Hepcidin-guided screen-and-treat interventions for young children with iron-deficiency anaemia in The Gambia: an individually randomised, three-arm, double-blind, controlled, proof-of-concept, non-inferiority trial.

BACKGROUND: Iron deficiency is the most prevalent nutritional disorder worldwide. Iron supplementation has modest efficacy, causes gastrointestinal side-effects that limit compliance, and has been associated with serious adverse outcomes in children across low-income settings. We aimed to compare two hepcidin-guided screen-and-treat regimens designed to reduce overall iron dosage by targeting its administration to periods when children were safe and ready to receive iron supplementation, with WHO's recommendation of universal iron supplementation. METHODS: We conducted an individually randomised, three-arm, double-blind, controlled, proof-of-concept, non-inferiority trial in 12 rural communities across The Gambia. Eligible participants were children aged 6-23 months with anaemia. Participants were randomly assigned (1:1:1) to either the WHO recommended regimen of one sachet of multiple micronutrient powder (MMP) daily containing 12·0 mg iron as encapsulated ferrous fumarate (control group); to MMP with 12·0 mg per day iron for the next 7 days if plasma hepcidin concentration was less than 5·5 µg/L, or to MMP without iron for the next 7 days if plasma hepcidin concentration was at least 5·5 µg/L (12 mg screen-and-treat group); or to MMP with 6·0 mg per day iron for the next 7 days if plasma hepcidin concentration was less than 5·5 µg/L, or to MMP without iron for the next 7 days if plasma hepcidin concentration was at least 5·5 µg/L (6 mg screen-and-treat group). Randomisation was done by use of a permuted block design (block size of 9), with stratification by haemoglobin and age, using computer-generated numbers. Participants and the research team (except for the data manager) were masked to group allocation. The primary outcome was haemoglobin concentration, with a non-inferiority margin of -5 g/L. A per-protocol analysis, including only children who had consumed at least 90% of the supplements (ie, supplement intake on ≥75 days during the study), was done to assess non-inferiority of the primary outcome at day 84 using a one-sided t test adjusted for multiple comparisons. Safety was assessed by use of ex-vivo growth tests of Plasmodium falciparum in erythrocytes and three species of sentinel bacteria in plasma samples from participants. This trial is registered with the ISRCTN registry, ISRCTN07210906. FINDINGS: Between April 23, 2014, and Aug 7, 2015, we prescreened 783 children, of whom 407 were enrolled into the study: 135 were randomly assigned to the control group, 136 to the 12 mg screen-and-treat group, and 136 to the 6 mg screen-and-treat group. 345 (85%) children were included in the per-protocol population: 115 in the control group, 116 in the 12 mg screen-and-treat group, and 114 in the 6 mg screen-and-treat group. Directly observed adherence was high across all groups (control group 94·8%, 12 mg screen-and-treat group 95·3%, and 6 mg screen-and-treat group 95·0%). 82 days of iron supplementation increased mean haemoglobin concentration by 7·7 g/L (95% CI 3·2 to 12·2) in the control group. Both screen-and-treat regimens were significantly less efficacious at improving haemoglobin (-5·6 g/L [98·3% CI -9·9 to -1·3] in the 12 mg screen-and-treat group and -7·8 g/L [98·3% CI -12·2 to -3·5] in the 6 mg screen-and-treat group) and neither regimen met the preset non-inferiority margin of -5 g/L. The 12 mg screen-and-treat regimen reduced iron dosage to 6·1 mg per day and the 6 mg screen-and-treat regimen reduced dosage to 3·0 mg per day. 580 adverse events were observed in 316 participants, of which eight were serious adverse events requiring hospitalisation mainly due to diarrhoeal disease (one [1%] participant in the control group, three [2%] in the 12 mg screen-and-treat group, and four [3%] in the 6 mg screen-and-treat group). The most common causes of non-serious adverse events (n=572) were diarrhoea (145 events [25%]), upper respiratory tract infections (194 [34%]), lower respiratory tract infections (62 [11%]), and skin infections (122 [21%]). No adverse events were deemed to be related to the study interventions. INTERPRETATION: The hepcidin-guided screen-and-treat strategy to target iron administration succeeded in reducing overall iron dosage, but was considerably less efficacious at increasing haemoglobin and combating iron deficiency and anaemia than was WHO's standard of care, and showed no differences in morbidity or safety outcomes. FUNDING: Bill & Melinda Gates Foundation and UK Medical Research Council.

Effect of parboiling conditions on zinc and iron retention in biofortified and non-biofortified milled rice.

