Rafael Flores-Ayala

Selling Sprinkles micronutrient powder reduces anemia, iron deficiency, and vitamin A deficiency in young children in Western Kenya: a cluster-randomized controlled trial

BACKGROUND Although the efficacy of micronutrient powders [MNPs; eg, Sprinkles MNP (Sprinkles Global Health Initiative)] in the reduction of anemia has been established, the effectiveness of these powders in real-world programs has seldom been assessed. OBJECTIVE In this study, we evaluated the effect of community-based marketing and distribution of Sprinkles MNP on childhood rates of anemia and iron and vitamin A deficiency. DESIGN In a cluster-randomized trial in children aged 6-35 mo in Western Kenya, 60 villages were randomly assigned to either intervention or control groups. Community vendors marketed and sold sachets of Sprinkles MNP in intervention villages. Biweekly household visits monitored the use of Sprinkles MNP. Hemoglobin, ferritin, retinol binding protein, malaria, and anthropometric measures were assessed at baseline (n = 1063) and 12 mo of follow-up (n = 862). Data were analyzed by using an intention-to-treat analysis and generalized linear mixed models. RESULTS On average, 33% of households in intervention villages purchased Sprinkles MNP; the average weekly intake per child was 0.9 sachets (∼11.3 mg Fe and ∼328 μg vitamin A). Compared with control subjects, intervention children had greater improvements in hemoglobin concentrations (increase of 0.9 compared with 0.6 g/dL, respectively; P = 0.02), iron deficiency (decrease of 19.3% compared with 5.3%, respectively; P = 0.001), and vitamin A deficiency (decrease of 7.5% compared with an increase of 2.5%, respectively; P = 0.01). Results adjusted for age, sex, socioeconomic status, and maternal education showed a significant association between the hemoglobin, iron, and vitamin A concentrations of children and the number of Sprinkles MNP sachets the children consumed. The prevalence of malaria, wasting, and stunting did not change significantly in either group. CONCLUSION Even with relatively low and infrequent use, Sprinkles MNP sales through community vendors were associated with decreased rates of anemia and iron and vitamin A deficiency in children in a resource-poor setting. This trial was registered at clinicaltrials.gov as NCT01088958.

Correcting for Inflammation Changes Estimates of Iron Deficiency among Rural Kenyan Preschool Children

The assessment of iron status where infections are common is complicated by the effects of inflammation on iron indicators and in this study we compared approaches that adjust for this influence. Blood was collected in 680 children (aged 6-35 mo) and indicators of iron status [(hemoglobin (Hb), zinc protoporphyrin (ZP), ferritin, transferrin receptor (TfR), and TfR/ferritin index)] and subclinical inflammation [(the acute phase proteins (APP) C-reactive protein (CRP), and α-1-acid glycoprotein (AGP)] were determined. Malaria parasitemia was assessed. Subclinical inflammation was defined as CRP >5 mg/L and/or AGP >1 g/L). Four groups were defined based on APP levels: reference (normal CRP and AGP), incubation (raised CRP and normal AGP), early convalescence (raised CRP and AGP), and late convalescence (normal CRP and raised AGP). Correction factors (CF) were estimated as the ratios of geometric means of iron indicators to the reference group of those for each inflammation group. Corrected values of iron indicators within inflammation groups were obtained by multiplying values by their respective group CF. CRP correlated with AGP (r = 0.65; P < 0.001), ferritin (r = 0.38; P < 0.001), Hb (r = -0.27; P < 0.001), and ZP (r = 0.16; P < 0.001); AGP was correlated with ferritin (r = 0.39; P < 0.001), Hb (r = -0.29; P < 0.001), and ZP (r = 0.24; P < 0.001). Use of CF to adjust for inflammation increased the prevalence of ID based on ferritin < 12 μg/L by 34% (from 27 to 41%). Applying the CF strengthened the expected relationship between Hb and ferritin (r = 0.10; P = 0.013 vs. r = 0.20; P < 0.001, before and after adjustment, respectively). Although the use of CF to adjust for inflammation appears indicated, further work is needed to confirm that this approach improves the accuracy of assessment of ID.

