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Iron therapy for preoperative anaemia.
Ng, O, Keeler, BD, Mishra, A, Simpson, JA, Neal, K, Al-Hassi, HO, Brookes, MJ, Acheson, AG
The Cochrane database of systematic reviews. 2019;(12):CD011588
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Abstract
BACKGROUND Preoperative anaemia is common and occurs in 5% to 76% of patients preoperatively. It is associated with an increased risk of perioperative allogeneic blood transfusion, longer hospital stay, and increased morbidity and mortality. Iron deficiency is one of the most common causes of anaemia. Oral and intravenous iron therapy can be used to treat anaemia. Parenteral iron preparations have been shown to be more effective in conditions such as inflammatory bowel disease, chronic heart failure and postpartum haemorrhage due to rapid correction of iron stores. A limited number of studies has investigated iron therapy for the treatment of preoperative anaemia. The aim of this Cochrane Review is to summarise the evidence for iron supplementation, both enteral and parenteral, for the management of preoperative anaemia. OBJECTIVES To evaluate the effects of preoperative iron therapy (enteral or parenteral) in reducing the need for allogeneic blood transfusions in anaemic patients undergoing surgery. SEARCH METHODS We ran the search on 30 July 2018. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic and Embase (Ovid), CINAHL Plus (EBSCO), PubMed, and clinical trials registries, and we screened reference lists. We ran a top-up search on 28 November 2019; one study is now awaiting classification. SELECTION CRITERIA We included all randomised controlled trials (RCTs) that compared preoperative iron monotherapy to placebo, no treatment, standard care or another form of iron therapy for anaemic adults undergoing surgery. We defined anaemia as haemoglobin values less than 13 g/dL for males and 12 g/dL for non-pregnant females. DATA COLLECTION AND ANALYSIS Two review authors collected data and a third review author checked all collected data. Data were collected on the proportion of patients who receive a blood transfusion, the amount of blood transfused per patient (units), quality of life, ferritin levels and haemoglobin levels, measured as continuous variables at the following predetermined time points: pretreatment (baseline), preoperatively but postintervention, and postoperatively. We performed statistical analysis using the Cochrane software, Review Manager 5. We summarised outcome data in tables and forest plots. We used the GRADE approach to describe the quality of the body of evidence. MAIN RESULTS Six RCTs, with a total of 372 participants, evaluated preoperative iron therapy to correct anaemia before planned surgery. Four studies compared iron therapy (either oral (one study) or intravenous (three studies)) with no treatment, placebo or usual care, and two studies compared intravenous iron therapy with oral iron therapy. Iron therapy was delivered over a range of periods that varied from 48 hours to three weeks prior to surgery. The 372 participants in our analysis fall far short of the 819 required - as calculated by our information size calculation - to detect a 30% reduction in blood transfusions. Five trials, involving 310 people, reported the proportion of participants who received allogeneic blood transfusions. Meta-analysis of iron therapy versus placebo or standard care showed no difference in the proportion of participants who received a blood transfusion (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.87 to 1.70; 4 studies, 200 participants; moderate-quality evidence). Only one study that compared oral versus intravenous iron therapy measured this outcome, and reported no difference in risk of transfusion between groups. There was no difference between the iron therapy and placebo/standard care groups for haemoglobin level preoperatively at the end of the intervention (mean difference (MD) 0.63 g/dL, 95% CI -0.07 to 1.34; 2 studies, 83 participants; low-quality evidence). However, intravenous iron therapy produced an increase in preoperative postintervention haemoglobin levels compared with oral iron (MD 1.23 g/dL, 95% CI 0.80 to 1.65; 2 studies, 172 participants; low-quality evidence). Ferritin levels were increased by intravenous iron, both when compared to standard care ((MD 149.00, 95% CI 25.84 to 272.16; 1 study, 63 participants; low-quality evidence) or to oral iron (MD 395.03 ng/mL, 95% CI 227.72 to 562.35; 2 studies, 151 participants; low-quality evidence). Not all studies measured quality of life, short-term mortality or postoperative morbidity. Some measured the outcomes, but did not report the data, and the studies which did report the data were underpowered. Therefore, uncertainty remains regarding these outcomes. The inclusion of new research in the future is very likely to change these results. AUTHORS' CONCLUSIONS The use of iron therapy for preoperative anaemia does not show a clinically significant reduction in the proportion of trial participants who received an allogeneic blood transfusion compared to no iron therapy. Results for intravenous iron are consistent with a greater increase in haemoglobin and ferritin when compared to oral iron, but do not provide reliable evidence. These conclusions are drawn from six studies, three of which included very small numbers of participants. Further, well-designed, adequately powered, RCTs are required to determine the true effectiveness of iron therapy for preoperative anaemia. Two studies are currently in progress, and will include 1500 randomised participants.
