Maternal Gestational Diabetes Mellitus as an Independent Risk Factor for Hearing Impairment in Hyperbilirubinemia Newborns: A Prospective Birth Cohort With Genetic Profiling.

BACKGROUND

Gestational diabetes mellitus (GDM) may exacerbate hyperbilirubinemia-induced auditory neurotoxicity via oxidative stress, whereas genetic susceptibility (e.g., GJB2 variants) heightens cochlear vulnerability. However, the tripartite interplay among maternal metabolic dysregulation, neonatal hyperbilirubinemia and genetic predisposition remains poorly characterized.

OBJECTIVE

This study aimed to investigate the synergistic interaction between GDM and neonatal hyperbilirubinemia in auditory dysfunction, focusing on the modifying role of deafness-associated genetic variants (GJB2, SLC26A4, and mtDNA).

METHODS

In this prospective cohort study (our hospital, 2023-2025), 350 neonates were classified by an exposure-based 2 × 2 factorial design into four groups: GDM-exposed hyperbilirubinemia ( n  = 98), non-GDM hyperbilirubinemia ( n  = 185), GDM-only ( n  = 42) and healthy controls ( n  = 25). Genetic screening was performed via Sanger sequencing. Serial audiological assessments (automated auditory brainstem response) and brainstem auditory evoked potential [BAEP]) and biochemical monitoring (bilirubin-to-albumin [B/A]), malondialdehyde [MDA] and superoxide dismutase) were conducted at birth, 72 h, 1 month, and 3 months. Cox proportional hazards models, multivariable logistic regression and bootstrapped causal mediation analysis were used to evaluate risk factors and oxidative stress-mediated pathways.

RESULTS

GDM-exposed hyperbilirubinemia neonates exhibited a 2.3-fold higher incidence of severe hearing loss compared with those with hyperbilirubinemia alone (34.7% vs. 15.1%, P < 0.001). GJB2 variant carriers showed significantly greater BAEP threshold elevation (Δ = 9.2 ± 3.1 dB vs. 3.1 ± 1.8 dB, P  = 0.002) than their counterparts. The B/A ratio was a GDM-dependent prognostic marker, with B/A > 5.5 predicting hearing loss only in the GDM subgroup (odds ratio = 4.17, 95% confidence interval [CI]: 2.33-7.45). MDA accounted for 38% of the total effect of GDM-hyperbilirubinemia on auditory impairment (indirect effect β  = 0.28, 95% CI: 0.19-0.39).

CONCLUSION

GDM significantly modifies hyperbilirubinemia-induced auditory toxicity through oxidative stress and genetic interaction, particularly in GJB2 carriers. Integrated screening of maternal glycemic status, neonatal bilirubin dynamics, and deafness-associated genes is warranted.