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Iron is an essential nutrient and a constituent of ferroproteins and enzymes crucial for human life. Generally, nonmenstruating individuals preserve iron very efficiently, losing less than 0.1% of their body iron content each day, an amount that is replaced through dietary iron absorption. Most of the iron is in the hemoglobin (Hb) of red blood cells (RBCs); thus, blood loss is the most common cause of acute iron depletion and anemia worldwide, and reduced hemoglobin synthesis and anemia are the most common consequences of low plasma iron concentrations. The term iron deficiency (ID) refers to the reduction of total body iron stores due to impaired nutrition, reduced absorption secondary to gastrointestinal conditions, increased blood loss, and increased needs as in pregnancy. Iron deficiency anemia (IDA) is defined as low Hb or hematocrit associated with microcytic and hypochromic erythrocytes and low RBC count due to iron deficiency. IDA most commonly affects women of reproductive age, the developing fetus, children, patients with chronic and inflammatory diseases, and the elderly. IDA is the most frequent hematological disorder in children, with an incidence in industrialized countries of 20.1% between 0 and 4 years of age and 5.9% between 5 and 14 years (39% and 48.1% in developing countries). The diagnosis, management, and treatment of patients with ID and IDA change depending on age and gender and during pregnancy. We herein summarize what is known about the diagnosis, treatment, and prevention of ID and IDA and formulate a specific set of recommendations on this topic

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UCLAUCLA Previously Published WorksTitleRecommendations for diagnosis, treatment, and prevention of iron deficiency and iron deficiency anemia.Permalinkhttps://escholarship.org/uc/item/3h08z6p1JournalHemaSphere, 8(7)AuthorsIolascon, AchilleAndolfo, ImmacolataRusso, Robertaet al.Publication Date2024-07-01DOI10.1002/hem3.108 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaReceived: 5 January 2024 | Accepted: 27 May 2024DOI: 10.1002/hem3.108GU I D E L I N E S ‐ CON S EN SU S ‐BA S EDRecommendations for diagnosis, treatment, and preventionof iron deficiency and iron deficiency anemiaAchille Iolascon1,2 | Immacolata Andolfo1,2 | Roberta Russo1,2 |Mayka Sanchez3 | Fabiana Busti4 | Dorine Swinkels5 | Patricia Aguilar Martinez6 |Rayan Bou‐Fakhredin7 | Martina U. Muckenthaler8,9,10 | Sule Unal11 |Graça Porto12 | Tomas Ganz13 | Antonis Kattamis14 | Lucia De Franceschi15 |Maria Domenica Cappellini16 | Malcolm G. Munro17 | Ali Taher18 | from EHA‐SWGRed Cell and IronCorrespondence: Achille Iolascon (achille.iolascon@unina.it); Immacolata Andolfo (immacolata.andolfo@unina.it)AbstractIron is an essential nutrient and a constituent of ferroproteins and enzymes crucial for human life. Generally, nonmenstruatingindividuals preserve iron very efficiently, losing less than 0.1% of their body iron content each day, an amount that is replacedthrough dietary iron absorption. Most of the iron is in the hemoglobin (Hb) of red blood cells (RBCs); thus, blood loss is the mostcommon cause of acute iron depletion and anemia worldwide, and reduced hemoglobin synthesis and anemia are the mostcommon consequences of low plasma iron concentrations. The term iron deficiency (ID) refers to the reduction of total body ironstores due to impaired nutrition, reduced absorption secondary to gastrointestinal conditions, increased blood loss, and increasedneeds as in pregnancy. Iron deficiency anemia (IDA) is defined as low Hb or hematocrit associated with microcytic and hypo-chromic erythrocytes and low RBC count due to iron deficiency. IDA most commonly affects women of reproductive age, thedeveloping fetus, children, patients with chronic and inflammatory diseases, and the elderly. IDA is the most frequent hema-tological disorder in children, with an incidence in industrialized countries of 20.1% between 0 and 4 years of age and 5.9%between 5 and 14 years (39% and 48.1% in developing countries). The diagnosis, management, and treatment of patients with IDand IDA change depending on age and gender and during pregnancy. We herein summarize what is known about the diagnosis,treatment, and prevention of ID and IDA and formulate a specific set of recommendations on this topic.HemaSphere. 2024;8:e108. hemaspherejournal.com | 1 of 16https://doi.org/10.1002/hem3.108This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in anymedium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.1Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universitàdegli Studi di Napoli Federico II, Napoli, Italy2CEINGE Biotecnologie Avanzate Franco Salvatore, Napoli, Italy3Department of Basic Sciences, Iron metabolism: Regulation and Diseases,Universitat Internacional de Catalunya (UIC), Barcelona, Spain4Department of Medicine, Section of Internal Medicine and AziendaOspedaliera Universitaria Integrata of Verona, EuroBloodNEt ReferralCenter for Iron Disorders, Policlinico G.B. Rossi, University of Verona,Verona, Italy5Department of Laboratory Medicine, Translational Metabolic Laboratory (TML830), Radboud University Medical Center, Nijmegen, The Netherlands6Department of Hematological Biology, Reference Center on Rare Red CellDisorders, Montpellier University Hospital, Montpellier, France7Department of Clinical Sciences and Community Health, University of Milan,Milan, Italy8Molecular Medicine Partnership Unit, European Molecular Biology Laboratory,Heidelberg, Germany9Translational Lung Research Center Heidelberg (TLRC), German Center forLung Research (DZL), University of Heidelberg, Heidelberg, Germany10German Centre for Cardiovascular Research, Partner Site, Heidelberg,Germany11Department of Pediatric Hematology, Hacettepe University, Ankara,Turkey12HematologyServiço de Imuno‐hemoterapia, CHUdSA‐Centro HospitalarUniversitário de Santo António, Porto, Portugal13Department of Medicine, David Geffen School of Medicine at UCLA, LosAngeles, California, USA14Division of Pediatric Hematology‐Oncology, First Department of Pediatrics,National & Kapodistrian University of Athens, “Aghia Sophia” Children'sHospital, Athens, Greece15Department of Medicine, University of Verona & AOUI Verona, Policlinico GBRossi, Verona, Italy16Department of Clinical Sciences and Community, University of Milan, CàGranda Foundation IRCCS Maggiore Policlinico Hospital, Milan, ItalyINTRODUCTIONIron is an essential nutrient and a constituent of ferroproteins andenzymes that are crucial for human life. Generally, nonmenstruatingindividuals preserve iron very efficiently, losing less than 0.1% of theirbody iron content each day, an amount that is replaced throughdietary iron absorption. Most of the iron is in the hemoglobin (Hb) ofred blood cells (RBCs); thus, blood loss is the main cause of irondeficiency (ID) worldwide, and reduced hemoglobin synthesis andanemia are the most common consequences of low plasma ironconcentrations. Severe ID can also affect the synthesis of ferropro-teins in nonerythroid cell types, causing cellular dysfunction andleading to additional manifestations including epithelial changes innails, tongue, and esophagus, deficits in cognitive function and muscleperformance, and impaired adaptive immune response.1The term ID refers to the reduction of total body iron storesdue to (a) decreased iron intake because of impaired nutrition, reducedabsorption secondary to gastrointestinal diseases, and use of protonpump inhibitors, (b) increased utilization (e.g., pregnancy), or (c) increasediron losses, usually because of bleeding. Heavy menstrual bleeding(HMB) in women is defined as the regular loss of more than 80mlof blood during a menstrual period, exceeding iron intake, and isconsidered the most common cause of iron deficiency (ID). Absolute IDoccurs when total body iron stores are insufficient to meet the needs ofthe individual. In functional ID, total body iron is preserved but iron ismaldistributed. Functional ID is explained by reduced iron export viaferroportin, which is controlled by hepcidin‐dependent and independentmechanisms in response to inflammation.1 Consequently, iron absorp-tion from the gastrointestinal system is inhibited, and iron is trapped inmacrophages, resulting in reduced circulating iron levels.2 Iron deficiencycan lead to chronic fatigue, poor concentration, impaired exercise per-formance, and poor quality of life.3 As ID becomes more