Iron deficiency in pregnancy: effects on the newborn

Iron deficiency during pregnancy affects a significant portion of women in countries with low economic wealth and is not uncommon in pregnant women in industrialized countries. Inadequate intake of iron related to diets poor in bioavailable iron is often responsible for iron deficiency before pregnancy, and metabolic adjustments (such as mobilization of iron stores and increased absorption) are insufficient to meet increasing needs during pregnancy. The effects of iron deficiency on the fetus are still controversial. Numerous measures, including the evaluation of erythrocyte ferritin, favor the hypothesis that the level of iron stores in newborns is related to maternal iron status and that the materno-fetal unit is dependent on exogenous iron, which is necessary to prevent iron deficiency in both mothers and infants. In industrialized countries, iron supplements should be prescribed for pregnant women in the third trimester, when the need for iron is prominent. In developing countries, supplementation should be initiated as soon as possible after conception because of the high prevalence of iron deficiency at the onset of pregnancy. The results of studies comparing intermittent with daily supplementation remain controversial.     

Nutritional iron requirements and food iron absorption

To prevent nutritional iron deficiency, sufficient iron must be absorbed from the diet to meet the normal physiological requirements. Daily iron losses in males are about 1 mg (14 micrograms kg-1), while the average additional requirements incurred in women include menstruation (0.6 mg), pregnancy (2.7 mg) and lactation (less than 0.3 mg). Requirements during pregnancy are not evenly distributed and increase to between 5-6 mg in the last trimester of pregnancy, which is more than can be absorbed from even an optimal diet. While the amounts absorbed are affected by the iron content of the diet, the composition of the latter is even more relevant. About one-quarter of the iron in haem proteins is absorbed regardless of the other components in the diet, while non-haem iron absorption is subject to the interplay of promoting and inhibiting substances in the diet. Thus diets rich in enhancers of non-haem iron absorption, chiefly meat and/or ascorbic acid, have high iron bioavailability (about 3 mg d-1) while diets in which inhibitors, such as polyphenols and phytates, predominate are poor sources of iron (less than 1 mg d-1). Examination of the relative proportions of promoters and inhibitors of iron absorption in individual foodstuffs and the measured iron absorption from them may be useful in predicting the overall iron bioavailability from mixed diets.     

Iron status in pregnant women: which measurements are valid?

Anaemia in pregnancy in developing countries continues to be a public health problem of significant proportion. At least 50% of the anaemia has been blamed on iron deficiency. In populations where chronic inflammation and iron deficiency anaemia coexist, the criteria to accurately define iron status are not always clear. Similarly, in pregnancy, with marked physiological changes, cut-off points for biochemical parameters need to be re-examined. In this study we examined the diagnostic accuracy of iron parameters including mean cellular volume (MCV), serum iron, transferrin, total iron binding capacity (TIBC) and its saturation, zinc protoporphyrin (ZPP), ferritin and serum transferrin receptor (TfR) for the assessment of iron status in a population of anaemic pregnant women in Malawi. Stained bone marrow aspirates were used as the standard for comparison.
Results show that for the purpose of screening, serum ferritin is the best single indicator of storage iron provided a cut-off point of 30 μg/l is used. A number of other commonly used parameters of iron status were shown to have limited diagnostic accuracy. Logistic regression was used to obtain mathematical models for the prediction of bone marrow iron status using a combination of available parameters.     

A comparison between intravenous iron polymaltose complex (Ferrum Hausmann®) and oral ferrous fumarate in the treatment of iron deficiency anaemia in pregnancy