BACKGROUND: Zinc-biofortified rice could contribute to zinc intake in deficient populations, but processing it into parboiled rice could affect this potential benefit. Zinc and iron true retention (TR) in milled rice produced under conditions resembling household and commercial parboiled methods was evaluated. Zinc and iron TR in milled rice obtained from biofortified and non-biofortified rice subjected to different soaking temperatures during parboiling was also evaluated. RESULTS: Conditions resembling commercial parboiling methods resulted in 52.2-59.7% zinc TR and 55.4-79.1% iron TR, whereas those used for household parboiling resulted in 70.7-79.6% zinc TR and 78.2-119.8% iron TR. Zinc TR in milled (8-16% bran removal) biofortified and non-biofortified parboiled rice was 50.6-66.8% when soaking rough rice at 20 °C and 29.9-56.0% when soaking rough rice at 65 °C; both had lower zinc TR than non-parboiled rice (58.0-80.6%). Iron TR was generally similar between milled non-parboiled and parboiled rice (26.2-67.6%) and between parboiled biofortified and non-biofortified milled rice. CONCLUSION: Parboiling conditions used to obtain milled rice targeted for own household consumption resulted in higher zinc and iron TR compared to parboiling conditions used for milled rice targeted for markets. More zinc from the inner endosperm moved towards the outer layers at high soaking temperature, resulting in lower zinc TR for milled parboiled rice soaked in hotter water. Parboiled rice soaked at temperatures used in households could provide more zinc to diets compared to rice soaked in hotter water commonly used in large rice mills, especially when rice is extensively milled. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Complementary Feeding Indicators in Relation to Micronutrient Status of Ghanaian Children Aged 6-23 Months: Results from a National Survey.

BACKGROUND: Optimal complementary feeding is critical for adequate growth and development in infants and young children. The associations between complementary feeding and growth have been studied well, but less is known about the relationship between complementary feeding and micronutrient status. METHODS: Using data from a national cross-sectional survey conducted in Ghana in 2017, we examined how multiple WHO-recommended complementary feeding indicators relate to anemia and the micronutrient status of children aged 6-23 months. RESULTS: In total, 42%, 38%, and 14% of the children met the criteria for minimum dietary diversity (MDD), minimum meal frequency (MMF), and minimum acceptable diet (MAD), respectively. In addition, 71% and 52% of the children consumed iron-rich foods and vitamin A-rich foods, respectively. The prevalence of anemia, iron deficiency (ID), iron deficiency anemia (IDA) and vitamin A deficiency (VAD) was 46%, 45%, 27%, and 10%, respectively. Inverse associations between MMF and socio-economic status were found, and MMF was associated with an increased risk of ID (55%; p < 0.013) and IDA (38%; p < 0.002). CONCLUSION: The pathways connecting complementary feeding and micronutrient status are complex. Findings related to MMF should be further investigated to ensure that complementary feeding programs account for the potential practice of frequent feeding with nutrient-poor foods.

Measurement of long-term iron absorption and loss during iron supplementation using a stable isotope of iron (57 Fe).

We report the first measurements of long-term iron absorption and loss during iron supplementation in African children using a stable isotope of iron (57 Fe). After uniform labelling of body iron with 57 Fe, iron absorption is proportional to the rate of decrease in the 57 Fe tracer concentration, while iron loss is proportional to the rate of decrease in the 57 Fe tracer amount. Anaemic Gambian toddlers were given 2 mg 57 Fe orally to equilibrate with total body iron over 8-11 months. After assignment to the positive control arm of the HIGH study, 22 toddlers consumed a micronutrient powder containing 12 mg iron for 12 weeks followed by 12 weeks without iron supplementation. Their daily iron absorption increased 3·8-fold during the iron supplementation period compared to the control period [median (interquartile range, IQR): 1·00 (0·82; 1·28) mg/day vs. 0·26 (0·22; 0·35) mg/day; P = 0·001]. Unexpectedly, during the supplementation period, daily iron loss also increased by 3·4-fold [0·75 (0·55; 0·87) mg/day vs. 0·22 (0·19; 0·29) mg/day; P = 0·005]. Consequently, most (~72%) of the absorbed iron was lost during supplementation. Long-term studies of iron absorption and loss are a promising and accurate method for assessing and quantifying long-term iron balance and may provide a reference method for evaluating iron intervention programs in vulnerable population groups. This study was registered as ISRCTN 0720906.

Iron Absorption from Iron-Biofortified Sweetpotato Is Higher Than Regular Sweetpotato in Malawian Women while Iron Absorption from Regular and Iron-Biofortified Potatoes Is High in Peruvian Women.

