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Pre-operative iron increases haemoglobin concentration before abdominal surgery: a systematic review and meta-analysis of randomized controlled trials.
Meyer, J, Cirocchi, R, Di Saverio, S, Ris, F, Wheeler, J, Davies, RJ
Scientific reports. 2022;(1):2158
Abstract
Professional surgical societies recommend the identification and treatment of pre-operative anaemia in patients scheduled for abdominal surgery. Our aim was to determine if pre-operative iron allows correction of haemoglobin concentration and decreased incidence of peri-operative blood transfusion in patients undergoing major abdominal surgery. MEDLINE, Embase and CENTRAL were searched for RCTs written in English and assessing the effect of pre-operative iron on the incidence of peri-operative allogeneic blood transfusion in patients undergoing major abdominal surgery. Pooled relative risk (RR), risk difference (RD) and mean difference (MD) were obtained using models with random effects. Heterogeneity was assessed using the Q-test and quantified using the I2 value. Four RCTs were retained for analysis out of 285 eligible articles. MD in haemoglobin concentration between patients with pre-operative iron and patients without pre-operative iron was of 0.81 g/dl (3 RCTs, 95% CI 0.30 to 1.33, I2: 60%, p = 0.002). Pre-operative iron did not lead to reduction in the incidence of peri-operative blood transfusion in terms of RD (4 RCTs, RD: - 0.13, 95% CI - 0.27 to 0.01, I2: 65%, p = 0.07) or RR (4 RCTs, RR: 0.57, 95% CI 0.30 to 1.09, I2: 64%, p = 0.09). To conclude, pre-operative iron significantly increases haemoglobin concentration by 0.81 g/dl before abdominal surgery but does not reduce the need for peri-operative blood transfusion. Important heterogeneity exists between existing RCTs in terms of populations and interventions. Future trials should target patients suffering from iron-deficiency anaemia and assess the effect of intervention on anaemia-related complications.
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The effect of vitamin D supplementation on hemoglobin concentration: a systematic review and meta-analysis.
Arabi, SM, Ranjbar, G, Bahrami, LS, Vafa, M, Norouzy, A
Nutrition journal. 2020;(1):11
Abstract
AIMS: The purpose of this review was to investigate the effect of vitamin D supplements on hemoglobin concentration in subjects aged 17.5-68 years old; using randomized controlled trials (RCTs). METHODS Relevant RCT studies were identified from January 2000 to January 2019 by using MeSH terms in PubMed, Embase, Cochrane Library, Clinical trials, Scopus databases and gray literature. The studies were reviewed systematically, and quality assessments were evaluated by the guidelines of the Cochrane risk of bias. The effect of vitamin D supplements (n = 14) on hemoglobin concentration was considered as primary outcome, while its effects on the levels of ferritin, transferrin saturation and iron status were derived as secondary outcomes. In total, 1385 subjects with age range of 17.5 to 68 years old were examined for 3 h to 6 months; Mean (standard deviation) or median interquartile changes in the hemoglobin concentration in each treatment group was recorded for meta-analysis. RESULTS Fourteen RCTs met the inclusion criteria. Current study findings propose that vitamin D supplementation leads to a non-significant reduction in hemoglobin levels in subjects (17.5-68 years old) [std. mean difference (SMD): 0.01; 95% CI: - 0.28, 0.29; P = 0.95], also it has no significant effect on ferritin concentrations [std. mean difference (SMD): -0.01; 95% CI: [- 0.20, 0.18; P = 0.91]. However, vitamin D supplementation demonstrated positive effects on transferrin saturation [mean difference (MD): 1.54; 95% CI: 0.31, 2.76; P = 0.01] and iron status [std. mean difference (SMD): 0.24; 95% CI: - 0.09, 0.39; P = 0.002]. CONCLUSION Current review concluded that supplementation with vitamin D had no significant effect on hemoglobin and ferritin levels while positive effects on transferrin saturation and iron status were observed. Further clinical studies are required to determine the actual effect of this intervention on hemoglobin levels.
