Iron homeostasis and perioperative management of iron deficiency

Key points.

• •Iron deficiency is the commonest cause of anaemia worldwide.
• •Most iron in the body is within the haemoglobin of red cells, but nearly all cells require iron for enzyme functions and nearly all cells hold iron within ferritin.
• •Hepcidin, which regulates iron, increases in response to inflammation and infection, when it limits the supply of iron to microorganisms and also, detrimentally, to developing red blood cells.
• •A serum ferritin concentration ≤12 μg L⁻¹ is diagnostic of absolute iron deficiency, but serum ferritin values are unreliable in the presence of inflammation or infection. In these circumstances, the percentage of hypochromic red cells, reticulocyte haemoglobin concentration, or transferrin saturation may help diagnose iron restriction.
• •If there is preoperative evidence of iron deficiency anaemia, then oral iron may be given; i.v. iron is recommended if the time to surgery is short, or the patient is refractory or intolerant to oral iron.

Learning objectives.

By reading this article, you should be able to:

• •Describe the physiology of iron and its importance for mammalian health and function.
• •Discuss which groups of patients require further investigation for iron deficiency anaemia, including those with normal serum ferritin values in whom a response to iron therapy is seen.
• •Explain the rationale and pitfalls of laboratory tests in assessing iron status.
• •Optimise iron status, particularly in patients scheduled for surgery.

Iron is an essential bioelement in human physiology. It has key roles in cellular respiration: facilitating the formation of Adenosine triphosphate (ATP), oxygen transport through iron-containing haem groups (haemoglobin [Hb] and myoglobin), and protection against infection via iron withholding in the immune system. Iron excess results in toxicity, most notably to the heart and liver. Iron deficiency (ID) affects more than 2 billion people worldwide and remains the leading cause of anaemia. This review gives an overview of the physiology of iron metabolism and its impact on key groups of patients presenting for surgery, and summarises how to investigate and treat ID.

Iron homeostasis

The human body contains approximately 3–4 g iron in males and 2.5 g in females; 2.5–3.5 g of this in males is contained as Hb, 0.3–0.4 g as myoglobin, 100 mg as haem/non-haem enzymes, 3 mg on transferrin, and 7 mg on intracellular carriers. The remaining 1,000 mg of iron is mostly stored in ferritin, largely in the liver and macrophages in the reticuloendothelial system (RES).¹ Roughly 25 mg of iron per day is required by the bone marrow to produce 200 billion red blood cells (RBCs), but dietary absorption from the intestine is limited to 1–2 mg day⁻¹. Therefore, the vast majority of iron is recycled from old RBCs by macrophages of the RES.

Dietary absorption

As humans are not able to excrete iron actively, regulating dietary absorption from the proximal duodenum is the only control of iron in the body.

Dietary iron can be absorbed in three forms:

• (i)Inorganic iron (non-haem iron)
• (ii)Haem-bound iron
• (iii)Iron incorporated in ferritin

Iron-rich foods include meat, fish, cereals, beans, egg yolks, dark green vegetables, potatoes, and fortified foods, whilst absorption is inhibited by tannins, calcium, dairy products, animal proteins, and micronutrients (such as zinc and copper). For iron to enter the circulation, it must pass through absorptive enterocytes crossing both the apical and basolateral membranes (Fig. 1). Haem iron is the form most effectively absorbed, but the mechanism is not fully understood. It is thought that haem carrier protein 1 transports it into the enterocyte where iron is liberated by haem oxygenase from protoporphyrin. Inorganic non-haem iron is predominately in the oxidised ferric (Fe³⁺) form. To be absorbed, it must be reduced to ferrous (Fe²⁺) iron by brush border ferrireductase. Ascorbic acid (vitamin C) enhances this process at low pH levels. The mechanism by which iron incorporated in ferritin is absorbed is uncertain, but it only makes a small contribution to total iron intake. Mixed diets provide 90% of dietary iron as inorganic non-haem iron.¹

Fig 1.