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Intermittent iron supplementation for reducing anaemia and its associated impairments in adolescent and adult menstruating women.
Fernández-Gaxiola, AC, De-Regil, LM
The Cochrane database of systematic reviews. 2019;(1):CD009218
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BACKGROUND Anaemia is a condition in which the number of red blood cells is insufficient to meet physiologic needs; it is caused by many conditions, particularly iron deficiency. Traditionally, daily iron supplementation has been a standard practice for preventing and treating anaemia. However, its long-term use has been limited, as it has been associated with adverse side effects such as nausea, constipation, and teeth staining. Intermittent iron supplementation has been suggested as an effective and safer alternative to daily iron supplementation for preventing and reducing anaemia at the population level, especially in areas where this condition is highly prevalent. OBJECTIVES To assess the effects of intermittent oral iron supplementation, alone or in combination with other nutrients, on anaemia and its associated impairments among menstruating women, compared with no intervention, a placebo, or daily supplementation. SEARCH METHODS In February 2018, we searched CENTRAL, MEDLINE, Embase, nine other databases, and two trials registers. In March 2018, we also searched LILACS, IBECS and IMBIOMED. In addition, we examined reference lists, and contacted authors and known experts to identify additional studies. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs with either individual or cluster randomisation. Participants were menstruating women; that is, women beyond menarche and prior to menopause who were not pregnant or lactating and did not have a known condition that impeded the presence of menstrual periods. The intervention was the use of iron supplements intermittently (one, two or three times a week on non-consecutive days) compared with placebo, no intervention, or the same supplements provided on a daily basis. DATA COLLECTION AND ANALYSIS Both review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies, checked data entry for accuracy, assessed the risk of bias of the included studies, and rated the quality of the evidence using GRADE. MAIN RESULTS We included 25 studies involving 10,996 women. Study methods were not well described in many of the included studies and thus assessing risk of bias was difficult. The main limitations of the studies were lack of blinding and high attrition. Studies were mainly funded by international organisations, universities, and ministries of health within the countries. Approximately one third of the included studies did not provide a funding source.Although quality across studies was variable, the results consistently showed that intermittent iron supplementation (alone or with any other vitamins and minerals) compared with no intervention or a placebo, reduced the risk of having anaemia (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.49 to 0.87; 11 studies, 3135 participants; low-quality evidence), and improved the concentration of haemoglobin (mean difference (MD) 5.19 g/L, 95% CI 3.07 to 7.32; 15 studies, 2886 participants; moderate-quality evidence), and ferritin (MD 7.46 μg/L, 95% CI 5.02 to 9.90; 7 studies, 1067 participants; low-quality evidence). Intermittent regimens may also reduce the risk of having iron deficiency (RR 0.50, 95% CI 0.24 to 1.04; 3 studies, 624 participants; low-quality evidence), but evidence was inconclusive regarding iron deficiency anaemia (RR 0.07, 95% CI 0.00 to 1.16; 1 study, 97 participants; very low-quality evidence) and all-cause morbidity (RR 1.12, 95% CI 0.82 to 1.52; 1 study, 119 participants; very low-quality evidence). Women in the control group were less likely to have any adverse side effects than those receiving intermittent iron supplements (RR 1.98, 95% CI 0.31 to 12.72; 3 studies, 630 participants; moderate-quality evidence).In comparison with daily supplementation, results showed that intermittent supplementation (alone or with any other vitamins and minerals) produced similar effects to daily supplementation (alone or with any other vitamins and minerals) on anaemia (RR 1.09, 95% CI 0.93 to 1.29; 8 studies, 