Vitamin A deficiency remains a nutritional concern in sub-Saharan Africa. Conventionally bred maize hybrids with high provitamin A carotenoid concentrations may have the potential to improve vitamin ...A status in maize-consuming populations.
We evaluated the efficacy of regular provitamin A carotenoid-biofortified "orange" maizemeal (∼15 μg β-carotene/g) consumption in improving vitamin A status and reducing vitamin A deficiency in children.
This was a cluster-randomized controlled trial in the rural farming district of Mkushi, Zambia. All 4- to 8-y-old children in an ∼400-km(2) area were identified and grouped by proximity into clusters of ∼15-25 children. We randomly assigned clusters to 1) orange maizemeal (n = 25), 2) white maizemeal (n = 25), or 3) a parallel, nonintervention group (n = 14). Children in intervention clusters (n = 1024) received 200 g maizemeal for 6 d/wk over 6 mo; the maizemeal was prepared according to standardized recipes and served in cluster-level kitchens. Staff recorded attendance and leftovers. We collected venous blood before and after the intervention to measure serum retinol, β-carotene, C-reactive protein, and α1-acid glycoprotein.
Intervention groups were comparable at baseline, and vitamin A status was better than anticipated (12.1% deficient on the basis of serum retinol <0.7 μmol/L). Although attendance at meals did not differ (85%), median daily maize intake was higher in white (154 g/d) than in orange (142 g/d) maizemeal clusters. At follow-up, mean serum β-carotene was 0.14 μmol/L (95% CI: 0.09, 0.20 μmol/L) higher in orange maizemeal clusters (P < 0.001), but mean serum retinol (1.00 ± 0.33 μmol/L overall) and deficiency prevalence (17.1% overall) did not differ between arms.
In this marginally nourished population, regular biofortified maizemeal consumption increased serum β-carotene concentrations but did not improve serum retinol. This trial was registered at clinicaltrials.gov as NCT01695148.
Antenatal multiple micronutrient (MM) supplementation improves birth outcomes relative to iron–folic acid (IFA) in developing countries, but limited data exist on its impact on pregnancy ...micronutrient status.
We assessed the efficacy of a daily MM (15 nutrients) compared with IFA supplement, each providing approximately 1 RDA of nutrients and given beginning at pregnancy ascertainment, on late pregnancy micronutrient status of women in rural Bangladesh. Secondarily, we explored other contributors to pregnancy micronutrient status.
Within a double-masked trial (JiVitA-3) among 44,500 pregnant women, micronutrient status indicators were assessed in n = 1526 women, allocated by cluster to receive daily MM (n = 749) or IFA (n = 777), at 10 wk (baseline: before supplementation) and 32 wk (during supplementation) gestation. Efficacy of MM supplementation on micronutrient status indicators at 32 wk was assessed, controlling for baseline status and other covariates (e.g., inflammation and season), in regression models.
Baseline status was comparable by intervention. Prevalence of deficiency among all participants was as follows: anemia, 20.6%; iron by ferritin, 4.0%; iron by transferrin receptor, 4.7%; folate, 2.5%; vitamin B-12, 35.4%; vitamin A, 6.7%; vitamin E, 57.7%; vitamin D, 64.0%; zinc, 13.4%; and iodine, 2.6%. At 32 wk gestation, vitamin B-12, A, and D and zinc status indicators were 3.7–13.7% higher, and ferritin, γ-tocopherol, and thyroglobulin indicators were 8.7–16.6% lower, for the MM group compared with the IFA group, with a 15–38% lower prevalence of deficiencies of vitamins B-12, A, and D and zinc (all P < 0.05). However, indicators typically suggested worsening status during pregnancy, even with supplementation, and baseline status or other covariates were more strongly associated with late pregnancy indicators than was MM supplementation.
