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Background: Anemia, iron deficiency, and iodine deficiency are problems of important public health concern in many parts of the world, with consequences for the health, development, and work capacity of populations. Several countries are beginning to implement double fortified salt (DFS) programs to simultaneously address iodine and iron deficiencies., Objective: Our objective was to summarize the evidence for efficacy and effectiveness of DFS on the full range of status and functional outcomes and across different implementation and evaluation designs essential to successful interventions., Methods: We conducted a systematic review and meta-analysis of published and gray literature examining the effects of DFS on nutritional status, cognition, work productivity, development, and morbidity of all population groups. We searched for articles in Medline, Embase, CINAHL, Cochrane Central Register, and ProQuest for randomized trials, quasi-randomized trials, and program effectiveness evaluations., Results: A total of 22 studies (N individuals = 52,758) were included. Efficacy studies indicated a significant overall positive effect on hemoglobin concentration [standardized mean difference (95% CI): 0.33 (0.18, 0.48)], ferritin [0.42 (0.08, 0.76)], anemia [risk ratio (95% CI): 0.80 (0.70, 0.92)], and iron deficiency anemia [0.36 (0.24, 0.55)]. Effects on urinary iodine concentration were not significantly different between DFS and iodized salt. The impact on functional outcomes was mixed. Only 2 effectiveness studies were identified. They reported programmatic challenges including low coverage, suboptimal DFS quality, and storage constraints., Conclusions: Given the biological benefits of DFS across several populations in efficacy research, additional evaluations of robust DFS programs delivered at scale, which consider effective implementation and measure appropriate biomarkers, are needed., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2021.)

Background: Anemia prevalence in India remains high despite preventive iron supplementation programs. Consequently, concurrent national policies of iron fortification of staple foods have been initiated., Objectives: This study evaluated the relation between dietary iron intake and anemia (hemoglobin <12 g/dL) in women of reproductive age (WRA; 15-49 y) with respect to iron fortification in India., Methods: Data from 2 national surveys were used. Data on hemoglobin in WRA were sourced from the National Family Health Survey-4, whereas dietary intakes were sourced from the National Sample Survey. Adjusted odds for anemia with increasing iron intake were estimated, along with the effect of modulating nutrients such as vitamins B-12 and C, from statistically matched household data from the 2 surveys. The risks of inadequate (less than the Estimated Average Requirement for WRA) and excess (more than the tolerable upper limit for WRA) intakes of iron were estimated by the probability approach., Results: The relation between iron intake and the odds of anemia was weak (OR: 0.992; 95% CI: 0.991, 0.994); increasing iron intake by 10 mg/d reduced the odds of anemia by 8%. Phytate and vitamin B-12 and C intakes modified this relation by reducing the odds by 1.5% when vitamin B-12 and C intakes were set at 2 μg/d and 40 mg/d, respectively. The additional intake of 10 mg/d of fortified iron reduced the risk of dietary iron inadequacy from 24-94% to 9-39% across states, with no risk of excess iron intake. Approximately doubling this additional iron intake reduced the risk of inadequacy to 2-12%, but the risk of excess intake reached 22%., Conclusions: Providing fortified iron alone may not result in substantial anemia reduction among WRA in India and could have variable benefits and risks across states. Geographically nuanced dietary strategies that include limited fortification and the intake of other beneficial nutrients should be carefully considered., (Copyright © American Society for Nutrition 2019.)

Background: Iron deficiency (ID) and vitamin D deficiency (VDD) are significant pediatric health issues in New Zealand and Australia and remain prevalent micronutrient deficiencies in young children globally., Objective: We aimed to investigate the effect of a micronutrient-fortified, reduced-energy growing-up milk (GUMLi) compared with cow milk (CM) consumed for 1 y on dietary iron and vitamin D intakes and the status of New Zealand and Australian children at 2 y of age., Methods: The GUMLi Trial was a multicenter, double-blind, randomized controlled trial in 160 healthy 1-y-old New Zealand and Australian children conducted in 2015-2017. Participants were randomly assigned 1:1 to receive GUMLi (1.7 mg Fe/100 mL; 1.3 µg cholecalciferol/100 mL) or CM (0.02 mg Fe/100 mL; 0.06 µg cholecalciferol/100 mL) for 12 mo. Secondary outcomes, reported here, included change in dietary iron and vitamin D intakes, iron status, and 25-hydroxyvitamin D [25(OH)D] concentrations from blood samples at age 2 y. All regression models were adjusted for baseline outcome and study center., Results: GUMLi was a large contributor to dietary intakes of iron and vitamin D after 12 mo when compared with intakes from food and CM. The adjusted mean difference between groups for serum ferritin concentrations was 17.8 µg/L (95% CI: 13.6, 22.0 µg/L; P < 0.0001), and for 25(OH)D it was 16.6 nmol/L (95% CI: 9.9, 23.3 nmol/L; P < 0.0001). After 12 mo, ID was present in 16 (24%) participants in the CM group and 5 (7%) participants in the GUMLi group (P = 0.009), and the prevalence of VDD in the CM group increased to 14% (n = 10) and decreased to 3% (n = 2) (P = 0.03) in the GUMLi group., Conclusion: In comparison with CM, GUMLi significantly improved dietary iron and vitamin D intakes and the iron and vitamin D status of healthy children at 2 y of age. This trial was registered with the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12614000918628.

Double-fortified salt (DFS) containing iron and iodine has been proposed as a feasible and cost-effective alternative for iron fortification in low- and middle-income countries (LMICs). We conducted a systematic review and meta-analysis from randomized and quasi-randomized controlled trials to 1) assess the effect of DFS on biomarkers of iron status and the risk of anemia and iron deficiency anemia (IDA) and 2) evaluate differential effects of DFS by study type (efficacy or effectiveness), population subgroups, iron formulation (ferrous sulfate, ferrous fumarate, and ferric pyrophosphate), iron concentration, duration of intervention, and study quality. A systematic search with the use of MEDLINE, EMBASE, Cochrane, Web of Science, and other sources identified 221 articles. Twelve efficacy and 2 effectiveness studies met prespecified inclusion criteria. All studies were conducted in LMICs: 10 in India, 2 in Morocco, and 1 each in Côte d'Ivoire and Ghana. In efficacy studies, DFS increased hemoglobin concentrations [standardized mean difference (SMD): 0.28; 95% CI: 0.11, 0.44; P < 0.001] and reduced the risk of anemia (RR: 0.59; 95% CI: 0.46, 0.77; P < 0.001) and IDA (RR 0.37; 95% CI: 0.25, 0.54; P < 0.001). In effectiveness studies, the effect size for hemoglobin was smaller but significant (SMD: 0.03; 95% CI: 0.01, 0.05; P < 0.01). Stratified analyses of efficacy studies by population subgroups indicated positive effects of DFS among women and school-age children. For the latter, DFS increased hemoglobin concentrations (SMD: 0.32; 95% CI: 0.03, 0.60; P < 0.05) and reduced the risk of anemia (SMD: 0.48; 95% CI: 0.34, 0.67; P < 0.001) and IDA (SMD: 0.37; 95% CI: 0.25, 0.54; P < 0.001). Hemoglobin concentrations, anemia prevalence and deworming at baseline, sample size, and study duration were not associated with effect sizes. The results indicate that DFS is efficacious in increasing hemoglobin concentrations and reducing the risk of anemia and IDA in LMIC populations. More effectiveness studies are needed.

Background & Aims: The main objective of this report is to measure to what extent folate or vitamin B12 given daily for 6 months to young North Indian Children improves hemoglobin (Hb) concentration., Methods: In a randomized placebo controlled trial in low-to-middle income neighborhoods in New Delhi, India, children were randomized into four groups in a 1:1:1:1 ratio and supplemented daily for 6 months with 2 RDAs of vitamin B12, folic acid, both, or placebo. All children with anemia at baseline were given iron supplementation daily for 2 months. We measured the plasma concentrations of soluble transferrin receptor (sTfR), folate, vitamin B12, total homocysteine (tHcy) and Hb in 262 children., Results: Mean Hb concentration decreased in all four study groups during the six months of follow up and supplementation of either or both of the vitamins did not improve the Hb concentration. Iron supplements for the initial 2 mo had limited effect on anemia at 6 mo as almost 90% were still anemic at study end., Conclusion: Supplementation of folic acid and/or vitamin B12 for 6 months does not improve Hb concentration in young children. Our findings do not argue for widespread vitamin B12 or folic acid supplementation to combat anemia. Our results also call for alternative strategies to improve iron status and treat iron deficiency anemia., Clinical Trial Registry: NCT00717730 at www.clinicaltrials.gov, CTRI No.: CTRI/2010/091/001090 at www.ctri.nic.in., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Low birth weight (LBW) (≤2500 g) is associated with iron deficiency in infancy and high blood pressure (BP) later in life. Objective: We investigated the effect of iron supplementation that was given to LBW infants on midchildhood BP. Design: The study was a randomized, double-blind, controlled trial that included 285 marginally LBW (2000-2500-g) infants at 2 Swedish centers between May 2004 and November 2007. The infants were randomly assigned to receive a placebo or 1 or 2 mg Fe · kg -1 · d -1 from 6 wk to 6 mo of age. In secondary analyses at the age of 7 y, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the prevalence of children with BP within the hypertensive range (>90th percentile) were compared between the groups. Results: BP was analyzed via intention to treat in 189 children (66%). The mean ± SD SBP was 103 ± 8.1, 101 ± 7.5, and 101 ± 7.8 mm Hg in children who had received the placebo ( n = 70), 1 mg Fe · kg -1 · d -1 ( n = 54), or 2 mg Fe · kg -1 · d -1 ( n = 65), respectively. When the iron-supplemented groups were combined in covariate-adjusted analyses, the mean SBP in LBW children who had received iron supplementation in infancy was 2.2 mm Hg (95% CI: 0.3, 4.2 mm Hg) lower than in those who were unsupplemented ( P = 0.026). Multivariate logistic regression showed that iron supplementation in infancy reduced the odds of having an SBP within the hypertensive range at 7 y of age (OR: 0.32; 95% CI: 0.11, 0.96). For DBP, there were no significant differences between the intervention groups. Conclusions: LBW children who receive iron supplementation (1 or 2 mg Fe · kg -1 · d -1 ) in infancy have lower SBP at 7 y. This (to our knowledge) novel observation suggests that the increased risk of hypertension that is observed in children and adults who are born small might be reduced with early micronutrient interventions. This trial was registered at clinicaltrials.gov as NCT00558454., (© 2017 American Society for Nutrition.)

