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Efficacy and safety of intravenous ferric carboxymaltose compared with oral iron for the treatment of iron deficiency anaemia in women after childbirth in Tanzania: a parallel-group, open-label, randomised controlled phase 3 trial.
Vanobberghen, F, Lweno, O, Kuemmerle, A, Mwebi, KD, Asilia, P, Issa, A, Simon, B, Mswata, S, Schmidlin, S, Glass, TR, et al
The Lancet. Global health. 2021;(2):e189-e198
Abstract
BACKGROUND Iron deficiency anaemia is of major concern in low-income settings, especially for women of childbearing age. Oral iron substitution efficacy is limited by poor compliance and iron depletion severity. We aimed to assess the efficacy and safety of intravenous ferric carboxymaltose versus oral iron substitution following childbirth in women with iron deficiency anaemia in Tanzania. METHODS This parallel-group, open-label, randomised controlled phase 3 trial was done at Bagamoyo District Hospital and Mwananyamala Hospital, Tanzania. Eligible participants were close to delivery and had iron deficiency anaemia defined as a haemoglobin concentration of less than 110 g/L and a ferritin concentration of less than 50 μg/L measured within 14 days before childbirth. Participants were randomly assigned 1:1 to receive intravenous ferric carboxymaltose or oral iron, stratified by haemoglobin concentration and site. Intravenous ferric carboxymaltose was administered at a dose determined by the haemoglobin concentration and bodyweight (bodyweight 35 kg to <70 kg and haemoglobin ≥100 g/L: 1000 mg in one dose; bodyweight 35 kg to <70 kg and haemoglobin <100 g/L, or bodyweight ≥70 kg and haemoglobin ≥100 g/L: 1500 mg in two doses at least 7 days apart; bodyweight ≥70 kg and haemoglobin <100 g/L: 2000 mg in two doses at least 7 days apart). Oral iron treatment consisted of three dried ferrous sulphate tablets of 200 mg containing 60 mg of elementary iron and 5 mg of folic acid every morning. Oral treatment was to be taken for 3 months after haemoglobin normalisation. The primary outcome was haemoglobin normalisation (>115 g/L) at 6 weeks. Follow-up visits were at 6 weeks, and 3, 6, and 12 months. Analyses were done in the modified intention-to-treat population of participants who had a 6-week haemoglobin concentration result, using logistic and linear regression models for binary and continuous outcomes, adjusted for baseline haemoglobin concentration and site. This trial is registered with ClinicalTrials.gov, NCT02541708. FINDINGS Between Oct 8, 2015, and March 14, 2017, 533 individuals were screened and 230 were enrolled and randomly assigned to a study group (114 to intravenous iron, 116 to oral iron). At 6 weeks, 94 (82%) participants in the intravenous iron group and 92 (79%) in the oral iron group were assessed for the primary outcome. 75 (80%) participants in the intravenous iron group and 47 (51%) in the oral iron group had normalised haemoglobin (odds ratio 4·65, 95% CI 2·33-9·27). There were two mild to moderate infusion-related adverse events; and five serious adverse events (three in the intravenous iron group, two in the oral iron group), unrelated to the study medication. INTERPRETATION Intravenous iron substitution with ferric carboxymaltose was safe and yielded a better haemoglobin response than oral iron. To our knowledge, this is the first study to provide evidence of the benefits and safety of intravenous iron substitution in a low-income setting. FUNDING Vifor Pharma, R Geigy-Stiftung, Freiwillige Akademische Gesellschaft, and Swiss Tropical and Public Health Institute.
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Impact of iron fortification on anaemia and iron deficiency among pre-school children living in Rural Ghana.
