Comparison of Total Body Vitamin A Stores Using Individual versus Population 13C-Natural Abundance of Serum Retinol in Preschool Children and Women Residing in 6 Diverse African Countries.

BACKGROUND: Stable isotope techniques using 13C to assess vitamin A (VA) dietary sources, absorption, and total body VA stores (TBSs) require determination of baseline 13C abundance. 13C-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 13C 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 13C-natural abundance was determined using GC-C-IRMS. TBSs were available in 7 studies that employed retinol isotope dilution (RID). Serum CRP and α1-acid-glycoprotein (AGP) were available from 6 studies in children. Multivariate mixed models assessed the impact of covariates on retinol 13C. Spearman correlations and Bland-Altman analysis compared serum and milk retinol 13C and evaluated the impact of using study- or global-retinol 13C estimates on calculated TBSs. RESULTS: 13C-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. 13C-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: 13C-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 13C measures are important and should be measured in all enrolled subjects.

Chronic and acute hypervitaminosis A are associated with suboptimal anthropometric measurements in a cohort of South African preschool children.

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.

Liver is widely eaten by preschool children in the Northern Cape province of South Africa: Implications for routine vitamin A supplementation.

Previous research has demonstrated a virtual absence of vitamin A deficiency and adequacy of vitamin A intake through consumption of liver in preschool children of a community in the Northern Cape province of South Africa where sheep farming is common, and liver, an exceptionally rich source of vitamin A, is frequently eaten. Only 60-75 g of liver per month is needed to meet the vitamin A requirement of preschool children. Because this may have implications for routine vitamin A supplementation, and because liver consumption for the rest of the province is unknown, the study aim was to establish the prevalence and frequency of liver intake in a provincial-wide survey. An unquantified liver-specific food frequency questionnaire, covering a period of 1 month, complemented by a 1-year recall, was administered to mothers of 2- to 5-year-old children (n = 2,864) attending primary health care facilities in all five districts and 26 subdistricts. A total of 86% of children were reported to eat liver, which was eaten in all districts by at least 80% of children. The overall median frequency of liver intake was 1.0 [25th, 75th percentiles: 0.5, 3.0] times per month and ranged from 1.0 [0.3, 2.0] to 2.0 [1.0, 4.0] for the various districts. Based on a previously reported portion size of 66 g, these results suggest vitamin A dietary adequacy in all districts and possibly also vitamin A intake exceeding the Tolerable Upper Intake Level in some children. Routine vitamin A supplementation in this province may not be necessary and should be reconsidered.

South African preschool children habitually consuming sheep liver and exposed to vitamin A supplementation and fortification have hypervitaminotic A liver stores: a cohort study.

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.

Overlapping vitamin A interventions in the United States, Guatemala, Zambia, and South Africa: case studies.

Vitamin A (VA) deficiency is a serious public health problem, especially in preschool children who are at risk of increased mortality. In order to address this problem, the World Health Organization recommends periodic high-dose supplementation to children 6-59 months of age in areas of highest risk. Originally, supplementation was meant as a short-term solution until more sustainable interventions could be adopted. Currently, many countries are fortifying commercialized common staple and snack foods with retinyl palmitate. However, in some countries, overlapping programs may lead to excessive intakes. Our review uses case studies in the United States, Guatemala, Zambia, and South Africa to illustrate the potential for excessive intakes in some groups. For example, direct liver analysis from 27 U.S. adult cadavers revealed 33% prevalence of hypervitaminosis A (defined as ≥1 µmol/g liver). In 133 Zambian children, 59% were diagnosed with hypervitaminosis A using a retinol isotope dilution, and 16% had ≥5% total serum VA as retinyl esters, a measure of intoxication. In 40 South African children who frequently consumed liver, 72.5% had ≥5% total serum VA as retinyl esters. All four countries have mandatory fortified foods and a high percentage of supplement users or targeted supplementation to preschool children.

Liver intake in 24-59-month-old children from an impoverished South African community provides enough vitamin A to meet requirements.

