Physiologically based trimester-specific serum ferritin thresholds for iron deficiency in US pregnant women.

ABSTRACT: Serum ferritin (SF) concentration is the most widely used indicator for iron deficiency (ID). During pregnancy, the World Health Organization recently recommended SF thresholds for ID of <15 µg/L for the first trimester of pregnancy, based on expert opinion, and made no recommendations for the second and third trimesters. We examined the relationship of SF with 2 independent indicators of the onset of iron-deficient erythropoiesis, hemoglobin and soluble transferrin receptor 1, in cross-sectional data from US National Health and Nutrition Examination Survey for 1999 to 2010 and 2015 to 2018. We included 1288 pregnant women aged 15 to 49 years and excluded women with inflammation or potential liver disease. We used restricted cubic spline (RCS) regression analysis to determine SF thresholds for iron-deficient erythropoiesis. SF decreased during pregnancy; geometric mean SF was higher during the first and lower during the second and third trimesters. Using RCS analysis, the SF thresholds identified during pregnancy were <25.8 µg/L (18.1-28.5) during first trimester, <18.3 µg/L (16.3-22.9) during second trimester, and <19.0 µg/L (14.4- 26.1) during third trimester. These SF threshold levels track concentrations of hepcidin, the iron-regulatory hormone controlling the mobilization of iron stores. An SF concentration of <15 µg/L as the criterion for ID may underestimate the true prevalence of ID throughout pregnancy. In our study, an additional 1 of every 10 pregnant women would be recognized as iron deficient by using the physiologically based thresholds at SF of ∼25 µg/L during the first and ∼20 µg/L during the second and third trimesters.

Trends in Micronutrient Interventions, Anemia, and Iron Deficiency among Women and Children in Guatemala, 2009-2019.

Background: Food fortification and micronutrient supplementation are public health strategies to improve micronutrient status in Guatemala; their population effectiveness has not been evaluated in recent years. Objective: We evaluated trends in food fortification, micronutrient supplementation, anemia, and iron deficiency among nonpregnant women aged 15-49 y [women of reproductive age (WRA)] and children 6-59 aged mo [preschool age children (PSC)]. Method: Nationally representative serial cross-sectional surveys were used to assess changes in hemoglobin, anemia, ferritin, iron deficiency, iron deficiency anemia, and self-reported consumption of fortifiable foods and micronutrient supplements during 2008/2009, 2013, 2015, 2016, 2017/2018, and 2018/2019. Predictors of hemoglobin and ferritin were assessed using generalized linear mixed models adjusted for survey year as random effects, and the consumption of fortifiable foods, supplements, and other potential confounders were fixed effects. Results: Multiple micronutrient powder consumption among PSC during the previous 3 mo was 53.3% (95% CI: 49.4, 57.2) in 2013 and 33.6% (28.8, 38.4) in 2018/2019. Anemia among PSC was 11.3% (8.0, 14.5) in 2008/2009 and 6.1% (3.6, 8.6) in 2018/2019. Anemia among WRA was 10.7% (7.2, 14.2) in 2008/2009 and 3.9% (2.7, 5.2) in 2018/2019. Iron deficiency among PSC was 15.5% (12.1, 19.0) in 2008/2009 and 10.9% (7.4, 14.5) in 2016 (lowest), but 17.1 (13.3, 21.0) in 2017/2018 (highest). Iron deficiency among WRA was 14.9% (11.6, 18.2) in 2008/2009, 13.8% (11.8, 15.8) in 2013 (lowest), and 18.9% (16.3, 21.6) in 2017/2018 (highest). Wheat flour/bread consumption was positively associated with hemoglobin among PSC, and sugar consumption was positively associated with hemoglobin among WRA. The reported consumption of fortifiable foods was not associated with ferritin among PSC or WRA. Conclusions: Guatemala has implemented multiple food fortification strategies, and anemia has declined. Increases in iron deficiency in 2017-2019 warrant further attention. Secular trends toward poverty alleviation, education, and development might be responsible for changes not explained by the micronutrient interventions evaluated.

Comparison of Current World Health Organization Guidelines with Physiologically Based Serum Ferritin Thresholds for Iron Deficiency in Healthy Young Children and Nonpregnant Women Using Data from the Third National Health and Nutrition Examination Survey.