BACKGROUND: Sweetpotato and potato are fast-maturing staple crops and widely consumed in low- and middle-income countries. Conventional breeding to biofortify these crops with iron could improve iron intakes. To our knowledge, iron absorption from sweetpotato and potato has not been assessed. OBJECTIVE: The aim was to assess iron absorption from regular and iron-biofortified orange-fleshed sweetpotato in Malawi and yellow-fleshed potato and iron-biofortified purple-fleshed potato in Peru. METHODS: We conducted 2 randomized, multiple-meal studies in generally healthy, iron-depleted women of reproductive age. Malawian women (n = 24) received 400 g regular or biofortified sweetpotato test meals and Peruvian women (n = 35) received 500 g regular or biofortified potato test meals. Women consumed the meals at breakfast for 2 wk and were then crossed over to the other variety. We labeled the test meals with 57Fe or 58Fe and measured cumulative erythrocyte incorporation of the labels 14 d after completion of each test-meal sequence to calculate iron absorption. Iron absorption was compared by paired-sample t tests. RESULTS: The regular and biofortified orange-fleshed sweetpotato test meals contained 0.55 and 0.97 mg Fe/100 g. Geometric mean (95% CI) fractional iron absorption (FIA) was 5.82% (3.79%, 8.95%) and 6.02% (4.51%, 8.05%), respectively (P = 0.81), resulting in 1.9-fold higher total iron absorption (TIA) from biofortified sweetpotato (P < 0.001). The regular and biofortified potato test meals contained 0.33 and 0.69 mg Fe/100 g. FIA was 28.4% (23.5%, 34.2%) from the regular yellow-fleshed and 13.3% (10.6%, 16.6%) from the biofortified purple-fleshed potato meals, respectively (P < 0.001), resulting in no significant difference in TIA (P = 0.88). CONCLUSIONS: FIA from regular yellow-fleshed potato was remarkably high, at 28%. Iron absorbed from both potato test meals covered 33% of the daily absorbed iron requirement for women of reproductive age, while the biofortified orange-fleshed sweetpotato test meal covered 18% of this requirement. High polyphenol concentrations were likely the major inhibitors of iron absorption. These trials were registered at www.clinicaltrials.gov as NCT03840031 (Malawi) and NCT04216030 (Peru).

Risk Factors for Anemia and Micronutrient Deficiencies among Women of Reproductive Age-The Impact of the Wheat Flour Fortification Program in Uzbekistan.

Food fortification can be effective in reducing the prevalence of anemia and micronutrient deficiencies. This study assessed risk factors for-and the impact of the wheat flour program in Uzbekistan on-anemia, and iron and folate deficiency (FD) in non-pregnant women (NPW) of reproductive age. National data were analyzed for risk factors using multivariable regression. Additional iron intake from fortified flour was not associated with iron deficiency (ID) and did not result in a significantly different prevalence of anemia regardless of the levels, whereas women with additional folic acid intake had a lower relative risk (RR) of FD (RR: 0.67 [95% CI: 0.53, 0.85]). RR for anemia was greater in women with ID (RR: 4.7; 95% CI: 3.5, 6.5) and vitamin A insufficiency (VAI; RR 1.5; 95% CI: 1.3, 1.9). VAI (RR: 1.4 [95% CI: 1.3, 1.6]) and breastfeeding (RR: 1.1 [95% CI: 0.99, 1.2]) were associated with increased risk of ID, while being underweight reduced the risk (RR: 0.74 [95% CI: 0.58, 0.96]). Breastfeeding (RR: 1.2 [95% CI: 1.1, 1.4]) and inflammation (RR: 1.2 [95% CI: 1.0, 1.3]) increased risk of FD. FD results indicate that the fortification program had potential for impact, but requires higher coverage of adequately fortified wheat flour and a more bioavailable iron fortificant.

Household Coverage with Adequately Iodized Salt and Iodine Status of Nonpregnant and Pregnant Women in Uzbekistan.

Background: Globally, iodine deficiency has been drastically reduced since the introduction of salt iodization programs; nonetheless, many populations remain at-risk for iodine deficiency. This study aimed to assess the iodine status among women of reproductive age in Uzbekistan and to identify factors associated with iodine deficiency, including the availability of adequately iodized salt at the household level. Methods: A cross-sectional household survey was conducted to produce region-specific estimates of the household coverage with adequately iodized salt and iodine status among women for each of the 14 regions in Uzbekistan. Other information, such as socioeconomic status, lactation and pregnancy, residence, age, and consumption of iodine supplements, was also collected. Results: Overall, 36% of 3413 households had adequately iodized salt (iodine concentration >15 ppm [parts per million (mg I/kg salt)]), 20% had inadequately iodized salt (5-14 ppm), and 44% had salt without detectable iodine (<5 ppm). Adequate iodization was found in 33.2% of the 2626 salt samples taken from retail packages labeled as "iodized," 36.5% of the 96 samples taken from retail packages without mention of iodization, and 50.5% of the 674 samples without the original packaging (p < 0.001). The median urinary iodine concentration (UIC) of 140.9 µg/L (95% confidence interval [CI 132.4-150.7]) in nonpregnant nonlactating women indicated adequate iodine status, while for nonpregnant lactating and pregnant women, the median UIC of 112.9 µg/L [CI 99.3-128.4] and 117.3 µg/L [CI 101.8-139.9], respectively, indicated borderline adequacy. Significant differences in UIC (p < 0.001) were found between nonpregnant nonlactating women living in households with adequately iodized salt (UIC 208.9 µg/L), inadequately iodized salt (UIC 139.1 µg/L), and noniodized salt (UIC 89.9 µg/L). Conclusions: Coverage with adequately iodized salt is low in Uzbekistan, and women in households with poorly iodized salt have substantially worse iodine status; claims on packaging about salt iodization do not reflect salt iodine content. This highlights the importance and effectiveness of salt iodization and the need to strengthen this program in Uzbekistan.

Hepcidin-guided screen-and-treat interventions against iron-deficiency anaemia in pregnancy: a randomised controlled trial in The Gambia.

