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Dual fortification of salt with iodine and micronized ferric pyrophosphate: a randomized, double-blind, controlled trial^1,2,3

¹ From the Human Nutrition Laboratory, Swiss Federal Institute of Technology, Zürich, Switzerland (MBZ, RW, CZ, FR, and RFH); the Ministry of Health, Rabat, Morocco (NC); the Ministry of Health, Chaouen, Morocco (MS); and the Department of Endocrinology, University Children's Hospital, Zürich, Switzerland (TT).

² Supported by the Thrasher Research Fund (Salt Lake City, UT), the Foundation for Micronutrients in Medicine (Rapperswil, Switzerland), and the Swiss Federal Institute of Technology (Zürich, Switzerland). Paul Lohmann AG (Emmerthal, Germany) supplied the iron pyrophosphate compound and the iron sulfate tablets used in the study.

³ Reprints not available. Address correspondence to MB Zimmermann, Human Nutrition Laboratory, Swiss Federal Institute of Technology Zürich, Seestrasse 72/Postfach 474, CH-8803 Rüschlikon, Switzerland. E-mail: michael.zimmermann{at}ilw.agrl.ethz.ch.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: In many developing countries, children are at high risk for both goiter and anemia. In areas of subsistence farming in rural Africa, salt is one of the few regularly purchased food items and could be a good fortification vehicle for iodine and iron, provided that a stable yet bioavailable iron fortificant is used.

Objective: We tested the efficacy of salt dual-fortified with iodine and micronized ferric pyrophosphate for reducing the prevalence of iodine and iron deficiencies in children.

Design: In rural northern Morocco, we fortified local salt with 25 µg I (as potassium iodate)/g salt and 2 mg Fe (as micronized ferric pyrophosphate; mean particle size = 2.5 µm)/g salt. After storage and acceptability trials, we compared the efficacy of the dual-fortified salt (DFS) with that of iodized salt in a 10-mo, randomized, double-blind trial in iodine-deficient 6–15-y-old children (n = 158) with a high prevalence of anemia.

Results: After storage for 6 mo, there were no significant differences in iodine content or color lightness between the DFS and iodized salt. During the efficacy trial, the DFS provided 18 mg Fe/d; iron absorption was estimated to be 2%. After 10 mo of treatment in the DFS group, mean hemoglobin increased by 16 g/L (P < 0.01), iron status and body iron stores increased significantly (P < 0.01), and the prevalence of iron deficiency anemia decreased from 30% at baseline to 5% (P < 0.001). In both groups, urinary iodine (P < 0.001) and thyroid volume (P < 0.01) improved significantly from baseline.

Conclusion: A DFS containing iodine and micronized ferric pyrophosphate can be an effective fortification strategy in rural Africa.

Key Words: Iodine • iron • micronized ferric pyrophosphate • iodine deficiency • iron deficiency • dual fortification of salt • anemia • goiter • children

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Iodine deficiency disorders and iron deficiency anemia (IDA) affect 30% of the global population (1, 2). These deficiencies often coexist—in regions of West and North Africa, 20–38% of schoolchildren may suffer from both goiter and IDA (3, 4). IDA impairs thyroid metabolism and reduces the efficacy of iodine prophylaxis in areas of endemic goiter (3, 5–7). Although universal salt iodization has proven highly effective against iodine deficiency disorders (2), effective iron fortification of foods remains a challenge (8, 9). Salt is a good potential vehicle for iron and iodine, particularly in rural West and North Africa, because in poor regions of subsistence farming, salt is one of the few regularly purchased food items (4, 10). In these regions, dual fortification of salt with iodine and iron could be an effective strategy.

However, maintaining iodine stability and iron bioavailability while avoiding color change in dual-fortified salt (DFS) is difficult, particularly in low-grade salt in developing countries (11–14). Water-soluble, highly bioavailable iron compounds react with moisture and impurities in salt, which causes color changes and iodine losses (14). We recently showed the efficacy of a DFS containing ferrous sulfate encapsulated with partially hydrogenated vegetable oil (4). However, despite encapsulation, the ferrous sulfate produced a yellow color change in the DFS when salt moisture content was high (4). Currently available forms of encapsulated ferrous sulfate and ferrous fumarate cause unacceptable color changes when added to low-grade salt in Africa (15).