severe, it willcause microcytic anemia.3Iron deficiency affects more than 2 billion people worldwide, withiron deficiency anemia (IDA) remaining the main cause of anemia. Inclinical practice, the current oral iron treatments are often inadequatebecause of suboptimal effectiveness and side effects that lead topoor compliance and premature therapy discontinuation. In ID, ironstorage must be severely depleted before anemia occurs since, whilein modest iron stores' reduction, the recycling of iron from thedaily RBC turnover provides sufficient iron for erythropoiesis andhemoglobin production.4IDA is defined as low Hb or hematocrit associated withmicrocytic (low mean corpuscular volume, MCV) and hypochromic(low mean corpuscular hemoglobin, MCH) erythrocytes and low RBCcount.4 IDA most commonly affects children, women of reproductiveage, patients with chronic and inflammatory diseases, and theelderly.4 IDA is the most frequent hematological disorder in children,with an incidence in industrialized countries of 20.1% between 0 and4 years of age and 5.9% between 5 and 14 years (39 and 48.1%in developing countries).4 The response to IDA includes increasedEPO secretion to stimulate erythropoiesis and decreased hepcidinproduction to increase intestinal iron uptake and mobilization ofiron stores.As discussed in the subsequent paragraphs, the diagnosis, man-agement, and treatment of patients with ID and IDA should be tailoredaccording to the age and gender and underlying conditions, like duringpregnancy. We herein summarize what is known about the diagnosis,treatment, and prevention of ID and IDA and formulate a specific set ofrecommendations on this topic.METHODSThe following set of recommendations is based on a systematicliterature search. All published articles in the literature that addressdifferent aspects of ID and IDA, including causes, diagnosis, andtreatment strategies, were identified by PubMed, Online MendelianInheritance in Man, and Textbook search, including all the additionalrelevant references cited in the articles found. The key searchterms “iron deficiency” and “iron deficiency anemia” were used.The examined period was from 1980 to 2022. Conference abstractswere included if deemed to be of relevance. The Grading ofRecommendations Assessment, Development, and Evaluation(GRADE) method was used to evaluate levels of evidence leveland assess the strength of recommendations (Figure 1). The GRADEcriteria can be found at http://www.gradeworkinggroup.org. Thisrecommendation paper was produced in collaboration with theEuropean Hematology Association (EHA), including the Red Cell andIron Specialized Working Group members.DIAGNOSISID and IDA can be diagnosed by evaluating specific hematological andiron biomarkers. In otherwise healthy individuals, ferritin levels reflectiron stores but are rarely informative about actual iron availability forerythropoiesis. For this reason, other parameters such as transferrinsaturation (TSAT), soluble transferrin receptor (sTfR), percentage ofhypochromic erythrocytes (%HYPO), and reticulocyte hemoglobincontent (CHr) are useful to identify an inadequate iron supply toerythropoiesis.A Hb level below the lower limit of normally indicates IDA. Ironstatus can be adequately characterized using multiple complementaryparameters, and its clinical relevance can be assessed.✓ 1a. How is the diagnosis of iron deficiency (ID) or iron deficiencyanemia (IDA) established across different age groups, includingchildren, adolescents, adults, and during pregnancy? Which testsare recommended for diagnosing patients with ID/IDA?Hematological and biochemical markers support the diagnosis ofID/IDA. The absence (in ID) and presence of anemia (in IDA) areconfirmed by Hb concentration, as shown by a complete blood count(CBC). According to the World Health Organization (WHO, 2011),anemia is defined as a Hb level of <130 g/L in men, <120 g/L innonpregnant women, and <110 g/L in both pregnancy and children>5 years. Specific thresholds at various stages of childhood andpregnancy are also commonly used (WHO 2011) (Figures 2 and 3). IDis the most common cause of anemia in pregnancy due to the growingfetus and placenta, and those with untreated ID are unnecessarilyat risk of anemia. Anemia in pregnancy is generally defined as ahemoglobin concentration <110 g/L in the first trimester, <105 g/L inthe second trimester, and <110 g/L in the third trimester. To defineID in pregnancy, there are no standardized serum ferritin thresholds.Ferritin is an acute phase reactant and may be elevated as a result ofpregnancy itself. While a low ferritin invariably indicates ID in thispopulation, a normal ferritin cannot reliably exclude it.The evaluation of the blood smear, which typically showsmicrocytosis, hypochromia, and pencil forms in IDA, is very useful.Additionally, it serves as an important, cost‐effective, and readily avail-able diagnostic tool. It is important to note that microcytosis visible on17Department of Obstetrics and Gynecology, David Geffen School of Medicine,Los Angeles, California, USA18Division of Hematology‐Oncology, Department of Internal Medicine,American University of Beirut Medical Center, Beirut, Lebanon2 of 16 | Recommendations for prevention of ID and IDAF IGURE 1 Recommendations and relative consensus.HemaSphere | 3 of 16the peripheral smear may be detected before abnormalities are evidenton the complete blood cell count.Measuring ferritin, serum iron, and TSAT is a routine method fordiagnosing ID in various conditions. In the absence of inflammation,specifically determined by C‐reactive protein (CRP) and erythrocytesedimentation rate dosage as reliable indicator of infectious and in-flammatory diseases, ferritin is the most accurate biomarker that cor-relates with total body iron stores, and it is the mainstay for diagnosingF IGURE 2 Iron deficiency (ID) diagnosis. Flow chart showing the crucial steps to make a diagnosis of ID.F IGURE 3 Iron deficiency anemia (IDA) diagnosis. Flow chart showing the crucial steps to make a diagnosis of IDA.4 of 16 | Recommendations for prevention of ID and IDAabsolute ID.5 A low serum ferritin concentration is a sensitive indicatorfor ID uncomplicated by other concurrent diseases long before chan-ges are observed in blood Hb concentrations. TheWHO defines ID asserum or plasma ferritin levels <15 ug/L in children older than 5 years,adolescents, and adults and less than 12 ug/L in children younger than5 years (WHO, 2022). Many authors suggested that the diagnosticaccuracy of ferritin could be improved by increasing the cutoff to30μg/L.6–8 Such a value has a higher sensitivity (from 85% to 92%) andunchanged specificity (98%), and it is the most accepted threshold usedto establish a diagnosis of ID, even in the mildest cases.9 However,little evidence is available from high‐quality studies to justify specificthresholds. Published cutoffs are often based on older studies that(i) were conducted without international standards or (ii) use assaysdifferent from those currently used.10,11 Altogether, this confounds theinterpretation of ferritin in clinical practice.The diagnosis of absolute ID is controversial in the elderlypopulation, with high prevalence of comorbidities, in whom theclassical cutoff of ferritin <15–30 μg/L has been claimed as toostringent. In some small studies on older patients, a serum ferritinlevel <45–50 μg/L showed greater reliability in predicting ID thanconventional cutoff values. For this reason, some authors suggestthat ferritin thresholds of at least 45 μg/L, if not 100 μg/L, couldbe reasonable in people aged >65 years, mainly when specificcomorbidities occur, such as advanced chronic kidney disease (CKD)or chronic heart failure (CHF).11–13An important issue in the diagnosis of ID and IDA is the differentialdiagnosis with beta thalassemia carriers. To confirm ID or IDA, trans-ferrin saturation along with ferritin levels are recommended parameters.An increase in red cell distribution width (RDW), reflecting variation inRBC size (anisocytosis), is typical in IDA. In contrast, thalassemia carriersexhibit RDW values within or close to the reference interval due toconsistent red cell size (microcytes). High RBC count relative to thedegree of anemia is typically encountered in thalassemia carriers incontrast to IDA where RBC count is low and commensurate with thedegree of anemia. Blood smear is very useful also in this differentialdiagnosis showing target cells, fine basophilic stippling, nucleated RBCsin