BACKGROUND: Current WHO serum ferritin (SF) thresholds for iron deficiency (ID) in children (<12 µg/L) and women (<15 µg/L) are derived from expert opinion based on radiometric assays in use decades ago. Using a contemporary immunoturbidimetry assay, higher thresholds (children, <20 µg/L; women, <25 µg/L) were identified from physiologically based analyses. OBJECTIVE: We examined relationships of SF measured using an immunoradiometric assay from the era of expert opinion with 2 independently measured indicators of ID, hemoglobin (Hb) and erythrocyte zinc protoporphyrin (eZnPP), using data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). The SF at which circulating Hb begins to decrease and eZnPP begins to increase provides a physiological basis for identifying the onset of iron-deficient erythropoiesis. METHODS: We analyzed NHANES III cross-sectional data from 2616 apparently healthy children, aged 12-59 mo, and 4639 apparently healthy nonpregnant women, aged 15-49 y. We used restricted cubic spline regression models to determine SF thresholds for ID. RESULTS: SF thresholds identified by Hb and eZnPP did not differ significantly in children, 21.2 µg/L (95% confidence interval: 18.5, 26.5) and 18.7 µg/L (17.9, 19.7), and, in women, were similar although significantly different, 24.8 µg/L (23.4, 26.9) and 22.5 µg/L (21.7, 23.3). CONCLUSIONS: These NHANES results suggest that physiologically based SF thresholds are higher than the thresholds from expert opinion established during the same era. SF thresholds found using physiological indicators detect the onset of iron-deficient erythropoiesis, whereas the WHO thresholds identify a later, more severe stage of ID.

Iron Deficiency in the United States: Limitations in Guidelines, Data, and Monitoring of Disparities.

Iron deficiency and the more severe sequela, iron deficiency anemia, are public health problems associated with morbidity and mortality, particularly among pregnant women and younger children. The 1998 Centers for Disease Control and Prevention recommendations for prevention and control of iron deficiency in the United States is old and does not reflect recent evidence but is a foundational reference for many federal, clinical, and program guidelines. Surveillance data for iron deficiency are sparse at all levels, with critical gaps for pregnant women and younger children. Anemia, iron deficiency, and iron deficiency anemia are often conflated but should not be. Clinical guidelines for anemia, iron deficiency, and iron deficiency anemia give inconsistent recommendations, causing nonsystematic assessment of iron deficiency. Screening for iron deficiency typically relies on identifying anemia, despite anemia's low sensitivity for iron deficiency. In the National Health and Nutrition Examination Survey, more than 70% of iron deficiency is missed among pregnant women and children by relying on hemoglobin for iron deficiency screening. To improve assessment and diagnosis and strengthen surveillance, better and more complete data and updated foundational guidance on iron deficiency and anemia are needed that consider new evidence for measuring and interpreting laboratory results. (Am J Public Health. 2022;112(S8):S826-S835. https://doi.org/10.2105/AJPH.2022.306998).

Physiologically based serum ferritin thresholds for iron deficiency in women of reproductive age who are blood donors.

Our objective is to develop a physiologically based method to determine serum ferritin thresholds for iron deficiency in healthy individuals. The current World Health Organization threshold of <15 µg/L for iron deficiency in women is based on expert opinion. We examined the relationship between serum ferritin and 2 independently measured indicators of iron-deficient erythropoiesis, soluble transferrin receptor (sTfR) and hemoglobin, in baseline data from 286 women, 20 to 49 years, who were first-time or reactivated donors in the Retrovirus Epidemiology Donor Study-II Donor Iron Status Evaluation (REDS-RISE) study. At lower serum ferritin concentrations, median sTfR increased as hemoglobin decreased. Using restricted cubic spline regression analysis to determine thresholds for iron-deficient erythropoiesis, the thresholds identified by sTfR (serum ferritin < 25.4 µg/L) and hemoglobin (serum ferritin < 25.3 µg/L) did not differ significantly. The thresholds found in the REDS-RISE study do not differ from those identified by sTfR (serum ferritin < 25.5 µg/L) and hemoglobin (serum ferritin < 26.6 µg/L) in a previous study of 5442 women, 20 to 49 years, in the US National Health and Nutrition Examination Survey 2003 to 2018 (P = .98 and 0.83, respectively). Although international comparisons are needed, these results with US data provide additional evidence for the potential usefulness of a physiologically based method to identify serum ferritin thresholds for iron deficiency.

