Eff ect of daily iron supplementation on health in children aged 4–23 months: a systematic review and meta-analysis of randomised controlled trials

Background About 47% of preschool children worldwide are anaemic. Daily oral iron supplementation is a commonly recommended intervention for treatment and prevention of anaemia, but the effi cacy and safety of iron supplementation programmes is debated. Thus, we systematically reviewed the evidence for benefi t and safety of daily iron supplementation in children aged 4–23 months. Methods We searched Scopus and Medline, from inception to Feb 5, 2013, WHO databases, theses repositories, grey literature, and references. Randomised controlled trials that assigned children 4–23 months of age to daily oral iron supplementation versus control were eligible. We calculated mean diff erence (MD) or standard MD (SMD) for continuous variables, risk ratios for dichotomous data, and rate ratios for rates. We quantifi ed heterogeneity with the I2 test and synthesised all data with a random-eff ects model. This review is registered with the International Prospective Register of Systematic Reviews, number CRD42011001208. Findings Of 9533 citations identifi ed by the search strategy, 49 articles from 35 studies were eligible; these trials included 42 306 children. Only nine studies were judged to be at low risk of bias. In children receiving iron supplements, the risk ratio for anaemia was 0·61 (95% CI 0·50–0·74; 17 studies, n=4825), for iron defi ciency was 0·30 (0·15–0·60; nine studies, n=2464), and for iron defi ciency anaemia was 0·14 (0·10–0·22; six studies, n=2145). We identifi ed no evidence of diff erence in mental (MD 1·65, 95% CI –0·63 to 3·94; six studies, n=1093) or psychomotor development (1·05, –1·36 to 3·46; six studies, n=1086). We noted no signifi cant diff erences in fi nal length or length-for-age, or fi nal weight or weight-for-age. Children randomised to iron had slightly lesser length (SMD –0·83, –1·53 to –0·12; eight studies, n=868) and weight gain (–1·12, –1·19 to –0·33) over the course of the studies. Vomiting (risk ratio 1·38, 95% CI 1·10–1·73) and fever (1·16, 1·02–1·31) were more prevalent in children receiving iron. Interpretation In children aged 4–23 months, daily iron supplementation eff ectively reduces anaemia. However, the adverse eff ect profi le of iron supplements and eff ects on development and growth are uncertain. Adequately powered trials are needed to establish the non-haematological benefi ts and risks from iron supplementation in this group

Reducing anaemia in low income countries: control of infection is essential.

In settings with high infection burdens, iron interventions for anaemia may be neither safe nor effective. Strategies to tackle the global burden of anaemia must take this into account, argue Sant-Rayn Pasricha and colleagues

A double blind randomised controlled trial comparing standard dose of iron supplementation for pregnant women with two screen-and-treat approaches using hepcidin as a biomarker for ready and safe to receive iron.

BACKGROUND: Until recently, WHO recommended daily iron supplementation for all pregnant women (60 mg/d iron combined with 400ug/d folic acid) where anaemia rates exceeded 40 %. Recent studies indicate that this may pose a risk to pregnant women. Therefore, there is a need to explore screen-and-treat options to minimise iron exposure during pregnancy using an overall lower dosage of iron that would achieve equivalent results as being currently recommended by the WHO. However, there is a lack of agreement on how to best assess iron deficiency when infections are prevalent. Here, we test the use of hepcidin a peptide hormone and key regulator of iron metabolism, as a potential index for 'safe and ready to receive' iron. DESIGN/METHODS: This is a 3-arm randomised-controlled proof-of-concept trial. We will test the hypothesis that a screen-and-treat approach to iron supplementation using a pre-determined hepcidin cut-off value of <2.5 ng/ml will achieve similar efficacy in preventing iron deficiency and anaemia at a lower iron dose and hence will improve safety. A sample of 462 pregnant women in rural Gambia will be randomly assigned to receive: a) UNU/UNICEF/WHO international multiple micronutrient preparation (UNIMMAP) containing 60 mg/d iron (reference arm); b) UNIMMAP containing 60 mg/d iron but based on a weekly hepcidin screening indicating if iron can be given for the next 7 days or not; c) or UNIMMAP containing 30 mg/d iron as in (b) for 12 weeks in rural Gambia. The study will test if the screen-and-treat approach is non-inferior to the reference arm using the primary endpoint of haemoglobin levels at a non-inferiority margin of 0.5 g/dl. Secondary outcomes of adverse effects, compliance and the impact of iron supplementation on susceptibility to infections will also be assessed. DISCUSSION: This trial is expected to contribute towards minimising the exposure of pregnant women to iron that may not be needed and therefore potentially harmful. If the evidence in this study shows that the overall lower dosage of iron is non-inferior to 60 mg/day iron, this may help decrease side-effects, improve compliance and increase safety. The potential for the use of hepcidin for a simple point-of-care (PoC) diagnostic for when it is most safe and effective to give iron may improve maternal health outcomes. TRIAL REGISTRATION: ISRCTN21955180

Serum Hepcidin Concentrations Decline during Pregnancy and May Identify Iron Deficiency: Analysis of a Longitudinal Pregnancy Cohort in The Gambia.