Iron homeostasis. This is a pictorial description of the key aspects of human iron physiology with relevance to its absorption from the GI tract and transport through the absorptive enterocytes and into the circulation attached to transferrin. The majority of iron is transported to the bone marrow to assist in the production of mature red blood cells. Sensient red blood cells are taken up by macrophages in the reticuloendothelial system (e.g. the liver and spleen) where iron is liberated from Hb and either stored in the storage molecule ferritin. Systemic iron homeostasis is under the control of hepcidin, which is produced largely by the liver. Hepcidin acts to limit systemic iron levels in response to raised body iron stores, infection, inflammation, and malignancy. Hepcidin inhibits the movement of iron into the circulation by blocking ferroportin-dependent iron efflux out of macrophages, hepatocytes, and enterocytes. Iron is trapped within the cell by the action of hepcidin, and therefore, not available for transport to the circulation. Reprinted from Am J Kidney Dis, 67/4, LE Ratcliffe et al., Diagnosis and Management of Iron Deficiency in CKD: A Summary of the NICE Guideline Recommendations and Their Rationale, 548–58, Copyright (2016) with permission from Elsevier.

Once inside the enterocyte, liberated iron from haem and non-haem follows a common pathway where it is either:

• (i)Retained within the cell to be utilised for cellular requirements or stored in ferritin
• (ii)Exported across the cell basolateral membrane by a transmembrane exporter ferroportin-1 into the portal vein circulation

Transport, erythropoiesis, storage, and recycling

Once iron has crossed the basolateral membrane, it is oxidised back to ferric (Fe³⁺) iron by ferroxidases (either hephaestin found on the cell membrane or circulating ceruloplasmin) to allow it into the circulation bound to plasma proteins.² Nearly all circulating iron is carried on transferrin, which can bind either one or two ferric iron molecules. Iron normally occupies around 30% of available binding sites.¹ Transferrin saturation (Tsat%) exhibits diurnal variation and is likely to be higher in the portal circulation where absorbed iron enters the circulation, and lower after leaving the bone marrow where iron is extracted for use by developing RBCs. These cells are the destination for approximately 80% of transferrin-bound iron where it binds with transferrin receptors on the cell membranes.¹ The iron-binding transferrin-receptor complex is then internalised within the cell as an endosome, and then iron is released, reduced to its ferrous state (Fe²⁺), and used by the mitochondria to form Hb and iron–sulphur crystals. Iron–sulphur clusters are primordial catalysts and enzyme cofactors that serve a number of functions, including oxidation–reduction reactions, electron transfer, and DNA damage repair.³

The liver acts both to store excess iron and mobilise iron to circulation when required. The macrophages in the RES recycle iron from senescent RBCs and store it in ferritin for later use.

Regulation of iron homeostasis

Iron deficiency can result in symptoms of fatigue, lethargy, and dyspnoea independent of anaemia. Further effects are seen on myocardial function, brain development in neonates, immune function, DNA repair and replication, and thyroid function.⁴ Iron overload can be equally detrimental because of the ability of free iron to catalyse the formation of reactive oxygen species that can damage cellular structures, leading to dysfunction, apoptosis, and necrosis primarily in the liver, heart, and endocrine system.

Iron homeostasis is maintained through controlling the absorption, transport, and intracellular storage of iron in ferritin on a systemic and cellular level.

Cellular iron homeostasis

Iron is stored in a non-toxic form in ferritin, a soluble intracellular protein that all mammalian cells are able to produce. It has a cage-like structure and can store up to 4,500 iron atoms. Ferritin accepts iron when in excess and allows mobilisation of iron when required. The regulation of iron within cells is largely through iron regulatory proteins (IRPs) binding to mRNA structures called iron-responsive elements. When iron levels are replete, iron–sulphur complexes are incorporated within IRPs, which act as iron sensors within the cell. These units then become unable to bind to mRNA, reducing further iron influx through a reduction in transferrin receptor protein synthesis and increasing intracellular storage through ferritin. When iron levels are depleted, the converse occurs.²

Systemic iron homeostasis

The majority of iron regulation at a systemic level is under the control of hepcidin, a peptide hormone produced primarily by hepatocytes in the liver but also in the heart, pancreas, and haematopoietic cells. Hepcidin inhibits the movement of iron into the circulation by blocking ferroportin-dependent iron efflux out of macrophages, hepatocytes, and enterocytes. Iron is trapped within the cell by the action of hepcidin, and therefore, unavailable for transport to the circulation. Hepcidin may also stop iron from being absorbed from the apical side of enterocytes, preventing dietary absorption.