Tchum, SK, Arthur, FK, Adu, B, Sakyi, SA, Abubakar, LA, Atibilla, D, Amenga-Etego, S, Oppong, FB, Dzabeng, F, Amoani, B, et al
PloS one. 2021;(2):e0246362
Abstract
Anaemia in young sub-Saharan African children may be due to the double burden of malaria and iron deficiency. Primary analysis of a double-blind, cluster randomized trial of iron containing micronutrient powder supplementation in Ghanaian children aged 6 to 35 months found no difference in malaria risk between intervention and placebo groups. Here, we performed a secondary analysis of the trial data to assess the impact of long-term prophylactic iron fortificant on the risk of iron deficiency and anaemia in trial subjects. This population-based randomized-cluster trial involved 1958 children aged between 6 to 35 months, identified at home and able to eat semi-solid foods. The intervention group (n = 967) received a daily dose containing 12.5 mg elemental iron (as ferrous fumarate), vitamin A (400 μg), ascorbic acid (30 mg) and zinc (5 mg). The placebo group (n = 991) received a similar micronutrient powder but without iron. Micronutrient powder was provided daily to both groups for 5 months. At baseline and endline, health assessment questionnaires were administered and blood samples collected for analysis. The two groups had similar baseline anthropometry, anaemia, iron status, demographic characteristics, and dietary intakes (p > 0.05). Of the 1904 (97.2%) children who remained at the end of the intervention, the intervention group had significantly higher haemoglobin (p = 0.0001) and serum ferritin (p = 0.0002) levels than the placebo group. Soluble transferrin receptor levels were more saturated among children from the iron group compared to non-iron group (p = 0.012). Anaemia status in the iron group improved compared to the placebo group (p = 0.03). Continued long-term routine use of micronutrient powder containing prophylactic iron reduced anaemia, iron deficiency and iron deficiency anaemia among pre-school children living in rural Ghana's malaria endemic area.
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Multi-Nutrient Fortified Dairy-Based Drink Reduces Anaemia without Observed Adverse Effects on Gut Microbiota in Anaemic Malnourished Nigerian Toddlers: A Randomised Dose-Response Study.
Owolabi, AJ, Senbanjo, IO, Oshikoya, KA, Boekhorst, J, Eijlander, RT, Kortman, GAM, Hageman, JHJ, Samuel, F, Melse-Boonstra, A, Schaafsma, A
Nutrients. 2021;(5)
Abstract
Prevalence of anaemia among Nigerian toddlers is reported to be high, and may cause significant morbidity, affects brain development and function, and results in weakness and fatigue. Although, iron fortification can reduce anaemia, yet the effect on gut microbiota is unclear. This open-label randomised study in anaemic malnourished Nigerian toddlers aimed to decrease anaemia without affecting pathogenic gut bacteria using a multi-nutrient fortified dairy-based drink. The test product was provided daily in different amounts (200, 400 or 600 mL, supplying 2.24, 4.48 and 6.72 mg of elemental iron, respectively) for 6 months. Haemoglobin, ferritin, and C-reactive protein concentrations were measured to determine anaemia, iron deficiency (ID) and iron deficiency anaemia (IDA) prevalence. Faecal samples were collected to analyse gut microbiota composition. All three dosages reduced anaemia prevalence, to 47%, 27% and 18%, respectively. ID and IDA prevalence was low and did not significantly decrease over time. Regarding gut microbiota, Enterobacteriaceae decreased over time without differences between groups, whereas Bifidobacteriaceae and pathogenic E. coli were not affected. In conclusion, the multi-nutrient fortified dairy-based drink reduced anaemia in a dose-dependent way, without stimulating intestinal potential pathogenic bacteria, and thus appears to be safe and effective in treating anaemia in Nigerian toddlers.
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Acute Administration of Bioavailable Curcumin Alongside Ferrous Sulphate Supplements Does Not Impair Iron Absorption in Healthy Adults in a Randomised Trial.
Lorinczova, HT, Begum, G, Renshaw, D, Zariwala, MG
Nutrients. 2021;(7)
Abstract
Ferrous sulphate (FS) is a cost effective, readily available iron supplement for iron deficiency (ID). The pro-oxidant effect of oral ferrous iron is known to induce inflammation, causing gastric side-effects and resulting in poor compliance. Curcumin is a potent antioxidant and has also been shown to exhibit iron chelation in-vitro, although it is not established whether these effects are retained in-vivo. The aim of this study was therefore to assess the influence of a formulated bioavailable form of curcumin (HydroCurcTM; 500 mg) on acute iron absorption and status in a double blind, placebo-controlled randomized trial recruiting 155 healthy participants (79 males; 26.42 years ± 0.55 and 76 females; 25.82 years ± 0.54). Participants were randomly allocated to five different treatment groups: iron and curcumin placebo (FS0_Plac), low dose (18 mg) iron and curcumin placebo (FS18_Plac), low dose iron and curcumin (FS18_Curc), high dose (65 mg) iron and curcumin placebo (FS65_Plac), and high dose iron and curcumin (FS65_Curc). Participants were provided with the supplements according to their relevant treatment groups at baseline (0 min), and blood collection was carried out at 0 min and at 180 min following supplementation. In the treatment groups, significant difference was observed in mean serum iron between baseline (0 min) and at end-point (180 min) (F (1, 144) = 331.9, p < 0.0001) with statistically significant intra-group increases after 180 min (p < 0.0001) in the FS18_Plac (8.79 µmol/L), FS18_Curc (11.41 µmol/L), FS65_Plac (19.09 µmol/L), and FS65_Curc (16.39 µmol/L) groups. A significant difference was also observed between the two time points in serum TIBC levels and in whole blood haemoglobin (HGB) in the treatment groups, with a significant increase (1.55%/2.04 g/L) in HGB levels from baseline to end-point observed in the FS65_Curc group (p < 0.05). All groups receiving iron demonstrated an increase in transferrin saturation (TS%) in a dose-related manner, demonstrating that increases in serum iron are translated into increases in physiological iron transportation. This study demonstrates, for the first time, that regardless of ferrous dose, formulated curcumin in the form of HydroCurc™ does not negatively influence acute iron absorption in healthy humans.
