPD" 2
• The premature infant has a poorly developed antioxidant system, making them particularly vulnerable to oxygen free radical damage 1

Oxygen Toxicity

• Prolonged exposure to high oxygen concentrations causes complex biochemical, microscopic, and gross anatomic lung tissue damage 1
• Free radical-mediated oxidation of proteins occurs in tracheal aspirates on Days 1-6, with lipid peroxidation peaking on Day 5 1
• Oxygen toxicity is considered one of the two major contributors to BPD pathogenesis 1

Mechanical Ventilation Injury (Barotrauma/Volutrauma)

• Baro- or volutrauma from mechanical ventilation is a critical causative factor, with an inverse relationship between hypocarbia and subsequent BPD development 1
• The most severe lung function abnormalities are found in children who required neonatal ventilation 1
• Pulmonary interstitial emphysema, a direct result of barotrauma, is associated with high BPD incidence 1
• The immature lung is typically exposed concurrently to the dual insults of oxygen toxicity and barotrauma, though oxygen toxicity causes more significant physiological, inflammatory, and histologic changes 1

Important Contributing Factors

Infection and Inflammation

• Postnatal infections (including cytomegalovirus and Ureaplasma urealyticum) significantly increase BPD risk, particularly in infants <1250g (relative risk 1.91) 1, 3
• Antenatal chorioamnionitis plays a key role in producing fetal inflammation that predisposes to BPD 1, 3
• Sepsis and systemic inflammatory response syndrome are key risk factors for BPD through endothelial immune activation and disruption of angiogenesis and alveologenesis 4
• Nosocomial infection potentiates the effect of patent ductus arteriosus on BPD risk 1

Patent Ductus Arteriosus (PDA)

• Many studies demonstrate an association between PDA and BPD, particularly in extremely low birth weight infants 1
• Late episodes of PDA in association with nosocomial infection are important in BPD development, even in infants who initially have no or mild respiratory distress 1
• Infection temporally related to PDA potentiates the effect on chronic lung disease risk 1

Adrenocortical Insufficiency

• Most preterm infants have relative adrenocortical insufficiency, which may potentiate the inflammatory effects of pulmonary insults 1

Fluid Balance (Controversial)

• Delayed diuresis may be more common in patients with BPD 1
• Infants with BPD may receive more fluid in the first days of life, and early sodium supplementation may impact unfavorably because patients receive higher parenteral fluid levels 1
• However, attempting to promote early diuresis with diuretics or albumin does not improve respiratory status 1

Pathophysiological Context

"New BPD" versus "Old BPD"

• The increasing survival of very low birth weight infants has changed the disease pattern 1
• "New BPD" presents with alveolar simplification due to interrupted lung development in extremely premature infants, rather than the fibrosis and architectural disruption of "old BPD" 1, 5
• The differing pathogenesis is based on postconceptional age at birth, with oxygen toxicity and barotrauma acting on increasingly immature and possibly more susceptible lungs 1

Genetic Susceptibility

• Genetic factors contribute to BPD pathogenesis, though specific mechanisms are complex and multifactorial 3, 5

Clinical Implications

The key clinical pitfall is underestimating the cumulative effect of multiple risk factors—an extremely premature infant exposed to mechanical ventilation, supplemental oxygen, and postnatal infection has exponentially higher BPD risk than any single factor alone 1. Prevention strategies must therefore address prematurity prevention (antenatal steroids), gentle ventilation strategies to minimize barotrauma, judicious oxygen use, infection prevention, and early PDA management 6, 5.