Limits of Detection in Acute-Phase Protein Biomarkers Affect Inflammation Correction of Serum Ferritin for Quantifying Iron Status among School-Age and Preschool-Age Children and Reproductive-Age Women.

BACKGROUND: Standardized practices are needed in the analysis of inflammation biomarker values outside limits of detection (LODs) when used for inflammation correction of nutritional biomarkers. OBJECTIVE: We assessed the direction and extent to which serum C-reactive protein (CRP) and α-1-acid-glycoprotein (AGP) values outside LODs (<0.05 mg/L and >4.0 g/L, respectively) affect inflammation regression correction of serum ferritin and compared approaches to addressing such values when estimating inflammation-adjusted ferritin and iron deficiency (ID). METHODS: We examined 29 cross-sectional datasets from 7 countries with reproductive-age women (age 15-49 y) (n = 12,944), preschool-age children (age 6-59 mo) (n = 18,208), and school-age children (age 6-14 y) (n = 4625). For each dataset, we compared 6 analytic approaches for addressing CRP

Factors associated with anaemia in a nationally representative sample of nonpregnant women of reproductive age in Nepal.

We used cross-sectional data from the 2016 Nepal National Micronutrient Status Survey to evaluate factors associated with anaemia among a nationally representative sample of nonpregnant women 15- 49 years (n = 1, 918). Haemoglobin, biomarkers of iron status and other micronutrients, infection, inflammation, and blood disorders were assessed from venous blood. Soil-transmitted helminth and Helicobacter pylori infections were assessed from stool. Sociodemographic, household, and health characteristics and diet were ascertained by interview. We conducted bivariate analyses between candidate predictors and anaemia (haemoglobin <12.0 g/ dL, altitude- and smoking-adjusted). Candidate predictors that were significant in bivariate models (P < 0.05) were included in the multivariable logistic regression model, accounting for complex sampling design. Anaemia prevalence was 20.2% (95% confidence interval [CI] [17.6, 22.8]). Associated with reduced anaemia odds were living in the Mountain and Hill ecological zones relative to the Terai (adjusted odds ratio [AOR] 0.35, 95% CI [0.21, 0.60] and AOR 0.41, 95% CI [0.29, 0.59], respectively), recent cough (AOR 0.56, 95% CI [0.38, 0.82]), hormonal contraceptive use (AOR 0.58; 95% CI [0.38, 0.88]), ln ferritin (micrograms per litre; AOR 0.43, 95% CI [0.35, 0.54]), and ln retinol binding protein (micrograms per litre; AOR 0.20, 95% CI [0.11, 0.37]). Residing in a house with an earth floor (AOR 1.74, 95% CI [1.18, 2.56]), glucose-6- phosphate dehydrogenase deficiency (AOR 2.44, 95% CI [1.66, 3.60]), and haemoglobinopathies (AOR 6.15, 95% CI [3.09, 12.26]) were associated with increased anaemia odds. Interventions that improve micronutrient status, ensure access to hormonal birth control, and replace dirt floors to reduce infection risk might help reduce anaemia in this population.

Factors associated with anaemia among adolescent boys and girls 10-19 years old in Nepal.

We used data from the 2016 Nepal National Micronutrient Status Survey to evaluate factors associated with anaemia (World Health Organization cut-points using altitude- and smoking-adjusted haemoglobin [Hb]) among nationally representative samples of adolescents 10-19 years. Hb, biomarkers of micronutrients, infection and inflammation were assessed from venous blood. Sociodemographic and household characteristics, dietary diversity, pica and recent morbidity were ascertained by interview. We explored bivariate relationships between candidate predictors and anaemia among boys (N = 967) and girls (N = 1,680). Candidate predictors with P < 0.05 in bivariate analyses were included in sex-specific multivariable logistic regression models. Anaemia prevalence was 20.6% (95% confidence interval [CI] [17.1, 24.1]) among girls and 10.9% (95% CI [8.2, 13.6]) among boys. Among girls, living in the Mountain and Hill ecological zones relative to the Terai (adjusted odds ratio [AOR] 0.28, 95% CI [0.15, 0.52] and AOR 0.42, 95% CI [0.25, 0.73], respectively), ln ferritin (µg/L) (AOR 0.53, 95% CI [0.42, 0.68]) and ln retinol binding protein (RBP) (µmol/L) (AOR 0.08, 95% CI [0.04, 0.16]) were associated with reduced anaemia odds. Older age (age in years AOR 1.19, 95% CI [1.12, 1.27]) and Janajati ethnicity relative to the Muslim ethnicity (AOR 3.04, 95% CI [1.10, 8.36]) were associated with higher anaemia odds. Among boys, ln RBP [µmol/L] (AOR 0.25, 95% CI [0.10, 0.65]) and having consumed flesh foods (AOR 0.57, 95% CI [0.33, 0.99]) were associated with lower anaemia odds. Open defecation (AOR 2.36, 95% CI [1.15, 4.84]) and ln transferrin receptor [mg/L] (AOR 3.21, 95% CI [1.25, 8.23]) were associated with increased anaemia odds. Anaemia among adolescents might be addressed through effective public health policy and programs targeting micronutrient status, diet and sanitation.

