|Year : 2019 | Volume
| Issue : 1 | Page : 58-64
Meta-analysis of efficacy of iron and iodine fortified salt in improving iron nutrition status
Kapil Yadav1, Akhil Dhanesh Goel2, Vikas Yadav3, Ravi Prakash Upadhyay4, Sarika Palepu5, Chandrakant S Pandav6
1 Associate Professor, Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Assistant Professor, Department of Community Medicine and Family Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
3 Assistant Professor, Department of Community Medicine and Family Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
4 Senior Resident, Department of Community Medicine, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
5 Senior Resident, Department of Community and Family Medicine, All India Institute of Medical Sciences, Bhubaneshwar, Odisha, India
6 Professor and Head, Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||12-Mar-2019|
Dr. Akhil Dhanesh Goel
All India Institute of Medical Sciences, Jodhpur, Rajasthan
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Salt fortification with iron is a potential strategy to increase population-level iron intake. The current evidence regarding double-fortified salt (DFS) in improving iron nutrition status is equivocal. Objective: To study the efficacy of DFS as compared to iodine fortified salt (IS) in improving iron nutrition status. Methods: Randomized controlled trials comparing DFS and IS until August 2016 were systematically searched across multiple databases to assess for change in mean hemoglobin (Hb), prevalence of anemia, iron deficiency (ID), ID anemia (IDA), serum ferritin, and serum transferrin receptor (TfR). Meta-analysis was performed using R software. Results: Of the initial 215 articles retrieved using the predetermined search strategy, data from 10 comparisons of DFS and IS across 8 randomized controlled trials are included. There was significant heterogeneity across included studies and the studies were of low to very low quality as per GRADE criteria. DFS significantly increased mean Hb by 0.44 g/dl (95% confidence interval [CI]: 0.16, 0.71) and significantly decreased anemia (risk difference −0.16; 95% CI: −0.26, −0.06) and ID (risk difference −0.20; 95% CI: −0.32, −0.08) as compared to IS. There was no statistically significant difference in change in ferritin levels (mean difference 0.62 μg/L; 95% CI: −0.12, 1.37), serum TfR levels (mean difference −0.23 mg/dL; 95% CI: −0.85, 0.38), and IDA (risk difference −0.08; 95% CI: −0.28, 0.11). Conclusion: DFS is a potentially efficacious strategy of addressing anemia as a public health problem at population level. There is a need for effectiveness trials before DFS can be scaled up in program mode at population level.
Keywords: Anemia, dietary/administration and dosage, food fortification, iodine/administration and dosage, iron-deficiency/epidemiology
|How to cite this article:|
Yadav K, Goel AD, Yadav V, Upadhyay RP, Palepu S, Pandav CS. Meta-analysis of efficacy of iron and iodine fortified salt in improving iron nutrition status. Indian J Public Health 2019;63:58-64
|How to cite this URL:|
Yadav K, Goel AD, Yadav V, Upadhyay RP, Palepu S, Pandav CS. Meta-analysis of efficacy of iron and iodine fortified salt in improving iron nutrition status. Indian J Public Health [serial online] 2019 [cited 2019 Jul 15];63:58-64. Available from: http://www.ijph.in/text.asp?2019/63/1/58/253893
| Introduction|| |
Anemia is one of the most common and intractable public health problems affecting around 2 billion people worldwide. Asia and Africa account for more than 85% of the anemia burden. In 2010, 8.8% of total global disability from all conditions was attributed to anemia. Iron deficiency (ID) is the single most important cause or anemia accounting for about one-third to half of the total anemia. The National Family Health Survey-4 shows that more than half (58.3%) of the children aged 6–59 months, 54% of women in reproductive age 15–49 years, and 22.1% of males aged 15–49 years were anemic in India. ID anemia (IDA) is a leading cause of disability in India  with an estimated lifetime intangible loss of 8.3 million disability-adjusted life years in 6–59 months birth cohort, production losses of 24,001 million USD corresponding to 1.3% gross domestic product of India. There is felt a need to explore and identify novel approaches to tackle IDA in the country.