Rural Bangladeshi women commonly entered pregnancy deficient in micronutrients other than iron and folic acid. Supplementation with MM improved micronutrient status, although deficiencies persisted. Preconception supplementation or higher nutrient doses may be warranted to support nutritional demands of pregnancy in undernourished populations. This trial was registered at clinicaltrials.gov as NCT00860470.
Four fortified complementary food supplements (CFSs) in a randomized controlled trial (RCT) were found to improve childhood linear growth in rural Bangladesh. We hypothesized children receiving these ...supplements would have improved micronutrient status.
In the RCT, we assessed hemoglobin and serum ferritin, retinol, zinc, C-reactive protein (CRP), and α-1-acid glycoprotein (AGP) at endline (18 mo) in a subsample of children (
= 752). The impact of supplementation on mean concentrations and the prevalence of nutrient deficiency and inflammation were evaluated using adjusted generalized estimating equation (GEE) linear and log-binomial regression models.
In the control arm at age 18 months, 13% of children were anemic (hemoglobin < 110 g/L), and 6% were iron (inflammation-adjusted ferritin < 12 μg/L), 8% vitamin A (inflammation-adjusted retinol < 0.70 μmol/L), and 5% zinc (zinc < 9.9 μmol/L) deficient. The prevalence of inflammation by CRP (>5 mg/L) and AGP (>1 g/L) was 23% and 66%, respectively, in the control group. AGP trended lower in CFS groups (
= 0.04), while CRP did not. Mean ferritin (
< 0.001) and retinol (
= 0.007) were higher in all supplemented groups relative to control, whereas hemoglobin improved with two of the four CFSs (
= 0.001), and zinc was equal or lower in supplemented groups relative to control (
= 0.017).
CFSs improved iron status and vitamin A concentrations and lowered inflammation in a context of low underlying nutrient deficiency but high inflammation.
Prenatal multiple micronutrient (MM) supplementation improves birth weight through increased fetal growth and gestational age, but whether maternal or fetal growth factors are involved is unclear. ...Our objective was to examine the effect of prenatal MM supplementation on intrauterine growth factors and the associations between growth factors and birth outcomes in a rural setting in Bangladesh. In a double-blind, cluster-randomized, controlled trial of MM vs. iron and folic acid (IFA) supplementation, we measured placental growth hormone (PGH) at 10 weeks and PGH and human placental lactogen (hPL) at 32 weeks gestation in maternal plasma (n = 396) and insulin, insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) in cord plasma (n = 325). Birth size and gestational age were also assessed. Early pregnancy mean (SD) BMI was 19.5 (2.4) kg/m2 and birth weight was 2.68 (0.41) kg. There was no effect of MM on concentrations of maternal hPL or PGH, or cord insulin, IGF-1, or IGFBP-1. However, among pregnancies of female offspring, hPL concentration was higher by 1.1 mg/L in the third trimester (95% CI: 0.2, 2.0 mg/L; p = 0.09 for interaction); and among women with height <145 cm, insulin was higher by 59% (95% CI: 3, 115%; p = 0.05 for interaction) in the MM vs. IFA group. Maternal hPL and cord blood insulin and IGF-1 were positively, and IGFBP-1 was negatively, associated with birth weight z score and other measures of birth size (all p<0.05). IGF-1 was inversely associated with gestational age (p<0.05), but other growth factors were not associated with gestational age or preterm birth. Prenatal MM supplementation had no overall impact on intrauterine growth factors. MM supplementation altered some growth factors differentially by maternal early pregnancy nutritional status and sex of the offspring, but this should be examined in other studies.
ClinicalTrials.gov NCT00860470.