Abstract: Anaemia is the most common medical disorder in pregnancy with iron deficiency anaemia accounting for the majority of cases. Over 90% of the iron deficiency anaemia is due to red cell iron deficiency associated with depleted iron stores and deficient intake. The two main modalities of treating iron deficiency anaemia are oral or parenteral iron. Ferrous Hausmann® (iron dextrin) is the latest iron preparation which can be used for intravenous parenteral administration as a total dose infusion. This study compares the efficacy of Ferrum Hausmann® with oral ferrous fumarate therapy in the treatment of iron deficiency anaemia in pregnancy. Our study shows that treatment with intravenous Ferrum Hausmann® (iron dextrin) resulted in a significantly better level and rate of increase of haemoglobin (p<0.001). Serum ferritin, which is the best indicator of iron stores, was significantly higher (p<0.001) in the intravenous group. Other indices of iron status such as serum iron, serum transferrin and zinc protoporphyrin also showed a significant improvement in the intravenous group compared to those given oral iron. The results suggest that intravenous iron as a total dose infusion is able to replenish iron stores more efficiently, completely and at a faster rate than oral iron therapy, thus providing the fuel for stimulation of full erythopoiesis compared to oral iron. There were also no reports of any adverse reactions with intravenous iron dextrin, whereas there were a considerable proportion of women on oral iron therapy who reported side effects. In conclusion, intravenous iron therapy with Ferrous Hausmann® (iron dextrin) is a suitable, effective and safe alternative to oral iron therapy in the treatment of iron deficiency anaemia in pregnancy.     

Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion

Anaemia is a common condition among patients admitted to hospital medicosurgical departments, as well as in critically ill patients. Anaemia is more frequently due to absolute iron deficiency (e.g. chronic blood loss) or functional iron deficiency (e.g. chronic inflammatory states), with other causes being less frequent. In addition, preoperative anaemia is one of the major predictive factors for perioperative blood transfusion. In surgical patients, postoperative anaemia is mainly caused by perioperative blood loss, and it might be aggravated by inflammation-induced inhibition of erythropoietin and functional iron deficiency (a condition that cannot be corrected by the administration of oral iron). All these mechanisms may be involved in the anaemia of the critically ill. Intravenous iron administration seems to be safe, as very few severe side-effects were observed, and may result in hastened recovery from anaemia and lower transfusion requirements. However, it is noteworthy that many of the recommendations given for intravenous iron treatment are not supported by a high level of evidence and this must be borne in mind when making decisions regarding its application to a particular patient. Nonetheless, this also indicates the need for further large, randomized controlled trials on the safety and efficacy of intravenous iron for the treatment of anaemia in different clinical settings.     

Management of iron deficiency in patients admitted to hospital: time for a rethink of treatment principles

Background: Iron deficiency is very common in patients admitted to hospital. Its management is changing with new insights into iron absorption and therapeutic options. Aims: The aims of this study were to develop guidelines for the correction of iron deficiency in patients admitted to hospital and to compare these with current practice. Methods: Based on current published evidence, guidelines were developed. All patients in whom iron deficiency was detected during hospital admission over a 2.5 year period were retrospectively studied. Their management was compared with that of the guidelines developed. Results: Three clinical scenarios were identified—(A) urgent attention to haemoglobin required: blood transfusion followed by i.v. iron recommended, (B) Semiurgent iron repletion: i.v. iron recommended and (C) non‐urgent iron repletion: oral or i.v. repletion recommended. A total of 119 patients was identified, age 18–99 (median 77) years, 29% men, and haemoglobin 33–130 (87) g/L. Of 66 given blood transfusion, 17 had subsequent i.v. iron, 25 oral iron and 24 no other form of iron repletion. Of the other 53, nine had i.v. iron, 32 oral iron and 12 had no treatment. Fifty‐five per cent of patients were managed according to the proposed guidelines and this occurred less frequently (9%) in those presenting with cardiovascular problems than in those with anaemia, gastrointestinal bleeding or other medical problems (all >60%; P < 0.0001, Fisher's exact test). Conclusion: Current management is haphazard, with underutilization of i.v. iron and failure to initiate any regimen for iron repletion being common. It may be time for a change in approach to repletion of iron in ill patients.     

Iron prophylaxis in pregnancy—general or individual and in which dose?