thalassemia carriers, and pencil forms in iron deficiency.When ID/IDA is diagnosed, a thorough investigation of etiologyis mandatory, in part because it may reveal underlying causes that arean even greater threat to health than ID/IDA. If the causes can beactively treated, recurrence will be avoided, and long‐term resolutionof ID/IDA will be more likely.1–3✓ 1b. How can iron deficiency (ID) or iron deficiency anemia (IDA)be diagnosed in patients with chronic disease, inflammation, ormalignancy? How should the diagnostic criteria for ID/IDA beadjusted in the presence of inflammation?In patients with functional ID, withholding iron from the plasmapromotes iron‐deficient erythropoiesis and anemia despite adequatebody iron stores.14,15 This process is common in patients withinflammation, malignancy, chronic infections, parasitic infections,such as hookworm infestations, malaria, iatrogenic blood loss fromprocedures, and blood sampling.16 In the developed world, thisdisease is easily identified and treated but frequently overlookedby physicians. In contrast, it is a health problem that affects majorportions of the population in underdeveloped countries; indeed, localeconomics generally dictate the level of nutrition worldwide. Overall,the prevention and successful treatment for iron deficiency anemiaremains woefully insufficient worldwide, especially among under-privileged women and children. ID may be further exacerbated byincreased demand for iron like in patients receiving erythropoiesis‐stimulating agents.16 Particularly in African children, malaria and irondeficiency (ID) are common and interrelated public health issues.Observational data indicate that interrupting malaria transmission canlead to a reduction in the prevalence of ID.4The traditional gold standard test for absolute ID is the finding ofabsent stainable bone marrow iron. Patients with functional ID havedetectable stainable bone marrow iron unless they have concomitantabsolute ID. Bone marrow aspiration is invasive and never doneroutinely to diagnosis ID, but it remains helpful in complex cases.In current practice, ID and IDA are usually diagnosed by bloodbiomarkers. Red cell indices can indicate anemia, microcytic, andhypochromic RBCs with an increased red blood cell distributionwidth (anisocytosis) and elongated (pencil‐shaped) cells.17 It's worthmentioning that in older individuals, there's a common occurrence ofvitamin B12 and folate deficiency, which can cause an increasein MCV, resulting in normocytic anemia. This can make interpretinglaboratory data challenging. Consequently, relying solely on MCVassessment isn't reliable for ruling out iron deficiency anemia in theelderly, particularly if they have accompanying comorbidities.13Because ferritin is an acute‐phase protein, the diagnosis of ID(based on ferritin alone) can be obscured by inflammation.18–20Strategies for adjusting ferritin concentration cutoffs in inflammationinclude raising of the ferritin threshold (WHO, 2020) or developinga regression equation based on the correlation between ferritinand inflammatory markers. When there is evidence of systemicinflammation, such as an increased erythrocyte sedimentation rate orelevated C‐reactive protein levels, the WHO defines ID at a ferritinconcentration of less than 30 µg/L in children under five yearsand less than 70 µg/L in older children and adults (WHO, 2020).Algorithms to correct ferritin for inflammation are not universallyapplicable in part because the changes in markers of inflammationvary with the etiology of inflammation and severity of the underlyingdisease.18,21 Diagnosing absolute ID in patients with inflammation isimportant to identify the underlying factors (such as bleeding) and forpopulation estimates of ID; however, treatment approaches shouldalso consider coexistent functional ID. Ferritin concentrations canalso increase in liver disease, including nonalcoholic fatty liverdisease.22 Moreover epidemiological data suggest that populationferritin concentrations are increasing with increasing obesity rates.17Serum iron concentration is reduced in ID and inflammation;hypoferremia alone does not indicate absolute ID. Transferrinsaturation (e.g., less than 15% in adult and less than 7% in pediatricsubjects) helps define low plasma iron availability to tissues inboth absolute and functional ID in adult subjects. Soluble transferrinreceptor (sTfR) is an index of tissue iron needs and of erythropoieticactivity. The sTfR:log(ferritin) ratio has been a useful predictiveindex for bone marrow iron stores, especially in patients withinflammation.23 Its utility is limited by low clinical availability anddifferent thresholds between sTfR assays.24Several modern automated hematology analyzers can measurereticulocyte‐specific hemoglobin content and related indices.25 Thepercentage of hypochromic red blood cells (%HYPO RBC) reflectsiron‐restricted erythropoiesis during the preceding 2–3 months.26The reticulocyte hemoglobin content (CHr) reflects iron availabilityfor erythropoiesis of the previous 3–4 days before testing.27 Bothparameters are useful to detect iron‐restricted erythropoiesis due toabsolute or functional ID and evaluate response to therapy.28,29Measurement of hepcidin concentration is under investigation as atest for ID and for distinguishing absolute from functional ID.30 Hep-cidin concentration has been studied in pregnant and nonpregnantwomen, in children, and in patients with rheumatoid arthritis,inflammatory bowel disease, cancer‐related anemia, or critical illness.30Suppressed hepcidin concentrations indicate a physiological iron need,predict responsiveness to iron, and enable personalization of the routeHemaSphere | 5 of 16of iron replenishment.31 In the absence of inflammation, the hepcidin/TSAT ratio has been proven to be an effective tool to identify patientswith iron‐refractory iron deficiency anemia (IRIDA) due to variants inthe TMPRSS6 gene among patients with chronic IDA.32,33 Measurementof hepcidin is limited primarily to research settings and rarely usedin the clinical setting in some European hospital laboratories. Usingcommutable calibration materials with human plasma or serum willallow for a standardization methodology that is essential to enableroutine clinical hepcidin testing.34Iron deficiency is the presenting manifestation of various pa-thological processes, and investigation to exclude serious pathologyand define the underlying cause is essential. Serological testing forcoeliac disease should be considered in patients with nonanemic IDand is recommended for all adult patients with IDA.35 Men andpostmenopausal women with IDA are at high risk of bleeding gas-trointestinal lesions and should be considered for upper and lowergastrointestinal endoscopy.36 Assessment for autoimmune gastritisand H. pylori should be considered in all patients with ID or IDA,especially in those who do not adequately respond to oral iron.4Furthermore, it's crucial to consider the involvement of gut bacteriaand their interactions with the host in shaping iron acquisition. Bacterialactivities impact the host's iron absorption, whereas the host's ironintake and levels affect the composition and function of gut bacteria,thereby influencing their virulence. Alterations in the host's innateimmune system and circulating factors such as hepcidin, lipocalin 2, andlactoferrin are associated with metabolic disorders occurring at theinterface between the host and the microbiota.37Premenopausal women with IDA should be considered forbidirectional endoscopy if they have symptoms of gastrointestinaldisease (e.g., altered bowel habit or overt bleeding), a personal historyor a first‐degree relative with a history of colorectal cancer, or if theydo not have a clear explanation for ID, such as HMB.37 Fecal occultblood testing should not be used to suggest endoscopy in patientswith ID. CT colonography can be considered when colonoscopy iscontraindicated but does not have the sensitivity for smaller mucosallesions (less than 6mm) and does not permit biopsy or polypectomy.Endoscopy is not recommended as a routine procedure in patients withnonanemic ID unless there are other concerns for gastrointestinalmalignancy or if ID is recurrent.37 If upper and lower endoscopicstudies exclude substantial pathology, it is reasonable to withholdfurther gastrointestinal investigation unless there is recurrent,refractory, or severe IDA.35 Small intestinal investigation can beaccomplished by video capsule endoscopy (a