BACKGROUND: WHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron. METHODS: We did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18-45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was <2·5 µg/L or UNIMMAP without iron if hepcidin was ≥2·5 µg/L), or a 30 mg screen-and-treat approach (ie, daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was <2·5 µg/L or UNIMMAP without iron if hepcidin was ≥2·5 µg/L). We used a block design stratified by amount of haemoglobin at enrolment (above and below the median amount of haemoglobin on every enrolment day) and stage of gestation (14-18 weeks vs 19-22 weeks). Participants and investigators were unaware of the random allocation. The primary outcome was the amount of haemoglobin at day 84 and was measured as the difference in haemoglobin in each screen-and-treat group compared with WHO's recommended regimen; the non-inferiority margin was set at -5·0 g/L. The primary outcome was assessed in the per-protocol population, which comprised all women who completed the study. This trial is registered with the ISRCTN registry, number ISRCTN21955180. FINDINGS: Between June 16, 2014, and March 3, 2016, 498 participants were randomised, of whom 167 were allocated to WHO's recommended regimen, 166 were allocated to the 60 mg per day screen-and-treat approach, and 165 were allocated to the 30 mg per day screen-and-treat approach. 78 participants were withdrawn or lost to follow-up during the study; thus, the per-protocol population comprised 140 women assigned to WHO's recommended regimen, 133 allocated to the 60 mg screen-and-treat approach, and 147 allocated to the 30 mg screen-and-treat approach. The screen-and-treat approaches did not exceed the non-inferiority margin. Compared with WHO's recommended regimen, the difference in the amount of haemoglobin at day 84 was -2·2 g/L (95% CI -4·6 to 0·1) with the 60 mg screen-and-treat approach and -2·7 g/L (-5·0 to -0·5) with the 30 mg screen-and-treat approach. Adherence, reported side-effects, and adverse events were similar between the three groups. The most frequent side-effect was stomachache, which was similar in the 60 mg screen-and-treat group (82 cases per 1906 person-weeks) and with WHO's recommended regimen (81 cases per 1974 person-weeks; effect 1·0, 95% CI 0·7 to 1·6); in the 30 mg screen-and-treat group the frequency of stomachache was slightly lower than with WHO's recommended regimen (58 cases per 2009 person-weeks; effect 0·7, 95% CI 0·5 to 1·1). No participants died during the study. INTERPRETATION: The hepcidin-guided screen-and-treat approaches had no advantages over WHO's recommended regimen in terms of adherence, side-effects, or safety outcomes. Our results suggest that the current WHO policy for iron administration to pregnant women should remain unchanged while more effective approaches continue to be sought. FUNDING: Bill & Melinda Gates Foundation and the UK Medical Research Council.

Micronutrient Deficiencies, Nutritional Status and the Determinants of Anemia in Children 0-59 Months of Age and Non-Pregnant Women of Reproductive Age in The Gambia.

Data on micronutrient deficiency prevalence, nutrition status, and risk factors of anemia in The Gambia is scanty. To fill this data gap, a nationally representative cross-sectional survey was conducted on 1354 children (0-59 months), 1703 non-pregnant women (NPW; 15-49 years), and 158 pregnant women (PW). The survey assessed the prevalence of under and overnutrition, anemia, iron deficiency (ID), iron deficiency anemia (IDA), vitamin A deficiency (VAD), and urinary iodine concentration (UIC). Multivariate analysis was used to assess risk factors of anemia. Among children, prevalence of anemia, ID, IDA, and VAD was 50.4%, 59.0%, 38.2%, and 18.3%, respectively. Nearly 40% of anemia was attributable to ID. Prevalence of stunting, underweight, wasting, and small head circumference was 15.7%, 10.6%, 5.8%, and 7.4%, respectively. Among NPW, prevalence of anemia, ID, IDA and VAD was 50.9%, 41.4%, 28.0% and 1.8%, respectively. Anemia was significantly associated with ID and vitamin A insufficiency. Median UIC in NPW and PW was 143.1 µg/L and 113.5 ug/L, respectively. Overall, 18.3% of NPW were overweight, 11.1% obese, and 15.4% underweight. Anemia is mainly caused by ID and poses a severe public health problem. To tackle both anemia and ID, programs such as fortification or supplementation should be intensified.

Effect of exogenous phytase added to small-quantity lipid-based nutrient supplements (SQ-LNS) on the fractional and total absorption of zinc from a millet-based porridge consumed with SQ-LNS in young Gambian children: a randomized controlled trial.

