Trial Of Iron Supplementation Research Articles

Safety and efficacy of iron supplementation with 3 months of daily ferrous sulphate in children living with HIV and mild-to-moderate anaemia in Uganda: a double-blind, randomised, placebo-controlled trial

Iron deficiency is the most common nutritional deficiency in the world, but iron supplementation can increase risk of opportunistic infections, especially in children living with HIV. We aimed to assess the effect of supplemental iron on haemoglobin concentration in children living with HIV and mild-to-moderate anaemia in Uganda. We did a double-blind, randomised, placebo-controlled trial of iron supplementation in children aged 6 months to 12 years living with HIV at two sites (ie, Kampala and Fort Portal, Uganda). Inclusion criteria were confirmed diagnosis of HIV and stable treatment with antiretroviral therapy for at least 6 months. Exclusion criteria were already taking iron supplementation, acute illness, current opportunistic infection, fever, known sickle cell disease, severe undernutrition, or any chronic illness requiring medical attention. Children were randomly assigned (1:1) via simple randomisation to an 84-day course of either ferrous sulphate or identical placebo tablets once per day. Randomisation codes were computer-generated and stratified by age (ie, 6-23 months or 24 months and older) by the Toronto Institute of Pharmaceutical Technology, the tablet manufacturer. Participants and all individuals giving the interventions, assessing outcomes, and analysing data were masked to group assignment. Children aged 6-23 months received tablets of 12·5 mg ferrous sulphate or identical placebo; children aged 24 months or older received tablets of 30·0 mg ferrous sulphate or identical placebo. Caregivers were instructed to give the supplement after a meal, preferably after an evening meal. The primary outcome was mean haemoglobin concentration at day 84. All analyses were intention to treat. This trial is registered at ClinicalTrials.gov (NCT03596996). Between May 5, 2018, and Nov 6, 2019, 973 children living with HIV were screened, of whom 200 (20%) met all inclusion criteria and were enrolled. 102 (51%) were randomly assigned to receive iron and 98 (49%) to receive placebo. In the iron group, 57 (56%) of 102 children were male and 45 (44%) were female. In the placebo group, 44 (45%) of 98 children were male and 54 (55%) were female. Iron supplementation was associated with improvement in haemoglobin in unadjusted analysis (p=0·029), but not adjusted analysis (p=0·10), and with improvement in ferritin and hepcidin in both adjusted (p=0·0046; p=0·0079) and unadjusted (p<0·0001; p<0·0001) analyses at day 84. There were four hospital admissions, all for children in the iron group; none were fatal: two children were admitted to hospital with pneumonia, one with severe malaria, and one with hepatitis. Frequency of admissions was not significantly different between groups (p=0·12). Iron could have haematological benefit and improve iron status in children living with HIV in Uganda. Future studies powered for morbidity outcomes with longer follow-up are needed, as are those that evaluate the effects of iron supplementation on neurocognitive outcomes. Minnesota Masonic Charities, the Department of Pediatrics at the University of Minnesota, the Hennepin Healthcare Research Institute, and the US National Institutes of Health.

Intravenous iron infusions in pediatric patients: A retrospective review of efficacy and safety.

Pediatric iron deficiency anemia (IDA) is often treated with oral iron supplementation as the first-line therapy despite poor adherence. This single-institution retrospective chart review of pediatric patients was conducted to assess the safety, efficacy, and adherence of intravenous (IV) iron infusions compared to oral iron therapy in patients who had failed a trial of oral iron supplementation. We reviewed medical records of patients aged 1-21 with IDA who received at least one IV iron infusion at Cooper University Hospital between 2016 and 2021. Paired t-tests compared pre-infusion and post-infusion hematologic indices of hemoglobin (Hgb), mean corpuscular volume, red blood cell count, red cell distribution width, ferritin, total iron binding capacity, iron stores, and iron saturation. We compared adherence and adverse reactions to both oral iron supplementation and IV iron infusions using McNemar's test. A total of 107 subjects were included (mean age of 12.7 years). Hgb, ferritin, iron, and iron saturation between pre-infusion and post-final infusion significantly improved (p < 0.001). Hgb, ferritin, and iron improved when subcategorizing by race and etiology of IDA. Adherence to IV iron infusions (70.1%) was significantly greater than adherence to oral iron therapy (43.0%). There were also significantly fewer adverse effects with IV iron infusions (3.7%) compared to oral iron (77.9%). We demonstrated the safety, efficacy, and improved adherence of IV iron infusions compared to oral iron supplementation for treatment of pediatric IDA in patients who were unable to tolerate oral iron supplementation. Future studies could compare adherence to multiple doses of IV iron infusions in contrast with other single-dosing IV iron formulations.