Poorly soluble iron compounds, such as elemental iron powders or iron phosphates, tend to cause fewer sensory changes in foods (8, 9). Ferric pyrophosphate (FePP) has a white color and produces negligible color change when added to local salt in West and North Africa (15). When FePP is added to salt containing potassium iodate (KIO₃), iodine stability is comparable to that in iodized salt (IS) (15). Although most commercial forms of FePP have a relative bioavailability (RBV) 50% of ferrous sulfate (8, 9), reducing the particle size of FePP increases its absorption. The absorption of FePP with a mean particle size (MPS) of 0.5 µm is comparable with that of ferrous sulfate (16). In rats, the RBV of FePP with an MPS of 2.5 µm is 70% of that of ferrous sulfate (R Wegmüller, personal communication, 2004). Micronized FePP may therefore have excellent potential as an iron fortificant in DFS.

We formulated a DFS containing potassium iodate and micronized FePP and tested its stability in local salt and its organoleptic qualities when added to local meals. We then compared the efficacy of the DFS with that of IS in a randomized, double-blind trial in iodine-deficient Moroccan children with a high prevalence of anemia.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study was conducted in villages in the Brikcha Rural Commune, an area of endemic goiter in northern Morocco (17). The region is 400–800 m above sea level, and the climate is temperate, with an 8-mo dry season (22–34 °C, mean rainfall of 23 cm/mo) and a 4-mo damp season (10–22 °C, mean rainfall of 77 cm/mo). The population is of mixed Berber and Arab descent. This region is isolated from commercial routes, >95% of the population is rural, and most available food is produced locally on small farms (18). Per capita salt and iron intakes in school-age children in this region are 7–12 g/d and 9–14 mg/d, respectively (4). Iron bioavailability from the local diet is estimated to be 2–4% (4) when adjusted for low body iron stores (19).

Salt preparation
A local cooperative supplies nearly all salt in this region; the salt is produced in drying ponds by using water from a salty spring. The salt (95.4% NaCl) is not washed or ground and has a milky-white color and an average crystal size of 1.4 mm. Its moisture content is <1% during the dry season but 3–4% during the damp season, and it contains 2.5% CaSO₄, <0.1% MgSO₄, and <2 parts per million iodine. Morocco legislated mandatory salt iodization in 1997; it is estimated that 45% of the population has access to IS (N Chaouki, personal communication, 2002). Because of financial constraints, this small local cooperative has not yet begun iodization. To prepare the IS and DFS, iodine was added as reagent-grade potassium iodate (Sigma & Aldrich, Buchs, Switzerland) at a concentration of 25 µg iodine/g salt. The DFS was fortified with food-grade micronized FePP (art. no. 3043448; Paul Lohmann AG, Emmerthal, Germany). This FePP contains 21% iron and has an MPS (d₅₀) of 2.5 µm (d₁₀, 0.4 µm; d₉₀, 6.1 µm). On the basis of mean local salt intakes of 7–12 g/d in children (4), iron bioavailability of 2–4% from the diet (4), and an RBV of 70% for the micronized FePP, we chose a fortification concentration of 2 mg Fe/g salt for the DFS. Our fortification goal was to provide 0.5 mg absorbed Fe/d to the children in the study. Concentrated premixes were made by adding 0.84 g KIO₃ (for the IS) or 0.84 g KIO₃ and 190 g FePP (for the DFS) to 2-kg batches of salt by using a small, electric, rotating-drum mixer (MINI 80; Engelsmann, Ludwigshafen, Germany) at 26 rpm for 10 min. The 2-kg premixes were then mixed into 18-kg batches of salt in a large, electric, rotating-drum mixer (ELTE 650, Engelsmann) at 30 rpm for 10 min.

Stability and acceptability testing
The IS and DFS were locally stored as 2-kg batches in closed, low-density, transparent polyethylene bags that were kept indoors and out of direct sunlight. After storage for 0, 2, 4, and 6 mo, 30-g salt aliquots (n = 3) were taken for measurement of iodine concentration in the IS and of iodine and iron concentrations in the DFS. A 6-mo study was done to approximate the time required for the production, distribution, and consumption of salt in this region. Color stability was determined by reflectance colorimetry as well as panel visual inspection by 6 local adults of unmarked samples side-by-side on white backgrounds. To judge DFS and IS acceptability after 10 mo of household salt use during the efficacy study, an interview was conducted in 50% of randomly selected households in the IS (n = 31) and DFS groups (n = 25). The head of the household, who was blind to group assignment, answered forced-choice questions on patterns of salt use, color and taste acceptability, and overall satisfaction with the salt.