noninvasive imagingapproach) or enteroscopy (an endoscopic approach enabling tissuesampling and therapeutic maneuvers).For reproductive‐aged women, the most common causes of IDand IDA are the symptoms of HMB and unreplenished losses fromprevious pregnancy.36,38,39 As discussed previously, HMB has a pre-valence much higher than that generally perceived from healthcaresystem‐based data; survey‐based studies indicate that up to 53% ofwomen of reproductive age may experience the symptom at anygiven time putting them at high risk for ID and IDA.40‐44 This risk isexemplified by evaluating iron‐dependent erythropoiesis in womenwith and without HMB,2 and a Finnish study of women with HMBshowed that 27% of its participants had IDA, 90% with a serumferritin less than 30 µg/L, and 60% with serum ferritin levels below15 µg/L.45 Effective diagnostic and therapeutic strategies exist forthe varying causes of the symptoms of HMB46,47; failure to identifyand address this issue will prolong or even prevent the sustainednormalization of iron stores. Moreover, it is of importance to screenfemales experiencing HMB and recurrent or refractory IDA withoututerine organic lesions for congenital bleeding disorders (CBDs) suchas platelet function disorders and von Willebrand disease (VWD).CBDs are present in approximately 20%–30% of females with HMBand can result in unnecessary hysterectomy.Recommendation 1The diagnosis of ID/IDA is based on evaluating several hematological andbiochemical markers, such as Hb, ferritin, and TSAT levels. The cutoff for eachspecific marker is based on age, sex, and pregnancy status (cutoff for Hb: menHb≥130 g/L; nonpregnant women≥120 g/L; pregnant women ≥110 g/L;and children <5 yrs≥110 g/L). In the absence of inflammation, ferritin is themost specific marker correlating with total body iron stores (cutoff forserum ferritin: adults, adolescents, children>5 yrs < 30 ug/L; children<5 yrs< 12 ug/L). In the context of multiple comorbidities, such as inflammation,ferritin thresholds<100 μg/L or higher values are suggested in combinationwithTSAT. In elderly patients (>65 years) with chronic kidney disease (CKD) orchronic heart failure (CHF), ferritin thresholds of at least 45μg/L can be used.The evaluation of individuals identified with ID/IDA should also consider thereason for the deficiency, with concomitant investigation and treatmentappropriate for identified causes or contributors.CLINICAL MANIFESTATIONS✓ 2.a What are the common clinical manifestations of ID/IDA?ID refers to iron deficiency without affecting hematopoiesis.Therefore, neither hemoglobin, MCV, nor MCH are abnormal.48 Becauseanemia is a very late consequence of ID, iron deprivation can also affectvarious cellular processes, including myoglobin synthesis (skeletal muscleand cardiomyocytes), DNA synthesis, mitochondrial respiration, heme,and nonhemic enzyme synthesis. In addition to serum ferritin, TSAT isrecommended as a marker to identify ID,49 particularly in chronicinflammatory conditions. Zinc protoporphyrin,48 sTFR, hepcidin, CHr,and %HYPO RBC can be used alternatively, although not widely avail-able.23 Invasive determination of bone marrow iron content should bereserved for rare situations. ID has been described in differentage groups or disease conditions. Typically, these populations involveindividuals whose dietary iron intake does not meet their needs(Table 1). Patients at risk of developing ID should be screened. Identi-fying these patients early, before developing IDA would prevent thedevelopment of severe complications. In adults with ID, iron supple-mentation is associated with a reduction in self‐reported fatigue but notwith objective measures of physical capacity, despite a significantincrease in hemoglobin concentration.50 In children and adolescents,TABLE 1 Target population and causes of iron deficiency (ID).• Children and adolescents, in whom there is an increased need for ironespecially during growth spurt.• Premature infants.• Athletes, vegetarians, and regular blood donors.• Any menstruating girl or woman of reproductive age, including, but not limitedto, those planning pregnancy.• In pregnancy, ID should be identified and treated as early as possible in the firsttrimester as it frequently evolves into IDA.• Elderly patients, especially those suffering from chronic disorders, such asheart failure with reduced ejection fraction, chronic kidney disease, or impaireddigestive absorption.• Patients with chronic bleeding diathesis (e.g., Von Willebrand disease orhemophilia carriers).• Patients on chronic therapy with anticoagulants, anti‐inflammatory drugs,antiplatelet drugs, or proton pump inhibitors.• Patients with a history of gastric surgery (for medical reasons, including obesity).• Patients with chronic infections, parasitic infections (e.g., hookworminfestations), and socioeconomically disadvantaged.6 of 16 | Recommendations for prevention of ID and IDAoral iron positively impacted intelligence test scoring and correlatedwith dosage but did not significantly affect attention, short‐termmemory, long‐term memory, or school performance.51 Iron deficiency,diagnosed in early pregnancy, typically reflects ID before conception, acircumstance that poses risks to the mother and the developing fetus.A recent Cochrane review concluded that current evidence isinsufficient to demonstrate the benefit of intravenous (IV) iron pre-parations for treating nonanemic ID in various patient populations.52However, in some indications, particularly heart failure with reducedejection fraction, iron replacement therapy (particularly IV) is in-dicated even in the absence of anemia.53 As for IDA, the underlyingcause of ID should always be sought and managed. Biofortificationof food has been proposed in several countries and for differenttarget populations to prevent ID, including its nonanemic form, and isempirically recommended in guidelines despite the lack of a universalconsensus.50,51Iron deficiency can cause symptoms both in the presence andabsence of anemia. Because many of its symptoms can be nonspecific,physicians and patients do not always recognize that ID/IDA is present.Subsequently, a diagnosis is not made, and the condition is leftuntreated and is thus further exacerbated.17,54,55 Common signsand symptoms of ID/IDA include fatigue, lethargy, chills, dizziness,dyspnea, tinnitus, pallor, heart palpitations, restless legs syndrome, andheadache.17,54,55 Other presentations commonly seen in these patientsinclude alopecia, dry hair or skin, koilonychia, and atrophic glossitis.The relevance of ID identified in early pregnancy lies in its frequentprogression to IDA due to increasing maternal and fetal iron require-ments as gestation progresses. Recent evidence suggests that theseeffects are most significant when IDA is diagnosed in the first trimesterrather than the third.56,57 Neonates born to women with ID and IDA arethemselves iron deficient, with ongoing risks of cognitive impairmentand delayed motor and cognitive development.56,57 However, controlledstudies on the consequences of ID in children are scarce, with mostconducted in low‐income countries where unfavorable socioeconomicconditions may also impair cognitive development. Therefore, the effi-cacy of routine antenatal iron supplementation on offspring neurode-velopment remains uncertain. Indeed, the physiological requirement foriron during the period of rapid and critical brain development in younginfants should be carefully evaluated, considering the risks associatedwith supplementing nonanemic infants with high iron levels.In adults, ID is associated with decreased physical performanceand quality of life; in the elderly, it is often associated with cognitivedecline.58,59 Moreover, several medical and chronic inflammatoryconditions, including heart failure, ischemic heart disease, inflammatorybowel disease, and chronic kidney disease, can be further exacerbatedwhen ID/IDA is present, thus worsening the prognosis and impairingthe overall quality of life.60‐67 This is particularly evident in elderlypatients who suffer from multiple morbidities, whereby even mildanemia can increase the chance of mortality.68Moreover, pica that refers to the craving or consumption ofnonfood items, such as dirt, clay, or ice, is considered anothersymptom of ID and IDA, particularly in young children and pregnantAfrican women. This unusual eating behavior can sometimes be amanifestation of the body's attempt to obtain missing nutrients, in-cluding iron, although the exact cause of pica is not fully understood.In the context of ID and IDA, pica may be an indicator of severe IDand should prompt further evaluation and treatment.Recommendation 2.aCommon symptoms and signs of ID and IDA to evaluate are fatigue,lethargy, chills, dizziness, dyspnea, tinnitus, pallor, heart palpitations,restless legs syndrome, and headache. Other presentations to assessinclude alopecia, dry hair or skin, koilonychia, and atrophic glossitis. Inchildren with ID, it is also important to analyze the motor and cognitivedevelopment. In adults, ID is associated with decreased physical performanceand quality of life; in the elderly, it is often related to cognitive decline.