A Randomized Trial of Intravenous Iron Supplementation and Exercise on Exercise Capacity in Iron-Deficient Nonanemic Patients With CKD

Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Among 75 randomized patients, mean (SD) age for iron therapy (n= 37) versus placebo (n= 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) μg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P< 0.02), and Hb at 12 weeks (P= 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

Markers of Iron Metabolism and Outcomes in Patients with Heart Failure: A Systematic Review

Iron deficiency (ID) in conjunction with heart failure (HF) poses a challenge for clinicians and is associated with worse HF outcomes. Treatment of ID with IV iron supplementation for patients with HF has demonstrated benefits in quality of life (QoL) and HF-related hospitalizations. The aim of this systematic review was to summarize the evidence linking iron metabolism biomarkers with outcomes in patients with HF to assist in the optimal use of these biomarkers for patient selection. A systematic review of observational studies in English from 2010 to 2022 was conducted using PubMed, with keywords of "Heart Failure" and respective iron metabolism biomarkers ("Ferritin", "Hepcidin", "TSAT", "Serum Iron", and "Soluble Transferrin Receptor"). Studies pertaining to HF patients, with available quantitative data on serum iron metabolism biomarkers, and report of specific outcomes (mortality, hospitalization rates, functional capacity, QoL, and cardiovascular events) were included, irrespective of left ventricular ejection fraction (LVEF) or other HF characteristics. Clinical trials of iron supplementation and anemia treatment were removed. This systematic review was conducive to formal assessment of risk of bias via Newcastle-Ottawa Scale. Results were synthesized based on their respective adverse outcomes and iron metabolism biomarker(s). Initial and updated searches identified 508 unique titles once duplicates were removed. The final analysis included 26 studies: 58% focused on reduced LVEF; age range was 53-79 years; males composed 41-100% of the reported population. Statistically significant associations of ID were observed with all-cause mortality, HF hospitalization rates, functional capacity, and QoL. Increased risk for cerebrovascular events and acute renal injury have also been reported, but these findings were not consistent. Varying definitions of ID were utilized among the studies; however, most studies employed the current European Society of Cardiology criteria: serum ferritin < 100 ng/mL or the combination of ferritin between 100-299 ng/mL and transferrin saturation (TSAT) < 20%. Despite several iron metabolism biomarkers demonstrating strong association with several outcomes, TSAT better predicted all-cause mortality, as well as long-term risk for HF hospitalizations. Low ferritin was associated with short-term risk for HF hospitalizations, worsening functional capacity, poor QoL, and development of acute renal injury in acute HF. Elevated soluble transferrin receptor (sTfR) levels were associated with worse functional capacity and QoL. Finally, low serum iron was significantly associated with increased risk for cardiovascular events. Considering the lack of consistency among the iron metabolism biomarkers for association with adverse outcomes, it is important to incorporate additional biomarker data, beyond ferritin and TSAT, when assessing for ID in HF patients. These inconsistent associations question how best to define ID to ensure proper treatment. Further research, potentially tailored to specific HF phenotypes, is required to optimize patient selection for iron supplementation therapy and appropriate targets for iron stores replenishment.

Dosing of iron supplementation for iron-deficient patients with heart failure: should we prefer more intensive or less intensive repletion targets?

Dosing of iron supplementation for iron-deficient patients with heart failure: should we prefer more intensive or less intensive repletion targets?