1749 participants; moderate-quality evidence). Intermittent supplementation may produce similar haemoglobin concentrations (MD 0.43 g/L, 95% CI -1.44 to 2.31; 10 studies, 2127 participants; low-quality evidence) but lower ferritin concentrations on average (MD -6.07 μg/L, 95% CI -10.66 to -1.48; 4 studies, 988 participants; low-quality evidence) compared to daily supplementation. Compared to daily regimens, intermittent regimens may also reduce the risk of having iron deficiency (RR 4.30, 95% CI 0.56 to 33.20; 1 study, 198 participants; very low-quality evidence). Women receiving iron supplements intermittently were less likely to have any adverse side effects than those receiving iron supplements daily (RR 0.41, 95% CI 0.21 to 0.82; 6 studies, 1166 participants; moderate-quality evidence). No studies reported on the effect of intermittent regimens versus daily regimens on iron deficiency anaemia and all-cause morbidity.Information on disease outcomes, adherence, economic productivity, and work performance was scarce, and evidence about the effects of intermittent supplementation on these outcomes unclear.Overall, whether the supplements were given once or twice weekly, for less or more than three months, contained less or more than 60 mg of elemental iron per week, or given to populations with different degrees of anaemia at baseline did not seem to affect the findings. Furthermore, the response did not differ in areas where malaria was frequent, although very few trials were conducted in these settings. AUTHORS' CONCLUSIONS Intermittent iron supplementation may reduce anaemia and may improve iron stores among menstruating women in populations with different anaemia and malaria backgrounds. In comparison with daily supplementation, the provision of iron supplements intermittently is probably as effective in preventing or controlling anaemia. More information is needed on morbidity (including malaria outcomes), side effects, work performance, economic productivity, depression, and adherence to the intervention. The quality of this evidence base ranged from very low to moderate quality, suggesting that we are uncertain about these effects.
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Dietary intake of heme iron and body iron status are associated with the risk of gestational diabetes mellitus: a systematic review and meta-analysis.
Zhao, L, Lian, J, Tian, J, Shen, Y, Ping, Z, Fang, X, Min, J, Wang, F
Asia Pacific journal of clinical nutrition. 2017;(6):1092-1106
Abstract
BACKGROUND AND OBJECTIVES Some potential role of iron overload in the development of diabetes mellitus have been suggested. Our study aimed to systematically assess the association between the risk of gestational diabetes mellitus (GDM) and iron intakes/body iron status. METHODS AND STUDY DESIGN PubMed and Web of Science were searched for relevant articles. Relative risks (RR) of GDM in relation to dietary iron intakes and body iron stores were pooled with the random-effects model. Weighted mean differences of iron blood markers between GDM and non-GDM individuals were also analyzed. RESULTS Twenty-five studies were included in the qualitative analysis, and 23 studies with 29,378 participants and 3,034 GDM patients were included in the quantitative analysis. Dietary intake of heme iron was significantly associated with GDM risk (RR=1.65, 95% CI: 1.28 to 2.12), and the pooled RR for each 1mg/day increment of heme iron intake was 1.38 (95% CI: 1.19 to 1.61). No association between GDM and the intakes of nonheme iron, total iron, or supplemental iron was detected. Body iron stores, as represented by serum ferritin level, were correlated with GDM risk (RR=1.64, 95% CI: 1.27 to 2.11). Moreover, the concentrations of both serum ferritin and serum iron were increased in GDM patients, compared with non-GDM individuals. CONCLUSIONS Increased dietary intake of heme iron and body iron status are positively associated with the risk of GDM development in pregnant women. Future studies are warranted to better understand the role of iron in GDM development.
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High maternal iron status, dietary iron intake and iron supplement use in pregnancy and risk of gestational diabetes mellitus: a prospective study and systematic review.
