• Jo-Anna B Baxter, Bianca Carducci, Mahdis Kamali, Stanley H Zlotkin, and Zulfiqar A Bhutta.
• Centre for Global Child Health, The Hospital for Sick Children, Toronto, Canada.
• Cochrane Db Syst Rev. 2022 Apr 21; 4: CD013463CD013463.

BackgroundIron deficiency is an important micronutrient deficiency contributing to the global burden of disease, and particularly affects children, premenopausal women, and people in low-resource settings. Anaemia is a possible consequence of iron deficiency, although clinical and functional manifestations of anemia can occur without iron deficiency (e.g. from other nutritional deficiencies, inflammation, and parasitic infections). Direct nutritional interventions, such as large-scale food fortification, can improve micronutrient status, especially in vulnerable populations. Given the highly successful delivery of iodine through salt iodisation, fortifying salt with iodine and iron has been proposed as a method for preventing iron deficiency anaemia. Further investigation of the effect of double-fortified salt (i.e. with iron and iodine) on iron deficiency and related outcomes is warranted.  OBJECTIVES: To assess the effect of double-fortified salt (DFS) compared to iodised salt (IS) on measures of iron and iodine status in all age groups.Search MethodsWe searched CENTRAL, MEDLINE, Embase, five other databases, and two trial registries up to April 2021. We also searched relevant websites, reference lists, and contacted the authors of included studies.Selection CriteriaAll prospective randomised controlled trials (RCTs), including cluster-randomised controlled trials (cRCTs), and controlled before-after (CBA) studies, comparing DFS with IS on measures of iron and iodine status were eligible, irrespective of language or publication status. Study reports published as abstracts were also eligible.Data Collection And AnalysisThree review authors applied the study selection criteria, extracted data, and assessed risk of bias. Two review authors rated the certainty of the evidence using GRADE. When necessary, we contacted study authors for additional information. We assessed RCTs, cRCTs and CBA studies using the Cochrane RoB 1 tool and Cochrane Effective Practice and Organisation of Care (EPOC) tool across the following domains: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other potential sources of bias due to similar baseline characteristics, similar baseline outcome assessments, and declarations of conflicts of interest and funding sources. We also assessed cRCTs for recruitment bias, baseline imbalance, loss of clusters, incorrect analysis, and comparability with individually randomised studies. We assigned studies an overall risk of bias judgement (low risk, high risk, or unclear).  MAIN RESULTS: We included 18 studies (7 RCTs, 7 cRCTs, 4 CBA studies), involving over 8800 individuals from five countries. One study did not contribute to analyses. All studies used IS as the comparator and measured and reported outcomes at study endpoint.  With regards to risk of bias, five RCTs had unclear risk of bias, with some concerns in random sequence generation and allocation concealment, while we assessed two RCTs to have a high risk of bias overall, whereby high risk was noted in at least one or more domain(s). Of the seven cRCTs, we assessed six at high risk of bias overall, with one or more domain(s) judged as high risk and one cRCT had an unclear risk of bias with concerns around allocation and blinding. The four CBA studies had high or unclear risk of bias for most domains. The RCT evidence suggested that, compared to IS, DFS may slightly improve haemoglobin concentration (mean difference (MD) 0.43 g/dL, 95% confidence interval (CI) 0.23 to 0.63; 13 studies, 4564 participants; low-certainty evidence), but DFS may reduce urinary iodine concentration compared to IS (MD -96.86 μg/L, 95% CI -164.99 to -28.73; 7 studies, 1594 participants; low-certainty evidence), although both salts increased mean urinary iodine concentration above the cut-off deficiency. For CBA studies, we found DFS made no difference in haemoglobin concentration (MD 0.26 g/dL, 95% CI -0.10 to 0.63; 4 studies, 1397 participants) or urinary iodine concentration (MD -17.27 µg/L, 95% CI -49.27 to 14.73; 3 studies, 1127 participants). No studies measured blood pressure. For secondary outcomes reported in RCTs, DFS may result in little to no difference in ferritin concentration (MD -3.94 µg/L, 95% CI -20.65 to 12.77; 5 studies, 1419 participants; low-certainty evidence) or transferrin receptor concentration (MD -4.68 mg/L, 95% CI -11.67 to 2.31; 5 studies, 1256 participants; low-certainty evidence) compared to IS. However, DFS may reduce zinc protoporphyrin concentration (MD -27.26 µmol/mol, 95% CI -47.49 to -7.03; 3 studies, 921 participants; low-certainty evidence) and result in a slight increase in body iron stores (MD 1.77 mg/kg, 95% CI 0.79 to 2.74; 4 studies, 847 participants; low-certainty evidence). In terms of prevalence of anaemia, DFS may reduce the risk of anaemia by 21% (risk ratio (RR) 0.79, 95% CI 0.66 to 0.94; P = 0.007; 8 studies, 2593 participants; moderate-certainty evidence). Likewise, DFS may reduce the risk of iron deficiency anaemia by 65% (RR 0.35, 95% CI 0.24 to 0.52; 5 studies, 1209 participants; low-certainty evidence).  Four studies measured salt intake at endline, although only one study reported this for both groups. Two studies reported prevalence of goitre, while one CBA study measured and reported serum iron concentration. One study reported adverse effects. No studies measured hepcidin concentration.Authors' ConclusionsOur findings suggest DFS may have a small positive impact on haemoglobin concentration and the prevalence of anaemia compared to IS, particularly when considering efficacy studies. Future research should prioritise studies that incorporate robust study designs and outcome measures (e.g. anaemia, iron status measures) to better understand the effect of DFS provision to a free-living population (non-research population), where there could be an added cost to purchase double-fortified salt. Adequately measuring salt intake, both at baseline and endline, and adjusting for inflammation will be important to understanding the true effect on measures of iron status.Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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