Iron-deficiency anaemia in calves and lambs

While iron-deficiency anaemia is well recognised in piglets, the importance of its diagnosis and treatment in calves and lambs has been highlighted more recently. In particular, housed lambs and calves fed on whole milk are prone to subclinical iron deficiency anaemia, with surveys showing prevalence figures from 20% to more than 50%. Many studies show reduced daily liveweight gain as a main clinical sign in both species; some also show health issues such as increased risk of pneumonia and diarrhoea in calves and an increase in abomasal bloat risk in lambs. Iron supplementation trials consistently led to higher growth rates pre-weaning and to improved haematological values. In the UK, there are no injectable iron preparations licensed for calves or lambs, but preparations licensed for pigs can be used off label.

Iron Supplementation May Selectively Reprofile the Gut Microbiome in Iron-Deficient Bangladeshi Infants

Children in low- and middle-income countries (LMICs) have a high burden of anemia, much of which is attributable to iron deficiency. The World Health Organization (WHO) recommends universal iron interventions in preschool-aged children in countries where there is a high anemia prevalence. However, oral iron supplementation is associated with increased risks of infection, including diarrhea. In small studies in Africa, iron has been shown to reprofile the intestinal microbiota leading to a reduction in commensal bacteria and an increase in pathogenic taxa. Gut dysbiosis has been implicated in the pathogenesis of gastrointestinal, autoimmune and inflammatory disease. The BRISC (Benefits and Risks of Iron Interventions in Children) trial was a double-blind, placebo-controlled randomized controlled trial of oral iron supplementation in 3,300 infants in Bangladesh. Children were randomized to receive one of iron syrup, iron-containing multiple micronutrient powder (MNP) or placebo daily for three months. The primary outcome of the trial was child cognitive development. Key findings from the trial were an improvement in hematological indices with iron but no effect on the functional outcomes assessed (Pasricha et al New Engl J Med 2021). We aimed to study the effect of iron on microbiome composition, diversity and function in the BRISC participants. To achieve this aim we undertook a substudy in which we collected stool samples from 925 children at the three time points of the main BRISC trial: at recruitment, end of intervention and at nine-month follow up. DNA was extracted and analyzed by 16S ribosomal RNA gene (rRNA) amplicon sequencing (2,339 samples across three timepoints) and shotgun metagenomics (965 samples across three timepoints). Episodes of infection were documented as per the main BRISC trial and included diarrhea, respiratory symptoms, antibiotic use, and clinic/hospital visits. The V4 hypervariable region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq instrument together with negative and positive controls. Demultiplexed forward and reverse FASTQ files for each sample were trimmed and processed using the DADA2 package in RStudio, and taxonomy was assigned using the SILVA 138 SSU Ref NR 99 reference database. Control samples and samples with fewer than 500 reads were removed (2,284 samples met this minimum read threshold). Taxonomic, alpha diversity and beta diversity measures were conducted using phyloseq and microbiomeSeq packages in RStudio. Differential abundance was calculated by two separate methods: i. limma voom (using trimmed mean of M values [TMM] normalization and log transformation) and ii. ANCOM-BC (using additive log-ratio transformation). Prior to implementing differential abundance methods a filter was applied such that operational taxonomic units (OTUs) found in under 10% of samples were pruned from the samples. As previously reported, there was no overall significant increase in diarrhea incidence among participants receiving iron compared to those given placebo among BRISC trial participants. Baseline iron deficiency, anemia and iron deficiency anemia prevalence among substudy participants was 33%, 42% and 26% respectively. 16S rRNA analysis demonstrated that recent antibiotic (12% of children at end of intervention) was associated with a significant reduction in alpha diversity. Accordingly, analysis was conducted to exclude recent antibiotic use from analysis by intervention arm. Using this analysis, there were no significant differences in alpha or beta diversity between trial intervention groups at the end of intervention (alpha diversity by Shannon index shown in Figure 1). Members of Ruminococcus torques group (limma voom and ANCOM-BC) and Leuconostoc (limma voom only) were more abundant in the intestinal microbiota of children randomized to iron, but no genus was found to be differentially abundant when controlling for multiple comparisons. However, several bacterial genera were differentially abundant in children who were iron deficient at baseline who received iron. Two forms of analyses (Limma voom and ANCOM-BC) showed agreement in finding a reduction in Sutterella and Lactococcus species in iron deficient children receiving iron. These results are shown in Table 1. These data indicate that reprofiling of the intestinal microbiota in response to iron supplementation is dependent on baseline host iron status. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of Hydraulic Retention Time of Aquaculture Effluent on Nutrient Film Technique Lettuce Productivity