Khambalia, AZ, Aimone, A, Nagubandi, P, Roberts, CL, McElduff, A, Morris, JM, Powell, KL, Tasevski, V, Nassar, N
Diabetic medicine : a journal of the British Diabetic Association. 2016;(9):1211-21
Abstract
AIM: High iron measured using dietary intake and biomarkers is associated with Type 2 diabetes. It is uncertain whether a similar association exists for gestational diabetes mellitus. The aim of this systematic review was to conduct a cohort study examining first trimester body iron stores and subsequent risk of gestational diabetes, and to include these findings in a systematic review of all studies examining the association between maternal iron status, iron intake (dietary and supplemental) and the risk of gestational diabetes. METHODS Serum samples from women with first trimester screening were linked to birth and hospital records for data on maternal characteristics and gestational diabetes diagnosis. Blood was analysed for ferritin, soluble transferrin receptor and C-reactive protein. Associations between iron biomarkers and gestational diabetes were assessed using multivariate logistic regression. A systematic review and meta-analysis, registered with PROSPERO (CRD42014013663) included studies of all designs published in English from January 1995 to July 2015 that examined the association between iron and gestational diabetes and included an appropriate comparison group. RESULTS Of 3776 women, 3.4% subsequently developed gestational diabetes. Adjusted analyses found increased odds of gestational diabetes for ferritin (OR 1.41; 95% CI 1.11, 1.78), but not for soluble transferrin receptor (OR 1.00; 95% CI 0.97, 1.03) per unit increase of the biomarker. Two trials of iron supplementation found no association with gestational diabetes. Increased risk of gestational diabetes was associated with higher levels of ferritin and serum iron and dietary haem iron intakes. CONCLUSIONS Increased risk of gestational diabetes among women with high serum ferritin and iron levels and dietary haem iron intakes warrants further investigation.
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The Relationship Between Body Iron Status, Iron Intake And Gestational Diabetes: A Systematic Review and Meta-Analysis.
Fu, S, Li, F, Zhou, J, Liu, Z
Medicine. 2016;(2):e2383
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Biological and epidemiological evidence have found that gestational diabetes mellitus (GDM) may be correlated with body iron status and dietary iron intake. Therefore, we investigated the relationship between dietary iron intake and body iron status and GDM risk.We conducted a systematic search in Embase, PubMed, Web of Science, and Cochrane Library up to April 2015. Prospective cohort studies or case-control studies which appraised the relationship between body iron status, dietary iron intake, and GDM risk were included. Relative risks (RRs), standard mean difference (SMD), and 95% confidence intervals [CIs] were used to measure the pooled data.A total of 8 prospective cohort studies and 7 case-control studies were in accordance with inclusive criteria, and 14 studies were included in meta-analysis. The overall RR comparing the highest and lowest levels of serum ferritin was 3.22 (95% CI: 1.73-6.00) for prospective cohort studies. Serum ferritin of GDM group is markedly higher than that of control (0.88 ng/mL; 95% CI: 0.40-1.35 ng/mL) for case-control studies. The comparison between the highest and the lowest serum ferritin levels and dietary total iron levels revealed pooled RRs of 1.53 (95% CI: 1.17-2.00) and 1.01 (95% CI: 1.00-1.01) for prospective cohort studies, respectively. The combined SMD comparing serum transferrin levels of cases and controls was -0.02 μmol/L (95% CI: -0.22 to 0.19 μmol/L) for case-control studies.Increased higher ferritin levels were significantly correlated with higher risk of GDM, and higher heme iron levels may be correlated with higher risk of GDM; however, the present conclusion did not constitute definitive proof that dietary total iron or serum transferrin have relation to GDM.
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Intermittent oral iron supplementation during pregnancy.
Peña-Rosas, JP, De-Regil, LM, Gomez Malave, H, Flores-Urrutia, MC, Dowswell, T
The Cochrane database of systematic reviews. 2015;(10):CD009997
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BACKGROUND Anaemia is a frequent condition during pregnancy, particularly among women in low- and middle-income countries. Traditionally, gestational anaemia has been prevented with daily iron supplements throughout pregnancy, but adherence to this regimen due to side effects, interrupted supply of the supplements, and concerns about safety among women with an adequate iron intake, have limited the use of this intervention. Intermittent (i.e. two or three times a week on non-consecutive days) supplementation has been proposed as an alternative to daily supplementation. OBJECTIVES To assess the benefits and harms of intermittent supplementation with iron alone or in combination with folic acid or other vitamins and minerals to pregnant women on neonatal and pregnancy outcomes. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2015), the WHO International Clinical Trials Registry Platform (ICTRP) (31 July 2015) and contacted relevant organisations for the identification of ongoing and unpublished studies (31 July 2015). SELECTION CRITERIA Randomised or quasi-randomised trials. DATA COLLECTION AND ANALYSIS We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. MAIN RESULTS This review includes 27 trials from 15 countries, but only 21 trials (with 5490 women) contributed data to the review. All studies compared daily versus intermittent iron supplementation. The methodological quality of included studies was mixed and most had high levels of attrition.The overall assessment of the quality of the evidence for primary infant outcomes was low and for maternal outcomes very low.Of the 21 trials contributing data, three studies provided intermittent iron alone, 14 intermittent iron + folic acid and four intermittent iron plus multiple vitamins and minerals in comparison with the same composition of supplements provided in a daily regimen.Overall, for women receiving any intermittent iron regimen (with or without other vitamins and minerals) compared with a daily regimen there was no clear evidence of differences between groups for any infant primary outcomes: low birthweight (average risk ratio (RR) 0.82; 95% confidence interval (CI) 0.55 to 1.22; participants = 1898; studies = eight; low quality evidence), infant birthweight (mean difference (MD) 5.13 g; 95% CI -29.46 to 39.72; participants = 1939; studies = nine; low quality evidence), premature birth (average RR 1.03; 95% CI 0.76 to 1.39; participants = 1177; studies = five; low quality evidence), or neonatal death (average RR 0.49; 95% CI 0.04 to 5.42; participants = 795; studies = one; very low quality). None of the studies reported congenital anomalies.For maternal outcomes, there was no clear evidence of differences between groups for anaemia at term (average RR 1.22; 95% CI 0.84 to 1.80; participants = 676; studies = four; I² = 10%; very low quality). Women receiving intermittent supplementation had fewer side effects (average RR 0.56; 95% CI 0.37 to 0.84; participants = 1777; studies = 11; I² = 87%; very low quality) and were at lower risk of having high haemoglobin (Hb) concentrations (greater than 130 g/L) during the second or third trimester of pregnancy (average RR 0.53; 95% CI 0.38 to 0.74; participants = 2616; studies = 15; I² = 52%; (this was not a primary outcome)) compared with women receiving daily supplements. There were no significant differences in iron-deficiency anaemia at term between women receiving intermittent or daily iron + folic acid supplementation (average RR 0.71; 95% CI 0.08 to 6.63; participants = 156; studies = one). There were no maternal deaths (six studies) or women with severe anaemia in pregnancy (six studies). None of the studies reported on iron deficiency at term or infections during pregnancy.Most of the studies included in the review (14/21 contributing data) compared intermittent oral iron + folic acid supplementation compared with daily oral iron + folic acid supplementation (4653 women) and findings for this comparison broadly reflect findings for the main comparison (any intermittent versus any daily regimen).Three studies with 464 women examined supplementation with intermittent oral iron alone compared with daily oral iron alone. There were no clear differences between groups for mean birthweight, preterm birth, maternal anaemia or maternal side effects. Other primary outcomes were not reported.Four studies with a combined sample size of 412 women compared intermittent oral iron + vitamins and minerals supplementation with daily oral iron + vitamins and minerals supplementation. Results were not reported for any of the review's infant primary outcomes. One study reported fewer maternal side effects in the intermittent iron group, and two studies that more women were anaemic at term compared with those receiving daily supplementation.Where sufficient data were available for primary outcomes, we set up subgroups to look for possible differences between studies in terms of earlier or later supplementation; women's anaemia status at the start of supplementation; higher and lower weekly doses of iron; and the malarial status of the region in which the trials were conducted. There was no clear effect of these variables on results. AUTHORS' CONCLUSIONS This review is the most comprehensive summary of the evidence assessing the benefits and harms of intermittent iron supplementation in pregnant women on haematological and pregnancy outcomes. Findings suggest that intermittent regimens produced similar maternal and infant outcomes as daily supplementation but were associated with fewer side effects and reduced the risk of high levels of Hb in mid and late pregnancy, although the risk of mild anaemia near term was increased. While the quality of the evidence was assessed as low or very low, intermittent may be a feasible alternative to daily iron supplementation among those pregnant women who are not anaemic and have adequate antenatal care.
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Dietary intake of iron, zinc, copper, and risk of Parkinson's disease: a meta-analysis.
