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

Abstract

Background: Previous investigations on the impact of oral zinc sulfate treatment on newborns' serum bilirubin levels have produced conflicting results. This meta-analysis aims to clarify the efficacy of zinc sulfate in infants with hyperbilirubinemia by combining the results 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; and the search was updated on 25 October 2025, for the RCTs that investigate the use of zinc sulfate in infants with hyperbilirubinemia. The primary outcome was the change in total serum bilirubin (TSB) (mg/dL). Mean difference (MD) with 95% confidence interval (95% CI) was used to estimate the overall effect of the outcomes. Random effects model was used to pool the results. Results: A total of 1405 infants pooled from the 14 RCTs were analysed. Zinc sulfate significantly reduced bilirubin levels at 24 hours (MD: -1.12 mg/dL, 95% CI [-1.73; -0.52], p=0.0003, I2= 90.5%), at 48 hours (MD: -1.23 mg/dL, 95% CI [-2.19; -0.28], p=0.0116, I2= 89.1%), at 72 hours (MD: -1.35 mg/dL, 95% CI [-2.57; -0.14], p=0.0294, I2= 95.4%), and at 4 days (MD: -1.57 mg/dl, 95% CI [-2.33; -0.81], p<0.0001, I2= 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, the full-term infants with normal birth weights benefited from the intervention. On the other hand, no significant difference in preterm and low-birth-weight infants was found. There were no significant differences between 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.