Nutrient film technique (NFT) is a popular, ergonomic, hydroponic system, but is not often used in commercial aquaponic systems due to lower efficiency in overall nutrient removal. Experiments were conducted to assess if NFT lettuce production could be improved by exchanging aquaculture effluent more frequently, and if so, determine the optimal water exchange rate. The AE was taken from a biofloc-based nile tiapia production system. Treatments consisted of increasing hydraulic retention time (HRT (d)) viz: four-, eight-, twelve-, or sixteen-day water exchanges arranged in a randomized complete block design with five blocks. In one trial (trial 1) where iron (Fe) was not supplemented, there was one replication. There were three replications for the second trial with iron supplementation. The analysis of lettuce plant size index and chlorophyll index (SPAD units) in trial 1 was statistically different among the HRTs beginning 14 days after planting, exhibiting negative linear trends with increasing HRT. However, most foliar micronutrients were borderline sufficient, and all treatments showed foliar Fe deficiency. After iron supplementation (trial 2), lettuce plant chlorophyll and size index exhibited quadratic trends with increasing HRT on 14 and 21 DAP, respectively. In trial 2, plant fresh mass decreased linearly from 162.1 g/head to 147.1 g/head, with increasing HRT. Furthermore, iron supplementation eliminated Fe deficiencies in the plants albeit only up to 14 DAP. Our findings suggest that shorter hydraulic retention times provide a solution to using the NFT system in aquaponics especially with iron supplementation.

Reticulocyte haemoglobin equivalent (RET-He) as an early marker of responsiveness to oral iron supplementation

AimWe investigated the potential of reticulocyte haemoglobin equivalent (RET-He) as an early marker of responsiveness to iron supplementation.MethodsData were obtained from a randomised controlled trial of daily iron supplementation in...

Iron supplementation given to nonanemic infants: neurocognitive functioning at 16 years

ABSTRACT Objective There is concern that high iron uptake during the critical period of early brain development carries potential risks, especially for nonanemic infants. This study examined the neurocognitive functioning of 16-year-olds who were nonanemic as infants and received iron supplementation. Methods We studied 562 Chilean adolescents (M 16.2 years; 52.7% female) who participated in a randomized controlled iron supplementation trial in infancy. Between 6 and 12 months, 346 consumed an iron-fortified formula (12.7 Fe mg/L) or, if primarily breastfed, liquid vitamins with 15 mg elemental iron as ferrous sulfate, and 216 consumed unmodified cow milk without iron or liquid vitamins without iron if primarily breastfed. Results Compared to adolescents in the no-added iron condition in infancy, those in the iron-supplemented condition had poorer visual-motor integration, quantitative reasoning skills, and incurred more errors on neurocognitive tasks. Consuming larger amounts of iron-fortified formula in infancy was associated with lower arithmetic achievement. Of adolescents who had high hemoglobin at 6 months (Hb ≥ 125 g/L), those in the iron supplemented condition had poorer performance on arithmetic, quantitative reasoning, and response inhibition tests than those in the no-added iron condition. Of adolescents who had marginally low 6-month hemoglobin (Hb > 100 and < 110 g/L), those who received no-added iron incurred more errors on a visual searching task than those in the iron-supplemented condition. Conclusion The physiologic need for iron during the period of rapid and critical brain development in young infants should be considered vis-à-vis the risks associated with supplementing nonanemic infants with high levels of iron. Clinical Trials number: NCT01166451