Background: Maternal health and nutrition play a crucial role in early child growth and development. However, little is known about the benefits of preconception micronutrient interventions beyond the role of folic acid (FA) and neural tube defects. Objective: We evaluated the impact of weekly preconception multiple micronutrient (MM) or iron and folic acid (IFA) supplementation on child growth and development through the age of 2 y compared with FA alone. Methods: We followed 1599 offspring born to women who participated in a randomized controlled trial of preconception supplementation in Vietnam. Women received weekly supplements that contained either 2800 μg FA, 60 mg Fe and 2800 μg FA, or 15 MMs including IFA, from baseline until conception followed by daily prenatal IFA supplements until delivery. Child anthropometry was measured at birth and at 3, 6, 12, 18, and 24 mo. Child development was measured with the use of the Bayley Scales for Infant Development III at 24 mo. Results: The groups were similar for baseline maternal and offspring birth characteristics. At 24 mo of age, the offspring in the IFA group had significantly higher length-for-age z scores (LAZs) (0.14; 95% CI: 0.03, 0.26), reduced risk of being stunted (0.87; 95% CI: 0.76, 0.99), and smaller yearly decline in LAZs (0.10; 95% CI: 0.04, 0.15) than the offspring in the FA group. Similar trends were found for the offspring in the MM group compared with the FA group for LAZs (0.10; 95% CI: -0.02, 0.22) and the risk of being stunted (0.88; 95% CI: 0.77, 1.01). Offspring in the IFA group had improved motor development ( P = 0.03), especially fine motor development (0.41; 95% CI: 0.05, 0.77), at the age of 24 mo, but there were no differences for measures of cognition or language. Conclusions: Preconception supplementation with IFA improved linear growth and fine motor development at 2 y of age compared with FA. Future studies should examine whether these effects persist and improve child health and schooling. The trial was registered at clinicaltrials.gov as NCT01665378., Competing Interests: Author disclosures: PHN, IG-C, MFY, TVT, HH, HN, SN, AMD, RM, and UR, no conflicts of interest., (© 2017 American Society for Nutrition.)

Background: Despite a high prevalence of anemia among nonpregnant Cambodian women, current reports suggest that iron deficiency (ID) prevalence is low. If true, iron supplementation will not be an effective anemia reduction strategy. Objective: We measured the effect of daily oral iron with or without multiple micronutrients (MMNs) on hemoglobin concentration in nonpregnant Cambodian women screened as anemic. Design: In this 2 × 2 factorial, double-blind, randomized trial, nonpregnant women (aged 18-45 y) with hemoglobin concentrations ≤117 g/L (capillary blood) were recruited from 26 villages in Kampong Chhnang province and randomly assigned to receive 12 wk of iron (60 mg; Fe group), MMNs (14 other micronutrients; MMN group), iron plus MMNs (Fe+MMN group), or placebo capsules. A 2 × 2 factorial intention-to-treat analysis with the use of a generalized mixed-effects model was used to assess the effects of iron and MMNs and the interaction between these factors. Results: In July 2015, 809 women were recruited and 760 (94%) completed the trial. Baseline anemia prevalence was 58% (venous blood). Mean (95% CI) hemoglobin concentrations at 12 wk in the Fe, MMN, Fe+MMN, and placebo groups were 121 (120, 121), 116 (116, 117), 123 (122, 123), and 116 (116, 117) g/L, with no iron × MMN interaction ( P = 0.66). Mean (95% CI) increases in hemoglobin were 5.6 g/L (3.8, 7.4 g/L) ( P < 0.001) among women who received iron ( n = 407) and 1.2 g/L (-0.6, 3.0 g/L) ( P = 0.18) among women who received MMNs ( n = 407). The predicted proportions (95% CIs) of women with a hemoglobin response (≥10 g/L at 12 wk) were 19% (14%, 24%), 9% (5%, 12%), 30% (24%, 35%), and 5% (2%, 9%) in the Fe, MMN, Fe+MMN, and placebo groups, respectively. Conclusions: Daily iron supplementation for 12 wk increased hemoglobin in nonpregnant Cambodian women; however, MMNs did not confer additional significant benefit. Overall, ∼24% of women who received iron responded after 12 wk; even fewer would be likely to respond in the wider population. This trial was registered at clinicaltrials.gov as NCT02481375., (© 2017 American Society for Nutrition.)

Background: India's high prevalence of iron-deficiency anemia has largely been attributed to the local diet consisting of nonheme iron, which has lower absorption than that of heme iron. Objective: We assessed the efficacy of the consumption of iron-supplement bars in raising hemoglobin concentrations and hematocrit percentages in anemic (hemoglobin concentration <12 g/dL) Indian women of reproductive age. Design: The Let's be Well Red study was a 90-d, pair-matched, cluster-randomized controlled trial. A total of 361 nonpregnant women (age 18-35 y) were recruited from 10 sites within Mumbai and Navi Mumbai, India. All participants received anemia education and a complete blood count (CBC). Random assignment of anemic participants to intervention and control arms occurred within 5 matched site-pairs. Intervention participants received 1 iron-supplement bar (containing 14 mg Fe)/d for 90 d, whereas control subjects received nothing. CBC tests were given at days 15, 45, and 90. Primary outcomes were 90-d changes from baseline in hemoglobin concentrations and hematocrit percentages. Linear mixed models and generalized estimating equations were used to model continuous and binary outcomes, respectively. Results: Of 179 anemic participants, 136 (76.0%) completed all follow-up assessments (65 intervention and 71 control participants). Baseline characteristics were comparable by arm. Mean hemoglobin and hematocrit increases after 90 d were greater for intervention than for control participants [1.4 g/dL (95% CI: 1.3, 1.6 g/dL) and 2.7% (95% CI: 2.2%, 3.2%), respectively]. The anemia prevalence at 90 d was lower for intervention (29.2%) than for control participants (98.6%) (OR: 0.007; 95% CI: 0.001, 0.04). Conclusions: The daily consumption of an iron-supplement bar leads to increased hemoglobin concentrations and hematocrit percentages and to a lower anemia prevalence in the target population with no reported side effects. This intervention is an attractive option to combat anemia in India. This trial was registered at clinicaltrials.gov as NCT02032615., (© 2017 American Society for Nutrition.)

Background: Food-based strategies to reduce nutritional iron deficiency have not been universally successful. Biofortification has the potential to become a sustainable, inexpensive, and effective solution., Objective: This randomized controlled trial was conducted to determine the efficacy of iron-biofortified beans (Fe-Beans) to improve iron status in Rwandan women., Methods: A total of 195 women (aged 18-27 y) with serum ferritin <20 μg/L were randomly assigned to receive either Fe-Beans, with 86 mg Fe/kg, or standard unfortified beans (Control-Beans), with 50 mg Fe/kg, 2 times/d for 128 d in Huye, Rwanda. Iron status was assessed by hemoglobin, serum ferritin, soluble transferrin receptor (sTfR), and body iron (BI); inflammation was assessed by serum C-reactive protein (CRP) and serum α1-acid glycoprotein (AGP). Anthropometric measurements were performed at baseline and at end line. Random weekly serial sampling was used to collect blood during the middle 8 wk of the feeding trial. Mixed-effects regression analysis with repeated measurements was used to evaluate the effect of Fe-Beans compared with Control-Beans on iron biomarkers throughout the course of the study., Results: At baseline, 86% of subjects were iron-deficient (serum ferritin <15 μg/L) and 37% were anemic (hemoglobin <120 g/L). Both groups consumed an average of 336 g wet beans/d. The Fe-Beans group consumed 14.5 ± 1.6 mg Fe/d from biofortified beans, whereas the Control-Beans group consumed 8.6 ± 0.8 mg Fe/d from standard beans (P < 0.05). Repeated-measures analyses showed significant time-by-treatment interactions for hemoglobin, log serum ferritin, and BI (P < 0.05). The Fe-Beans group had significantly greater increases in hemoglobin (3.8 g/L), log serum ferritin (0.1 log μg/L), and BI (0.5 mg/kg) than did controls after 128 d. For every 1 g Fe consumed from beans over the 128 study days, there was a significant 4.2-g/L increase in hemoglobin (P < 0.05)., Conclusion: The consumption of iron-biofortified beans significantly improved iron status in Rwandan women. This trial was registered at clinicaltrials.gov as NCT01594359., (© 2016 American Society for Nutrition.)

