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.

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. 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. 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. 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. 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. 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. CRD42020196984.

Iron supplementation and fortification are used to treat iron deficiency, which is often associated with gastrointestinal conditions, such as inflammatory bowel disease and colorectal cancer. Within the gut, commensal bacteria contribute to maintaining systemic iron homeostasis. Disturbances that lead to excess iron promote the replication and virulence of enteric pathogens. Consequently, research has been interested in better understanding the effects of iron supplementation and fortification on gut bacterial composition and overall gut health. While animal and human trials have shown seemingly conflicting results, these studies emphasize how numerous factors influence gut microbial composition. Understanding how different iron formulations and doses impact specific bacteria will improve the outcomes of iron supplementation and fortification in humans. Furthermore, discerning the nuances of iron supplementation and fortification will benefit subpopulations that currently do not respond well to treatment.

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. 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). 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. 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 ∼10% 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). RTM may have accounted for ∼10% 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.

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.

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).