Seasonal patterns of malaria, genital infection, nutritional and iron status in non-pregnant and pregnant adolescents in Burkina Faso: a secondary analysis of trial data

BackgroundAdolescents are considered at high risk of developing iron deficiency. Studies in children indicate that the prevalence of iron deficiency increased with malaria transmission, suggesting malaria seasonally may drive iron deficiency. This paper examines monthly seasonal infection patterns of malaria, abnormal vaginal flora, chorioamnionitis, antibiotic and antimalarial prescriptions, in relation to changes in iron biomarkers and nutritional indices in adolescents living in a rural area of Burkina Faso, in order to assess the requirement for seasonal infection control and nutrition interventions.MethodsData collected between April 2011 and January 2014 were available for an observational seasonal analysis, comprising scheduled visits for 1949 non-pregnant adolescents (≤19 years), (315 of whom subsequently became pregnant), enrolled in a randomised trial of periconceptional iron supplementation. Data from trial arms were combined. Body Iron Stores (BIS) were calculated using an internal regression for ferritin to allow for inflammation. At recruitment 11% had low BIS (< 0 mg/kg). Continuous outcomes were fitted to a mixed-effects linear model with month, age and pregnancy status as fixed effect covariates and woman as a random effect. Dichotomous infection outcomes were fitted with analogous logistic regression models.ResultsSeasonal variation in malaria parasitaemia prevalence ranged between 18 and 70% in non-pregnant adolescents (P < 0.001), peaking at 81% in those who became pregnant. Seasonal variation occurred in antibiotic prescription rates (0.7–1.8 prescriptions/100 weekly visits, P < 0.001) and chorioamnionitis prevalence (range 15–68%, P = 0.026). Mucosal vaginal lactoferrin concentration was lower at the end of the wet season (range 2–22 μg/ml, P < 0.016), when chorioamnionitis was least frequent. BIS fluctuated annually by up to 53.2% per year around the mean BIS (5.1 mg/kg2, range 4.1–6.8 mg/kg), with low BIS (< 0 mg/kg) of 8.7% in the dry and 9.8% in the wet seasons (P = 0.36). Median serum transferrin receptor increased during the wet season (P < 0.001). Higher hepcidin concentration in the wet season corresponded with rising malaria prevalence and use of prescriptions, but with no change in BIS. Mean Body Mass Index and Mid-Upper-Arm-Circumference values peaked mid-dry season (both P < 0.001).ConclusionsOur analysis supports preventive treatment of malaria among adolescents 15–19 years to decrease their disease burden, especially asymptomatic malaria. As BIS were adequate in most adolescents despite seasonal malaria, a requirement for programmatic iron supplementation was not substantiated.

Baseline Hemoglobin, Hepcidin, Ferritin, and Total Body Iron Stores are Equally Strong Diagnostic Predictors of a Hemoglobin Response to 12 Weeks of Daily Iron Supplementation in Cambodian Women.

The WHO recommends daily iron supplementation for all women in areas where the population-level anemia prevalence is≥40%, despite the fact that hemoglobin (Hb) concentration is generally considered to be a poor prognostic indicator of iron status. In this secondary analysis, we investigated the predictive power of ten baseline hematological biomarkers towards a 12-week Hb response to iron supplementation. Data were obtained from a randomized controlled trial of daily iron supplementation in 407 nonpregnant Cambodian women (18-45 years) who received 60mg elemental iron as ferrous sulfate for 12 weeks. Ten baseline biomarkers were included: Hb, measured with both a hematology analyzer and a HemoCue; inflammation-adjusted ferritin; soluble transferrin receptor; reticulocyte Hb; hepcidin; mean corpuscular volume; inflammation-adjusted total body iron stores (TBIS); total iron binding capacity; and transferrin saturation. Receiver operating characteristic (ROC) curves from fitted logistic regression models were used to make discrimination comparisons and variable selection methods were used to construct a multibiomarker prognostic model. Only 25% (n=95/383) of women who completed the trial experienced a 12-week Hb response ≥10g/L. The strongest univariate predictors of a Hb response were Hb as measured with a hematology analyzer, inflammation-adjusted ferritin, hepcidin, and inflammation-adjusted TBIS (AUCROC=0.81, 0.83, 0.82, and 0.82, respectively), and the optimal cutoffs to identify women who were likely to experience a Hb response were 117g/L, 17.3μg/L, 1.98nmol/L, and 1.95mg/kg, respectively. Hb as measured with a hematology analyzer, inflammation-adjusted ferritin, and hepcidin had the best combined predictive ability (AUCROC=0.86). Hb measured with the HemoCue had poor discrimination ability (AUCROC=0.65). Baseline Hb as measured with a hematology analyzer was as strong a predictor of Hb response to iron supplementation as inflammation-adjusted ferritin, hepcidin, and inflammation-adjusted TBIS. This is positive given that the WHO currently uses the population-level anemia prevalence to guide recommendations for untargeted iron supplementation.