Iron is mandatory for normal fetal development, including the brain. Iron deficiency may have deleterious effects for intelligence and behavioral development. It is important to prevent iron deficiency in the fetus by preventing iron deficiency in the pregnant woman. Iron deficiency anemia during pregnancy is a risk factor for preterm delivery and low birth weight. In the Western countries there is no consensus on iron prophylaxis to pregnant women. An adequate iron balance during pregnancy implies body iron reserves of ≥500 mg at conception. The physiologic iron requirements in the second half of gestation cannot be fulfilled solely through dietary iron. Iron supplements during gestation consistently increase serum ferritin and hemoglobin and reduce the prevalence of iron deficiency anemia. Iron has a negative influence on absorption of other divalent metals and increases oxidative stress in pregnancy, for which reason minimum effective iron dose should be advised. From a physiologic point of view, individual iron prophylaxis according to serum ferritin concentration should be preferred to general prophylaxis. Suggested guidelines are (1) ferritin >70 μg/l: no iron supplements; (2) ferritin 30–70 μg/l: 40 mg ferrous iron daily; and (3) ferritin <30 μg/l: 80–100 mg ferrous iron daily. In controlled studies, there are no documented side effects of iron supplements below 100 mg/day. Iron supplements should be taken at bedtime or between meals to ensure optimum absorption.     

Postpartum anemia II: prevention and treatment

This review focuses on the prevention and treatment of anemia in women who have just given childbirth (postpartum anemia). The problem of anemia both prepartum and postpartum is far more prevalent in developing countries than in the Western societies. The conditions for mother and child in the postpartum, nursing, and lactation period should be as favorable as possible. Many young mothers have a troublesome life due to iron deficiency and iron deficiency anemia (IDA) causing a plethora of symptoms including fatigue, physical disability, cognitive problems, and psychiatric disorders. Routine screening for postpartum anemia should be considered as part of the national maternal health programs. Major causes of postpartum anemia are prepartum iron deficiency and IDA in combination with excessive blood losses at delivery. Postpartum anemia should be defined as a hemoglobin level of <110 g/l at 1 week postpartum and <120 g/l at 8 weeks postpartum. Bleeding exceeding normal blood losses of approximately 300 ml may lead to rapid depletion of body iron reserves and may, unless treated, elicit long-standing iron deficiency and IDA in the postpartum period. The prophylaxis of postpartum anemia should begin already in early pregnancy in order to ensure a good iron status prior to delivery. The most reliable way to obtain this goal is to give prophylactic oral ferrous iron supplements 30–50 mg daily from early pregnancy and take obstetric precautions in pregnancies at risk for complications. In the treatment of slight-to-moderate postpartum IDA, the first choice should be oral ferrous iron 100 to 200 mg daily; it is essential to analyze hemoglobin after approximately 2 weeks in order to check whether treatment works. In severe IDA, intravenous ferric iron in doses ranging from 800 to 1,500 mg should be considered as first choice. In a few women with severe anemia and blunted erythropoiesis due to infection and/or inflammation, additional recombinant human erythropoietin may be considered. Blood transfusion should be restricted to women who develop circulatory instability due to postpartum hemorrhage. National health authorities should establish guidelines to combat iron deficiency in pregnancy and postpartum in order to facilitate a prosperous future for both mothers and children in a continuing globalized world.     

Iron deficiency: definition and diagnosis

There has been a continuous refinement over the past several decades of methods to detect iron deficiency and assess its magnitude. The optimal combination of measurements differs for clinical and epidemiological assessment. Clinically, the major problem is to distinguish true iron deficiency from other causes of iron-deficient erythropoiesis, such as the anaemia of chronic disease. Epidemiologically, techniques that provide quantified estimates of body iron are preferable. For both purposes, the serum ferritin is the focal point of the laboratory detection of iron deficiency. Serum ferritin measurements provide a reliable index of body iron stores in healthy individuals, a cost-effective method of screening for iron deficiency, and a useful alternative to bone marrow examinations in the evaluation of anaemic patients. Preliminary studies indicate that measurement of the serum transferrin receptor may be the most reliable way to assess deficits in tissue iron supply.     

