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Background: Stable isotope techniques using 13 C to assess vitamin A (VA) dietary sources, absorption, and total body VA stores (TBSs) require determination of baseline 13 C abundance. 13 C-natural abundance is approximately 1.1% total carbon, but varies with foods consumed, supplements taken, and food fortification with synthetic retinyl palmitate., Objectives: We determined 13 C variation from purified serum retinol and the resulting impact on TBSs using pooled data from preschool children in Burkina Faso, Cameroon, Ethiopia, South Africa, Tanzania, and Zambia and Zambian women., Methods: Seven studies included children (n = 639; 56 ± 25 mo; 48% female) and one in women (n = 138; 29 ± 8.5 y). Serum retinol 13 C-natural abundance was determined using GC-C-IRMS. TBSs were available in 7 studies that employed retinol isotope dilution (RID). Serum CRP and α 1 -acid-glycoprotein (AGP) were available from 6 studies in children. Multivariate mixed models assessed the impact of covariates on retinol 13 C. Spearman correlations and Bland-Altman analysis compared serum and milk retinol 13 C and evaluated the impact of using study- or global-retinol 13 C estimates on calculated TBSs., Results: 13 C-natural abundance (%, median [Q1, Q3]) differed among countries (low: Zambia, 1.0744 [1.0736, 1.0753]; high: South Africa, 1.0773 [1.0769, 1.0779]) and was associated with TBSs, CRP, and AGP in children and with TBSs in women. 13 C-enrichment from serum and milk retinol were correlated (r = 0.52; P = 0.0001). RID in children and women using study and global estimates had low mean bias (range, -3.7% to 2.2%), but larger 95% limits of agreement (range, -23% to 37%)., Conclusions: 13 C-natural abundance is different among human cohorts in Africa. Collecting this information in subgroups is recommended for surveys using RID. When TBSs are needed on individuals in clinical applications, baseline 13 C measures are important and should be measured in all enrolled subjects., (Copyright © 2023. Published by Elsevier Inc.)

Background: Vitamin A (VA) assessment is important for targeting public health programs. Retinol isotope dilution (RID) is a sensitive method to estimate total body VA stores (TBSs) and total liver reserves (TLRs), but the impact of subclinical inflammation on RID is unclear., Objective: We determined the association between TBSs and TLRs, estimated by RID, and inflammation among preschool children without clinical infection in Burkina Faso, Cameroon, Ethiopia, South Africa, and Tanzania., Methods: Five studies (n = 532; 47.9 ± 8.3 mo; 49.0% male) included 13 C-RID and measurement of inflammation markers, CRP, and α 1 -acid glycoprotein (AGP). Spearman correlations were used to evaluate TBSs and TLRs with inflammation biomarkers. Wilcoxon and Kruskal-Wallis tests were used to compare TBSs and TLRs by inflammation categories [normal vs. elevated CRP (>5 mg/L) or AGP (>1 g/L)] and inflammation stage [reference, incubation (elevated CRP), early convalescence (elevated CRP and AGP), and late convalescence (elevated AGP)]., Results: Complete data were available for 439 children. Median (Q1, Q3) TLRs ranged from 0.12 (0.07, 0.18) μmol/g in Ethiopia to 1.10 (0.88, 1.38) μmol/g in South Africa. Elevated CRP ranged from 4% in Burkina Faso to 42% in Cameroon, and elevated AGP from 20% in Tanzania to 58% in Cameroon. Pooled analysis (excluding Cameroon) showed a negative correlation between TBSs and AGP (ρ = -0.131, P = 0.01). Children with elevated AGP had higher probability of having lower TBSs (probability = 0.61, P = 0.002). TBSs differed among infection stages (P = 0.020). Correlations between TLRs and CRP or AGP were not significant., Conclusions: No indication of systematic bias in RID-estimated TLRs was found due to subclinical inflammation among preschool children. The inverse relationship between TBSs and AGP may reflect decreased stores after infection or an effect of inflammation on isotope partitioning. Further research should investigate potential confounding variables to improve TBS-estimate validity., (Copyright © 2022. Published by Elsevier Inc.)