Organoleptic testing
To evaluate potential sensory changes in local foods, IS and DFS were added to meals that were prepared by local women in their kitchens with the use of traditional recipes. Each type of salt was added in identical amounts in parallel to separate portions of 4 common foods: bread (made with mainly white flour), bisarra (fava bean and olive oil purée), chaaria (semolina noodles in milk), and couscous (semolina). The flavor, odor, and color of these foods were then compared by a panel of 18 local adults ( age: 33 y; 59% female) with the use of triangle tests (20). During the triangle test, 3 coded samples of each of the 4 foods were given in random order in a private setting. The panelists were to determine which sample differed from the other 2 samples and describe how they differed (20).

Efficacy study
The subjects were 6–15-y-old children from 2 neighboring primary schools. Informed written consent was obtained from the chief medical officer and school directors, and informed oral consent was obtained from the parents of the children. The Swiss Federal Institute of Technology in Zürich, Switzerland, and the Ministry of Health in Rabat, Morocco, gave ethical approval for the study. All children from the schools were invited to participate in the 10-mo study, and all accepted (n = 163) and were enrolled. At baseline, weight and height were measured, and a casual spot urine sample was collected for measurement of urinary iodine (UI) concentration. Five milliliters of whole blood was collected by venipuncture for determination of hemoglobin, C-reactive protein (CRP), serum ferritin (SF), whole-blood zinc protoporphyrin (ZnPP), and serum transferrin receptor (TfR). Thyroid gland volume (T_vol) was measured by using a portable Aloka SSD-500 Echocamera (Aloka, Mure, Japan) with a high-resolution, 7.5-MHz linear transducer (21).

Because each participating family shared a monthly salt portion, children were randomly assigned at the household level into 2 groups: one group (n = 86) was given the IS and the second group (n = 77) was given the DFS. Both investigators and households were blind to group assignment. The IS and the DFS were prepared as described above. For monitoring, 30-g aliquots (n = 6) of the IS and the DFS were taken and measured for iodine and iron content at each monthly mixing. On the basis of a per capita salt intake of 12 g/d and local census data indicating an average of 7.5 members per household, each household was provided 2 kg salt to supply all household needs at the beginning of each month for 10 mo. The salt was dispensed directly to the head of the household from a central supply at the local health center. At baseline, the study was carefully explained to the participating families, and it was emphasized that the new salt should be used for all cooking and food preparation, as well as at the table. This message was reinforced at each of the monthly salt distributions.

At 5 and 10 mo, the weight and height of the children were measured, and casual spot urine samples were collected for measurement of UI. Whole blood was collected by venipuncture for determination of hemoglobin, CRP, SF, ZnPP, and TfR. T_vol was measured with the use of ultrasound. After completion of the fortification trial, all remaining children with IDA were treated with oral iron (60 mg Fe as ferrous sulfate 4 d/wk for 12 wk).

Laboratory analyses
Serum and urine samples were separated into aliquots and frozen at –20 °C until analysis. UI was measured by using the Pino modification of the Sandell-Kolthoff reaction (22). At UI concentrations of 47 and 79 µg/L, the interrun CV of this assay in our laboratory was 10.3% and 12.7%, respectively. The limit of detection was 2 µg/L; samples below this limit were assigned a value of 0. T_vol was calculated by using the method of Brunn et al (23). MBZ performed all ultrasound measurements during the study. To estimate intraobserver variability, duplicate T_vol measurements were taken in 20 children at the 5- and 10-mo time points; the mean (±SD) intraobserver variability was 3.9 ± 2.1%. Goiter was defined by using sex- and body surface area–specific reference criteria for T_vol (21).

Hemoglobin was measured by using an AcT8 Counter (Beckman Coulter, Krefeld, Germany). Anemia was defined as a hemoglobin concentration < 130 g/L in boys aged 15 y, a hemoglobin concentration < 120 g/L in children aged 12 y and in girls aged 15 y, and a hemoglobin concentration < 115 g/L in children aged 5–11 y (24). ZnPP was measured on washed red blood cells by using a hematofluorometer (Aviv Biomedical, Lakewood, NJ). SF and TfR were measured by using enzyme-linked immunosorbent assays (RAMCO, Houston). CRP was measured by using nephelometry (TURBOX; Orion Diagnostica, Espoo, Finland). Normal reference values are as follows: ZnPP, 40 µmol/mol heme; SF, 15–300 µg/L; TfR, 2.9–8.5 mg/L; CRP, <10 mg/L. Iron deficiency was defined as either an SF concentration < 15 µg/L or as a TfR concentration > 8.5 mg/L plus a ZnPP concentration > 40 µmol/mol heme (24, 25). Body iron was estimated by using the method of Cook et al (26) with the following formula:

(1)

To measure salt color, 10 g salt was transferred into a glass container for color determination on the Hunter scale with the use of a Spectral Photometer (Chroma Meter CR-310; Minolta, Osaka, Japan) with illuminant D₆₅ (average daylight, including ultraviolet spectra), a 0° observer angle, and a large reflectance spectrum. On the Hunter scale, the L value measures light reflection (a value of 100 is pure white; a value of 0 is pure black), the a value is a measure of redness and greenness, and the b value is a measure of yellowness and blueness. Each sample was measured 3 times, and the glass container was rotated 90° after each measurement. The color of the DFS was then compared with that of the IS, and the absolute color difference was expressed by E (15). E was calculated by using the following equation:

(2)

where L, a, and b describe the difference between the color of the DFS and the reference color (IS).

For DFS, determination of iodine content by titration with thiosulfate (27) is complicated by interference from iron in the salt. We therefore measured iodine in salt aliquots dissolved in distilled water by using a modification of the Sandell-Kolthoff reaction (15, 28). At iodine concentrations of 30 µg/g salt, the interrun CV of this assay in our laboratory was 7%. This method shows good agreement (r² = 0.97) with isotope abundance ratio measurements by mass spectrometry (28). The iron content of the salt was analyzed by using a standard addition method with flame atomic absorption spectroscopy (SpectrAA-400; Varian, Mulgrave, Australia). The mineral composition of the native salt was analyzed by using inductively coupled plasma optical emission spectrometry (Spectro Modula; Spectro Analytic Instruments GmbH and Co KG, Kleve, Germany), and the particle size distribution was measured by sieve analysis.

Statistical analyses
Data processing and statistical analyses were performed with the use of SPLUS (2000; Insightful Corporation, Seattle), PRISM (version 3; GraphPad, San Diego), and EXCEL (XP 2002; Microsoft, Seattle). Two-factor repeated-measures analysis of variance was done to compare the effects of group x time for hemoglobin, CRP, SF, TfR, ZnPP, body iron, T_vol, UI, and salt color and iodine content. If the interaction effect was significant (P < 0.05), t tests between groups and paired t tests within groups were done and adjusted for multiple comparisons (Bonferroni correction). Proportions were compared by using the chi-square test. When data were not normally distributed, statistical analysis was done after log transformation. Logistic regression was done to compare effects of group x time for the binary variables of anemia, IDA, iron deficiency without anemia, and goiter. Significance was set at P < 0.05.

	RESULTS

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Stability
The color stability, iodine content, and iron content of the IS and the DFS at 0, 2, 4, and 6 mo after mixing are shown in Table 1. By colorimetry, there was no significant difference between the IS and the DFS in the L color value, and no significant color change in the IS or the DFS over 6 mo of storage. In comparing the DFS with the IS, the E of 6–7 for the DFS was due to the slight difference in color shade between the DFS (light beige) and the IS (milky white). There was no significant difference between the DFS and the IS in iodine content during storage; both salts lost 20% of their iodine content after 6 mo.

Table 2

Table 3

Table 4

Table 4

Figure 1

View larger version (15K): [in this window] [in a new window]   FIGURE 1.. Prevalence of anemia, iron deficiency anemia (IDA), and iron deficiency (ID) without anemia in 6–15-y-old children receiving dual-fortified salt (DFS) containing iron and iodine or iodized salt (IS) for 10 mo. By logistic regression, in comparison with the children who received the IS, those who received the DFS had significantly decreased prevalences of anemia, IDA, and ID without anemia. The difference between the groups increased with time (P < 0.001; comparison of time-and-treatment model with time-only model).

Table 5

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

We recently showed the efficacy of a DFS containing ferrous sulfate encapsulated with partially hydrogenated soybean oil (4). In a 40-wk trial in schoolchildren, mean hemoglobin concentrations increased by 14 g/L, and the prevalence of IDA decreased from 35% to 8%. In this previous efficacy study, although the iodine was stable in the DFS, iron encapsulation did not prevent color changes; the DFS developed a yellow color when the moisture content of the salt was 3–4% (4). We recently tested the stability of 16 different forms of encapsulated iron in local salt in West and North Africa (15) and found that encapsulated ferrous iron caused unacceptable color changes in salt. Current encapsulation technology, which uses hydrogenated plant oils, does not sufficiently reduce moisture penetration and iron solubility, and capsule integrity is further compromised by mechanical abrasion during salt mixing. An additional barrier to the use of encapsulated iron in salt fortification is the relatively low melting point of the capsules (45–65 °C), which may cause unwanted sensory changes during food preparation (33). Finally, high processing costs for encapsulation may limit applications in developing countries.

FePP has a white color and produces negligible color change when added to low-grade, high-moisture salt in West and North Africa, even during prolonged storage (15). Ferric iron is relatively stable and nonreactive in the presence of potassium iodate, which is the iodine compound recommended for salt fortification in developing countries (34). When FePP is added to salt containing potassium iodate, iodine stability is comparable with that in IS (15). In contrast, ferrous iron reacts strongly with potassium iodate to form ferric oxides and iodine (I₂), which causes color change and iodine losses. For these reasons, FePP has clear advantages as a component of a DFS.

However, FePP is a poorly soluble iron compound, and its low bioavailability—only 30–50% of ferrous sulfate—reduces its nutritional value (8, 9). Stable-isotope studies have reported that the RBV of FePP with MPSs > 10 µm is only one-third that of ferrous sulfate and ferrous fumarate (35, 36). Particle size is an important determinant of iron absorption from poorly soluble iron compounds in foods. Decreasing the particle size of elemental iron powders by 50–60%, to an MPS of 7–10 µm, increases iron absorption by 50% in rats (37, 38). In a human study, iron absorption from hydrogen-reduced elemental iron with particle sizes between 5 and 10 µm was comparable with that of iron sulfate (39). Similarly, reducing the particle size of FePP increases its absorption. Conventional grinding can decrease the MPS of FePP to 2–3 µm. Further reduction in MPS to <1 µm is possible by generating FePP particles in aqueous solutions and adding emulsifiers to prevent agglomeration (40). In a human study, decreasing the MPS of FePP from 8.5 to 6.7 µm increased its RBV compared with iron sulfate from 36% to 52% (36). In a stable-isotope study, the RBV of a dispersible FePP with an MPS of 0.5 µm was comparable with that of ferrous sulfate (16). Recent hemoglobin repletion studies in rats have shown that the RBV of FePP with MPSs of 2.5 and 0.5 µm is 70% and 95% that of ferrous sulfate, respectively (R Wegmüller, personal communication, 2004). Although FePP with an MPS of 0.5 µm may be more bioavailable, we chose to use FePP with an MPS of 2.5 µm in this study because it is less expensive and has better handling characteristics and because the commercially available FePP with an MPS of 0.5 µm is a patented compound (40). In the single previously reported efficacy study of FePP (41), Pakistani infants received a wheat- and milk-based food supplement fortified with either FePP, ferrous fumarate, or control from 4 to 12 mo of age. Both iron-fortified supplements contained 7.5 mg Fe/100 g; the total daily iron dose was 3 mg. After 12 mo, the iron status of the 2 iron groups was not significantly different, and the iron status of both groups was higher than that of the control group (mean hemoglobin: 10.4 compared with 9.9 g/dL; mean SF: 13.3 compared with 8.8 µg/L; P < 0.05).

In the present study, micronized FePP with an MPS of 2.5 µm showed good bioavailability. The total dose of iron delivered by the DFS during the 10-mo trial was 5.4 g, on the basis of a study period of 300 d, mean salt intakes of 9 g/d in children, and a fortification concentration of 2 mg Fe/g salt. The mean increase in total body iron in the DFS group was 106 mg, whereas the mean decrease in body iron in the IS group was 10 mg (26). On the basis of these data, the mean daily gain in body iron in the DFS group was 0.38 mg, which suggests that 2% of the fortification iron was absorbed over the 10-mo trial.

Several factors favorably contributed to iron efficacy in this study. We provided a relatively large (18 mg/d) iron dose to growing children with poor iron status. The children ate 3 main meals, as well as mid-morning and mid-afternoon snacks, 7 d/wk, and all meals and snacks contained appreciable amounts of salt. Thus, absorption was probably enhanced by iron delivery in repeated small doses throughout the day, because fractional absorption of nonheme iron increases with decreasing dose (42). In this region, IDA is primarily due to low dietary iron bioavailability and not increased iron losses. There is no malaria in northern Morocco, and hookworm and other intestinal parasites that cause blood loss are rare (M Bousfiha, personal communication, 2002). Moreover, the low prevalence of infection or inflammation in the children (only 5% had elevated CRP) sharpened our ability to rely on SF and other iron indexes to clearly define IDA and detect changes in iron status (25, 43).

