Document 03 : Cost comparison, efficacy and safety of intravenous iron infusion versus push in maintenance haemodialysis patients in a tertiary care centre
Summary  : 5%
We did a comparison of the cost, safety and efficacy of paraenteral iron in two groups of patients who were on maintenance haemodialysis at a tertiary care centre. Group B (20) received iron as a push at the end of dialysis. It was administered as an infusion in normal saline 100ml over 30 to 60minutes for fear of serious adverse reactions some of which could be life threatening1. The aim of the present study was to investigate the cost, safety and efficacy of administering a 100mg IV bolus (push) of Iron sucrose to prevalent MHD patients. Administration of 100 mg of Iron Sucrose as an intravenous bolus injection over 2 to 3 minutes is a practical dosing regimen in patients on MHD.

Document 03 : Cost comparison, efficacy and safety of intravenous iron infusion versus push in maintenance haemodialysis patients in a tertiary care centre
Summary  : 10%
We did a comparison of the cost, safety and efficacy of paraenteral iron in two groups of patients who were on maintenance haemodialysis at a tertiary care centre. Group A (18) received iron as an infusion therapy in normal saline over 30-60 minutes at the end of dialysis. Group B (20) received iron as a push at the end of dialysis. It was administered as an infusion in normal saline 100ml over 30 to 60minutes for fear of serious adverse reactions some of which could be life threatening1. The aim of the present study was to investigate the cost, safety and efficacy of administering a 100mg IV bolus (push) of Iron sucrose to prevalent MHD patients. Thirty Eight patients were receiving recombinant human erythropoietin alpha or beta 75 to 125 units/kg weight (4000 IU to 10000IU/week) In addition to recording demographic data, hemoglobin and Serum Iron, TIBC, TSAT levels, epoetin doses were recorded at the time of the injection. Administration of 100 mg of Iron Sucrose as an intravenous bolus injection over 2 to 3 minutes is a practical dosing regimen in patients on MHD. In some patients, IV iron may improve hemoglobin levels even before erythropoietic therapy is started, whereas concomitant use of IV iron along with EPO can enhance the eyrythropoietic response and reduce dose requirements of EPO. Infusions of iron lasting an hour or more are impractical for administration in the outpatient setting and the ability to administer IV iron as a bolus injection over a few minutes has obvious advantages. As a result of the outcome of this study, our unit has adopted this protocol (which administers IV iron sucrose more rapidly than the product license stipulates) for the administration of IV iron to patients with CKD.

Document 03 : Cost comparison, efficacy and safety of intravenous iron infusion versus push in maintenance haemodialysis patients in a tertiary care centre
Summary  : 25%
Dialysis Unit, Chennai Transplant Centre - Madras Medical Mission and SRMC, Chennai. We did a comparison of the cost, safety and efficacy of paraenteral iron in two groups of patients who were on maintenance haemodialysis at a tertiary care centre. Group A (18) received iron as an infusion therapy in normal saline over 30-60 minutes at the end of dialysis. Group B (20) received iron as a push at the end of dialysis. A total of 194 injections were given including 93 times in group A and 101 times in group B. There were no serious adverse reactions in either group and the efficacy was similar. However there was a great difference in the cost analysis favoring intravenous push as the treatment of choice. Hence, we recommend intravenous push in patients who are receiving paraenteral iron. Paraenteral Iron supplementation is an integral part of the management of anemia in dialysis patients who are iron deficient. This was accomplished through intramuscular or intravenous route. It was administered as an infusion in normal saline 100ml over 30 to 60minutes for fear of serious adverse reactions some of which could be life threatening1. The additional cost incurred in administering iron as IV infusion added to the overall cost. Hence, we conducted a prospective study in maintenance haemodialysis patients (MHD) of the administration of Iron Sucrose as IV push2. The aim of the present study was to investigate the cost, safety and efficacy of administering a 100mg IV bolus (push) of Iron sucrose to prevalent MHD patients. No test dose was given to any of the patients in the current study. Thirty Eight patients were receiving recombinant human erythropoietin alpha or beta 75 to 125 units/kg weight (4000 IU to 10000IU/week) In addition to recording demographic data, hemoglobin and Serum Iron, TIBC, TSAT levels, epoetin doses were recorded at the time of the injection. These patients were closely observed for adverse reaction such as metallic taste, fever, hypotension, pruritis, phlebitis, dyspnea, nausea, vomiting and anaphylaxis. Administration of 100 mg of Iron Sucrose as an intravenous bolus injection over 2 to 3 minutes is a practical dosing regimen in patients on MHD. The importance of intravenous (IV) iron as an adjunctive treatment had been increasingly recognized1. This is particularly true in hemodialysis patients, for whom iron losses are greater and IV iron supplementation often is necessary to optimize the erythropoietic activity. In some patients, IV iron may improve hemoglobin levels even before erythropoietic therapy is started, whereas concomitant use of IV iron along with EPO can enhance the eyrythropoietic response and reduce dose requirements of EPO. Data from studies have been pivotal in generating the recommendation in the recently published revised European Best Practice Guidelines on renal anaemia management that IV iron supplementation is likely to be required in all hemodialysis patients3. Infusions of iron lasting an hour or more are impractical for administration in the outpatient setting and the ability to administer IV iron as a bolus injection over a few minutes has obvious advantages. As a result of the outcome of this study, our unit has adopted this protocol (which administers IV iron sucrose more rapidly than the product license stipulates) for the administration of IV iron to patients with CKD. The cause of anaphylactoid reactions to all IV iron preparations is not yet proven, but now it is generally believed that they are not immunologically mediated (in contrast to the true anaphylaxis seen with iron dextran, caused by preformed dextran antibodies). In one study 10 doses of iron sucrose were administered, each administered undiluted as a 100mg IV push over 5 minutes, and recorded blood pressure and adverse events after the injection were recorded.

Document 04 : Iron Supplementation In Pregnancy And The Postpartum: Evidence And Controversies -- ITO
Summary  : 5%
Red blood cell (RBC) production is a dynamic process; at sea level, we each produce 2 to 3 million new RBCs every second, and the bone marrow is capable of producing cells at 10 times this rate. In healthy individuals RBC production and destruction are balanced to maintain Hb concentration at normal levels (12-15 g/dL). There are many ways of dealing with this; one possibility has been through blood transfusion. However, if we recognize that anemia is a disordered process we also recognize that blood transfusion -- which may give a temporary elevation in Hb concentration -- cannot address the fundamental issue and restore balance. Oral iron therapy has been shown to be effective in correcting irondeficiency anemia in most cases.4 Its efficacy may, however, be limited in many patients due to dose-dependent side effects, lack of compliance and insufficient duodenal iron absorption.5,6 Furthermore, while there is evidence supporting the correction of hematological and iron status parameters with oral iron supplementation, data on improving birth weight and decreasing preterm delivery are still lacking.7 By using IV iron rather than oral iron it is possible to increase Hb concentration to the ideal threshold. As well as in renal anemia, perisurgical anemia or anemia of prematurity IV iron is used increasingly in obstetrics.8-16 At present, three classes of IV iron complexes are principally used in clinical practice: iron dextrans, iron sucrose and ferric gluconate. Dr. Gay concludes that although oral iron is the standard treatment for iron deficiency it is poorly tolerated and has low efficacy in the rapid correction of anemia. A recent study shows that in 2004, 32% of all transfusions in the peripartum were inappropriate and excessive.29 In France and other countries, transfusion remains the emergency treatment for hemorrhages. In order to reduce postpartum transfusion the implementation of prevention strategies during pregnancy and peripartum need to be considered. Dr. Cavill's closing remarks underlined the importance of correcting anemia in pregnancy and the postpartum: anemia that affects the mother affects the family, which affects the children and their behavior. 10. Krafft A, Breymann C, Huch R, Huch A. Intravenous iron sucrose in two pregnant women with inflammatory bowel disease and severe iron deficiency anemia.

Document 04 : Iron Supplementation In Pregnancy And The Postpartum: Evidence And Controversies -- ITO
Summary  : 10%
A survey during this session indicated that anemia is seen as an important issue in routine practice; 73% of the audience use oral iron, and 2% use blood transfusions to treat anemia in this setting. Many also use intravenous (IV) iron therapy, and, based on the survey performed during the session, if IV iron is not used it is mainly due to lack of experience and safety concerns. Dr. Ivor Cavill, from the University of Wales in Cardiff, UK, opened the session by explaining that erythropoiesis and iron metabolism are intimately related, erythropoiesis does not result in well hemoglobinized red cells without a matching iron supply. Red blood cell (RBC) production is a dynamic process; at sea level, we each produce 2 to 3 million new RBCs every second, and the bone marrow is capable of producing cells at 10 times this rate. In healthy individuals RBC production and destruction are balanced to maintain Hb concentration at normal levels (12-15 g/dL). There are many ways of dealing with this; one possibility has been through blood transfusion. However, if we recognize that anemia is a disordered process we also recognize that blood transfusion -- which may give a temporary elevation in Hb concentration -- cannot address the fundamental issue and restore balance. The iron stored in the macrophages is either within intra-cellular ferritin or in hemosiderin; the concentration of serum ferritin (SF), which is not derived from tissue ferritin and which contains no iron, indirectly reflects the level of tissue ferritin and iron stores. Professor Breymann presented statistics on maternal morbidity and mortality related to anemia. Patients have a right to normal Hb during pregnancy and to receive safe and efficient treatment; it is the physician's responsibility to ensure this and, where possible, avoid blood transfusion. Oral iron therapy has been shown to be effective in correcting irondeficiency anemia in most cases.4 Its efficacy may, however, be limited in many patients due to dose-dependent side effects, lack of compliance and insufficient duodenal iron absorption.5,6 Furthermore, while there is evidence supporting the correction of hematological and iron status parameters with oral iron supplementation, data on improving birth weight and decreasing preterm delivery are still lacking.7 By using IV iron rather than oral iron it is possible to increase Hb concentration to the ideal threshold. As well as in renal anemia, perisurgical anemia or anemia of prematurity IV iron is used increasingly in obstetrics.8-16 At present, three classes of IV iron complexes are principally used in clinical practice: iron dextrans, iron sucrose and ferric gluconate. Over seven days, the mean increase of Hb was 0.8 g/dL for oral iron, 3.5 g/dL for blood transfusion and 1.9 g/dL for IV iron, rising to 3.1 g/dL over 14 days. Dr. Gay concludes that although oral iron is the standard treatment for iron deficiency it is poorly tolerated and has low efficacy in the rapid correction of anemia. A recent study shows that in 2004, 32% of all transfusions in the peripartum were inappropriate and excessive.29 In France and other countries, transfusion remains the emergency treatment for hemorrhages. In order to reduce postpartum transfusion the implementation of prevention strategies during pregnancy and peripartum need to be considered. These could include antepartum screening of women potentially suffering from severe anemia, antepartum monitoring of these women, peripartum prevention of parturition hemorrhage and biological and clinical evaluation of anemic women. The aim of IV iron therapy is not only to avoid allergenic reactions in young mothers, but also to be able to offer them effective iron supplementation over a shorter period and to reduce maternal morbidity and infection. Dr. Cavill's closing remarks underlined the importance of correcting anemia in pregnancy and the postpartum: anemia that affects the mother affects the family, which affects the children and their behavior. 10. Krafft A, Breymann C, Huch R, Huch A. Intravenous iron sucrose in two pregnant women with inflammatory bowel disease and severe iron deficiency anemia. 11. Sal Momen AK, al Meshari A, al Nuaim L et al. Intravenous iron sucrose complex in the treatment of iron deficiency anemia during pregnancy. 15. Perewusnyk G, Huch R, Huch A, Breymann C. Parenteral iron therapy in obstetrics: 8 years experience with iron-sucrose complex. 16. Breymann C. Iron deficiency and anaemia in pregnancy: modern aspects of diagnosis and therapy.

Document 04 : Iron Supplementation In Pregnancy And The Postpartum: Evidence And Controversies -- ITO
Summary  : 25%
In this satellite session that took place on June 3, 2005, during the 6th Congress of the European Society of Gynecology (SEG) that was held on June 2-4, 2005, in Helsinki, Finland, leading specialists in anemia management discussed iron supplementation in pregnancy and the postpartum. A survey during this session indicated that anemia is seen as an important issue in routine practice; 73% of the audience use oral iron, and 2% use blood transfusions to treat anemia in this setting. Many also use intravenous (IV) iron therapy, and, based on the survey performed during the session, if IV iron is not used it is mainly due to lack of experience and safety concerns. Dr. Ivor Cavill, from the University of Wales in Cardiff, UK, opened the session by explaining that erythropoiesis and iron metabolism are intimately related, erythropoiesis does not result in well hemoglobinized red cells without a matching iron supply. Red blood cell (RBC) production is a dynamic process; at sea level, we each produce 2 to 3 million new RBCs every second, and the bone marrow is capable of producing cells at 10 times this rate. Each cell must have synthesized 30 pg hemoglobin (Hb). The result is the creation of 6 g of new Hb each day. In healthy individuals RBC production and destruction are balanced to maintain Hb concentration at normal levels (12-15 g/dL). When production ceases to match destruction, Hb starts to fall. This is a relatively slow process especially in a chronic setting where it takes several months for Hb concentrations to fall to levels that reflect the reduced erythropoietic activity. Viewed in this way, anemia can be seen to be a disordered dynamic process and its therapy must be aimed at restoring the process to balance production and destruction. There are many ways of dealing with this; one possibility has been through blood transfusion. However, if we recognize that anemia is a disordered process we also recognize that blood transfusion -- which may give a temporary elevation in Hb concentration -- cannot address the fundamental issue and restore balance. Blood transfusion does not rebalance the production and destruction of RBCs, it is simply a transient and often ineffective Hb "fix"; it is not part of a rational approach to the anemic process. The consequences of anemia are great as it not only affects quality of life, but also impacts on the central nervous (CNS), gastrointestinal (GI), vascular, immune and cardio-respiratory systems. It is these physiological responses to anemia that cause the pathology. The chief of these is the left ventricular hypertrophy which results from chronic increased cardic output in response to reduced Hb levels. How well the RBCs are supplied with iron controls red cell Hb content. However, Dr. Cavill explained that measuring the reticulocyte Hb content (CHr) enables a more dynamic and immediate assessment of RBCs. The CHr is a direct measure of reticulocyte Hb and is effective in assessing the adequacy of the current supply of iron to the bone marrow. The iron stored in the macrophages is either within intra-cellular ferritin or in hemosiderin; the concentration of serum ferritin (SF), which is not derived from tissue ferritin and which contains no iron, indirectly reflects the level of tissue ferritin and iron stores. Dr. Cavill emphasized the magnitude of iron requirements during pregnancy; iron stores are virtually denuded by the end of pregnancy unless some support is given. In the latter stages of pregnancy, the fetus is absolutely dependent on the residual iron stores of the mother and failing to support that level can impact not only on the mother's postpartum experience, but also on the child's. Professor Breymann presented statistics on maternal morbidity and mortality related to anemia. In countries with sub-optimal anemia management, maternal mortality can reach 450/100,000 pregnancies, a similar figure to Europe 200 years ago. In areas with poor standards of treatment, mortality is around 100 times that in high-standard areas. Patients have a right to normal Hb during pregnancy and to receive safe and efficient treatment; it is the physician's responsibility to ensure this and, where possible, avoid blood transfusion. Oral iron therapy has been shown to be effective in correcting irondeficiency anemia in most cases.4 Its efficacy may, however, be limited in many patients due to dose-dependent side effects, lack of compliance and insufficient duodenal iron absorption.5,6 Furthermore, while there is evidence supporting the correction of hematological and iron status parameters with oral iron supplementation, data on improving birth weight and decreasing preterm delivery are still lacking.7 By using IV iron rather than oral iron it is possible to increase Hb concentration to the ideal threshold. As well as in renal anemia, perisurgical anemia or anemia of prematurity IV iron is used increasingly in obstetrics.8-16 At present, three classes of IV iron complexes are principally used in clinical practice: iron dextrans, iron sucrose and ferric gluconate. The average Hb value was recorded at weeks 1 and 2. Over seven days, the mean increase of Hb was 0.8 g/dL for oral iron, 3.5 g/dL for blood transfusion and 1.9 g/dL for IV iron, rising to 3.1 g/dL over 14 days. Dr. Gay concludes that although oral iron is the standard treatment for iron deficiency it is poorly tolerated and has low efficacy in the rapid correction of anemia. A recent study shows that in 2004, 32% of all transfusions in the peripartum were inappropriate and excessive.29 In France and other countries, transfusion remains the emergency treatment for hemorrhages. IV iron is both quick and efficient in treating anemia; it is well tolerated and avoids RBC transfusions. In order to reduce postpartum transfusion the implementation of prevention strategies during pregnancy and peripartum need to be considered. These could include antepartum screening of women potentially suffering from severe anemia, antepartum monitoring of these women, peripartum prevention of parturition hemorrhage and biological and clinical evaluation of anemic women. The aim of IV iron therapy is not only to avoid allergenic reactions in young mothers, but also to be able to offer them effective iron supplementation over a shorter period and to reduce maternal morbidity and infection. This recent treatment is filling a rift between transfusion and oral iron and contributes to maternal well-being. Dr. Cavill's closing remarks underlined the importance of correcting anemia in pregnancy and the postpartum: anemia that affects the mother affects the family, which affects the children and their behavior. He advocates the rational use of IV iron in dealing with iron deficiency as a consequence of pregnancy and the consequence of postpartum conditions. 2. Llewelyn CA, Hewitt PE, Knight RS. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. 3. Williamson LM, Lowe S, Love EM et al. Serious hazards of transfusion (SHOT) initiative: analysis of the first two annual reports. Response to orally and parenterally administered iron preparations. Anemia and iron deficiency: effects on pregnancy outcome. 6. Mungen E. Iron supplementation in pregnancy. 7. Rasmussen KM. Iron deficiency anemia: reexamining the nature and magnitude of the public health problem. 8. Bayoumeu F, Subiran-Buisset C, Baka NE et al. Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. 9. Gravier A, Descargues G, Marpeau L. [How to avoid transfusion in the post-partum period: importance of an intravenous iron supplement]. 10. Krafft A, Breymann C, Huch R, Huch A. Intravenous iron sucrose in two pregnant women with inflammatory bowel disease and severe iron deficiency anemia. 11. Sal Momen AK, al Meshari A, al Nuaim L et al. Intravenous iron sucrose complex in the treatment of iron deficiency anemia during pregnancy. 12. Broche DE, Gay C, Armand-Branger S, Grangeasse L, Terzibachian JJ. 15. Perewusnyk G, Huch R, Huch A, Breymann C. Parenteral iron therapy in obstetrics: 8 years experience with iron-sucrose complex. 16. Breymann C. Iron deficiency and anaemia in pregnancy: modern aspects of diagnosis and therapy. 17. Burns DL, Mascioli EA, Bistrian BR. 18. Breymann C, Zimmermann R, Huch R, Huch A. Use of recombinant human erythropoietin in combination with parenteral iron in the treatment of postpartum anaemia. 19. Breymann C. Iron deficiency and anaemia in pregnancy: modern aspects of diagnosis and therapy.