✓ 2.b What is the significance of maternal ID/IDA during preg-nancy, at the time of delivery, and postpartum?The maternal consequences of ID/IDA may manifest duringpregnancy, at the time of delivery, or during the postpartum periodand may or may not include any signs and symptoms.69 Commonpregnancy symptoms often overlap with ID/IDA symptoms and canthus prevent the recognition of anemia, thus increasing the risk ofmaternal morbidity and mortality.70 In a recent systematic review,maternal IDA was associated with a significantly increased risk ofcesarean delivery, postpartum anemia, and blood transfusion.71Maternal consequences of ID/IDA also include abnormal thyroidfunction, placental abruption, pre‐eclampsia, and eclampsia.72‐74Studies have also identified anemia as a significant risk factorfor postpartum hemorrhage.75‐77 In fact, one study showed that therisk of death for women who experience a postpartum hemorrhageis almost seven‐fold higher if they are anemic at the onset ofpregnancy.78Iron deficiency anemia in pregnancy may also adversely impact thefetus, resulting in an increased risk of prematurity, low birth weight,physical developmental delay, and morbidity.79‐80 These infants alsoshow an increased risk of developing neurocognitive developmentaldysfunctions such as reduced recognition, difficulty processing,and slower processing speed, as well as neurological disorders suchas autism spectrum disorder, attention deficit disorder, and otherintellectual disabilities.38,81‐83 These impacts should be seen aspermanent as available evidence reveals their effects persist throughthe third decade of life.36 It is apparent that the fetal vulnerability tothe adverse impacts of ID is greatest in the first trimester of pregnancyand that these associated neurocognitive disorders persist into adultlife. Considering these risks, identification and appropriate treatment ofID in women before conception becomes imperative.Maternal or prepartum IDA and excessive blood loss at deliveryare the leading causes of postpartum anemia.73,84,85 Reduced milkproduction and resultant shortening of lactation periods are alsocharacteristic of ID/IDA during the postpartum period. The emotionalwell‐being of postpartum women with IDA can also be seriouslyaffected, with an increased risk of postpartum anxiety and depressionand a decreased quality of life.85,86Recommendation 2.bIn periconceptual and pregnancy‐related ID/IDA, it is crucial to evaluatethe possible fetal developmental delay and neurocognitive disorders inthe newborn. ID and IDA are also linked to increased risks of thyroiddysfunction, preterm labor, placental abruption, pre‐eclampsia, eclamp-sia, cesarean delivery, postpartum anemia, and blood transfusion. Pre-conceptual normalization of iron status and prompt, effective treatmentof IDA identified during pregnancy or postpartum should be urgentpriorities for healthcare delivery systems.THERAPY/MANAGEMENT✓ 3.1 What oral/IV iron formulations are available? What arethe advantages and disadvantages of oral versus IV? How is theiron made available from these formulations for systemic use?HemaSphere | 7 of 16Are some formulations preferred compared to others in differentclinical settings? What are the potential side effects?During absolute ID empty liver iron stores and low transferrinsaturation are regulatory signals that reduce the mRNA expression ofthe iron‐regulated hormone hepcidin. Consequently, iron export fromduodenal enterocytes increases, promoting the uptake of dietary ironand supplemented oral iron into the bloodstream. Although ferrousiron preparations are better absorbed than ferric iron preparationsbecause of the low solubility of ferric iron and the physiology of ironabsorption, ferrous iron is more irritating to mucosal surfaces and lesswell tolerated by patients than ferric iron, prompting a resurgence ofinterest in ferric iron therapy. The absorption of iron includes hemeiron sourced from animal‐based foods and nonheme iron found inplant‐based foods and supplements. Heme iron, which is abundant inmeats, poultry, and seafood, is absorbed more efficiently and hasgreater bioavailability compared to nonheme iron. Iron is mainlyavailable as ferric iron and must be reduced by the ferrireductasedCytb to be transported into the duodenal enterocyte via the divalentmetal transporter (DMT1). Iron is exported from the enterocyte viaferroportin. Likewise, low hepcidin levels enable efficient ferroportin‐mediated iron export from macrophages that recycle iron fromsenescent red blood cells and efficiently phagocytose and digestparenteral iron products.87Oral iron products are well established in the clinic and includeferrous salts; other iron salts include ferrous fumarate, glycinesulfate, bisglycinate, ascorbate, carbonate, tartrate, iodine, chloride,sodium citrate, aspartate. or succinate (Table 2). Oral iron is widelyavailable, inexpensive, and safe. However, nonadherence to therapyis considered one of the most significant causes of nonresponse orrecurrence of ID during iron replacement therapy. Main adverseevents include abdominal pain, constipation, nausea, vomiting, anddiarrhea.88 More recently, novel oral therapies with improvedabsorption properties and lesser gastrointestinal side effects havebeen found on the market. These are generally carriers bound toferric iron, such as ferric maltol (now approved for the treatment ofIDA in Europe and the USA); sucrosomial iron (assessed in patientswith cancer, kidney disease, and inflammatory bowel disease); ironhydroxide adipate tartrate, a medication currently being tested inchildren in developing countries; or ferric citrate.89‐93 Treatmentof ID has changed by the availability of iron preparations that areapplied intravenously. These circumvent the gastrointestinal issuesexperienced with oral iron preparations and can be used in higherdoses. IV iron preparations consist of a carbohydrate shell with aniron core at its center. Iron sucrose or iron gluconate consists of lessstable shells, which limits the amount of iron that can be infused.More stable shells that hallmark ferumoxytol, ferric carboxymaltose,and ferric derisomaltose release iron slowly, thus permitting theadministration of higher iron doses. Avni et al. performed a sys-tematic review of clinical trials testing parenteral iron formulationsand concluded that serious adverse side effects, severe infusionreactions, or a higher prevalence of infections are rare.92 Of note,IV administration of ferric carboxymaltose may cause hypopho-sphatemia due to increased FGF23 levels that induce phosphaturia,although it can be observed at lower frequency, also during treat-ment with other IV iron preparations. Hypophosphatemia is usuallyof short duration (8–10 weeks), but severe cases have been re-ported after chronic treatment.94,95 Importantly, parenteral ironshould not be applied in patients with sepsis as bacterial growth maybe stimulated.Generally, oral iron is the first line treatment in uncomplicatedcases of ID. Parenteral iron is applied in cases of moderate to severeanemia, when the response to oral iron is poor, in patients intolerantto oral iron, or when a rapid response to iron is required (e.g., in theperioperative setting). The administration of IV iron is more efficientin improving Hb values.95 Higher costs of IV iron formulations are aclear disadvantage compared to oral preparations.Recommendation 3.aThe treatment of ID and IDA comprises both oral iron formulations andIV iron preparations. Oral iron formulations include ferrous salts, such asferrous sulfate or iron polymaltose. However, patient compliance is poordue to gastrointestinal adverse events, such as constipation, nausea, anddiarrhea. More recently, novel oral therapies with improved absorptionproperties and lesser gastrointestinal side effects have reached themarket, such as sucrosomial iron (assessed in patients with cancer, kidneydisease, and inflammatory bowel disease) iron hydroxide adipate tartrate,a medication currently being tested in children in developing countries, orferric citrate (mainly used in patients with chronic kidney disease where italso functions as a phosphate binder).IV iron preparations consist of a carbohydrate shell with an iron core.Parenteral iron is applied in cases with moderate to severe anemia orwhen the response to oral iron is poor. Intravenous iron application ismore efficient in improving hemoglobin values, but the higher costs ofintravenous iron formulations are a clear disadvantage compared to oralpreparations.