Adverse Effects of Excessive Zinc Intake in Infants and Children Aged 0-3 Years: A Systematic Review and Meta-Analysis

Abstract

Zinc supplementation reduces morbidity, but evidence suggests that excessive intakes may have negative health consequences. Current guidelines of upper limits (ULs) of zinc intake for young children are extrapolated from adult data. This systematic review (PROSPERO; registration no. CRD42020215187) aimed to determine the levels of zinc intake at which adverse effects are observed in young children. Studies reporting potential adverse effects of zinc intake in children aged 0–3 years were identified (from inception to August 2020) in MEDLINE, EMBASE and the Cochrane Library, with no limits on study design. Adverse clinical and physical effects of zinc intake were synthesized narratively, and meta-analyses of biochemical outcomes were conducted. Random effects models, forest plots were generated to examine the evidence by age category, dose, dose duration, chemical formula of zinc, and zinc vs placebo. The Joanna Briggs Institute Critical Appraisal Checklist, Cochrane Risk of Bias 2, and Grading of Recommendations Assessment, Development and Evaluation guideline (GRADE) were employed to assess risk of bias and to appraise the certainty of evidence. Fifty-eight studies assessed possible adverse effects of zinc doses ranging from 3 to 70 mg/d. Data from 39 studies contributed to meta-analyses. Zinc supplementation had an adverse effect on serum ferritin, plasma/serum copper concentration, sTfR, hemoglobin, hematocrit, and the odds of anemia in at least one of the subgroups investigated. Lactulose: mannitol ratio was improved with zinc supplementation, and no significant effect was observed on CRP, eSOD, ZPP and blood cholesterol and iron deficiency anemia. The certainty of the evidence, as assessed using GRADE, was very low to moderate. Although possible adverse effects of zinc supplementation were observed in some subgroups, it is unclear whether these findings are clinically important. The synthesized data can be used to undertake a dose-response analysis to update current guidelines of ULs of zinc intake for young children.