Document 05 : Treatments For Iron-Deficiency Anaemia In Pregnancy (Review) -- The Cochrane Collaboration
Summary  : 5%
Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. T A B L E O F C O N T E N T S HEADER. Comparison 1 Oral iron versus placebo, Outcome 2 Haemoglobin levels (g/dl). Comparison 1 Oral iron versus placebo, Outcome 3 Ferritin levels (ug/l). Comparison 1 Oral iron versus placebo, Outcome 4 Serum iron (mg/l). Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. iv Analysis 20.1. Comparison 20 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg, Outcome 1 Haemoglobin level at delivery. Comparison 20 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg, Outcome 3 Moderate abdominal pain. Comparison 21 Intravenous iron sucrose 500 mg versus intramuscular iron sorbitol, Outcome 1 Maternal haemoglobin level at birth. Comparison 22 Intravenous iron sucrose 200 mg versus intramuscular iron sorbitol, Outcome 1 Haemoglobin level at delivery. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 1 Haematocrit (%) at 4 weeks of treatment. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 2 Haematocrit (%) at 8 weeks of treatment. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 3 Neonatal jaundice. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 4 Viral hepatitis. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 5 Severe allergic reaction. Several studies considered anaemia (haemoglobin levels between 7 g/dl and 10 g/dl) as a risk factor for fetal death, premature delivery, low birthweight and other adverse outcomes (Williams 1992). The suggestion that low iron stores in the mother during preg nancy may affect the child's later development, means that long term outcomes on the baby should be outcome measures in any study on the treatment of anaemia in pregnancy. mild In developing countries, anaemia in pregnancy is frequent and has been attributed to poor nutrition and a high incidence of concurrent diseases, and can potentially complicate conditions such as postpartum haemorrhage which is a major contributor to maternal mortality in many developing countries (WHO 1992). However, anaemia may only be a marker of various social and nutritional conditions, and raising haemoglobin levels coul d have little, if any, effect on morbidity or mortality if other condi tions are not improved (Goroll 1997). Iron can be given by mouth, by intramuscular (IM) injection or intravenous (IV) injection. Anecdotal evid ence suggests that oral iron given to anaemic pregnant and non-pre gnant women is associated with gastrointestinal side-effects s uch as nausea and constipation. Furtherm ore, they may not take into account important adverse effects such as allergic reactions, viral or parasitic transmission from bloo d transfusions, gastrointestinal complications, and discomfort gen erated by common side-effects of iron. The aim of this review was to use a systematic approach to identify and synthesise the evidence of randomised controlled tri als evaluating the effects of treatments for iron-deficiency anaemi a in pregnancy, and provide robust valid and useful evidence to inf orm clinical practice. The principal objective was to determine the overall effects of iron therapy given to women diagnosed with iron-deficiency anaemia in pregnancy, measuring neonatal and maternal morbidity and mortality, haematological parameters and side-effects, espe cially adverse effects of treatment. Another Cochrane systematic review focuses on the effe of routine oral iron supplementation with or without folic a for women during pregnancy (Pena-Rosas 2006). 3. Oral iron in combination with other haematinics versus regular oral iron. 4. Oral iron in combination with substances that could increase its absorption versus regular oral iron. If was clear that the study did not refer to a randomised controlle trial on iron-deficiency anaemia in pregnancy, it was excluded. If it was unclear, then we obtained the full text of the study for i pendent assessment by LR and G Gyte (GG). Clinical outcome s were assessed in six RCTs (Al 2005; Bayoumeu 2002; Breymann 2001; Oluboyede 1980; Singh 1998; Zutschi 2004) although Breymann and Singh's data were unpublished; these data were provided by the main author of Singh 1998 and have been incorporated into the review. Seven groups of RCTs were described according to the type of intervention. However, groups were further divided accordin g to co-interventions, dose, regimen, route, or type of chemical components of the intervention (i.e. iron sucrose, dextran), as fo llows. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. For example, when RCTs had a high withdrawal rates and therefore incomplete data on o utcomes at the end of follow up, but still offered complete data at a given time that fulfilled our predefined inclusion criteria, th e later data were used. None of the RCTs masked the interventi ons to people assessing outcomes. An RCT from France had three withdrawals (6%) (Bayoumeu 2002). The RCT was focused on assessing adverse effects. No significant differences were found on data of initial hematological parameters, gestation, parity or literacy between women who completed the study and women who withdrew. However, withdrawals were different for women receiving oral treatment (13.5%) and those receiving IM treatment (38.5%). Overall, we found insufficie nt assessment of the outcomes relevant to the focus of this review, especially of clinical outcomes. The effect size for these are represented in this review using the relat ive risk (RR) and weighted mean difference (WMD). Data from the first RCT showed that women receiving iron (ferrous sulphate) had a lower risk of being ana emic during the second trimester (one RCT, 125 women; RR 0.38; 95% CI 0.26 to 0.55; graph 01.01). Adding vitamin A to regular iron (ferrous sulphate), resulted in improved haemoglobin level. It found no si gnificant differences between IV iron and placebo for: nausea and vomiting (one RCT, 54 women; RR 0.33; 95% CI 0.01 to 7.84), abdominal cramps (not estimable), and constipation (one RCT, 54 women; RR 0.25; 95% CI 0.03 to 2.09). We found four RCTs (571 women) comparing IM and oral administration of iron (Komolafe 2003; Ogunbode 1980; Kumar 2005; Zutschi 2004). The first RCT, from India, (Zutschi 2004) evaluated 150 mg IM iron sorbitol (via three injections a day) at four-weekly inter vals versus 100 mg of elemental oral iron for at least 100 days. Adverse effects were not included in the reports of the article. The second RCT, from India, compared IM sorbitol citric acid dose versus oral ferrous sulphate (100 mg of elemental iron) p lus 5 mg of folic acid at 36 weeks of pregnancy (Kumar 2005). Adverse effects were reported by 4 0 women receiving IM treatment versus 16 receiving oral treatme nt at 36 weeks of treatment (graphs 16.03 to 16.15). No significant differences wer e found in maternal haemoglobin levels at four weeks of treatm ent, haemoglobin levels in excess of 12 g/dl, neonatal haemoglobi n, ferritin levels, and birthweight. An RCT conducted in Turkey (Al 2005) compared IV iron sucrose calculated according to a formula described in the article (total dose was administered over five days and maximum daily dose administered was 400 mg elemental iron) versus 300 mg of elemental iron (polymaltose complex); all women were given 5 mg of folic acid daily. No mat ernal or neonatal deaths were recorded in this RCT, which was the only one specifically assessing these outcomes in women receiving ora l or IV treatments. Two women were reported as suffering severe allergic reactio ns with IV dextran in an RCT comparing the latter with oral ferrou s sulphate (Sood 1979). Neonates were assessed for any complicati on at birth and within the first week of life; one neonate in each treatment group developed neonatal jaundice. It found that IM iron was more frequently associated with pain in the injection site. The RCT was too small to rule out importan t clinical differences in measured adverse effects outcomes such as shivering, itching, metallic taste in mouth, severe delayed allergic reaction (graphs 06.04 to 06.09). An RCT conducted in the UK compared iron-dextran infusion plus hydrocortisone versus iron-dextran infusion without hy drocortisone (Dawson 1965). The objective of this review was to address the effects of iron anaemia treatments on maternal and neonatal morbidity and mortality. These RCTs assessed many different questions and a broad range of treatments resulting in very limited opport unities to pool useful data. The paucity of robust studies assessing cl inical effects of treatments makes it impossible to balance the benefi ts and harms of differing treatments for different levels of an aemia in pregnancy, in a meaningful and useful way. We cannot determine if women with mild anaemia, but otherwise healthy, will benefit from anaemia treatment; adverse effects can potentially outweigh benefits. It also remai ns unclear which treatments are safer and more effective in women wit h moderate or severe anaemia with and without associated illne ss. Although iron treatments consistently increase maternal hae matological indices in women diagnosed with iron-deficiency anaemia in pregnancy, we found no evidence that these laboratory improvements reflected in clinical improvements such as reduced preterm delivery, reduced infant low birthweight, lower rat es of pre-eclampsia, sepsis or postpartum haemorrhage and its compl ications (Scholl 1992; Scholl 2000). The findings suggest that gastrointestinal adverse effects a re more frequent with oral iron treatments, compared with other rout es of iron administration. The findings of this review suggest that adding vitamin A to re iron (ferrous sulphate) resulted in improved haemoglobin le Another Cochrane review that focused on vitamin A supplementation during pregnancy suggested beneficial effects for women areas of poor nutritional intake (Van den Broek 2002). Evidence of a relations hip between doses of IV iron and risk of adverse allergic reaction s is inconclusive. Stratification according to anaemia severity can help address questions of the effects in different populations, and balan ferently the benefits and harms. Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. Kaisi M, Ngwalle EWK, Runyoro DE, Rogers J. Evaluation of tolerance of and response to iron dextran (Imferon) adminisered by to tal dose infusion to pregnant women with iron deficiency anemia. Kumar 2005 {published data only} hate Journal of Kumar A, Jain S, Singh NP, Singh T. Oral versus high dose parentera l iron supplementation in pregnancy. The effect of parenteral iron administration in the control of anaemia of pregnancy. Al-Momen A, Al-Meshari A, Al-Nuaim L, Saddique A, Abotalib Z Khashogji T, et al.Intravenous iron sucrose complex in the trea ment of iron deficiency anemia during pregnancy. Allaire B, Campagna F. Iron-deficiency anemia in pregnancy. Evaluation of diagnosis and therapy by bone marrow hemosiderin. Bare W, Sullivan A. Comparison of intravenous saccharated iro ide and whole blood in treatment of hypochromic anemia of pregnancy. J, et al.Ferritin levels in newborn after prepartal iron medica tion. Breymann C, Visca E, Huch R, Huch A. Recombinant human erythropoietin (rhEPO) for the therapy of severe iron deficiency a during pregnancy. Breymann 2002 {published data only} naemia Breymann C. Iron deficiency and anaemia in pregnancy: modern aspects of diagnosis and therapy. A comparative study of the effectiveness of iron preparations in the treatment of iron defi ciency anemias in pregnant women. Journal of Obstetrics and Gynaecology of the British Commonwealth 1965;72:374--5. Dommisse J, Du Toit ED, Nicholson N. Folic acid - has it a role in the treatment of severe iron deficiency anaemia in pregnancy?. Ekstrom EC, Hyder SM, Chowdhury AM, Chowdhury SA, Lonnerdal B, Habicht JP, et al.Efficacy and trial effectiveness of wee kly and daily iron supplementation among pregnant women in rural Bangladesh: disentangling the issues. Antenatal clinics as trial units in evalu ating treatment of anaemia in pregnancy. Relative efficacy of sustained release iron and iron wit folic acid treatment in pregnancy. WHO sponsored collaborative studies on nutritional anaemia in India. Cuervo LG, Mahomed K. Treatments for iron deficiency anaemia in pregnancy. Group allocation was predetermined by one of the authors who w as not involved with women's care. Authors used opaque envelopes that were consecutively-number ed by means of a computer-generated randomisation table. As each woman gave consent for the study, the next envelope was opened to assign the participant to either of the 2 groups. A sample-size analysis was performed before initiation of th e study. Anaemia from causes other than iron-deficiency, multiple pregna ncy, previous blood transfusion, history of hematological disease, risk of preterm labour, intolerance to iron derivatives, recent administrat ion of iron for the treatment of iron-deficiency anaemia, or current usage of iron supplement were the reasons for other exclusions. Both groups were supplemented by 0.5 mg folic acid treatment p ted from the following formula: weight nfusion, the maximum total dose fused in 20-30 minutes. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Women were assigned to the group treatment by a randomisatio Sample size and power calculation was described. It is unclear if the outcome assessor was blind that 3 (6%) women were excluded from the study and that 2 others w n table. Exclusion criteria: women with anaemia not caused by iron deficie chronic bleeding; renal failure. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Women were randomly distributed into 3 groups, 1 receiving da twice-weekly and the 3rd one-weekly iron supplementation for 1 l haemoglobin of < 11 g/dL and> 8 g/dL. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 24 Experiment group: IM iron: parenteral iron group were given as iron sorbitol citric acid in a injection volume of 5 ml at an int An initial test dose of 0.5 ml was given. The trial measured values of blood indices at 36 weeks as well a side-effects. 2 IM injections of 250 mg elemental iron erval of 4-6 weeks in the antenatal clinic. e reaction to the test dose, then a full 250 ing Z-tract technique. The women and the investigator were blinded to th e allocation of treatment group (daily vs twice weekly) at initial recruitment and the 3 follow-up visits. The appearance of the capsules and the blister packs of the 2 groups were identical. Published by J ohn Wiley & Sons, Ltd. visit and for serum ferritin at the 1st, ital disorders such as thalassemia minor. There was no information on methods of randomisation. Yes Description A - Adequate clinical outcomes and side-effects that sity of Singapore was the contacted author. No des calculation was described and researchers kept unmasked the 5 gr dropped in the group receiving IV Fe due to severe delayed adve 151 pregnant women. The manufacturers of the active treatments provided pla labelled the active and placebo preparations. Unclear Description B - Unclear and side-effects. There was no information on methods of randomisation. No wom or were lost to follow up. Neither the women nor treating phys No description of the sample size or power calculation was descri en were reported to have dropped out icians were blinded to the interventions. 200 women with uncomplicated pregnancy enrolled at 24-26 weeks o> 8 gm% but < 11 gm% were included. Women dropped out of study if Hb fell below 8 g/l or if severe pr Group A (100 women) received injectable iron-sorbitol-citrate in intervals and group B (100 women) were given oral iron having 1 100 days. The trial measured haemoglobin levels at the time of inclusio delivery as well as the proportion of caesarean delivery. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. f gestation with a haemoglobin of oblems arose. This is no Insufficient information for critical appraisal was provided. The study is in women with haemoglobin levels over 10 g/dl. Tr Although the authors state that allocation was random, the gr authors used an inappropriate control group of healthy women method. We tried to contact to verify dat lists are considered inadequate since there is no concealment an The trial evaluated folic acid + iron versus iron. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 38 9 Spontaneous abortion No. of studies No. of participants 9 Need transfusion No. of studies No. of participants 4 Caesarean section No. of studies No. of participants Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 39 Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 40 Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 41 3 Moderate abdominal pain No. of studies No. of participants 2 Haematocrit (%) at 8 weeks of treatment No. of studies No. of participants Comparison 3 Oral iron + vitamin A versus oral i trimester. Total events: 2 (Oral iron + vit A), 20 (Oral iron) Heterogeneity: not applicable Test for overall effect: Z = 3.20 (P = 0.0014) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. sus regular oral iron, Outcome 1 Side-effects. Total events: 7 (Ctrl release iron), 7 (Regular oral iron) Heterogeneity: not applicable Test for overall effect: Z = 0.09 (P = 0.93) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 4 Controlled release oral iron ver vomiting. sus regular oral iron, Outcome 3 Constipation. Total events: 1 (Ctrl release iron), 4 (Regular oral iron) Heterogeneity: not applicable Test for overall effect: Z = 1.32 (P = 0.19) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 4 Controlled release oral iron ver cramps. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 1 Pain at injection site. Total events: 13 (IM iron sorb-cit), 12 (IM iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.01 (P = 0.99) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 2 Skin discolouration at injection site. Total events: 4 (IM iron sorb-cit), 4 (IM iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.13 (P = 0.90) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 8 Metallic taste in mouth. Comparison 6 Intramuscular iron dextran vers injection site. Total events: 12 (IM iron dextran), 3 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 2.61 (P = 0.0091) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers us intravenous iron dextran, Outcome 2 Skin discolouration at injection site. Comparison 6 Intramuscular iron dextran vers thrombosis. Total events: 0 (IM iron dextran), 4 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.42 (P = 0.16) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers Nausea or vomiting. Comparison 6 Intramuscular iron dextran vers Headaches. Total events: 7 (IM iron dextran), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.84 (P = 0.066) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers Shivering. us intravenous iron dextran, Outcome 7 Itching. Comparison 7 Intramuscular iron sorbitol cit ric acid versus intravenous iron dextran, Outcome 1 Pain at injection site. Total events: 0 (IV iron), 1 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.68 (P = 0.50) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. oral iron, Outcome 2 Nausea or vomiting or epigastric discomfort. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Total events: 0 (IV iron), 2 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 1.13 (P = 0.26) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regular required. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regular hemoglobin. Comparison 9 Intravenous iron versus regular birth. Heterogeneity: not applicable Test for overall effect: Z = 3.57 (P = 0.00035) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. r oral iron, Outcome 11 Neonates ferritin level. r oral iron, Outcome 19 Neonatal birthweight. Comparison 9 Intravenous iron versus regula age. Total events: 8 (IV iron), 5 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 0.88 (P = 0.38) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regula score under seven. r oral iron, Outcome 22 Neonatal mortality. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 9 Intravenous iron versus regula g/dL at 30 days. Comparison 9 Intravenous iron versus regula hypertension. Total events: 2 (IV iron), 0 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 1.05 (P = 0.29) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio r oral iron, Outcome 25 Gestational diabetes. Comparison 12 2/3 dose intravenous iron vers us full dose intravenous iron, Outcome 1 Allergic reaction during infusion. us full dose intravenous iron, Outcome 4 Discomfort needing analgesics after infusion. Total events: 15 (2/3 dose IV iron), 31 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 2.33 (P = 0.020) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers us full dose intravenous iron, Outcome 5 Immobilised by painful joints. Comparison 12 2/3 dose intravenous iron vers live births. Total events: 9 (2/3 dose IV iron), 11 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 0.36 (P = 0.72) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers Neonatal death. Total events: 6 (2/3 dose IV iron), 9 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 0.70 (P = 0.49) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 1 (rhEPO +IV Fe sucrose), 5 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 1.53 (P = 0.12) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 6 (rhEPO +IV Fe sucrose), 6 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 13 Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 4 Metallic taste. adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 5 Warm feeling. Total events: 1 (rhEPO +IV Fe sucrose), 1 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 13 Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 6 Birthweight. Total events: 24 (IM iron), 22 (Oral iron) Heterogeneity: not applicable Test for overall effect: Z = 0.34 (P = 0.74) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 14 Intramuscular iron sorbitol c itric acid versus oral iron, Outcome 5 Haematocrit (%) at 4 weeks of treatment. itric acid versus oral iron, Outcome 6 Haematocrit (%) at 8 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.79 (P = 0.00015) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 14 Intramuscular iron sorbitol c itric acid versus oral iron, Outcome 7 Haematocrit (%) at 4 weeks of treatment. itric acid versus oral iron, Outcome 8 Haematocrit (%) at 8 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.23 (P = 0.0012) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 11 (IM iron dextran), 1 (Oral Fe+vitC+folic a) Heterogeneity: not applicable Test for overall effect: Z = 2.37 (P = 0.018) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c itric acid versus oral iron + folic acid, Outcome 1 Mean haemoglobin at 36 weeks. Total events: 42 (IM iron), 51 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.50 (P = 0.13) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. itric acid versus oral iron + folic acid, Outcome 3 Caesarean section. itric acid versus oral iron + folic acid, Outcome 4 Mean birthweight (kg). Heterogeneity: not applicable Test for overall effect: Z = 0.27 (P = 0.79) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. citric acid versus oral iron + folic acid, Outcome 14 Vaso-vagal due to apprehension. Total events: 4 (IM iron), 0 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.48 (P = 0.14) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. citric acid versus oral iron + folic acid, Outcome 15 Systemic ache. Total events: 11 (IMiron), 21 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.93 (P = 0.053) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 17 Oral iron daily versus oral iro at 4 weeks. Comparison 17 Oral iron daily versus oral iro at 8 weeks. Comparison 17 Oral iron daily versus oral iro at 12 weeks. Comparison 17 Oral iron daily versus oral iro at 16 weeks. Heterogeneity: not applicable Test for overall effect: Z = 1.89 (P = 0.059) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 1 (Oral iron daily), 7 (Oral iron twice week) Heterogeneity: not applicable Test for overall effect: Z = 1.78 (P = 0.075) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 18 Oral iron daily versus oral iro 16 weeks. Total events: 23 (Oral iron daily), 13 (Oral iron once week) Heterogeneity: not applicable Test for overall effect: Z = 1.95 (P = 0.051) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 20 Intravenous iron sucrose 500 m g versus intravenous iron sucrose 200 mg, Outcome 1 Haemoglobin level at delivery. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 20 Intravenous iron sucrose 500 m g versus intravenous iron sucrose 200 mg, Outcome 3 Moderate abdominal pain. Comparison 21 Intravenous iron sucrose 500 m Outcome 1 Maternal haemoglobin level at birth. Heterogeneity: not applicable Test for overall effect: Z = 4.30 (P = 0.000017) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. g versus intramuscular iron sorbitol, Outcome 1 Haemoglobin level at delivery. Heterogeneity: not applicable Test for overall effect: Z = 3.51 (P = 0.00044) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Heterogeneity: not applicable Test for overall effect: Z = 0.63 (P = 0.53) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 1 Haematocrit (%) at 4 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.04 (P = 0.0024) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 2 Haematocrit (%) at 8 weeks of treatment. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 3 Neonatal jaundice. Total events: 1 (IM iron sorb-gluc), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.05 (P = 0.96) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 4 Viral hepatitis.