Pregnancy exacerbates vitamin A (VA) deficiency and anaemia among women in developing countries. Improving circulating haemoglobin (Hb) requires erythrocyte production and availability of iron. ...Insulin-like growth factor- 1 (IGF-1) functions in erythropoiesis, but its association with VA status and pregnancy-associated anaemia has not been studied. The aim of this study was to examine the relationship between serum retinol, IGF-1, and Hb among pregnant women in extant samples collected during a placebo-controlled trial of VA and beta-carotene (BC) supplementation in rural Nepal conducted from 1994 to 1997. Mid-pregnancy serum IGF-1 was measured in serum from n=589 randomly selected women of n=1186 in whom anthropometric, VA (retinol) and iron (Hb, erythrocyte zinc protoporphyrin (ZP), and ferritin) status data were available. Associations of IGF-1 with retinol, Hb or anaemia, and iron status were determined using multiple linear and logistic regression. Path analysis was used to explore the role of IGF-1 as a mediator between retinol and Hb, accounting for iron status. A 2.6 g/L increase in IGF-1 was observed per 0.1 mol/L increment in retinol (p<0.0001). Hb increased with each quartile of IGF-1, and odds of anaemia declined 68.8% from the 1st to 4th quartile. Improved iron status indicators explained only 29.1% of the association between IGF-1 and Hb, while IGF-1 explained 25.6% of the association between retinol and Hb. Increasing IGF-1 was likely one mechanism by which retinol improved circulating Hb in pregnant women of rural Nepal, although IGF-1 worked primarily through pathways independent of improved iron status indicators, perhaps by stimulating erythrocyte production.
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.
Subclinical micronutrient deficiencies remain a hidden aspect of malnutrition for which comprehensive data are lacking in school-aged children. We assessed the micronutrient status of Nepalese ...children, aged 6 to 8 y, born to mothers who participated in a community-based antenatal micronutrient supplementation trial from 1999 to 2001. Of 3305 participants, plasma indicators were assessed in a random sample of 1000 children. Results revealed deficiencies of vitamins A (retinol <0.70 μ mol/L, 8.5%), D (25-hydroxyvitamin D <50 nmol/L, 17.2%), E (α-tocopherol <9.3 μ mol/L, 17.9%), K (decarboxy prothombin >2 μ g/L, 20%), B-12 (cobalamin <150 pmol/L, 18.1%), B-6 pyridoxal-5′-phosphate (PLP) <20 nmol/L, 43.1%, and β-carotene (41.5% <0.09 μ mol/L), with little folate deficiency (6.2% <13.6 nmol/L). Deficiencies of iron ferritin <15 μ g/L, 10.7%; transferrin receptor (TfR) >8.3 mg/L, 40.1%; TfR:ferritin >500 μ g/μ g, 14.3%, iodine (thyroglobulin >40 μ g/L, 11.4%), and selenium (plasma selenium <0.89 μ mol/L, 59.0%) were observed, whereas copper deficiency was nearly absent (plasma copper <11.8 μ mol/L, 0.7%). Hemoglobin was not assessed. Among all children, 91.7% experienced at least 1 micronutrient deficiency, and 64.7% experienced multiple deficiencies. Inflammation (α-1 acid glycoprotein >1 g/L, C-reactive protein >5 mg/L, or both) was present in 31.6% of children, affecting the prevalence of deficiency as assessed by retinol, β-carotene, PLP, ferritin, TfR, selenium, copper, or having any or multiple deficiencies. For any nutrient, population deficiency prevalence estimates were altered by ≤5.4% by the presence of inflammation, suggesting that the majority of deficiencies exist regardless of inflammation. Multiple micronutrient deficiencies coexist in school-aged children in rural Nepal, meriting more comprehensive strategies for their assessment and prevention.
Higher iron stores, defined by serum ferritin (SF) concentration, may increase malaria risk.
We evaluated the association between SF assessed during low malaria season and the risk of malaria during ...high malaria season, controlling for inflammation.
