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BACKGROUND: Global guidelines recommend untargeted iron supplementation for women in regions of anemia prevalence ≥40%, such as Cambodia. However, the potential harms of untargeted iron on the gut have not been rigorously studied in women and likely vary depending on iron dose and form. OBJECTIVES: We investigated if a lower dose of a highly bioavailable iron amino acid chelate was as effective as the standard dose of iron salts in increasing ferritin concentrations and whether any differences were observed in gut inflammation or enteropathogen detection. METHODS: A double-blind, randomized placebo-controlled noninferiority trial was conducted in Cambodia. Nonpregnant women (n = 480, 18-45 y) were randomly assigned to 60-mg ferrous sulfate, 18-mg ferrous bisglycinate, or placebo for 12 wk. Nonfasting blood and stool specimens were collected at baseline and 12 wk. Ferritin and fecal calprotectin were measured with an ELISA. A molecular assay was used to detect 11 enteropathogens in a random subset of n = 100 women. Generalized linear mixed-effects models were used to estimate the adjusted mean difference in ferritin concentrations at 12 wk (primary outcome), as compared with our 'a priori' noninferiority margin of 20 µg/L. RESULTS: Baseline anemia and iron deficiency prevalence was low (17% and 6%, respectively). The adjusted mean difference in ferritin concentrations between the iron groups was 14.6 (95% confidence interval [CI]: 7.6, 21.6) µg/L. Mean ferritin concentration at 12 wk was higher in the ferrous sulfate (99 [95% CI: 95, 103] µg/L, P < 0.001) than in ferrous bisglycinate (84 [95% CI: 80, 88] µg/L) and placebo groups (78 [95% CI: 74, 82] µg/L). No differences in fecal calprotectin concentrations or enteropathogen detection were observed across groups at 12 wk. CONCLUSIONS: Ferrous bisglycinate (18-mg) was not as effective as ferrous sulfate (60-mg) in increasing ferritin concentrations and did not differentially influence biomarkers of gut health in this predominantly iron-replete population of Cambodian women. This trial was registered at clinicaltrials.gov registry as NCT04017598.
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Anemia Ferropénica , Anemia , Humanos , Femenino , Hierro , Cambodia/epidemiología , Compuestos Ferrosos , Ferritinas , Anemia/epidemiología , Inflamación/tratamiento farmacológico , Hemoglobinas/metabolismo , Suplementos DietéticosRESUMEN
BACKGROUND: Riboflavin is required for erythropoiesis, which is increased in people with hemoglobinopathies due to increased hemolysis and erythrocyte turnover. Dietary intake and status of riboflavin is poor in Cambodia, where hemoglobinopathies are common. OBJECTIVE: We assessed the association between genetic hemoglobin disorders and riboflavin status in women of reproductive age in Cambodia. METHODS: Venous blood samples from 515 Cambodian women of reproductive age, 18-45 y, were analyzed for biomarker status of riboflavin [erythrocyte glutathione reductase activation coefficient (EGRac)], genetic hemoglobin (Hb) disorders, and hematological indices. Linear regression analysis was used to estimate the association between EGRac with Hb, ferritin, and Hb genotypes. EGRac was log transformed in the analyses, and the regression coefficients represent the geometric mean differences. RESULTS: Genetic Hb disorders were present in 57% of the population, with the homozygous hemoglobin E variant (Hb EE) occurring in â¼10% of women (n = 53). Deficient (EGRac ≥1.40) or marginal riboflavin status (EGRac ≥1.30 and <1.40) was observed in 92% (n = 475) of women. The variant Hb EE genotype was associated with 18% (95% CI: 9%, 28%) higher geometric mean EGRac values than the normal Hb AA genotype (P < 0.001). CONCLUSIONS: Although riboflavin biomarker deficiency or marginal status is widely prevalent in Cambodian women, lower riboflavin status was observed more frequently in women with the Hb EE genotype than in women with normal Hb AA. The relation between genetic Hb disorders and riboflavin warrants further investigation. This trial was registered at clinicaltrials.gov as NCT01593423 and NCT02481375.
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Variación Genética , Hemoglobinas/genética , Estado Nutricional , Riboflavina/sangre , Adulto , Cambodia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Deficiencia de Riboflavina/epidemiología , Deficiencia de Riboflavina/genética , Adulto JovenRESUMEN
Objectives This is the protocol for a Campbell systematic review. The objectives are as follows: The aim of this systematic review is to examine the scientific evidence available from low- and middle-income countries on the association of breakfast consumption habits and anthropometry/adiposity- and nutrition-related outcomes in adolescents aged 10-19 years old.