A prospective randomized,controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy

Abstract. Khalafallah A, Dennis A, Bates J, Bates G, Robertson IK, Smith L, Ball MJ, Seaton D, Brain T, Rasko JEJ Launceston General Hospital (LGH), Australia; University of Tasmania, Australia; and Centenary Institute, University of Sydney, NSW, Australia) A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy. J Intern Med 2010; 268 : 286–295. Background. Iron deficiency anaemia is the most common deficiency disorder in the world, affecting more than one billion people, with pregnant women at particular risk. Objectives and design. We conducted a single site, prospective, nonblinded randomized‐controlled trial to compare the efficacy, safety, tolerability and compliance of standard oral daily iron versus intravenous iron Subjects. We prospectively screened 2654 pregnant women between March 2007 and January 2009 with a full blood count and iron studies, of which 461 (18%) had moderate IDA. Two hundred women matched for haemoglobin concentration and serum ferritin level were recruited. Interventions. Patients were randomized to daily oral ferrous sulphate 250 mg (elemental iron 80 mg) with or without a single intravenous iron polymaltose infusion. Results. Prior to delivery, the intravenous plus oral iron arm was superior to the oral iron only arm as measured by the increase in haemoglobin level (mean of 19.5 g/L vs. 12 g/L; P < 0.001); the increase in mean serum ferritin level (222 μg/L vs. 18 ug/L; P < 0.001); and the percentage of mothers with ferritin levels below 30 μg/L (4.5% vs. 79%; P < 0.001). A single dose of intravenous iron polymaltose was well tolerated without significant side effects. Conclusions. Our data indicate that intravenous iron polymaltose is safe and leads to improved efficacy and iron stores compared to oral iron alone in pregnancy‐related IDA.     

The impact of iron fortification on nutritional anaemia

Iron deficiency continues to be the most prevalent nutritional deficiency disorder in the world, affecting an estimated two billion people, most of whom live in developing countries. It has far-reaching effects on the health, well-being and productivity of those affected. Iron fortification of food is regarded as the most cost-effective method for reducing the prevalence of nutritional iron deficiency. In industrialized countries this has had an important beneficial effect; however, nutritional anaemia remains very prevalent in developing countries, and iron fortification appears until recently to have had little impact. Two important reasons for the latter situation are inadequate documentation of the magnitude of the iron deficiency component of anaemia in different regions of the world, and the use of iron compounds that are poorly bioavailable in fortification programmes. Several recent interventions using innovative approaches to dietary fortification that ensure the delivery of adequate quantities of bioavailable iron have demonstrated that iron fortification of food can be an effective and implementable strategy for controlling nutritional iron deficiency in non-industrialized countries.     

Reduced Frequency of Iron Deficiency Anaemia in Sickle Cell Trait

The prevalence and causes of anaemia among the inhabitants of a Southern Lebanese village were studied. Of the 317 patients examined 75, or 24% were found to be heterozygotes for Hb S. There was a reciprocal relation between the presence of sickle cell trait and of iron deficiency anaemia. The prevalence of iron deficiency anaemia defined as the coexistence of Hb below 13 g/dl in adult males and below 12 in adult females and children with two laboratory indicators of iron deficiency, was 10.3 % in the normal population as against 1.3 % in the sickle cell trait group (P < 0.008). The reduced frequency of iron deficiency anaemia in sickle cell trait may be explained by increased iron absorption, or alternatively by reduced iron requirements and a lower risk of discrepancy between iron supply and demand. Because of the central role of iron in the function of a great number of enzymes and proteins, it is possible that protection against iron deficiency anaemia by the sickle cell trait may result in improved working capacity and a lower incidence of infections.     

The role of iron repletion in adult iron deficiency anemia and other diseases

Iron deficiency anemia (IDA) is the most prevalent and treatable form of anemia worldwide. The clinical management of patients with IDA requires a comprehensive understanding of the many etiologies that can lead to iron deficiency including pregnancy, blood loss, renal disease, heavy menstrual bleeding, inflammatory bowel disease, bariatric surgery, or extremely rare genetic disorders. The treatment landscape for many causes of IDA is currently shifting toward more abundant use of intravenous (IV) iron due to its effectiveness and improved formulations that decrease the likelihood of adverse effects. IV iron has found applications beyond treatment of IDA, and there is accruing data about its efficacy in patients with heart failure, restless leg syndrome, fatigue, and prevention of acute mountain sickness. This review provides a framework to diagnose, manage, and treat patients presenting with IDA and discusses other conditions that benefit from iron supplementation.     