Document 05 : Treatments For Iron-Deficiency Anaemia In Pregnancy (Review) -- The Cochrane Collaboration
Summary  : 10%
Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. T A B L E O F C O N T E N T S HEADER. Comparison 1 Oral iron versus placebo, Outcome 2 Haemoglobin levels (g/dl). Comparison 1 Oral iron versus placebo, Outcome 3 Ferritin levels (ug/l). Comparison 1 Oral iron versus placebo, Outcome 4 Serum iron (mg/l). Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. iv Analysis 20.1. Comparison 20 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg, Outcome 1 Haemoglobin level at delivery. Comparison 20 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg, Outcome 3 Moderate abdominal pain. Comparison 21 Intravenous iron sucrose 500 mg versus intramuscular iron sorbitol, Outcome 1 Maternal haemoglobin level at birth. Comparison 22 Intravenous iron sucrose 200 mg versus intramuscular iron sorbitol, Outcome 1 Haemoglobin level at delivery. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 1 Haematocrit (%) at 4 weeks of treatment. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 2 Haematocrit (%) at 8 weeks of treatment. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 3 Neonatal jaundice. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 4 Viral hepatitis. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 5 Severe allergic reaction. a health problem for pregnant women and their babies (Letsky 2001). Several studies considered anaemia (haemoglobin levels between 7 g/dl and 10 g/dl) as a risk factor for fetal death, premature delivery, low birthweight and other adverse outcomes (Williams 1992). Some suggest a link between maternal anaemia in pregnancy on the later developmental problems of the children (Letsky 2001; Williams 1992). There is evidence indicating that maternal haemoglobin levels under 7 g/dl are associated with a higher risk in the mother of developing cardiac heart failur e, which has adverse consequences on the mother and fetus (Lops 1995; WHO 1992; Williams 1992). A cohort study done in Pakistan found that the risk of low birthweight and preterm deli very among the anaemic women (haemoglobin under 11 g/dl) was 1.9 and 4 times higher, respectively, than the non-anaemic women. In addition, the neonates of anaemic women had a 3.7 greater risk of intrauterine fetal death and 1.8 times increased risk having low Apgar scores at one minute when compared to non-anaemic women (Lone 2004). The suggestion that low iron stores in the mother during preg nancy may affect the child's later development, means that long term outcomes on the baby should be outcome measures in any study on the treatment of anaemia in pregnancy. There is also a strong case for studying separately physiological anaemia, anaemia and severe anaemia in pregnancy. mild In developing countries, anaemia in pregnancy is frequent and has been attributed to poor nutrition and a high incidence of concurrent diseases, and can potentially complicate conditions such as postpartum haemorrhage which is a major contributor to maternal mortality in many developing countries (WHO 1992). However, anaemia may only be a marker of various social and nutritional conditions, and raising haemoglobin levels coul d have little, if any, effect on morbidity or mortality if other condi tions are not improved (Goroll 1997). There are various possible forms of treatment for iron-deficie ncy anaemia. Iron can be given by mouth, by intramuscular (IM) injection or intravenous (IV) injection. It is also possible to deli ver iron by giving a blood transfusion, and recombinant erythropoiet in in conjunction with iron is a further possibility. Anecdotal evid ence suggests that oral iron given to anaemic pregnant and non-pre gnant women is associated with gastrointestinal side-effects s uch as nausea and constipation. IM or IV iron is thought to be associat ed with allergic reactions and anaphylactic shock, as well as veno us thrombosis and occasionally cardiac arrest and death. Blood tr ansfusion carries the risk of transmitting parasitic or viral in fections including HIV, hepatitis, and Chagas disease (trypanosomias is), despite preventive blood screening. There is also the possib ility of bovine spongiform encephalitis, and as yet unknown viral i nfections. Recommendations for the treatm ent of anaemia are frequently based on the expectation that they m ay be benevolent but are seldom supported by reproducible robus t studies, especially randomised controlled trials. Furtherm ore, they may not take into account important adverse effects such as allergic reactions, viral or parasitic transmission from bloo d transfusions, gastrointestinal complications, and discomfort gen erated by common side-effects of iron. Therefore, it is difficult to balance the benefits and harms of treatments, let alone determine if there is a case to recommend a particular anaemia treatment for all women with anaemia in pregnancy. The aim of this review was to use a systematic approach to identify and synthesise the evidence of randomised controlled tri als evaluating the effects of treatments for iron-deficiency anaemi a in pregnancy, and provide robust valid and useful evidence to inf orm clinical practice. The principal objective was to determine the overall effects of iron therapy given to women diagnosed with iron-deficiency anaemia in pregnancy, measuring neonatal and maternal morbidity and mortality, haematological parameters and side-effects, espe cially adverse effects of treatment. The review also compared differ ent forms of iron therapy for iron-deficiency anaemia on neonatal an d maternal morbidity and mortality, haematological paramete rs and adverse effects on women and their offspring. The review aime d to assess the effects of iron treatments when delivered to wom en categorised in three groups (mild, moderate or severe, as defin ed by trialists) at inception into the randomised controlled tri al. The review did not address the need for iron supplementation non-anaemic women; this question has been addressed in sever other reviews and evidence summaries. Similarly, it did not f cus on vitamin A, vitamin B12, micronutrients, folate deficiency infectious or genetic anaemia, which will be covered in other re views. Another Cochrane systematic review focuses on the effe of routine oral iron supplementation with or without folic a for women during pregnancy (Pena-Rosas 2006). Types of studies of al o, cts cid This review considered randomised controlled trials assessi ng the effects of treatments for iron-deficiency anaemia in pregnancy. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. reviewed the 'materials and methods' of the reports. 3. Oral iron in combination with other haematinics versus regular oral iron. 4. Oral iron in combination with substances that could increase its absorption versus regular oral iron. If was clear that the study did not refer to a randomised controlle trial on iron-deficiency anaemia in pregnancy, it was excluded. If it was unclear, then we obtained the full text of the study for i pendent assessment by LR and G Gyte (GG). We actively tried to contact the authors using contact information provided in their articles and on the interne t. 1996. We were unable to contact the authors for the articles by Stein 1991 and Wu 1998. Most focused on laboratory results rather than clinical outcomes. Clinical outcome s were assessed in six RCTs (Al 2005; Bayoumeu 2002; Breymann 2001; Oluboyede 1980; Singh 1998; Zutschi 2004) although Breymann and Singh's data were unpublished; these data were provided by the main author of Singh 1998 and have been incorporated into the review. LR and GG independently extracted data from the articles. LGC was expected to act as arbiter if differen ces arose in the data extraction, but this did not happen. LR did da ta entries, and GG double checked data entries for accuracy. Seven groups of RCTs were described according to the type of intervention. However, groups were further divided accordin g to co-interventions, dose, regimen, route, or type of chemical components of the intervention (i.e. iron sucrose, dextran), as fo llows. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. IV administered iron sucrose with and without adjuvant recombinant human erythropoietin (Breymann 2001) For details of included and excluded studies, of included studies' and the 'Characteristics of excluded studi tables. al seethe 'Characteristics es' Ludovic Reveiz and Gill Gyte assessed the methodological qua lity of the included studies independently as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). Differences in interpretations were sorted by consensus among all three authors, after checking the criteria agr eed in the original review protocol. When RCTs had potential valid ity or interpretation problems and just part of the data were dee med useful, we would only use such data. For example, when RCTs had a high withdrawal rates and therefore incomplete data on o utcomes at the end of follow up, but still offered complete data at a given time that fulfilled our predefined inclusion criteria, th e later data were used. The quality assessment included an evaluation of the followi ng components for each included study, since there is some evidence that these are associated with biased estimates of treatment effect (Juni 2001): (a) the method of generation of the randomisation sequence; (b) the method of allocation concealment, which was considered adequate if the assignment could not be foreseen; (c) parties masked to the intervention (i.e. blinding of partici pants, clinicians, outcome evaluators); (d) how many participants were lost to follow up in each arm and whether participants were analysed in the groups to which they were originally randomised (intention to treat). The randomisation list generation strategy was consid ered inadequate for the trial by Dawson 1965. Published details of the randomisation were insufficient in the Singh 1998 and Breymann 2001 articles, but additional details were provided by the authors upon request. The allocation strategy and concealment were considered adequa te in 3 of the 17 studies (Al 2005; Breymann 2001; Mumtaz 2000). In most RCTs, blinding was not used; these were open RCTs. Two RCTs described blinding (masking) but it is unclear whether they were blinding the participants or healthcare providers t o the interventions (Mumtaz 2000; Suharno 1993); both RCTs assessed oral administration. None of the RCTs masked the interventi ons to people assessing outcomes. Loss to follow up Withdrawal rates (drop outs and losses to follow up) were reported in seven RCTs. Less than 5%: withdrawal rates were lower than 5% in two RCTs (Oluboyede 1980; Sood 1979). ©5% to 9.9%: an RCT from Pakistan (Wali 2002) had five withdrawals (8.3%) due to intolerance in the intramuscular (IM) iron group. An RCT from France had three withdrawals (6%) (Bayoumeu 2002). 10% to 19.9%: the West Java RCT (Suharno 1993) had complete data available on 251 (83%) women: reasons for withdrawals are further described in the article. More than 20%: an RCT from Pakistan (Mumtaz 2000) recruited 191 women; of these, 160 were successfully followed for at least four weeks and supplemented for an average of 10.9 weeks. The RCT was focused on assessing adverse effects. No significant differences were found on data of initial hematological parameters, gestation, parity or literacy between women who completed the study and women who withdrew. However, withdrawals were different for women receiving oral treatment (13.5%) and those receiving IM treatment (38.5%). Overall, we found insufficie nt assessment of the outcomes relevant to the focus of this review, especially of clinical outcomes. The effect size for these are represented in this review using the relat ive risk (RR) and weighted mean difference (WMD). Data from the first RCT showed that women receiving iron (ferrous sulphate) had a lower risk of being ana emic during the second trimester (one RCT, 125 women; RR 0.38; 95% CI 0.26 to 0.55; graph 01.01). Adding vitamin A to regular iron (ferrous sulphate), resulted in improved haemoglobin level. We found one RCT involving 63 women conducted in Nigeria (Oluboyede 1980). We found one small RCT involving 54 women and conducted in Australia (Symonds 1969). The RCT provided data on adverse effects. It found no si gnificant differences between IV iron and placebo for: nausea and vomiting (one RCT, 54 women; RR 0.33; 95% CI 0.01 to 7.84), abdominal cramps (not estimable), and constipation (one RCT, 54 women; RR 0.25; 95% CI 0.03 to 2.09). However, the small sample size and broad confidence intervals illustrate that the sample size is clearly insufficient to rule out any such adverse effe cts. We found four RCTs (571 women) comparing IM and oral administration of iron (Komolafe 2003; Ogunbode 1980; Kumar 2005; Zutschi 2004). The first RCT, from India, (Zutschi 2004) evaluated 150 mg IM iron sorbitol (via three injections a day) at four-weekly inter vals versus 100 mg of elemental oral iron for at least 100 days. A higher proportion of women were found to be non-anaemic at labour (one RCT, 200 women; RR 1.23; 95% CI 1.01 to 1.48; graph 14.01). Adverse effects were not included in the reports of the article. The second RCT, from India, compared IM sorbitol citric acid dose versus oral ferrous sulphate (100 mg of elemental iron) p lus 5 mg of folic acid at 36 weeks of pregnancy (Kumar 2005). Women receiving oral iron plus folic acid had a higher haemoglobin le vel (one RCT, 150 women; WMD 0.26; 95% CI 0.04 to 0.48; graph 16.01). No significant differences were found for caesarean secti on rates or mean birthweight. Adverse effects were reported by 4 0 women receiving IM treatment versus 16 receiving oral treatme nt at 36 weeks of treatment (graphs 16.03 to 16.15). No anaphylactic reaction or abscess formation were observed, but too few women participated in the RCT to assess these and other important adverse effects. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. The third RCT, from Nigeria, (Ogunbode 1980) was a three-arm RCT comparing iron sorbitol versus 600 mg oral ferrous sulpha te versus 1200 mg oral ferrous sulphate. All women received a dai ly supplement of 5 mg of folic acid and 25 mg of pyrimethamine. The fourth RCT, conducted in Nigeria, compared IM iron dextran (250 mg iron dextran thrice-weekly until total calculated dose was given) versus 600 mg of oral ferrous sulphate plus vitami n C and folic acid (Komolafe 2003). A French RCT compared IV iron sucrose given in six slow IV injections on days 1, 4, 8, 12, 15 and 21 according to a formula described in the article, with 240 mg of elemental iron sulphat e tablets (Bayoumeu 2002); all women received folic acid 15 mg of folic acid in addition to iron. No significant differences wer e found in maternal haemoglobin levels at four weeks of treatm ent, haemoglobin levels in excess of 12 g/dl, neonatal haemoglobi n, ferritin levels, and birthweight. Similarly, no significant differences were found in the incidence of diarrhea, postpartum haemorrha ge, blood transfusion required, or neonatal mortality. The RCT s were underpowered to assess these outcomes properly. An RCT conducted in Turkey (Al 2005) compared IV iron sucrose calculated according to a formula described in the article (total dose was administered over five days and maximum daily dose administered was 400 mg elemental iron) versus 300 mg of elemental iron (polymaltose complex); all women were given 5 mg of folic acid daily. No significant differences were found for caesarean section rates, neonatal birt hohn Wiley & Sons, Ltd. 10 A comparison of oral ferrous fumarate 200 mg three times a day versus IV iron dextrin (calculated according to described formula) found that oral treatments increased constipation, compared w ith IV treatments (Singh 1998) (one RCT, 100 women; RR 0.04; 95% CI 0.00 to 0.61; graph 09.03). No significant differences were found for constipation when IV iron was compared to controlledrelease iron. However, only one small RCT (Symonds 1969) assessed this and it seemed to be underpowered to rule out clinically important effects (one RCT, 51 women; RR 0.22; 95% CI 0.03 to 1.85; graph 09.03). One RCT, recruiting mostly Malayan and Chinese women, found that higher haemoglobin levels wer e found at the end of gestation with IV versus oral treatments (Singh 1998). No mat ernal or neonatal deaths were recorded in this RCT, which was the only one specifically assessing these outcomes in women receiving ora l or IV treatments. Two women were reported as suffering severe allergic reactio ns with IV dextran in an RCT comparing the latter with oral ferrou s sulphate (Sood 1979). Neonates were assessed for any complicati on at birth and within the first week of life; one neonate in each treatment group developed neonatal jaundice. It found that IM iron was more frequently associated with pain in the injection site. The RCT was too small to rule out importan t clinical differences in measured adverse effects outcomes such as shivering, itching, metallic taste in mouth, severe delayed allergic reaction (graphs 06.04 to 06.09). An RCT conducted in the UK compared iron-dextran infusion plus hydrocortisone versus iron-dextran infusion without hy drocortisone (Dawson 1965). Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. The objective of this review was to address the effects of iron anaemia treatments on maternal and neonatal morbidity and mortality. The review included 17 randomised controlled tria ls (RCTs), most of which were small and with significant methodological flaws. These RCTs assessed many different questions and a broad range of treatments resulting in very limited opport unities to pool useful data. The paucity of robust studies assessing cl inical effects of treatments makes it impossible to balance the benefi ts and harms of differing treatments for different levels of an aemia in pregnancy, in a meaningful and useful way. We cannot determine if women with mild anaemia, but otherwise healthy, will benefit from anaemia treatment; adverse effects can potentially outweigh benefits. It also remai ns unclear which treatments are safer and more effective in women wit h moderate or severe anaemia with and without associated illne ss. Although iron treatments consistently increase maternal hae matological indices in women diagnosed with iron-deficiency anaemia in pregnancy, we found no evidence that these laboratory improvements reflected in clinical improvements such as reduced preterm delivery, reduced infant low birthweight, lower rat es of pre-eclampsia, sepsis or postpartum haemorrhage and its compl ications (Scholl 1992; Scholl 2000). We found very few RCTs assessing clinical outcomes, and these RCTs were too small to esti mate important clinical effects. Moreover, the studied popula tions turned out to be too small to deliver clear-cut answers to this re view's questions. The findings suggest that gastrointestinal adverse effects a re more frequent with oral iron treatments, compared with other rout es of iron administration. Higher doses of iron were not associa ted with improved haematological values. The assessment of the e ffects of controlled versus regular oral iron were mostly inconclusiv e; there seems to be a reduced incidence of constipation. Most oral iron studies were marred by high withdrawal rates, highligh ting the importance of assessing adverse effects and compliance issu es with these frequently-prescribed treatments. The findings of this review suggest that adding vitamin A to re iron (ferrous sulphate) resulted in improved haemoglobin le Another Cochrane review that focused on vitamin A supplementation during pregnancy suggested beneficial effects for women areas of poor nutritional intake (Van den Broek 2002). in Compared with oral iron, intramuscular (IM) iron sorbitol and iron dextran improved haematological values, reduced the pro portion of women without anaemia, and resulted in lower gastroi nohn Wiley & Sons, Ltd. 12 But these preparations were associate d with higher rates of systemic reactions especially with IM iron. The findings of this review also suggest that intravenous (IV) iron sucrose is effective, but there is uncertainty whether it may in crease the incidence of serious adverse effects such as thrombosis, which was frequent (9/41; 22%). Similarly, there are worry ing trends towards an increased risk of severe allergic reaction w ith IV dextran iron, but data were few. One study suggests that the r isk of venous thrombosis may be lowered by adding hydrocortisone to the infusion, but it is unclear what the real impact of this mi ght be and whether it has any other effects. Evidence of a relations hip between doses of IV iron and risk of adverse allergic reaction s is inconclusive. No effectiveness assessments were done for the co mpared doses of IV drugs. Compared with IM iron sucrose, IV iron sucrose significantly increased haematological indices but it is unclear what the effects are on maternal and neonatal morbidity. RCTs were insufficient to determine the clinical effects of treat ments in women with iron-deficiency anaemia during pregnancy. Avoidable limitations in the included randomised controlled trials (RCTs) resulted in these failing to provide sound evidence tha t currently available treatments for iron-deficiency anaemia in p regnant women are beneficial for women or their children. We found no scientific basis to suggest that in otherwise healthy women, the benefits of treatments for mild anaemia in pregnancy will outw eigh the adverse effects associated with them. Compared with oral iron, intramuscular (IM) iron improves haematological indices. But aga in, the support from clinical research seems to be missing and adver se effects remain poorly evaluated despite indications that tre atments can result in important adverse outcomes. This review is an invitati on for researchers, especially those working towards the improveme nt of health of communities in under-resourced settings, to imple ment high quality RCTs addressing knowledge gaps (such as thos e flagged up by this review), for this common condition. Stratification according to anaemia severity can help address questions of the effects in different populations, and balan ferently the benefits and harms. Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. Kaisi M, Ngwalle EWK, Runyoro DE, Rogers J. Evaluation of tolerance of and response to iron dextran (Imferon) adminisered by to tal dose infusion to pregnant women with iron deficiency anemia. Kumar 2005 {published data only} hate Journal of Kumar A, Jain S, Singh NP, Singh T. Oral versus high dose parentera l iron supplementation in pregnancy. The effect of parenteral iron administration in the control of anaemia of pregnancy. Al-Momen A, Al-Meshari A, Al-Nuaim L, Saddique A, Abotalib Z Khashogji T, et al.Intravenous iron sucrose complex in the trea ment of iron deficiency anemia during pregnancy. Allaire B, Campagna F. Iron-deficiency anemia in pregnancy. Evaluation of diagnosis and therapy by bone marrow hemosiderin. Ob-Amir M, Ahmad SH, Ansari Z, Dutta AK, Husain I. Total dose iron infusion during third trimester to iron deficient mothers a influences on anemia of early infancy. Bare W, Sullivan A. Comparison of intravenous saccharated iro ide and whole blood in treatment of hypochromic anemia of pregnancy. J, et al.Ferritin levels in newborn after prepartal iron medica tion. Barrada M, Salzer H, Schatten C, Pateisky N, Vavra N, Spona J, et al.Influence of prepartal iron-medication on newborns. Basu RN, Sood SK, Ramachandan K, Mathur M, Ramalingaswami V. Ethiopathogenesis of nutritional anemia in pregnancy: a therapeutic approach. Breymann C. rhEPO/parenteral iron vs parenteral iron only in the treatment of severe pregnancy anemia. Breymann C, Visca E, Huch R, Huch A. Recombinant human erythropoietin (rhEPO) for the therapy of severe iron deficiency a during pregnancy. 21st Conference of the Swiss Society of Gynecology and Obstetrics; 1988; Switzerland. Breymann 2002 {published data only} naemia Breymann C. Iron deficiency and anaemia in pregnancy: modern aspects of diagnosis and therapy. A comparative study of the effectiveness of iron preparations in the treatment of iron defi ciency anemias in pregnant women. Chanarin I, Rothman D. Response to folic and folinic acid in megaloblastic anaemia in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1965;72:374--5. Evaluation of a new coba chelate with iron in pregnancy anemia. Coelho K, Ramdas S, Pillai S. A comparative study of changes in haemoglobin with high and low dose iron preparations in pregnant women. Dede D, Uygur B, Yilmaz T, Mungan M, Ugur M. Intravenous iron sucrose complex vs. oral ferrous sulfate for postpartu m iron deficiency anemia. Dommisse J, Du Toit ED, Nicholson N. Folic acid - has it a role in the treatment of severe iron deficiency anaemia in pregnancy?. Ekstrom EC, Hyder SM, Chowdhury AM, Chowdhury SA, Lonnerdal B, Habicht JP, et al.Efficacy and trial effectiveness of wee kly and daily iron supplementation among pregnant women in rural Bangladesh: disentangling the issues. Finzi C, Bailo U. Treatment of anemia in pregnancy: comparison of an iron delayed-action preparation and conventional preparati ons. Fochi F, Ciampini M, Ceccarelli G. Efficacy of iron therapy: a c omparative evaluation of four iron preparations administered t o anaemic pregnant women. Halksworth G, Moseley L, Carter K, Worwood M. Iron absorption from spatone (a natural mineral water) for prevention of iron deficiency in pregnancy. Antenatal clinics as trial units in evalu ating treatment of anaemia in pregnancy. The use and abuse of drugs and chemicals in Tropical Africa. Proceedings of the 1973 Annual Scientific Conference of the East African Research Council; 1973; Nairobi, Kenya. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Hampel K, Roetz R. Influence of a long-time substitution with fo-late-iron combination in pregnancy on serum folate and serum iro n and on hematological parameters. Relative efficacy of sustained release iron and iron wit folic acid treatment in pregnancy. Obstetrics & Gynecology 1955;5:562--Izak G, Levy S, Rachmilewitz M, Grossowicz N. The effect of iron and folic acid therapy on combined iron and folate deficiency anaemia: the results of a clinical trial. Jackson 1982 {published data only} Scandinavian Journal of Jackson RT, Latham MC. Anemia of pregnancy in Liberia, West Africa: a therapeutic trial. WHO sponsored collaborative studies on nutritional anaemia in India. Relative effectiveness of iron bis-glycinate chelate (Ferrochel) and ferrous sulfate in the control of iron deficienc y in pregnant women. Cuervo LG, Mahomed K. Treatments for iron deficiency anaemia in pregnancy. Group allocation was predetermined by one of the authors who w as not involved with women's care. Authors used opaque envelopes that were consecutively-number ed by means of a computer-generated randomisation table. As each woman gave consent for the study, the next envelope was opened to assign the participant to either of the 2 groups. A sample-size analysis was performed before initiation of th e study. The analysis was based on the intention-to-treat principle. No participants were lost to follow up, and there were no dropo uts. 90 pregnant women, between the 26th and 34th weeks of gestati on, with established iron-deficiency anemia who had hemoglobin levels between 8 and 10.5 g/dL and f erritin levels less than 13 g/ L. Women were excluded when serum folate and vitamin B12 levels w ere found to be less than 4 pg/mL and 100 pg/mL respectively. Anaemia from causes other than iron-deficiency, multiple pregna ncy, previous blood transfusion, history of hematological disease, risk of preterm labour, intolerance to iron derivatives, recent administrat ion of iron for the treatment of iron-deficiency anaemia, or current usage of iron supplement were the reasons for other exclusions. Both groups were supplemented by 0.5 mg folic acid treatment p ted from the following formula: weight nfusion, the maximum total dose fused in 20-30 minutes. Total dose ered was 400 mg elemental iron. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Women were assigned to the group treatment by a randomisatio Sample size and power calculation was described. It is unclear if the outcome assessor was blind that 3 (6%) women were excluded from the study and that 2 others w n table. men nor caregivers were blinded to the ed to the interventions. The trialists reported here lost to follow up. a; cirrhosis; viral hepatitis; multiple pregnteral iron treatment before inclusion; inExperiment group: IV iron sucrose. Given in 6 slow Control group: oral iron. 3 x 80 mg iron sulphate tablets (Tar elemental iron a day for 4 weeks). Women asked to note compliance "Women were also given 15 mg folic acid per day to prevent an eve eliminate the influence of such a deficiency on the results." dyferon) per day for 4 weeks (i.e. 240 mg in calendar. ntual folic-acid deficiency and to of any continuing iron treatment." The trial measured haematological response, transferrin le vel and saturation coefficient, erythrocytic folates, ferritin level, baby's ferritin level and full blood cell count and adverse reactions. Women randomly assigned to 2 treatment groups by means of a com puter-generated list. It is unclear whether participants, clinicians and outcome assessor were bli nded to the interventions. No description of the sample size or power calcula tion was recorded. Exclusion criteria: women with anaemia not caused by iron deficie chronic bleeding; renal failure. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Women were randomised to receive IV administered iron sucrose (200 mg IV administered twice weekly 72 to 96 hours apart) with vs without adjuvant recombinant hum an erythropoietin (300 U/kg body weight). All women received orally administered iron sulfate (80 mg twice daily) for = 2 weeks before starting. Median durations of th erapy were 18 days in group 1 and 25 days in group 2. Women were randomly distributed into 3 groups, 1 receiving da twice-weekly and the 3rd one-weekly iron supplementation for 1 l haemoglobin of < 11 g/dL and> 8 g/dL. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 24 Experiment group: IM iron: parenteral iron group were given as iron sorbitol citric acid in a injection volume of 5 ml at an int An initial test dose of 0.5 ml was given. The trial measured values of blood indices at 36 weeks as well a side-effects. 2 IM injections of 250 mg elemental iron erval of 4-6 weeks in the antenatal clinic. e reaction to the test dose, then a full 250 ing Z-tract technique. The women and the investigator were blinded to th e allocation of treatment group (daily vs twice weekly) at initial recruitment and the 3 follow-up visits. The appearance of the capsules and the blister packs of the 2 groups were identical. The randomisatio n code was opened only after the follow up for all participants had been completed. This trial had 86 participants, (45%) that did not complete the entire duratio n of follow up (i.e., 4 follow-up visits). However data on 83.8% of the participants were available for 4 weeks of follow up. 191 pregnant women between the age of 17-35 years, with an init included. All given health education materials on importance of diet in p Experiment group: daily iron - plus daily folate. Control group: twice weekly iron - plus daily folate. Placebo was given for the rest of the days. sulphate (60 mg elemental Fe) each day and on sulphate (60 mg elemental) twice weekly Venous blood samples were taken for complete blood count at each 3rd and 4th visits. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. visit and for serum ferritin at the 1st, ital disorders such as thalassemia minor. Yes Description A - Adequate red with those who continued in the 2 treatment groups (41 versus 45). There was no information on methods of randomisation. No des calculation was described and both the participants and treatin tions. No participants were reported to have dropped out or we cription of the sample size or power g physicians were blinded to the intervenre lost to follow up. 91 women in the first or second trimester of pregnancy with a PCV o to 3 treatment groups. f 33% or less were randomly allocated In group A, 32 participants received 200 mg of oral ferrous sulp received 400 mg of oral ferrous sulphate 3 times daily; in grou (sorbitol gluconic acid) complex rerastral (500 mg Fe) on alterna dose (between 1250 to 2500 mg of iron). Unclear Description B - Unclear hate thrice daily; in group B 28 participants p C, 31 women received IM iron poly te days until completion of the required ate the dose was described. Participants were allocated by restricted random allocation. T here was no further information on methods of randomisation. No description of the sample size or power ca lculation was described and neither the participants nor treating physicians were blinded to the inte rventions. One participant from the imferon group was reported to have dropped out due to a severe reaction. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Yes Description A - Adequate clinical outcomes and side-effects that sity of Singapore was the contacted author. No des calculation was described and researchers kept unmasked the 5 gr dropped in the group receiving IV Fe due to severe delayed adve 151 pregnant women. The manufacturers of the active treatments provided pla labelled the active and placebo preparations. Unclear Description B - Unclear and side-effects. There was no information on methods of randomisation. No wom or were lost to follow up. Neither the women nor treating phys No description of the sample size or power calculation was descri en were reported to have dropped out icians were blinded to the interventions. 200 women with uncomplicated pregnancy enrolled at 24-26 weeks o> 8 gm% but < 11 gm% were included. Women dropped out of study if Hb fell below 8 g/l or if severe pr Group A (100 women) received injectable iron-sorbitol-citrate in intervals and group B (100 women) were given oral iron having 1 100 days. The trial measured haemoglobin levels at the time of inclusio delivery as well as the proportion of caesarean delivery. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. f gestation with a haemoglobin of oblems arose. This is no Insufficient information for critical appraisal was provided. that lead to infer levels of Hg at the beginning t considered random. There are no explicit inclusion or exclusion Randomisation method not posed. No information is provided that completed the trial or that were accounted for each result. regarding blinding or number of women Centers were randomly assign (not women) and only some women h No random allocation. The paper does not explai No randomisation method. Allocation was done using a haphazard strategy, not a random o Used a haphazard allocation method (day of diagnosis). Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. The study evaluates the use of medication in women with hemogl random strategy for allocation. The study is in women with haemoglobin levels over 10 g/dl. Tr Although the authors state that allocation was random, the gr authors used an inappropriate control group of healthy women method. More than 50% of their women were lost to follow up. We tried to contact to verify dat lists are considered inadequate since there is no concealment an The trial evaluated folic acid + iron versus iron. This study has dropouts that surpasses the limit establishe obin levels over 10.5 g/dl and uses noneatment allocation was not random. They do not explain the randomisation a but it was impossible. Open-randomisation d it is prone to bias. The trial evaluated group 1 Fe + pteroylmonoglutamic acid and acid versus group 1 + calcium caseinate. The and 11.6 g/dL in both groups of treatment. Health centers were randomised, rather than individuals. This study has a high proportion of women lost to follow up exce review. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. mean baseline haemoglobin was 11.3 eding the cut-off point established for this alment. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 38 9 Spontaneous abortion No. of studies No. of participants 9 Need transfusion No. of studies No. of participants 4 Caesarean section No. of studies No. of participants Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 39 Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 40 Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 41 3 Moderate abdominal pain No. of studies No. of participants 2 Haematocrit (%) at 8 weeks of treatment No. of studies No. of participants Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 42 Outcome or subgroup title No. of studies No. of participants Total events: 7 (Oral iron), 4 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.21 (P = 0.23) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 4 (Oral iron), 4 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.18 (P = 0.86) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 3 Oral iron + vitamin A versus oral i trimester. Total events: 2 (Oral iron + vit A), 20 (Oral iron) Heterogeneity: not applicable Test for overall effect: Z = 3.20 (P = 0.0014) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. sus regular oral iron, Outcome 1 Side-effects. Total events: 7 (Ctrl release iron), 7 (Regular oral iron) Heterogeneity: not applicable Test for overall effect: Z = 0.09 (P = 0.93) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 4 Controlled release oral iron ver vomiting. sus regular oral iron, Outcome 3 Constipation. Total events: 1 (Ctrl release iron), 4 (Regular oral iron) Heterogeneity: not applicable Test for overall effect: Z = 1.32 (P = 0.19) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 4 Controlled release oral iron ver cramps. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 1 Pain at injection site. Total events: 13 (IM iron sorb-cit), 12 (IM iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.01 (P = 0.99) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 2 Skin discolouration at injection site. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 3 Venous thrombosis. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 4 Nausea or vomiting. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 5 Headaches. Total events: 1 (IM iron sorb-cit), 7 (IM iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.97 (P = 0.049) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 6 Shivering. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 7 Itching. Total events: 4 (IM iron sorb-cit), 4 (IM iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.13 (P = 0.90) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 8 Metallic taste in mouth. Comparison 6 Intramuscular iron dextran vers injection site. Total events: 12 (IM iron dextran), 3 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 2.61 (P = 0.0091) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers us intravenous iron dextran, Outcome 2 Skin discolouration at injection site. Comparison 6 Intramuscular iron dextran vers thrombosis. Total events: 0 (IM iron dextran), 4 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.42 (P = 0.16) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers Nausea or vomiting. Comparison 6 Intramuscular iron dextran vers Headaches. Total events: 7 (IM iron dextran), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.84 (P = 0.066) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers Shivering. us intravenous iron dextran, Outcome 7 Itching. Total events: 4 (IM iron dextran), 3 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.58 (P = 0.56) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers Metallic taste in mouth. us intravenous iron dextran, Outcome 9 Severe delayed allergic reaction. Total events: 0 (IM iron dextran), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.01 (P = 0.31) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 7 Intramuscular iron sorbitol cit ric acid versus intravenous iron dextran, Outcome 1 Pain at injection site. ric acid versus intravenous iron dextran, Outcome 2 Skin discolouration at injection site. Total events: 3 (IM iron sorb-cit), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.02 (P = 0.31) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 7 Intramuscular iron sorbitol cit ric acid versus intravenous iron dextran, Outcome 3 Venous thrombosis. ric acid versus intravenous iron dextran, Outcome 4 Nausea or vomiting. Total events: 1 (IM iron sorb-cit), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.55 (P = 0.58) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ric acid versus intravenous iron dextran, Outcome 5 Headaches. Total events: 0 (IM iron sorb-cit), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.03 (P = 0.30) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 7 Intramuscular iron sorbitol cit Outcome 7 Itching. ric acid versus intravenous iron dextran, Outcome 8 Metallic taste in mouth. Total events: 4 (IM iron sorb-cit), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.32 (P = 0.19) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 0 (IV iron), 1 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.68 (P = 0.50) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. oral iron, Outcome 2 Nausea or vomiting or epigastric discomfort. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Total events: 0 (IV iron), 2 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 1.13 (P = 0.26) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regular required. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regular hemoglobin. Comparison 9 Intravenous iron versus regular birth. Heterogeneity: not applicable Test for overall effect: Z = 3.57 (P = 0.00035) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. r oral iron, Outcome 11 Neonates ferritin level. Comparison 9 Intravenous iron versus regula at 4 weeks. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. r oral iron, Outcome 13 Maternal mortality. r oral iron, Outcome 14 Preterm labour. r oral iron, Outcome 15 Caesarean section. r oral iron, Outcome 16 Operative vaginal birth. Total events: 3 (IV iron), 2 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 0.46 (P = 0.65) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regula haemorrhage. r oral iron, Outcome 19 Neonatal birthweight. Comparison 9 Intravenous iron versus regula age. Total events: 8 (IV iron), 5 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 0.88 (P = 0.38) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regula score under seven. r oral iron, Outcome 22 Neonatal mortality. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 9 Intravenous iron versus regula g/dL at 30 days. Comparison 9 Intravenous iron versus regula hypertension. Total events: 2 (IV iron), 0 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 1.05 (P = 0.29) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio r oral iron, Outcome 25 Gestational diabetes. Comparison 9 Intravenous iron versus regula g/dL at birth. Total events: 43 (IV iron), 28 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 3.56 (P = 0.00037) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regula reaction. Total events: 1 (IV iron), 1 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio olled release oral iron, Outcome 1 Side-effects. Comparison 10 Intravenous iron versus contr vomiting. Total events: 0 (IV iron), 4 (Control release iron) Heterogeneity: not applicable Test for overall effect: Z = 1.55 (P = 0.12) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. olled release oral iron, Outcome 3 Constipation. Comparison 10 Intravenous iron versus contr cramps. Total events: 0 (IV iron), 1 (Control release iron) Heterogeneity: not applicable Test for overall effect: Z = 0.73 (P = 0.47) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 11 Intravenous iron + hydrocorti sone versus intravenous iron, Outcome 1 Tenderness or erythema. Total events: 0 (IV iron + hydrocort), 5 (IV iron) Heterogeneity: not applicable Test for overall effect: Z = 1.67 (P = 0.095) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers us full dose intravenous iron, Outcome 1 Allergic reaction during infusion. us full dose intravenous iron, Outcome 2 Allergic reaction after infusion. Total events: 47 (2/3 dose IV iron), 77 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 2.86 (P = 0.0042) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers us full dose intravenous iron, Outcome 3 Lifethreatening allergic reaction during infusion. us full dose intravenous iron, Outcome 4 Discomfort needing analgesics after infusion. Total events: 15 (2/3 dose IV iron), 31 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 2.33 (P = 0.020) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers us full dose intravenous iron, Outcome 5 Immobilised by painful joints. Comparison 12 2/3 dose intravenous iron vers live births. Total events: 9 (2/3 dose IV iron), 11 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 0.36 (P = 0.72) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers Neonatal death. Total events: 6 (2/3 dose IV iron), 9 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 0.70 (P = 0.49) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 1 (rhEPO +IV Fe sucrose), 5 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 1.53 (P = 0.12) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 6 (rhEPO +IV Fe sucrose), 6 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 13 Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 4 Metallic taste. adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 5 Warm feeling. Total events: 1 (rhEPO +IV Fe sucrose), 1 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 13 Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 6 Birthweight. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. M-H,Fixed,95% CI ohn Wiley & Sons, Ltd. M-H,Fixed,95% CI Comparison 14 Intramuscular iron sorbitol c anaemic at term. itric acid versus oral iron, Outcome 2 Mean maternal haemoglobin at birth. Heterogeneity: not applicable Test for overall effect: Z = 4.41 (P = 0.000010) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 14 Intramuscular iron sorbitol c itric acid versus oral iron, Outcome 3 Mean maternal hematocrit level at birth. Comparison 14 Intramuscular iron sorbitol c section. Total events: 24 (IM iron), 22 (Oral iron) Heterogeneity: not applicable Test for overall effect: Z = 0.34 (P = 0.74) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 14 Intramuscular iron sorbitol c itric acid versus oral iron, Outcome 5 Haematocrit (%) at 4 weeks of treatment. itric acid versus oral iron, Outcome 6 Haematocrit (%) at 8 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.79 (P = 0.00015) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 14 Intramuscular iron sorbitol c itric acid versus oral iron, Outcome 7 Haematocrit (%) at 4 weeks of treatment. itric acid versus oral iron, Outcome 8 Haematocrit (%) at 8 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.23 (P = 0.0012) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 11 (IM iron dextran), 1 (Oral Fe+vitC+folic a) Heterogeneity: not applicable Test for overall effect: Z = 2.37 (P = 0.018) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c itric acid versus oral iron + folic acid, Outcome 1 Mean haemoglobin at 36 weeks. Total events: 42 (IM iron), 51 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.50 (P = 0.13) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. itric acid versus oral iron + folic acid, Outcome 3 Caesarean section. itric acid versus oral iron + folic acid, Outcome 4 Mean birthweight (kg). Heterogeneity: not applicable Test for overall effect: Z = 0.27 (P = 0.79) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c Diarrhoea. itric acid versus oral iron + folic acid, Outcome 6 Constipation. Total events: 0 (IM iron), 8 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.96 (P = 0.050) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c Dyspepsia. itric acid versus oral iron + folic acid, Outcome 8 Local site mainly pain. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c Staining. Total events: 6 (IM iron), 0 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.76 (P = 0.079) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. citric acid versus oral iron + folic acid, Outcome 11 Itching and rash. Total events: 8 (IM iron), 0 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.96 (P = 0.050) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. citric acid versus oral iron + folic acid, Outcome 14 Vaso-vagal due to apprehension. Total events: 4 (IM iron), 0 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.48 (P = 0.14) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. citric acid versus oral iron + folic acid, Outcome 15 Systemic ache. Total events: 11 (IMiron), 21 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.93 (P = 0.053) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 17 Oral iron daily versus oral iro at 4 weeks. Comparison 17 Oral iron daily versus oral iro at 8 weeks. Comparison 17 Oral iron daily versus oral iro at 12 weeks. Comparison 17 Oral iron daily versus oral iro at 16 weeks. Heterogeneity: not applicable Test for overall effect: Z = 1.89 (P = 0.059) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 1 (Oral iron daily), 7 (Oral iron twice week) Heterogeneity: not applicable Test for overall effect: Z = 1.78 (P = 0.075) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 18 Oral iron daily versus oral iro 16 weeks. Total events: 23 (Oral iron daily), 13 (Oral iron once week) Heterogeneity: not applicable Test for overall effect: Z = 1.95 (P = 0.051) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 19 Oral iron twice week versus ora level at 16 weeks. Heterogeneity: not applicable Test for overall effect: Z = 2.10 (P = 0.035) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Total events: 7 (Oral iron twice week), 20 (Oral iron once wee Heterogeneity: not applicable Test for overall effect: Z = 2.94 (P = 0.0033) k) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 20 Intravenous iron sucrose 500 m g versus intravenous iron sucrose 200 mg, Outcome 1 Haemoglobin level at delivery. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 20 Intravenous iron sucrose 500 m g versus intravenous iron sucrose 200 mg, Outcome 3 Moderate abdominal pain. Comparison 21 Intravenous iron sucrose 500 m Outcome 1 Maternal haemoglobin level at birth. Heterogeneity: not applicable Test for overall effect: Z = 4.30 (P = 0.000017) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. g versus intramuscular iron sorbitol, Outcome 1 Haemoglobin level at delivery. Heterogeneity: not applicable Test for overall effect: Z = 3.51 (P = 0.00044) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Heterogeneity: not applicable Test for overall effect: Z = 0.63 (P = 0.53) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 1 Haematocrit (%) at 4 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.04 (P = 0.0024) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 2 Haematocrit (%) at 8 weeks of treatment. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 3 Neonatal jaundice. Total events: 1 (IM iron sorb-gluc), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.05 (P = 0.96) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 4 Viral hepatitis. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 5 Severe allergic reaction. Total events: 0 (IM iron sorb-gluc), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.72 (P = 0.47) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. For the 2006 update, Ludovic Reveiz and Gill Gyte appraised t review, with Gill Gyte and Luis Gabriel Cuervo providing comm editorial feedback. An updated search of the Pregnancy and Childbirth Group's Trials Register on 31 January 2007 identified seven new trial reports which have been added to the awaiting assessment section for assessment in the next update. There are now a total of 17 trials included in the review. The inclusion of these trials have generally not changed the conclusions although there are now concerns about possible important adverse effects. Ludovic Reveiz is now the guarantor of the review. Ludovic Reveiz took the lead on wri ents on the various drafts, and revised the review in respons The first published review was prepared by Luis Gabriel Cuerv Treatments for iron deficiency anaemia in pregnancy. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. and Kassam Mahomed, and cited as: Cuervo LG, Mahomed K. tabase of Systematic Reviews 2001, Issue 2. Luis Gabriel Cuervo has contributed to this systematic revie were made before joining the Pan American Health Organizatio for the statements contained therein. w in a personal capacity and during his spare time. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright ©2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 120