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Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.
Oskarsson, GR, Oddsson, A, Magnusson, MK, Kristjansson, RP, Halldorsson, GH, Ferkingstad, E, Zink, F, Helgadottir, A, Ivarsdottir, EV, Arnadottir, GA, et al
Communications biology. 2020;(1):189
Abstract
Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = -1.61 SD, CI95 = [-1.98, -1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.
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Effects of increased hemoglobin on child growth, development, and disease: a systematic review and meta-analysis.
Larson, LM, Kubes, JN, Ramírez-Luzuriaga, MJ, Khishen, S, H Shankar, A, Prado, EL
Annals of the New York Academy of Sciences. 2019;(1):83-104
Abstract
In children under 5, a hemoglobin (Hb) cutoff of 11 g/dL is recommended by the World Health Organization to define anemia, yet few studies have examined whether this cut point accurately coincides with negative functional consequences. This systematic review and meta-analysis of iron intervention and observational studies aimed to clarify the consequences of low Hb concentration in children under age 5 years on growth, development, and chronic disease (functional outcomes) across the full range of Hb values. A literature search returned 5049 studies; of these, 56 intervention and 20 observational studies fit the inclusion criteria. Among iron supplementation trials, a metaregression indicated significant associations between intervention effects on Hb and their effects on motor and mental development. For each 1 standard deviation (SD) increase in Hb, motor scores increased by 0.28 SD and mental scores increased by 0.24 SD. Iron supplementation trials among children with lower Hb concentrations at baseline showed stronger associations between their effects on Hb and their effects on mental development (P-interaction = 0.008). Heterogeneity among observational studies precluded calculation of pooled associations between Hb and functional outcomes. Available evidence was not able to establish an inflection point at which decreasing Hb begins to be associated with negative functional outcomes. Future research is needed to examine associations of Hb with growth and development in populations with varying levels of Hb, inflammation, and in different ages and settings.
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Maternal hemoglobin concentrations across pregnancy and maternal and child health: a systematic review and meta-analysis.
Young, MF, Oaks, BM, Tandon, S, Martorell, R, Dewey, KG, Wendt, AS
Annals of the New York Academy of Sciences. 2019;(1):47-68
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Abstract
Maternal anemia is a well-recognized global health problem; however, there remain questions on specific hemoglobin (Hb) thresholds that predict health risk or protection for mother and child. We conducted a systematic review and meta-analysis to examine the associations of maternal Hb concentrations with a range of maternal and infant health outcomes, accounting for the timing of measurement (preconception, and first, second, and third trimesters), etiology of anemia, and cutoff category. The systematic review included 272 studies and the meta-analysis included 95 studies. Low maternal Hb (<110 g/L) was associated with poor birth outcomes (low birth weight, preterm birth, small-for-gestational-age (SGA), stillbirth, and perinatal and neonatal mortality) and adverse maternal outcomes (postpartum hemorrhage, preeclampsia, and blood transfusion). High maternal Hb (>130 g/L) was associated with increased odds of SGA, stillbirth, preeclampsia, and gestational diabetes. Relationships varied by the timing of measurement and cutoff category (stronger associations with lower cutoffs); limited data were available on anemia etiology. There were insufficient data for other maternal outcomes and long-term child health outcomes. Current data are insufficient for determining if revisions to current Hb cutoffs are required. Pooled high-quality individual-level data analyses, as well as prospective cohort studies, would be valuable to inform the reevaluation of Hb cutoffs.
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The Effect of Perioperative Iron Therapy in Acute Major Non-cardiac Surgery on Allogenic Blood Transfusion and Postoperative Haemoglobin Levels: A Systematic Review and Meta-analysis.
