Metabolome-wide Association Study of Bronchopulmonary Dysplasia in Extremely Premature Infants

Rationale: Untargeted metabolomics may identify novel pathways involved in bronchopulmonary dysplasia (BPD), a poorly understood lung disease in extremely premature infants. Objective: To identify metabolites and pathways altered in infants who develop BPD through a metabolome-wide association study. Methods: We performed untargeted urinary metabolomics in 314 infants (<29 weeks gestational age) at two time points between postnatal days 5-15 and 23-32, with detailed time-series for 28 infants. We compared metabolite levels between infants with and without BPD at 36 weeks postmenstrual age using logistic regression and pathway enrichment analysis. A stratified analysis by nutrition type was performed at 23-32 days. Results: Among the 913 analyzed urinary metabolites, 23 and 68 were nominally associated with BPD between postnatal days 5-15 and 23-32, respectively (p<0.05). We found enrichment in the lactoyl amino acid sub-pathway (5-15 days; p=0.005, q=0.4) and xanthine metabolism and fatty acid metabolism (23-32 days; p≤0.002, q<0.1). Most BPD-differential metabolites were lower in infants with BPD at days 23-32 (OR=7.1, p=2x10-6), with similar patterns among infants receiving parenteral (OR=9.2, p=7x10-7) and full enteral nutrition (OR=6.1, p=0.003). Twenty-four metabolites, including vitamins C, B1, and B6, were lower in infants on parenteral nutrition with BPD at postnatal days 23-32. Discussion: BPD in extremely premature infants was associated with lower levels of vitamin-related metabolites and dysregulation of lactoyl amino acids, xanthine, and fatty acid metabolism. BPD-differential metabolites were lower in infants with BPD during the fourth week of life, potentially related to higher energy demand, metabolic dysregulation, insufficient nutrient availability, and/or impaired intestinal absorption.