BACKGROUND: Dietary phytate inhibits zinc absorption from composite meals in adults. OBJECTIVE: The objective of this study was to investigate the effect of adding exogenous phytase to a small-quantity lipid-based nutrient supplement (SQ-LNS) on zinc absorption among young children. METHODS: In a double-blind randomized controlled trial, intraindividual differences in fractional and total absorption of zinc (FAZ and TAZ, respectively) from a millet-based porridge containing SQ-LNS with and without phytase were measured in 30 asymptomatic children 18-23 mo of age in the Kiang West district of The Gambia. Using a crossover design, children received for 1 d each porridge test meals with 20 g SQ-LNS containing 8 mg zinc and either 1) exogenous phytase or 2) no exogenous phytase. The test meals were provided on consecutive days in randomized order. FAZ was measured using a triple stable isotope tracer ratio technique with Zn-67 and Zn-70 as oral tracers and Zn-68 as the intravenous tracer. RESULTS: Twenty-six participants completed the study. The prevalence of stunting and wasting were 20% and 13%, respectively; no children had low plasma zinc concentrations (<65 µg/dL). Total mean ± SD dietary zinc intake from the test meals was 7.3 ± 2.2 mg (phytate:zinc molar ratio = 3.1 ± 0.3, not accounting for phytase activity). Mean FAZ increased from 8.6% ± 1.3% to 16.0% ± 1.3% when exogenous phytase was added to the SQ-LNS product (P < 0.001). Mean TAZ from test meals containing SQ-LNS with phytase was more than double that from test meals containing SQ-LNS without phytase (1.1 ± 0.1 mg and 0.5 ± 0.1 mg, respectively; P < 0.001). CONCLUSIONS: The addition of exogenous phytase to SQ-LNS increased both FAZ and TAZ. These results suggest that phytate reduction may be an important strategy to increase zinc absorption among young children. This trial was registered at clinicaltrials.gov as NCT02668133.

Zinc Absorption From Agronomically Biofortified Wheat Is Similar to Post-Harvest Fortified Wheat and Is a Substantial Source of Bioavailable Zinc in Humans.

BACKGROUND: Limited data exist on human zinc absorption from wheat biofortified via foliar (FBW) or root (hydroponically fortified wheat, HBW) zinc application. Stable isotope labels added at point of consumption (extrinsic labeling) might not reflect absorption from native zinc obtained by intrinsic labeling. OBJECTIVES: We measured fractional and total zinc absorption (FAZ, TAZ) in FBW and HBW wheat, compared with control wheat (CW) and fortified wheat (FW). The effect of labeling method was assessed in HBW (study 1), and the effect of milling extraction rate (EXR, 80% and 100%) in FBW (studies 2 and 3). METHODS: Generally healthy adults (n = 71, age: 18-45 y, body mass index: 18.5-25 kg/m2) were allocated to 1 of the studies, in which they served as their own controls. In study 1, men and women consumed wheat porridges colabeled intrinsically and extrinsically with 67Zn and 70Zn. In studies 2 and 3, women consumed wheat flatbreads (chapatis) labeled extrinsically. Zinc absorption was measured with the oral to intravenous tracer ratio method with a 4-wk wash-out period between meals. Data were analyzed with linear mixed models. RESULTS: In study 1 there were no differences in zinc absorption from extrinsic versus intrinsic labels in either FW or HBW. Similarly, FAZ and TAZ from FW and HBW did not differ. TAZ was 70-76% higher in FW and HBW compared with CW (P < 0.01). In studies 2 and 3, TAZ from FW and FBW did not differ but was 20-48% higher compared with CW (P < 0.001). Extraction rate had no effect on TAZ. CONCLUSIONS: Colabeling demonstrates that extrinsic zinc isotopic labels can be used to accurately quantify zinc absorption from wheat in humans. Biofortification through foliar zinc application, root zinc application, or fortification provides higher TAZ compared with unfortified wheat. In biofortified wheat, extraction rate (100-80%) has a limited impact on total zinc absorption. These studies were registered on clinicaltrials.gov (NCT01775319).

Thyroglobulin Is Markedly Elevated in 6- to 24-Month-Old Infants at Both Low and High Iodine Intakes and Suggests a Narrow Optimal Iodine Intake Range.

BACKGROUND: In areas with incomplete salt iodization coverage, infants and children aged 6-24 months weaning from breast milk and receiving complementary foods are at risk of iodine deficiency. However, few data exist on the risk of excessive iodine intake in this age group. Thyroglobulin (Tg) is a sensitive marker of iodine intake in school-age children and adults and may be used to estimate the optimal iodine intake range in infancy. The aim of this study was to assess the association of low and high iodine intakes with Tg and thyroid function in weaning infants. METHODS: This multicenter cross-sectional study recruited infants aged 6-24 months (n = 1543; Mage = 12.2 ± 4.6 months) receiving breast milk with complementary foods, from seven countries in areas with previously documented deficient, sufficient, or excessive iodine intake in schoolchildren or pregnant women. Urinary iodine concentration (UIC) and Tg, total thyroxine, and thyrotropin were measured using dried blood spot testing. RESULTS: Median UIC ranged from 48 µg/L (interquartile range 31-79 µg/L) to 552 µg/L (interquartile range 272-987 µg/L) across the study sites. Median Tg using dried blood spot testing was high (>50 µg/L) at estimated habitual iodine intakes <50 µg/day and >230 µg/day. Prevalence of overt thyroid disorders was low (<3%). Yet, subclinical hyperthyroidism was observed in the countries with the lowest iodine intake. CONCLUSIONS: Tg is a sensitive biomarker of iodine intake in 6- to 24-month-old infants and follows a U-shaped relationship with iodine intake, suggesting a relatively narrow optimal intake range. Infants with low iodine intake may be at increased risk of subclinical thyroid dysfunction. In population monitoring of iodine deficiency or excess, assessment of iodine status using UIC and Tg may be valuable in this young age group.

Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy.

Anaemia and malaria are both common in pregnant women in Sub-Saharan Africa. Previous evidence has shown that iron supplementation may increase malaria risk. In this observational cohort study, we evaluated P. falciparum pathogenesis in vitro in RBCs from pregnant women during their 2nd and 3rd trimesters. RBCs were collected and assayed before (n = 327), 14 days (n = 82), 49 days (n = 112) and 84 days (n = 115) after iron supplementation (60 mg iron as ferrous fumarate daily). P. falciparum erythrocytic stage growth in vitro is reduced in anaemic pregnant women at baseline, but increased during supplementation. The elevated growth rates parallel increases in circulating CD71-positive reticulocytes and other markers of young RBCs. We conclude that Plasmodium growth in vitro is associated with elevated erythropoiesis, an obligate step towards erythroid recovery in response to supplementation. Our findings support current World Health Organization recommendations that iron supplementation be given in combination with malaria prevention and treatment services in malaria endemic areas.

Iron Fortified Complementary Foods Containing a Mixture of Sodium Iron EDTA with Either Ferrous Fumarate or Ferric Pyrophosphate Reduce Iron Deficiency Anemia in 12- to 36-Month-Old Children in a Malaria Endemic Setting: A Secondary Analysis of a Cluster-Randomized Controlled Trial.

Iron deficiency anemia (IDA) is a major public health problem in sub-Saharan Africa. The efficacy of iron fortification against IDA is uncertain in malaria-endemic settings. The objective of this study was to evaluate the efficacy of a complementary food (CF) fortified with sodium iron EDTA (NaFeEDTA) plus either ferrous fumarate (FeFum) or ferric pyrophosphate (FePP) to combat IDA in preschool-age children in a highly malaria endemic region. This is a secondary analysis of a nine-month cluster-randomized controlled trial conducted in south-central Côte d'Ivoire. 378 children aged 12-36 months were randomly assigned to no food intervention (n = 125; control group), CF fortified with 2 mg NaFeEDTA plus 3.8 mg FeFum for six days/week (n = 126; FeFum group), and CF fortified with 2 mg NaFeEDTA and 3.8 mg FePP for six days/week (n = 127; FePP group). The outcome measures were hemoglobin (Hb), plasma ferritin (PF), iron deficiency (PF < 30 µg/L), and anemia (Hb < 11.0 g/dL). Data were analyzed with random-effect models and PF was adjusted for inflammation. The prevalence of Plasmodium falciparum infection and inflammation during the study were 44-66%, and 57-76%, respectively. There was a significant time by treatment interaction on IDA (p = 0.028) and a borderline significant time by treatment interaction on iron deficiency with or without anemia (p = 0.068). IDA prevalence sharply decreased in the FeFum (32.8% to 1.2%, p < 0.001) and FePP group (23.6% to 3.4%, p < 0.001). However, there was no significant time by treatment interaction on Hb or total anemia. These data indicate that, despite the high endemicity of malaria and elevated inflammation biomarkers (C-reactive protein or α-1-acid-glycoprotein), IDA was markedly reduced by provision of iron fortified CF to preschool-age children for 9 months, with no significant differences between a combination of NaFeEDTA with FeFum or NaFeEDTA with FePP. However, there was no overall effect on anemia, suggesting most of the anemia in this setting is not due to ID. This trial is registered at clinicaltrials.gov (NCT01634945).

Dietary strategies for improving iron status: balancing safety and efficacy.

In light of evidence that high-dose iron supplements lead to a range of adverse events in low-income settings, the safety and efficacy of lower doses of iron provided through biological or industrial fortification of foodstuffs is reviewed. First, strategies for point-of-manufacture chemical fortification are compared with biofortification achieved through plant breeding. Recent insights into the mechanisms of human iron absorption and regulation, the mechanisms by which iron can promote malaria and bacterial infections, and the role of iron in modifying the gut microbiota are summarized. There is strong evidence that supplemental iron given in nonphysiological amounts can increase the risk of bacterial and protozoal infections (especially malaria), but the use of lower quantities of iron provided within a food matrix, ie, fortified food, should be safer in most cases and represents a more logical strategy for a sustained reduction of the risk of deficiency by providing the best balance of risk and benefits. Further research into iron compounds that would minimize the availability of unabsorbed iron to the gut microbiota is warranted.

Efficacy and safety of hepcidin-based screen-and-treat approaches using two different doses versus a standard universal approach of iron supplementation in young children in rural Gambia: a double-blind randomised controlled trial.