Data for this prospective study were collected from children aged 4–8 y (n = 745) participating in a biofortified maize efficacy trial in rural Zambia. All malaria cases were treated at baseline (September 2012). We used baseline SF and malaria status indicated by positive microscopy at endline (March 2013) to define exposure and outcome, respectively. Iron status was defined as deficient (corrected or uncorrected SF <12 or <15 μg/L, depending on age <5 or ≥5 y, respectively), moderate (<75 μg/L, excluding deficient), or high (≥75 μg/L). We used a modified Poisson regression to model the risk of malaria in the high transmission seasons (endline) as a function of iron status assessed in the low malaria seasons (baseline).
We observed an age-dependent, positive dose-response association between ferritin in the low malaria season and malaria incidence during the high malaria season in younger children. In children aged <6 y (but not older children), we observed a relative increase in malaria risk in the moderate iron status incidence rate ratio (IRR) with SF: 1.56; 95% CI: 0.64, 3.86; IRR with inflammation-corrected SF: 1.92; 95% CI: 0.75, 4.93 and high iron status (IRR with SF: 2.66; 95% CI: 1.10, 6.43; or IRR with corrected SF: 2.93; 95% CI: 1.17, 7.33) categories compared with the deficient iron status category. The relative increase in malaria risk for children with high iron status was statistically significant only among those with a concurrently normal serum soluble transferrin receptor concentration (<8.3 mg/L; IRR: 1.97; 95% CI: 1.20, 7.37).
Iron adequacy in 4- to 8-y-old children in rural Zambia was associated with increased malaria risk. Our findings underscore the need to integrate iron interventions with malaria control programs. This trial was registered at clinicaltrials.gov as NCT01695148.
Abstract only
Iron status remains difficult to assess in settings where iron deficiency coexists with inflammation, and hepcidin has been proposed as an indicator of the body's iron requirement. ...Hepcidin reduces iron availability in iron sufficiency or inflammation, while low hepcidin may signal the body's need for iron. We sought to identify proteins that may be closely linked to iron metabolism using quantitative proteomics to characterize the plasma proteome in 500 plasma samples, depleted of the 6 most abundant proteins including transferrin, collected from 6–8 year old children in rural Nepal. We related relative abundance of proteins with conventional iron status indicators and hepcidin using linear mixed effects models with an imposed false discovery rate <10%. Among the children, inflammation (by C‐reactive protein, CRP, > 5 mg/L and/or α‐1 acid glycoprotein, AGP, > 1.0 g/L) occurred in 30%, and low iron stores (ferritin < 15 μg/L) were observed in 10% and tissue iron demand (transferrin receptor, TfR, >8.3 mg/L) in 40%. Fifty proteins were associated with hepcidin, 35 with ferritin, and 7 with TfR. A large overlap in the proteomes for hepcidin and ferritin with CRP and AGP, previously characterized, was observed. To further explore for proteins related to iron status independent of inflammation, hepcidin and ferritin were regressed against CRP and AGP, respectively, to generate residuals, to reflect the variability in hepcidin and ferritin unexplained by inflammation indexed by CRP and AGP. Thirty‐seven proteins remained associated with hepcidin, with the majority still associated with the inflammation proteome. These proteins have functions in the immune system (e.g. lipopolysaccharide‐binding protein), complement system (complement component 9 and 8 beta subunit), transcription and translation regulation (RNA polymerase II elongation factor), and glycoprotein formation (mannosyl‐oligosaccharide 1,2‐ α‐mannosidase IA). Nine proteins remained associated with ferritin residuals, but ficolin‐3, with a role in the lectin pathway and complement activation, was the only protein observed in common between hepcidin and ferritin inflammation‐adjusted residuals. Ficolin‐3 may be biologically linked to iron sequestration, given its unique association with hepcidin and ferritin. Plasma proteomics did not reveal new potential markers of iron status per se, but confirmed an extensive and complex association of iron metabolism with inflammation.
Support or Funding Information
Supported by Gates Foundation grants OPPGH5241 and GH614 (Global Control of Micronutrient Deficiency).