Schack, A, Berkfors, AA, Ekeloef, S, Gögenur, I, Burcharth, J
World journal of surgery. 2019;(7):1677-1691
Abstract
BACKGROUND Perioperative anaemia in relation to surgery is associated with adverse clinical outcomes. In an elective surgical setting, it is possible to optimize patients prior to surgery, often by iron supplementation with correction of anaemia. Possibilities for optimization prior to and during acute surgical procedures are limited. This review investigates whether iron treatment initiated perioperatively improves outcomes in patients undergoing major acute non-cardiac surgery. METHOD This systematic review was performed using PubMed, EMBASE (Ovid) and Scopus to identify current evidence on iron supplementation in acute surgery. Primary outcomes were allogenic blood transfusion (ABT) rate and changes in haemoglobin. Secondary outcomes were postoperative mortality, length of stay (LOS), and postoperative complications. Iron was administered at latest within 24 h after end of surgery. RESULTS Of the 5413 studies screened, four randomized controlled trials and nine observational cohort studies were included. Ten studies included patients with hip fractures. A meta-analysis of seven studies showed a risk reduction of transfusion (OR = 0.35 CI 95% (0.20-0.63), p = 0.0004, I2 = 66%). No influence on plasma haemoglobin was found. Postoperative mortality was reduced in the iron therapy group in a meta-analysis of four observational studies (OR 0.50 (CI 95% 0.26-0.96) p = 0.04). No effect was found on LOS, but a reduction in postoperative infection was seen in four studies. CONCLUSIONS This review examined perioperative iron therapy in acute major non-cardiac surgery. IV iron showed a lower 30-day mortality, a reduction in postoperative infections and a reduction in ABT largely due to the observational studies. The review primarily consisted of small observational studies and does not have the power to formally recommend this practice.
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Intravenous iron therapy for non-anaemic, iron-deficient adults.
Miles, LF, Litton, E, Imberger, G, Story, D
The Cochrane database of systematic reviews. 2019;(12):CD013084
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Abstract
BACKGROUND Iron deficiency is one of the most common nutritional deficiencies, and has a number of physiological manifestations. Early, or non-anaemic iron deficiency can result in fatigue and diminished exercise capacity. Oral iron preparations have a high incidence of intolerable side effects, and are ineffective in certain forms of iron deficiency. Consequently, intravenous iron preparations are increasingly used in the treatment of non-anaemic iron deficiency. The newer, more stable iron preparations in particular purport to have a lower incidence of side effects, and are now used across a range of different patient populations. OBJECTIVES To assess the effects of intravenous iron therapy in the treatment of adults with non-anaemic iron deficiency. SEARCH METHODS On 18 October 2019 we electronically searched CENTRAL, MEDLINE, Embase, two further databases and two trials registries 2019. We handsearched the references of full-text extracted studies, and contacted relevant study authors for additional data. SELECTION CRITERIA We included randomised controlled trials that compared any intravenous iron preparation to placebo in adults. We excluded other forms of comparison such as oral iron versus placebo, intramuscular iron versus placebo, or intravenous iron studies where other iron preparations were used as the comparator. We also excluded studies involving erythropoietin therapy or obstetric populations. DATA COLLECTION AND ANALYSIS Two review authors screened references for eligibility, extracted data and assessed risk of bias. We resolved differences in opinion through discussion and consensus, and where necessary, involved a third review author to adjudicate disputes. We contacted study authors to request additional data where appropriate. The primary outcome measures were haemoglobin concentration at the end of follow-up, and quality-of-life scores at end of follow-up. Secondary outcome measures were serum ferritin, peak oxygen consumption (as measured by cardiopulmonary exercise testing), adverse effects (graded as mild to moderate and severe) and bacterial infection. We pooled data for continuous outcomes, which we then reported as mean differences (MDs) with 95% confidence intervals (CIs). We reported quality-of-life metrics as standardised mean difference (SMD), and then converted them back into a more familiar measure, the Piper Fatigue Scale. We