✓ 3.2 What is the optimal schedule/dosing strategy for PO ironsupplementation and dietary co‐adjuvants? What are theminimal safety conditions (environment of administration) for IVTABLE 2 Oral iron formulations.Formulations Accessibility to therapy and possible side effectsFerrous ascorbate Affordable and readily accessible but often associated with gastrointestinal side effects.Ferrous fumarate Affordable and readily accessible but often associated with gastrointestinal side effects.Ferrous gluconate Affordable and readily accessible but often associated with gastrointestinal side effects.Ferrous sulfate Affordable and readily accessible but often associated with gastrointestinal side effects.Polysaccharide‐iron complex With a reduced likelihood of gastrointestinal discomfort and a more favorable taste profile.Carbonyl iron Cost‐effective with no discernible advantage in terms of efficacy or side effects when compared.Iron proteinsuccinylate There are some data suggesting potential improvements in tolerability and efficacy compared toferrous salts. However, it is unsuitable for individuals with hypersensitivity to milk protein.Iron amino acid chelates (ferrousbisglycinate,ferrictrisglycinate)Less prone to dietary interactions but potentially higher in cost compared to ferrous salts.8 of 16 | Recommendations for prevention of ID and IDAiron administration? What are the best markers for monitoringthe response to iron replacement therapy?Patients with IDA should receive iron replacement therapy (IRT).Furthermore, the benefit of treating ID, even in the absence of an-emia, is increasingly recognized in patients with some comorbidities,such as chronic heart failure (CHF).96The choice of an iron compound and the route of administration(oral vs. IV) primarily depend on the presence and degree of anemia,underlying cause, clinical status (age, symptoms, long‐standing vs. recentonset, comorbidities), and, in some instances, patient preference.Traditionally, oral iron has been administered at 100–200mg dailyin adults and 3‐6mg/kg in children, in 2–3 divided doses, preferablywithout food. However, the rapid increase of hepcidin in response toiron administration, which persists for up to 48 hours, has a negativeinfluence on the absorption of the subsequent doses. Indeed, studiesmeasuring the absorption of an iron isotope in nonanemic ID womendemonstrated that less frequent administration (from daily to alternateday and from multiple to single doses) and lower dosages (40–80mgFe) could improve efficacy and tolerability of oral iron treatment, bymaximizing fractional iron absorption, reducing gastrointestinal sideeffects, and potentially increasing compliance. In a randomized trialcomparing treatment regimes in subjects with IDA, 60mg of elementaliron two times a day produced Nb increments similar to 120mgon alternate days after the same total dose, with a lower prevalenceof nausea.97Although the absorption of oral iron is theoretically favored by anacidic environment, administration of vitamin C is not recommended,based on a large randomized clinical trial (RCT) demonstrating thatvitamin C neither enhances the hematological response nor di-minishes the side effects.98In anemic patients, oral iron should be continued until the Hbnormalizes, which may take 6–12 weeks (depending on the severityof anemia). After Hb restoration, oral supplements should be con-tinued for at least three months to adequately replenish iron stores(with an ideal target of ferritin >100 μg/L).91,99Hb response to oral iron should be checked in the first fourweeks when a rise in Hb of 20 g/L or into the normal range is con-sidered an optimal response.100The optimal follow‐up protocol after IRT remains to be established,but periodic monitoring is advised, given the possibility of recurrences.Monitoring Hb periodically (every 3 months for 12 months and thenevery 6 months for 2–3 years) appears appropriate. Although ferritin isa reliable measure of total body iron stores, there are insufficient datato recommend its routine use for monitoring.99,100In patients who do not respond to IRT (i.e., anemic patients withHb increase <10 g/L after 2–4 weeks of oral iron) despite adequateadherence, further investigations for unrecognized causes of anemia/ID are warranted.101,102No ideal markers can predict which patients will respond to oraliron. Low serum hepcidin levels could help identify patients in whoma response is probable.31 Other studies have indicated that a rise inthe Hb content of reticulocytes (CHr) may provide an early predictionof response to oral iron.29,103Indications for IV iron are expanding, thanks to the increasedawareness that modern compounds are safer and better tolerated thanthe “old” preparations.13,104‐106 However, based on postmarketingreports, the European Medicine Agency (EMA) recommendations arestill restrictive, suggesting that the relationship between risks andbenefits should always be evaluated, and several rules should beadopted when considering parenteral iron.107✓ 3.3 How to treat ID/IDA in adults?Management and work‐up for determination of the underlyingetiology of ID/IDA are summarized in Figures 4 and 5.Transfusion with packed red blood cells is only reserved for se-verely symptomatic patients with cardiovascular complications. Slowinfusion of restrictive transfusion should be followed with IRT.99Oral IRT with iron salts is the standard first‐line treatment inotherwise healthy and asymptomatic patients. Recent results in-dicate that lower doses and every‐other‐day regimens have anequivalent or even better iron absorption than daily dosing withfewer adverse events and increased tolerability.99,108,109 Initiat-ing oral ferrous salts once daily and if not tolerated alternating toonce every other day is recommended. The oral iron formulationsare summarized in Table 2.Oral iron salts are inexpensive and, therefore, advantageous forunder‐sourced areas. They are generally effective with high toler-ability problems due to gastrointestinal (GI) side effects. These GIeffects are more common with ferrous sulfate formulations andwithin the elderly population. In older adults, considering regimens ofnot more than once daily and even once every other day may bepreferable to decrease GI effects, and intravenous IRT may be con-sidered earlier.Oral iron salts, including ferrous sulfate, ferrous gluconate, andferrous fumarate, are available in liquids, tablets, and capsules containingvarious amounts of elemental iron with pills and capsules ranging from30 to just over 100mg. To facilitate absorption, iron salts should betaken on an empty stomach, as calcium‐containing food and drinksespecially, but those containing phosphates, phytates, and tannates,as well as tea or coffee, can impair iron absorption.110 The absorptionof ferrous iron also depends on gastric acidity which maintains thesolubility of iron; therefore, antacids, histamine receptor blockers, andproton pump inhibitors decrease the absorption of ferrous salts.Other oral formulations include heme iron polypeptide (HIP),polysaccharide iron complex (PIC), and ferric citrate, which shouldbe taken with meals. Of these, HIP and PIC are expensive buthave better tolerability; however, there are limited clinical data onboth.100 On the other hand, due to unpredictable absorption,enteric‐coated or sustained‐release formulations are usually notrecommended.The duration of treatment is at least three months to correctanemia, but it should also be extended to 6 months to replenishiron stores. To check for recurrence due to ongoing blood losses,cessation after three months of oral IRT and follow‐up of the patient isapplicable.Intravenous IRT is recommended for specific indications. The riskof allergic reactions, anaphylaxis, and shock are less