OBJECTIVE: To assess the contribution of liver to the vitamin A intake of 24-59-month-old children from an impoverished South African community where liver is frequently consumed and vitamin A deficiency previously shown to be absent. DESIGN: Cross-sectional. SETTING: Northern Cape Province, South Africa. SUBJECTS: Children aged 24-59 months (n 150). Vitamin A intake from liver was assessed using a single 24 h recall and a quantified liver frequency questionnaire. In addition, information on vitamin A intake via the national fortification programme was obtained from the 24 h recall and information on vitamin A supplementation from the Road-to-Health Chart. Height, weight and socio-economic data were also collected. RESULTS: Stunting, underweight and wasting were prevalent in 36·9 %, 25·5 % and 12·1 % of children. Mean daily vitamin A intake from liver was 537 and 325 µg retinol equivalents measured by the 24 h recall and liver frequency questionnaire, respectively. Liver was consumed in 92·7 % of households and by 84·7 % of children; liver intake was inversely related to socio-economic status (P < 0·05). The food fortification programme contributed 80 µg retinol equivalents and the vitamin A supplementation programme 122 µg retinol equivalents to daily vitamin A intake. CONCLUSIONS: The study showed that liver alone provided more than 100 % of the Estimated Average Requirement of the pre-school children in this impoverished community. The results also challenge the notion generally held by international health bodies that vitamin A deficiency, poor anthropometric status and poverty go together, and reinforces the fact that South Africa is a culturally diverse society for which targeted interventions are required.

Serum retinol in 1-6-year-old children from a low socio-economic South African community with a high intake of liver: implications for blanket vitamin A supplementation.

OBJECTIVE: To assess serum retinol, liver intake patterns, breast-feeding history and anthropometric status in pre-school children of a low socio-economic community where liver is regularly consumed. DESIGN: Cross-sectional study. SETTING: Northern Cape Province, South Africa. SUBJECTS: Children aged 1-6 years (n 243) who attended the local primary health-care facility and had not received a vitamin A supplement in the 6 months preceding the study. Non-pregnant female caregivers (n 225), below 50 years of age, were also assessed. RESULTS: Despite stunting, underweight and wasting being prevalent in 40·5%, 23·1% and 8·4% of the children, only 5·8% had serum retinol concentrations < 20 µg/dl, which is in sharp contrast to the national prevalence of 63·6%. None of the caregivers were vitamin A deficient. Liver was eaten by 89·2% of children, with 87% of households eating liver at least once monthly and 30% eating it at least once weekly; liver was introduced into the diet of the children at a median age of 18 months. Ninety-three per cent of the children were being breast-fed or had been breast-fed in the past; children were breast-fed to a median age of 18 months. A significant negative correlation was found between educational level of the caregiver and frequency of liver intake (r = -0·143, P=0·032). There was no correlation between serum retinol and indicators of anthropometric or socio-economic status. CONCLUSIONS: The blanket approach in applying the national vitamin A supplementation programme may not be appropriate for all areas in the country, even though the community may be poor and undernourished.

The effect of vitamin A and zinc supplementation on treatment outcomes in pulmonary tuberculosis: a randomized controlled trial.

BACKGROUND: Low serum concentrations of vitamin A and zinc are common in tuberculosis and may have an adverse effect on host cell-mediated responses. The role of adjunctive micronutrient supplementation on treatment outcomes is uncertain. OBJECTIVE: The objective was to assess the efficacy of vitamin A and zinc supplementation on sputum smear and culture conversion and time to culture detection in adults with sputum smear-positive pulmonary tuberculosis. DESIGN: Participants attending a primary care tuberculosis clinic in Cape Town, South Africa, were randomly assigned to receive micronutrients (single dose of 200,000 IU retinyl palmitate plus 15 mg Zn/d for 8 wk) or matching placebo. Sputum was collected weekly for 8 wk for auramine staining and culture on liquid media (BACTEC MGIT 960; Becton Dickinson, Sparks, MD). Performance status, chest radiographs, and anthropometric measures were assessed at baseline and again at 8 wk. RESULTS: The participants (n = 154) were randomly assigned to the micronutrient (n = 77) or placebo (n = 77) group. Twenty participants were HIV infected (13%), and 12 participants had an unknown HIV status (8%). No differences in time to smear or culture conversion were observed between the treatment groups by Kaplan-Meier analysis (P = 0.15 and P = 0.38, respectively; log-rank test). Log-logistic regression analysis found no significant group interaction effect in time to culture detection over the 8-wk period (P = 0.32). No significant differences in weight gain (2.3 ± 3.5 compared with 2.2 ± 2.4 kg, P = 0.68) or radiologic resolution were observed between the treatment groups. CONCLUSION: Supplementation with vitamin A and zinc did not affect treatment outcomes in participants with pulmonary tuberculosis at 8 wk. This trial was registered at controlled-trials.com as ISRCTN80852505.

Fortifying brown bread with sodium iron EDTA, ferrous fumarate, or electrolytic iron does not affect iron status in South African schoolchildren.

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.

Estimating the burden of disease attributable to vitamin A deficiency in South Africa in 2000.