Background: Excessive vitamin A (VA) can cause bone resorption and impair growth. Government-mandated VA supplementation (VAS) and adequate intake through dietary fortification and liver consumption led to excessive VA in South African children., Objectives: We evaluated the relation between VAS and underlying hypervitaminosis A assessed by retinol isotope dilution (RID) with measures of growth and bone turnover in this cohort., Methods: Primary outcomes in these children (n = 94, 36-60 mo) were anthropometric measurements [height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ) z scores], serum bone turnover markers [C-terminal telopeptide of type I collagen (CTX) and N-terminal propeptide of type I procollagen (P1NP)], and inflammation defined as C-reactive protein (CRP; ≥5 mg/L) and/or α1-acid glycoprotein (AGP; ≥1 g/L). VA status was previously measured by RID-estimated total body VA stores (TBSs) and total liver VA reserves (TLRs), and serum retinol and carotenoid concentrations, before and 4 wk after children were administered 200,000 IU VAS. Serum 25-hydroxyvitamin D3 was measured by ultra-performance LC., Results: In this largely hypervitaminotic A cohort, HAZ, WAZ, and WHZ were negatively associated with increasing TLRs, where TLRs predicted 6-10% of the variation before VAS (P < 0.05), increasing to 14-19% 4 wk after VAS (P < 0.01). Bone resorption decreased after VAS (P < 0.0001), whereas formation was unaffected. Neither CTX nor P1NP were correlated with TLRs at either time. Serum carotenoids were low. One child at each time point was vitamin D deficient (<50 nmol/L). CRP and AGP were not associated with growth measurements., Conclusions: Excessive TLRs due to dietary VA intake and VAS are associated with lower anthropometric measures and bone resorption decreased after supplementation. VA supplementation programs should monitor VA status with biomarkers sensitive to TLRs to avoid causing negative consequences in children with hypervitaminosis A. This trial is registered at clinicaltrials.gov as NCT02915731., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: In some regions, multiple vitamin A (VA) interventions occur in the same target groups, which may lead to excessive stores. Retinol isotope dilution (RID) is a more sensitive technique than serum retinol to measure VA status., Objective: We evaluated VA status before and after a high-dose supplement in preschool children living in a region in South Africa with habitual liver consumption and exposed to VA supplementation and fortification., Methods: After baseline blood samples, subjects (46.7 ± 8.4 mo; n = 94) were administered 1.0 μmol [14,15]-13C2-retinyl acetate to estimate total liver retinol reserves by RID with a follow-up 14-d blood sample. Liver intake was assessed with a frequency questionnaire. In line with current practice, a routine 200,000 IU VA capsule was administered after the RID test. RID was repeated 1 mo later. Serum retinyl esters were evaluated using ultra-performance liquid chromatography., Results: At baseline, 63.6% of these children had hypervitaminosis A defined as total liver retinol reserves ≥1.0 μmol/g liver, which increased to 71.6% after supplementation (1.13 ± 0.43 to 1.29 ± 0.46 μmol/g; P < 0.001). Total serum VA as retinyl esters was elevated in 4.8% and 6.1% of children before and after supplementation. The odds of having hypervitaminosis A at baseline were higher in children consuming liver ≥1/mo (ratio 3.70 [95% CI: 1.08, 12.6]) and in children receiving 2 (4.28 [1.03, 17.9]) or 3 (6.45 [0.64, 65.41]) supplements in the past 12 mo. Total body stores decreased after the supplement in children in the highest quartile at baseline compared with children with lower stores, who showed an increase (P = 0.007)., Conclusions: In children, such as this cohort in South Africa, with adequate VA intake through diet, and overlapping VA fortification and supplementation, preschool VA capsule distribution should be re-evaluated. This trial was registered at https://clinicaltrials.gov/ct2/show/NCT02915731 as NCT02915731., (Copyright © American Society for Nutrition 2019.)

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.