Document 05 : Treatments For Iron-Deficiency Anaemia In Pregnancy (Review) -- The Cochrane Collaboration
Summary  : 25%
Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. T A B L E O F C O N T E N T S HEADER. Comparison 1 Oral iron versus placebo, Outcome 2 Haemoglobin levels (g/dl). Comparison 1 Oral iron versus placebo, Outcome 3 Ferritin levels (ug/l). Comparison 1 Oral iron versus placebo, Outcome 4 Serum iron (mg/l). Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. iv Analysis 20.1. Comparison 20 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg, Outcome 1 Haemoglobin level at delivery. Comparison 20 Intravenous iron sucrose 500 mg versus intravenous iron sucrose 200 mg, Outcome 3 Moderate abdominal pain. Comparison 21 Intravenous iron sucrose 500 mg versus intramuscular iron sorbitol, Outcome 1 Maternal haemoglobin level at birth. Comparison 22 Intravenous iron sucrose 200 mg versus intramuscular iron sorbitol, Outcome 1 Haemoglobin level at delivery. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 1 Haematocrit (%) at 4 weeks of treatment. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 2 Haematocrit (%) at 8 weeks of treatment. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 3 Neonatal jaundice. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 4 Viral hepatitis. Comparison 25 Intramuscular iron sorbitol-gl u acid versus intravenous iron dextran, Outcome 5 Severe allergic reaction. a health problem for pregnant women and their babies (Letsky 2001). Several studies considered anaemia (haemoglobin levels between 7 g/dl and 10 g/dl) as a risk factor for fetal death, premature delivery, low birthweight and other adverse outcomes (Williams 1992). Some suggest a link between maternal anaemia in pregnancy on the later developmental problems of the children (Letsky 2001; Williams 1992). There is evidence indicating that maternal haemoglobin levels under 7 g/dl are associated with a higher risk in the mother of developing cardiac heart failur e, which has adverse consequences on the mother and fetus (Lops 1995; WHO 1992; Williams 1992). A cohort study done in Pakistan found that the risk of low birthweight and preterm deli very among the anaemic women (haemoglobin under 11 g/dl) was 1.9 and 4 times higher, respectively, than the non-anaemic women. In addition, the neonates of anaemic women had a 3.7 greater risk of intrauterine fetal death and 1.8 times increased risk having low Apgar scores at one minute when compared to non-anaemic women (Lone 2004). The suggestion that low iron stores in the mother during preg nancy may affect the child's later development, means that long term outcomes on the baby should be outcome measures in any study on the treatment of anaemia in pregnancy. There is also a strong case for studying separately physiological anaemia, anaemia and severe anaemia in pregnancy. mild In developing countries, anaemia in pregnancy is frequent and has been attributed to poor nutrition and a high incidence of concurrent diseases, and can potentially complicate conditions such as postpartum haemorrhage which is a major contributor to maternal mortality in many developing countries (WHO 1992). However, anaemia may only be a marker of various social and nutritional conditions, and raising haemoglobin levels coul d have little, if any, effect on morbidity or mortality if other condi tions are not improved (Goroll 1997). There are various possible forms of treatment for iron-deficie ncy anaemia. Iron can be given by mouth, by intramuscular (IM) injection or intravenous (IV) injection. It is also possible to deli ver iron by giving a blood transfusion, and recombinant erythropoiet in in conjunction with iron is a further possibility. Anecdotal evid ence suggests that oral iron given to anaemic pregnant and non-pre gnant women is associated with gastrointestinal side-effects s uch as nausea and constipation. IM or IV iron is thought to be associat ed with allergic reactions and anaphylactic shock, as well as veno us thrombosis and occasionally cardiac arrest and death. Blood tr ansfusion carries the risk of transmitting parasitic or viral in fections including HIV, hepatitis, and Chagas disease (trypanosomias is), despite preventive blood screening. There is also the possib ility of bovine spongiform encephalitis, and as yet unknown viral i nfections. Recommendations for the treatm ent of anaemia are frequently based on the expectation that they m ay be benevolent but are seldom supported by reproducible robus t studies, especially randomised controlled trials. Furtherm ore, they may not take into account important adverse effects such as allergic reactions, viral or parasitic transmission from bloo d transfusions, gastrointestinal complications, and discomfort gen erated by common side-effects of iron. Therefore, it is difficult to balance the benefits and harms of treatments, let alone determine if there is a case to recommend a particular anaemia treatment for all women with anaemia in pregnancy. The aim of this review was to use a systematic approach to identify and synthesise the evidence of randomised controlled tri als evaluating the effects of treatments for iron-deficiency anaemi a in pregnancy, and provide robust valid and useful evidence to inf orm clinical practice. The principal objective was to determine the overall effects of iron therapy given to women diagnosed with iron-deficiency anaemia in pregnancy, measuring neonatal and maternal morbidity and mortality, haematological parameters and side-effects, espe cially adverse effects of treatment. The review also compared differ ent forms of iron therapy for iron-deficiency anaemia on neonatal an d maternal morbidity and mortality, haematological paramete rs and adverse effects on women and their offspring. The review aime d to assess the effects of iron treatments when delivered to wom en categorised in three groups (mild, moderate or severe, as defin ed by trialists) at inception into the randomised controlled tri al. The review did not address the need for iron supplementation non-anaemic women; this question has been addressed in sever other reviews and evidence summaries. Similarly, it did not f cus on vitamin A, vitamin B12, micronutrients, folate deficiency infectious or genetic anaemia, which will be covered in other re views. Another Cochrane systematic review focuses on the effe of routine oral iron supplementation with or without folic a for women during pregnancy (Pena-Rosas 2006). Types of studies of al o, cts cid This review considered randomised controlled trials assessi ng the effects of treatments for iron-deficiency anaemia in pregnancy. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. reviewed the 'materials and methods' of the reports. Quasi-r studies were not eligible for this review. Iron-deficiency anaemia definitions may be problematic due to the controversy about which diagnostic tests are sufficient and able enough to rule out other causes of anaemia, and that anaem causes are frequently combined. Therefore, for this review we cepted the diagnosis of iron-deficiency anaemia defined by the authors of the studies. Types of participants andom reliia acPregnant women with a diagnosis of anaemia (haemoglobin leve under 11 g/dl) attributed to iron deficiency. 1. All types of iron preparations versus placebo or no treatment. 2. Different forms of oral iron preparations used for the treatment of anaemia. 3. Oral iron in combination with other haematinics versus regular oral iron. 4. Oral iron in combination with substances that could increase its absorption versus regular oral iron. 5. Slow-release preparations versus regular oral iron. 6. Intramuscular (IM) iron versus regular oral iron. 7. Intravenous (IV) iron versus regular oral iron. 9. Different dosages of the above combinations. 10. Blood transfusion versus oral iron therapy. 12. Recombinant erythropoietin versus oral iron therapy. 13. Recombinant erythropoietin versus parenteral iron therapy. For the purpose of this review, regular oral iron will includ preparations different from controlled-release oral iron. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. 4. weekly current awareness search of a further 36 journals plus BioMed Central email alerts. Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, a nd the list of journals reviewed via the current awareness servi ce can be found in the 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnan cy and Childbirth Group. Trials identified through the searching activities described a bove are given a code (or codes) depending on the topic. The codes are linked to review topics. We also searched trials registers such as www.controlled-trial s.com, www.clinicaltrials.gov, NHS Trusts Clinical Trials Register, National Health Service Research and Development Health Technology Assessment Programme (HTA), Action Medical Research, King's College London (UK), Medical Research Council (UK), The Wellcome Trust, in January 2006. We searched the bibliographies of all papers identified by the se strategies and relevant articles obtained. We did not apply a ny language restrictions and eligible randomised controlled tr ials have been included regardless of the language of publication of the ir report. Two review authors (L Reveiz (LR) and LG Cuervo (LGC)) checked the titles and abstracts identified from the searches. If was clear that the study did not refer to a randomised controlle trial on iron-deficiency anaemia in pregnancy, it was excluded. If it was unclear, then we obtained the full text of the study for i pendent assessment by LR and G Gyte (GG). LR and GG assessed each trial for inclusion and resolved any disagreements throu discussion, with referral to a third author (LGC) when necessar Excluded studies and reasons for exclusion are described in the 'Characteristics of excluded studies' table. Assessment of methodological quality it d ndegh y. We assessed trials under consideration for methodological qu ality and for appropriateness for inclusion without consideration of their results. We processed data from included trials as descri bed in the Cochrane Handbook for Systematic Reviews of Interventio ns (Higgins 2005). We undertook quality assessment by evaluating the following components for each included study, since there wa s some evidence that these are associated with biased estimates of treatment effect: (a) the method of generation of the randomisation sequence; if it delivered a known chance allocation to each given group but individual allocation could not be anticipated; (b) the method of allocation concealment, which was considered 'adequate' when the assignment could not be foreseen; (c) who was blinded or not blinded (participants, clinicians, outcome assessors); (d) participants lost to follow up in each arm of the study (split into postrandomisation exclusions and later losses if possi ble), and whether participants were analysed in the groups to which they were originally randomised (intention to treat). The information was recorded in a table of quality criteria and a description of the quality of each study was given based on a summary of these components. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Data extraction Data extraction was carried out independently by one author (LR) using a data extraction form. Data were extracted for all outcom es for all relevant drugs, paying particular attention to the do sage and periodicity of treatment. We resolved disagreements by discussion until we reached consens us. We obtained missing data from the trial authors, when possib le. Analysis To estimate differences between treatments, we pooled the re sults of randomised controlled trials (RCTs) that evaluated simila r interventions (and controls), and calculated a weighted treatment effect across RCTs using a fixed-effect model. Results were expressed as number needed to treat where appropriate. We summarised the inform ation we found available. Quasi-randomised and non-randomise d controlled studies were identified and listed, but were not fu rther discussed. A qualitative description was provided for advers e effects when this was available. See:Characteristics of included studies;Characteristics of excluded studies. The search identified 111 references: two unpublished trials, five congress abstracts, and 104 published trials. An initial t rawl through this list (LR) excluded 55 references of non-randomised controlled trials (RCTs). This left 56 trials for a more detaile d evaluation. Two authors (Ludovic Reveiz (LR) and Gill Gyte (GG)) independently checked the trials against the inclusion criteri a, and a third author (Luis Gabriel Cuervo (LGC)) acted as the arbiter. Thirty-eight studies were further excluded after first review because they were not RCTs; included mostly non-anaemic women; evaluated postpartum iron treatments; focused on non iron-de ficiency anaemia; or had methodological flaws that seriously compromised their validity or resulted in insufficient useful re liable information. We actively tried to contact the authors using contact information provided in their articles and on the interne t. We contacted the authors listed in the articles by Singh (Singh 1998), Visca (Visca 1996), Suharno (Suharno 1993), Mumtaz (Mumtaz 2000), Siega-Riz (Siega-Riz 2001), De Souza (De Souza 2004) and Breymann (Breymann 2001). We received responses from the authors of the Visca, Suharno, Mumtaz, De Souza and Breymann articles. 1996. We were unable to contact the authors for the articles by Stein 1991 and Wu 1998. Most focused on laboratory results rather than clinical outcomes. Clinical outcome s were assessed in six RCTs (Al 2005; Bayoumeu 2002; Breymann 2001; Oluboyede 1980; Singh 1998; Zutschi 2004) although Breymann and Singh's data were unpublished; these data were provided by the main author of Singh 1998 and have been incorporated into the review. LR and GG independently extracted data from the articles. LGC was expected to act as arbiter if differen ces arose in the data extraction, but this did not happen. LR did da ta entries, and GG double checked data entries for accuracy. Seven groups of RCTs were described according to the type of intervention. However, groups were further divided accordin g to co-interventions, dose, regimen, route, or type of chemical components of the intervention (i.e. iron sucrose, dextran), as fo llows. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. IV administered iron sucrose with and without adjuvant recombinant human erythropoietin (Breymann 2001) For details of included and excluded studies, of included studies' and the 'Characteristics of excluded studi tables. al seethe 'Characteristics es' Ludovic Reveiz and Gill Gyte assessed the methodological qua lity of the included studies independently as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). Differences in interpretations were sorted by consensus among all three authors, after checking the criteria agr eed in the original review protocol. When RCTs had potential valid ity or interpretation problems and just part of the data were dee med useful, we would only use such data. For example, when RCTs had a high withdrawal rates and therefore incomplete data on o utcomes at the end of follow up, but still offered complete data at a given time that fulfilled our predefined inclusion criteria, th e later data were used. The quality assessment included an evaluation of the followi ng components for each included study, since there is some evidence that these are associated with biased estimates of treatment effect (Juni 2001): (a) the method of generation of the randomisation sequence; (b) the method of allocation concealment, which was considered adequate if the assignment could not be foreseen; (c) parties masked to the intervention (i.e. blinding of partici pants, clinicians, outcome evaluators); (d) how many participants were lost to follow up in each arm and whether participants were analysed in the groups to which they were originally randomised (intention to treat). The randomisation list generation strategy was consid ered inadequate for the trial by Dawson 1965. Published details of the randomisation were insufficient in the Singh 1998 and Breymann 2001 articles, but additional details were provided by the authors upon request. The allocation strategy and concealment were considered adequa te in 3 of the 17 studies (Al 2005; Breymann 2001; Mumtaz 2000). In most RCTs, blinding was not used; these were open RCTs. Two RCTs described blinding (masking) but it is unclear whether they were blinding the participants or healthcare providers t o the interventions (Mumtaz 2000; Suharno 1993); both RCTs assessed oral administration. None of the RCTs masked the interventi ons to people assessing outcomes. Loss to follow up Withdrawal rates (drop outs and losses to follow up) were reported in seven RCTs. Less than 5%: withdrawal rates were lower than 5% in two RCTs (Oluboyede 1980; Sood 1979). 5% to 9.9%: an RCT from Pakistan (Wali 2002) had five withdrawals (8.3%) due to intolerance in the intramuscular (IM) iron group. An RCT from France had three withdrawals (6%) (Bayoumeu 2002). 10% to 19.9%: the West Java RCT (Suharno 1993) had complete data available on 251 (83%) women: reasons for withdrawals are further described in the article. More than 20%: an RCT from Pakistan (Mumtaz 2000) recruited 191 women; of these, 160 were successfully followed for at least four weeks and supplemented for an average of 10.9 weeks. Fifty-five per cent completed the entire duration of follow up; 15% of the women recruited did not return for a single visit and were excluded from the analysis. The remaining 30% did not complete the entire 12 weeks of planned follow up. No significant differences were found for population characteristics (age, socioeconomic status score, parity, time since last pregnancy, body mass index, initial haemoglobin, dependants or family and the duration of follow up) between women who withdrew and those who completed the study. The Brazilian RCT (De Souza 2004) had 41 (21.5%) women who withdrew or were lost to follow up; the reasons were described in the article. The analysis was done using data at 16 weeks of treatment. The UK RCT (Dawson 1965) had high rates of losses to follow up. The RCT was focused on assessing adverse effects. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. on adverse effects were used for this review. No significant differences were found on data of initial hematological parameters, gestation, parity or literacy between women who completed the study and women who withdrew. However, withdrawals were different for women receiving oral treatment (13.5%) and those receiving IM treatment (38.5%). Intention-to-treat analysis One RCT seemed to have a proper intention-to-treat analysis (Mumtaz 2000). Seventeen randomised controlled trials (RCTs), involving 257 8 women, met the inclusion criteria. Overall, we found insufficie nt assessment of the outcomes relevant to the focus of this review, especially of clinical outcomes. Most results were provided by o ne or two small RCTs with methodological limitations. The effect size for these are represented in this review using the relat ive risk (RR) and weighted mean difference (WMD). Uncertainty levels are quantified using 95% confidence intervals (CI). Data from the first RCT showed that women receiving iron (ferrous sulphate) had a lower risk of being ana emic during the second trimester (one RCT, 125 women; RR 0.38; 95% CI 0.26 to 0.55; graph 01.01). Similarly, the mean serum ferritin was higher f or women receiving iron (one RCT, 125 women; WMD 0.70; 95% CI 0.52 to 0.88; graph 01.03). A trend towards increased adverse effects (for example, nausea, vomiting, constipation an d abdominal cramps) was also noticed in the second RCT (Ferrous gluconate), but figures were small to allow worthy comparisons (11/51 women with adverse effects). No other assessments were found for clinical outcomes. Hence, it is difficult to establish th e clinical effects of treatments in women and newborns. Conclusions need to be approached with care because they are drawn from a small sample of participants (125 women). Furthermore, one RCT assessed outcomes at the second trimester (Suharno 1993) and it is unclear if those women sustained similar haemoglobi n levels during the rest of their pregnancy, and no assessment o f haematological results was done at delivery. We found one RCT involving 125 women (Suharno 1993). It included anaemic women with a high risk of suffering vitamin A deficiency. Adding vitamin A to regular iron (ferrous sulphate), resulted in improved haemoglobin level. Anaemia during the se cond trimester was lower with oral iron plus vitamin A, compared wi th placebo (one RCT, 125 women; RR 0.04; 95% CI 0.01 to 0.15; graph 02.01). The difference was not as big when the comparator was iron therapy only (see below). The applicability of these results may be limited to women in populations with vitamin A deficiency. One RCT involving 126 women (Suharno 1993) found a reduction in anaemia during the second trimester with oral iron plu s vitamin A, compared with oral iron alone (RR 0.10; 95% CI 0.02 to 0.41; graph 03.01). This study was carried out amongst women living in areas of Indonesia where vitamin A deficiency is preva lent. An RCT from Pakistan (Mumtaz 2000) found that daily oral iron (ferrous sulphate) significant increased haemoglobin levels a t 4 weeks, 8 weeks, and 12 weeks, compared with twice-weekly oral iron. In women receiving daily versus twice-weekly oral iron therapy (ferrous su lphate), an RCT from Brazil (De Souza 2004) found no significant difference in haemoglobin levels (one RCT, 102 women; WMD 0.30; CI -0.01 to 0.61; graph 17.04) or anaemia (one RCT, 102 women; RR 1.38; 95% CI 0.86 to 2.23; graph 17.05) at 16 weeks of treatment. No further description of adverse effects was provided. One RCT done in Brazil (De Souza 2004) found that daily oral treatment (ferrous sulphate) increased haemoglobin level af ter 16 weeks of treatment, compared with weekly oral iron (one RCT, 97 women; WMD 0.70; 95% CI 0.36 to 1.04; graph 18.01), the proportion of women non-anaemic at the end of follow up (one RCT, 97 women; RR 1.73; 95% CI 1.00 to 3.01; graph 18.02) and reduced treatment failure (one RCT, 97 women; RR 0.05; 95% CI 0.01 to 0.35; graph 18.03). Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. One RCT done in Brazil (De Souza 2004) found that a twiceweekly regimen of ferrous sulphate resulted in a modest incre ase in haemoglobin levels, compared with a weekly iron regimen (on e RCT, 101 women; WMD 0.40; 95% CI 0.03 to 0.77; graph 19.01) and reduced treatment failure (one RCT, 101 women; RR 0.32; 95% CI 0.15 to 0.68; graph 19.03). However, no significant differences were found in the proportion of women non anaemic at 16 weeks of treatment (one RCT, 101 women; RR 1.25; 95% CI 0.69 to 2.28; graph 19.02). All women received daily 5 mg of folic acid and 25 mg of pyrimethamine daily, in addition to ferrous sulphate. One RCT done in Australia (Symonds 1969) compared con-trolled-release oral iron versus other iron preparations. I t provided information on adverse effects, but data on effectiveness wer e not included because it had a very high withdrawal rate. It found no differences in nausea and vomiting, constipation and abdomin al cramps at one month between controlled-release iron and regula r oral iron. The small sample size and broad confidence intervals illustrate that the sample size is clearly insufficient to rule out any difference (graphs 04.01 to 04). Intramuscular (IM) iron We found no RCTs comparing IM iron versus placebo. These findings are inconclusive given the limitations of this single study. We found one RCT involving 63 women conducted in Nigeria (Oluboyede 1980). We found one small RCT involving 54 women and conducted in Australia (Symonds 1969). The RCT provided data on adverse effects. It found no si gnificant differences between IV iron and placebo for: nausea and vomiting (one RCT, 54 women; RR 0.33; 95% CI 0.01 to 7.84), abdominal cramps (not estimable), and constipation (one RCT, 54 women; RR 0.25; 95% CI 0.03 to 2.09). However, the small sample size and broad confidence intervals illustrate that the sample size is clearly insufficient to rule out any such adverse effe cts. We found four RCTs (571 women) comparing IM and oral administration of iron (Komolafe 2003; Ogunbode 1980; Kumar 2005; Zutschi 2004). The first RCT, from India, (Zutschi 2004) evaluated 150 mg IM iron sorbitol (via three injections a day) at four-weekly inter vals versus 100 mg of elemental oral iron for at least 100 days. A higher proportion of women were found to be non-anaemic at labour (one RCT, 200 women; RR 1.23; 95% CI 1.01 to 1.48; graph 14.01). Adverse effects were not included in the reports of the article. The second RCT, from India, compared IM sorbitol citric acid dose versus oral ferrous sulphate (100 mg of elemental iron) p lus 5 mg of folic acid at 36 weeks of pregnancy (Kumar 2005). Women receiving oral iron plus folic acid had a higher haemoglobin le vel (one RCT, 150 women; WMD 0.26; 95% CI 0.04 to 0.48; graph 16.01). No significant differences were found for caesarean secti on rates or mean birthweight. Adverse effects were reported by 4 0 women receiving IM treatment versus 16 receiving oral treatme nt at 36 weeks of treatment (graphs 16.03 to 16.15). No anaphylactic reaction or abscess formation were observed, but too few women participated in the RCT to assess these and other important adverse effects. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. The third RCT, from Nigeria, (Ogunbode 1980) was a three-arm RCT comparing iron sorbitol versus 600 mg oral ferrous sulpha te versus 1200 mg oral ferrous sulphate. All women received a dai ly supplement of 5 mg of folic acid and 25 mg of pyrimethamine. The fourth RCT, conducted in Nigeria, compared IM iron dextran (250 mg iron dextran thrice-weekly until total calculated dose was given) versus 600 mg of oral ferrous sulphate plus vitami n C and folic acid (Komolafe 2003). A French RCT compared IV iron sucrose given in six slow IV injections on days 1, 4, 8, 12, 15 and 21 according to a formula described in the article, with 240 mg of elemental iron sulphat e tablets (Bayoumeu 2002); all women received folic acid 15 mg of folic acid in addition to iron. No significant differences wer e found in maternal haemoglobin levels at four weeks of treatm ent, haemoglobin levels in excess of 12 g/dl, neonatal haemoglobi n, ferritin levels, and birthweight. Similarly, no significant differences were found in the incidence of diarrhea, postpartum haemorrha ge, blood transfusion required, or neonatal mortality. The RCT s were underpowered to assess these outcomes properly. An RCT conducted in Turkey (Al 2005) compared IV iron sucrose calculated according to a formula described in the article (total dose was administered over five days and maximum daily dose administered was 400 mg elemental iron) versus 300 mg of elemental iron (polymaltose complex); all women were given 5 mg of folic acid daily. No significant differences were found for caesarean section rates, neonatal birt hohn Wiley & Sons, Ltd. 10 A comparison of oral ferrous fumarate 200 mg three times a day versus IV iron dextrin (calculated according to described formula) found that oral treatments increased constipation, compared w ith IV treatments (Singh 1998) (one RCT, 100 women; RR 0.04; 95% CI 0.00 to 0.61; graph 09.03). No significant differences were found for constipation when IV iron was compared to controlledrelease iron. However, only one small RCT (Symonds 1969) assessed this and it seemed to be underpowered to rule out clinically important effects (one RCT, 51 women; RR 0.22; 95% CI 0.03 to 1.85; graph 09.03). One RCT, recruiting mostly Malayan and Chinese women, found that higher haemoglobin levels wer e found at the end of gestation with IV versus oral treatments (Singh 1998). However, the standard deviations are 50 to 100 times narrower than those found in other studies, raising questions a bout their validity (Al 2005; Suharno 1993). We exclude data from the analysis pending a response from the trial's authors. No mat ernal or neonatal deaths were recorded in this RCT, which was the only one specifically assessing these outcomes in women receiving ora l or IV treatments. Three RCTs (Al 2005; Singh 1998; Symonds 1969), including one that assessed controlled-release iron (Symonds 1969), found that oral iron was more frequently associated with complaints of nausea than IV preparations, and the magnitude of the effects was consistent across all three RCTs (three trial, 244 women; RR 0.3 3; 95% CI 0.15 to 0.74; graph 09.02). Two women were reported as suffering severe allergic reactio ns with IV dextran in an RCT comparing the latter with oral ferrou s sulphate (Sood 1979). Data on other relevant outcomes were not available for comparison. One women receiving IV iron suffered a severe allergic reaction wh ereas one participant of the IM group had viral hepatitis three mont hs later. Authors reported that no significant differences in new born weight and Apgar score at birth were found between groups (no data were provided). Neonates were assessed for any complicati on at birth and within the first week of life; one neonate in each treatment group developed neonatal jaundice. Maternal outco mes were not reported for each group of treatment. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. One RCT compared two IM preparations (Dawson 1965). It found that women receiving IM iron-sorbitol complex had lower incidence of skin discoloration at injection sites at eight week s (one RCT, 48 women; RR 0.21; 95% CI 0.07 to 0.65; graph 05.02) and fewer headaches (one RCT, 48 women; RR 0.13; 95% CI 0.02 to 0.99; graph 05.05) compared with IM iron dextran. Results should be interpreted with care as they come from a single, smal l RCT. However, this particular RCT had a robust randomisation and concealment strategy. One factorial RCT conducted in the UK compared IM treatments with IV treatment (Dawson 1965). It found that IM iron was more frequently associated with pain in the injection site. Th is factorial design had some problems that were not addressed du ring the analysis: active treatments were compared with a single con trol group and no adjustments for multiple comparisons were done. This increases the possibilities of finding spurious associat ions. The RCT found a higher risk of skin discoloration in women receiving IM iron dextran compared to IV iron. Findings sugges ted a trend towards a higher risk of venous thrombosis with IV iro n versus IM iron, but no statistical differences were found (one R CT, 49 women; 4/26 with IV iron dextran (15%) versus 0/23 with IM iron; RR 0.13; 95% CI 0.01 to 2.20, graph 06.03). However, this raises concern and an association can not be ruled out; the RCTs were underpowered to assess these outcomes properly, and the se are very serious adverse effects. The RCT found that IM iron dextran was not associated with higher complaints of headaches, compared with IV infusion of iron dextran (one RCT, 49 women; RR 3.96; 95% CI 0.91 to 17.17; graph 06.05). The RCT was too small to rule out importan t clinical differences in measured adverse effects outcomes such as shivering, itching, metallic taste in mouth, severe delayed allergic reaction (graphs 06.04 to 06.09). An RCT conducted in the UK compared iron-dextran infusion plus hydrocortisone versus iron-dextran infusion without hy drocortisone (Dawson 1965). An RCT conducted in Tanzania compared two doses of IV iron dextran by total dose infusion (Kaisi 1988). All participants were given the full dose recommended by the manufacturer; group A received an additional 10 ml whereas group B was given two-thir ds of that total dose. No significant differences were found for life threatening allergic re This RCT was not used to assess effectiveness as it failed to fu our quality criteria. lfil An RCT conducted in Pakistan (Wali 2002) evaluated two doses of IV iron sucrose (500 mg versus 200 mg) and IM iron sorbitol. The participants were divided into three groups. 200 mg of iron being given for storage instead of 500; in group C, iron was administered IM daily or alternate days; after pare nteral administration, oral iron therapy (ferrous gluconate 250 mg) was continued till the time of giving birth. No significant differe nces were found regarding haemoglobin level and the proportion o f non-anaemic women (with haemoglobin levels greater than 11 g/dl at delivery) when the two different doses of IV iron were compared. Abdominal pain was reported by one woman in each group. In the IV groups 2/35 (5.7%) women had shivering and feeling of weakness within a few hours, and 3/35 (8.6%) had phlebitis at the site where IV canula was retained. In the IM group, 5/25 (20%) withdrew from the study due to intolerance (no further description was provided) and the majority complained of pain at the injection site. IV administered iron sucrose with and without adjuvant recombinant human erythropoietin (comparison 13) One small size study evaluated adjuvant recombinant human er ythropoietin when iron sucrose was administered intravenous ly (Breymann 2001). No statistically significant differences were found in the number of women with a rise of haemoglobin greate r than 11 g/dl or caesarean delivery. The author provided unpub lished data concerning birthweight and mean maternal blood pressure at the end of therapy; no significant differences were found (comparison 13.06 and 08) for these outcomes. None of the women required additional antepartum or postpartum blo od transfusion. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. The objective of this review was to address the effects of iron anaemia treatments on maternal and neonatal morbidity and mortality. The review included 17 randomised controlled tria ls (RCTs), most of which were small and with significant methodological flaws. These RCTs assessed many different questions and a broad range of treatments resulting in very limited opport unities to pool useful data. The paucity of robust studies assessing cl inical effects of treatments makes it impossible to balance the benefi ts and harms of differing treatments for different levels of an aemia in pregnancy, in a meaningful and useful way. We cannot determine if women with mild anaemia, but otherwise healthy, will benefit from anaemia treatment; adverse effects can potentially outweigh benefits. It also remai ns unclear which treatments are safer and more effective in women wit h moderate or severe anaemia with and without associated illne ss. Although iron treatments consistently increase maternal hae matological indices in women diagnosed with iron-deficiency anaemia in pregnancy, we found no evidence that these laboratory improvements reflected in clinical improvements such as reduced preterm delivery, reduced infant low birthweight, lower rat es of pre-eclampsia, sepsis or postpartum haemorrhage and its compl ications (Scholl 1992; Scholl 2000). We found very few RCTs assessing clinical outcomes, and these RCTs were too small to esti mate important clinical effects. Moreover, the studied popula tions turned out to be too small to deliver clear-cut answers to this re view's questions. The findings suggest that gastrointestinal adverse effects a re more frequent with oral iron treatments, compared with other rout es of iron administration. Higher doses of iron were not associa ted with improved haematological values. The assessment of the e ffects of controlled versus regular oral iron were mostly inconclusiv e; there seems to be a reduced incidence of constipation. Most oral iron studies were marred by high withdrawal rates, highligh ting the importance of assessing adverse effects and compliance issu es with these frequently-prescribed treatments. The findings of this review suggest that adding vitamin A to re iron (ferrous sulphate) resulted in improved haemoglobin le Another Cochrane review that focused on vitamin A supplementation during pregnancy suggested beneficial effects for women areas of poor nutritional intake (Van den Broek 2002). in Compared with oral iron, intramuscular (IM) iron sorbitol and iron dextran improved haematological values, reduced the pro portion of women without anaemia, and resulted in lower gastroi nohn Wiley & Sons, Ltd. 12 But these preparations were associate d with higher rates of systemic reactions especially with IM iron. The findings of this review also suggest that intravenous (IV) iron sucrose is effective, but there is uncertainty whether it may in crease the incidence of serious adverse effects such as thrombosis, which was frequent (9/41; 22%). Similarly, there are worry ing trends towards an increased risk of severe allergic reaction w ith IV dextran iron, but data were few. One study suggests that the r isk of venous thrombosis may be lowered by adding hydrocortisone to the infusion, but it is unclear what the real impact of this mi ght be and whether it has any other effects. Evidence of a relations hip between doses of IV iron and risk of adverse allergic reaction s is inconclusive. No effectiveness assessments were done for the co mpared doses of IV drugs. Compared with IM iron sucrose, IV iron sucrose significantly increased haematological indices but it is unclear what the effects are on maternal and neonatal morbidity. RCTs were insufficient to determine the clinical effects of treat ments in women with iron-deficiency anaemia during pregnancy. Avoidable limitations in the included randomised controlled trials (RCTs) resulted in these failing to provide sound evidence tha t currently available treatments for iron-deficiency anaemia in p regnant women are beneficial for women or their children. We found no scientific basis to suggest that in otherwise healthy women, the benefits of treatments for mild anaemia in pregnancy will outw eigh the adverse effects associated with them. We found no evidence that in women with iron-deficiency anaemia in pregnancy, improvement in women's haematological indices translate into cl inical improvements for them or their children. However, treatme nts are associated with frequent adverse effects such as gastroint estinal disturbances and poor compliance. Compared with oral iron, intramuscular (IM) iron improves haematological indices. But aga in, the support from clinical research seems to be missing and adver se effects remain poorly evaluated despite indications that tre atments can result in important adverse outcomes. Intravenous iron so rbitol improves haematological values compared to IM or oral ir on, but serious adverse effects are possible and remain poorly st udied; knowledge of their magnitude and mitigation strategies is m issing. Potential adverse effects may include venous thrombosis and severe allergic reactions. Treatment of mild anaemia in preg nancy remains controversial and unsupported by scientific proof. It is also unclear what treatments work better for severe anaemia i n pregnancy. Iron-deficiency anaemia in pregnancy is frequently diagnosed an d treated, but the effects of these treatments remain largely u nknown. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. women in developing countries and may have considerable impact on maternal and neonatal health. Considerable resources are being used globally to diagnose a nd treat anaemia in pregnant women, but it remains unclear if the se efforts are worthy and beneficial to individuals or populatio ns. Also, it is unclear if there is a positive return for this inves tment, and if it improves people's lives. This review is an invitati on for researchers, especially those working towards the improveme nt of health of communities in under-resourced settings, to imple ment high quality RCTs addressing knowledge gaps (such as thos e flagged up by this review), for this common condition. In particular, determining when treatments are worthwhile, and prov iding sufficient information to allow better balancing of the benefit s and harms of treatments. The authors of this systematic review co nsider that a solution to this would be to conduct a large multicen ter RCT assessing the clinical effects of a selection of commonly used treatments in different regions of the world. The sampl e and duration of the follow up in such an RCT should be estimated to allow the identification of important, frequent, and long-t erm effects in women and babies. Large RCTs such as the MAGPIE trial or the CRASH trial illustrate how gaps in knowledge can b e effectively addressed through research, and how this can reduce harmful practices and inappropriate use of resources. We found a compelling case for a similar approach to be taken on iron-defi-ciency anaemia in pregnancy. Some important considerations for future research are as foll ows. There is an urgent need to determine what treatments impro maternal and neonatal prognosis in women with severe and mod erate anaemia in poorly-resourced settings. The effects of different doses, regimens and routes of admi trations for commonly-used treatments remain to be determine The suitability of the route of administration may be influen by the setting or cultural background. Stratification according to anaemia severity can help address questions of the effects in different populations, and balan ferently the benefits and harms. Clinical outcomes, including adverse effects and quality of l need to be better addressed and considered for study sample si calculations. Offspring outcomes are particularly important given the po sibility that iron has been associated with adverse effects in observational studies. RCTs need to have sample sizes big enough to allow assessin g adverse effects such as venous thrombosis, allergic reactions, infections, and rare but serious adverse effects, as well as long -term outcomes. For women with mild iron-deficiency anaemia, it would be helpful to assess whether oral iron is overall beneficial compa with placebo or no treatment. Researchers need to remain aware about the clinical effects of high iron on haemoglobin levels, a possible overdosing. We found no studies on oral erythropoietin or transfusion these need to be evaluated in populations where they remain l to be used. But providing scientific support for commonly used treatments seems to be the priority; we do not know if more har then good is being done and yet these interventions remain wi prescribed and used. Studies are needed to determine the effects in specific popu tions such as pregnant women who are anaemic and also infected with human immunodeficiency virus. We are grateful to Lynn Hampson, from the Cochrane Pregnancy and Childbirth Group, for her assistance with trials search. W e thank Professor Jianping Liu, from the Evidence-Based Chines e Medicine Center for Clinical Research and Evaluation (Beijing University of Chinese Medicine), for translating a Chinese tr ial. We thank the Cochrane Pregnancy and Childbirth Group editoria l staff for arranging commentaries to improve this manuscript. Al RA, Unlubilgin E, Kandemir O, Yalvac S, Cakir L, Haberal A. Intravenous versus oral iron for treatment of anemia in pregnancy: a randomized trial. Bayoumeu F, Subiran-Buisset C, Baka NE, Legagneur H, Monnier-Barbarino P, Laxenaire MC. Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Dawson D, Goldthorp W, Spencer D. Parenteral iron therapy in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1965;72:89--93. De Souza AI, Batista Filho M, Ferreira LO, Figueiroa JN. The effectiveness of three regimens using ferrous sulfate to treat ane pregnant women. Kaisi M, Ngwalle EWK, Runyoro DE, Rogers J. Evaluation of tolerance of and response to iron dextran (Imferon) adminisered by to tal dose infusion to pregnant women with iron deficiency anemia. Komolafe JO, Kuti O, Ijadunola KT, Ogunniyi SO. A comparative study between intramuscular iron dextran and oral ferrous sulp in the treatment of iron deficiency anaemia in pregnancy. Kumar 2005 {published data only} hate Journal of Kumar A, Jain S, Singh NP, Singh T. Oral versus high dose parentera l iron supplementation in pregnancy. International Journal of Gynecology & Obstetrics 2005;89(1):7--13. Mumtaz Z, Shahab S, Butt N, Rab MA, DeMuynck A. Daily iron supplementation is more effective than twice weekly iron suppl tation in pregnant women in Pakistan in a randomized double-blind clinical trial. Ogunbode 1980 {published data only} emenOgunbode O, Damole IO, Oluboyede OA. Current Therapeutic Research, Clinical and Experimental 1980;27(1):75--80. Ogunbode O, Oluboyede O, Ayeni O. Iron deficiency anaemia during pregnancy: a comparative trial of treatment by iron poly (sorbitol-gluconic acid) complex, Ferastral and intravenous i ron dextran (Imferon) infusion [abstract]. 9th World Congress of Gynec ology and Obstetrics; 1979 October 26-31; Tokyo, Japan. Oluboyede OA, Ogunbode O, Ayeni O. Iron deficiency anaemia during pregnancy. A comparison between intravenous iron polymaltose complex (Ferrum Hausmann) and oral ferrous fu marate in the treatment of iron deficiency anaemia in pregnancy. Sood SK, Ramachandran K, Rani K, Ramalingaswami V, Mathan VI, Ponniah J, Baker, SJ. WHO sponsored collaborative studies on nutritional anaemia in India. The effect of parenteral iron administration in the control of anaemia of pregnancy. Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Symonds E, Radden H, Cellier K. Controlled-release iron therapy in pregnancy. Australian and New Zealand Journal of Obstetrics and Gynaecology 1969;9(1):21--5. Comparative study--efficacy, sa compliance of intravenous iron sucrose and intramuscular iron so fety and rTreatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. bitol in iron deficiency anemia of pregnancy. Zutschi 2004 {published data only} Journal of the Pakistan Zutschi V, Batra S, Ahmad SS, Khera N, Chauhan G, Ghandi G, et al.Injectable iron supplementation instead of oral therapy fo r antenatal care. Al-Momen A, Al-Meshari A, Al-Nuaim L, Saddique A, Abotalib Z Khashogji T, et al.Intravenous iron sucrose complex in the trea ment of iron deficiency anemia during pregnancy. Allaire B, Campagna F. Iron-deficiency anemia in pregnancy. Evaluation of diagnosis and therapy by bone marrow hemosiderin. Ob-Amir M, Ahmad SH, Ansari Z, Dutta AK, Husain I. Total dose iron infusion during third trimester to iron deficient mothers a influences on anemia of early infancy. Bare W, Sullivan A. Comparison of intravenous saccharated iro ide and whole blood in treatment of hypochromic anemia of pregnancy. J, et al.Ferritin levels in newborn after prepartal iron medica tion. Barrada M, Salzer H, Schatten C, Pateisky N, Vavra N, Spona J, et al.Influence of prepartal iron-medication on newborns. Basu RN, Sood SK, Ramachandan K, Mathur M, Ramalingaswami V. Ethiopathogenesis of nutritional anemia in pregnancy: a therapeutic approach. Breymann C. rhEPO/parenteral iron vs parenteral iron only in the treatment of severe pregnancy anemia. Breymann C, Visca E, Huch R, Huch A. Recombinant human erythropoietin (rhEPO) for the therapy of severe iron deficiency a during pregnancy. 