Hepcidin production is increased in response to:

• (i)Increase in body iron stores
• (ii)Infection
• (iii)Inflammation
• (iv)Malignancy

Hepcidin production is inhibited by:

• (i)Decrease in body iron stores
• (ii)Anaemia
• (iii)Hypoxaemia
• (iv)Increased erythropoietic demand²

Pathophysiology of iron homeostasis

Iron overload can be seen in a number of conditions associated with low hepcidin levels. Suppression of hepcidin expression is seen in thalassemia and dyserythropoietic anaemia. In hereditary haemochromatosis, a group of iron overload disorders commonly resulting in hepatic dysfunction, diabetes, and cardiomyopathy are caused by either mutation in:

• (i)HFE gene, which encodes hepcidin-regulatory proteins (Types 1+2)
• (ii)TRF2, which encodes transferrin receptor (Type 3)
• (iii)SLC40A1, which encodes ferroportin (Type 4)⁵

Iron is also essential for invading microbes, and hepcidin has an important role in host defences against infection. Hepcidin expression is stimulated in response to infection or inflammation, which removes iron from the circulation, making it unavailable to extracellular pathogens and limiting their spread. Acutely, this helps limit infection, but in chronic inflammatory conditions persistently high levels of hepcidin result in ‘functional ID’ (FID). An example would be chronic kidney disease (CKD), in which there are apparently normal iron stores but poor availability to the developing RBCs.⁶ Functional ID is a major component of the anaemia of chronic disease.

ID in patients presenting for surgery

The prevalence of anaemia globally is decreasing, but worldwide prevalence is still 32.9%, and anaemia accounts for approximately 8.8% of the total disease burden of all conditions.⁷ The prevalence of iron-deficiency anaemia (IDA) is increased in Central Asia, South Africa, and Andean Latin America, and is lower in high-income areas of North America.⁷ Overall, IDA generates approximately half the cases of anaemia worldwide. The variation in dietary iron combined with blood loss from hookworm and ID from pregnancy accounts for most cases.

Causes of ID

As the levels of available iron become deficient, the body prioritises RBC production above other requirements. If iron delivery remains restricted, it becomes insufficient for full Hb production in mature RBCs. The causes of ID are often multifactorial, but these are broadly characterised into causes of absolute ID and FID.

The individual causes are summarised as follows.

Absolute ID

• (i)Increased demand: infancy, adolescence, pregnancy, and treatment with erythropoietin
• (ii)Insufficient intake: poverty, malnutrition, and diet (vegetarian, vegan, and iron-poor foods)
• (iii)Decreased absorption: gastrectomy, duodenal bypass, bariatric surgery, inflammatory bowel disease, Helicobacter pylori infection, and use of proton pump inhibitors
• (iv)
  Chronic blood loss

  • (a)
    Gastrointestinal (GI): oesophagitis, erosive gastritis, peptic ulcer disease, diverticulitis, malignancy, inflammatory bowel disease, haemorrhoids, hookworm infection, and use of NSAIDs/anticoagulants
  • (b)
    Genitourinary: menorrhagia
  • (c)
    Bleeding defects: haemorrhagic telangiectasia, chronic schistosomiasis, and intravascular haemolysis

Functional iron deficiency

• (i)
  Increased hepcidin concentrations

  • (a)
    Genetic: iron-refractory IDA
  • (b)
    Chronic inflammatory state: chronic heart failure, CKD, inflammatory bowel disease, obesity, cancer, after surgery⁸

ID in different groups

Cardiovascular disease and cardiac surgery

Increased iron stores were once thought to be a risk factor for ischaemic heart disease, with vigorous exercise and phlebotomy suggested to prevent iron accumulation. Current evidence suggests the opposite with ID being an independent risk factor for both developing coronary artery disease and death in high-risk patients. High rates of anaemia are seen in patients presenting for elective cardiac surgery, with ID being confirmed on bone-marrow samples in 48% of patients with stable coronary artery disease.⁹ Increased hepcidin concentrations are associated with poor outcome after surgery.¹⁰

Whilst the evidence for iron supplementation for ID in coronary artery disease is currently limited, there is more established evidence in heart failure: ID has been demonstrated in 37–61% of patients, and its presence is an independent predictor of unfavourable outcome.¹¹ Multiple RCTs have shown an improvement in Hb, quality of life, and functional status with i.v. iron treatment.¹² I.V. iron supplementation is currently not recommended in patients who have undergone cardiac transplantation because of possible potentiation of rejection by T-cell activation.

