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3 Nutritional Intervention Research Unit and 4 Biostatistics Unit, Medical Research Council, Cape Town, South Africa and 5 School of Physiology, Nutrition and Consumer Science, North-West University, Potchefstroom, South Africa
* To whom correspondence should be addressed. E-mail: lize.van.stuijvenberg{at}mrc.ac.za.
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ABSTRACT |
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 TOP ABSTRACT IntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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125 g/L were randomly assigned to 1 of 4 groups that received 4 slices of brown bread supplying either: 1) no fortification iron 2) 2.35 mg iron as NaFeEDTA; 3) 4.70 mg iron as ferrous fumarate; and 4) 8.30 mg iron as electrolytic iron per intervention day. These amounts simulated a bread intake of 6 slices per day over the 34-wk study period at fortification levels of 0, 10, 20, and 35 mg/kg flour, respectively. Hb concentration and iron status were assessed at baseline and after 34 wk of intervention. The iron interventions did not affect Hb concentration, transferrin saturation, or serum ferritin, iron, or transferrin receptor concentrations relative to the control group. Our results suggest that electrolytic iron at the level currently used in South Africa is not effective in improving iron or Hb status. Neither do NaFeEDTA or ferrous fumarate appear to be suitable alternatives for the fortification of wheat flour when included at levels that do not cause color changes.
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Introduction |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Electrolytic iron, at a level of 35 mg/kg flour, is currently being used by South Africa for its mandatory national food fortification program as iron fortificant in wheat and maize flour (4). However, because of uncertainty regarding its effectiveness as a fortificant (5,6), especially at the level used in South Africa, alternative iron compounds are also being considered, e.g., ferrous fumarate and sodium iron EDTA (NaFeEDTA).6
Ferrous fumarate has a relative bioavailability similar to ferrous sulfate, the reference against which the bioavailability of all other iron compounds is measured (2). Being less soluble in water than ferrous sulfate, it has the advantage of causing fewer organoleptic problems. Ferrous fumarate is, as is ferrous sulfate, subject to the inhibitory effects on iron absorption of phytates present in cereal flours (7). NaFeEDTA is a chelated iron compound in which the iron is protected from the inhibitors of iron absorption. It has a bioavailability 2–4 times that of ferrous sulfate, especially in meals with a high phytate content (8). Its efficacy as fortificant has been demonstrated in several fortification trials and in vehicles such as curry powder (9), sugar (10), fish sauce (11), and maize flour (12).
Although both ferrous fumarate and NaFeEDTA thus seem to be good alternatives for electrolytic iron, the matrix of the food vehicle will determine the amount that can be used and hence its efficacy as fortificant. It is therefore important that the efficacy of these 2 compounds is evaluated at levels that are compatible with the vehicle in which they are used. This may not necessarily be the same for all countries and situations (13).
The aim of this study therefore was to evaluate the efficacy of NaFeEDTA and ferrous fumarate as fortificants in brown bread in South African primary school children at levels tolerated by the food matrix in terms of aroma, taste, crumb color, bread volume, dough strength, and cell structure in a randomized controlled trial. A secondary aim was to evaluate the efficacy of electrolytic iron at the level currently used by South Africa in its national food fortification program.
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Subjects and Methods |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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The study was conducted in the Western Cape, South Africa, in a primary school serving a low socioeconomic community. A total of 794 children were screened for low hemoglobin (Hb) concentrations and those with Hb 125 g/L (n = 362) were selected to take part in the study. One child with a Hb concentration of 72 g/L was not randomized and was referred to the local clinic for treatment (Fig. 1). All participants were dewormed (500 mg mebendazole) 4 wk prior to the baseline assessment. Based on the results of a previous iron fortification study in primary school children (14), we estimated that if only children with low Hb concentrations were included in the study and a common SD of 0.5 for Hb was assumed, a sample size of 60 children per group would be sufficient to detect a 3% increase in Hb at 5% significance level with 90% power. For practical reasons, as well as to make a provision for drop-outs, all children meeting the inclusion criteria were included in the study. The study was approved by the Ethics Committee of the South African Medical Research Council and permission was obtained from the Western Cape Department of Education and the school governing body. Written informed consent was obtained from the parents or guardians of all participants.
