Bronchopulmonary dysplasia and brain white matter damage in the preterm infant: a complex relationship

We analysed the relationship between bronchopulmonary dysplasia (BPD) and brain white matter damage (WMD) in very preterm infants, adjusting for common risk factors and confounders. We studied a cohort of infants <32 weeks gestational age (GA) and <1500 g, admitted to 12 hospitals in Northern Italy in 1999-2002. The association between BPD and WMD was estimated by generalised estimating equations and conditional logistic models, adjusting for centre, GA, propensity score for prolonged ventilation and other potential confounders. Directed acyclic graphs (DAG) were used to depict the underlying causal structure and guide analysis. Of the 1209 infants reaching 36 weeks, 192 (15.8%) developed BPD (supplemental oxygen at 36 weeks) and 88 (7.3%) ultrasound-defined WMD (cystic periventricular leukomalacia). In crude analysis, BPD was a strong risk factor for WMD [odds ratio (OR) = 5.9]. With successive adjustments, the OR progressively decreased to 3.88 when adjusting for GA, to 2.72 adding perinatal risk factors, and further down to 2.16 [95% confidence interval 1.1, 3.9] when ventilation was also adjusted for. Postnatal factors did not change the OR. Significant risk factors for WMD, in addition to BPD, were a low GA, a lower Apgar score, a higher illness severity score, ventilation and early-onset sepsis, while antenatal steroids, being small for GA, and surfactant were associated with a reduced risk. In conclusion, our data suggest that BPD is associated with an increased risk of WMD; most of the effect is due to shared risk factors and causal pathways. DAGs helped clarify the complex confounding of this scenario.