Obstetrics

Worldwide, the prevalence of anaemia in pregnancy has decreased from 43% in 1995 to 38% in 2011, with the highest prevalence in central and west African regions (56%) and the lowest in high-income regions (22%).¹³ Pregnancy is thought to require 1 g of additional iron because of the increase in red cell mass (450 mg), fetal growth (225 mg), placental development (80 mg), and blood losses through a normal vaginal delivery (250 mg).¹⁴ In addition, breastfeeding requires an additional 1 mg day⁻¹. When combined, the impact of the iron deficit resulting from each pregnancy would take 2 yrs of normal dietary iron to correct.¹⁴ It is therefore easy to understand why ID is the main cause of anaemia in pregnancy, but it is difficult to assess the direct effect of ID and IDA on pregnancy, as most studies are retrospective and subject to confounding factors. Iron deficiency with or without anaemia has been associated with an increased risk of maternal death, and babies born to mothers with ID have an increased risk of low birthweight and preterm delivery.¹⁵

The WHO advises that iron supplementation be given to all women in pregnancy in regions where the incidence of anaemia is >40%. This is controversial, as ID may be protective against malaria. In the UK, the British Society for Haematology and National Institute for Health and Care Excellence (NICE) guidelines recommend starting oral iron in microcytic or normocytic anaemia found at routine screening at 28 weeks or at other ad hoc time points during pregnancy. The Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA) consensus statement also advocates checking serum ferritin (SF) routinely in high-risk patients or those whose Hb does not increase with oral iron.¹⁴

Bariatric surgery

Obesity can cause a chronic inflammatory state, stimulating hepcidin production and leading to FID and anaemia. The prevalence of anaemia and ID in patients with morbid obesity are around 14% and 28%, respectively.¹⁶ Bariatric surgery and the ensuing weight loss often lead ultimately to a reduction in the inflammatory state and recovery from FID. However, in the immediate postoperative period, the incidence of ID and anaemia often increases because:

• (i)Of GI blood loss from surgery
• (ii)Stomach reduction and the use of proton-pump inhibitors mean non-haem ferric (Fe³⁺) cannot be reduced effectively and absorbed by duodenal enterocytes
• (ii)Gastric bypass delays the interaction between food and the biliopancreatic juices and haem release from myoglobin and haemoglobin is impaired.
• (iii)The principal sites of iron absorption in the duodenum and proximal jejunum are often bypassed¹⁶

Cancer surgery

Anaemia is reported frequently in patients presenting for cancer surgery. The European Cancer Anaemia Survey in 2004 reported on data from 14,520 patients with cancer from 24 countries. With a definition of anaemia of Hb <120 g L⁻¹, the incidence of anaemia at enrolment in the study was 39.3% with up to 67% being anaemic at some point during their treatment.¹⁷ The causes of anaemia in this group are multifactorial:

• (i)Chemotherapy
• (ii)Direct effects of cancer on RBC production, destruction, or blood loss
• (iii)CKD with impairment of erythropoietin

In one study, the highest prevalence of anaemia during treatment occurred in patients with gynaecological cancer (81.4%) and lung cancer (77%), and patients undergoing chemotherapy (75%).¹⁷ The incidence of ID varies between patients with different types of cancer, with the highest seen in patients with colorectal cancer (60%), largely as a result of chronic blood loss through the GI tract.¹⁸ Iron deficiency is a common feature of other solid tumour types, being seen in 46% of patients with pancreatic or lung cancer, and often presenting as an FID with normal-to-high ferritin levels.¹⁹ There is a significant correlation between iron status and WHO performance score in cancer, but evidence for improvement with iron supplementation is still awaited.

As iron is an essential requirement for cellular proliferation contributing to tumour initiation and growth, iron metabolism is a target for many chemotherapy agents currently being developed. Iron supplementation in patients with IDA and cancer is recommended by current guidelines from the National Comprehensive Cancer Network.²⁰ There is no evidence from the current literature that administration of i.v. iron to patients with ID over a short period of time has any impact on cancer progression.

How to investigate ID

Iron-deficiency anaemia is one of the commonest reasons for referral to the gastroenterology clinic. Where a diet is considered adequate, IDA should be assumed to be a result of blood (or haem) loss until proved otherwise. The British Society of Gastroenterology published guidelines for the management of IDA in 2011; these are widely available, and readers are directed to them for further information.²¹ Investigations should always be targeted to the potential cause for the iron loss. The hallmark blood test for ID is the SF; when low, it is almost always reflective of low iron stores. Stores can be low (typically when SF decreases to <30 μg L⁻¹) without anaemia, but once SF is generally below 12 μg L⁻¹ further iron loss is associated with the development of IDA.²²

Tests for ID: what do they assess?