commonlyencountered with current formulations. Particularly, IV iron should beadministered only by staff trained to evaluate and manage anaphy-lactic and anaphylactoid reactions in a suitable location with rapidaccess to resuscitation facilities. Iron infusion should always be slow,especially in the first minutes of administration, and the patientshould be carefully monitored. Patients with a history of allergiesshould be carefully evaluated before treatment. Due to the lack ofsafety data, women in the first trimester of pregnancy should beexcluded from IV treatment. The intravenous iron formulations aresummarized in Table 3.Indications for intravenous iron treatment include99,100,111‐115:1. Intolerance to oral IRT (including daily and alternate‐daily dosing)2. Inadequate response to oral IRT (Hb < 10 g/dL by the 4th weekof oral IRT)3. Rapid iron replacement is required (moderately symptomaticpatient or preoperative anemic patient whenever less than sixweeks is available up to surgery)HemaSphere | 9 of 164. Inflammatory bowel disease5. Chronic kidney disease6. Chronic heart failure7. In patients with intestinal malabsorption like short bowel syn-drome, allergic enteritis, atrophic gastritis8. After bariatric surgery or9. Ongoing abnormal uterine bleeding in case gynecological inter-vention is delayed10. IDA in the second or third trimester of pregnancy11. IRIDA.Low‐molecular‐weight iron dextran is recommended to be appliedafter a test dose with an infusion time of 2–6 hours. In the otherformulations, a test dose is not required. Premedication is notrecommended before infusions except for patients with asthma or ahistory of drug allergy.116 Ganzoni formula may be used to determinethe amount of iron that will be infused but is no longer used for newformulations like ferric carboxymaltose and ferric derisomaltose.117,118The total amount of iron that will be infused=Patient's weight inkg x (target Hb‐patient's Hb in g/dL) x 2.4 + storage iron. Target Hbfor patients below and above 35 kg is 13 and 15 g/dL, respectively.Storage iron is calculated as 15mg/kg for patients below 35 kg.Storage iron is considered 500mg for patients above 35 kg.Ferric carboxymaltose and iron isomaltoside are two formulationsthat give the opportunity to apply higher doses of iron at a singletime. A dose of 1000mg of ferric carboxymaltose or iron isomaltosidecan be infused with re‐evaluation after four weeks to determine theneed for additional doses. Additional doses may be required, espe-cially in patients with ongoing bleeding and inflammatory boweldisease.For other formulations, the total amount of iron calculated isgiven at divided doses every 1 to 2 weeks until iron stores are re-plenished. Before each infusion, Hb, serum ferritin, and reticulocytesHb are measured. Reassessment of the patient three months afterthe final infusion dose is recommended to evaluate for recurrenceof ID/IDA.F IGURE 4 Management of adult patients with iron deficiency (ID)/iron deficiency anemia (IDA). Flow chart showing the crucial steps to manage adult patientswith ID/IDA. AUB, abnormal uterine bleeding; FIT, fecal immunochemical testing; HMB, heavy menstrual bleeding; GI, gastrointestinal; ID, iron deficiency; IDA, irondeficiency anemia; IRT, iron replacement therapy. *Oral IRT may interfere with colon preparation of colonoscopy by causing constipation. **May be delayed in elderlyun‐fit populations or those with severe co‐morbidities, or CT cholangiography may be an alternative to colonoscopy.10 of 16 | Recommendations for prevention of ID and IDARecommendation 3.bThe choice of an iron compound and the route of administration (oral vs.IV) largely depend on the presence and degree of anemia, underlyingcause, clinical status (age, symptoms, long‐standing vs. recent onset,comorbidities), and, in some instances, patient preference. Traditionally,oral iron is administered at 100–200 daily in adults and 3‐6 mg/kg inchildren, in 2–3 divided doses, preferably without food. However, recentresults indicate that lower doses (e.g., 60–80mg) and every‐other‐dayregimens have equivalent or even better iron absorption than daily dosingwith fewer adverse events and increased tolerability. In anemic patients,oral iron should be continued until the Hb normalizes, which may take6–12 weeks (depending on the severity of the anemia). After Hbrestoration, oral supplements should be continued for at leastthree months to adequately replenish iron stores (with an ideal target offerritin > 100 μg/L).Intravenous IRT is recommended for specific indications such asintolerance or inadequate response to oral IRT; requirement of rapid ironreplacement; inflammatory bowel disease; chronic kidney disease;chronic heart failure; in patients with intestinal malabsorption like allergicenteritis and atrophic gastritis; after bariatric surgery; in women withabnormal uterine bleeding; during the second or third trimester ofpregnancy in women with IDA (only if highly necessary and strictlymonitored); and in patients with IRIDA. It is important to evaluate therisk of allergic reactions, anaphylaxis, and shock. Due to the lack of safetydata, women in the first trimester of pregnancy should be excluded fromIV treatment.✓ 3.4 How to treat ID/IDA in infants, children, and adolescents?The nutritional status must be assessed; indeed, prolonged ex-clusive breastfeeding in infants or the insufficient intake of iron‐richfoods considering the growth velocity at any age or menstruation andepistaxis in adolescent girls, vegan diet, and obesity may be theetiology bases of IDA. Moreover, low iron stores in the neonatalperiod may be due to a short gestation duration in the case of apreterm birth or a low birthweight, a maternal IDA, or an earlycord clamping.Transfusion with packed red blood cell transfusion is only reservedfor severely symptomatic patients with cardiovascular compromise andF IGURE 5 Treatment of iron deficiency (ID)/iron deficiency anemia (IDA) in adult patients. Flow chart showing the possible therapeutic options in adult patientswith ID/IDA.TABLE 3 Intravenous iron formulations.Formulation Amount per dose (mg) Infusion timeLMW‐iron dextran 25mg initial test dose 2–6 hours100mg/doseIron sucrose 200–300mg/dose 100mg/30minFerrous gluconate 125mg 12.5mg/minFerumoxytol 510mg 15minFerric carboxymaltose 750–1000mg (differsaccording to brand)15minIron isomaltoside Differs according to brand Differs according tobrandAbbreviations: LMW, low‐molecular‐weight; min, minute.HemaSphere | 11 of 16for those who have Hb below 5 g/dL. Slow infusion (3–4 hours) ofrestrictive (4–5mL/kg) transfusion should be followed with IRT.Oral IRT is recommended as a first‐line treatment in infants,children, and adolescents. Ferrous sulfate or other iron salts at a doseof 3–6mg elemental iron/kg/day is recommended. In adolescents,65–130mg of elemental iron, once daily, is suggested. There arelimited data on the efficacy of alternate‐day use of oral iron salts inthe pediatric age group. Oral iron salts should be given on an emptystomach; calcium‐containing food and drinks, such as milk and otherdairy products, should not be taken with oral iron salts. Liquid ironsalts may stain the teeth; the family must be warned about this.Rinsing the mouth and brushing the teeth after iron salt ingestion isrecommended. Patients who are intolerant to GI effects may beadvised to use alternate day dosing at lower doses; however, thedata on the efficacy of this application in children and adolescentsare limited.A follow‐up visit with blood testing to assess the response isrecommended. Patients with a Hb below 9 g/dL at diagnosis mayhave an earlier control of Hb by 2nd week of oral IRT initiation, and atleast 1 g/dL of Hb rise is targeted to be considered as a responder atthat time. It is usually difficult to catch the reticulocyte crisis whichmay be as early as 3rd day of treatment initiation and may vary indifferent patients; therefore, it is not recommended routinely. OralIRT is recommended to be continued for at least 3 months. By the 3rdmonth of treatment initiation, hemogram analyses is recommendedfor a decision to stop iron. Serum ferritin may also be ordered on ahealthy day to evaluate whether the iron stores were replenished.Intravenous IRT is reserved for patients severely intolerant to oralIRT, malabsorption, inflammatory bowel disease, chronic kidney disease,and IRIDA. Iron sucrose is the most commonly preferred formulation(100mg/infusion in children and 200mg/infusion in adolescents)119;other