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Meta-Analysis
. 2022 Dec 22;13(6):2488-2518.
doi: 10.1093/advances/nmac088.

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

Marena Ceballos-Rasgado  1 , Nicola M Lowe  1 , Simonette Mallard  2 , Andrew Clegg  3 , Victoria H Moran  1 , Catherine Harris  3 , Jason Montez  4 , Maria Xipsiti  5
Affiliations
Meta-Analysis

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

Marena Ceballos-Rasgado et al. Adv Nutr. .

Abstract

Zinc supplementation reduces morbidity, but evidence suggests that excessive intakes can 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 y 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 were used to generate forest plots to examine the evidence by age category, dose, dose duration, chemical formula of zinc, and zinc compared with placebo. The Joanna Briggs Institute Critical Appraisal Checklist, Cochrane Risk of Bias 2, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guideline 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, serum transferrin receptor, hemoglobin, hematocrit, and the odds of anemia in ≥1 of the subgroups investigated. Lactulose:mannitol ratio was improved with zinc supplementation, and no significant effect was observed on C-reactive protein, erythrocyte superoxide dismutase, zinc protoporphyrin, 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.

Keywords: children; dietary requirements; meta-analysis; systematic review; upper limits; zinc.

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Figures

FIGURE 1
FIGURE 1
PRISMA-2020 flow diagram of the search procedure. 1See Supplemental File 2 for further information on how studies were selected. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. (Note: Reports refers to ‘articles’ in the main text).
FIGURE 2
FIGURE 2
Effect of zinc supplementation on hemoglobin (g/L) in children aged 0–90 d by zinc dose. IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo.
FIGURE 3
FIGURE 3
Effect of zinc supplementation on hemoglobin (g/L) in children aged 91–180 d by zinc dose. IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; Pl, placebo.
FIGURE 4
FIGURE 4
Effect of zinc supplementation on hemoglobin (g/L) in children aged >6 mo to 12 mo by zinc dose. FA, folic acid.; IFA, iron plus folic acid; IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo; Vit A, vitamin A; Vit C, vitamin C.
FIGURE 5
FIGURE 5
Effect of zinc supplementation on hemoglobin (g/L) in children aged >12 mo by zinc dose. IV, inverse variance, Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo; Vit A, vitamin A.
FIGURE 6
FIGURE 6
Effect of zinc supplementation on anemia (OR) in children aged 91–180 d by zinc dose. M-H, Mantel-Haenszel test; Random, random effect model; 95% CI, 95% confidence interval; Pl, placebo.
FIGURE 7
FIGURE 7
Effect of zinc supplementation on anemia (OR) in children aged >6 mo to 12 mo by zinc dose. FA, folic acid; M-H, Mantel-Haenszel test; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo; Vit A, vitamin A; Vit C, vitamin C.
FIGURE 8
FIGURE 8
Effect of zinc supplementation on anemia (OR) in children aged >12 mo by zinc dose. M-H, Mantel-Haenszel test; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo; Vit A, vitamin A.
FIGURE 9
FIGURE 9
Effect of zinc supplementation on serum ferritin (μg/L) in children aged 0–90 d by zinc dose. IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo.
FIGURE 10
FIGURE 10
Effect of zinc supplementation on serum ferritin (μg/L) in children aged 91–180 d by zinc dose. IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; Pl, placebo.
FIGURE 11
FIGURE 11
Effect of zinc supplementation on serum ferritin (μg/L) in children aged >6 mo to 12 mo by zinc dose. IFA, iron plus folic acid; IV, inverse variance; Random, random effect model, 95% CI; 95% confidence interval; MMN, multiple micronutrients; Pl, placebo.
FIGURE 12
FIGURE 12
Effect of zinc supplementation on serum ferritin (μg/L) in children aged >12 mo by zinc dose. IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo.
FIGURE 13
FIGURE 13
Effect of zinc supplementation on serum/plasma copper (μg/dL) in children aged 91–180 d by zinc dose. IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; Pl, placebo.
FIGURE 14
FIGURE 14
Effect of zinc supplementation on serum/plasma copper (μg/dL) in children aged >6 mo to 12 mo by zinc dose. MMN, multiple micronutrients; IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval Pl, placebo.
FIGURE 15
FIGURE 15
Effect of zinc supplementation on serum/plasma copper (μg/dL) in children aged >12 mo by zinc dose. IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval ; MMN, multiple micronutrients; OA, open arm; Pl, placebo.
FIGURE 16
FIGURE 16
Effect of zinc supplementation in infants and children aged ≤3 y on iron deficiency (OR) by age group. Note: Zinc exposure corresponds to mg/d except for Rosado et al. (59) for which doses were given 6 d/wk. FA, folic acid; IFA, iron plus folic acid; M-H, Mantel-Haenszel test; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo; Vit C, vitamin C.
FIGURE 17
FIGURE 17
Effect of zinc supplementation in infants and children aged ≤3 y on iron deficiency anemia (OR) by age group. Note: Zinc exposure corresponds to mg/d. M-H, Mantel-Haenszel test; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo.
FIGURE 18
FIGURE 18
Effect of zinc supplementation in infants and children aged ≤3 y on serum/soluble transferrin receptor (mg/L) by age group. Note: Zinc exposure corresponds to mg/d except for Baqui et al. (28) for which dose was 20 mg/d once weekly, and Chang et al. (36) for which dose was given in alternate days. FA, folic acid; IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo.
FIGURE 19
FIGURE 19
Effect of zinc supplementation in infants and children aged ≤3 y on hematocrit (proportion) by age group. Note: Zinc exposure corresponds to mg/d. IFA, iron folic acid; IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo.
FIGURE 20
FIGURE 20
Effect of zinc supplementation in infants and children aged ≤3 y on raised C-reactive protein by age group. Note: Zinc exposure corresponds to mg/d except for Chang et al. (36) for which dose was given in alternate days. FA, folic acid; M-H, Mantel-Haenszel test; Random, random effect model; 95% CI, 95% confidence interval; MMN, multiple micronutrients; Pl, placebo.
FIGURE 21
FIGURE 21
Effect of zinc supplementation on erythrocyte superoxide dismutase (IU/mg Hb) in children aged >12 mo by zinc dose. Note: Zinc exposure corresponds to mg/d. IV inverse variance; Random, random effect model; 95% CI, 95% confidence interval; Pl, placebo.
FIGURE 22
FIGURE 22
Effect of zinc supplementation on zinc protoporphyrin (μmol/mol heme) in children >6 mo to 12 mo by zinc dose. Note: Zinc exposure corresponds to mg/d. FA, folic acid; IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; Pl, placebo.
FIGURE 23
FIGURE 23
Effect of zinc supplementation in infants and children aged ≤3 y on serum total cholesterol (mg/dL) by duration of treatment. Note: Zinc exposure corresponds to mg/d except for Hambidge et al. (17) for which doses were given 6 days per week. IV, inverse variance; Random, random effect model; 95% CI, 95% confidence interval; Pl, placebo.
FIGURE 24
FIGURE 24
Effect of zinc supplementation in infants and children aged ≤3 y on lactulose:mannitol ratio by age group. Note: Zinc exposure corresponds to mg/d except for Bates et al. (18) for which doses of 70 mg/d were given twice weekly. IV, inverse variance; Pl, placebo.
FIGURE 25
FIGURE 25
Effect of zinc supplementation in infants and children aged ≤3 y on serum iron concentration (μg/dL) by age group. IV, inverse variance; Random, random effect model, 95% CI, 95% confidence interval; Pl, placebo.
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