Overview of the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) Project

Anemia remains a widespread public health problem. Although iron deficiency is considered the leading cause of anemia globally, the cause of anemia varies considerably by country. To achieve global targets to reduce anemia, reliable estimates of the contribution of nutritional and non-nutritional causes of anemia are needed to guide interventions. Inflammation is known to affect many biomarkers used to assess micronutrient status and can thus lead to incorrect diagnosis of individuals and to overestimation or underestimation of the prevalence of deficiency in a population. Reliable assessment of iron status is particularly needed in settings with high infectious disease burden, given the call to screen for iron deficiency to mitigate potential adverse effects of iron supplementation. To address these information gaps, in 2012 the CDC, National Institute for Child Health and Human Development, and Global Alliance for Improved Nutrition formed a collaborative research group called Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA). Data from nationally and regionally representative nutrition surveys conducted in the past 10 y that included preschool children and/or women of childbearing age were pooled. Of 25 data sets considered for inclusion, 17 were included, representing ∼30,000 preschool children, 26,000 women of reproductive age, and 21,000 school-aged children from all 6 WHO geographic regions. This article provides an overview of the BRINDA project and describes key research questions and programmatic and research implications. Findings from this project will inform global guidelines on the assessment of anemia and micronutrient status and will guide the development of a research agenda for future longitudinal studies.

Randomized trial of the effect of zinc supplementation on the mental health of school-age children in Guatemala

BACKGROUND Rates of mental illness in children are increasing throughout the world. Observational studies of depression, anxiety, and attention-deficit hyperactivity disorder suggest that zinc is an alternative treatment. OBJECTIVE We examined the effect of zinc supplementation on the mental health of school-age children in Guatemala. DESIGN From January to October 2006, we conducted a 6-mo randomized, double-blind, controlled trial comparing zinc supplementation (10 mg ZnO/d for 5 d/wk) with a placebo (10 mg glucose) in 674 Guatemalan children in grades 1-4. Outcome measures included internalizing (ie, depression and anxiety) and externalizing (ie, hyperactivity and conduct disorder) problem behaviors, positive behaviors (ie, socialization and leadership), and serum zinc concentrations. RESULTS Zinc and placebo groups did not differ significantly in any behavioral measures at baseline or at follow-up. At baseline, 21.4% of children had serum zinc concentrations <65 μg/dL. At follow-up, both groups improved significantly, and zinc concentrations were higher in the zinc group. Increases in serum zinc concentrations were inversely associated with decreases in depressive symptoms (estimate: -0.01 points per μg Zn/dL; P = 0.01), anxiety (estimate: -0.012 points per μg Zn/dL; P = 0.02), internalizing symptoms (estimate: -0.021 points per μg Zn/dL; P = 0.02), and social skills (estimate: -0.019 points per μg Zn/dL; P = 0.01) in adjusted models that were controlled for child age, sex, socioeconomic status, household, and treatment group. CONCLUSIONS Six months of zinc supplementation did not induce differences in mental health outcomes between zinc and placebo groups. However, increases in serum zinc concentrations were associated with decreases in internalizing symptoms (ie, depression and anxiety) in a community-based sample of children at risk of zinc deficiency. This trial was registered at clinicaltrials.gov as NCT00283660.