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CONTEXT: Iron deficiency and anemia have serious consequences, especially for children and pregnant women. Iron salts are commonly provided as oral supplements to prevent and treat iron deficiency, despite poor bioavailability and frequently reported adverse side effects. Ferrous bisglycinate is a novel amino acid iron chelate that is thought to be more bioavailable and associated with fewer gastrointestinal (GI) adverse events as compared with iron salts. OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the effects of ferrous bisglycinate supplementation compared with other iron supplements on hemoglobin and ferritin concentrations and GI adverse events. DATA SOURCES: A systematic search of electronic databases and grey literature was performed up to July 17, 2020, yielding 17 RCTs that reported hemoglobin or ferritin concentrations following at least 4 weeks' supplementation of ferrous bisglycinate compared with other iron supplements in any dose or frequency. DATA EXTRACTION: Random-effects meta-analyses were conducted among trials of pregnant women (n = 9) and children (n = 4); pooled estimates were expressed as standardized mean differences (SMDs). Incidence rate ratios (IRRs) were estimated for GI adverse events, using Poisson generalized linear mixed-effects models. The remaining trials in other populations (n = 4; men and nonpregnant women) were qualitatively evaluated. DATA ANALYSIS: Compared with other iron supplements, supplementation with ferrous bisglycinate for 4-20 weeks resulted in higher hemoglobin concentrations in pregnant women (SMD, 0.54 g/dL; 95% confidence interval [CI], 0.15-0.94; P < 0.01) and fewer reported GI adverse events (IRR, 0.36; 95%CI, 0.17-0.76; P < 0.01). We observed a non-significant trend for higher ferritin concentrations in pregnant women supplemented with ferrous bisglycinate. No significant differences in hemoglobin or ferritin concentrations were detected among children. CONCLUSION: Ferrous bisglycinate shows some benefit over other iron supplements in increasing hemoglobin concentration and reducing GI adverse events among pregnant women. More trials are needed to assess the efficacy of ferrous bisglycinate against other iron supplements in other populations. PROSPERO REGISTRATION NO: CRD42020196984.
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Anemia Ferropénica , Suplementos Dietéticos , Deficiencias de Hierro , Hierro , Adulto , Niño , Femenino , Humanos , Masculino , Embarazo , Anemia Ferropénica/tratamiento farmacológico , Suplementos Dietéticos/efectos adversos , Ferritinas/sangre , Ferritinas/efectos de los fármacos , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Hemoglobinas/uso terapéutico , Hierro/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Sales (Química)/metabolismo , Sales (Química)/uso terapéutico , Compuestos FerrososRESUMEN
The World Health Organization recommends untargeted iron supplementation for women of reproductive age (WRA) in countries where anemia prevalence is greater than 40%, such as Cambodia. Iron supplements, however, often have poor bioavailability, so the majority remains unabsorbed in the colon. The gut houses many iron-dependent bacterial enteropathogens; thus, providing iron to individuals may be more harmful than helpful. We examined the effects of two oral iron supplements with differing bioavailability on the gut microbiomes in Cambodian WRA. This study is a secondary analysis of a double-blind, randomized controlled trial of oral iron supplementation in Cambodian WRA. For 12 weeks, participants received ferrous sulfate, ferrous bisglycinate, or placebo. Participants provided stool samples at baseline and 12 weeks. A subset of stool samples (n = 172), representing the three groups, were randomly selected for gut microbial analysis by 16S rRNA gene sequencing and targeted real-time PCR (qPCR). At baseline, 1% of women had iron-deficiency anemia. The most abundant gut phyla were Bacteroidota (45.7%) and Firmicutes (42.1%). Iron supplementation did not alter gut microbial diversity. Ferrous bisglycinate increased the relative abundance of Enterobacteriaceae, and there was a trend towards an increase in the relative abundance of Escherichia-Shigella. qPCR detected an increase in the enteropathogenic Escherichia coli (EPEC) virulence gene, bfpA, in the group that received ferrous sulfate. Thus, iron supplementation did not affect overall gut bacterial diversity in predominantly iron-replete Cambodian WRA, however, evidence does suggest an increase in relative abundance within the broad family Enterobacteriaceae associated with ferrous bisglycinate use. IMPORTANCE To the best of our knowledge, this is the first published study to characterize the effects of oral iron supplementation on the gut microbiomes of Cambodian WRA. Our study found that iron supplementation with ferrous bisglycinate increases the relative abundance of Enterobacteriaceae, which is a family of bacteria that includes many Gram-negative enteric pathogens like Salmonella, Shigella, and Escherichia coli. Using qPCR for additional analysis, we were able to detect genes associated with enteropathogenic E. coli, a type of diarrheagenic E. coli known to be present around the world, including water systems in Cambodia. The current WHO guidelines recommend blanket (untargeted) iron supplementation for Cambodian WRA despite a lack of studies in this population examining iron's effect on the gut microbiome. This study can facilitate future research that may inform evidence-based global practice and policy.