options include ferric gluconate, low‐molecular‐weight irondextran, and ferric carboxymaltose. There are limited data on the use offerric carboxymaltose in children. Only low‐molecular‐weight irondextran requires a test dose.120 Premedication is not recommendedin any formulation unless the patient has asthma or a previous drugallergy history.Potential causes of nonresponse or relapse ID include chronicinflammation, celiac disease, allergic enteritis, inflammatory boweldisorders, and menorrhagia in adolescent females. A rare geneticcause of IDA called IRIDA usually presents in childhood. Cautionshould be placed to not misdiagnose thalassemia carriers with IDA asboth present with hypochromic microcytic anemia.Finally, it is important to consider the potential usefulness ofiron‐fortified formula in preventing iron deficiency in infants. A cross‐sectional observational study conducted in primary care pediatricianoffices throughout France from 2016 to 2017 included consecutivelyinfants aged 24 months for a food survey and blood sampling.Associations between consumption of iron‐fortified formula and serumferritin (SF) levels were studied using multivariable regression afteradjusting for sociodemographic, perinatal, and dietary characteristics,including other sources of dietary iron. The study revealed that theuse of infant formulas was associated with a low prevalence of irondeficiency in infants aged 24 months.121✓ 3.5 How to treat ID/IDA in pregnant women?It is suggested by the American College of Obstetricians andGynecologists and the Centers for Disease Control and Preventionthat all pregnant women initiate oral iron supplementation to reducethe risk of ID/IDA during pregnancy.122 Once daily or every otherday, applications of single‐dose oral iron salts are recommended.Every other day dosing has been reported to increase iron absorptionwith higher tolerability to GI side effects in nonpregnant women. Oraliron salts are the only IRT formulations recommended during the firsttrimester of pregnancy. Due to a lack of safety data during the 1sttrimester, intravenous iron formulations are only used during the 2ndor 3rd trimester.74 Iron sucrose, low‐molecular‐weight iron dextran,ferric carboxymaltose, ferumoxytol, and iron isomaltoside could beused during these trimesters of pregnancy (doses are similar to thoseused in adults). Of note, European Medicines Agency currentlyrecommend that all pregnant women with ID should be monitoredwhile they are receiving IV iron because of the risk of fetal bradycardia.Intravenous iron should therefore not be used during pregnancy unlessclearly necessary. Treatment should be confined to the second or thirdtrimester, provided the benefits of treatment clearly outweigh the risksto the unborn baby. It also recommended further activities, includingyearly reviews of allergic reaction reports and a study to confirm thesafety of intravenous iron medicines.There is no evidence‐based screening time for ID/IDA duringpregnancy. Whenever IDA is diagnosed during pregnancy, oral IRTshould be used for treatment in the first trimester (initial 14 weeks ofgestation). For patients who were diagnosed with IDA during 2nd or3rd trimesters, intravenous IRT is recommended. Four to 6 weeksafter IRT initiation, testing for serum ferritin is recommended.✓ 3.6 How to treat ID/IDA in particular conditions? How tomanage ID and IDA in the setting of patient blood managementfor major surgery?In some conditions, there is a particular need to optimize patients'iron status to guarantee blood preservation. In the setting of major sur-gery, the risks of significant blood loss can be high. Allogenic bloodtransfusions (ABT) are commonly used as “life‐saving” measures but arefrequently overused. Concerns about conserving patients' blood startedwith the introduction of the so‐called “bloodless surgery” to accom-modate Jehovah's Witnesses request for treatment without ABT.122 Thisconcept evolved with generalized modalities to preserve all patients'blood, standing on three pillars: minimizing surgical and iatrogenic bloodlosses, managing coagulopathic bleeding, and focusing on diagnosing andtimely treating anemia and ID. In 2005, Isbister introduced the term“patient blood management” (PBM),123 recently defined as a “patient‐centered, systematic, evidence‐based approach to improve patient out-comes by managing and preserving patients' own blood”.123 In 2017, theEuropean Commission proposed PBM as a standard of care procedure.124In 2021, WHO released an awareness policy about the urgent need toimplement PBM.125 A set of clinical and research recommendations wasthen established through an international consensus.126 There is still anunmet need to formally prove the long‐term clinical benefits or cost‐effectiveness of PBM.127 Nevertheless, preoperative iron deficiency an-emia (IDA) is common, is associated with poorer postoperative outcomes,and is a major predictive factor of peri‐operative ABT.128 Good clinicalpractice dictates that the underlying cause of IDA should be diagnosedand treated appropriately. The main challenge in PBM is how to do itpromptly, particularly when the interval between diagnosis and surgery istoo short. Another challenge is the management of ID withoutanemia. While difficult to determine, it probably represents a much higherpopulation than IDA, but many of those patients probably do not needABT, although they may need PBM.Recommendation 3.cIn the setting of major surgery, we recommend systematically screeningfor ID, offering oral iron before and after surgery in IDA patients, andconsidering intravenous iron for patients with IDA who cannot tolerate or12 of 16 | Recommendations for prevention of ID and IDAabsorb oral iron or if the interval between the diagnosis and surgery is tooshort for oral iron be effective. It is also recommended that larger, pre-ferably multi‐institutional/multinational surveillance prospective studiesbe performed to further support PBM implementation.AUTHOR CONTRIBUTIONSAchille Iolascon, Immacolata Andolfo, Roberta Russo, Mayka Sanchez,Fabiana Busti, Dorine Swinkels, Patricia Aguilar Martinez, RayanBou‐Fakhredin, Martina U. Muckenthaler, Sule Unal, Graça Porto,Tomas Ganz, Antonis Kattamis, Lucia De Franceschi, Maria DomenicaCappellini, Malcolm G. Munro, and Ali Taher all took part in the datasynthesis and writing of the recommendations.CONFLICT OF INTEREST STATEMENTPatricia Aguilar Martinez: Nothing to Disclose. Dorine Swinkels: Nothingto Disclose. Sule Unal: Nothing to Disclose. Fabiana Busti: Nothing toDisclose. Myka Sanchez: Co‐Founder of SME BLOODGENETICS SL (agenetic company www.bloodgenetics.com); Participation in 2 clinical trialsone for IRIDA (KEROS THERAPEUTICS), one for atransferrinemia (San-quinBlood Netherland). Achille Iolascon: Nothing to Disclose. Ali Taher—Outside Work: Novartis Pharmaceuticals: Consultancy, Research funding;Bristol‐Myers Squibb (Celgene): Consultancy, Research funding; IonisPharmaceuticals: Consultancy, Research Funding; Vifor: Consultancy,Research Funding; Agios: Consultancy. Rayan Bou Fakhredin: Nothing toDisclose. Graça Porto: Nothing to Disclose. Immacolata Andolfo: Nothingto Disclose. Roberta Russo: Nothing to Disclose. Martina MuckenthalerSilence Therapeutics PLC, Editorial Board/Blood Journal/HemaSphere.Malcolm. G. Munro: Consultancies Pharmacosmos, Vifor, Daichi‐Sankyo,Shield Therapeutics, Myovant, Abbvie; Immediate Past Chair, FIGOMenstrual Disorders Committee. Tomas Ganz: shareholder and scientificadvisor of Intrinsic LifeSciences, and consultant for Ionis Pharmaceuticals,Disc Medicine, Silence Therapeutics, Chugai, Vifor, Akebia, Dexcel, andAvidity Bio.DATA AVAILABILITY STATEMENTData sharing is not applicable to this article as no data sets weregenerated or analyzed during the current study.FUNDINGNextGenerationEU and Italian Ministry of Research PNRR ‐ NationalCenter for gene therapy and Drugs based on RNA technology ‐ Spoke1‐CN3 “Genetic Diseases” (E63C22000940007).ORCIDImmacolata Andolfo http://orcid.org/0000-0003-0493-812XRoberta Russo http://orcid.org/0000-0002-3624-7721Martina U. Muckenthaler https://orcid.org/0000-0002-3778-510XREFERENCES1. Nemeth E, Ganz T. Hepcidin and iron in health and disease. AnnuRev Med. 2023;74:261‐277. doi:10.1146/annurev-med-043021-0328162. Lo JO, Benson AE, Martens KL, et al. The role of oral iron in thetreatment of adults with iron deficiency. Eur J Haematol. 2023;110:123‐130. doi:10.1111/ejh.138923. 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