analysed dichotomous outcomes as risk ratios (RRs). Given an expected degree of heterogeneity, we used a random-effects model for all outcomes. We performed the analysis with the software package Review Manager 5. MAIN RESULTS This review includes 11 studies with 1074 participants. Outcome metrics for which data were available (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Consequently, many outcomes are reported with small group sizes and wide confidence intervals, with a subsequent downgrading in the quality of evidence. The level of bias in many included studies was high, further reducing confidence in the robustness of the results. We found that intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L, 95% CI 0.65 to 5.42; I2 = 42%; 8 studies, 548 participants; low-quality evidence). Quality-of-life scores (Piper Fatigue Scale MD 0.73, 95% CI 0.29 to 1.18; I2 = 0%; studies = 3) and peak oxygen consumption (MD 2.77 mL/kg/min, 95% CI -0.89 to 6.43; I2 = 36%; 2 studies, 32 participants) were associated with very low-quality evidence, and we remain uncertain about the role of intravenous iron for these metrics. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity. Ultimately, despite the results of the meta-analysis, the low- or very low-quality evidence for all outcomes precludes any meaningful interpretation of results beyond suggesting that further research is needed. We performed a Trial Sequential Analysis for all major outcomes, none of which could be said to have reached a necessary effect size. AUTHORS' CONCLUSIONS Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient populations, beyond stating that it may result in a small, clinically insignificant increase in haemoglobin concentration. However, the certainty for even this outcome remains limited. Robust data for the effectiveness of intravenous iron for non-anaemic iron deficiency is still lacking, and larger studies are required to assess the effect of this therapy on laboratory, patient-centric, and adverse-effect outcomes.
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Impact of Double-Fortified Salt with Iron and Iodine on Hemoglobin, Anemia, and Iron Deficiency Anemia: A Systematic Review and Meta-Analysis.
Ramírez-Luzuriaga, MJ, Larson, LM, Mannar, V, Martorell, R
Advances in nutrition (Bethesda, Md.). 2018;(3):207-218
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Abstract
Double-fortified salt (DFS) containing iron and iodine has been proposed as a feasible and cost-effective alternative for iron fortification in low- and middle-income countries (LMICs). We conducted a systematic review and meta-analysis from randomized and quasi-randomized controlled trials to 1) assess the effect of DFS on biomarkers of iron status and the risk of anemia and iron deficiency anemia (IDA) and 2) evaluate differential effects of DFS by study type (efficacy or effectiveness), population subgroups, iron formulation (ferrous sulfate, ferrous fumarate, and ferric pyrophosphate), iron concentration, duration of intervention, and study quality. A systematic search with the use of MEDLINE, EMBASE, Cochrane, Web of Science, and other sources identified 221 articles. Twelve efficacy and 2 effectiveness studies met prespecified inclusion criteria. All studies were conducted in LMICs: 10 in India, 2 in Morocco, and 1 each in Côte d'Ivoire and Ghana. In efficacy studies, DFS increased hemoglobin concentrations [standardized mean difference (SMD): 0.28; 95% CI: 0.11, 0.44; P < 0.001] and reduced the risk of anemia (RR: 0.59; 95% CI: 0.46, 0.77; P < 0.001) and IDA (RR 0.37; 95% CI: 0.25, 0.54; P < 0.001). In effectiveness studies, the effect size for hemoglobin was smaller but significant (SMD: 0.03; 95% CI: 0.01, 0.05; P < 0.01). Stratified analyses of efficacy studies by population subgroups indicated positive effects of DFS among women and school-age children. For the latter, DFS increased hemoglobin concentrations (SMD: 0.32; 95% CI: 0.03, 0.60; P < 0.05) and reduced the risk of anemia (SMD: 0.48; 95% CI: 0.34, 0.67; P < 0.001) and IDA (SMD: 0.37; 95% CI: 0.25, 0.54; P < 0.001). Hemoglobin concentrations, anemia prevalence and deworming at baseline, sample size, and study duration were not associated with effect sizes. The results indicate that DFS is efficacious in increasing hemoglobin concentrations and reducing the risk of anemia and IDA in LMIC populations. More effectiveness studies are needed.
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The effect of vitamin B12 and folic acid supplementation on routine haematological parameters in older people: an individual participant data meta-analysis.