Iron deficiency and anaemia in pregnancy: modern aspects of diagnosis and therapy

The prevalence of iron-deficiency anemia in different regions of the world ranges from 12 to 43%. The increased iron requirement in pregnancy and the puerperium carry with it an increased susceptibility to iron deficiency and iron-deficiency anemia and perioperative or peripartal blood transfusion. Prevention and correction presuppose reliable laboratory parameters and a thorough understanding of the mechanisms of iron therapy. The Hb level alone is insufficient to guide management. A complete work-up (ferritin, transferrin saturation) is essential, preferably with hematological indices such as hypochromic and microcytic red cells and reticulocytes, classified by degree of maturity, in particular, before parenteral therapy is given. Since ferritin acts as both an iron-storage and acute-phase protein, it cannot be used to evaluate iron status in the presence of inflammation. A high ferritin level thus requires the presence of an inflammatory process to be eliminated before it can be taken at face value. If the C-reactive protein level is also raised, the soluble TfR concentration can be used, since it is unaffected by inflammation. Inadequate understanding of the complex chemistry of parenteral iron administration was previously responsible for serious side effects, such as toxic and allergic reactions, and even anaphylactic shock, in particular with dextran preparations. However, the current type II iron complexes that release iron to the endogenous iron-binding proteins with a half-life of about 6 hours are not only effective but carry a minimal risk of allergic accident and overload, especially after a comprehensive pretreatment work-up. Our departmental data collected over 8 years and backed by postmarketing experience in 25 countries indicate that iron sucrose complex therapy is a valid first-line option for the safe and rapid reversal of iron-deficiency anemia.     

Reduced soluble transferrin receptor concentrations in acute malaria in Vanuatu.

Soluble transferrin receptor (sTfR) concentration is a sensitive index of iron deficiency when used in conjunction with ferritin measurements in adults. One advantage of this assay is that unlike ferritin it does not appear to be affected by a range of infectious and inflammatory conditions or by pregnancy, rendering it a promising adjunct to the diagnosis of iron deficiency in tropical populations. We have measured plasma sTfR concentrations in a group of malaria patients (n = 21) and asymptomatic (18) and aparasitemic (76) controls in Vanuatu. Plasma sTfR concentration was significantly reduced in individuals with acute malaria (P = 0.003). While this observation provides evidence that erythropoeitic suppression may be an important etiologic component in malarial anemia, it also suggests that malaria may be a confounding factor when interpreting sTfR concentrations in such populations. The role of sTfR in the diagnosis of iron deficiency in tropical populations remains to be established.     

Plasma Iron and Erythrocytic Glutathione Peroxidase Activity

The red cell glutathione-peroxidase (GSH-Px) activity of 9 normal subjects is compared with that of 15 cases of iron deficiency anaemia and with 13 cases of heterozygous beta-thalassaemia with the same degree of anaemia and hypochromia. 2 cases of sideroblastic anaemia with high serum iron levels were also examined. Enzymatic activity was found to be significantly decreased in iron deficiency anaemia (about 55 % of normal range), while it was not affected in heterozygous betathalassaemia and it was increased in the 2 cases of sideroblastic anaemia. Moreover, GSH-Px activity exhibited a significant correlation with serum iron levels in all the patients studied. The observed modifications in GSH-Px activity are not correlated with erythrocyte ageing because reticulocyte-poor fractions exhibited GSH-Px activity which was not significantly reduced in respect of the reticulocyte-rich ones. These data seem to suggest that iron has a crucial connection with erythrocyte GSH-Px and that the enzyme deficiency may be of some importance in explaining the decreased red cell survival observed in severe iron-deficiency anaemias.     

How do we manage iron deficiency after blood donation?

