Zinc supplementation for prevention of neonatal hyperbilirubinemia: A systematic review and meta-analysis

Given the potential of enteral zinc to reduce enterohepatic circulation of unconjugated bilirubin, we aimed to synthesize evidence from randomized controlled trials (RCTs) on zinc supplementation for prevention of neonatal hyperbilirubinemia (NNH). We searched PubMed, Embase, Scopus, and CENTRAL for RCTs evaluating zinc supplementation in healthy or at-risk neonates for prevention of NNH. Primary outcomes were incidence of significant NNH and requirement for phototherapy. Secondary outcomes included duration of phototherapy, bilirubin levels, and adverse effects. Two reviewers independently screened, extracted data and assessed risk of bias. Random-effects meta-analysis was performed with RevMan 5.4. The certainty of evidence was assessed using the GRADE approach. We included six RCTs, enrolling 725 neonates, in this review. Four trials were judged to have high risk, while two had some concerns of bias. Low certainty evidence suggested no significant effect of zinc on the incidence of significant NNH (RR 0.91, 95% CI 0.58 to 1.44; five trials, 657 participants) or need for phototherapy (RR 0.73, 95% CI 0.42 to 1.28; five trials, 618 participants). Zinc supplementation was associated with a shorter duration of phototherapy (MD -14.79, 95% CI -21.27 to -8.30; four trials, 108 participants). No significant differences were observed in bilirubin levels on day 3 or 7. Adverse events were rare and comparable between groups. In conclusion, there is limited evidence to support or refute the role of zinc supplementation in the prevention of NNH. Rigorous multicenter RCTs with standardized dosing and outcome definitions are needed to further explore its utility.