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Microbioma Gastrointestinal , Hierro , Humanos , Femenino , Hierro/farmacología , Cambodia , Escherichia coli/genética , ARN Ribosómico 16S/genética , Suplementos Dietéticos , Bacterias/genéticaRESUMEN
In adolescents, iron-deficiency anemia is the leading cause of disability-adjusted life years lost. The World Health Organization recommends delivering iron supplementation through school-based platforms, requiring partnerships with the education sector. This anemia-reduction intervention is valued for the perceived benefits of improved learning and school performance. This article aims to systematically review the available evidence on the relationship between iron status and anemia and impacts of iron interventions on cognitive and academic performance in adolescents. Fifty studies were included: n = 26 cross-sectional and n = 24 iron-containing interventions. Our review suggests that iron status and anemia may be associated with academic performance in some contexts and that iron supplementation during adolescence may improve school performance, attention, and concentration. However, nearly all supplementation trials were judged to have moderate or high risk of bias. We did not find evidence suggesting that iron status and anemia influenced or were associated with attention, intelligence, nor memory in adolescents. Further, iron supplementation did not improve memory and recall or intelligence. Overall, more high-quality research is needed to guide programmers and policy makers to understand the relationships between anemia and educational performance and the potential impacts of iron interventions, which effectively reduce anemia, on adolescents' learning and school performance.
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Rendimiento Académico , Anemia Ferropénica/psicología , Cognición , Hierro/sangre , Estado Nutricional , Adolescente , Anemia Ferropénica/terapia , Estudios Transversales , Suplementos Dietéticos , Años de Vida Ajustados por Discapacidad , Femenino , Humanos , Hierro/administración & dosificación , MasculinoRESUMEN
The human microbiome has received significant attention over the past decade regarding its potential impact on health. Epidemiological and intervention studies often rely on at-home stool collection methods designed for high-resource settings, such as access to an improved toilet with a modern toilet seat. However, this is not always appropriate or applicable to low-resource settings. Therefore, the design of a user-friendly stool collection kit for low-resource rural settings is needed. We describe the development, assembly, and user experience of a simple and low-cost at-home stool collection kit for women living in rural Cambodia as part of a randomized controlled trial in 2020. Participants were provided with the stool collection kit and detailed verbal instruction. Enrolled women (n = 480) provided two stool specimens (at the start of the trial and after 12 weeks) at their home and brought them to the health centre that morning in a sterile collection container. User specimen collection compliance was high, with 90% (n = 434) of women providing a stool specimen at the end of the trial (after 12 weeks). This feasible and straightforward method has strong potential for similar or adapted use among adults residing in other rural or low-resource contexts.
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Microbiota , Adulto , Cambodia , Estudios de Factibilidad , Heces , Femenino , Humanos , Manejo de EspecímenesRESUMEN
Oral contraceptive use has been associated with decreased menstrual blood losses; thus, can independently reduce the risk of anemia and iron deficiency in women. Manufacturers have recently started to include supplemental iron in the non-hormonal placebo tablets of some contraceptives. The aims of this narrative review are: (i) to describe the relationship between oral contraceptive use and both anemia and iron status in women; (ii) to describe the current formulations of iron-containing oral contraceptives (ICOC) available on the market; and (iii) to systematically review the existing literature on the effect of ICOC on biomarkers of anemia and iron status in women. We discovered 21 brands of ICOC, most commonly including 25 mg elemental iron as ferrous fumarate, for seven days, per monthly tablet package. Our search identified one randomized trial evaluating the effectiveness of ICOC use compared to two non-ICOC on increasing hemoglobin (Hb) and iron status biomarker concentrations in women; whereafter 12 months of contraception use, there were no significant differences in Hb concentration nor markers of iron status between the groups. ICOC has the potential to be a cost-effective solution to address both family planning needs and iron deficiency anemia. Yet, more rigorous trials evaluating the effectiveness of ICOC on improving markers of anemia and iron deficiency, as well as investigating the safety of its consumption among iron-replete populations, are warranted.
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Anticonceptivos Orales/química , Compuestos Ferrosos/sangre , Hemoglobinas/efectos de los fármacos , Hierro/administración & dosificación , Adulto , Anemia Ferropénica/sangre , Anemia Ferropénica/tratamiento farmacológico , Biomarcadores/sangre , Anticonceptivos Orales/administración & dosificación , Servicios de Planificación Familiar/métodos , Femenino , Humanos , Hierro/análisisRESUMEN
Genetic hemoglobinopathies are the most common single-gene disorder worldwide. Some automated hematology analyzers have the capability of flagging individuals who may have hematological disorders based on complete blood count (CBC) biomarkers. We aimed to evaluate the accuracy of a hematology analyzer in identifying genetic hemoglobinopathies in Cambodian women and to determine which hematological biomarkers are the best predictors. A CBC was completed using a Sysmex XN-1000 analyzer and hemoglobinopathies were determined with capillary hemoglobin electrophoresis for 808 nonpregnant Cambodian women. Sysmex XN-1000 Interpretive Program (IP) messages, which flag potential hematological disorders, were produced from CBC results. Then, 2 × 2 tables were used to determine sensitivity and specificity of the IP message "Hemoglobin defect" to detect a genetic hemoglobinopathy. Receiver operating characteristic (ROC) analyses assessed the diagnostic ability of six CBC biomarkers to predict a genetic hemoglobinopathy. In total, 74% of women had a hemoglobinopathy (predominantly Hb E and α-thalassemia). "Hb defect" IP message sensitivity and specificity for genetic hemoglobinopathy detection were 10.4% and 98.6%, respectively. Variable selection strategies yielded a two-variable model including mean corpuscular volume (MCV) and red blood cell (RBC) count (AIC = 99.83, AUCROC = 0.98 (95% CI: 0.97, 0.99)) for the prediction of a homozygous EE disorder. Sensitivity and specificity values do not justify the use of Sysmex XN-1000 IP flag messages for identification of genetic hemoglobinopathies in Cambodian women. Development of an algorithm based on MCV and RBC biomarkers may optimize the screening ability of automated hematology analyzers.
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BACKGROUND: Regression to the mean (RTM) is a statistical phenomenon where second measurements are more likely to be closer to the mean. This is particularly observed in those with baseline values further from the mean. Anemic individuals (hemoglobin <120 g/L) are often recruited when evaluating iron supplementation programs, as they are more likely to elicit a greater hemoglobin response; however, they are also at greater risk for RTM as their baseline values are lower than the overall population mean. OBJECTIVE: The aim was to calculate and apply RTM to a previously conducted iron supplementation trial of women in Cambodia at increasingly severe baseline anemia cutoffs (hemoglobin <120 g/L, <115 g/L, and <110 g/L). METHODS: Women received either 60 mg/d iron (n = 191) or placebo (n = 185) for 12 wk. Hemoglobin was measured at baseline and at 12 wk (endline), and change in hemoglobin was calculated in each group for each cutoff. RTM was calculated in the placebo group at each cutoff and applied to the change observed at each cutoff in the iron group to obtain the RTM-free effect. RESULTS: In the placebo group, mean change in hemoglobin increased as cutoffs became more extreme (0.9 g/L to 1.9 g/L in those with baseline hemoglobin <120 g/L and <110 g/L, respectively). RTM estimates similarly increased: 1.0 g/L (<120 g/L), 1.3 g/L (<115 g/L), and 1.8 g/L (<110g/L). When applying RTM to the iron group, we found that â¼10% of the "treatment effect" could be attributable to RTM at each cutoff. However, iron supplementation was still effective in increasing hemoglobin, with an increased effect in those with lower baseline values, as proven by the RTM-free effect at each cutoff: 8.7 g/L (<120 g/L), 10.9 g/L (<115 g/L), and 13.6g/L (<110 g/L). CONCLUSIONS: RTM may have accounted for â¼10% of the observed change in hemoglobin following iron supplementation; however, appropriate use of a placebo group in the statistical analyses of the trial controls for this potential RTM effect.
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INTRODUCTION: The WHO recommends daily oral iron supplementation for 12 weeks in women and adolescents where anaemia prevalence is greater than 40%. However, if iron deficiency is not a major cause of anaemia, then, at best, untargeted iron supplementation is a waste of resources; at worst, it could cause harm. Further, different forms of iron with varying bioavailability may present greater risks of harm. METHODS AND ANALYSIS: A 12-week three-arm, double-blind, randomised controlled supplementation trial was conducted in Cambodia to determine if there is potential harm associated with untargeted iron supplementation. We will recruit and randomise 480 non-pregnant women (ages 18-45 years) to receive one of three interventions: 60 mg elemental iron as ferrous sulfate (the standard, commonly used form), 18 mg ferrous bisglycinate (a highly bioavailable iron amino acid chelate) or placebo. We will measure ferritin concentrations (to evaluate non-inferiority between the two forms of iron), as well as markers of potential harm in blood and stool (faecal calprotectin, gut pathogen abundance and DNA damage) at baseline and 12 weeks. Mixed-effects generalised linear models will be used to assess the effect of iron on ferritin concentration and markers of potential harm at 12 weeks. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of British Columbia Clinical Research Ethics Board (H18-02610), the Children's and Women's Health Centre of British Columbia Research Ethics Board (H18-02610) and the National Ethics Committee for Health Research in Cambodia (273-NECHR). Findings will be published in peer-reviewed journals, presented to stakeholders and policymakers globally and shared within participants' communities. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04017598).