The World Health Organization has proposed a three-pronged strategy for addressing IDA comprising of increased iron intake through dietary diversification, food fortification, and iron supplementation; immunization and control of malaria, hookworm, and schistosomiasis; and prevention and control of nutritional deficiencies such as Vitamin B12, folate, and Vitamin A. Anemia control has been on India's policy mandate since 1970 when the erstwhile the National Nutrition Anemia Prophylaxis Programme  was launched. However, India is still grappling with high anemia burden. The National Iron Plus Initiative  2013 has heavily focused on iron supplementation for the prevention and cure of anemia mainly in children, adolescents, and women. Strategies such as iron syrups for pediatric age, weekly iron supplementation to adolescents, directly observed iron consumption  have been shown to be effective in controlled conditions. However, compliance, effective programmatic implementation, and coverage in remote and underserved areas continue to pose a challenge.
In this context, fortification of staple food vehicles with iron can be one of the strategies to supplement iron intake. Fortification of staple food items that are culturally acceptable, affordable, and available is a potentially useful and scalable intervention. The success of iron fortification of staple food is dependent consumption pattern, effect of the fortificant on the taste and appearance of the food vehicle, shelf life, bioavailability of the iron fortificant, and the baseline iron status of the population.,
The expert panel of Copenhagen Consensus, 2008 has ranked iron and iodine fortification of salt as one of the most cost-effective interventions available to address the challenge of global malnutrition. Salt is a regularly purchased and consumed entity and therefore, might ensure a daily supply of iron. The unique characteristics of salt and its success story  as a vehicle for iodization, render it as one of the most suitable food vehicles for iron fortification as well. Salt-fortification with both iodine and iron has been a long-cherished goal; the process has been slow due to unstable physiochemical properties, unacceptable organoleptic changes, and low bioavailability of the combination. Initial technological concerns regarding the stability of iron and iodine in salt have been now overcome with encapsulation, micro ionization, and addition of stabilizers.
However, there is limited scientific evidence on the effect of iron fortification of salt on hematological parameters of anemia. The current meta-analysis attempts to collate and summarize available literature on the efficacy of double-fortified salt (DFS) on iron nutritional parameters. The objectives of the study were to estimate the efficacy of DFS as compared to iodine fortified salt (IS) in improving iron nutrition status as measured by changes in levels of hemoglobin (Hb), serum ferritin (SF), and transferrin receptor (TfR) concentrations and proportion of anemia, ID and IDA.
| Materials and Methods|| |
Data sources and search strategy
Literature search using a defined search strategy was performed in PubMed, Web of Science databases, and Cochrane Central Register of Controlled Trials (Search strategy - Supplement 1). Cross-references from all the eligible articles were further searched for relevant studies. The bibliographies of relevant guidelines, reviews, and reports were also searched to identify relevant primary reports. Online searches of major conference proceedings were conducted to identify unpublished literature. All studies published up till August 2016 were included, and no restriction on language was imposed. For studies with missing data or requiring clarification, principal investigators of the studies were contacted.
Study selection and data extraction
Randomized controlled trials comparing (iron and IS) DFS and iodine only fortified salt (IS) across all age and gender groups were included in the review. Uncontrolled trials, nonhuman studies, and articles with incomplete data were excluded from this review. The primary outcome variable was difference in change in mean Hb at baseline and endline in intervention and control groups. Secondary outcome variables were changes in the prevalence of anemia, prevalence of ID, prevalence of IDA, mean SF, and mean serum TfR levels.
Two authors independently ran the search strategy for identifying articles. Titles and abstracts were studied and full text of potentially relevant studies was assessed according to the prespecified inclusion and exclusion criteria. Disagreement on study inclusion was resolved by discussion with a third author. A data extraction form was developed, pilot tested on a small number of selected studies, and necessary changes were incorporated. The following information was extracted: study descriptors (author and year), geographical settings, population characteristics (age and gender distribution), intervention details (sample size, iron form, concentration, and duration of intervention), and data on outcomes (mean and standard deviation [SD] of baseline and endline Hb, prevalence of anemia, ID, IDA, mean SF, and TfR).
Two reviewers independently assessed the quality of studies included in the review using the Cochrane Risk of Bias tool. Studies were ranked as low, high, or unclear risk of bias across various domains, i.e., random sequence generation, allocation concealment, blinding of participants and persons involved in the study, blinding of outcome assessment, incomplete outcome data, and selective reporting. In addition, for each of the six identified outcomes, Grade assessment was done using GRADEpro GDT software (McMaster University and Evidence Prime Inc., Hamilton, Ontario, Canada) to assess the quality of the evidence generated.
Effect size estimation
The effect size was defined as the difference between the standardized mean change in the intervention and control groups. Effect Size estimation of Hb was done as suggested by Morris for Pretest-Posttest Control Group Designs. SF and serum transferrin when summarized as median (range) values and were converted to mean (SD) using the method described by Hozo et al. before calculating the standardized mean difference.
Cochran's Q (based on Chi-square test) and I2 tests were used to assess the heterogeneity of the studies. The heterogeneity of the trials was regarded as low-level when P < 0.10 for the Chi-square test and I2 < 25%. Random effect model was used to calculate pooled effect size as a “substantial” degree of heterogeneity (I2 ≥ 50%) was noted among the included studies. Forest plots showing the point estimate and confidence intervals (CIs) for each study were created. Sensitivity analysis was performed by excluding any study with extreme observations. Egger's linear regression test  and rank test  were used to assess publication bias. The effect of individual studies on heterogeneity was assessed using graphical method suggested by Baujat et al. The statistical tests were performed using the Meta and Metafor package in R version 3.3.0 (Boston, MA, USA). Two-sided P ≤ 0.05 was considered statistically significant.
| Results|| |
Description of studies
A total of 215 relevant studies were retrieved from different databases (web of science = 103, PubMed = 95, and Cochrane library = 17) [Figure 1]. After removing duplicates (n = 58), title and abstract of 157 items were screened. Seventy-nine studies were excluded at this stage as 34 were not related to fortification, 24 pertained to iodine fortification only, 7 studies were on iron fortification of foodstuffs other than salt, and 14 studies were nonhuman studies. Full-texts of 78 articles were reviewed for the inclusion criteria of which 70 studies were excluded. The reasons for exclusion at this stage were study design not being randomized controlled trial (n = 53), studies only on bioavailability or stability or organoleptic properties (n = 12), data incomplete for review and meta-analysis (n = 3), and duplicate data already mentioned in studies included in the current review (n = 2).
Finally, eight studies were included in the review [Table 1]. Out of these, Andersson et al. had conducted a three-arm trial comparing two different fortificants for the difference from control-ferric pyrophosphate and ferrous fumarate with controls receiving only iodized salt. Asibey-Berko et al. studied DFS intervention in two separate groups, namely nonpregnant, nonlactating mothers, and their under-five children. Thus, 10 studies were effectively available for analysis. Based on the availability of data pertaining to relevant biomarker, 7 studies were pooled for the prevalence of anemia, 6 studies for serum TfR levels, 5 studies for the prevalence of ID, and ferritin levels and 4 for the prevalence of IDA.
|Table 1: Characteristics of included randomized controlled trials comparing double fortified salt and iodine fortified salt|
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Five studies were conducted in India;,,, two each were from Morocco , and Ghana  and one study was from Ivory Coast. A total of 3219 participants were randomized into DFS intervention group (n = 1620) and iodized salt control group (n = 1591). A total of seven studies were done in children, two in adult females and one community-based study covered both adults and children. Only three studies had duration of the intervention of 1 year or more. Concurrent deworming was conducted in five studies. The three distinct types of iron compound used for fortifying the DFS were ferrous fumarate (4 studies), ferric pyrophosphate (3 studies), and ferrous sulfate (3 studies).
Risk of bias assessment
More than 50% of studies addressed allocation concealment (5/10), blinding of participants and study personnel (8/10), and incomplete outcome data (7/10). Only one study gave details of random sequence generation. None of the studies gave sufficient information to assess for blinding of outcome assessment [Figure 2].
There was no publication bias [Figure 3] as linear regression test (P = 0.9263) and Rank correlation test (P = 0.7884) were nonsignificant.
Effect on intervention
The pooled estimate shows that consumption of DFS increased Hb concentration by 0.44 g/dl (95% CI: 0.16–0.71, P < 0.01) in intervention group as compared to control group [Figure 2]. Individually, all studies except one (Wegmuller et al.) showed improvement of Hb, ferritin, and transferrin.
Intervention group had a significant reduction in anemia (risk difference −0.16; 95% CI: −0.26, −0.06) and ID (risk difference −0.20; 95% CI: −0.32, −0.08) but not in IDA (risk difference −0.08; 95% CI: −0.28, 0.11) [Figure 2].
No significant effect of the intervention was seen on ferritin levels (Standardized Mean Difference 0.62 μg/L; 95% CI, −0.12–1.37) [Figure 3]. Similarly, DFS altered transferrin levels by only −0.23 mg/L (95% CI: −0.85–0.38) but failed to reach statistical significance [Figure 2].
After assessing the effect of individual studies on heterogeneity  [Supplement 5], a sensitivity analysis was performed excluding Zimmerman et al. 2004 which gave a pooled estimate of 0.33 (95% CI: 0.18, 0.49).
| Discussion|| |
The current review shows that with consumption of DFS, Hb levels significantly improved the risk of anemia and ID reduced in the controlled settings of the trials included in the review. However, there was no significant effect on serum transferrin, ferritin levels, and the risk of IDA in the studies included in the review. Gera et al. have shown that in principle food fortification can lead to significant improvements in various indicators of iron nutrition. The current review gives further evidence for using salt as a potential fortificant for not only iodine but also iron. The results of the study support the scientific rationale behind the introduction of DFS as part of the public funded nutrition program. However, larger effectiveness trials of greater methodological rigor are required to establish the feasibility of DFS in program mode.
The individual trials may not have conclusively established the efficacy of DFS in improving the iron status of the study subjects primarily due to the shorter duration of the studies. Factoring in the bioavailable iron from DFS and the requirement of iron for improving iron nutrition status, it has been estimated that a duration of at least 2 years is required before a change of 1 g of Hb can be observed after DFS consumption. However, most of the available studies are of much shorter duration (<1 years).
The iron fortificants used in various studies ranged from ferric pyrophosphate, ferrous fumarate, and ferrous sulfate. However, the formulation type did not have a significant effect on the intervention effect size [supplement 3]. Most bioavailable fortificant is water-soluble ferrous sulfate, but it also causes organoleptic problems, such as precipitation and changes in color and flavor. Ferrous fumarate although a relatively water-insoluble compound, however, dissolves adequately in gastric juice and is almost as bioavailable as the freely water-soluble fortificants except in cases of reduced gastric acid generation like mucosal atrophy from protein-energy malnutrition  or bacterial-induced gastritis. Indians have a comparatively lower basal acid output compared to the western population, and this could, therefore, be a reason for low bioavailability if fumarate salts are used for fortification. Ferric pyrophosphate is poorly soluble in both water and gastric juice, however, it has been shown that particle-size reduction and encapsulation improves bioavailability. Similarly, sodium iron EDTA (NaFeEDTA) has been demonstrated to have good iron bioavailability  Identifying the ideal iron compound, and the formulation for DFS will enable scaling up of the program, and further research is warranted. Very few studies are currently available to undertake a meaningful comparative analysis of different iron compounds and formulations used for DFS.
With a mean salt consumption of 10 g/day per person and fortification standard of 1 mg iron per gram salt, DFS is likely to provide nearly 60% of recommended dietary allowance for iron in adults. Thus, DFS can significantly contribute to dietary iron requirement, and if consumed over a long period in maintaining adequate iron stores. Currently, however, there is limited evidence from effectiveness trials to support the introduction of DFS in the national public health program. There is a potential danger of iron overload especially if combined with parallel interventions like iron supplementation and in certain special subgroups like patients with hemoglobinopathies.
The strength of this review includes a large collated sample size resulting in highly precise pooled estimate. There was no observed publication bias, which further increased the validity of our estimate. Grade analysis and assessment of the quality of evidence were generated with respect to each of the outcomes considered in the review (Supplement 4). Limitations of the review included the significant heterogeneity that could not be explained substantially by prespecified subgroups. In most of the included studies randomization procedures were poorly reported and also the overall quality assessed as per Grade criterion varied from very low to low.
DFS is a potentially efficacious strategy of addressing anemia at the population level. However, considering the paucity of effectiveness trials, it may be too early to introduce DFS program in program mode. Further research will be prudent to substantiate effectiveness, nationwide scalability with quality assurance and cost implications of DFS as a strategy to address IDA.
The authors acknowledge sincerely the contribution of Dr. Dipti Dabar, Assistant Professor, Dept of Community and Family Medicine, AIIMS, Bhopal in the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
De Benoist B, McLean E, Egli I, Cogswell M. Worldwide Prevalence of Anaemia 1993-2005: WHO Global Database on Anaemia. Geneva: WHO Library Cataloguing-in-Publication Data; 2008.
Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, et al.
A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014;123:615-24.
Petry N, Olofin I, Hurrell RF, Boy E, Wirth JP, Moursi M, et al.
The proportion of anemia associated with iron deficiency in low, medium, and high human development index countries: A systematic analysis of national surveys. Nutrients 2016;8. pii: E693.
Global Burden of Disease. Profile-India 2015. Institute for Health Metrics and Evaluation. Available from: http://www.healthdata.org/india
. [Last accessed on 2017 Mar 01].
Plessow R, Arora NK, Brunner B, Tzogiou C, Eichler K, Brügger U, et al.
Social costs of iron deficiency anemia in 6-59-month-old children in India. PLoS One 2015;10:e0136581.
Kapil U, Chaturvedi S, Nayar D. National nutrition supplementation programmes. Indian Pediatr 1992;29:1601-13.
Anand T, Rahi M, Sharma P, Ingle GK. Issues in prevention of iron deficiency anemia in India. Nutrition 2014;30:764-70.
Deb S. Emplementation of national iron plus initiative for child health: Challanges ahead. Indian J Public Health 2015;59:1-2.
] [Full text]
Bairwa M, Ahamed F, Sinha S, Yadav K, Kant S, Pandav CS, et al.
Directly observed iron supplementation for control of iron deficiency anemia. Indian J Public Health 2017;61:37-42.
] [Full text]
Sushila G, Ritu H, Smiti N, Sonika M. To study compliance of antenatal women in relation to iron supplementation in routine ante-natal clinic at a tertiary health care centre. J Drug Deliv Ther 2013;3:71-5.
Gera T, Sachdev HS, Boy E. Effect of iron-fortified foods on hematologic and biological outcomes: Systematic review of randomized controlled trials. Am J Clin Nutr 2012;96:309-24.
Swain JH, Newman SM, Hunt JR. Bioavailability of elemental iron powders to rats is less than bakery-grade ferrous sulfate and predicted by iron solubility and particle surface area. J Nutr 2003;133:3546-52.
Hernández M, Sousa V, Moreno A, Villapando S, López-Alarcón M. Iron bioavailability and utilization in rats are lower from lime-treated corn flour than from wheat flour when they are fortified with different sources of iron. J Nutr 2003;133:154-9.
Pandav CS. Evolution of iodine deficiency disorders control program in India: A journey of 5,000 years. Indian J Public Health 2013;57:126-32.
] [Full text]
Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; 2011. Available from: http://www.handbook.cochrane.org
. [Last accessed on 2017 Mar 22].
GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. Ontario, Canada: McMaster University, (Developed by Evidence Prime, Inc.); 2015. Available from: https://gradepro.org/
. [Last accessed on 2017 Mar 22].
Morris SB. Estimating effect sizes from pretest-posttest-control group designs. Organ Res Methods 2008;11:364-86.
Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101.
Baujat B, Mahé C, Pignon JP, Hill C. A graphical method for exploring heterogeneity in meta-analyses: Application to a meta-analysis of 65 trials. Stat Med 2002;21:2641-52.
Viechtbauer W. Conducting Meta-Analyses in R with the metafor Package. J Stat Softw 2010;36:1-48.
Andersson M, Thankachan P, Muthayya S, Goud RB, Kurpad AV, Hurrell RF, et al
. Dual fortification of salt with iodine and iron: A randomized, double-blind, controlled trial of micronized ferric pyrophosphate and encapsulated ferrous fumarate in southern India. Am J Clin Nutr 2008;88:1378-87.
Asibey-Berko E, Zlotkin SH, Yeung GS, Nti-Nimako W, Ahunu B, Kyei-Faried S, et al
. Dual fortification of salt with iron and iodine in women and children in rural Ghana. East Afr Med J 2007;84:473-80.
Sivakumar B, Brahmam GN, Madhavan Nair K, Ranganathan S, Vishnuvardhan Rao M, Vijayaraghavan K, et al
. Prospects of fortification of salt with iron and iodine. Br J Nutr 2001;85 Suppl 2:S167-73.
Vinodkumar M, Rajagopalan S, Bhagwat IP, Singh S, Parmar BS, Mishra OP, et al
. A multicenter community study on the efficacy of double-fortified salt. Food Nutr Bull 2007;28:100-8.
Haas JD, Rahn M, Venkatramanan S, Marquis GS, Wenger MJ, Murray-Kolb LE, et al
. Double-fortified salt is efficacious in improving indicators of iron deficiency in female Indian tea pickers. J Nutr 2014;144:957-64.
Zimmermann MB, Zeder C, Chaouki N, Saad A, Torresani T, Hurrell RF. Dual fortification of salt with iodine and microencapsulated iron: A randomized, double-blind, controlled trial in Moroccan schoolchildren. Am J Clin Nutr 2003;77:425-32.
Zimmermann MB, Wegmueller R, Zeder C, Chaouki N, Rohner F, Saïssi M, et al
. Dual fortification of salt with iodine and micronized ferric pyrophosphate: A randomized, double-blind, controlled trial. Am J Clin Nutr 2004;80:952-9.
Wegmuller R, Camara F, Zimmermann MB, Adou P, Hurrell RF, Wegmüller R, et al
. Salt dual-fortified with iodine and micronized ground ferric pyrophosphate affects iron status but not hemoglobin in children in Cote d'Ivoire. J Nutr 2006;136:1814-20.
Hurrell RF. Preventing iron deficiency through food fortification. Nutr Rev 1997;55:210-22.
Gracey M, Cullity GJ, Suharjono, Sunoto. The stomach in malnutrition. Arch Dis Child. 1977;52:325-7.
Kusters JG, van Vliet AHM, Kuipers EJ. Pathogenesis of Helicobacter pylori Infection. Clin Microbiol Rev 2006;19:449-90.
Wegmüller R, Zimmermann MB, Moretti D, Arnold M, Langhans W, Hurrell RF. Particle size reduction and encapsulation affect the bioavailability of ferric pyrophosphate in rats. J Nutr 2004;134:3301-4.
Karn SK, Chavasit V, Kongkachuichai R, Tangsuphoom N. Shelf Stability, Sensory Qualities, and Bioavailability of Iron-Fortified Nepalese Curry Powder. Food Nutr Bull 2011;32:13-22.
Nutrient Requirements And Recommended Dietary Allowances For Indians: A Report of Expert Group of the Indian Council of Medical Research. Hyderabad; 2009.
[Figure 1], [Figure 2], [Figure 3]