Comparison of indicators of iron deficiency in Kenyan children

BACKGROUND In the absence of a feasible, noninvasive gold standard, iron deficiency (ID) is best measured by the use of multiple indicators. However, the choice of an appropriate single iron biomarker to replace the multiple-criteria model for screening for ID at the population level continues to be debated. OBJECTIVE We compared ID defined as ≥ 2 of 3 abnormal ferritin (< 12 μg/L), soluble transferrin receptor (TfR; > 8.3 mg/L), or zinc protoporphyrin (ZP; > 80 μmol/mol) concentrations (ie, multiple-criteria model) with ID defined by abnormal concentrations of any of the independent candidate iron biomarkers (ferritin alone, TfR alone, or ZP alone) and TfR/ferritin index (ID, > 500). Values either were adjusted for inflammation [as measured by C-reactive protein (> 5 mg/L) and α(1)-acid glycoprotein (> 1 g/L) before applying cutoffs for ID] or were unadjusted. DESIGN In this community-based cluster survey, capillary blood was obtained from 680 children (aged 6-35 mo) for measurement of iron status by using ferritin, TfR, and ZP. RESULTS On the basis of the multiple-criteria model, the mean (±SE) prevalence of ID was 61.9 ± 2.2%, whereas the prevalences based on abnormal ferritin, TfR, or ZP concentrations or an abnormal TfR/ferritin index were 26.9 ± 1.7%, 60.9 ± 2.2%, 82.8 ± 1.6%, and 43.1 ± 2.3%, respectively, for unadjusted values. The prevalences of ID were higher for adjusted values only for low ferritin and an elevated TfR/ferritin index compared with the unadjusted values. The κ statistics for agreement between the multiple-criteria model and the other iron indicators ranged from 0.35 to 0.88; TfR had the best agreement (κ = 0.88) with the multiple-criteria model. Positive predictive values of ID based on the other iron indicators in predicting ID based on the multiple-criteria model were highest for ferritin and TfR. Receiver operating characteristic curve analysis indicated that TfR (AUC = 0.94) was superior to the other indicators in diagnosing ID based on the multiple-criteria model (P < 0.001). The inflammation effect did not appear to alter these observations appreciably. CONCLUSION TfR better estimates the prevalence of ID in preschoolers than do ferritin, ZP, and the TfR/ferritin index on the basis of multiple indexes in a high inflammation, resource-poor setting. This trial was registered at clinicaltrials.gov as NCT101088958.

Growth to age 18 months following prenatal supplementation with docosahexaenoic acid differs by maternal gravidity in Mexico.

Little is known about the long-term effects of DHA intake during pregnancy. Offspring of primagravid Mexican women who received 400 mg/d DHA from wk 20 of gestation through delivery were heavier and had larger head circumferences at birth than children whose mothers received placebo; no effect was observed in offspring of multigravidae. We have followed these children (n = 739; 76% of the birth cohort), measuring length, weight, and head circumference at 1, 3, 6, 9, 12, and 18 mo. At 18 mo, intent-to-treat differences between placebo and DHA, adjusted for maternal height and child sex and age at measurement, were: length, -0.21 cm (95% CI = -0.58, 0.15); weight, -0.03 kg (95% CI =-0.19, 0.13); and head circumference, 0.02 cm (95% CI = -0.18, 0.21) (all P > 0.05). There was heterogeneity of associations by maternal gravidity for weight (P < 0.08), length (P < 0.02), and head circumference (P < 0.05). Among offspring of primagravid women, length at 18 mo was increased by 0.72 cm (95% CI = 0.11, 1.33) following DHA supplementation, representing 0.26 length-for-age Z-score units; among offspring of multigravidae, the estimate was -0.13 cm (95% CI = -0.59, 0.32) (P > 0.5). Maternal DHA supplementation during the second half of gestation may enhance growth through 18 mo of children born to primagravid women.

Effectiveness evaluation of the food fortification program of Costa Rica: impact on anemia prevalence and hemoglobin concentrations in women and children

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

Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project

Background: The accurate estimation of iron deficiency is important in planning and implementing interventions. Ferritin is recommended as the primary measure of iron status, but interpretability is challenging in settings with infection and inflammation. Objective: We assessed the relation between ferritin concentrations and inflammation and malaria in preschool children (PSC) (age range: 6–59 mo) and women of reproductive age (WRA) (age range: 15–49 y) and investigated adjustment algorithms to account for these effects. Design: Cross-sectional data from 15 surveys for PSC (n = 27,865) and 8 surveys for WRA (24,844), from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined with the use of a meta-analysis. Several approaches were explored to estimate depleted iron stores (ferritin concentration <12 μg/L in PSC and <15 μg/L in WRA) in inflammation and malaria settings as follows: 1) increase ferritin-concentration cutoff to <30 μg/L; 2) exclude individuals with C-reactive protein (CRP) concentrations >5 mg/L or α-1-acid glycoprotein (AGP) concentrations >1 g/L; 3) apply arithmetic correction factors; and 4) use a regression correction approach. Results: Depleted iron-store estimates incrementally increased as CRP and AGP deciles decreased (4% compared with 30%, and 6% compared with 29% from highest compared with lowest CRP deciles for pooled PSC and WRA, respectively, with similar results for AGP). Depending on the approach used to adjust for inflammation (CRP plus AGP), the estimated prevalence of depleted iron stores increased by 7–25 and 2–8 absolute median percentage points for PSC and WRA, respectively, compared with unadjusted values. Adjustment for malaria in addition to CRP and AGP did not substantially change the estimated prevalence of depleted iron stores. Conclusions: Our results lend support for the use of internal regression correction to estimate the prevalence of depleted iron stores in regions with inflammation. This approach appears to mathematically reflect the linear relation of ferritin concentrations with acute-phase proteins. More research is warranted to validate the proposed approaches, but this study contributes to the evidence base to guide decisions about how and when to adjust ferritin for inflammation.

