Efficacy of zinc sulfate in neonatal hyperbilirubinemia: a meta-analysis of randomized controlled trials

Background Previous investigations into the impact of oral zinc sulfate on serum bilirubin levels of newborns have yielded conflicting results. This meta-analysis aimed to clarify the efficacy of zinc sulfate in infants with hyperbilirubinemia by combining the evidence from published randomized controlled trials (RCTs). Methods In this systematic review, PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science were searched in August 2024, with an update on 25 October 2025, for the RCTs investigating zinc sulfate in infants with hyperbilirubinemia. The primary outcome was the change in total serum bilirubin (mg/dL). Mean difference (MD) with 95% confidence interval [95% confidence interval (CI)] was used to estimate the overall effect of the outcomes. A random-effects model was used to pool the results. Results A total of 14 RCTs comprising 1,405 infants were analyzed. Zinc sulfate significantly reduced bilirubin levels at 24 h [MD: −1.12 mg/dL, 95% CI (−1.73; −0.52), p = 0.0003, I 2 = 90.5%], at 48 h [MD: −1.23 mg/dL, 95% CI (−2.19; −0.28), p = 0.0116, I 2 = 89.1%], at 72 h [MD: −1.35 mg/dL, 95% CI (−2.57; −0.14), p = 0.0294, I 2 = 95.4%], and at 4 days [MD: −1.57 mg/dL, 95% CI (−2.33; −0.81), p < 0.0001, I 2 = 0.0%]. The high heterogeneity might be raised from the different clinical settings, such as gestational age, zinc sulfate doses, different therapy protocols among the regions and inconsistent phototherapy durations across the different regions. In the subgroup analysis, full-term infants with normal birth weights benefited from the intervention. On the other hand, no significant differences were observed in preterm and low-birth-weight infants. There were no significant differences between the zinc sulfate and placebo groups in phototherapy and hospital stay durations. GRADE assessment showed that most outcomes ranged from low to very low certainty of evidence. Conclusion This meta-analysis showed that zinc sulfate may reduce total serum bilirubin levels in full-term, normal-birth-weight infants during the first 4 days with a modest effect. However, this conclusion is limited by the high heterogeneity and low certainty of evidence. There was no significant reduction in phototherapy and hospital stay durations.