Objectives: To examine the prevalence and determinants of iron supplement use and the amount of iron consumed from iron-containing supplements., Methods: A cross-sectional survey was performed in antenatal clinics in two tertiary hospitals in Sydney, Australia between January and March 2014., Results: Of 612 (91% response rate) pregnant women, 589 with complete data were analysed. Overall iron-containing supplement use was 88.0%, of which 70.1% was multivitamin (MV) only, 7.2% was iron-only and 22.2% was both. Use of iron-containing supplements was associated with increased gestational age, a diagnosis of anaemia or iron deficiency (ID) in the current pregnancy and pre-pregnancy use of an iron-containing supplement. Several risk factors for ID or anaemia such as non-red meat eating and previous miscarriage were not associated with current iron supplement use. About 65% of women diagnosed with ID, and 62.3% of women diagnosed with anaemia were taking an iron-only supplement, with or without a MV. The proportion of women consuming low (<30), preventative (30-99) and treatment (≥100) mg/day doses were 36.8%, 45.4%, and 17.8%, respectively. Only 46.7% of women diagnosed with ID were taking ≥100 mg/day iron from supplements, while 23.3% were taking <30 mg/day., Conclusion: Women are consuming varying doses of iron and some high-risk women are taking inadequate doses of iron to prevent or treat ID or iron deficiency anaemia. Healthcare professionals are best positioned to advise women on iron supplement use in pregnancy and should educate women individually about the type and dose of supplement best suited to their needs., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Phytic acid (PA) is a major inhibitor of iron bioavailability from beans, and high PA concentrations might limit the positive effect of biofortified beans (BBs) on iron status. Low-phytic acid (lpa) bean varieties could increase iron bioavailability., Objective: We set out to test whether lpa beans provide more bioavailable iron than a BB variety when served as part of a composite meal in a bean-consuming population with low iron status., Methods: Dietary iron absorption from lpa, iron-biofortified, and control beans (CBs) (regular iron and PA concentrations) was compared in 25 nonpregnant young women with low iron status with the use of a multiple-meal crossover design. Iron absorption was measured with stable iron isotopes., Results: PA concentration in lpa beans was ∼10% of BBs and CBs, and iron concentration in BBs was ∼2- and 1.5-fold compared with CBs and lpa beans, respectively. Fractional iron absorption from lpa beans [8.6% (95% CI: 4.8%, 15.5%)], BBs [7.3% (95% CI: 4.0%, 13.4%)], and CBs [8.0% (95% CI: 4.4%, 14.6%)] did not significantly differ. The total amount of iron absorbed from lpa beans and BBs was 421 μg (95% CI: 234, 756 μg) and 431 μg (95% CI: 237, 786 μg), respectively, and did not significantly differ, but was >50% higher (P < 0.005) than from CBs (278 μg; 95% CI: 150, 499 μg). In our trial, the lpa beans were hard to cook, and their consumption caused transient adverse digestive side effects in ∼95% of participants. Gel electrophoresis analysis showed phytohemagglutinin L (PHA-L) residues in cooked lpa beans., Conclusion: BBs and lpa beans provided more bioavailable iron than control beans and could reduce dietary iron deficiency. Digestive side effects of lpa beans were likely caused by PHA-L, but it is unclear to what extent the associated digestive problems reduced iron bioavailability. This trial was registered at clinicaltrials.gov as NCT02215278., (© 2016 American Society for Nutrition.)

Background: The provision of iron with antimalarial treatment is the standard of care for concurrent iron deficiency and malaria. However, iron that is given during a malaria episode may not be well absorbed or used, particularly in children with severe malaria and profound inflammation., Objectives: We aimed to 1) determine baseline values of iron and inflammatory markers in children with severe malarial anemia (SMA), children with cerebral malaria (CM), and community children (CC) and 2) compare markers in iron-deficient children in each group who received 28 d of iron supplementation during antimalarial treatment with those in children who did not receive iron during treatment.., Design: Seventy-nine children with CM, 77 children with SMA, and 83 CC who presented to Mulago Hospital, Kampala, Uganda, were enrolled in a 28-d iron-therapy study. Children with malaria received antimalarial treatment. All children with CM or SMA, as well as 35 CC, had zinc protoporphyrin (ZPP) concentrations ≥80 μmol/mol heme and were randomly assigned to receive a 28-d course of iron or no iron. We compared iron markers at day 0 among study groups (CM, SMA, and CC groups) and at day 28 between children in each group who were randomly assigned to receive iron or to not receive iron., Results: At day 0, children with CM and SMA had greater values of C-reactive protein, ferritin, and hepcidin than those of CC. At day 28, interactions between study and treatment group were NS. Children in the no-iron compared with iron groups had similar mean values for hemoglobin (115 compared with 113 g/L, respectively; P = 0.73) and ZPP (124 compared with 124 μmol/mol heme, respectively; P = 0.96) but had lower median ferritin [101.0 μg/L (95% CI: 84.2, 121.0 μg/L) compared with 152.9 μg/L (128.8, 181.6 μg/L), respectively; P ≤ 0.001] and hepcidin [45.8 ng/mL (36.8, 56.9 ng/mL) compared with 83.1 ng/mL (67.6, 102.2 ng/mL), respectively; P < 0.011]., Conclusions: Severe inflammation is a characterization of children with CM and SMA. The withholding of iron from children with severe malaria is associated with lower ferritin and hepcidin at day 28 but not a lower hemoglobin concentration. This trial was registered at clinicaltrials.gov as NCT01093989., (© 2016 American Society for Nutrition.)

Paramount among the challenges to our ability to address the role of food and nutrition in health promotion and disease prevention is how to design and implement context-specific interventions and guidance. The Integration to Effective Implementation (I-to-I) concept is intended to address the complexities of the global health context through engagement of the continuum of stakeholders involved in the food and nutrition enterprise. The 2014 Micronutrient Forum (MNF) Global Conference held in Addis Ababa, Ethiopia, in June 2014 offered the opportunity to apply the I-to-I approach with the use of current concerns about the safety and effectiveness of interventions to prevent and treat iron deficiency (ID) as a case study. ID is associated with a range of adverse outcomes, especially in pregnant and nonpregnant women, infants, and primary school-age children. Strategies to combat ID include iron supplementation, multiple micronutrient powders, and food-based interventions to enhance dietary iron intake. Recent reports indicate potential increased adverse risks when iron is provided in areas with high infection burdens (e.g., malaria). This paradox has weakened iron intervention programs. Furthermore, the selection and interpretation of available biomarkers for assessing iron nutrition have been found to be compromised by the inflammatory process. These issues highlight the need for a comprehensive approach that considers basic biology, assessment, interventions, and how these can be translated into appropriate programs and policies. The application of the I-to-I with the use of the MNF offered an opportunity to explore how that might be achieved., (© 2016 American Society for Nutrition.)

Background: Guidelines on the diagnosis and treatment of iron deficiency (ID) vary widely across indications., Objective: We reviewed all available guidelines on the management of ID worldwide., Design: A literature search was conducted in PubMed, Cochrane, and EMBASE and in main professional association websites, limited to documents published between 1 January 2004 and 30 June 2014., Results: Of 127 guidelines identified, 29 were selected, involving 29 professional associations and issued from the United States (n = 8), Europe (n = 6), Britain (n = 4), Canada (n = 3), international organizations (n = 2), France (n = 2), Poland (n = 1), Australia (n = 1), Mexico (n = 1), and Japan (n = 1). A total of 22 and 27 guidelines provided recommendations on diagnosis and treatment of ID, respectively. To define ID, all guidelines recommended a concentration for serum ferritin. One-half of them (10 of 22) proposed transferrin saturation (TSAT) as an alternative or complementary diagnostic test. To treat ID, most of the guidelines (18 of 27) recommended preferentially the oral route if possible, particularly in children and in women in the pre- or postpregnancy period. Iron supplementation should be administered intravenously according to 13 of 27 guidelines, particularly in patients with chronic kidney disease (CKD) (n = 7) and chemotherapy-induced anemia (n = 5). Treatment targets for ID included an increase in hemoglobin concentrations to 10-12 g/dL or normalization (n = 8) and serum ferritin >100 μg/L (n = 7) or 200 μg/L (n = 4). For the latter, in some situations, such as CKD, ferritin concentrations should not exceed 500 μg/L (n = 5) or 800 μg/L (n = 5). Only 9 guidelines recommended TSAT as a target, proposing various thresholds ranging from 20% to 50%., Conclusions: It appears that for the diagnosis of ID, a cutoff of 100 μg/L for serum ferritin concentration should be considered in most conditions and 20% for TSAT, except in particular situations, including young healthy women with heavy menstrual flow. New indications of intravenous iron supplementation are emerging., (© 2015 American Society for Nutrition.)