A major problem with the reliance upon SF is that it acts as an acute-phase reactant. When SF is low, there is absolute ID. However, iron deficiency can be present with a normal SF, for example, when inflammation or infection is present. In essence, this is because the ferritin leakage from cells (particularly macrophages) is no longer proportionally reflective of the iron content of the stores. In addition, hepcidin also limits the iron influx to the developing RBCs. The clinical utility of serum hepcidin levels is currently unknown.

Performing blood tests of inflammatory markers alongside SF, such as C-reactive protein, erythrocyte sedimentation rate, or plasma viscosity, may indicate that SF is no longer reliable. Another approach is to evaluate iron in the RBC population. The mean cell Hb, when low, indicates an issue either with globin (such as thalassaemia) or iron restriction because of absolute ID or FID. A low mean corpuscular volume can be viewed in much the same way but may be affected more adversely by prolonged storage at room temperature, and its value may depend upon the analytical platform used.

Iron studies, such as Tsat%, serum transferrin, iron, and total iron binding capacity, are often advocated, but their use in patients with CKD was shown to be inferior to red cell markers in the 2015 NICE Anaemia in CKD appraisal when predicting responses to i.v. iron.²³ Tsat% essentially offers a measure of trafficking iron, but its value fluctuates depending on recent dietary iron intake.

Red cell markers represent either the percentage of hypochromic red cells (%hypo or %HRC) or how much Hb the early red cells contain by using reticulocyte Hb content (designated mean reticulocyte Hb content, reticulocyte Hb equivalent, and mean cell Hb reticulocyte count [MCHr] on analysers produced by Siemens, Sysmex, and Abbott, respectively). These tests show how iron is being used by the bone marrow. High %hypo or low reticulocyte Hb in non-thalassaemia-carrying persons indicates iron restriction. Reticulocyte Hb (retic Hb) measurements are often preferred, as they are less affected by the transport time of samples. Cut-off values indicative of ID are shown in Table 1.

Table 1.

Reference values and interpretation of tests commonly used to investigate iron deficiency and iron-deficiency anaemia. CHr, mean reticulocyte Hb content; CKD, chronic kidney disease; MCHr, mean cellular Hb content of reticulocytes; Ret-He, reticulocyte Hb equivalent; Tsat%, transferrin saturation. *CHr, MCHr, and Ret-He all measure the content of Hb in reticulocytes, but analyser manufacturers use different terms. Threshold values shown for these only apply if carriage of thalassaemia is not present. Carriage of thalassaemia also causes a low value (in which case a combination of serum ferritin and Tsat% should be used).

Test	Hb	Serum ferritin	Tsat%	CHr*	MCHr*	Ret-He*
Result suggests iron restriction	<130 g L−1 (males); <120 g L−1 (females) indicates anaemia	≤12 μg L−1; with <30 μg L−1 suggesting stores are low	<20% (patients with CKD); <16% (patients without CKD)	<29 pg	<27.6 pg	<29 pg

When to order tests

The earlier that iron restriction is diagnosed, the better chance that it can be corrected before surgery. The 2016 NICE guidance on routine preoperative tests for elective surgery does not recommend measuring full blood count (FBC) for minor surgery or patients of ASA grade 1 or 2 undergoing ‘intermediate’ surgery. FBC measurement is recommended for all major or complex testing.²⁴ Taking this further, the 2017 international consensus statement on the perioperative management of anaemia and ID suggests a full laboratory work-up should be undertaken if the risk of transfusion is >10% or the estimated blood loss is >500 ml with a target Hb for both males and females of 130 g L⁻¹.²⁵

Treatment modalities

The primary aim of treatment must be to establish the cause and correct this if possible. Arguably, the best test for iron restriction is whether the patient responds to iron or not. Haemoglobin improvement after 2–4 weeks of iron therapy (with Hb increase of 10–20 g L⁻¹, respectively) may suggest absolute IDA. Once the IDA is no longer present, continuing therapy for a further 3 months to rebuild stores is advised.

Ferrous sulphate 200 mg once or twice daily would be the advisable starting dose if tolerated. In the elderly and pregnant patients, lower doses of 15 and 100 mg day⁻¹, respectively, have been shown to be efficacious with fewer adverse GI effects. However, there is little evidence that one oral preparation is better than any other, although oral ferric compounds may be better tolerated. For those who are truly intolerant of oral iron or there is (i) evidence of FID or (ii) a short interval before surgery, i.v. iron is suggested. The international consensus statement on the perioperative management of anaemia and ID recommends i.v. iron be used as front-line treatment when surgery is planned for <6 weeks.²⁵

Patients with CKD may respond to iron supplementation even if their SF is markedly raised. In patients without CKD, it would not be advised to give i.v. iron if the SF is significantly above the upper limit of normal. Our own algorithm (where there is a very low local carriage of thalassaemia) allows for iron supplementation where the SF is below the upper limit of normal with a low retic Hb.