The DFS was also an effective vehicle for iodine. The iodine concentration in the DFS was not significantly different from that in the IS over 6 mo of storage. At baseline, the children were severely iodine deficient: the median UI concentration was 12 µg/L, and the goiter rate was 70%. The iodine in both salts was highly bioavailable: median UI concentrations increased by 10 mo in both groups to values indicative of iodine sufficiency. Thyroid volume and goiter prevalence decreased significantly in both groups, but consistent with previous reports, the addition of iron to IS improved iodine efficacy (5–7). Compared with the IS group, the DFS group had a significantly greater reduction in thyroid size and goiter prevalence. After 10 mo of salt use, which included the damp winter season, 98–100% of households receiving the DFS rated its color and taste as acceptable. The DFS did not change color during 6 mo of storage, and there was only a small absolute color difference (E value of 7) compared with the IS. On the basis of studies in West and North Africa, the color of a DFS is usually acceptable if the absolute color difference (E value) compared with the local IS is <10 (15).

In previous iron-fortification trials that clearly improved iron status in target populations (44–48), the iron-fortified food was consumed with an enhancer of iron absorption (ascorbic acid or EDTA), which was added to overcome absorption inhibitors. In the present study, despite the high phytic acid content of the diet, iron fortification of salt without an enhancer significantly improved iron status. Our findings indicate that micronized FePP as part of DFS is an effective iron-fortification strategy and may provide new opportunities for the global control of IDA. The cost of the micronized FePP used in this study is 4 times the cost of ferrous sulfate on a per iron basis (W Vogl, personal communication, 2004). Because the performance of DFS may vary depending on climate, salt quality, and dietary habits, we are currently repeating these studies in West Africa, where environmental conditions are harsher and the salt quality is poorer.

	ACKNOWLEDGMENTS

 
We thank the participating children and teachers, as well as the staff at the Brikcha Health Center. We especially thank R Rahmouni (Brikcha, Morocco), M El-Yazami (Chefchaouen, Morocco), and M-H Balsat, S Mattmann, A Huber, and N Hurrell (Swiss Federal Institute of Technology, Zürich, Switzerland).