Objective
In 4‐ to 8‐year‐old Zambian children (n = 744), we evaluated the effects of adjusting for inflammation (α1‐acid glycoprotein >1 g/l), with or without additional adjustment for malaria, on ...prevalence estimates of iron deficiency (ID) and iron deficiency anaemia (IDA) during low malaria (LowM) and high malaria (HighM) transmission seasons.
Methods
To estimate adjustment factors, children were classified as: (i) reference (malaria negative without inflammation), (ii) inflammation without malaria (I), (iii) malaria without inflammation (M) and (iv) inflammation with malaria (IM). We estimated the unadjusted ID or IDA prevalence, and then adjusted for inflammation alone (IDI or IDAI) or inflammation and malaria (IDIM or IDAIM).
Results
Mean ferritin was 38 (reference), 45 (I), 43 (M) and 54 μg/l (IM) in LowM, increasing to 44, 56, 96 and 167 μg/l, respectively, in HighM. Corresponding mean sTfR was 6.4, 6.9, 7.9 and 8.4 mg/l in LowM, increasing to 8.2, 9.2. 8.7 and 9.7 mg/l in HighM. Ferritin‐based ID, IDI and IDIM were 7.8%, 8.7% or 9.1%, respectively, in LowM and 4.6%, 10.0% or 11.7%, respectively, in HighM. Corresponding soluble transferrin receptor (sTfR)‐based estimates were 27.0%, 24.1% and 19.1%, respectively, in LowM, increasing to 53.6%, 46.5% and 45.3%, respectively, in HighM. Additional adjustment for malaria resulted in a ~1‐ to 2‐percentage point change in IDA, depending on biomarker and season.
Conclusions
In this population, malaria substantially increased ferritin and sTfR concentrations, with modest effects on ID and IDA prevalence estimates.
Objectif
Chez les enfants zambiens de 4 à 8 ans (n = 744), nous avons évalué les effets de l'ajustement pour l'inflammation (α1‐glycoprotéine acide > 1 g/L), avec ou sans ajustement additionnel pour le paludisme, sur les estimations de prévalence de la carence en fer (CF) et l'anémie ferriprive (AF) lors des saisons de transmission faible (LowM) et élevée (HighM) du paludisme.
Méthodes
Pour estimer les facteurs d'ajustement, les enfants ont été classés en: a) référence (paludisme négatif sans inflammation), b) inflammation sans paludisme (I), c) paludisme sans inflammation (M), et d) inflammation avec paludisme (IM). Nous avons estimé la prévalence non ajustée de la CF ou de l’AF, puis avons ajusté pour l'inflammation seule (CFI ou AFI) ou l'inflammation avec le paludisme (CFIM ou AFIM).
Résultats
La ferritine moyenne était de 38 (référence), 45 (I), 43 (M) et 54 (IM) μg/L dans la LowM, augmentant à 44, 56, 96 et 167 μg/L respectivement, dans la HighM. Les valeurs moyennes correspondantes du récepteur soluble de la transferrine (sTfR) étaient de 6,4; 6,9; 7,9 et 8,4 mg/L dans la LowM, augmentant à 8,2; 9,2; 8,7 et 9,7 mg/L dans la HighM. Les CF sur base de la ferritine, de CFI et CFIM étaient respectivement de 7,8%, 8,7% et 9,1% dans la LowM et de 4,6%, 10,0% et 11,7% respectivement, dans la HighM. Les estimations correspondantes du sTfR étaient respectivement de 27,0%, 24,1% et 19,1% dans la LowM, augmentant à 53,6%, 46,5% et 45,3%, respectivement, dans la HighM. Des ajustements supplémentaires pour le paludisme ont entraîné une variation d'environ 1 à 2 points de pourcentage de l’AF selon le biomarqueur et la saison.
Conclusions
Dans cette population, le paludisme a considérablement augmenté les concentrations de ferritine et du sTfR, avec des effets modestes sur les estimations de prévalence la CF et de l'AF.
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