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The bioavailability of iron picolinate is comparable to iron sulfate when fortified into a complementary fruit yogurt: a stable iron isotope study in young women.
Sabatier, M, Grathwohl, D, Beaumont, M, Groulx, K, Guignard, LF, Kastenmayer, P, Dubascoux, S, Richoz, J, Habeych, E, Zeder, C, et al
European journal of nutrition. 2020;(4):1371-1378
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PURPOSE A technological gap exists for the iron (Fe) fortification of difficult-to-fortify products, such as wet and acid food products containing polyphenols, with stable and bioavailable Fe. Fe picolinate, a novel food ingredient, was found to be stable over time in this type of matrix. The objective of this study was to measure the Fe bioavailability of Fe picolinate in a complementary fruit yogurt. METHODS The bioavailability of Fe picolinate was determined using stable iron isotopes in a double blind, randomized cross-over design in non-anemic Swiss women (n = 19; 25.1 ± 4.6 years). Fractional Fe absorption was measured from Fe picolinate (2.5 mg 57Fe per serving in two servings given morning and afternoon) and from Fe sulfate (2.5 mg 54Fe per serving in two servings given morning and afternoon) in a fortified dairy complementary food (i.e. yogurt containing fruits). Fe absorption was determined based on erythrocyte incorporation of isotopic labels 14 days after consumption of the last test meal. RESULTS Geometric mean (95% CI) fractional iron absorption from Fe picolinate and Fe sulfate were not significantly different: 5.2% (3.8-7.2%) and 5.3% (3.8-7.3%) (N.S.), respectively. Relative bioavailability of Fe picolinate versus Fe sulfate was 0.99 (0.85-1.15). CONCLUSION Therefore, Fe picolinate is a promising compound for the fortification of difficult-to-fortify foods, to help meet Fe requirements of infants, young children and women of childbearing age.
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Effect of Ferric Citrate versus Ferrous Sulfate on Iron and Phosphate Parameters in Patients with Iron Deficiency and CKD: A Randomized Trial.
Womack, R, Berru, F, Panwar, B, Gutiérrez, OM
Clinical journal of the American Society of Nephrology : CJASN. 2020;(9):1251-1258
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BACKGROUND AND OBJECTIVES Ferric citrate is an oral medication approved for treatment of iron deficiency anemia in patients with CKD not requiring dialysis. The relative efficacy of ferric citrate versus ferrous sulfate in treating iron deficiency in patients with CKD is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We randomized 60 adults with moderate to severe CKD (eGFR 15-45 ml/min per 1.73 m2) and iron deficiency (transferrin saturation [TSAT] ≤30% and ferritin ≤300 ng/ml) to ferric citrate (2 g three times a day with meals, n=30) or ferrous sulfate (325 mg three times a day, n=30) for 12 weeks. Primary outcomes were change in TSAT and ferritin from baseline to 12 weeks. Secondary outcomes were change in hemoglobin, fibroblast growth factor 23 (FGF23), and hepcidin. RESULTS Baseline characteristics were well balanced between study arms. There was a greater increase in TSAT (between-group difference in mean change, 8%; 95% confidence interval [95% CI], 1 to 15; P=0.02) and ferritin (between-group difference in mean change, 37 ng/ml; 95% CI, 10 to 64; P=0.009) from baseline to 12 weeks in participants randomized to ferric citrate as compared with ferrous sulfate. Similarly, as compared with ferrous sulfate, treatment with ferric citrate resulted in a greater increase in hepcidin from baseline to 12 weeks (between-group difference, 69 pg/ml; 95% CI, 8 to 130). There were no between-group differences in mean change for hemoglobin (0.3 g/dl; 95% CI, -0.2 to 0.8), intact FGF23 (-29 pg/ml; 95% CI, -59 to 0.1), or C-terminal FGF23 (61 RU/ml; 95% CI, -181 to 58). The incidence of adverse events did not differ between treatment arms. CONCLUSIONS As compared with ferrous sulfate, treatment with ferric citrate for 12 weeks resulted in a greater mean increase in TSAT and ferritin concentrations in individuals with moderate to severe CKD and iron deficiency. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Impact of Ferric Citrate vs Ferrous Sulfate on Iron Parameters and Hemoglobin in Individuals With Moderate to Severe Chronic Kidney Disease (CKD) With Iron Deficiency, NCT02888171.