A Qualitative Analysis of Program Fidelity and Perspectives of Educators and Parents after Two Years of the Girls' Iron-Folate Tablet Supplementation (GIFTS) Program in Ghanaian Secondary Schools.

BACKGROUND: To address the burden of anemia in adolescent girls in Ghana, the Girls' Iron-Folate Tablet Supplementation (GIFTS) program was established in 2017. An evaluation found that although iron and folic acid (IFA) supplementation reached nearly all adolescent girls in schools during year 1, most girls received fewer than the minimum effective number of tablets over the school year. Barrier analyses highlighted schools as drivers of adherence, though information was incomplete on the reasons for the disparities among schools. Information was also lacking on the implementation of health and nutrition education. OBJECTIVES: At the start of year 3 of an integrated adolescent anemia prevention program with IFA supplementation, the present study sought to illuminate differences in program fidelity among schools and across time and potential factors that drive such differences. METHODS: After stratifying by school level, size, geographic location, and intake adherence during year 1, 16 schools were purposively selected. For each school, semistructured key informant interviews were conducted with 1 coordinator at the district level, 3 educators at the school level, and 1 parent leader. Following thematic analysis methods, recorded and transcribed interviews were coded and organized into deductive and inductive themes. RESULTS: Limited training, challenges during distribution of IFA, lack of incentives, and inconsistent health and nutrition education diminished program fidelity. Strong supply chain, widespread awareness promotion, improved acceptability, and intrinsically motivated educators improved program fidelity. After 2 y of implementation, schools had made program adaptations, and widespread changes in attitudes and beliefs about the IFA tablets had improved their acceptability. However, limitations remained related to supply chain, program ownership, communication between health and education sectors, training, motivation, and resources. CONCLUSIONS: The fidelity of Ghana's GIFTS program is strengthened by its supply chain, acceptability, and motivated stakeholders; however, training, curricula, clear communication, and incentives could improve it.

Physiologically based serum ferritin thresholds for iron deficiency in children and non-pregnant women: a US National Health and Nutrition Examination Surveys (NHANES) serial cross-sectional study.

BACKGROUND: Serum ferritin concentrations are the most widely used indicator for iron deficiency. WHO determined that insufficient data are available to revise the serum ferritin thresholds of less than 12 µg/L for children and less than 15 µg/L for women, which were developed on the basis of expert opinion, to define iron deficiency. We aimed to derive new physiologically based serum ferritin concentration thresholds for iron deficiency in healthy young children and non-pregnant women using data from the US National Health and Nutrition Examination Survey (NHANES). METHODS: In this serial cross-sectional study, we examined the relationship of serum ferritin with two independent indicators of iron-deficient erythropoiesis, haemoglobin and soluble transferrin receptor (sTfR), in children (12-59 months) and non-pregnant women (15-49 years) using cross-sectional NHANES data from 2003-06, 2007-10, and 2015-18. NHANES is a US national stratified multistage probability sample that includes a household interview followed by a standardised physical examination in a mobile examination centre. We excluded individuals with missing serum ferritin, sTfR, haemoglobin, or white blood cell counts measurements; non-pregnant women with missing C-reactive protein (CRP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) data were also excluded. In addition, individuals with infection (white blood cell counts >10·0×109/L) and non-pregnant women with possible liver disease (ALT >70 IU/L or AST >70 IU/L) and inflammation (CRP >5·0 mg/L) were excluded. We examined distributions of haemoglobin and sTfR with serum ferritin and used restricted cubic spline regression models to determine serum ferritin thresholds for iron-deficient erythropoiesis. FINDINGS: 5964 children and 10 462 non-pregnant women had physical examinations and were screened for inclusion in the study, of whom 2569 (43·1%) children and 7498 (71·7%) non-pregnant women were included. At lower serum ferritin concentrations, median haemoglobin concentration decreased as sTfR concentration increased, with each varying in a curvilinear manner. Using restricted cubic spline plateau points to determine the onset of iron-deficient erythropoiesis, the serum ferritin thresholds identified by haemoglobin and sTfR concentrations were not different. For children, the haemoglobin identified serum ferritin threshold was 19·9 µg/L (95% CI 18·8-22·6) and the sTfR identified serum ferritin threshold was 20·0 µg/L (19·4-20·9; p=0·89). For women the haemoglobin identified serum ferritin threshold was 25·2 µg/L (24·2-26·2) and the sTfR identified serum ferritin threshold was 24·0 µg/L (23·3-24·6; p=0·05). INTERPRETATION: The association between two independent indicators of iron-deficient erythropoiesis, haemoglobin and sTfR, identified serum ferritin concentration thresholds of about 20 µg/L for children and 25 µg/L for non-pregnant women, providing physiological evidence of potential new thresholds for consideration when determining the prevalence and distribution of iron deficiency in populations. In healthy children and non-pregnant women, physiologically based thresholds for iron deficiency might be more clinically and epidemiologically relevant than those based on expert opinion. Validation of this physiologically based approach in non-US populations might help the international harmonisation of serum ferritin thresholds for iron deficiency. FUNDING: None.