The IHAT-GUT Iron Supplementation Trial in Rural Gambia: Barriers, Facilitators, and Benefits.

Introduction: In most sub-Saharan African countries iron deficiency anaemia remains highly prevalent in children and this has not changed in the last 25 years. Supplementation with iron hydroxide adipate tartrate (IHAT) was being investigated in anaemic children in a phase two clinical trial (termed IHAT-GUT), conducted at the Medical Research Council Unit the Gambia at the London School of Hygiene and Tropical Medicine (LSHTM) (abbreviated as MRCG hereof). This qualitative study aimed to explore the personal perceptions of the trial staff in relation to conducting a clinical trial in such settings in order to highlight the health system specific needs and strengths in the rural, resource-poor setting of the Upper River Region in the Gambia. Methods: Individual interviews (n = 17) were conducted with local trial staff of the IHAT-GUT trial. Data were analysed using inductive thematic analysis. Results: Potential barriers and facilitators to conducting this clinical trial were identified at the patient, staff, and trial management levels. Several challenges, such as the rural location and cultural context, were identified but noted as not being long-term inhibitors. Participants believed the facilitators and benefits outnumbered the barriers, and included the impact on education and healthcare, the ambitious and knowledgeable locally recruited staff, and the local partnership. Conclusions: While facilitators and barriers were identified to conducting this clinical trial in a rural, resource-poor setting, the overall impact was perceived as beneficial, and this study is a useful example of community involvement and partnership for further health improvement programs. To effectively implement a nutrition intervention, the local health systems and context must be carefully considered through qualitative research beforehand.

Regression to the Mean: A Statistical Phenomenon of Worthy Consideration in Anemia Research.

ABSTRACTBackgroundRegression 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.ObjectiveThe 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).MethodsWomen 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.ResultsIn 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).ConclusionsRTM 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.

Iron Status of Burkinabé Adolescent Girls Predicts Malaria Risk in the Following Rainy Season.

High levels of storage iron may increase malaria susceptibility. This risk has not been investigated in semi-immune adolescents. We investigated whether baseline iron status of non-pregnant adolescent girls living in a high malaria transmission area in Burkina Faso affected malaria risk during the following rainy season. For this prospective study, we analysed data from an interim safety survey, conducted six months into a randomised iron supplementation trial. We used logistic regression to model the risk of P. falciparum infection prevalence by microscopy, the pre-specified interim safety outcome, in relation to iron status, nutritional indicators and menarche assessed at recruitment. The interim survey was attended by 1223 (82%) of 1486 eligible participants, 1084 (89%) of whom were <20 years at baseline and 242 (22%) were pre-menarcheal. At baseline, prevalence of low body iron stores was 10%. At follow-up, 38% of adolescents had predominantly asymptomatic malaria parasitaemias, with no difference by menarcheal status. Higher body iron stores at baseline predicted an increased malaria risk in the following rainy season (OR 1.18 (95% CI 1.05, 1.34, p = 0.007) after adjusting for bed net use, age, menarche, and body mass index. We conclude that routine iron supplementation should not be recommended without prior effective malaria control.