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Delayed iron improves iron status without altering malaria risk in severe malarial anemia.
Cusick, SE, Opoka, RO, Ssemata, AS, Georgieff, MK, John, CC
The American journal of clinical nutrition. 2020;(5):1059-1067
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BACKGROUND WHO guidelines recommend concurrent iron and antimalarial treatment in children with malaria and iron deficiency, but iron may not be well absorbed or utilized during a malaria episode. OBJECTIVES We aimed to determine whether starting iron 28 d after antimalarial treatment in children with severe malaria and iron deficiency would improve iron status and lower malaria risk. METHODS We conducted a randomized clinical trial on the effect of immediate compared with delayed iron treatment in Ugandan children 18 mo-5 y of age with 2 forms of severe malaria: cerebral malaria (CM; n = 79) or severe malarial anemia (SMA; n = 77). Asymptomatic community children (CC; n = 83) were enrolled as a comparison group. Children with iron deficiency, defined as zinc protoporphyrin (ZPP) ≥ 80 µmol/mol heme, were randomly assigned to receive a 3-mo course of daily oral ferrous sulfate (2 mg · kg-1 · d-1) either concurrently with antimalarial treatment (immediate arm) or 28 d after receiving antimalarial treatment (delayed arm). Children were followed for 12 mo. RESULTS All children with CM or SMA, and 35 (42.2%) CC, were iron-deficient and were randomly assigned to immediate or delayed iron treatment. Immediate compared with delayed iron had no effect in any of the 3 study groups on the primary study outcomes (hemoglobin concentration and prevalence of ZPP ≥ 80 µmol/mol heme at 6 mo, malaria incidence over 12 mo). However, after 12 mo, children with SMA in the delayed compared with the immediate arm had a lower prevalence of iron deficiency defined by ZPP (29.4% compared with 65.6%, P = 0.006), a lower mean concentration of soluble transferrin receptor (6.1 compared with 7.8 mg/L, P = 0.03), and showed a trend toward fewer episodes of severe malaria (incidence rate ratio: 0.39; 95% CI: 0.14, 1.12). CONCLUSIONS In children with SMA, delayed iron treatment did not increase hemoglobin concentration, but did improve long-term iron status over 12 mo without affecting malaria incidence.This trial was registered at clinicaltrials.gov as NCT01093989.
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Iron Absorption is Greater from Apo-Lactoferrin and is Similar Between Holo-Lactoferrin and Ferrous Sulfate: Stable Iron Isotope Studies in Kenyan Infants.