Each of the authors contributed to the study design. The fieldwork and data collection were performed by MBZ, RW, FR, CZ, NC, and MS. MBZ, RW, FR, CZ, TT, and RFH completed the final laboratory and data analysis. The statistical analysis was done by MBZ. The first draft of the manuscript was written by MBZ, with editing by all the remaining authors. None of the authors had any financial or personal conflicts of interest in regard to this study.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. WHO/UNICEF/UNU. IDA: prevention, assessment and control. Report of a joint WHO/UNICEF/UNU consultation. Geneva: World Health Organization, 1998:1–9.
2. WHO/UNICEF/ICCIDD. Assessment of iodine deficiency disorders and monitoring their elimination. WHO/NHD/01.1. Geneva: World Health Organization, 2001.
3. Zimmermann MB, Adou P, Zeder C, Torresani T, Hurrell RF. Persistence of goiter despite oral iodine supplementation in goitrous children with iron deficiency anemia in the Côte d'Ivoire. Am J Clin Nutr 2000;71:88–93.[Abstract/Free Full Text]
4. 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.[Abstract/Free Full Text]
5. Zimmermann MB, Adou P, Torresani T, Zeder C, Hurrell RF. Iron supplementation in goitrous, iron-deficient children improves their response to oral iodized oil. Eur J Endocrinol 2000;142:217–23.[Abstract]
6. Hess SY, Zimmermann MB, Adou P, Torresani T, Hurrell RF. Treatment of iron deficiency in goitrous children improves the efficacy of iodized salt in Côte d'Ivoire. Am J Clin Nutr 2002;75:743–8.[Abstract/Free Full Text]
7. Zimmermann MB, Zeder C, Chaouki N, Saad A, Torresani T, Hurrell RF. Addition of microencapsulated iron to iodized salt improves the efficacy of iodine in goitrous, iron-deficient children: a randomized, double-blind, controlled trial. Eur J Endocrinol 2002;147:747–53.[Abstract]
8. Hurrell RF. Fortification: overcoming technical and practical barriers. J Nutr 2002;132:806S–12S.[Abstract/Free Full Text]
9. Hurrell RF. How to ensure adequate iron absorption from iron-fortified food. Nutr Rev 2002;60:S7–15.
10. Hess S, Zimmermann MB, Staubli F, Tebi A, Hurrell RF. An evaluation of salt intake and iodine nutrition in the Côte d'Ivoire. Eur J Clin Nutr 1999;53:680–6.[Medline]
11. Madhavan Nair K, Brahman GNV, Ranganathan S, et al. Impact evaluation of iron and iodine fortified salt. Indian J Med Res 1998;108:203–11.[Medline]
12. Sattarzadeh M, Zlotkin SH. Iron is well absorbed by healthy adults after ingestion of double-fortified table salt and urinary excretion is unaffected. J Nutr 1999;129:117–21.[Abstract/Free Full Text]
13. Sivakumar B, Brahmam GNV, Nair KM, et al. Prospects of fortification of salt with iron and iodine. Br J Nutr 2001;85:S167–73.
14. Mannar MGV, Diosady LL. Double fortification of salt with iron and iodine. In: The Micronutrient Initiative, ed. Food fortification to end micronutrient malnutrition. Ottawa: The Micronutrient Initiative, 1998:89–94.
15. Wegmüller R, Zimmermann MB, Hurrell RF. Dual fortification of salt with iodine and encapsulated iron compounds: stability and acceptability testing in Morocco and Côte d'Ivoire. J Food Sci 2003;68:2129–35.
16. Fidler MC, Walczyk T, Davidsson L, et al. A micronised, dispersible ferric pyrophosphate with high relative bioavailability in man. Br J Nutr 2004;91:107–12.[Medline]
17. Chaouki N, Ottmani S, Saad A, et al. The prevalence of iodine deficiency disorders in children 6–12 years old in Morocco. Bull Epidemiol Morocco 1996;1:2–23 (in French).
18. Larbi A. Iron intake, sources and bioavailability in Chefchaouen Province, Morocco. PhD dissertation. Oregon State University, Corvallis, Oregon, 1991.
19. Cook JD, Dassenko SA, Lynch SR. Assessment of the role of nonheme-iron availability in iron balance. Am J Clin Nutr 1991;54:717–22.[Abstract/Free Full Text]
20. Meilgaard M, Civille GV, Carr BT. Sensory evaluation techniques. Boca Raton, FL: CRC Press, 1991.
21. Zimmermann MB, Hess SY, Molinari L, et al. New reference values for thyroid volume by ultrasound in iodine-sufficient schoolchildren: a WHO/NHD Iodine Deficiency Study Group Report. Am J Clin Nutr 2004;79:231–7.[Abstract/Free Full Text]
22. Pino S, Fang SL, Braverman LE. Ammonium persulfate: a safe alternative oxidizing reagent for measuring urinary iodine. Clin Chem 1996;42:239–43.[Abstract/Free Full Text]
23. Brunn J, Block U, Ruf G, Bos I, Kunze WP, Scriba PC. Volume measurement of the thyroid gland using real-time sonography. Dtsch Med Wochenschr 1981;106:1338–40 (in German).[Medline]
24. UNICEF/WHO/UNU/MI. Preventing iron deficiency in women and children: background and consensus on key technical issues and resources for advocacy, planning and implementing national programmes. Boston: International Nutrition Foundation, 1998:10.