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Fortification level
The amount of NaFeEDTA and ferrous fumarate added to the wheat flour was based on the results of sensory studies in brown bread that preceded the trial (details to be published elsewhere). According to these studies, neither fortificant had a negative effect on bread in terms of aroma, taste, bread volume, or dough strength, even at levels of up to 200 mg/kg. However, changes in crumb color (a dull grayish color unacceptable to the food industry) began to appear at 5–10 mg/kg for NaFeEDTA and at 20–25 mg/kg for ferrous fumarate. It was therefore decided to evaluate the efficacy of NaFeEDTA at 10 mg/kg and that of ferrous fumarate at 20 mg/kg. Electrolytic iron was evaluated at 35 mg/kg, the level currently used in the South African food fortification program. The usual bread intake in this age group is 6–7 slices per day (our unpublished data). Only 4 slices could, however, be consumed during school hours. The iron content, for the purposes of this study, was therefore increased by a factor of 2.5 in all 3 iron groups. This simulated a bread intake of 6 slices per day at flour fortification levels of 10, 20, and 35 mg/kg flour for the NaFeEDTA, ferrous fumarate, and electrolytic iron groups, respectively, and also compensated for weekends and holidays when bread was not distributed. The 4 slices of bread thus supplied 2.35 mg, 4.70 mg, and 8.30 mg of fortification iron per intervention day, which translated into a mean daily intake of fortification iron over the 34-wk study period of 1.26 mg, 2.53 mg, and 4.46 mg for the 3 groups, respectively. NaFeEDTA (Ferrazone) was supplied by Akzo Nobel Functional Chemicals and ferrous fumarate and electrolytic iron (particle size < 45 µm; 325 mesh) by DSM Nutritional Products SA. The other fortificants in the wheat flour (bread), according to the South African food fortification regulations, were zinc, vitamin A, thiamin, riboflavin, niacin, pyridoxine, and folic acid (Table 1). The control bread was fortified with all of the latter components but not with iron.
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A baking company (Sasko Bakeries) was provided with unfortified wheat flour and 4 types of premixes, containing no iron, NaFeEDTA, ferrous fumarate, and electrolytic iron, respectively. Color coding was employed to keep the 4 types of bread apart throughout the baking process, from the premix through to the final product. The first few batches of bread were baked under the supervision of a member of the research team. Bread was baked once a week and a week's supply (presliced by machine and prepacked in color-coded plastic sleeves) was delivered to the school where it was kept frozen at –20°C until used. A sample of each bread type (as delivered) was drawn once every (or alternate) week and sent to the Southern African Grain Laboratory, Pretoria, SA for the determination of iron content (Table 2).
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Biochemical indices. Blood (5 mL) was obtained by antecubital venipuncture. All blood samples were collected between 0830 and 1300, and the 4 treatment groups were distributed evenly over this period. Hb was measured in the field by means of the direct cyanmethemoglobin method using Drabkins solution and a standard photometer. The rest of the blood was centrifuged and the serum stored at –80°C until analyzed. Serum ferritin was determined by an immunoradiometric assay (Ferritin MAb Solid Phase Component System, ICN Pharmaceuticals) using an Auto Gamma 500C counting system (United Technologies Packard). Serum iron and total iron binding capacity were spectrophotometrically determined by means of an Autohumalyzer A5, using a photometric colorimetric method (Iron liquicolor/TIBC, Human); these values were then used to calculate transferrin saturation. C-reactive protein (CRP) was determined by means of a simple sandwich enzyme-linked immunosorbent assay (18) and serum transferrin receptor by an enzyme immunoassay (TfR, Ramco Laboratories).
Anthropometry. Weight was measured (in light clothing) to the nearest 0.05 kg and height (without shoes) to the nearest 0.1 cm. Height-for-age, weight-for-age, and weight-for-height were expressed as Z-scores using the National Center for Health Statistics (NCHS) median as reference (19). The birth date of each child was obtained from the school register.