Mikulic, N, Uyoga, MA, Mwasi, E, Stoffel, NU, Zeder, C, Karanja, S, Zimmermann, MB
The Journal of nutrition. 2020;(12):3200-3207
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BACKGROUND Whether lactoferrin (Lf) binds iron to facilitate its absorption or to sequester iron from potential enteropathogens remains uncertain. Bovine Lf is added to many infant formulas, but previous studies in infants reported that Lf had no effect on or inhibited iron absorption. The effects of the apo (iron-free) or the holo (iron-loaded) forms of Lf on iron absorption are unclear. OBJECTIVES Our objective was to compare iron absorption from a maize-based porridge containing: 1) labeled ferrous sulfate (FeSO4) alone; 2) labeled FeSO4 given with bovine apo-Lf; and 3) intrinsically labeled bovine holo-Lf. METHODS In a crossover study, we measured iron absorption in Kenyan infants (n = 25; mean ± SD age 4.2 ± 0.9 months; mean ± SD hemoglobin 109 ± 11 g/L) from maize-based test meals containing: 1) 1.5 mg of iron as 54Fe-labeled FeSO4; 2) 1.42 mg of iron as 58Fe-labeled FeSO4, given with 1.41 g apo-Lf (containing 0.08 mg iron); and 3) 1.41 g holo-Lf carrying 1.5 mg iron as 57Fe. The iron saturation levels of apo- and holo-Lf were 0.56% and 47.26%, respectively primary outcome was fractional iron absorption (FIA), assessed by erythrocyte incorporation of isotopic labels. RESULTS The FIA from the meal containing apo-Lf + FeSO4 (geometric mean, 9.8%; -SD and +SD, 5.4% and 17.5%) was higher than from the meals containing FeSO4 (geometric mean, 6.3%; -SD and +SD, 3.2% and 12.6%; P = 0.002) or holo-Lf (geometric mean, 5.0%; -SD and +SD, 2.8% and 8.9%; P <0.0001). There was no significant difference in FIA when comparing the meals containing holo-Lf versus FeSO4 alone (P = 0.24). CONCLUSIONS The amount of iron absorbed from holo-Lf was comparable to that of FeSO4, and the addition of apo-Lf to a test meal containing FeSO4 significantly increased (+56%) iron absorption. These findings suggest that Lf facilitates iron absorption in young infants. Because Lf binds iron with high affinity, it could be a safe way to provide iron to infants in low-income countries, where iron fortificants can adversely affect the gut microbiome and cause diarrhea. This study was registered at clinicaltrials.gov as NCT03617575.
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Effects of 6-months of oral ferrous and ferric supplement therapy in patients who were hospitalized for decompensated chronic heart failure.
Zdravkovic, SC, Nagorni, SP, Cojbasic, I, Mitic, V, Cvetkovic, P, Nagorni, I, Govedarovic, N, Davinic, I, Stanojevic, D
The Journal of international medical research. 2019;(7):3179-3189
Abstract
OBJECTIVE Anemia is common in patients with chronic heart failure (CHF). This study aimed to examine the frequency of iron deficiency anemia in patients with CHF. We investigated the effects of oral ferrous or ferric supplementation on prognosis of CHF and quality of life. METHODS A total of 201 patients with chronic decompensated heart failure were enrolled in a 6-month prospective study. Patients were randomly assigned to two groups. Patients in group I (n = 100) received ferrous fumarate and those in group II (n = 101) received ferric hydroxide polymaltose complex. Quality of life was measured by the 6-minute walking test (6MWT). RESULTS A total of 49% of the patients had iron-dependent anemia in group I and 53.3% were anemic in group II. In group I, the number of anemic patients was significantly lower at 6 months after admission compared with at initial admission (49% versus 45%). Significant improvements were observed in hemoglobin values, the 6MWT distance, and New York Heart Association class after 6 months in both groups. CONCLUSIONS Iron deficiency is a significant comorbidity in CHF, even without anemia. Iron should be replaced orally or intravenously because it significantly improves the quality of life of patients.
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Comparison of ferrous sulfate, polymaltose complex and iron-zinc in iron deficiency anemia.
Ozsurekci, Y, Unal, S, Cetin, M, Gumruk, F
Minerva pediatrica. 2019;(5):449-454
Abstract
BACKGROUND The purpose of this study was to compare the effectiveness of different oral iron preparations in children with iron deficiency anemia (IDA). METHODS Sixty children with IDA, aged between 6 months and 180 months, were randomly assigned into three treatment groups. Group I included children with IDA who received ferrous sulfate (Fe-S); Group II included children receiving iron polymaltose complexes (Fe-OH-PM), and Group III included children receiving a single preparation of combined iron and zinc (Fe-Zn). The effect of different iron preparations were evaluated and compared. The duration of treatment was 8 weeks. Hemoglobin (Hgb) levels, as well as other hematological parameters were determined at admission and the first, fourth, and eighth weeks of the treatment. RESULTS The Hgb levels of patients in all three groups were statistically higher in the fourth (P=0.001) and eighth (P<0.001) weeks compared to baseline; although there was no difference between the groups at the end of the treatment period (P>0.05). CONCLUSIONS Our results indicate that, Fe-OH-PM and Fe-Zn preparations may also be preferred as a choice like Fe-S for treatment of children with IDA.