Background: Low iron absorption from important staple foods may contribute to iron deficiency in developing countries. To date, few studies have examined the iron bioavailability of pulse crops as commonly prepared and consumed by humans., Objective: The objectives were to characterize the iron absorption from a test meal of intrinsically labeled (57)Fe lentils prepared as dal, to compare the bioavailability of iron from (57)Fe in dal with that observed for a reference dose of (58)Fe as ferrous sulfate, and to assess associations between iron absorption and iron status indicators., Methods: This crossover study included 19 nonpregnant women (n = 6 anemic; hemoglobin: <12.0 g/dL) who consumed 2 test meals on consecutive days in a counter-balanced order, ferrous sulfate (7 mg FeSO4 plus 1 mg (58)Fe) and 330 g dal (lentils enriched to 85.1% with (57)Fe, 8 mg native (57)Fe). Iron absorption was determined by analyzing blood samples taken 14 d after dosing with the use of magnetic sector thermal ionization mass spectrometry., Results: We found that the mean iron absorption from the dal was 2.20% ± 3.40% and was significantly lower than the 23.6% ± 13.2% observed from the same iron load given as ferrous sulfate (P < 0.001). Absorption of non-heme iron from dal and from ferrous sulfate was inversely associated with serum ferritin (SF; r = -0.50, P = 0.05 and r = -0.81, P < 0.001, respectively) and serum hepcidin (r = -0.45, P = 0.05 and r = -0.60, P = 0.007, respectively). Anemic women absorbed more iron from either source (1.20% from dal, P = 0.10; 18.3% from ferrous sulfate, P = 0.001) compared with women who were iron replete., Conclusions: Iron absorption from the dal was low overall but upregulated in anemic women. Both SF and hepcidin were inversely associated with iron absorption from both a supplemental and a food-based non-heme iron source in nonanemic and anemic women., (© 2015 American Society for Nutrition.)

Background: Although iron supplementation in malaria-free areas mostly reduces infectious morbidity, it can sometimes increase morbidity from infections as a result of the dependence of pathogenic microorganisms on iron. Supplementation with n-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) improved morbidity in several human studies. However, information on the combined effect of iron and n-3 LCPUFA supplementation on infectious morbidity is limited., Objective: We determined whether n-3 LCPUFAs and iron supplementation, alone or in combination, affected absenteeism and illness in iron-deficient schoolchildren with low fish intake., Design: A total of 321 South African children (aged 6-11 y) with iron deficiency (ID) were randomly divided into 4 groups to receive 1) iron plus placebo, 2) a mixture of docosahexaenoic acid and eicosapentaenoic acid (DHA/EPA) plus placebo, 3) iron plus DHA/EPA, or 4) placebo plus placebo as oral supplements 4 times/wk for 8.5 mo. Morbidity was recorded, and iron-status indexes were measured. The total phospholipid fatty acid composition of peripheral blood mononuclear cell membranes was analyzed in a subsample (n = 130)., Results: Iron supplementation increased the number of days with illness when all symptoms were considered (B: 0.87; 95% CI: 0.71, 1.03) as well as illness that was specifically caused by respiratory symptoms (B: 1.45; 95% CI: 1.21, 1.70), whereas DHA/EPA reduced the number of days with illness at school (B: -0.96; 95% CI: -1.33, -0.59). The increases caused by iron were reduced to the levels seen in the placebo plus placebo group when iron was provided in combination with DHA/EPA as indicated by significant iron × DHA/EPA interactions (both P < 0.001)., Conclusion: Iron supplementation increased morbidity (mostly respiratory) in iron-deficient South African schoolchildren with low DHA/EPA intake, but when iron was given in combination with DHA/EPA, this effect was prevented., (© 2015 American Society for Nutrition.)

Background: Complementary feeding recommendations (CFRs) with the use of locally available foods can be developed by using linear programming (LP). Although its potential has been shown for planning phases of food-based interventions, the effectiveness in the community setting has not been tested to our knowledge., Objective: We aimed to assess effectiveness of promoting optimized CFRs for improving maternal knowledge, feeding practices, and child intakes of key problem nutrients (calcium, iron, niacin, and zinc)., Design: A community-intervention trial with a quasi-experimental design was conducted in East Lombok, West Nusa Tenggara Province, Indonesia, on children aged 9-16 mo at baseline. A CFR group (n = 240) was compared with a non-CFR group (n = 215). The CFRs, which were developed using LP, were promoted in an intervention that included monthly cooking sessions and weekly home visits. The mother's nutrition knowledge and her child's feeding practices and the child's nutrient intakes were measured before and after the 6-mo intervention by using a structured interview, 24-h recall, and 1-wk food-frequency questionnaire., Results: The CFR intervention improved mothers' knowledge and children's feeding practices and improved children's intakes of calcium, iron, and zinc. At the end line, median (IQR) nutrient densities were significantly higher in the CFR group than in the non-CFR group for iron [i.e., 0.6 mg/100 kcal (0.4-0.8 mg/100 kcal) compared with 0.5 mg/100 kcal (0.4-0.7 mg/100 kcal)] and niacin [i.e., 0.8 mg/100 kcal (0.5-1.0 mg/100 kcal) compared with 0.6 mg/100 kcal (0.4-0.8 mg/100 kcal)]. However, median nutrient densities for calcium, iron, niacin, and zinc in the CFR group (23, 0.6, 0.7, and 0.5 mg/100 kcal, respectively) were still below desired densities (63, 1.0, 0.9, and 0.6 mg/100 kcal, respectively)., Conclusions: The CFRs significantly increased intakes of calcium, iron, niacin, and zinc, but nutrient densities were still below desired nutrient densities. When the adoption of optimized CFRs is constrained by economic access for or acceptability of nutrient-dense foods, other strategies need to be incorporated into interventions to ensure adequate intakes of these nutrients., (© 2015 American Society for Nutrition.)

Background: Food fortification is one approach for addressing anemia, but information on program effectiveness is limited., Objective: We evaluated the impact of Costa Rica's fortification program on anemia in women aged 15-45 y and children aged 1-7 y., Design: Reduced iron, an ineffective fortificant, was replaced by ferrous fumarate in wheat flour in 2002, and ferrous bisglycinate was added to maize flour in 1999 and to liquid and powdered milk in 2001. We used a one-group pretest-posttest design and national survey data from 1996 (baseline; 910 women, 965 children) and 2008-2009 (endline; 863 women, 403 children) to assess changes in iron deficiency (children only) and anemia. Data were also available for sentinel sites (1 urban, 1 rural) for 1999-2000 (405 women, 404 children) and 2008-2009 (474 women, 195 children), including 24-h recall data in children. Monitoring of fortification levels was routine., Results: Foods were fortified as mandated. Fortification provided about one-half the estimated average requirement for iron in children, mostly and equally through wheat flour and milk. Anemia was reduced in children and women in national and sentinel site comparisons. At the national level, anemia declined in children from 19.3% (95% CI: 16.8%, 21.8%) to 4.0% (95% CI: 2.1%, 5.9%) and in women from 18.4% (95% CI: 15.8%, 20.9%) to 10.2% (95% CI: 8.2%, 12.2%). In children, iron deficiency declined from 26.9% (95% CI: 21.1%, 32.7%) to 6.8% (95% CI: 4.2%, 9.3%), and iron deficiency anemia, which was 6.2% (95% CI: 3.0%, 9.3%) at baseline, could no longer be detected at the endline., Conclusions: A plausible impact pathway suggests that fortification improved iron status and reduced anemia. Although unlikely in the Costa Rican context, other explanations cannot be excluded in a pre/post comparison., (© 2015 American Society for Nutrition.)

Background: Effects of prenatal iron supplementation on maternal postpartum iron status and early infant iron homeostasis remain largely unknown., Objective: We examined iron absorption and growth in exclusively breastfed infants in relation to fetal iron exposure and iron status during early infancy., Design: Longitudinal, paired iron-absorption (⁵⁸Fe) studies were conducted in 59 exclusively breastfed Peruvian infants at 2-3 mo of age (2M) and 5-6 mo of age (5M). Infants were born to women who received ≥ 5100 or ≤ 1320 mg supplemental prenatal Fe. Iron status was assessed in mothers and infants at 2M and 5M., Results: Infant iron absorption from breast milk averaged 7.1% and 13.9% at 2M and 5M. Maternal iron status (at 2M) predicted infant iron deficiency (ID) at 5M. Although no infants were iron deficient at 2M, 28.6% of infants had depleted iron stores (ferritin concentration <12 μg/L) by 5M. Infant serum ferritin decreased (P < 0.0001), serum transferrin receptor (sTfR) increased (P < 0.0001), and serum iron decreased from 2M to 5M (P < 0.01). Higher infant sTfR (P < 0.01) and breast-milk copper (P < 0.01) predicted increased iron absorption at 5M. Prenatal iron supplementation had no effects on infant iron status or breast-milk nutrient concentrations at 2M or 5M. However, fetal iron exposure predicted increased infant length at 2M (P < 0.01) and 5M (P < 0.05)., Conclusions: Fetal iron exposure affected early infant growth but did not significantly improve iron status or absorption. Young, exclusively breastfed infants upregulated iron absorption when iron stores were depleted at both 2M and 5M.

Despite growing wealth and a strengthening government commitment to improve livelihoods and welfare, many students across rural China have inadequate access to micronutrient-rich diets. Poor diets can lead to nutritional problems, such as iron-deficiency anemia, that can adversely affect health, attention, learning, and mental health. The overall goal of this paper is to assess the impact of multiple micronutrient supplementation (MMS) on anemia and anxiety among students in poor areas of rural China. To achieve this goal, we conducted a randomized controlled trial in 54 randomly chosen elementary schools in 8 of the poorest counties in Shaanxi Province in Northwest China. Study participants were 2730 fourth-grade students, mostly aged 10-12 y. Schools were randomly assigned to 1 of 2 groups: a control group that received no intervention and an intervention group that received a daily MMS with 5 mg of iron (ferrous sulfate) for 5 mo. Our primary outcome measures were hemoglobin (Hb) concentrations (assessed by HemoCue 201+ technology), anemia prevalence (defined as Hb) concentrations ≤120 g/L), and anxiety (using a written mental health test). The results showed that 42.4% of students were anemic at baseline. The Hb concentration was 121.7 ± 10.7 g/L in the treatment group and 123.4 ± 11.4 g/L in the control group. MMS increased Hb concentrations by 1.7 g/L ± 0.15 and reduced anemia rates by 7.0 percentage points (P < 0.05). Anxiety was reduced by 0.30 SDs (P < 0.01). MMS reduced both anemia and anxiety. Our results should encourage further research on the linkages between nutrition and mental health in a development context.

Excessive iron consumption during pregnancy can lead to increased oxidative stress in the maternal body, which may result in adverse pregnancy outcomes. Glutathione S-transferases (GSTs) originate from a superfamily of detoxifying enzymes that play a role in reducing xenobiotic compounds and oxidative stress. The aim of this study was to determine the relationship among GST gene expression, maternal iron intake during pregnancy, and neonatal birth weight. The study participants were 1087 Korean gravidas and their newborns recruited for the Mothers and Children's Environmental Health study between 2006 and 2010. A 24-h dietary recall interview was conducted to estimate iron intake; additional intake through nutritional supplements was thoroughly investigated. Deletion polymorphisms of GSTM1 and GSTT1 were genotyped using PCR. Dietary iron consumption during pregnancy was positively associated with birth weight in pregnant women who were GSTM1-present after adjustment for the following covariates: maternal age, prepregnancy BMI, mother's education level, log-transformed urinary cotinine level, infant gender, gestational age at term, log-transformed energy intake, parity, and the use of folic acid supplements (P < 0.05). There were interactions between the GSTM1 genotype and iron intakes from animal foods (P < 0.05), diet (P < 0.05), and diet with supplements (P < 0.05). No relationship was found between maternal iron intake and birth weight for the GSTT1 polymorphism. This study demonstrates that increased iron consumption during pregnancy may improve infant birth weight for mothers who are GSTM1-present, but it might not be beneficial for mothers with the GSTM1-null genotype.

Background: Little is known about the combined effects of iron and n-3 (omega-3) fatty acid (FA) supplementation on cognitive performance. The provision of either DHA/EPA or iron alone in rats with combined iron and n-3 FA deficiency has been reported to exacerbate cognitive deficits associated with deficiency., Objective: We investigated the effects of iron and DHA/EPA supplementation, alone and in combination, in children with poor iron and n-3 FA status., Design: In a 2-by-2 factorial trial, children with iron deficiency (ID) (n = 321; aged 6-11 y) were allocated to receive 1) iron (50 mg) plus DHA/EPA (420/80 mg), 2) iron plus placebo, 3) placebo plus a mixture of DHA and EPA (DHA/EPA), or 4) placebo plus placebo as oral supplements (4/wk) for 8.5 mo. Cognition was assessed at baseline and endpoint by using the Hopkins Verbal Learning Test (HVLT) and subscales of the Kaufman Assessment Battery for Children., Results: Both iron and DHA/EPA significantly increased weight-for-age z scores. Iron increased the number of words recalled at HVLT recall 2 (intervention effect: 0.90; 95% CI: 0.18, 1.62), and in anemic children, iron increased scores in the Atlantis Delayed test (1.51; 95% CI: 0.03, 2.99) and HVLT recall 2 (2.02; 95% CI: 0.55, 3.49). DHA/EPA showed no benefit in any of the cognitive tests but decreased Atlantis test scores (-2.48; 95% CI: -3.99, -0.96) in children who were anemic at baseline and decreased Atlantis delayed scores (-0.9; 95% CI: -1.45, -0.36) in girls with ID, whereas boys tended to perform better., Conclusions: In children with poor iron and n-3 FA status, iron supplementation improved verbal and nonverbal learning and memory, particularly in children with anemia. In contrast, DHA/EPA supplementation had no benefits on cognition and impaired working memory in anemic children and long-term memory and retrieval in girls with ID.

Background: The effect of bariatric surgery on iron absorption is only partially known., Objective: The objective was to study the effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGBP) on heme- and nonheme-iron absorption and iron status., Design: Fifty-eight menstruating women were enrolled in this prospective study [mean (±SD) age: 35.9 ± 9.1 y; weight: 101.7 ± 13.5 kg; BMI (in kg/m²): 39.9 ± 4.4]. Anthropometric, body-composition, dietary, and hematologic indexes and heme- and nonheme-iron absorption-using a standardized meal containing 3 mg Fe-were determined before and 12 mo after surgery. Forty-three subjects completed the 12-mo follow-up. Iron supplements were strictly controlled., Results: Heme-iron absorption was 23.9% before and 6.2% 12 mo after surgery (P < 0.0001). Nonheme-iron absorption decreased from 11.1% to 4.7% (P < 0.0001). No differences were observed by type of surgery. Iron intakes from all sources of supplements were 27.9 ± 6.2 mg/d in the SG group and 63.2 ± 21.1 mg/d in the RYGBP group (P < 0.001). Serum ferritin and total-body iron decreased more after RYGBP than after SG., Conclusions: Iron (heme and nonheme) absorption is markedly reduced after SG and RYGBP. The magnitude of the decrease in heme-iron absorption is greater than that of nonheme iron. The amounts suggested as iron supplements may need to be increased to effectively prevent iron-status impairment.

Iron supplementation strategies in the developing world remain controversial because of fears of exacerbating prevalent infectious diseases. Understanding the conditions in which iron will be absorbed and incorporated into erythrocytes is therefore important. We studied Gambian children with either postmalarial or nonmalarial anemia, who were given oral iron supplements daily for 30 days. Supplements administered on days 1 and 15 contained the stable iron isotopes (57)Fe and (58)Fe, respectively, and erythrocyte incorporation was measured in blood samples drawn 14 days later. We investigated how the iron-regulatory hormone hepcidin and other inflammatory/iron-related indices, all measured on the day of isotope administration, correlated with erythrocyte iron incorporation. In univariate analyses, hepcidin, ferritin, C-reactive protein, and soluble transferrin receptor (sTfR) strongly predicted incorporation of (57)Fe given on day 1, while hepcidin, ferritin, and sTfR/log ferritin correlated with (58)Fe incorporation. In a final multivariate model, the most consistent predictor of erythrocyte isotope incorporation was hepcidin. We conclude that under conditions of competing signals (anemia, iron deficiency, and infection), hepcidin powerfully controls use of dietary iron. We suggest that low-cost point-of-care hepcidin assays would aid iron supplementation programs in the developing world.

Questions have been raised about potentially negative effects of antenatal folic acid use in populations with a high prevalence of vitamin B-12 deficiency. Our objective was to examine the association between maternal folate and vitamin B-12 status in pregnancy on offspring insulin resistance and examine whether the effects of maternal micronutrient supplementation varied by baseline maternal folate and/or vitamin B-12 status. Pregnant women were cluster randomized to receive daily supplements containing vitamin A alone or with folic acid, folic acid+iron, folic acid+iron+zinc, or a multiple micronutrient. In a subsample (n = 1132), micronutrient status biomarkers were analyzed at baseline and late pregnancy. Children born to the women who participated in the trial were visited at 6-8 y of age. Fasting plasma glucose and insulin were used to estimate insulin resistance using the homeostasis model assessment (HOMA-IR). Children whose mothers were deficient in vitamin B-12 (<148 pmol/L, 27%) during early pregnancy had a 26.7% increase in HOMA-IR (P = 0.02), but there was no association with maternal folate status. Among children born to women who were vitamin B-12 deficient at baseline, the percent difference in HOMA-IR compared to the control group was 15.1% (95% CI: -35.9, 106.4), 4.9% (-41.6, 88.5), 3.3% (-38.4, 73.5), and 18.1% (-29.0, 96.7) in the folic acid, folic acid-iron, folic acid-iron-zinc, and multiple micronutrient supplementation groups, respectively, none of which were significant. Maternal vitamin B-12 deficiency is associated with an elevated risk of insulin resistance, but supplementation with folic acid or other micronutrients led to no significant change in insulin resistance in school-aged offspring.