Background: Antenatal anemia is a risk factor for adverse maternal and fetal outcomes and is prevalent in sub-Saharan Africa. Less than half of antenatal anemia is considered responsive to iron; identifying women in need of iron may help target interventions. Iron absorption is governed by the iron-regulatory hormone hepcidin.Objective: We sought to characterize changes in hepcidin and its associations with indexes of iron stores, erythropoiesis, and inflammation at weeks 14, 20, and 30 of gestation and to assess hepcidin's diagnostic potential as an index of iron deficiency.Methods: We measured hemoglobin and serum hepcidin, ferritin, soluble transferrin receptor (sTfR), and C-reactive protein (CRP) at 14, 20, and 30 wk of gestation in a cohort of 395 Gambian women recruited to a randomized controlled trial. Associations with hepcidin were measured by using linear regression, and hepcidin's diagnostic test accuracy [area under the receiver operating characteristic curve (AUCROC), sensitivity, specificity, cutoffs] for iron deficiency at each time point was analyzed.Results: The prevalence of anemia increased from 34.6% at 14 wk of gestation to 50.0% at 20 wk. Hepcidin concentrations declined between study enrollment and 20 wk, whereas ferritin declined between 20 and 30 wk of gestation. The variations in hepcidin explained by ferritin, sTfR, and CRP declined over pregnancy. The AUCROC values for hepcidin to detect iron deficiency (defined as ferritin <15 μg/L) were 0.86, 0.83, and 0.84 at 14, 20, and 30 wk, respectively. Hepcidin was superior to hemoglobin and sTfR as an indicator of iron deficiency.Conclusions: In Gambian pregnant women, hepcidin appears to be a useful diagnostic test for iron deficiency and may enable the identification of cases for whom iron would be beneficial. Hepcidin suppression in the second trimester suggests a window for optimal timing for antenatal iron interventions. Hemoglobin does not effectively identify iron deficiency in pregnancy. This trial was registered at www.isrctn.com as ISRCTN49285450

Decreased Hepcidin Levels Are Associated with Low Steady-state Hemoglobin in Children With Sickle Cell Disease in Tanzania.

BACKGROUND: The contribution of hepcidin as a regulator of iron metabolism & erythropoiesis on the severity of anemia in sickle cell disease (SCD) remains poorly characterized, especially in Sub-Saharan African populations. The aims of the study were to determine if hepcidin is associated with severity of steady-state anemia in SCD and to investigate factors associated with hepcidin and anemia in SCD. METHODS: Archived samples from 199 Tanzanian children, 56% boys aged 3-18 with laboratory-confirmed SCD were analysed based on recorded averaged steady-state hemoglobin (ASSH) quartiles (lowest vs. highest). Univariable and multivariable logistic regression was used to assess associations with ASSH quartiles. FINDINGS: In univariable analysis, hepcidin <5·5 ng/mL was associated with increased odds of being in the lowest ASSH quartile (OR 2·20; 95%CI 1·2-3·93) but which was limited to girls (OR 4·85, 95%CI 1·79-13·09, p = .046 for interaction). In multivariable analyses including either reticulocyte percentage or erythropoietin, lower hepcidin remained significantly associated with lowest ASSH quartile, although the hepcidin-sex interaction no longer reached statistical significance. No associations with ASSH quartile were observed for markers of inflammation, hemolysis or potential iron markers except for microcytosis, associated with higher ASSH, but which was confounded by reticulocyte percentage and alpha-thalassaemia status. INTERPRETATION: Hepcidin is lower in more severely anaemic children with SCD independent of inflammation or markers of erythropoiesis. FUNDING: Funding sources include The Wellcome Trust (080025, 095009, 094780 & 070114), MRC-UK (MC-A760-5QX00), NIHR Oxford Biomedical Research Centre, and the Bill and Melinda Gates Foundation ("Hepcidin and Iron in Global Health", OPP1055865)

Protocol for a multicentre, parallelgroup, open-label randomised controlled trial comparing ferric carboxymaltose with the standard of care in anaemic Malawian pregnant women: the REVAMP trial