A School-Based Weekly Iron and Folic Acid Supplementation Program Effectively Reduces Anemia in a Prospective Cohort of Ghanaian Adolescent Girls.

BACKGROUND: School-based iron and folic acid (IFA) supplementation is recommended for adolescent girls in countries with high burdens of anemia. OBJECTIVES: We aimed to evaluate the context-specific effectiveness of a school-based, integrated anemia control program with IFA supplementation in Ghana. METHODS: Using data from a pre-post, longitudinal program evaluation, we evaluated the effectiveness of school-based weekly IFA supplementation in reducing the burden of anemia and increasing hemoglobin concentrations (Hb; primary outcomes) in 2 regions of Ghana. Generalized linear mixed effects models with schools (clusters) as random effects were used to quantify the change in the anemia prevalence and the mean Hb associated with cumulative IFA tablet consumption over 1 school year (30-36 weeks), controlling for participant-level potential confounders. A cut point for minimum effective cumulative IFA consumption that is reflective of adequate Hb was derived following logistic regression. This cut point was verified by a restricted cubic spline model of IFA consumption and Hb. RESULTS: The analytical sample included 60 schools and 1387 girls ages 10-19 years. The prevalence of anemia declined during 1 school year of the intervention, from 25.1% to 19.6% (P = 0.001). Students consumed a mean of 16.4 IFA tablets (range, 0-36). IFA consumption was positively associated with Hb and negatively associated with anemia. Each additional IFA tablet consumed over the school year was associated with a 5% (95% CI, 1-10%) reduction in the adjusted odds of anemia at follow-up, though the relationship is nonlinear. The cut point for minimum effective consumption was 26.7 tablets over a 30-36-week school year, with tablets provided weekly. CONCLUSIONS: School-based weekly IFA supplementation is effective in improving Hb and reducing the anemia prevalence among schoolgirls in Ghana, though most participants consumed fewer than the minimum effective number of IFA tablets. Increasing intake adherence may further improve anemia outcomes in this population.

An Integrated Infant and Young Child Feeding and Micronutrient Powder Intervention Does Not Affect Anemia, Iron Status, or Vitamin A Status among Children Aged 12-23 Months in Eastern Uganda.

BACKGROUND: Micronutrient powders (MNP) can reduce iron deficiency and anemia in children. OBJECTIVE: We evaluated the impact of an integrated infant and young child feeding (IYCF)-MNP intervention on anemia and micronutrient status among children aged 12-23 mo in Eastern Uganda. The intervention focused on MNP distribution, IYCF education, and caregiver behavior change. METHODS: Population-based cross-sectional surveys representative of children aged 12-23 mo in Amuria (intervention) and Soroti (nonintervention) districts were collected in June/July 2015 at baseline (n = 1260) and 12 mo after implementation at endline in 2016 (n = 1490). From pooled capillary blood, we assessed hemoglobin, malaria, ferritin, retinol binding protein (RBP), C-reactive protein, and ɑ1-acid glycoprotein. Ferritin and RBP were regression-adjusted to correct for inflammation. Caregivers reported sociodemographic characteristics and MNP knowledge and practices. Linear regression estimated the difference-in-difference (DiD) effect of MNP on hemoglobin, ferritin, and RBP, and logistic regression estimated DiD effect of MNP on anemia (hemoglobin <11.0 g/dL), iron deficiency (ferritin <12.0 µg/L), iron deficiency anemia (hemoglobin <11.0 g/dL and ferritin <12.0 µg/L), and vitamin A deficiency (VAD; RBP equivalent to <0.70 µmol/L retinol: <0.79 µmol/L at baseline and RBP <0.67 µmol/L at endline). RESULTS: In Amuria, 96% of children had ever consumed MNP versus <1% of children in Soroti. Fifty-four percent of caregivers reported organoleptic changes when MNP were added to foods cooked with soda ash. Adjusting for age, sex, malaria, recent morbidity, and household-level factors, the intervention was associated with -0.83 g/dL lower hemoglobin (95% CI, -1.36, -0.30 g/dL; P = 0.003) but not with anemia, ferritin, iron deficiency, iron deficiency anemia, RBP, or VAD. CONCLUSIONS: Despite high program fidelity, the intervention was associated with reduced hemoglobin concentrations but not with change in anemia or micronutrient status among children aged 12-23 mo in Eastern Uganda. Contextual factors, such as cooking with soda ash, might explain the lack of effectiveness.

Changes in growth, anaemia, and iron deficiency among children aged 6-23 months in two districts in Nepal that were part of the post-pilot scale-up of an integrated infant and young child feeding and micronutrient powder intervention.

There is limited research on integrated infant and young child feeding (IYCF) and micronutrient powders (MNPs) programmes operating at scale, despite widespread implementation. This study uses cross-sectional baseline (n = 2,542) and endline (n = 2,578) surveys representative of children 6-23 months in two districts in Nepal that were part of a post-pilot scale-up of a IYCF-MNP programme. Multivariable log-binomial regression models were used to estimate prevalence ratios (PRs) for stunting (length-for-age z-score <-2), wasting (weight-for-length z-score <-2), underweight (weight-for-age z-score <-2), anaemia (altitude-adjusted haemoglobin <110 µg/L), moderate or severe anaemia (altitude-adjusted haemoglobin <100 g/L), iron deficiency (inflammation-adjusted ferritin <12 µg/L), and iron deficiency anaemia (iron deficiency + anaemia [IDA]) at endline versus baseline and also to compare children in the endline survey based on frequency of mothers' interactions with female community health volunteers (FCHVs; >1× per month or monthly vs. <1× per month) and MNP coverage (1 or ≥2 distributions vs. none among children 12-23 months). Endline children were significantly less likely to be stunted than baseline children in both districts (multivariable-adjusted PR [95% CI]: 0.77 [0.69, 0.85], P < 0.001 and 0.82 [0.75, 0.91], P < 0.001 in Kapilvastu and Achham, respectively); however, only Achham had significantly lower prevalences of underweight, moderate/severe anaemia, iron deficiency, and IDA at endline. At endline, 53.5% and 71.4% of children had tried MNP in Kapilvastu and Achham districts, respectively, consuming an average of 24 sachets from the last distribution. Frequent maternal-FCHV interactions were associated with a reduced risk of stunting and underweight at endline, whereas repeat MNP coverage was associated with reduced risk of anaemia and IDA. Future research using experimental designs should verify the potential of integrated IYCF-MNP programmes to improve children's nutritional status.

Point-of-use fortification of foods with micronutrient powders containing iron in children of preschool and school-age.

BACKGROUND: Approximately 600 million children of preschool and school age are anaemic worldwide. It is estimated that at least half of the cases are due to iron deficiency. Point-of-use fortification of foods with micronutrient powders (MNP) has been proposed as a feasible intervention to prevent and treat anaemia. It refers to the addition of iron alone or in combination with other vitamins and minerals in powder form, to energy-containing foods (excluding beverages) at home or in any other place where meals are to be consumed. MNPs can be added to foods either during or after cooking or immediately before consumption without the explicit purpose of improving the flavour or colour. OBJECTIVES: To assess the effects of point-of-use fortification of foods with iron-containing MNP alone, or in combination with other vitamins and minerals on nutrition, health and development among children at preschool (24 to 59 months) and school (five to 12 years) age, compared with no intervention, a placebo or iron-containing supplements. SEARCH METHODS: In December 2016, we searched the following databases: CENTRAL, MEDLINE, Embase, BIOSIS, Science Citation Index, Social Science Citation Index, CINAHL, LILACS, IBECS, Popline and SciELO. We also searched two trials registers in April 2017, and contacted relevant organisations to identify ongoing and unpublished trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs trials with either individual or cluster randomisation. Participants were children aged between 24 months and 12 years at the time of intervention. For trials with children outside this age range, we included studies where we were able to disaggregate the data for children aged 24 months to 12 years, or when more than half of the participants were within the requisite age range. We included trials with apparently healthy children; however, we included studies carried out in settings where anaemia and iron deficiency are prevalent, and thus participants may have had these conditions at baseline. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of trials against the inclusion criteria, extracted data from included trials, assessed the risk of bias of the included trials and graded the quality of the evidence. MAIN RESULTS: We included 13 studies involving 5810 participants from Latin America, Africa and Asia. We excluded 38 studies and identified six ongoing/unpublished trials. All trials compared the provision of MNP for point-of-use fortification with no intervention or placebo. No trials compared the effects of MNP versus iron-containing supplements (as drops, tablets or syrup).The sample sizes in the included trials ranged from 90 to 2193 participants. Six trials included participants younger than 59 months of age only, four included only children aged 60 months or older, and three trials included children both younger and older than 59 months of age.MNPs contained from two to 18 vitamins and minerals. The iron doses varied from 2.5 mg to 30 mg of elemental iron. Four trials reported giving 10 mg of elemental iron as sodium iron ethylenediaminetetraacetic acid (NaFeEDTA), chelated ferrous sulphate or microencapsulated ferrous fumarate. Three trials gave 12.5 mg of elemental iron as microencapsulated ferrous fumarate. Three trials gave 2.5 mg or 2.86 mg of elemental iron as NaFeEDTA. One trial gave 30 mg and one trial provided 14 mg of elemental iron as microencapsulated ferrous fumarate, while one trial gave 28 mg of iron as ferrous glycine phosphate.In comparison with receiving no intervention or a placebo, children receiving iron-containing MNP for point-of-use fortification of foods had lower risk of anaemia prevalence ratio (PR) 0.66, 95% confidence interval (CI) 0.49 to 0.88, 10 trials, 2448 children; moderate-quality evidence) and iron deficiency (PR 0.35, 95% CI 0.27 to 0.47, 5 trials, 1364 children; moderate-quality evidence) and had higher haemoglobin (mean difference (MD) 3.37 g/L, 95% CI 0.94 to 5.80, 11 trials, 2746 children; low-quality evidence).Only one trial with 115 children reported on all-cause mortality (zero cases; low-quality evidence). There was no effect on diarrhoea (risk ratio (RR) 0.97, 95% CI 0.53 to 1.78, 2 trials, 366 children; low-quality evidence). AUTHORS' CONCLUSIONS: Point-of-use fortification of foods with MNPs containing iron reduces anaemia and iron deficiency in preschool- and school-age children. However, information on mortality, morbidity, developmental outcomes and adverse effects is still scarce.

Development and use of the generic WHO/CDC logic model for vitamin and mineral interventions in public health programmes.

OBJECTIVE: Nutrition interventions are critical to achieve the Millennium Development Goals; among them, micronutrient interventions are considered cost-effective and programmatically feasible to scale up, but there are limited tools to communicate the programme components and their relationships. The WHO/CDC (Centers for Disease Control and Prevention) logic model for micronutrient interventions in public health programmes is a useful resource for planning, implementation, monitoring and evaluation of these interventions, which depicts the programme theory and expected relationships between inputs and expected Millennium Development Goals. DESIGN: The model was developed by applying principles of programme evaluation, public health nutrition theory and programmatic expertise. The multifaceted and iterative structure validation included feedback from potential users and adaptation by national stakeholders involved in public health programmes' design and implementation. RESULTS: In addition to the inputs, main activity domains identified as essential for programme development, implementation and performance include: (i) policy; (ii) products and supply; (iii) delivery systems; (iv) quality control; and (v) behaviour change communication. Outputs encompass the access to and coverage of interventions. Outcomes include knowledge and appropriate use of the intervention, as well as effects on micronutrient intake, nutritional status and health of target populations, for ultimate achievement of the Millennium Development Goals. CONCLUSIONS: The WHO/CDC logic model simplifies the process of developing a logic model by providing a tool that has identified high-priority areas and concepts that apply to virtually all public health micronutrient interventions. Countries can adapt it to their context in order to support programme design, implementation, monitoring and evaluation for the successful scale-up of nutrition interventions in public health.