Statistical analysis
A per protocol analysis was done using SPSS for Windows (version 13.0) and Stata (StataCorp, version 10). For serum ferritin, children with CRP concentrations > 10 mg/L at baseline or follow-up were excluded from the analysis. A linear regression model was used to estimate the treatment effects for the study outcomes: Hb, serum iron, transferrin saturation, and serum transferrin receptor. The model included terms for the design effects group, school grade, and Hb stratification, as well as the corresponding baseline measurement of the outcome of each participant. For serum ferritin, the same model structure was used, but quintile regression for the median was used to account for the positively skewed distribution of this variable. For both these models, the contrast of the active treatment in comparison to the control treatment was estimated. Results are presented as effect estimates with 95% CI; baseline values are presented as means ± SD, except for serum ferritin concentrations, which are expressed as median (10th, 90th percentiles).
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Results |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Discussion |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Despite the high relative bioavailability of NaFeEDTA and ferrous fumarate, neither compound therefore appears to be suitable for use as a fortificant in brown bread baked under South African conditions. Organoleptic problems most commonly encountered with iron fortification of cereals are rancidity and off-flavors in products stored for long periods, color and taste changes, and fermentation problems affecting bread volume (3,20). In our sensory studies, the only factor limiting the amount of NaFeEDTA and ferrous fumarate in bread was the color change observed at relatively low levels. Electrolytic iron had no effect on bread color, even at fortification levels of up to 70 mg/kg.
Our results with regard to electrolytic iron confirms the results of a previous South African study, where electrolytic iron in brown bread, evaluated at the same level, had no effect on iron and Hb status in schoolchildren who were iron deficient (5). A study in 3- to 8-y-old Kenyan children also failed to demonstrate an improvement in iron status with whole maize meal fortified with electrolytic iron at 56 mg/kg (12). These findings are in contrast to the findings of Zimmermann et al. (21), who showed electrolytic iron to be effective in improving iron stores in adult Thai women. In the latter study, however, low extraction wheat flour was used and the daily amount of iron provided by the intervention was more than double the daily amount provided by the present study (12 mg vs. 
5 mg).
Mandatory fortification of wheat flour at 35 mg/kg was introduced in South Africa in 2003. Fortification at this level clearly does not seem to be sufficient. The WHO/FAO guidelines for food fortification, published in 2006 (13), recommend electrolytic iron concentrations that are double those used in South Africa and it is unfortunate that we were not able to include an additional group with double the amount of electrolytic iron in our study design. Logistical constraints, however, limited us from having more than 4 intervention groups.
We did not interfere with the food intake of the children at home; because it was a randomized controlled trial, it was assumed that the background diet at home would be the same for all 4 groups. Neither did we interfere with usual school feeding practices, whereby whole milk was occasionally available to the children during their first meal period. Although the milk might to some degree have inhibited the absorption of iron (22), its consumption during the school day could also be reflective of real-life situations where one cannot prescribe or control what people consume in combination with the fortified product. This trial thus was not merely an evaluation of efficacy but also contained elements of a pragmatic trial, simulating the intake of the fortified product within the context of the normal diet.
The study was conducted in a mild to moderately anemic population (23). Our initial aim was to include only children with Hb concentrations < 120 g/L in the trial. However, due to a lower than expected prevalence of anemia in this school, it was decided to include all children with Hb 125 g/L. The study population was not therefore strictly anemic, but at least the children with Hb concentrations at the upper end of the scale, i.e. those most unlikely to respond to the intervention, were excluded from the study.
In conclusion, our study shows that electrolytic iron at the level currently used in South Africa for the fortification of wheat flour does not appear to be effective in improving Hb or iron status. Neither do NaFeEDTA and ferrous fumarate appear to be suitable alternatives because of color changes at relatively low levels of fortification. Finding a suitable iron fortificant for wheat flour in South Africa thus remains a challenge. Whether electrolytic iron at double the current dose will be effective is not known and needs to be investigated.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author disclosures: M. E. van Stuijvenberg, C. M. Smuts, C. J. Lombard, and M. A. Dhansay, no conflicts of interest.