Introduction Anaemia in pregnancy remains a critical global health problem, affecting 46% of pregnant women in Africa and 49% in Asia. Oral iron therapy requires extended adherence to achieve correction of anaemia and replenishment of iron stores. Ferric carboxymaltose (FCM) is a recently established intravenous iron formulation associated with substantial advantages in safety, speed of delivery and total dose deliverable in a single infusion. We aim to determine whether FCM given once during the second trimester of pregnancy compared with standard oral iron distributed through routine antenatal services is effective and safe for treatment of moderate to severe maternal anaemia in sub-Saharan Africa. Methods and analysis The randomized controlled trial of the effect of intravenous iron on anaemia in Malawian pregnant women (REVAMP) is a two-arm confirmatory individually randomised trial set in Blantyre and Zomba districts in Malawi. The trial will randomise 862 women in the second trimester of pregnancy with a capillary haemoglobin concentration below 100.0 g/L. The study comprises two arms: (a) intravenous FCM (20 mg/kg up to 1000 mg) given once at randomisation, and (b) standard of care oral iron (65 mg elemental iron two times per day) for 90 days (or the duration of pregnancy, whichever is shorter) provided according to local healthcare practices. Both arms receive sulfadoxine-pyrimethamine as intermittent preventive treatment in pregnancy. The primary outcome is the prevalence of anaemia (Hb <110.0 g/L) at 36 weeks’ gestation. Secondary outcomes include birth weight, gestation duration and safety outcomes, including clinical malaria, serious perinatal events and postpartum haematologic and health-related outcomes in the mother and child. Ethics and dissemination Ethical approval was granted by the Research Ethics Committee (COMREC P.02/18/2357) in Malawi and the Human Research Ethics Committee (WEHI: 18/02), Melbourne, Australia. The protocol is registered with the Australian and New Zealand Clinical Trials Registry. The results will be shared with the local community that enabled the research, and also to the international fora.publishedVersio

Biological dosimetry after radiosynoviorthesis with rhenium-186 sulphide and erbium-169 citrate

Zur Abschätzung der radiobiologischen Sicherheit des Verfahrens wird in dieser Arbeit die Radiosynoviorthese (RSO) mit Re-186 und Er-169 hinsichtlich biologischer Strahleneffekte untersucht. Bei 23 Patienten wurde eine RSO mit Rhenium-186-Sulfid- (10 Patienten) oder Erbium-169-Zitratkolloid (13 Patienten) durchgeführt. Das behandelte Gelenk wurde anschließend ruhig gestellt. Bei allen Patienten erfolgte vor und 17–19 Tage (Re-186) bzw. 45–50 Tage (Er-169) nach der RSO eine venöse Blutentnahme. Zur Analyse der Strahlenexposition wurde die Häufigkeit von dizentrischen Chromosomen in Lymphozyten der ersten Zellteilung in vitro bestimmt. Pro Patient wurden mindestens 1000 Zellen vor und nach der RSO untersucht, was nach längerer Einwirkung niederenergetischer Strahlung ausreichend ist, um im bestrahlten Kollektiv die im Rahmen der RSO erwarteten Strahlendosen nachzuweisen. Ergänzend wurde bei den mit Re-186 behandelten Patienten der Aktivitätsabtransport aus dem Gelenk mittels Ganzkörperszintigraphie bestimmt. In der Untersuchung von insgesamt 47017 Zellen fanden sich vor RSO mit Re-186 bzw. Er-169 40 bzw. 88, danach 59 bzw. 105 dizentrische Chromosomen in Lymphozyten des peripheren Blutes. Eine signifikante Zunahme der dizentrischen Chromosomen nach der RSO zeigte sich nicht. Der Aktivitätsabtransport nach RSO mit Re-186 lag durchschnittlich unter 5 % (unter 3 MBq) und ist damit als gering einzustufen. Die Ergebnisse der Untersuchung von Chromosomenaberrationen und des Aktivitätsabtransports nach Radiosynoviorthese mit Rhenium-186 und Erbium-169 sprechen für eine geringe Strahlenexposition der Patienten und damit für die Sicherheit des Verfahrens.The aim of the present studies was to investigate the biological radiation effect of radiosynoviorthesis (RSO) with Re-186 and Er-169 in order to evaluate the safety of this procedure. RSO with rhenium-186 sulfide colloid (10 patients) or erbium-169 citrate colloid (13 patients) was carried out in a total of 23 patients. Afterwards, the treated joint was immobilised for three days using splints. From all patients, blood was drawn immediately before and 17 to 19 days (Re-186) or 45 to 50 days (Er-169) after RSO. To evaluate the radiation dose, the yield of dicentric chromosomes in lymphocytes was determined exclusively in metaphases of the first cell cycle in vitro. At least 1000 cells per patient have been analysed before and after RSO which is sufficient to find potential radiation effects after long-term exposure to low energy radiation such as to expect after RSO. In addition, for Re-186 the activity leakage from the treated joint was measured by whole-body scintigraphy. In a total of 47017 cells analysed from 46 blood samples, 40 and 88 before and 59 and 105 dicentrics after RSO with Re-186 and Er-169 were found. This showed no statistically significant increase in the number of dicentric chromosomes. The measured average activity leakage of less than 5 % (less than 3 MBq) was considered to be low. The results of chromosome analysis and activity measurement after RSO prove that this procedure is associated with a low effective dose in treated patients and thus can be considered a safe treatment