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.

Intermittent iron supplementation for improving nutrition and development in children under 12 years of age.

BACKGROUND: Approximately 600 million children of preschool and school age are anaemic worldwide. It is estimated that half of the cases are due to iron deficiency. Consequences of iron deficiency anaemia during childhood include growth retardation, reduced school achievement, impaired motor and cognitive development, and increased morbidity and mortality. The provision of daily iron supplements is a widely used strategy for improving iron status in children but its effectiveness has been limited due to its side effects, which can include nausea, constipation or staining of the teeth. As a consequence, intermittent iron supplementation (one, two or three times a week on non-consecutive days) has been proposed as an effective and safer alternative to daily supplementation. OBJECTIVES: To assess the effects of intermittent iron supplementation, alone or in combination with other vitamins and minerals, on nutritional and developmental outcomes in children from birth to 12 years of age compared with a placebo, no intervention or daily supplementation. SEARCH METHODS: We searched the following databases on 24 May 2011: CENTRAL (2011, Issue 2), MEDLINE (1948 to May week 2, 2011), EMBASE (1980 to 2011 Week 20), CINAHL (1937 to current), POPLINE (all available years) and WHO International Clinical Trials Registry Platform (ICTRP). On 29 June 2011 we searched all available years in the following databases: SCIELO, LILACS, IBECS and IMBIOMED. We also contacted relevant organisations (on 3 July 2011) to identify ongoing and unpublished studies. SELECTION CRITERIA: Randomised and quasi-randomised trials with either individual or cluster randomisation. Participants were children under the age of 12 years at the time of intervention with no specific health problems. The intervention assessed was intermittent iron supplementation compared with a placebo, no intervention or daily supplementation. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies and assessed the risk of bias of the included studies. MAIN RESULTS: We included 33 trials, involving 13,114 children (˜49% females) from 20 countries in Latin America, Africa and Asia. The methodological quality of the trials was mixed.Nineteen trials evaluated intermittent iron supplementation versus no intervention or a placebo and 21 studies evaluated intermittent versus daily iron supplementation. Some of these trials contributed data to both comparisons. Iron alone was provided in most of the trials.Fifteen studies included children younger than 60 months; 11 trials included children 60 months and older, and seven studies included children in both age categories. One trial included exclusively females. Seven trials included only anaemic children; three studies assessed only non-anaemic children, and in the rest the baseline prevalence of anaemia ranged from 15% to 90%.In comparison with receiving no intervention or a placebo, children receiving iron supplements intermittently have a lower risk of anaemia (average risk ratio (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.72, ten studies) and iron deficiency (RR 0.24, 95% CI 0.06 to 0.91, three studies) and have higher haemoglobin (mean difference (MD) 5.20 g/L, 95% CI 2.51 to 7.88, 19 studies) and ferritin concentrations (MD 14.17 µg/L, 95% CI 3.53 to 24.81, five studies).Intermittent supplementation was as effective as daily supplementation in improving haemoglobin (MD -0.60 g/L, 95% CI -1.54 to 0.35, 19 studies) and ferritin concentrations (MD -4.19 µg/L, 95% CI -9.42 to 1.05, 10 studies), but increased the risk of anaemia in comparison with daily iron supplementation (RR 1.23, 95% CI 1.04 to1.47, six studies). Data on adherence were scarce and it tended to be higher among those children receiving intermittent supplementation, although this result was not statistically significant.We did not identify any differential effect of the type of intermittent supplementation regimen (one, two or three times a week), the total weekly dose of elemental iron, the nutrient composition, whether recipients were male or female or the length of the intervention. AUTHORS' CONCLUSIONS: Intermittent iron supplementation is efficacious to improve haemoglobin concentrations and reduce the risk of having anaemia or iron deficiency in children younger than 12 years of age when compared with a placebo or no intervention, but it is less effective than daily supplementation to prevent or control anaemia. Intermittent supplementation may be a viable public health intervention in settings where daily supplementation has failed or has not been implemented. Information on mortality, morbidity, developmental outcomes and side effects, however, is still lacking.