Smelt, AF, Gussekloo, J, Bermingham, LW, Allen, E, Dangour, AD, Eussen, SJ, Favrat, B, De Groot, LC, Kok, FJ, Kwok, T, et al
European journal of clinical nutrition. 2018;(6):785-795
Abstract
BACKGROUND/OBJECTIVES Low vitamin B12 and folate levels in community-dwelling older people are usually corrected with supplements. However, the effect of this supplementation on haematological parameters in older persons is not known. Therefore, we executed a systematic review and individual participant data meta-analysis of randomised placebo-controlled trials (RCTs). SUBJECTS/METHODS We performed a systematic search in PubMed, EMBASE, Web of Science, Cochrane and CENTRAL for RCTs published between January 1950 and April 2016, where community-dwelling elderly (60+ years) who were treated with vitamin B12 or folic acid or placebo. The presence of anaemia was not required. We analysed the data on haematological parameters with a two-stage IPD meta-analysis. RESULTS We found 494 full papers covering 14 studies. Data were shared by the authors of four RCTs comparing vitamin B12 with placebo (n = 343) and of three RCTs comparing folic acid with placebo (n = 929). We found no effect of vitamin B12 supplementation on haemoglobin (change 0.00 g/dL, 95% CI: -0.19;0.18), and no effect of folic acid supplementation (change -0.09 g/dL, 95% CI: -0.19;0.01). The effects of supplementation on other haematological parameters were similar. The effects did not differ by sex or by age group. Also, no effect was found in a subgroup of patients with anaemia and a subgroup of patients who were treated >4 weeks. CONCLUSIONS Evidence on the effects of supplementation of low concentrations of vitamin B12 and folate on haematological parameters in community-dwelling older people is inconclusive. Further research is needed before firm recommendations can be made concerning the supplementation of vitamin B12 and folate.
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Efficacy and Safety of Ferric Carboxymaltose and Other Formulations in Iron-Deficient Patients: A Systematic Review and Network Meta-analysis of Randomised Controlled Trials.
Rognoni, C, Venturini, S, Meregaglia, M, Marmifero, M, Tarricone, R
Clinical drug investigation. 2016;(3):177-94
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BACKGROUND Iron deficiency is very common in a number of medical conditions. Ferric carboxymaltose is a new stable iron preparation that can be administered in single infusions over short periods of time. The aim of this study was to conduct a systematic review of randomised controlled trials (RCTs) regarding the efficacy and safety of the novel complex compared with other iron formulations. In addition, the feasibility of a network meta-analysis for indirect comparisons was investigated. METHODS A systematic literature review was performed for published RCTs on the use of ferric carboxymaltose in iron deficiency between July and October 2014. Indirect comparisons were also addressed using terms referring to competing iron formulations. We further supported the qualitative results of the systematic review by a network meta-analysis that allows pooling the evidence around different intervention outcomes in the absence of trials involving a direct comparison. RESULTS The initial search yielded 1027 citations, which was decreased to 21 studies eligible for inclusion in the review. Studies were heterogeneous in the number of patients randomised, iron deficiency-related conditions addressed, trial inclusion criteria, time horizon, treatment dosage and outcomes assessed. Six studies with the same time horizon (i.e. 6 weeks) were included in the network meta-analysis. Considering the differences between final and initial outcome values for each iron formulation, the mean difference of these differences (delta) was estimated for each couple of treatments involving ferric carboxymaltose. Significant improvements in serum ferritin (µg/l) were obtained with ferric carboxymaltose compared to oral iron (delta 172.8; 95 % CI 66.7-234.4) and in haemoglobin (g/dl) with respect to ferric gluconate (delta 0.6; 95 % CI 0.2-0.9), oral iron (delta 0.8; 95 % CI 0.6-0.9) and placebo (delta 2.1; 95 % CI 1.2-3.0). CONCLUSIONS All currently available intravenous iron preparations appear to be safe and effective, but ferric carboxymaltose seems to provide a better and quicker correction of haemoglobin and serum ferritin levels in iron-deficient patients.