Respiratory infections drive hepcidin-mediated blockade of iron absorption leading to iron deficiency anemia in African children.

Iron deficiency anemia (IDA) is the most prevalent nutritional condition worldwide. We studied the contribution of hepcidin-mediated iron blockade to IDA in African children. We measured hepcidin and hemoglobin weekly, and hematological, inflammatory, and iron biomarkers at baseline, 7 weeks, and 12 weeks in 407 anemic (hemoglobin < 11 g/dl), otherwise healthy Gambian children (6 to 27 months). Each child maintained remarkably constant hepcidin levels (P < 0.0001 for between-child variance), with half consistently maintaining levels that indicate physiological blockade of iron absorption. Hepcidin was strongly predicted by nurse-ascribed adverse events with dominant signals from respiratory infections and fevers (all P < 0.0001). Diarrhea and fecal calprotectin were not associated with hepcidin. In multivariate analysis, C-reactive protein was the dominant predictor of hepcidin and contributed to iron blockade even at very low levels. We conclude that even low-grade inflammation, especially associated with respiratory infections, contributes to IDA in African children

Hepcidin-guided screen-and-treat interventions against iron-deficiency anaemia in pregnancy: a randomised controlled trial in The Gambia.

BACKGROUND: WHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron. METHODS: We did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18-45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L), or a 30 mg screen-and-treat approach (ie, daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L). We used a block design stratified by amount of haemoglobin at enrolment (above and below the median amount of haemoglobin on every enrolment day) and stage of gestation (14-18 weeks vs 19-22 weeks). Participants and investigators were unaware of the random allocation. The primary outcome was the amount of haemoglobin at day 84 and was measured as the difference in haemoglobin in each screen-and-treat group compared with WHO's recommended regimen; the non-inferiority margin was set at -5·0 g/L. The primary outcome was assessed in the per-protocol population, which comprised all women who completed the study. This trial is registered with the ISRCTN registry, number ISRCTN21955180. FINDINGS: Between June 16, 2014, and March 3, 2016, 498 participants were randomised, of whom 167 were allocated to WHO's recommended regimen, 166 were allocated to the 60 mg per day screen-and-treat approach, and 165 were allocated to the 30 mg per day screen-and-treat approach. 78 participants were withdrawn or lost to follow-up during the study; thus, the per-protocol population comprised 140 women assigned to WHO's recommended regimen, 133 allocated to the 60 mg screen-and-treat approach, and 147 allocated to the 30 mg screen-and-treat approach. The screen-and-treat approaches did not exceed the non-inferiority margin. Compared with WHO's recommended regimen, the difference in the amount of haemoglobin at day 84 was -2·2 g/L (95% CI -4·6 to 0·1) with the 60 mg screen-and-treat approach and -2·7 g/L (-5·0 to -0·5) with the 30 mg screen-and-treat approach. Adherence, reported side-effects, and adverse events were similar between the three groups. The most frequent side-effect was stomachache, which was similar in the 60 mg screen-and-treat group (82 cases per 1906 person-weeks) and with WHO's recommended regimen (81 cases per 1974 person-weeks; effect 1·0, 95% CI 0·7 to 1·6); in the 30 mg screen-and-treat group the frequency of stomachache was slightly lower than with WHO's recommended regimen (58 cases per 2009 person-weeks; effect 0·7, 95% CI 0·5 to 1·1). No participants died during the study. INTERPRETATION: The hepcidin-guided screen-and-treat approaches had no advantages over WHO's recommended regimen in terms of adherence, side-effects, or safety outcomes. Our results suggest that the current WHO policy for iron administration to pregnant women should remain unchanged while more effective approaches continue to be sought. FUNDING: Bill & Melinda Gates Foundation and the UK Medical Research Council

Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and β-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6–hepcidin response to oral and parenteral iron is impaired, and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6–hepcidin axis, improving iron homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in β-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to the control of systemic iron homoeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders