Clinical Factors Associated with Postnatal Urinary Titin N-Fragment in Neonates

Background: Titin is a large sarcomeric protein (~ 3,800 kDa) essential for muscle function. The urinary N-terminal fragment of titin (N-titin) has emerged as a noninvasive biomarker for muscle injury in adults, but its clinical significance in neonates remains unclear. Methods: A retrospective cohort study involving 523 neonates admitted to the NICU/GCU at Nihon University Itabashi Hospital between October 2021 and December 2023 was conducted. Urinary N-titin, collected within 24 hours of birth, was measured using enzyme-linked immunosorbent assay (ELISA) and normalized to creatinine (N-titin/Cr). Associations among neonatal, maternal, and delivery factors were analyzed. A subgroup analysis was performed in neonates with asphyxia. Reference percentiles of N-titin/Cr were separately established for neonates with and without asphyxia. Clinical courses were reviewed for neonates whose N-titin/Cr ratio exceeded the 95th percentile as well as for those with neuromuscular diseases or chromosomal abnormalities. Results: Urinary N-titin levels negatively correlated with gestational age (p = 0.0035) and Apgar score (p < 0.0001). Positive correlations were found among AST, ALT, LDH, creatine kinase (CK), and lactate levels (all p < 0.0001). Stronger correlations with muscle-derived enzymes were observed in neonates with asphyxia. Higher N-titin levels were associated with non-reassuring fetal status, placental abruption, and emergency cesarean delivery. Six neonates with asphyxia exceeded the 95th percentile; three died and two had mild developmental delays. No neuromuscular disease was identified. Seven patients with Down syndrome were identified in this study. Conclusions: Urinary N-titin levels reflect acute perinatal stress, particularly neonatal asphyxia. The establishment of reference values may support its use as an early biomarker in neonates.