6 Abbreviations used: CRP, C-reactive protein; Hb, hemoglobin; NaFeEDTA, sodium iron EDTA; NCHS, National Center for Health Statistics.
Manuscript received 5 October 2007. Initial review completed 5 November 2007. Revision accepted 27 December 2007.
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LITERATURE CITED |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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1. ACN/SCN. Third report on the world nutrition situation. Geneva: WHO; 1997.
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4. Department of Health. Regulations relating to the fortification of certain foodstuffs. 2003 [cited 2007 Aug 10]. Available from: http://www.doh.gov.za/docs/regulations/2003/ffortification.html.
5. Van Stuijvenberg ME, Smuts CM, Wolmarans P, Lombard CJ, Dhansay MA. The efficacy of ferrous bisglycinate and electrolytic iron as fortificants in bread in iron deficient schoolchildren. Br J Nutr. 2006;95:532–8.[Medline]
6. Nestel P, Nalubola R, Sivakaneshan R, Wickramasinghe AR, Atukorala S, Wickramanayake T. The use of iron-fortified wheat flour to reduce anemia among the estate population in Sri Lanka. Int J Vitam Nutr Res. 2004;74:35–51.[Medline]
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9. Ballot DE, MacPhail AP, Bothwell TH, Gillooly M, Mayet FG. Fortification of curry powder with NaFe(III)EDTA in an iron deficient population: report of a controlled iron-fortification trail. Am J Clin Nutr. 1989;49:162–9.
10. Viteri FE, Alvarez E, Batres R, Torún B, Pineda O, Mejía LA, Sylvi J. Fortification of sugar with iron sodium ethylenediaminotetraacetate (FeNaEDTA) improves iron status in semirural Guatemalan populations. Am J Clin Nutr. 1995;61:1153–63.
11. Garby L, Areekul S. Iron supplementation in Thai fish-sauce. Ann Trop Med Parasitol. 1974;68:467–76.[Medline]
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13. WHO/FAO. Guidelines on food fortification with micronutrients. Geneva: WHO; 2006.
14. Van Stuijvenberg ME, Kvalsvig JD, Faber M, Kruger M, Kenoyer DG, Benadé AJS. Effect of iron-, iodine- and β-carotene-fortified biscuits on the micronutrient status of primary school children: a randomized controlled trial. Am J Clin Nutr. 1999;69:497–503.
15. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2001.
16. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998.
17. Langenhoven ML, Kruger M, Gouws E, Faber M. MRC food composition tables. 3rd ed. Parow: Medical Research Council, South Africa; 1991.
18. Erhardt JG, Estes JE, Pfeiffer CM, Biesalski HK, Craft NE. Combined measurement of ferritin, soluble transferrin receptor, retinol binding protein, and C-reactive protein by an inexpensive, sensitive, and simple sandwich enzyme-linked immunosorbent assay technique. J Nutr. 2004;134:3127–32.
19. Hamill PVV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr. 1979;32:607–29.
20. Dary O. Lessons learned with iron fortification in Central America. Nutr Rev. 2002;60:S30–3.[Medline]
21. Zimmermann MB, Winichagoon P, Gowachirapant S, Hess SY, Harrington M, Chavasit V, Lynch SR, Hurrell RF. Comparison of the efficacy of wheat-based snacks fortified with ferrous sulphate, electrolytic iron, or hydrogen-reduced elemental iron: randomized, double-blind, controlled trial in Thai women. Am J Clin Nutr. 2005;82:1276–82.
22. Hallberg L, Brune M, Erlandsson M, Sandberg A-S, Rossander-Hultén L. Calcium: effect of different amounts on nonheme- and heme-iron absorption in humans. Am J Clin Nutr. 1991;53:112–9.
23. WHO/UNICEF/UNU. Iron deficiency anaemia: assessment, prevention, and control: a guide for program managers. Geneva: WHO; 2001.
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