Systematic review links elevated bilirubin and infections to hearing loss in NICU neonates

BackgroundInfants admitted to neonatal intensive care units are at increased risk of hearing loss, yet early identification remains challenging. Understanding circulating biomarkers of hearing loss may improve risk stratification and inform targeted surveillance and intervention.ObjectivesTo assess whether biological factors measured in bodily fluids predict hearing loss in neonates admitted to the neonatal intensive care.MethodsSystematic review and meta-analyses were conducted (registration ID: CRD42024531492). Comprehensive searches were undertaken to identify peer-reviewed studies published between 2000 and 2025 evaluating fluid biomarkers and hearing outcomes in neonates. Risk of bias was assessed across five domains. Biomarkers were grouped by biological domain and synthesised narratively. Where feasible, random-effects meta-analyses were performed using odds ratios and restricted maximum likelihood estimation for calculation of pooled effect sizes.ResultsEighty-six studies were included, predominantly retrospective cohorts with substantial methodological heterogeneity. Elevated bilirubin exposure (n = 44 studies) was consistently associated with hearing loss, with unbound bilirubin demonstrating superior predictive performance. Infective conditions (n = 32 studies), particularly congenital cytomegalovirus, meningitis, and invasive fungal infections showed significant associations with hearing loss. Risk of bias was moderate to high across studies, driven by inconsistent hearing outcomes measures, poor repeatability of biomarker measures and limited inclusion of risk factors and confounders which affect biomarker concentrations.DiscussionSystemic neonatal biomarkers, particularly unbound bilirubin and infective markers, show consistent associations with hearing loss, though high heterogeneity limits precision. Evidence was heterogeneous and largely exploratory. Future studies should utilise integrated databases where data have rigorous confounder adjustment, standardised biomarker assessments, and validated hearing outcome measures to identify clinically meaningful biomarkers of hearing loss.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024531492.