Untargeted Urinary Metabolomic Profiles and Nutritional Status in Newborns with Congenital Heart Disease

Background Congenital heart disease (CHD) represents the most common birth defect worldwide and remains a leading cause of morbidity and mortality in the neonatal period. Newborns with complex CHD frequently require early intervention and prolonged hospital stay. This population is particularly vulnerable to metabolic stress, feeding difficulties and impaired growth. Metabolomics approaches in pediatric CHD have identified metabolic alterations associated with disease process and preoperative stress, but the relationship between metabolomic profiles and nutritional status (one of the key determinants of growth and recovery) in neonates with CHD remains underexplored. Objectives Primary objectives of this study were to assess whether urinary metabolomics profiles at birth (TP0) are associated with birth WAZ and whether early post-operative urinary metabolomics profiles (TP2) are associated with discharge WAZ. Secondary objectives focused on describing pre-operative feeding practices and evaluating nutritional support during hospitalization in relation to nutritional status assessed by WAZ. Methodology A prospective, single-center observational study was conducted in full-term neonates with congenital heart disease requiring corrective or palliative cardiac surgery at the Neonatal Intensive Care Unit of Padua University Hospital. Urine samples collected at birth (TP0) and in the early post-operative period (TP2) underwent untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomic analysis. Clinical, anthropometric, and nutritional data were retrospectively collected from electronic medical records. Associations between metabolomic profiles and WAZ were evaluated using multiple linear regression (MLR) and partial least squares (PLS) regression, while nutritional characteristics were described according to WAZ. Results Twenty-four full-term neonates (mean birth weight 3093 ± 550 g) with LVOTO (41.7%), TGA (29.2%), or other complex CHD (29.2%), with complete metabolomic and clinical data were included. At birth (TP0), metabolites associated with birth WAZ were predominantly related to amino acid, aromatic amino acid, and purine metabolism. Post-operative metabolomic profiles (TP2) associated with discharge WAZ - particularly involved pathways related to amino acid metabolism, fatty acid oxidation, and energy metabolism. Pre-operatively, most infants (n=23) received combined enteral and parenteral nutrition (73.9%), with good tolerance overall (91.3%). Post-operatively (n=22), most infants required parenteral nutrition initially, with progression toward enteral feeding and good tolerance overall (95.5%). At discharge, all surviving infants tolerated full oral feeding, most commonly with breast milk or mixed feeding as the predominant diet types. Most infants (13/20) had a normal WAZ ≥ -2 at discharge; however, mean WAZ declined progressively across timepoints from birth (-0.45 ± 1.28) to discharge (-1.76 ± 1.36). Conclusions These findings provide preliminary evidence that neonates with CHD experience metabolic and nutritional challenges during hospitalization, underlining the need for individualized optimal feeding strategies in this population. Urinary metabolomic profiling in relation to WAZ scores may provide additional insight into nutritional status and growth optimization in neonates with CHD. Further validation in larger longitudinal cohorts is required to determine the clinical relevance of this approach and the potential contribution to more individualized nutritional assessment and clinical management in the pediatric CHD population.