Cheng, P, Yu, J, Huang, W, Bai, S, Zhu, X, Qi, Z, Shao, W, Xie, P
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2015;(12):2269-75
Abstract
Although some studies have reported the associations between specific metal element intake and risk of Parkinson's disease (PD), the associations between specific metal element intake such as iron intake and PD are still conflicted. We aimed to determine whether intake of iron, zinc, and copper increases/decreases the risk of PD. PubMed, Embase, Web of Knowledge, and Google Scholar were searched. We pooled the multivariate-adjusted relative risks (RRs) or odds ratios using random effects. Study quality was evaluated by the Newcastle-Ottawa Scale. Five studies including 126,507 individuals remained for inclusion, pooled RRs of Parkinson's disease for moderate dietary iron intake was 1.08 (95 % CI 0.61-1.93, P = 0.787), and for high dietary iron intake was (1.03, 95 % CI 0.83-1.30, P = 0.766), respectively. The pooled RRs of Parkinson's disease for the highest compared with the lowest dietary iron intake were 1.47 (95 % CI 1.17-1.85, P = 0.001) in western population and in males (RR = 1.43, 95 % CI 1.01-2.01, P = 0.041). The pooled RRs of Parkinson's disease for moderate or high intake of zinc, and copper were not statistically different (P > 0.05). PD increased by 18 % (RR 1.18, 95 % CI 1.02-1.37) for western population by every 10-mg/day increment in iron intake. Higher iron intake appears to be not associated with overall PD risk, but may be associated with risk of PD in western population. Sex may be a factor influencing PD risk for higher iron intake. However, further studies are still needed to confirm the sex-selective effects.
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Intakes of heme iron and zinc and colorectal cancer incidence: a meta-analysis of prospective studies.
Qiao, L, Feng, Y
Cancer causes & control : CCC. 2013;(6):1175-83
Abstract
BACKGROUND Epidemiologic findings concerning the associations between intakes of heme iron and zinc and colorectal cancer (CRC) incidence yielded conflicting results. We aimed to investigate the associations by performing a meta-analysis of prospective studies. METHODS We conducted a literature search on PubMed and EMBASE databases up to December 2012 to identify the prospective studies that investigated the relationships between heme iron or zinc intake and risk of CRC. We also reviewed the bibliographies of the retrieved articles to identify additional studies. We used a random-effects model to calculate the summary relative risks (RRs) with 95 % confidence intervals (CIs). RESULTS Eight studies on heme iron intake and six studies on zinc intake met the inclusion criteria. The summary RR of CRC for the highest versus the lowest intake was 1.14 (95 % CI = 1.04-1.24) for heme iron and 0.83 (95 % CI = 0.72-0.94) for zinc, respectively. The observed associations were not significantly modified by subsites within the colorectum, sex, geographic area, study duration, the number of cases, or the range of intakes. In the dose-response analyses, the summary RR of CRC was 1.11 (95 % CI = 1.03-1.18) for heme iron intake of 1 mg/day, and 0.86 (95 % CI = 0.78-0.96) for zinc intake of 5 mg/day, respectively. There was little evidence of publication bias. CONCLUSION This meta-analysis suggests a significant positive dose-response association of heme iron intake and a significant inverse dose-response association of zinc intake with risk of CRC.
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Intermittent oral iron supplementation during pregnancy.
Peña-Rosas, JP, De-Regil, LM, Dowswell, T, Viteri, FE
The Cochrane database of systematic reviews. 2012;(7):CD009997
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BACKGROUND Anaemia is a frequent condition during pregnancy, particularly among women from developing countries who have insufficient iron intake to meet increased iron needs of both the mother and the fetus.Traditionally, gestational anaemia has been prevented with the provision of daily iron supplements throughout pregnancy, but adherence to this regimen due to side effects, interrupted supply of the supplements, and concerns about safety among women with an adequate iron intake, have limited the use of this intervention. Intermittent (i.e. one, two or three times a week on non-consecutive days) supplementation with iron alone or in combination with folic acid or other vitamins and minerals has recently been proposed as an alternative to daily supplementation. OBJECTIVES To assess the benefits and harms of intermittent supplementation with iron alone or in combination with folic acid or other vitamins and minerals to pregnant women on neonatal and pregnancy outcomes. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 March 2012). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) for ongoing studies and contacted relevant organisations for the identification of ongoing and unpublished studies (23 March 2012). SELECTION CRITERIA Randomised or quasi-randomised trials. DATA COLLECTION AND ANALYSIS We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. MAIN RESULTS This review includes 21 trials from 13 different countries, but only 18 trials (with 4072 women) reported on our outcomes of interest and contributed data to the review. All of these studies compared daily versus intermittent iron supplementation.Three studies provided iron alone, 12 iron+folic acid and three more iron plus multiple vitamins and minerals. Their methodological quality was mixed and most had high levels of attrition. Overall, there was no clear evidence of differences between groups for infant primary outcomes: low birthweight (average risk ratio (RR) 0.96; 95% confidence interval (CI) 0.61 to 1.52, seven studies), infant birthweight (mean difference MD -8.62 g; 95% CI -52.76 g to 35.52 g, eight studies), premature birth (average RR 1.82; 95% CI 0.75 to 4.40, four studies). None of the studies reported neonatal deaths or congenital anomalies.For maternal outcomes, there was no clear evidence of differences between groups for anaemia at term (average RR 1.22; 95% CI 0.84 to 1.80, four studies) and women receiving intermittent supplementation had less side effects (average RR 0.56; 95% CI 0.37 to 0.84, 11 studies) than those receiving daily supplements. Women receiving intermittent supplements were also at lower risk of having high haemoglobin (Hb) concentrations (greater than 130 g/L) during the second or third trimester of pregnancy (average RR 0.48; 95% CI 0.35 to 0.67, 13 studies). There were no significant differences in iron-deficiency anaemia between women receiving intermittent or daily iron+folic acid supplementation (average RR 0.71; 95% CI 0.08 to 6.63, 1 study). There were no maternal deaths (six studies) or women with severe anaemia in pregnancy (six studies). None of the studies reported on iron deficiency at term or infections during pregnancy.Where sufficient data were available for primary outcomes, we set up subgroups to look for possible differences between studies in terms of earlier or later supplementation; women's anaemia status at the start of supplementation; higher and lower weekly doses of iron; and the malarial status of the region in which the trials were conducted. There was no clear effect of these variables on the results of the review. AUTHORS' CONCLUSIONS The present systematic review is the most comprehensive summary of the evidence assessing the benefits and harms of intermittent iron supplementation regimens in pregnant women on haematological and pregnancy outcomes. The findings suggest that intermittent iron+folic acid regimens produce similar maternal and infant outcomes at birth as daily supplementation but are associated with fewer side effects. Women receiving daily supplements had increased risk of developing high levels of Hb in mid and late pregnancy but were less likely to present mild anaemia near term. Although the evidence is limited and the quality of the trials was low or very low, intermittent may be a feasible alternative to daily iron supplementation among those pregnant women who are not anaemic and have adequate antenatal care.
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Effect of iron intake on iron status: a systematic review and meta-analysis of randomized controlled trials.
Casgrain, A, Collings, R, Harvey, LJ, Hooper, L, Fairweather-Tait, SJ
The American journal of clinical nutrition. 2012;(4):768-80
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BACKGROUND The response of status biomarkers to an increase in iron supply depends on several physiologic and environmental factors, which make it difficult to predict the outcome of an intervention. OBJECTIVE We assessed effects of baseline iron status, sex, menopausal status, duration of intervention, iron form, and daily dose on the change in iron status in response to iron supplementation. DESIGN A systematic review of randomized controlled trials (RCTs) of iron-supplementation and -fortification trials that assessed effects on hemoglobin, serum ferritin (SF), soluble transferrin receptor, or body iron was conducted. Subgrouping and straight-line and curved metaregression were used to describe the magnitude and dose-responsiveness of effect modifiers with respect to changes in status. RESULTS Forty-one RCTs were included; none of the RCTs were judged at low risk of bias. Random-effects meta-analyses showed that iron supplementation significantly improved iron status but with high levels of heterogeneity. Metaregression explained approximately one-quarter of between-study variance in effect size. There were clear effects on SF with study duration (increase in SF concentration/wk: 0.51 μg/L; 95% CI: 0.02, 1.00 μg/L; P = 0.04) and dose (increase in SF concentration/g Fe: 0.10 μg/L; 95% CI: 0.01, 0.20 μg/L; P = 0.036) and on hemoglobin concentrations with baseline iron status [-0.08 g/dL (95% CI: 0.15, 0.00 g/dL) per 10-μg/L increase in baseline SF concentration; P = 0.02]. Insufficient data were available to assess effects on body iron, sex, or menopausal status. CONCLUSION Quantitative relations between baseline iron status, study duration, and iron dose on changes in iron-status biomarkers, which were generated from the meta-analyses, can be used to predict effects of trials of iron supplementation and fortification and to design iron-intervention programs.