21st Conference of the Swiss Society of Gynecology and Obstetrics; 1988; Switzerland. Breymann 2002 {published data only} naemia Breymann C. Iron deficiency and anaemia in pregnancy: modern aspects of diagnosis and therapy. A comparative study of the effectiveness of iron preparations in the treatment of iron defi ciency anemias in pregnant women. Chanarin I, Rothman D. Response to folic and folinic acid in megaloblastic anaemia in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1965;72:374--5. Evaluation of a new coba chelate with iron in pregnancy anemia. Coelho K, Ramdas S, Pillai S. A comparative study of changes in haemoglobin with high and low dose iron preparations in pregnant women. Dede D, Uygur B, Yilmaz T, Mungan M, Ugur M. Intravenous iron sucrose complex vs. oral ferrous sulfate for postpartu m iron deficiency anemia. Dommisse J, Du Toit ED, Nicholson N. Folic acid - has it a role in the treatment of severe iron deficiency anaemia in pregnancy?. Ekstrom EC, Hyder SM, Chowdhury AM, Chowdhury SA, Lonnerdal B, Habicht JP, et al.Efficacy and trial effectiveness of wee kly and daily iron supplementation among pregnant women in rural Bangladesh: disentangling the issues. Finzi C, Bailo U. Treatment of anemia in pregnancy: comparison of an iron delayed-action preparation and conventional preparati ons. Fochi F, Ciampini M, Ceccarelli G. Efficacy of iron therapy: a c omparative evaluation of four iron preparations administered t o anaemic pregnant women. Halksworth G, Moseley L, Carter K, Worwood M. Iron absorption from spatone (a natural mineral water) for prevention of iron deficiency in pregnancy. Antenatal clinics as trial units in evalu ating treatment of anaemia in pregnancy. The use and abuse of drugs and chemicals in Tropical Africa. Proceedings of the 1973 Annual Scientific Conference of the East African Research Council; 1973; Nairobi, Kenya. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Hampel K, Roetz R. Influence of a long-time substitution with fo-late-iron combination in pregnancy on serum folate and serum iro n and on hematological parameters. Relative efficacy of sustained release iron and iron wit folic acid treatment in pregnancy. Obstetrics & Gynecology 1955;5:562--Izak G, Levy S, Rachmilewitz M, Grossowicz N. The effect of iron and folic acid therapy on combined iron and folate deficiency anaemia: the results of a clinical trial. Jackson 1982 {published data only} Scandinavian Journal of Jackson RT, Latham MC. Anemia of pregnancy in Liberia, West Africa: a therapeutic trial. Jaud W. Folate- and iron- deficiency in pregnancy. Juarez-Vazquez J, Bonizzoni E, Scotti A. Iron plus folate is mor effective than iron alone in the treatment of iron deficiency anae in pregnancy: a randomised, double blind clinical trial. New schedule of intramuscular iron administration for pregnant women. Asia-Oceania Journal of Obstetrics and Gynaecology 1993;19:141--4. Mathan BVI, Baker SH, Sood SK, Ramachandran K, Ramalingaswami V. WHO sponsored collaborative studies on nutritional anaemia in India. The effects of ascorbic acid and protein supple mentation on the response of pregnant women to iron, pteroyglutamic acid and cyanocobalamin therapy. Minganti E, Farina A, Farina F, Calora A, d Aloja P, Dossi L, et al.Clinical study on the therapeutic efficacy and tolerabilit y of fer-rimannitol-albumin in pregnancy [Indagine clinica sull efficacia t erapeutica e sulla tollerabilita della ferri--mannitol--albumi na in gravidanza]. Giornale Italiano di Ostetricia e Ginecologia 1995;10:597--600. Mukhopadhyay A, Bhatla N, Kriplani A, Pandey RM, Saxena R. Erythrocyte indices in pregnancy: effect of intermittent iron su mentation. Mukhopadhyay A, Bhatla N, Kriplani A, Pandey RM, Saxena R. Daily versus intermittent iron supplementation in pregnant women: hematological and pregnancy outcome. Journal of Obstetrics and Gynaecology Research 2004;30(6):409--17. Treatment of anaemia in obstetric patients with sustained-release (Ferrograd Folic 500 Plus) and co tional fersolate and folic acid as separate drugs. Preziosi P, Prual A, Galan P, Daouda H, Boureima H, Hercberg S. Effect of iron supplementation on the iron status of pregnant wom en: consequences for newborns. Reddy PS, Adsul BB, Gandewar K, Desai A. Mumfer (iron polymaltose complex) in the management of anaemia in pregnancy--an Indian study. Ridwan E, Schultink W, Dillon D, Gross R. Effects of weekly iron supplementation on pregnant indonesian women are similar to those of daily supplementation. Sharma JB, Jain S, Mallika V, Singh T, Kumar A, Arora R, et al.A prospective, partially randomized study of pregnancy outcome s and hematologic responses to oral and intramuscular iron treatment in moderately anemic pregnant women. Sood SK, Ramachandran K, Mathur M, Gupta K, Ramalingaswami V, Swarnabai, C, et al.WHO sponsored collaborative studies on nutritional anaemia in India. 1. The effects of supplemental oral ir on administration to pregnant women. Iron dextran in the treatment of iron-deficiency anaemia of pregnancy. Steiner H, Hilgarth M. Treatment of anemia in pregnancy. Szarfarc SC, de Cassana LM, Fujimori E, Guerra-Shinohara EM, de Oliveira IM. Relative effectiveness of iron bis-glycinate chelate (Ferrochel) and ferrous sulfate in the control of iron deficienc y in pregnant women. Valli Rani N, Pandey J, Das B, Shruti, Talib VH, Singh K, et al.Pregnancy associated anemia and iron: a pilot study. Indian Journal of Pathology and Microbiology 1995;38(3):293--7. Visca E, Breymann CC, Huch R, Huch A. Recombinant erythropoietin (rhEPO) and iron vs. parenteral iron only for the treatme of pregnancy anemia; a prospective and randomised study. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Von Peiker G, Muller B, Schwarz A, Dawcsynski H, Linke E. The diagnosis and treatment of iron deficiency anaemia in pregnancy. Wu Y, Weng L, Wu L. Clinical experience with iron supplementation in pregnancy. Young MW, Lupafya E, Kapenda E, Bobrow EA. The effectiveness of weekly iron supplementation in pregnant women of rural northern malawi. Bhutta Z. Severe anemia treatment trials, Pakistan. Dochi T. Clinical evaluation of combined therapy with slow-rele iron preparations and Aldioxa (Isalon) in pregnant women with anemia [Nimpu Hinketsu ni Taisuru Johosei Seizai to Arujiokisa Se (Isaron) Heiyo Ryoho]. Ethacrynic acid and packed-blood-cell transfusion in treatment of severe anaemia in pregna Lancet 1971;1(7688):11--4. Role of modified drug release system [abstract]. 49th Al Congress of Obstetrics and Gynaecology; 2006 January 6-9; Cochin, Kerala State, India. The effect of simultaneous administration of zinc sulfate and ferrous sulfate in the treatme mic pregnant women. Siega-Riz A, Hartzema A, Turnbull C, Thorp JJ, McDonald T. A trial of selective versus routine iron supplementation to pre trimester anemia during pregnancy. Tomar R, Dubey K, Pandit U. Comparative study - efficacy, safety, compliance of intravenous iron and intra muscular iron in severe iron deficiency [abstract]. 49th All India Congress of Obstetric Gynaecology; 2006 January 6-9; Cochin, Kerala State, India. Zhou SJ, Gibson RA, Crowther CA, Baghurst P, Makrides M. Prevalence and risk factors for anaemia in pregnant women of eastern Sudan. Brabin BJ, Hakimi M, Pelletier D. An analysis of anemia and preg-nancy-related maternal mortality. Primary care medicine on CD Vol 1, Number 1. Cochrane Handbook for Systematic Reviews of Interventions 4.2.4 [updated March 2005]. Chichester, UK: John Wiley & Sons, Ltd. Juni 2001 Juni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. Maternal anaemia in pregnancy, iron and pregnancy a haematologist's viewpoint. Lone FW, Qureshi RN, Emmanuel F. Maternal anaemia and its impact on perinatal outcome in a tertiary care hospital in Pakis tan. Mahomed K, Hytten F. Iron and folate supplementation in pregnancy. Effective care in pregnancy and childbirth. Effects of routine oral iron suppleme with or without folic acid for women during pregnancy. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Scholl TO, Reilly T. Anemia, iron and pregnancy outcome. Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs iron deficiency: increased risk of preterm delivery in a prospectiv American Journal of Clinical Nutrition 1992;55:985--8. Steer P, Alam MA, Wadsworth J, Welch A. Relation between maternal haemoglobin concentration and birth weight in different ethnic groups. Van den Broek N, Kulier R, Gülmezoglu AM, Villar J. Vitamin A supplementation during pregnancy. Walter T. Effect of iron-deficiency anaemia on cognitive skills i n infancy and childhood. Preventing and controlling iron deficiency anaemia through primary health care. The prevalence of anaemia in women: a tabulation of available information (WHO/MCH/MSM/92). Geneva: WHO, Maternal Health and Safe Motherhood Programme, Division of Family Health, 1992. Estimat es developed by WHO, UNICEF and UNFPA. Iron deficiency anaemia, assessment, prevention, and control: a guide for programme managers. Cuervo LG, Mahomed K. Treatments for iron deficiency anaemia in pregnancy. Group allocation was predetermined by one of the authors who w as not involved with women's care. Authors used opaque envelopes that were consecutively-number ed by means of a computer-generated randomisation table. As each woman gave consent for the study, the next envelope was opened to assign the participant to either of the 2 groups. A sample-size analysis was performed before initiation of th e study. The analysis was based on the intention-to-treat principle. No participants were lost to follow up, and there were no dropo uts. 90 pregnant women, between the 26th and 34th weeks of gestati on, with established iron-deficiency anemia who had hemoglobin levels between 8 and 10.5 g/dL and f erritin levels less than 13 g/ L. Women were excluded when serum folate and vitamin B12 levels w ere found to be less than 4 pg/mL and 100 pg/mL respectively. Anaemia from causes other than iron-deficiency, multiple pregna ncy, previous blood transfusion, history of hematological disease, risk of preterm labour, intolerance to iron derivatives, recent administrat ion of iron for the treatment of iron-deficiency anaemia, or current usage of iron supplement were the reasons for other exclusions. Both groups were supplemented by 0.5 mg folic acid treatment p ted from the following formula: weight nfusion, the maximum total dose fused in 20-30 minutes. Total dose ered was 400 mg elemental iron. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Women were assigned to the group treatment by a randomisatio Sample size and power calculation was described. It is unclear if the outcome assessor was blind that 3 (6%) women were excluded from the study and that 2 others w n table. men nor caregivers were blinded to the ed to the interventions. The trialists reported here lost to follow up. a; cirrhosis; viral hepatitis; multiple pregnteral iron treatment before inclusion; inExperiment group: IV iron sucrose. Given in 6 slow Control group: oral iron. 3 x 80 mg iron sulphate tablets (Tar elemental iron a day for 4 weeks). Women asked to note compliance "Women were also given 15 mg folic acid per day to prevent an eve eliminate the influence of such a deficiency on the results." dyferon) per day for 4 weeks (i.e. 240 mg in calendar. ntual folic-acid deficiency and to of any continuing iron treatment." The trial measured haematological response, transferrin le vel and saturation coefficient, erythrocytic folates, ferritin level, baby's ferritin level and full blood cell count and adverse reactions. Women randomly assigned to 2 treatment groups by means of a com puter-generated list. It is unclear whether participants, clinicians and outcome assessor were bli nded to the interventions. No description of the sample size or power calcula tion was recorded. Exclusion criteria: women with anaemia not caused by iron deficie chronic bleeding; renal failure. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Women were randomised to receive IV administered iron sucrose (200 mg IV administered twice weekly 72 to 96 hours apart) with vs without adjuvant recombinant hum an erythropoietin (300 U/kg body weight). All women received orally administered iron sulfate (80 mg twice daily) for = 2 weeks before starting. Median durations of th erapy were 18 days in group 1 and 25 days in group 2. Method of allocation was a random-number table. 74 pregnant women in the 3rd trimester with haemoglobin with less than 10 g/dl, MCHC under 30% and a marrow aspiration indicating iron deficiency. Women with toxem ia, infection or antepartum haemorrhage were excluded. All women received prophylactic folate and oral iron was stopped prior to randomisation. Women were followed for 8 weeks and outcomes assessed at admis sion, 2, 4 and 8 weeks. Side-effects were assessed during the treatment period. Iron sorbitol-citric acid complex (Jectofer) IM 25 women. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Other outcomes were not considered due to a high dropout rate. H due to 81% dropouts at predelivery. Unclear Description B - Unclear aemoglobin level data are not included ional trial of iron dextran IV vs iron his had any effect on the rate of side-effects. Method of allocation generation and concealment are unclear. Neither the women nor treating physicians were blinded to the laboratory was blind to the interventions. 41 (21.5%) women w to follow up and the reasons described. Intention-to-treat ana Sample size and power calculation were described. 150 pregnant women at 16-20 weeks of gestation, with an initia interventions. Trialists reported that the ere reported to drop the trial or were lost lysis was not used. Women were randomly distributed into 3 groups, 1 receiving da twice-weekly and the 3rd one-weekly iron supplementation for 1 l haemoglobin of < 11 g/dL and> 8 g/dL. The trial measured haemoglobin concentration, MCV and ferrit in before and after the treatment. A randomisation list was used to generate the randomisation sequence. The study was done in a population of indi 1. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 314 women received the full dose while 309 women received the 2/ of pregnancy and basal haemoglobin levels were similar for th had haemoglobin levels under 7.0 g/dl in both groups. Nearly one forth of the women The dose of the 2 studied treatments was determined according t the intervention group, women received 2/3 of the total dose ca in the control group they received the total dose of iron dextra pregnant women. The iron dextran was diluted in 500 ml of 5% de 40 drops per minute. A test dose was given at the start of each in at a rate of 5 drops per minute over 10 minutes. Women were followed up regularly throughout the remaining p and for 16 weeks postpartum. Infants were examined at the tim were assessed at each visit to the antenatal clinic and 6 and 16 w was measured as well. Women were analysed by intention to treat. Loss to follow up f results were not included in this review. For other clinical out so they were included. In lculated of iron dextran 'Imferon' while n plus 10 additional ml as suggested for xtrose and infused at a steady rate of fusion. This test dose was administered art of their pregnancy, during delivery e of birth. Cord haemoglobin or haemoglobin result was 47% so these comes, loss to follow up was 18% and 20% The women were assigned randomly by offering them a choice from generated random numbers. No description of the sample size o neither the participants nor treating physicians were blinde withdrawals. sealed envelopes containing computerr power calculation was described and d to the interventions. This trial had no 60 women at 14-32 weeks of pregnancy were included. Inclusion criteria: PCV 22-26% due to iron-deficiency anaemia. Fe d AA; MCV < 75 pg; MCHC < 32 g/dl; blood film - picture of Fe def. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Exclusion criteria: symptomatic anaemia; acute malaria; acute parenteral Fe; multiple pregnancy atopic individual and hae urinary tract infection; history of allergy to moglobinopathy. 50 mg iron dextran into buttock preceded by 25 m before. If no untoward reaction after 48 hours, 250 mg (5 ml) iro dose given. Control group: 30 women Oral Fe: 200 mg ferrous sulphate 3 times daily between meals, 5 mg folic acid. Both groups were treated for 6 weeks. g promethazine tablet 30 minutes n dextran thrice weekly I = until total with vitamin C 100 mg 3 times daily and The trial measured the mean PCV, corrected anaemia at the end of treatment and the side-effects. Results given in % and not specific numbers. Participants were randomly allocated to 2 groups. Both the participants and treating physicians were not blinde Sample size considerations were not provided. 47 women in par iron group were lost to follow up. the follow period, the cost of the location generation and allocation cond to the interventions. 220 pregnant women were including according to the following cri teria. Inclusion criteria: women with gestation period of 16-24 weeks, were selected according to the following inclusion criteria: singleton pregnancy, moderate anemia (Hb 8 -11 g%) by cyanmethaemoglobin method, microcytic hypochromic blood smear and willingness for enroll ment to the study. Exclusion criteria: the women with anemia due to hemoglobinop athies, chronic bleeding, parasitosis, diseases of liver, cardiovascular system and kidney; medical d isorders like tuberculosis, diabetes mellitus; women who had any form of parenteral iron therapy for anemia d uring pregnancy; women with antepartum hemorrhage and intolerance to test dose (0.5 ml) of IM admin istration of iron were excluded from the study. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 24 Experiment group: IM iron: parenteral iron group were given as iron sorbitol citric acid in a injection volume of 5 ml at an int An initial test dose of 0.5 ml was given. The trial measured values of blood indices at 36 weeks as well a side-effects. 2 IM injections of 250 mg elemental iron erval of 4-6 weeks in the antenatal clinic. e reaction to the test dose, then a full 250 ing Z-tract technique. The women and the investigator were blinded to th e allocation of treatment group (daily vs twice weekly) at initial recruitment and the 3 follow-up visits. The appearance of the capsules and the blister packs of the 2 groups were identical. The randomisatio n code was opened only after the follow up for all participants had been completed. This trial had 86 participants, (45%) that did not complete the entire duratio n of follow up (i.e., 4 follow-up visits). However data on 83.8% of the participants were available for 4 weeks of follow up. 191 pregnant women between the age of 17-35 years, with an init included. All given health education materials on importance of diet in p Experiment group: daily iron - plus daily folate. Control group: twice weekly iron - plus daily folate. Placebo was given for the rest of the days. sulphate (60 mg elemental Fe) each day and on sulphate (60 mg elemental) twice weekly Venous blood samples were taken for complete blood count at each 3rd and 4th visits. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. visit and for serum ferritin at the 1st, ital disorders such as thalassemia minor. Yes Description A - Adequate red with those who continued in the 2 treatment groups (41 versus 45). There was no information on methods of randomisation. No des calculation was described and both the participants and treatin tions. No participants were reported to have dropped out or we cription of the sample size or power g physicians were blinded to the intervenre lost to follow up. 91 women in the first or second trimester of pregnancy with a PCV o to 3 treatment groups. f 33% or less were randomly allocated In group A, 32 participants received 200 mg of oral ferrous sulp received 400 mg of oral ferrous sulphate 3 times daily; in grou (sorbitol gluconic acid) complex rerastral (500 mg Fe) on alterna dose (between 1250 to 2500 mg of iron). Unclear Description B - Unclear hate thrice daily; in group B 28 participants p C, 31 women received IM iron poly te days until completion of the required ate the dose was described. Participants were allocated by restricted random allocation. T here was no further information on methods of randomisation. No description of the sample size or power ca lculation was described and neither the participants nor treating physicians were blinded to the inte rventions. One participant from the imferon group was reported to have dropped out due to a severe reaction. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 26 63 pregnant women with established iron-deficiency anaemia defi ned as a PCV of 30% or less were included. Exclusion criteria: if had previously had iron therapy. 30 minutes then 60 drops a minute until completion. 500 mg ferestral (5 ml in each buttock) dose given in 540 ml normal saline and ore infusion. Drip ran slowly for first home though 10 kept in. Weekly or 2-weekly PCV estimations were done on all participan function tests were repeated and after 6 weeks bone marrow asp trial also measured the reticulocyte response in 10 women rand birthweights and any complication within the first week of life. Unclear Description B - Unclear ts, after 4 weeks of treatment liver irations were repeated on 21 women. The omly selected from each group and babies Women were allocated using sealed envelopes with consecutive n umbers. First 100 women with diagnosed iron-deficiency anaemia while at tending for antenatal care at the National University Hospital, Singapore. Data provided by on e of the authors reveals that compared groups had similar age distribution, parity, mean total income, wei ght, height, history of anaemia in previous pregnancies, history of intrauterine growth retardation in previous pregnancies and similar time-gap between pregnancies. Races were distributed as follows: Chinese (10% parenteral an d 6% of oral iron therapy), Malayan (46% and 78% in the same order), Indian (16 and 8%). History of preterm delivery was seen in 16% of the parenteral treatment group and 12% of oral iron group. The dose was determined according to deficiency. This paper provided data at 36 weeks, delivery and 6 weeks pos outcomes. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. The authors were contacted and provided precise data on were included too. Contact was established through a search on internet. Further units used for serum iron and ferritin estimations, then fur review. Yes Description A - Adequate clinical outcomes and side-effects that sity of Singapore was the contacted author. contact is being undertaken to check the ther comparison tables can be added to this There was no information on methods of randomisation. No des calculation was described and researchers kept unmasked the 5 gr dropped in the group receiving IV Fe due to severe delayed adve 151 pregnant women. cription of the sample size or power oups. 2 women were reported to have rse allergic reaction. ivided into 3 strata according to their Hb; who had received haematinics during Within each stratum they were randomised to one of the followi providing 120 mg of 120 mg elemental Fe, given once per day 6 wee 2. Haemoglobin, PCV was estimated 48 before the treatment was s injection or tablet was given. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Allocation was done using a random-number list from 1 to 305 and list. The manufacturers of the active treatments provided pla labelled the active and placebo preparations. Coding colours w codes were opened once the data for all analyses had been entere allocating women sequentially in the cebos. An independent researcher randomly ere given to the preparations and these d in the computer and cleaned. The study was conducted from April to Septe subdistricts of Bogor, West Java. Participants came from middl were aged between 17 and 35 years, with parity in the ranges of weeks. mber 1992 in 20 rural villages in 3 e and low socio-economic groups. Women receiving iron or vitamin e excluded. All preparations were given daily Haemoglobin, ferritin and serum iron mean values and standa from the published paper. Percentage of women that became non-a as a dichotomic variable. Results for vitamin A + placebo were not considered since this is combined with iron was included in this review. Serum iron leve to mg/l by the authors (umol/l x 0.056 = mg/l). Loss to follow up a Analysis was done by intention to treat. Women were assigned randomly although the method is not clear groups compared are very similar. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Vitamin A ls were given in umol/l and converted ccounted for 17% of the women. Baseline data for the 4 le, Australia. Inclusion criteria were a 10.8 g/dl or less. 1. Ferrous gluconate 108 mg of elemental iron daily divided in 3 doses given orally throughout pregnancy. 2. Ferrogradumet tablets (controlled release) iron tablets w ith 105 mg elemental iron given once daily throughout pregnancy. 3. Placebo for the controlled release iron tablets provided by the same pharmaceutical laboratory. Initial test dose of 2 ml IV fol lowed by 5 injections of 5 ml (100 mg). Participants received controlled-release iron or placebo for th e first month. After that time side-effects were evaluated, and then all participants were given a daily d ose of active controlled-release oral iron. The trial was masked only the first 2 months and only for these 2 gro ups. The other data w deviations of mean values and irrelevant due to important fla ere incomplete, without reported standard ws in the design of the study. Haemoglobin results were presented as increases in haemoglo bin. Since standard deviations for the values cannot be added to baseline data, the data were not included. There was no information on methods of randomisation describ physicians were blinded to the interventions. ed and neither the participants nor treating of the sample size or power calculation was 60 pregnant women with anaemia were included in the study. IV iron sucrose 500 mg for iron storage. After parenteral iron, oral iron given till birth of baby. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Unclear Description B - Unclear and side-effects. There was no information on methods of randomisation. No wom or were lost to follow up. Neither the women nor treating phys No description of the sample size or power calculation was descri en were reported to have dropped out icians were blinded to the interventions. 200 women with uncomplicated pregnancy enrolled at 24-26 weeks o> 8 gm% but < 11 gm% were included. Women dropped out of study if Hb fell below 8 g/l or if severe pr Group A (100 women) received injectable iron-sorbitol-citrate in intervals and group B (100 women) were given oral iron having 1 100 days. The trial measured haemoglobin levels at the time of inclusio delivery as well as the proportion of caesarean delivery. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. f gestation with a haemoglobin of oblems arose. This is no Insufficient information for critical appraisal was provided. that lead to infer levels of Hg at the beginning t considered random. There are no explicit inclusion or exclusion Randomisation method not posed. No information is provided that completed the trial or that were accounted for each result. regarding blinding or number of women Centers were randomly assign (not women) and only some women h No random allocation. The paper does not explai No randomisation method. Allocation was done using a haphazard strategy, not a random o Used a haphazard allocation method (day of diagnosis). Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. The study evaluates the use of medication in women with hemogl random strategy for allocation. The study is in women with haemoglobin levels over 10 g/dl. Tr Although the authors state that allocation was random, the gr authors used an inappropriate control group of healthy women method. More than 50% of their women were lost to follow up. We tried to contact to verify dat lists are considered inadequate since there is no concealment an The trial evaluated folic acid + iron versus iron. This study has dropouts that surpasses the limit establishe obin levels over 10.5 g/dl and uses noneatment allocation was not random. They do not explain the randomisation a but it was impossible. Open-randomisation d it is prone to bias. The trial evaluated group 1 Fe + pteroylmonoglutamic acid and acid versus group 1 + calcium caseinate. The and 11.6 g/dL in both groups of treatment. Health centers were randomised, rather than individuals. This study has a high proportion of women lost to follow up exce review. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. mean baseline haemoglobin was 11.3 eding the cut-off point established for this alment. They used sequential strategy for allocation and not a random No fundamental data to assess validity. The differences between the groups was not iron, but vitamins one. The numbers of participants in the 3 groups are not similar (93 f 35 for ferroids) and is higher at follow up than at the beginni allocated to the groups and whether therefore they are simila or maternal, 50 for ferrous sulphate and ng of the trial. It is unclear how they were r at baseline. A weekly iron/folate supplement was compared with a standard women living in rural Malawi. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 35 8 Metallic taste in mouth No. of studies No. of participants 9 Severe delayed allergic reaction No. of studies No. of participants Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 36 8 Metallic taste in mouth No. of studies No. of participants Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 37 2 Venous thrombosis No. of studies No. of participants Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 38 9 Spontaneous abortion No. of studies No. of participants 9 Need transfusion No. of studies No. of participants 4 Caesarean section No. of studies No. of participants Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 39 Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 40 Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 41 3 Moderate abdominal pain No. of studies No. of participants 2 Haematocrit (%) at 8 weeks of treatment No. of studies No. of participants Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 42 Outcome or subgroup title No. of studies No. of participants Total events: 7 (Oral iron), 4 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.21 (P = 0.23) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Total events: 4 (Oral iron), 4 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.18 (P = 0.86) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 3 Oral iron + vitamin A versus oral i trimester. Total events: 2 (Oral iron + vit A), 20 (Oral iron) Heterogeneity: not applicable Test for overall effect: Z = 3.20 (P = 0.0014) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. sus regular oral iron, Outcome 1 Side-effects. Total events: 7 (Ctrl release iron), 7 (Regular oral iron) Heterogeneity: not applicable Test for overall effect: Z = 0.09 (P = 0.93) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 4 Controlled release oral iron ver vomiting. sus regular oral iron, Outcome 3 Constipation. Total events: 1 (Ctrl release iron), 4 (Regular oral iron) Heterogeneity: not applicable Test for overall effect: Z = 1.32 (P = 0.19) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 4 Controlled release oral iron ver cramps. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 1 Pain at injection site. Total events: 13 (IM iron sorb-cit), 12 (IM iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.01 (P = 0.99) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 2 Skin discolouration at injection site. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 3 Venous thrombosis. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 4 Nausea or vomiting. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 5 Headaches. Total events: 1 (IM iron sorb-cit), 7 (IM iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.97 (P = 0.049) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 6 Shivering. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 7 Itching. Total events: 4 (IM iron sorb-cit), 4 (IM iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.13 (P = 0.90) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 5 Intramuscular iron sorbito-cit ric acid versus intramuscular dextran, Outcome 8 Metallic taste in mouth. Comparison 6 Intramuscular iron dextran vers injection site. Total events: 12 (IM iron dextran), 3 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 2.61 (P = 0.0091) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers us intravenous iron dextran, Outcome 2 Skin discolouration at injection site. Comparison 6 Intramuscular iron dextran vers thrombosis. Total events: 0 (IM iron dextran), 4 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.42 (P = 0.16) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers Nausea or vomiting. Comparison 6 Intramuscular iron dextran vers Headaches. Total events: 7 (IM iron dextran), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.84 (P = 0.066) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers Shivering. us intravenous iron dextran, Outcome 7 Itching. Total events: 4 (IM iron dextran), 3 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.58 (P = 0.56) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 6 Intramuscular iron dextran vers Metallic taste in mouth. us intravenous iron dextran, Outcome 9 Severe delayed allergic reaction. Total events: 0 (IM iron dextran), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.01 (P = 0.31) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 7 Intramuscular iron sorbitol cit ric acid versus intravenous iron dextran, Outcome 1 Pain at injection site. ric acid versus intravenous iron dextran, Outcome 2 Skin discolouration at injection site. Total events: 3 (IM iron sorb-cit), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.02 (P = 0.31) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 7 Intramuscular iron sorbitol cit ric acid versus intravenous iron dextran, Outcome 3 Venous thrombosis. ric acid versus intravenous iron dextran, Outcome 4 Nausea or vomiting. Total events: 1 (IM iron sorb-cit), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.55 (P = 0.58) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ric acid versus intravenous iron dextran, Outcome 5 Headaches. Total events: 0 (IM iron sorb-cit), 2 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.03 (P = 0.30) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 7 Intramuscular iron sorbitol cit Outcome 7 Itching. ric acid versus intravenous iron dextran, Outcome 8 Metallic taste in mouth. Total events: 4 (IM iron sorb-cit), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 1.32 (P = 0.19) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Total events: 0 (IV iron), 1 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.68 (P = 0.50) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. oral iron, Outcome 2 Nausea or vomiting or epigastric discomfort. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Total events: 0 (IV iron), 2 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 1.13 (P = 0.26) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regular required. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regular hemoglobin. Comparison 9 Intravenous iron versus regular birth. Heterogeneity: not applicable Test for overall effect: Z = 3.57 (P = 0.00035) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. r oral iron, Outcome 11 Neonates ferritin level. Comparison 9 Intravenous iron versus regula at 4 weeks. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. r oral iron, Outcome 13 Maternal mortality. r oral iron, Outcome 14 Preterm labour. r oral iron, Outcome 15 Caesarean section. r oral iron, Outcome 16 Operative vaginal birth. Total events: 3 (IV iron), 2 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 0.46 (P = 0.65) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regula haemorrhage. r oral iron, Outcome 19 Neonatal birthweight. Comparison 9 Intravenous iron versus regula age. Total events: 8 (IV iron), 5 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 0.88 (P = 0.38) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regula score under seven. r oral iron, Outcome 22 Neonatal mortality. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 9 Intravenous iron versus regula g/dL at 30 days. Comparison 9 Intravenous iron versus regula hypertension. Total events: 2 (IV iron), 0 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 1.05 (P = 0.29) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio r oral iron, Outcome 25 Gestational diabetes. Comparison 9 Intravenous iron versus regula g/dL at birth. Total events: 43 (IV iron), 28 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 3.56 (P = 0.00037) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio Comparison 9 Intravenous iron versus regula reaction. Total events: 1 (IV iron), 1 (Oral regular iron) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. ohn Wiley & Sons, Ltd. Risk Ratio olled release oral iron, Outcome 1 Side-effects. Comparison 10 Intravenous iron versus contr vomiting. Total events: 0 (IV iron), 4 (Control release iron) Heterogeneity: not applicable Test for overall effect: Z = 1.55 (P = 0.12) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. olled release oral iron, Outcome 3 Constipation. Comparison 10 Intravenous iron versus contr cramps. Total events: 0 (IV iron), 1 (Control release iron) Heterogeneity: not applicable Test for overall effect: Z = 0.73 (P = 0.47) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 11 Intravenous iron + hydrocorti sone versus intravenous iron, Outcome 1 Tenderness or erythema. Total events: 0 (IV iron + hydrocort), 5 (IV iron) Heterogeneity: not applicable Test for overall effect: Z = 1.67 (P = 0.095) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers us full dose intravenous iron, Outcome 1 Allergic reaction during infusion. us full dose intravenous iron, Outcome 2 Allergic reaction after infusion. Total events: 47 (2/3 dose IV iron), 77 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 2.86 (P = 0.0042) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers us full dose intravenous iron, Outcome 3 Lifethreatening allergic reaction during infusion. us full dose intravenous iron, Outcome 4 Discomfort needing analgesics after infusion. Total events: 15 (2/3 dose IV iron), 31 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 2.33 (P = 0.020) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers us full dose intravenous iron, Outcome 5 Immobilised by painful joints. Comparison 12 2/3 dose intravenous iron vers live births. Total events: 9 (2/3 dose IV iron), 11 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 0.36 (P = 0.72) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 12 2/3 dose intravenous iron vers Neonatal death. Total events: 6 (2/3 dose IV iron), 9 (Full dose IV iron) Heterogeneity: not applicable Test for overall effect: Z = 0.70 (P = 0.49) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Total events: 1 (rhEPO +IV Fe sucrose), 5 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 1.53 (P = 0.12) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Total events: 6 (rhEPO +IV Fe sucrose), 6 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 13 Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 4 Metallic taste. adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 5 Warm feeling. Total events: 1 (rhEPO +IV Fe sucrose), 1 (IV Fe sucrose) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 13 Intravenous iron sucrose with adjuvant recombinant human erythropoietin versus intravenous iron sucrose, Outcome 6 Birthweight. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. M-H,Fixed,95% CI ohn Wiley & Sons, Ltd. M-H,Fixed,95% CI Comparison 14 Intramuscular iron sorbitol c anaemic at term. itric acid versus oral iron, Outcome 2 Mean maternal haemoglobin at birth. Heterogeneity: not applicable Test for overall effect: Z = 4.41 (P = 0.000010) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 14 Intramuscular iron sorbitol c itric acid versus oral iron, Outcome 3 Mean maternal hematocrit level at birth. Comparison 14 Intramuscular iron sorbitol c section. Total events: 24 (IM iron), 22 (Oral iron) Heterogeneity: not applicable Test for overall effect: Z = 0.34 (P = 0.74) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 14 Intramuscular iron sorbitol c itric acid versus oral iron, Outcome 5 Haematocrit (%) at 4 weeks of treatment. itric acid versus oral iron, Outcome 6 Haematocrit (%) at 8 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.79 (P = 0.00015) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 14 Intramuscular iron sorbitol c itric acid versus oral iron, Outcome 7 Haematocrit (%) at 4 weeks of treatment. itric acid versus oral iron, Outcome 8 Haematocrit (%) at 8 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.23 (P = 0.0012) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Total events: 11 (IM iron dextran), 1 (Oral Fe+vitC+folic a) Heterogeneity: not applicable Test for overall effect: Z = 2.37 (P = 0.018) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c itric acid versus oral iron + folic acid, Outcome 1 Mean haemoglobin at 36 weeks. Total events: 42 (IM iron), 51 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.50 (P = 0.13) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. itric acid versus oral iron + folic acid, Outcome 3 Caesarean section. itric acid versus oral iron + folic acid, Outcome 4 Mean birthweight (kg). Heterogeneity: not applicable Test for overall effect: Z = 0.27 (P = 0.79) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c Diarrhoea. itric acid versus oral iron + folic acid, Outcome 6 Constipation. Total events: 0 (IM iron), 8 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.96 (P = 0.050) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c Dyspepsia. itric acid versus oral iron + folic acid, Outcome 8 Local site mainly pain. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 16 Intramuscular iron sorbitol c Staining. Total events: 6 (IM iron), 0 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.76 (P = 0.079) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. citric acid versus oral iron + folic acid, Outcome 11 Itching and rash. Total events: 8 (IM iron), 0 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.96 (P = 0.050) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. citric acid versus oral iron + folic acid, Outcome 14 Vaso-vagal due to apprehension. Total events: 4 (IM iron), 0 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.48 (P = 0.14) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. citric acid versus oral iron + folic acid, Outcome 15 Systemic ache. Total events: 11 (IMiron), 21 (Oral iron+folic acid) Heterogeneity: not applicable Test for overall effect: Z = 1.93 (P = 0.053) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 17 Oral iron daily versus oral iro at 4 weeks. Comparison 17 Oral iron daily versus oral iro at 8 weeks. Comparison 17 Oral iron daily versus oral iro at 12 weeks. Comparison 17 Oral iron daily versus oral iro at 16 weeks. Heterogeneity: not applicable Test for overall effect: Z = 1.89 (P = 0.059) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Total events: 1 (Oral iron daily), 7 (Oral iron twice week) Heterogeneity: not applicable Test for overall effect: Z = 1.78 (P = 0.075) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 18 Oral iron daily versus oral iro 16 weeks. Total events: 23 (Oral iron daily), 13 (Oral iron once week) Heterogeneity: not applicable Test for overall effect: Z = 1.95 (P = 0.051) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 19 Oral iron twice week versus ora level at 16 weeks. Heterogeneity: not applicable Test for overall effect: Z = 2.10 (P = 0.035) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Total events: 7 (Oral iron twice week), 20 (Oral iron once wee Heterogeneity: not applicable Test for overall effect: Z = 2.94 (P = 0.0033) k) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 20 Intravenous iron sucrose 500 m g versus intravenous iron sucrose 200 mg, Outcome 1 Haemoglobin level at delivery. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 20 Intravenous iron sucrose 500 m g versus intravenous iron sucrose 200 mg, Outcome 3 Moderate abdominal pain. Comparison 21 Intravenous iron sucrose 500 m Outcome 1 Maternal haemoglobin level at birth. Heterogeneity: not applicable Test for overall effect: Z = 4.30 (P = 0.000017) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. g versus intramuscular iron sorbitol, Outcome 1 Haemoglobin level at delivery. Heterogeneity: not applicable Test for overall effect: Z = 3.51 (P = 0.00044) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Heterogeneity: not applicable Test for overall effect: Z = 0.63 (P = 0.53) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 1 Haematocrit (%) at 4 weeks of treatment. Heterogeneity: not applicable Test for overall effect: Z = 3.04 (P = 0.0024) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 2 Haematocrit (%) at 8 weeks of treatment. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 3 Neonatal jaundice. Total events: 1 (IM iron sorb-gluc), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.05 (P = 0.96) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 4 Viral hepatitis. Comparison 25 Intramuscular iron sorbitol- glu acid versus intravenous iron dextran, Outcome 5 Severe allergic reaction. Total events: 0 (IM iron sorb-gluc), 1 (IV iron dextran) Heterogeneity: not applicable Test for overall effect: Z = 0.72 (P = 0.47) Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. For the 2006 update, Ludovic Reveiz and Gill Gyte appraised t review, with Gill Gyte and Luis Gabriel Cuervo providing comm editorial feedback. An updated search of the Pregnancy and Childbirth Group's Trials Register on 31 January 2007 identified seven new trial reports which have been added to the awaiting assessment section for assessment in the next update. There are now a total of 17 trials included in the review. The inclusion of these trials have generally not changed the conclusions although there are now concerns about possible important adverse effects. Ludovic Reveiz is now the guarantor of the review. Ludovic Reveiz took the lead on wri ents on the various drafts, and revised the review in respons The first published review was prepared by Luis Gabriel Cuerv Treatments for iron deficiency anaemia in pregnancy. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. and Kassam Mahomed, and cited as: Cuervo LG, Mahomed K. tabase of Systematic Reviews 2001, Issue 2. Luis Gabriel Cuervo has contributed to this systematic revie were made before joining the Pan American Health Organizatio for the statements contained therein. w in a personal capacity and during his spare time. Treatments for iron-deficiency anaemia in pregnancy (Revie w) Copyright © 2009 The Cochrane Collaboration. Published by J ohn Wiley & Sons, Ltd. 120

Document 01 : Iron deficiency anemia in pregnancy: is intravenous iron sucrose an alternative to the oral iron-folate supplementation program in India?
Objectives:
To determine the current prevalence and severity of Iron Deficiency Anemia in pregnancy in rural and urban India, to prospectively document the response to an IFA supplementation program, and to pilot the response to intravenous iron-sucrose.
Patients & Methods: We measured haemoglobin (Hb) levels in 10,000 unselected pregnant women in 4 rural centers, and in 1985 women in one urban centre. we studied the efficacy, safety and acceptability of two doses of 200mg intravenous iron sucrose as against oral iron folate
Results: We found an IDA prevalence of 69.4% in the rural and 61.4% in the urban setting. Ninety seven (30.7%) of the women receiving oral iron showed an increase in Hb as against 64 of the 69 women (92.8%) receiving iron-sucrose, mean rise in Hb of 1.31gm/dl (sd 0.77).
Conclusions: Thirty years of the IFA program have failed to eradicate IDA in pregnancy in India. The challenge is whether the costs and logistic difficulties posed by the use of iron sucrose on a population scale can be overcome.

Document 02 : Rapid versus slow intravenous iron sucrose administration: efficacy, safety and potential cost-savings in an Indian rural pregnant population with iron deficiency anemia.
Background: The Iron-Folic Acid (IFA) program launched in India some 30 years ago to provide free iron and folate to pregnant women to eradicate iron deficiency anemia (IDA) has failed, since the prevalence of IDA in pregnancy is still in excess of 50%. Intravenous iron sucrose circumvents many of the obstacles that have contributed to the failure of the IFA program, but requires careful and rigorous evaluation in a low resource setting such as India. Objectives: To compare the efficacy, safety and cost of two methods of administering intravenous iron sucrose, the conventional slow intravenous infusion versus the rapid “bolus- push� technique.

Patient & Methods: 152 pregnant women with iron deficiency anemia (Haemoglobin < 11g/dl) attending a rural antenatal clinic in India between Nov 2008 and Feb 2009 were randomized to receive two doses of intravenous iron sucrose by one or other of the two methods under comparison. Irrespective of the pre-treatment haemoglobin (Hb), all women received the same total dose of iron sucrose of 400mg divided into two equal doses administered 2-4 days apart at 20-24 weeks gestation. The 75 women randomized to Group A received iron sucrose by the slow infusion (over half an hour) technique, while the 77 women randomized to Group B had the iron sucrose administered by the rapid “bolus-push� technique over 2-5 minutes. Any adverse reactions were recorded after the first injection. Per unit additional costs incurred were calculated for each method.

Results: There were no differences in patient demographics or pre-treatment Hb between the two groups. Both groups recorded a statistically significant increase in the mean Hb level in response to treatment ( p<0.05), but there were no differences between the two groups. No woman experienced major adverse reactions, but minor reactions were reported in 5 (6.7%) women in Group A and 15 (19.5%) women in Group B (p>0.05). Only two women experiencing minor reactions required intravenous hydrocortisone, and symptoms resolved within 20 minutes in both. Cost analysis revealed that the slow infusion was seven times more expensive than the bolus push technique (200 versus 30 INR)

Conclusions: The administration of iron sucrose by the bolus-push technique has similar efficacy to the conventional slow infusion technique, but is seven times cheaper. Although 2 associated with a higher incidence of adverse reactions, all were minor, and all resolved rapidly. The bolus-push technique may represent a cost-effective approach to the eradication of iron deficiency anemia in pregnancy in low-resource settings. Keywords: Iron deficiency anemia (IDA), iron-folic acid (IFA), Pregnancy, haemoglobin (Hb), iv iron sucrose