Purpose: The purpose of this study was to investigate the use of herbal drugs by pregnant women in relation to concurrent use of conventional drugs, delivery, and pregnancy outcome., Method: 600 women at Stavanger University Hospital Norway were interviewed using a structured questionnaire within five days after delivery. Medical birth charts were reviewed with respect to pregnancy outcome., Results: In all, 39.7% of the women reported having used herbal drugs during pregnancy, most commonly ginger, iron-rich herbs, echinacea and cranberry. Although 86.3% of the women reported having used conventional drugs during pregnancy there were few potential interactions between herbal drugs and conventional drugs. There was a significant association between the use of iron-rich herbs during pregnancy and high birthweight, and use of raspberry leaves and caesarean delivery., Conclusion: Use of herbal drugs is common during pregnancy and indicates a need for documentation about their safety in pregnancy., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Iron deficiency is among the most prevalent of nutrient-related diseases worldwide, but the long-term consequences of maternal and neonatal iron deficiency on offspring are not well characterized. We investigated the effects of a postweaning iron-adequate diet following neonatal iron deficiency on the expression of genes involved in iron acquisition and homeostasis. Pregnant rats were fed an iron-adequate diet (0.08 g iron/kg diet) until gestational d 15, at which time they were divided into 2 groups: 1) a control group fed an iron-adequate diet, and 2) an iron-deficient group fed an iron-deficient diet (0.005 g iron/kg diet) through postnatal d (P) 23 (weaning). After weaning, pups from both dietary treatment groups were fed an iron-adequate diet until adulthood (P75). Rat pups that were iron deficient during the neonatal period (IDIA) had reduced weight gain and hemoglobin concentrations and decreased levels of serum, liver, and spleen iron on P75 compared with rats that were iron sufficient throughout early life (IA). IDIA rats developed erythrocytosis during postweaning development. Further, hepatic expression of hepcidin in IDIA rats was 1.4-fold greater than in IA rats, which paralleled an upregulation of IL-1 expression in the serum. Our data suggest that an iron-adequate diet following neonatal iron deficiency induced an inflammatory milieu that affected iron homeostasis and early growth and development.

Iron deficiency is a common health problem. The most severe consequence of this disorder is iron deficiency anemia (IDA), which is considered the most common nutritional deficiency worldwide. Newborn piglets are an ideal model to explore the multifaceted etiology of IDA in mammals, as IDA is the most prevalent deficiency disorder throughout the early postnatal period in this species and frequently develops into a critical illness. Here, we report the very low expression of duodenal iron transporters in pigs during the first days of life. We postulate that this low expression level is why the iron demands of the piglet body are not met by iron absorption during this period. Interestingly, we found that a low level of duodenal divalent metal transporter 1 and ferroportin, two iron transporters located on the apical and basolateral membrane of duodenal absorptive enterocytes, respectively, correlates with abnormally high expression of hepcidin, despite the poor hepatic and overall iron status of these animals. Parenteral iron supplementation by a unique intramuscular administration of large amounts of iron dextran is current practice for the treatment of IDA in piglets. However, the potential toxicity of such supplemental iron implies the necessity for caution when applying this treatment. Here we demonstrate that a modified strategy for iron supplementation of newborn piglets with iron dextran improves the piglets' hematological status, attenuates the induction of hepcidin expression, and minimizes the toxicity of the administered iron.

Background: Iron status degrades in female soldiers during military training. Inflammation-mediated up-regulation of hepcidin, a key mediator of iron homeostasis, may be a contributing factor., Objective: We measured the efficacy of an iron-fortified food product for maintaining iron status in female soldiers during basic combat training (BCT) and examined relations between iron status, serum hepcidin concentrations, and inflammation., Design: A randomized, double-blind, placebo-controlled trial was conducted. Volunteers received an iron-fortified food product (total dose = 56 mg Fe/d) or a placebo twice daily during the 9-wk BCT course. Iron-status indicators, serum hepcidin concentrations, and markers of inflammation were measured pre- and post-BCT., Results: BCT affected iron status; serum ferritin concentrations decreased (P < or = 0.05), and concentrations of soluble transferrin receptor (sTfR) and hemoglobin and the red cell distribution width increased (P < or = 0.05). Consumption of the iron-fortified food product attenuated declines in iron status in iron-deficient anemic soldiers; a group-by-time interaction was observed for hemoglobin and sTfR concentrations (P < or = 0.05). Serum hepcidin concentrations were not affected by BCT; however, hepcidin concentrations were lower in iron-deficient anemic soldiers than in those with normal iron status (P < or = 0.05) and were positively associated with serum ferritin (P < or = 0.05) and C-reactive protein (P < or = 0.05) concentrations pre- and post-BCT., Conclusions: Twice-daily consumption of an iron-fortified food product improved iron status in iron-deficient anemic soldiers but not in iron-normal or iron-deficient nonanemic soldiers. Serum hepcidin concentrations were not affected by training but were associated with iron status and inflammation pre- and post-BCT. This trial was registered at clinicaltrials.gov as NCT01100905.

Background: Dual fortification of salt with iodine and iron could be a sustainable approach to combating iodine and iron deficiencies., Objective: We compared the efficacy of dual-fortified salt (DFS) made by using 2 proposed contrasting formulas-one fortifying with iron as micronized ground ferric pyrophosphate (MGFePP) and the other with iron as encapsulated ferrous fumarate (EFF)-with the efficacy of iodized salt (IS) in schoolchildren in rural southern India., Design: After stability and acceptability testing, a double-blind, household-based intervention was conducted in 5-15-y-old children (n = 458) randomly assigned into 3 groups to receive IS or DFS with iron as MGFePP or EFF, both at 2 mg/g salt. We measured hemoglobin, iron status, and urinary iodine at baseline, 5 mo, and 10 mo., Results: Median serum ferritin and calculated median body iron improved significantly in the 2 groups receiving iron. After 10 mo, the prevalence of anemia decreased from 16.8% to 7.7% in the MGFePP group (P < 0.05) and from 15.1% to 5.0% in the EFF group (P < 0.01). The median urinary iodine concentration increased significantly in the IS and EFF groups (P < 0.001) but not in the MGFePP group. Losses of iodine in salt with 1.8% moisture were high for MGFePP, whereas the EFF segregated in salt with 0.5% moisture and caused color changes in some local foods., Conclusions: Both DFSs were efficacious in reducing the prevalence of anemia and iron deficiency in school-age children. Local salt characteristics should be taken into consideration when choosing an iron fortificant for DFS to achieve optimal iodine stability and color.

Iron deficiency is one of the leading risk factors for disability and death worldwide, affecting an estimated 2 billion people. Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from diet. Dietary iron bioavailability is low in populations consuming monotonous plant-based diets. The high prevalence of iron deficiency in the developing world has substantial health and economic costs, including poor pregnancy outcome, impaired school performance, and decreased productivity. Recent studies have reported how the body regulates iron absorption and metabolism in response to changing iron status by upregulation or downregulation of key intestinal and hepatic proteins. Targeted iron supplementation, iron fortification of foods, or both, can control iron deficiency in populations. Although technical challenges limit the amount of bioavailable iron compounds that can be used in food fortification, studies show that iron fortification can be an effective strategy against nutritional iron deficiency. Specific laboratory measures of iron status should be used to assess the need for fortification and to monitor these interventions. Selective plant breeding and genetic engineering are promising new approaches to improve dietary iron nutritional quality.

Background: Nightblindness affects 16-52% of pregnant women in areas of Nepal and in some cases persists after vitamin A treatment. Iron and riboflavin affect vitamin A utilization and photoreceptor function, respectively, and pilot data in the study population showed a high prevalence of iron and riboflavin deficiencies., Objective: The objective was to assess the effect of supplemental iron and riboflavin on pupillary threshold (PT) and plasma retinol in nightblind, pregnant Nepali women given vitamin A-fortified rice., Design: Nightblind pregnant women were randomly assigned to receive, 6 d/wk under supervision for 6 wk, a vitamin A-fortified rice curry dish providing 850 microg retinal activity equivalents/d with either a 30-mg Fe and 6-mg riboflavin (FeR + VA) capsule or a placebo control (VA only) capsule. Hemoglobin, erythrocyte riboflavin, and plasma ferritin and retinol were measured before and after the intervention. Dark adaptation was assessed by PT score., Results: Women who were iron deficient at baseline (n=38) had significantly greater improvement in PT score with iron and riboflavin supplementation than without (P=0.05). Iron and riboflavin supplements significantly reduced the prevalences of riboflavin deficiency (from 60% to 6%; P<0.0001), iron deficiency anemia (from 35% to 15%; P<0.007), and abnormal PT (from 87% to 30%; P<0.05) from baseline. Mean increases in erythrocyte riboflavin (P<0.0001) and plasma ferritin (P=0.01) were greater in the FeR + VA group than in the VA only group., Conclusions: Iron deficiency may limit the efficacy of vitamin A to normalize dark adaptation in pregnant Nepali women. Further studies are needed to assess the effect of simultaneous delivery of iron and vitamin A for the treatment of nightblindness.