Some Indicators of Nutritional Status Are Associated with Activity and Exploration in Infants at Risk for Vitamin and Mineral Deficiencies

Severe malnutrition, both protein-energy and micronutrient deficiency, results in decreased activity, but the results regarding mild-to-moderate malnutrition are equivocal. Our objective in this investigation was to describe the activity and exploratory behavior of Mexican infants and describe the relationship among nutritional status, activity, and exploration in this population at high risk for mild-to-moderate micronutrient deficiency, but at low risk for severe malnutrition. The participants were infants, 4-12 mo old, of low socioeconomic status from 3 states in southern Mexico. We measured anthropometrics using standard techniques. We measured hemoglobin (Hb) concentration in the field and adjusted values for altitude before analysis. We measured activity and exploration by direct observation during 15 min of individual play in a novel environment. Cluster analysis generated mutually exclusive activity clusters and exploration clusters based on patterns of bodily movement and exploratory behavior, respectively. We categorized the clusters as higher or lower activity or higher or lower exploration. A higher Hb concentration and height-for-age Z-score (HAZ) significantly increased the odds of being in the high-activity cluster. Iron deficiency, stunting, and wasting significantly decreased the odds of being in the high-activity cluster. Higher HAZ and weight-for-age Z-score significantly increased the odds of being in a higher exploration cluster. In Mexican infants at risk for mild-to-moderate micronutrient deficiency but at low risk of severe malnutrition, some indicators of nutritional status were related to increased activity and exploration.

Serum soluble transferrin receptor concentrations in US preschool children and non-pregnant women of childbearing age from the National Health and Nutrition Examination Survey 2003–2010☆

BACKGROUND Serum soluble transferrin receptor (sTfR) is recommended as a sensitive and accurate measure of iron deficiency (ID) in populations when only a single indicator can be used. The lack of assay standardization and of representative data on the distribution of sTfR in at-risk populations currently limits its utility. METHODS Using data from NHANES 2003-2010, we examined the distribution of sTfR and developed assay-specific cutoff values for defining elevated sTfR in 2 US populations groups: children aged 1-5 y (n=2820) and non-pregnant women aged 15-49 y (n=6575). RESULTS On average, children had higher geometric mean sTfR concentrations (4.09 mg/l; 95% CI: 4.04-4.14) than non-pregnant women (3.31 mg/l; 95% CI: 3.26-3.35) (p<0.001). Among children, those aged 1-2 y (compared to those aged 3-5 y), boys (compared to girls), and non-Hispanic black (NHB) children (compared to non-Hispanic white (NHW) and Mexican-American (MA) children) had higher sTfR concentrations. Among non-pregnant women, adolescents (15-19 y) had higher sTfR concentrations than adults aged 20-34 y but not compared to adults aged 35-49 y; NHB women (compared to NHW and MA women) and multiparous women (compared to nulliparous women) had higher sTfR concentrations. The derived cutoff values (97.5th percentile in a defined healthy reference population) for defining elevated sTfR in the US were 6.00 mg/l for children 1-5 y and 5.33 mg/l for non-pregnant women 15-49 y. CONCLUSIONS A different sTfR cutoff value may be needed in children and non-pregnant women to define ID.