OBJECTIVES: To estimate the burden of disease attributable to vitamin A deficiency in children aged 0 - 4 years and pregnant women aged 15 - 49 years in South Africa in 2000. DESIGN: The framework adopted for the most recent World Health Organization comparative risk assessment (CRA) methodology was followed. Population-attributable fractions were calculated from South African Vitamin A Consultative Group (SAVACG) survey data on the prevalence of vitamin A deficiency in children and the relative risks of associated health problems, applied to revised burden of disease estimates for South Africa in the year 2000. Small community studies were used to derive the prevalence in pregnant women. Monte Carlo simulation-modelling techniques were used for the uncertainty analysis. SETTING: South Africa. SUBJECTS: Children under 5 years and pregnant women 15 - 49 years. OUTCOME MEASURES: Direct sequelae of vitamin A deficiency, including disability-adjusted life years (DALYs), as well as mortality associated with measles, diarrhoeal diseases and other infections, and mortality and DALYs associated with malaria in children and all-cause maternal mortality. RESULTS: One-third of children aged 0 - 4 years and 1 - 6% of pregnant women were vitamin A-deficient. Of deaths among young children aged 0 - 4 years in 2000, about 28% of those resulting from diarrhoeal diseases, 23% of those from measles, and 21% of those from malaria were attributed to vitamin A deficiency, accounting for some 3,000 deaths. Overall, about 110,467 ( 95% uncertainty interval 86,388 - 136,009) healthy years of life lost, or between 0.5% and 0.8% of all DALYs in South Africa in 2000 were attributable to vitamin A deficiency. CONCLUSIONS: The vitamin A supplementation programme for children and the recent food fortification programme introduced in South Africa in 2003 should prevent future morbidity and mortality related to vitamin A deficiency. Monitoring the effectiveness of these interventions is strongly recommended.

The efficacy of ferrous bisglycinate and electrolytic iron as fortificants in bread in iron-deficient school children.

Food fortification is an important long-term strategy for addressing micronutrient deficiencies. Finding the ideal Fe fortification compound, however, remains a challenge. In the present study the effect of ferrous bisglycinate as fortificant in brown bread was compared with that of electrolytic Fe among Fe-deficient school children in a randomised controlled trial. Children (n 160), aged 6-11 years, with serum ferritin <20 microg/l, were randomly assigned to one of three treatment categories: (i) standard unfortified bread; (ii) bread with electrolytic Fe as fortificant; and (iii) bread with ferrous bisglycinate as fortificant. Each child received four slices of bread (120 g) on school days, which supplied an average of 3.66 mg elemental Fe per intervention day for 137 d (2.52 mg/d for 75 d and 5.04 mg/d for 62 d) over a period of 7.5 months. Hb, serum ferritin, serum Fe and transferrin saturation were measured at baseline and at the end of the intervention. Significant treatment effects were observed for Hb (P = 0.013), serum Fe (P = 0.041) and transferrin saturation (P = 0.042) in the ferrous bisglycinate group, but not in the electrolytic Fe group. There were no significant intervention effects for serum ferritin in either treatment group. Overall, ferrous bisglycinate as Fe fortificant in brown bread performed better than electrolytic Fe in a group of Fe-deficient school children over a period of 7.5 months.

Efficacy of a foodlet-based multiple micronutrient supplement for preventing growth faltering, anemia, and micronutrient deficiency of infants: the four country IRIS trial pooled data analysis.

Diets of infants across the world are commonly deficient in multiple micronutrients during the period of growth faltering and dietary transition from milk to solid foods. A randomized placebo controlled trial was carried out in Indonesia, Peru, South Africa, and Vietnam, using a common protocol to investigate whether improving status for multiple micronutrients prevented growth faltering and anemia during infancy. The results of the pooled data analysis of the 4 countries for growth, anemia, and micronutrient status are reported. A total of 1134 infants were randomized to 4 treatment groups, with 283 receiving a daily placebo (P), 283 receiving a weekly multiple micronutrient supplement (WMM), 280 received a daily multiple micronutrient (DMM) supplement, and 288 received daily iron (DI) supplements. The DMM group had a significantly greater weight gain, growing at an average rate of 207 g/mo compared with 192 g/mo for the WMM group, and 186 g/mo for the DI and P groups. There were no differences in height gain. DMM was also the most effective treatment for controlling anemia and iron deficiency, besides improving zinc, retinol, tocopherol, and riboflavin status. DI supplementation alone increased zinc deficiency. The prevalence of multiple micronutrient deficiencies at baseline was high, with anemia affecting the majority, and was not fully controlled even after 6 mo of supplementation. These positive results indicate the need for larger effectiveness trials to examine how to deliver supplements at the program scale and to estimate cost benefits. Consideration should also be given to increasing the dosages of micronutrients being delivered in the foodlets.

Efficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, and growth in South African infants.

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.