BACKGROUND: Iron deficiency prevalence rates frequently exceed 50 % in young children in low-income countries. The World Health Organization (WHO) recommended universal supplementation of young children where anaemia rates are >40 %. However, large randomized trials have revealed that provision of iron to young children caused serious adverse effects because iron powerfully promotes microbial growth. Hepcidin - the master regulator of iron metabolism that integrates signals of infection and iron deficiency - offers the possibility of new solutions to diagnose and combat global iron deficiency. We aim to evaluate a hepcidin-screening-based iron supplementation intervention using hepcidin cut-offs designed to indicate that an individual requires iron, is safe to receive it and will absorb it. METHODS: The study is a proof-of-concept, three-arm, double blind, randomised controlled, prospective, parallel-group non-inferiority trial. Children will be randomised to receive, for a duration of 12 weeks, one of three multiple micronutrient powders (MNP) containing: A) 12 mg iron daily; B) 12 mg or 0 mg iron daily based on a weekly hepcidin screening indicating if iron can be given for the next seven days or not; C) 6 mg or 0 mg iron daily based on a weekly hepcidin screening indicating if iron can be given for the next seven days or not. The inclusion criteria are age 6-23 months, haemoglobin (Hb) concentration between 7 and 11 g/dL, z-scores for Height-for-Age, Weight-for-Age and Weight-for-Height > -3 SD and free of malaria. Hb concentration at 12 weeks will be used to test whether the screen-and-treat approaches are non-inferior to universal supplementation. Safety will be assessed using caregiver reports of infections, in vitro bacterial and P. falciparum growth assays and by determining the changes in the gut microbiota during the study period. DISCUSSION: A screen-and-treat approach using hepcidin has the potential to make iron administration safer in areas with widespread infections. If this proof-of-concept study shows promising results the development of a point-of-care diagnostic test will be the next step. TRIAL REGISTRATION: ISRCTN07210906 , 07/16/2014.

A double blind randomised controlled trial comparing standard dose of iron supplementation for pregnant women with two screen-and-treat approaches using hepcidin as a biomarker for ready and safe to receive iron.

BACKGROUND: Until recently, WHO recommended daily iron supplementation for all pregnant women (60 mg/d iron combined with 400ug/d folic acid) where anaemia rates exceeded 40 %. Recent studies indicate that this may pose a risk to pregnant women. Therefore, there is a need to explore screen-and-treat options to minimise iron exposure during pregnancy using an overall lower dosage of iron that would achieve equivalent results as being currently recommended by the WHO. However, there is a lack of agreement on how to best assess iron deficiency when infections are prevalent. Here, we test the use of hepcidin a peptide hormone and key regulator of iron metabolism, as a potential index for 'safe and ready to receive' iron. DESIGN/METHODS: This is a 3-arm randomised-controlled proof-of-concept trial. We will test the hypothesis that a screen-and-treat approach to iron supplementation using a pre-determined hepcidin cut-off value of <2.5 ng/ml will achieve similar efficacy in preventing iron deficiency and anaemia at a lower iron dose and hence will improve safety. A sample of 462 pregnant women in rural Gambia will be randomly assigned to receive: a) UNU/UNICEF/WHO international multiple micronutrient preparation (UNIMMAP) containing 60 mg/d iron (reference arm); b) UNIMMAP containing 60 mg/d iron but based on a weekly hepcidin screening indicating if iron can be given for the next 7 days or not; c) or UNIMMAP containing 30 mg/d iron as in (b) for 12 weeks in rural Gambia. The study will test if the screen-and-treat approach is non-inferior to the reference arm using the primary endpoint of haemoglobin levels at a non-inferiority margin of 0.5 g/dl. Secondary outcomes of adverse effects, compliance and the impact of iron supplementation on susceptibility to infections will also be assessed. DISCUSSION: This trial is expected to contribute towards minimising the exposure of pregnant women to iron that may not be needed and therefore potentially harmful. If the evidence in this study shows that the overall lower dosage of iron is non-inferior to 60 mg/day iron, this may help decrease side-effects, improve compliance and increase safety. The potential for the use of hepcidin for a simple point-of-care (PoC) diagnostic for when it is most safe and effective to give iron may improve maternal health outcomes. TRIAL REGISTRATION: ISRCTN21955180.

Zinc Absorption by Adults Is Similar from Intrinsically Labeled Zinc-Biofortified Rice and from Rice Fortified with Labeled Zinc Sulfate.

BACKGROUND: Biofortification of staple food crops is a promising strategy to combat zinc deficiency, and it is of particular interest for rice and crops that are not consumed as flours and therefore not suitable for postharvest fortification. Because zinc absorption is decreased by phytic acid (PA) and perhaps other dietary components, it is important to measure the absorption of zinc from a biofortified crop before determining its efficacy. OBJECTIVE: In this study, we compared the zinc absorption from zinc-biofortified rice (hydroponically enriched with (70)Zn) with that from a control rice of the same variety fortified with (70)ZnSO4 at point of use to reach the same total zinc content of 1.1 mg/meal. Both rice meals had a PA:Zn molar ratio of 12. METHODS: Fractional absorption of zinc (FAZ) was measured with the use of the double-isotope tracer ratio method in 16 apparently healthy adults [18-45 y old; BMI (in kg/m(2)) 19-25] who consumed 2 single meals at 4-wk intervals in random order in a crossover design. RESULTS: The FAZ from the biofortified rice (mean ± SD: 25.1 ± 8.7%) did not differ significantly from that of the point-of-use fortified rice (mean ± SD: 20.8 ± 7.1%) (P = 0.08). CONCLUSIONS: These results suggest that the native zinc accumulated in the biofortified rice was readily released from the rice matrix and that its absorption by adults was influenced by PA and other food components in a similar way to the inorganic zinc compound added to the rice at point of use. Moreover, rice biofortification is likely to be as good as postharvest zinc fortification as an intervention strategy to combat zinc deficiency. This trial was registered at clinicaltrials.gov as NCT01633450.