I.V. iron formulations: dosing strategies and how to assess response

There are a number of i.v. iron formulations available. These are the total dose iron infusions, such as Ferinject®, Monofer®, and CosmoFer®, and low-dose infusions, such as Venofer®. Adverse-effect profile, duration of administration, and cost play a role in the choice of formulation used. Ferinject and Monofer have the advantage of being given via a short-duration infusion. In significant anaemia and body weights above 70 kg, Ferinject doses, for example, need to be split over 2 weeks, with a maximum dose of 1,000 mg in one single dose. A response can be considered to occur if the Hb increases by 10 g L⁻¹ or more after 2 weeks. The algorithm used in our institution based on ferritin and MCHr levels is shown in Figure 2. An example of an algorithm based on Tsat% can be found in the international consensus statement on the perioperative management of anaemia and ID.²⁵

Fig 2.

Local algorithm for optimisation of preoperative iron deficiency. This is the algorithm used at University Hospitals Plymouth to guide the diagnosis and treatment of IDA in patients presenting to the preoperative assessment clinic. In patients less than 6 weeks before the scheduled date of surgery, there will be insufficient time to build up stores: give i.v. iron instead, as this reduces the chances of needing blood transfusion more so than oral iron. Patients with macrocytosis and increased ferritin >300 are not suitable for this pathway and should be discussed with the surgeon or anaesthetist. Patients with macrocytosis should have serum B12 and folate checked alongside Liver function tests (LFTs). Patients with estimated Glomerular filtration rate (eGFR) <30 ml min⁻¹ should be discussed with a nephrologist. Patients in whom carriage of haemoglobinopathy cannot be excluded; use transferrin saturation <20% in the place of MCHr below cut-off values.

Adverse effects/contraindications of iron therapy

Oral iron is often poorly tolerated, with around 50% of persons suffering some adverse GI effects. Much of this intolerance may be associated with using too high an initial dose with unabsorbed iron entering the colon. Reducing the dose to 100 mg daily or alternate day dosing may help to reduce this.

With i.v. iron preparations, the ease of administration of the high-dose iron sugars, such as Ferinject (ferric carboxymaltose) and Monofer (ferric isomaltoside), would generally be preferred over the iron dextrans (CosmoFer). Whilst the costs of these preparations are higher, the infusion duration, and therefore, hospital stay are significantly lower.

All i.v. iron preparations are associated with the possibility of hypersensitivity reactions and should be administered in a healthcare setting with appropriate monitoring and resuscitation facilities. Hypersensitivity reactions are thought to less frequent with newer preparations, such as Ferinject and Monofer, with a recent evaluation study suggesting rates of <10 per 100,000.²⁶ All preparations can cause staining of the skin if extravasation occurs during infusion. Care should be taken to ensure that the cannula is correctly sited in a vein before infusion occurs, and patients counselled on risks during consent.

Contraindications to i.v. iron infusion are iron overload, the presence of disorders of iron utilisation, and known hypersensitivity to any parenteral preparations. The European Medicines Agency advises against i.v. iron administration during the first trimester of pregnancy.²⁷

Physicians should be aware of the risk of hypophosphataemia (usually asymptomatic) with i.v. irons, particularly ferric carboxymaltose.

Whilst i.v. iron administration has associated risks, the European Medicines Agency concluded that its benefits outweigh these risks in the context of treating ID.²⁷

Declaration of Interest

The authors declare that they have no conflicts of interest.

MCQs

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Biographies

Stuart Cleland BSc FRCA is a consultant in anaesthesia with clinical interests in upper gastrointestinal, hepatobiliary, and obstetric anaesthesia, and the preoperative assessment and optimisation of high-risk patients. He chairs his hospital's transfusion committee, and is the departmental lead for the management of perioperative anaemia.

Wayne Thomas BSc (Hons) MRCP FRCPath is a consultant haematologist with a subspecialty interest in haemostasis, thrombosis, and iron deficiency. He is the laboratory lead for general haematology for his Trust, and clinical lead for blood transfusion. He is ex-chairman of the British Society of Haematology general haematology guidelines committee, and chairman of the UKNEGAS steering committee for haematology.

Matrix codes: 1A01, 1A02, 2A03, 3G00