Iron deficiency is a common disorder in general population and independently predicts all-cause mortality: results from the Gutenberg Health Study

BackgroundIron deficiency is now accepted as an independent entity beyond anemia. Recently, a new functional definition of iron deficiency was proposed and proved strong efficacy in randomized cardiovascular clinical trials of intravenous iron supplementation. Here, we characterize the impact of iron deficiency on all-cause mortality in the non-anemic general population based on two distinct definitions.MethodsThe Gutenberg Health Study is a population-based, prospective, single-center cohort study. The 5000 individuals between 35 and 74 years underwent baseline and a planned follow-up visit at year 5. Tested definitions of iron deficiency were (1) functional iron deficiency—ferritin levels below 100 µg/l, or ferritin levels between 100 and 299 µg/l and transferrin saturation below 20%, and (2) absolute iron deficiency—ferritin below 30 µg/l.ResultsAt baseline, a total of 54.5% of participants showed functional iron deficiency at a mean hemoglobin of 14.3 g/dl; while, the rate of absolute iron deficiency was 11.8%, at a mean hemoglobin level of 13.4 g/dl. At year 5, proportion of newly diagnosed subjects was 18.5% and 4.8%, respectively. Rate of all-cause mortality was 7.2% (n = 361); while, median follow-up was 10.1 years. After adjustment for hemoglobin and major cardiovascular risk factors, the hazard ratio with 95% confidence interval of the association of iron deficiency with mortality was 1.3 (1.0–1.6; p = 0.023) for the functional definition, and 1.9 (1.3–2.8; p = 0.002) for absolute iron deficiency.ConclusionsIron deficiency is very common in the apparently healthy general population and independently associated with all-cause mortality in the mid to long term.Graphic abstract

Hemoglobin and hepcidin have good validity and utility for diagnosing iron deficiency anemia among pregnant women.

BackgroundScreening and diagnosis of iron deficiency anemia (IDA) is cumbersome as it may require testing for hemoglobin, ferritin, and an inflammatory biomarker.ObjectiveThe aim of this study was to compare the diagnostic capacity of hematologic biomarkers to detect IDA among pregnant women in Tanzania.MethodsWe pooled data from an iron supplementation trial of 1500 iron replete pregnant woman and a prospective cohort of 600 iron deficient pregnant women. Receiver operating characteristic curves (ROC) for hematologic biomarkers were used to assess the sensitivity, specificity, and area under the curve (AUC) for iron deficiency (ID) and iron deficiency anemia (IDA), crude, or corrected for inflammation. Regression models assessed the relationship of baseline biomarker categories (gestational age <27 weeks) and IDA at delivery.ResultsHemoglobin had the largest AUC for crude ID (0.96) while hepcidin had the largest AUC for corrected ID (0.80). The optimal hepcidin cut-off for the diagnosis of corrected IDA based on maximal sensitivity and specificity was ≤1.6μg/L. An hepcidin cutoff of <4.3 μg/L had a sensitivity of 95% for regression-corrected ID. Among iron-replete women who did not receive iron, the association of baseline hemoglobin >110g/L with IDA at delivery (RR = 0.73; 95% CI: 0.47, 1.13) was attenuated. Baseline hepcidin>1.6μg/L was associated with reduced risk of anemia at delivery by 49% (95% CI: 27%, 45%).ConclusionAscertaining hemoglobin and hepcidin levels may improve the targeting of iron supplementation programs in resource-limited countries, though hepcidin’s high costs may limit its use.

Infant iron deficiency, iron supplementation, and psychosocial stress as predictors of neurocognitive development in Chilean adolescents

