Zinc Supplementation in Neonatal Hyperbilirubinemia: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background and objectives: In vitro studies suggest that oral zinc supplementation reduces enterohepatic circulation of unconjugated bilirubin and serum bilirubin levels. Multiple randomized controlled trials (RCTs) have assessed the efficacy of oral zinc supplementation in reducing bilirubin levels and the need for phototherapy. However, the evidence remains conflicting. Therefore, we aimed to evaluate the effects of oral zinc supplementation in neonatal hyperbilirubinemia.

Methods: We searched PubMed, Embase, Web of Science, and various clinical registries for RCTs published until May 25, 2025, and compared zinc with placebo/routine care in neonates with or at risk of hyperbilirubinemia. A random-effects meta-analysis was conducted. The Risk of Bias Version 2 tool was used.

Results: Seventeen studies (1565 participants) were included in this systematic review. Only 1 study provided data on the need for exchange transfusion for extreme hyperbilirubinemia, in which no events were reported in either group. There was no significant difference in the incidence of significant hyperbilirubinemia (4 studies, 577 neonates, risk ratio [RR]: 0.96, 95% confidence interval [CI]: 0.41-2.27) or the need for phototherapy (5 studies, 619 neonates, RR: 0.72, 95% CI: 0.32-1.60) (very low certainty). Oral zinc supplementation also led to a statistically significant reduction in the duration of phototherapy (12 studies, 1528 neonates, mean difference: 8.6 hours, 95% CI: 3.7-13.6 hours, low certainty). No differences were observed in adverse events or the duration of hospital stay.

Conclusions: Oral Zn supplementation may reduce the duration of phototherapy but does not affect other outcomes.