Deficiencies of iron and iodine are common in West Africa, and salt is one of very few food vehicles available for fortification. Salt dual-fortified with iodine and micronized ground ferric pyrophosphate (FePP) was tested for its efficacy in rural, tropical Côte d'Ivoire. First, salt and iron intakes, and iron bioavailability were estimated using 3-d weighed food records in 24 households. Local iodized salt was then fortified with 3 mg Fe/g salt as ground FePP (mean particle size = 2.5 mum), and stability, sensory and acceptability trials were done. The dual fortified salt (DFS) was distributed to households and its efficacy compared with that of iodized salt (IS) in a 6-mo, double-blind trial in 5- to 15-y-old iron-deficient children (n = 123). All children were dewormed at baseline. After 6 mo, serum ferritin (SF) and transferrin receptor (TfR) concentrations as well as body iron stores improved significantly in the DFS group but not in the IS GROUP (P < 0.05). Body iron increased from 4.6 +/- 2.7 to 5.9 +/- 2.7 mg/kg (mean +/- SD) in the DFS group; concentrations before and after treatment in the IS group were 5.5 +/- 2.9 and 5.6 +/- 3.1 mg/kg, respectively. The hemoglobin concentration and the prevalence of anemia did not change in either group. The prevalences of malaria, soil-transmitted helminths, and riboflavin deficiency were 55, 14, and 66%, respectively. In tropical West Africa, low-grade salt fortified with micronized ground FePP increased body iron stores but not hemoglobin in children. Iron utilization may have been impaired by the high prevalence of malaria and concurrent nutrient deficiencies.

Background: Although iron deficiency is a major cause of anemia, other micronutrient deficiencies may also play a role., Objective: We examined whether multiple micronutrient supplementation is more efficacious than is supplementation with iron and folic acid alone for improving the hemoglobin and iron status of anemic adolescent girls in Bangladesh., Design: Anemic (hemoglobin < 12.0 g/dL) girls (n = 197) aged 14-18 y from rural schools in Dhaka District were entered into a randomized double-blind trial and received twice-weekly supplements of iron and folic acid (IFA group) or multiple micronutrients (15 micronutrients, including iron and folic acid; MMN group) for 12 wk., Results: At recruitment, the characteristics of the girls in the 2 groups were not significantly different, except for family size and body mass index. At the end of the study, although both groups benefited significantly from supplementation, mean changes in hemoglobin and serum ferritin concentrations were not significantly different between groups. Compared with the IFA group, girls in the MMN group had significantly greater increases in mean serum vitamin A, plasma vitamin C, red blood cell folic acid, and riboflavin concentrations (assessed as erythrocyte glutathione reductase activation coefficient). After 12 wk of supplementation, only the prevalence of vitamins A and C and riboflavin deficiencies decreased more significantly in the MMN group than in the IFA group., Conclusions: Twice-weekly MMN supplementation for 12 wk significantly improved the status of the micronutrients assessed but was not more efficacious than was supplementation with iron and folic acid alone in improving the hematologic status of anemic adolescent girls. More frequent doses may be needed to achieve full benefit.

Supplementation with iron is generally recommended during pregnancy to meet the iron needs of both mother and fetus. When detected early in pregnancy, iron deficiency anemia (IDA) is associated with a > 2-fold increase in the risk of preterm delivery. Maternal anemia when diagnosed before midpregnancy is also associated with an increased risk of preterm birth. Results of recent randomized clinical trials in the United States and in Nepal that involved early supplementation with iron showed some reduction in risk of low birth weight or preterm low birth weight, but not preterm delivery. During the 3rd trimester, maternal anemia usually is not associated with increased risk of adverse pregnancy outcomes and may be an indicator of an expanded maternal plasma volume. High levels of hemoglobin, hematocrit, and ferritin are associated with an increased risk of fetal growth restriction, preterm delivery, and preeclampsia. While iron supplementation increases maternal iron status and stores, factors that underlie adverse pregnancy outcome are considered to result in this association, not iron supplements. On the other hand, iron supplements and increased iron stores have recently been linked to maternal complications (eg, gestational diabetes) and increased oxidative stress during pregnancy. Consequently, while iron supplementation may improve pregnancy outcome when the mother is iron deficient it is also possible that prophylactic supplementation may increase risk when the mother does not have iron deficiency or IDA. Anemia and IDA are not synonymous, even among low-income minority women in their reproductive years.

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 microg I (as potassium iodate)/g salt and 2 mg Fe (as micronized ferric pyrophosphate; mean particle size = 2.5 microm)/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 approximately 18 mg Fe/d; iron absorption was estimated to be approximately 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.

Background: Iron and zinc deficiency are prevalent during infancy in low-income countries., Objectives: The objectives were to examine whether a weekly supplement of iron, zinc, iron+zinc, or a micronutrient mix (MM) of 16 vitamins and minerals would alter infant development and behavior., Design: The participants were 221 infants from rural Bangladesh at risk of micronutrient deficiencies. Development and behavior were evaluated at 6 and 12 mo of age by using the Bayley Scales of Infant Development II and the Home Observation Measurement of Environment (HOME) scale. In this double-blind trial, the infants were randomly assigned to 1 of 5 treatment conditions: iron (20 mg), zinc (20 mg), iron+zinc, MM (16 vitamins and minerals, including iron and zinc), or riboflavin weekly from 6 to 12 mo. Multivariate analyses were conducted to examine the change in development and behavior for each supplementation group, with control for maternal education, HOME score, months breastfed, anemia, growth at 6 mo, and change in growth from 6 to 12 mo., Results: Iron and zinc administered together and with other micronutrients had a beneficial effect on infant motor development. Iron and zinc administered individually and in combination had a beneficial effect on orientation-engagement. Two-thirds of the infants were mildly anemic, no treatment effects on hemoglobin concentration were observed, and hemoglobin was not associated with measures of development or behavior., Conclusion: The beneficial effects of weekly iron and zinc supplementation on motor development and orientation-engagement suggest that infants benefit from these minerals when administered together.

Objective: A decrease in iron concentration is accompanied by alterations in catecholaminergic and GABAergic neurotransmission systems, important in learning, memory and attention. It was hypothesized that iron deficient children would present attention deficits. A visual-event related potentials (ERPs) study is presented using an oddball paradigm in order to determine the P300 in ID children., Methods: After medical examination, blood was obtained from 201 children for a complete hematological study. Two groups were selected, iron deficient (ID) (serum iron <60 microg/dl) and control (C) (serum iron >60 microg/dl). In both groups ERPs were recorded while executing a continuous performance task (oddball paradigm). Afterwards iron levels were restored in ID children by iron supplementation (ID-IS group) and all tests reapplied., Results: ID children almost lacked a P300 in central and parietal regions. After iron supplementation, P300 clearly became evident although its Pz amplitude remained smaller compared to C children., Conclusions: A clear and strong correlation was found between ID and attention alterations in children. Iron supplementation nearly brings the P300 to normal levels although it is not known if the P300 difference in Pz is due to other nutritional/environmental deficits or to developmental psychomotor impairments in ID children., Significance: It has been long known that iron deficient children have cognitive impairments but there is an insufficient number of electrophysiological works allowing to identify the source of this problem. In this work an attention deficit is demonstrated in ID children through a severely reduced P300, which recovers substantially after iron supplementation.

Background: In many developing countries, children are at high risk of both goiter and iron deficiency anemia., Objective: In a series of studies in northern Morocco, we developed and tested a dual-fortified salt (DFS) containing iodine and microencapsulated iron., Design: To establish the DFS fortification concentration, we measured salt intake by 3-d weighed food records and estimated iron bioavailability from the local diet by using published algorithms. We then formulated a DFS containing 25 micro g iodine/g salt (as potassium iodide) and 1 mg iron/g salt (as ferrous sulfate hydrate encapsulated with partially hydrogenated vegetable oil). After storage and acceptability trials, we compared the efficacy of the DFS to that of iodized salt in a 9-mo, randomized, double-blind trial in iodine-deficient, 6-15-y-old children (n = 377)., Results: Mean salt intake in school-age children was 7-12 g/d, and estimated iron bioavailability from the local diet was 0.4-4.3%. After storage for 20 wk, the DFS and iodized salt were not significantly different in iodine content, and color stability was acceptable when the compounds were added to local meals. During the efficacy trial, urinary iodine concentrations and thyroid volumes improved significantly (P < 0.001 and < 0.05, respectively) from baseline in both groups. At 40 wk, mean hemoglobin concentrations in the DFS group had increased by 14 g/L (P < 0.01), and serum ferritin, transferrin receptor, and zinc protoporphyrin concentrations were significantly better (P < 0.05) in the DFS group than in the iodized salt group. The prevalence of iron deficiency anemia in the DFS group decreased from 35% at baseline to 8% at 40 wk (P < 0.001)., Conclusion: A DFS containing iodine and encapsulated iron can be an effective fortification strategy.