Oral iron acutely elevates bacterial growth in human serum.

Iron deficiency is the most common nutrient deficiency worldwide and routine supplementation is standard policy for pregnant mothers and children in most low-income countries. However, iron lies at the center of host-pathogen competition for nutritional resources and recent trials of iron administration in African and Asian children have resulted in significant excesses of serious adverse events including hospitalizations and deaths. Increased rates of malaria, respiratory infections, severe diarrhea and febrile illnesses of unknown origin have all been reported, but the mechanisms are unclear. We here investigated the ex vivo growth characteristics of exemplar sentinel bacteria in adult sera collected before and 4 h after oral supplementation with 2 mg/kg iron as ferrous sulfate. Escherichia coli, Yersinia enterocolitica and Salmonella enterica serovar Typhimurium (all gram-negative bacteria) and Staphylococcus epidermidis (gram-positive) showed markedly elevated growth in serum collected after iron supplementation. Growth rates were very strongly correlated with transferrin saturation (p < 0.0001 in all cases). Growth of Staphylococcus aureus, which preferentially scavenges heme iron, was unaffected. These data suggest that even modest oral supplements with highly soluble (non-physiological) iron, as typically used in low-income settings, could promote bacteremia by accelerating early phase bacterial growth prior to the induction of immune defenses.

The effect of iron-fortified complementary food and intermittent preventive treatment of malaria on anaemia in 12- to 36-month-old children: a cluster-randomised controlled trial.

BACKGROUND: Iron deficiency (ID) and malaria co-exist in tropical regions and both contribute to high rates of anaemia in young children. It is unclear whether iron fortification combined with intermittent preventive treatment (IPT) of malaria would be an efficacious strategy for reducing anaemia in young children. METHODS: A 9-month cluster-randomised, single-blinded, placebo-controlled intervention trial was carried out in children aged 12-36 months in south-central Côte d'Ivoire, an area of intense and perennial malaria transmission. The study groups were: group 1: normal diet and IPT-placebo (n = 125); group 2: consumption of porridge, an iron-fortified complementary food (CF) with optimised composition providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferrous fumarate 6 days per week (CF-FeFum) and IPT-placebo (n = 126); group 3: IPT of malaria at 3-month intervals, using sulfadoxine-pyrimethamine and amodiaquine and no dietary intervention (n = 127); group 4: both CF-FeFum and IPT (n = 124); and group 5: consumption of porridge, an iron-fortified CF with the composition currently on the Ivorian market providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferric pyrophosphate 6 days per week (CF-FePP) and IPT-placebo (n = 127). The primary outcome was haemoglobin (Hb) concentration. Linear and logistic regression mixed-effect models were used for the comparison of the five study groups, and a 2 × 2 factorial analysis was used to assess treatment interactions of CF-FeFum and IPT (study groups 1-4). RESULTS: After 9 months, the Hb concentration increased in all groups to a similar extent with no statistically significant difference between groups. In the 2 × 2 factorial analysis after 9 months, no treatment interaction was found on Hb (P = 0.89). The adjusted differences in Hb were 0.24 g/dl (95 % CI -0.10 to 0.59; P = 0.16) in children receiving IPT and -0.08 g/dl (95 % CI -0.42 to 0.26; P = 0.65) in children receiving CF-FeFum. At baseline, anaemia (Hb <11.0 g/dl) was 82.1 %. After 9 months, IPT decreased the odds of anaemia (odds ratio [OR], 0.46 [95 % CI 0.23-0.91]; P = 0.023), whereas iron-fortified CF did not (OR, 0.85 [95 % CI 0.43-1.68]; P = 0.68), although ID (plasma ferritin <30 µg/l) was decreased markedly in children receiving iron fortified CF (OR, 0.19 [95 % CI 0.09-0.40]; P < 0.001). CONCLUSIONS: IPT alone only modestly decreased anaemia, but neither IPT nor iron fortified CF significantly improved Hb concentration after 9 months. Additionally, IPT did not augment the effect of the iron fortified CF. CF fortified with highly bioavailable iron improved iron status but not Hb concentration, despite three-monthly IPT of malaria. Thus, further research is necessary to develop effective combination strategies to prevent and treat anaemia in malaria endemic regions. TRIAL REGISTRATION: http://www.clinicaltrials.gov ; identifier NCT01634945; registered on July 3, 2012.