Micronutrient powders (MNP) are often added to complementary foods high in inhibitors of iron and zinc absorption. Most MNP therefore include high amounts of iron and zinc, but it is no longer recommended in malarial areas to use untargeted MNP that contain the Reference Nutrient Intake for iron in a single serving. The aim was to test the efficacy of a low-iron and -zinc (each 2.5 mg) MNP containing iron as NaFeEDTA, ascorbic acid (AA), and an exogenous phytase active at gut pH. In a double-blind controlled trial, South African school children with low iron status (n = 200) were randomized to receive either the MNP or the unfortified carrier added just before consumption to a high-phytate maize porridge 5 d/wk for 23 wk; primary outcomes were iron and zinc status and a secondary outcome was somatic growth. Compared with the control, the MNP increased serum ferritin (P < 0.05), body iron stores (P < 0.01) and weight-for-age Z-scores (P < 0.05) and decreased transferrin receptor (P < 0.05). The prevalence of iron deficiency fell by 30.6% (P < 0.01) and the prevalence of zinc deficiency decreased by 11.8% (P < 0.05). Absorption of iron from the MNP was estimated to be 7-8%. Inclusion of an exogenous phytase combined with NaFeEDTA and AA may allow a substantial reduction in the iron dose from existing MNP while still delivering adequate iron and zinc. In addition, the MNP is likely to enhance absorption of the high native iron content of complementary foods based on cereals and/or legumes.

The choice of iron fortificant usually represents a balance between bioavailability of the compound and its tendency to cause organoleptic problems. The aim of this study was to evaluate the efficacy of sodium iron EDTA (NaFeEDTA) and ferrous fumarate at levels compatible with South African brown bread (10 mg/kg flour for NaFeEDTA and 20 mg/kg flour for ferrous fumarate) in a randomized controlled trial; electrolytic iron was evaluated at the level currently used in South Africa (35 mg/kg flour). Schoolchildren (n = 361), aged 6-11 y, from a low socioeconomic community with hemoglobin (Hb) < or = 125 g/L were randomly assigned to 1 of 4 groups that received 4 slices of brown bread supplying either: 1) no fortification iron 2) 2.35 mg iron as NaFeEDTA; 3) 4.70 mg iron as ferrous fumarate; and 4) 8.30 mg iron as electrolytic iron per intervention day. These amounts simulated a bread intake of 6 slices per day over the 34-wk study period at fortification levels of 0, 10, 20, and 35 mg/kg flour, respectively. Hb concentration and iron status were assessed at baseline and after 34 wk of intervention. The iron interventions did not affect Hb concentration, transferrin saturation, or serum ferritin, iron, or transferrin receptor concentrations relative to the control group. Our results suggest that electrolytic iron at the level currently used in South Africa is not effective in improving iron or Hb status. Neither do NaFeEDTA or ferrous fumarate appear to be suitable alternatives for the fortification of wheat flour when included at levels that do not cause color changes.

Growth faltering, anemia, and multiple micronutrient deficiency are common during infancy in developing countries. This South African trial was part of a multicenter study aimed at testing the efficacy of multiple micronutrient supplementation on growth, anemia, micronutrient status, and morbidity during infancy across 4 countries. A total of 265 infants aged 6-12 mo were individually randomized to 1 of 4 intervention groups: a daily multiple micronutrient supplement (DMM), a daily placebo supplement (P); a multiple micronutrient supplement 1 d of the week and placebo supplement on the other days of the week (WMM), and a daily iron supplement (DI). For 6 mo, the blinded supplements were provided to mothers at monthly health clinic sessions, and consumption was verified during weekly household visits by community health workers, when morbidity was also checked. Weight and height of the infants were measured monthly, and blood samples were taken at the beginning and at the end for assessing the infants micronutrient status. There were no significant differences in nutritional status of the groups at baseline with 40% of infants with anemia (hemoglobin < 110 g/L), 16% vitamin A deficiency (plasma retinol < 0.7 micromol/L), 47% zinc deficiency (plasma zinc < 10.7 micromol/L), 2% underweight, and 11% stunting. There was no difference in growth or morbidity between the micronutrient supplemented groups and the P group during the 6-mo study. The DMM was the most effective intervention tested, not only for improving anemia but also for improving iron, zinc, riboflavin, and tocopherol status.