Toxic concentration of arsenic (400 microg/kg body weight/day) was administered orally for 8 weeks to both iron-supplemented and iron-deficient rats. The results showed greater amount of arsenic in both the duodenum and liver of iron-deficient rats, compared to iron-supplemented ones. Duodenum containing high concentration of arsenic in iron-deficient rats showed significant reduction of ferrireductase (the enzyme responsible for the conversion of ferric iron to ferrous one) activity. Our results suggest that anemic rats are more prone to develop arsenic poisoning following chronic ingestion of high content of arsenic.

The need for combined and integrated strategies to address iron deficiency is widely recognized, utilizing targeted supplementation, as well as food based strategies including both fortified and nonfortified foods. The challenge is not so much knowing "what" to do as is understanding "how" to implement effective and sustainable interventions. Because the causes of iron and other micronutrient deficiencies are complex, including inadequate food intake, unsanitary conditions and inadequate health services, the solutions may also be complex, requiring multisectoral and interdisciplinary approaches. Top-down strategies are unlikely to be effective and sustainable. Rather, the beneficiaries of the program at the community level must be able to understand malnutrition in simple terms, to envisage potential solutions and to become "demanders" of services. The experience in Thailand provides an example of a country-wide, community-based and participatory approach utilizing facilitators and motivators at the local level to implement and sustain interventions. The experience in Thailand indicates the potential for developing effective and sustainable interventions to address iron deficiency and other micronutrient problems as part of a broad, community-based effort.

This paper provides a synopsis of the experience in combating iron deficiency in industrialized countries and identifies the reasons for the considerable success and future challenges. Significant progress has been made over the last century in reducing and even eliminating iron deficiency in many industrialized countries. Current estimates are that the prevalence of iron deficiency has declined to <20% in many of these countries, even among women and young children, compared with 30 to 70% in many developing countries. The reasons for this success cannot be attributed solely to a single approach but rather to a range of factors that have occurred over time as a result of both economic development and the implementation of specific policies. Several factors have contributed to improving both iron intakes and reducing iron losses; these include fortification, supplementation, dietary diversification and public health measures. For example, the decline in anemia in infants can be attributed to the introduction of iron-fortified formula and complementary foods in the 1960s to 1970s. Similarly, the enrichment and fortification of cereals with iron that began during World War II in North America and Europe is a result of effective public-private partnerships. Despite these successes, iron deficiency remains a public health concern in industrialized countries for selected subgroups such as women of reproductive age with excess menstrual losses and pregnant women who cannot meet increased requirements from the diet alone. Constant vigilance and innovative approaches for screening and combating this problem are thus still required even in developed countries.

Iron fortification has been used to enhance iron intake in many developed countries for more than 50 years, but only in the last decade has this strategy been applied on a large scale to other parts of the world. Iron fortification of rice is being instituted in the Philippines. Initially, the rice will be produced in government-controlled rice mills and sold at low cost mainly to low income families. Efforts to improve the technology (using coating or extrusion techniques) are currently underway to reduce cost and minimize losses during storage and washing. Effectiveness and feasibility studies are required to test the new technologies and processing/distribution systems. In Venezuela in 1993, the government instituted a mandatory program of iron fortification to enrich precooked corn flour followed by the voluntary fortification of wheat flour. Surveys in school children subsequently showed a sharp drop in iron deficiency. Fortification of fish sauce in Vietnam has shown promising initial results in reducing anemia among anemic, nonpregnant female factory workers. Iron-fortified soy sauce has been shown to reduce anemia in initial studies in children in China, and a large-scale efficacy trial is now underway. These examples indicate that iron fortification of staple foods and condiments holds great promise for the prevention of iron deficiency.

Iron supplementation is probably the best available option to effectively address iron deficiency in pregnant women and young children because it can be targeted specifically to these high-risk groups. However, technical and practical barriers exist: limited information on the effectiveness of supplementation interventions, side effects that affect compliance, and supply/distribution constraints. An innovative approach to addressing these constraints is the use of sprinkles of powdered, microencapsulated ferrous fumarate that can be added directly to any semi-liquid food without changing their taste or consistency. This technique has been tested in initial trials in Ghana and found to be as effective as iron drops. Another approach to improve the effectiveness of iron interventions is through information, education and communication (IEC) programs. These interventions can help modify consumer behavior in some cases, but in some countries, geographic location, variations in language and population size can make the cost of IEC programs very high. IEC strategies in Indonesia aimed at increasing demand for iron supplements by systematic dissemination of specific messages, improving the quality and variety of tablets, increasing the availability and access to supplements by engaging the commercial sector, enrolling traditional birth attendants and other community volunteers in selling supplements. Key issues to be addressed include clarifying optimal starting points and duration of supplementation interventions--based on individual status or population prevalence, defining hemoglobin and ferritin cutoffs at which treatment should be instigated and evaluating the effectiveness of intermittent supplementation with multiple micronutrients.

Industrialized nations have been successful in reducing incidences of iron deficiency through utilization of multifaceted strategies that build on the capabilities of successful alliances between the public and private sectors. In comparison to developing nations, which have an estimated prevalence of iron deficiency of approximately 40%, the prevalence in industrialized countries is approximately 5%. Such low rates were achieved by various initiatives including widespread availability of affordable iron-fortified foods and implementation of national, science-based programs. Despite these successes, however, iron deficiency remains a critical problem among certain subpopulations (e.g., people of low socioeconomic status or recent immigrants who do not consume iron-fortified foods). Strengthening alliances among the private and public sectors and academia in communications efforts about iron deficiency and promoting iron-rich foods as well as iron-fortified foods is necessary to reduce iron deficiency in these populations.

Kazakhstan and the central Asian republics of Uzbekistan, the Kyrgyz Republic, Tajikistan and Turkmenistan have developed anemia prevention and control (APC) policies based on multiple interventions, including education and promotion, oral supplementation of high risk groups and fortification of wheat flour with iron and other micronutrients. These national strategies are aimed at reducing the prevalence of anemia and iron deficiency among young children and women of child-bearing age. Strategy development has been assisted by funding and technical assistance from the United Nations Children's Fund (UNICEF) with additional technical support from the International Nutrition Foundation, the United Nations University and various national institutions. These countries have been among the most advanced in adopting national strategies that include multiple interventions in an overall package, and national interest in APC remains high. However, reviews of APC activities conducted in 2001 suggests the need for modification and enhancement of current efforts and for a shift to national-level actions if these countries are to progress toward current and future goals. Increased commitment and determination, by both national groups and international organizations, are required to achieve and sustain improvement in micronutrient nutrition.

The main barriers to successful iron fortification are the following: 1) finding an iron compound that is adequately absorbed but causes no sensory changes to the food vehicle; and 2) overcoming the inhibitory effect on iron absorption of dietary components such as phytic acid, phenolic compounds and calcium. These barriers have been successfully overcome with some food vehicles but not with others. Iron-fortified fish sauce, soy sauce, curry powder, sugar, dried milk, infant formula and cereal based complementary foods have been demonstrated to improve iron status in targeted populations. The reasons for this success include the use of soluble iron such as ferrous sulfate, the addition of ascorbic acid as an absorption enhancer or the use of NaFeEDTA to overcome the negative effect of phytic acid. In contrast, at the present time, it is not possible to guarantee a similar successful fortification of cereal flours or salt. There is considerable doubt that the elemental iron powders currently used to fortify cereal flours are adequately absorbed, and there is an urgent need to investigate their potential for improving iron status. Better absorbed alternative compounds for cereal fortification include encapsulated ferrous sulfate and NaFeEDTA, which, unlike ferrous sulfate, do not provoke fat oxidation of cereals during storage. Encapsulated compounds also offer a possibility to fortify low grade salt without causing off-colors or iodine loss. Finally, a new and useful additional approach to ensuring adequate iron absorption from cereal based complementary foods is the complete degradation of phytic acid with added phytases or by activating native cereal phytases.

Iron fortification of food is a methodology utilized worldwide to address iron deficiency. A critical problem in some food fortification programs is the lack of bioavailability of iron compounds. This article reviews presentations on iron fortification programs in the Americas and the technical and practical barriers faced by the programs. Effective programmatic strategies will incorporate systematic consideration of sound program management, ensure consumption of fortified foods, and promote advocacy and supportive legislation. However, these factors are often overlooked or are not addressed coherently. Key components to consider in implementation of iron fortification programs include: utilization of foods and condiments containing fortificants that are bioavailable; program development and its implementation coordinated with targeted communications; utilizing resources from public/private sector partnerships; and operational research on how to overcome practical barriers for successful implementation of fortification.