ABSTRACT Objective: The aim of the current study was to examine the unique and joint contributions of iron deficiency, iron supplementation, and psychosocial stress in infancy and stress in adolescence to neurocognitive functioning in adolescence. Methods: The current study (N = 796; M age = 14.4y) involved a prospective cohort of low- and middle-socioeconomic status adolescents in Santiago, Chile. As infants, they had participated in an iron supplementation trial. Infant iron status was assessed at 12–18 months, and mothers answered questions about family psychosocial stress at 6–12 months and in adolescence (maternal depressive symptoms, home support for child development, stressful life events, father absence, socioeconomic status, and parental education). Neurocognitive functioning was assessed in adolescence using the Balloon Analogue Risk Task, Stockings of Cambridge, Trail Making Test, Purdue Pegboard Test, and Wisconsin Card Sorting Test. Results: Greater psychosocial stress in infancy predicted less risk-taking, poorer planning abilities and fluid cognition, and slower processing speed in adolescence. Iron deficiency anemia in infancy predicted less risk-taking. Greater adolescent psychosocial stress predicted difficulties in set-shifting. There were no interactions between infant psychosocial stress and iron deficiency predicting adolescent neurocognitive functioning. Conclusion: These results suggest that interventions to reduce infant psychosocial stress may be more likely to prevent multiple neurocognitive deficits in adolescence than interventions to reduce infant iron deficiency.

Pathways to inflammation in adolescence through early adversity, childhood depressive symptoms, and body mass index: A prospective longitudinal study of Chilean infants

Early adversity, depression, and obesity are associated with increases in low-grade inflammation. However, there are few prospective and longitudinal studies to elucidate how these associations unfold in children. The present study used latent growth curve models to examine pathways between family adversity in infancy, depressive symptoms in childhood, body mass index (BMI) in childhood, and inflammation in adolescence (age = 16–18). The study is an adolescent follow-up of infants from working-class communities around Santiago, Chile, who participated in a preventive trial of iron supplementation at 6 months of age. Anthropometrics, stressful life events, maternal depression, socioeconomic status, and developmental assessments were measured at 12 months, 5 years, 10 years, and adolescence. In adolescence, participants provided blood samples for high-sensitivity C-reactive protein (hsCRP) assessment. Greater exposure to early adversity in the form of interpersonal conflict stress in infancy indirectly associated with increased hsCRP through its association to increased intercept and slope of childhood BMI. Depressive symptoms at any time were not directly or indirectly associated with increased hsCRP. These findings contribute to our understanding of how early family adversity and its associations with obesity and depressive symptoms across childhood are linked to low-grade, chronic inflammation in adolescence. The model identified as best capturing the data supported the pivotal role of childhood BMI in explaining how early-life adversity is associated with inflammation in adolescence.

Mucosal lactoferrin response to genital tract infections is associated with iron and nutritional biomarkers in young Burkinab\xe9 women

Background/ObjectivesThe iron-binding affinity of vaginal lactoferrin (Lf) reduces iron available to genital pathogens. We describe host reproductive, nutritional, infection and iron biomarker profiles affecting vaginal Lf concentration in young nulliparous and primigravid women in Burkina Faso.Subjects/MethodsVaginal eluates from women who had participated in a randomized, controlled periconceptional iron supplementation trial were used to measure Lf using a competitive double-sandwich ELISA. For this analysis samples from both trial arms were combined and pregnant and non-pregnant cohorts compared. Following randomization Lf was measured after 18 months (end assessment) for women remaining non-pregnant, and at two antenatal visits for those becoming pregnant. Associations between log Lf levels and demographic, anthropometric, infection and iron biomarker variables were assessed using linear mixed models.ResultsLf samples were available for 712 non-pregnant women at end assessment and for 303 women seen at an antenatal visit. Lf concentrations of pregnant women were comparable to those of non-pregnant, sexually active women. Lf concentration increased with mid-upper-arm circumference, (P = 0.047), body mass index (P = 0.018), Trichomonas vaginalis (P < 0.001) infection, bacterial vaginosis (P < 0.001), serum C-reactive protein (P = 0.048) and microbiota community state types III/IV. Adjusted Lf concentration was positively associated with serum hepcidin (P = 0.047), serum ferritin (P = 0.018) and total body iron stores (P = 0.042). There was evidence that some women maintained persistently high or low Lf concentrations from before, and through, pregnancy.ConclusionLf concentrations increased with genital infection, higher BMI, MUAC, body iron stores and hepcidin, suggesting nutritional and iron status influence homeostatic mechanisms controlling vaginal Lf responses.