Summary

Blood donors and the RBCs and other components they willingly provide are essential in the delivery of healthcare in all parts of the world. Nearly 70% of donated blood comes from repeat or committed donors. The amount of iron removed in the 10 min or so it takes to withdraw a unit of blood (500 ml, plus 25 ml for testing) requires over 24 weeks to replace on a “standard” diet, i.e., without added iron in the form of supplements The cumulative effect of repeat blood donations without adequate iron replacement or a longer wait between donations results in iron deficiency (ID) in many donors, low haemoglobin deferral (~8% of donation attempts), and frank anaemia in some. Moreover, ID can be associated with side effects that can impact a blood donor's health, such as fatigue, cognitive changes and other neuromuscular symptoms. In an effort to better identify and prevent ID, blood collection agencies are recommending various strategies, including changes in the donation interval, donation frequency, testing of iron status and iron supplementation. In this review, we present the evidence basis for these strategies and suggest our own approaches to improving iron balance in blood donors.

     

Use of advanced red blood cell and reticulocyte indices improves the accuracy in diagnosing iron deficiency in pregnant women at term

Objectives: Detection of iron deficiency during pregnancy with hemoglobin (Hb) and serum measurements is insignificant as the measurements may be affected by e.g. hemodilution or accelerated erythropoiesis. This study tests whether cell indices will give a more reliable measure of iron deficiency in pregnant women at term. Methods: The population was 202 pregnant women. Using the ADVIA 120 hematology system, Hb, mean cell volume (MCV), percentage of hypochromic red blood cells (%HYPOm) and reticulocytes (%HYPOr), and cellular hemoglobin in reticulocytes (CHr) were tested. Additionally, transferrin saturation (TfSat), ferritin, and transferrin receptor (TfR) were analyzed. Receiver operating characteristic (ROC) curves and area under the ROC curves (AUC) were used as statistical methods. Results: When TfSat (≤11%) was used as the reference test for iron deficiency, %HYPOm and CHr had a sensitivity of 58.1% and 80.7%, while the specificities were 82.6% and 71.3%, respectively. Additionally, the AUC values were %HYPOr 0.80, CHr 0.79, ferritin 0.77, %HYPOm 0.75, TfR 0.67, MCV 0.63 and Hb 0.64. The results provided by the cell indices alone (%HYPOm or CHr) were in good agreement with the results based on the usage of a combination of three commonly used tests (Hb, MCV, ferritin). Conclusions: This study suggests that the most practical way to diagnose iron deficiency in pregnant women at term is to use cell indices such as CHr and %HYPOm provided by the automated hematological analyzer. Further studies are needed to determine the usefulness of the cell indices in diagnosing iron deficiency longitudinally during the course of pregnancy.     

A screening test for assessing iron status

Intervention strategies to combat iron deficiency anemia in developing countries may hasten the development of iron overload in patients with an inherited defect in hemoglobin synthesis. This risk could be diminished if there was a rapid and simple method available for detecting iron overload in population screening programs. We have developed such a method, which is in effect a semiquantitative ferritin measurement based on a modification of a two-site enzyme-linked immunoassay. The assay requires only 2 drops of whole blood and a total incubation time of 90 min. The procedure, which can readily distinguish iron deficiency from even a modest increase in storage iron, has a potentially wide application in settings where a prompt assessment of iron status is required.     

Diagnosis and management of anaemia of chronic disease: current status

Anaemia of chronic disease is the second most common form of anaemia worldwide, and is seen in a variety of inflammatory, infective and malignant diseases. Functional iron deficiency is fundamental to the pathogenesis of the anaemia, and the polypeptide, hepcidin, plays a key role. Diagnosis may be difficult, but new automated red cell indices, algorithms for detection of functional iron deficiency, and assays for hepcidin levels are being developed. Management of the causative disease process will usually improve haemoglobin levels, but where this is not possible, erythropoietic stimulating agents are often used, although there are still concerns about potential adverse effects, especially thromboembolism. There is increasing evidence that supplemental iron given parenterally can safely overcome the functional iron deficiency. Inhibitors of hepcidin, and various inflammatory modulators show promise for the future.