25. Cook JD, Baynes RD, Skikne BS. Iron deficiency and the measurement of iron status. Nutr Res Rev 1992;5:189–202.
26. Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood 2003;101:3359–64.[Abstract/Free Full Text]
27. WHO/UNICEF/ICCIDD. Recommended iodine levels in salt and guidelines for monitoring their adequacy and effectiveness. WHO/NUT/96.13. Geneva: WHO, 1996.
28. Haldimann M, Wegmüller R, Zimmermann MB. Determination of iodine concentration in salt dual fortified with iron and iodine. Eur Food Res Technol 2003;218:96–8.
29. Mannar MGV, Jayapal S, Pandav CS. Double fortification of salt with iron and iodine. In: Young KW, Cha LY, Yull LK, Soou J, Sook K, eds. Proceedings of the 14th International Congress of Nutrition. Seoul, Korea: International Congress of Nutrition, 1989:1035–7.
30. Rao BSN. Fortification of salt with iron and iodine to control anemia and goiter: development of a new formula with good stability and bioavailability of iron and iodine. Food Nutr Bull 1994;15:32–9.
31. Lofti M, Mannar MGV, Merx RJHM, van den Heuvel PN. Micronutrient fortification of foods. Ottawa: The Micronutrient Initiative, 1996:81–2.
32. Rajagopalan S, Vinodkumar M. Effects of salt fortified with iron and iodine on the hemoglobin levels and productivity of tea pickers. Food Nutr Bull 2000;21:323–9.
33. Hurrell RF. Nonelemental sources. In: Clydesdale FM, Wiemer KL, eds. Iron fortification of foods. Orlando, FL: Academic Press, 1985:39–53.
34. Evaluation of certain food additives and contaminants. Thirty-seventh report of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser 1991;806:1–52.[Medline]
35. Davidsson L, Kastenmayer P, Szajewska H, Hurrell RF, Barclay D. Iron bioavailability in infants from an infant cereal fortified with ferric pyrophosphate or ferrous fumarate Am J Clin Nutr 2000;71:1597–602.[Abstract/Free Full Text]
36. Fidler MC, Davidsson L, Zeder C, Walczyk T, Marti I, Hurrell RF. Effect of ascorbic acid and particle size on iron absorption from ferric pyrophosphate in adult women. Int J Vitam Nutr Res (in press).
37. Motzok I, Pennell MD, Davies MI, Ross HU. Effect of particle size on the bioavailability of reduced iron. J Assoc Off Anal Chem 1975;58:99–103.[Medline]
38. Verma RS, Motzok I, Chen SS, Rasper J, Ross HU. Effect of storage in flour and of particle size on the bioavailability of elemental iron powders for rats and humans. J Assoc Off Anal Chem 1977;60:759–65.[Medline]
39. JD Cook, V Minnich, CV Moore, A Rasmussen, WB Bradley, CA Finch. Absorption of fortification iron in bread. Am J Clin Nutr 1973;26:861–72.[Abstract]
40. Nanbu H, Nakata K, Sakaguchi N, Yamazaki Y, inventors; Taiyo Kagaku Co Ltd, assignee. Mineral composition. European patent EP 0870435A1. October 14, 1998.
41. Javaid N, Haschke F, Pietschnig B, et al. Interactions between infections, malnutrition and iron nutritional status in Pakistani infants. A longitudinal study. Acta Paediatr Scand Suppl 1991;374:141–50.[Medline]
42. Skikne B, Baynes RD. Iron absorption. In: Brock JH, Halliday JW, Pippard MJ, Powell LW, eds. Iron metabolism in health and disease. London: Saunders, 1993:152–87.
43. Staubli-Asobayire F, Adou P, Davidsson L, Cook JD, Hurrell RF. Prevalence of iron deficiency with and without concurrent anemia in population groups with high prevalences of malaria and other infections: a study in Côte d'Ivoire. Am J Clin Nutr 2001;74:776–82.[Abstract/Free Full Text]
44. Walter T, Olivares M, Hertrampf E. Field trials of food fortification with iron: the experience of Chile. In: Lönnerdal B, ed. Iron metabolism in infants. Boca Raton, FL: CRC Press, 1990:127–55.
45. Walter T, Pino P, Pizarro F, Lozoff B. Prevention of iron-deficiency anemia: comparison of high- and low-iron formulas in term healthy infants after six months of life. J Pediatr 1998;132:635–40.[Medline]
46. Viteri FE, Alvarez E, Batres R, et al. Fortification of sugar with iron sodium ethylenediaminotetracetate (NaFeEDTA) improves iron status in semirural Guatemalan populations. Am J Clin Nutr 1995;61:1153–63.[Abstract/Free Full Text]
47. Thuy PV, Berger J, Davidsson L, et al. Regular consumption of NaFeEDTA-fortified fish sauce improves iron status and reduces the prevalence of anemia in anemic Vietnamese women. Am J Clin Nutr 2003;78:284–90.[Abstract/Free Full Text]
48. Ballot DE, MacPhail AP, Bothwell TH, Gillooly M, Mayet FG. Fortification of curry powder with NaFe(111)EDTA in an iron-deficient population: report of a controlled iron-fortification trial. Am J Clin Nutr 1989;49:162–9.[Abstract/Free Full Text]

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