|Year : 2021 | Volume
| Issue : 2 | Page : 59-69
Pathophysiologic and anaesthetic considerations in iron deficiency anaemia and pregnancy; An update
Sunanda Gupta1, Karuna Sharma1, Charu Sharma1, Alka Chhabra1, Lalita Jeengar1, Nalini Sharma2
1 Department of Anaesthesia and Critical Care, Geetanjali Medical College and Hospital, Udaipur, Rajasthan, India
2 Department of Obstetric and Gynaecology, Geetanjali Medical College and Hospital, Udaipur, Rajasthan, India
|Date of Submission||14-Jun-2021|
|Date of Acceptance||03-Jul-2021|
|Date of Web Publication||01-Oct-2021|
Dr. Karuna Sharma
E-704, Krishnangan, New Vidhya Nagar, Sector -4, Hiran Magri, Udaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
Anaemia is common during pregnancy, especially in low- and middle-income countries, and iron deficiency is the most common cause of anaemia worldwide. Symptoms relating to iron deficiency can be diverse, which relate to the depletion of cellular Fe function in different tissue organs and may exist long before Fe deficiency restricts erythropoiesis and anaemia develops. It is important to understand the pathophysiological and adaptation changes occurring during anaemia as long-standing changes affect the various organ systems and may impact both maternal and neonatal outcomes. There is growing evidence linking maternal IDA with subsequent neonatal cognitive and neurobehavioral outcomes, which makes it imperative that IDA should be treated early in pregnancy. Preoperative optimization with iron therapy (oral or parenteral) and erythropoiesis-stimulating agents vs replenishing O2-carrying capacity by transfusion must always be balanced against transfusion-associated risks. The anaesthetic management in parturients with severe anaemia depends on a multitude of factors, such as severity of iron deficiency anaemia, co-morbid diseases, extent of physiological compensation, and type and nature of anticipated haemorrhagic loss. This review summarizes the pathophysiological changes and adaptations consequent to oxygen delivery and iron homeostasis, therapeutic management, and anaesthetic challenges in pregnancy with IDA. It is based on electronic search strategies from Ovid Medline, Ovid Embase and PubMed (up to June 2021) along with relevant college and society web-based resources, including Royal College of Obstetricians and Anaesthesiologists, National Institute for Health and Clinical Excellence College and Society (NICE), Patient Blood Management Guidelines and American College of Obstetricians and Gynaecologists (ACOG) practice bulletins.
Keywords: Anaemia, blood transfusion, iron, morbidity, mortality, pregnancy
|How to cite this article:|
Gupta S, Sharma K, Sharma C, Chhabra A, Jeengar L, Sharma N. Pathophysiologic and anaesthetic considerations in iron deficiency anaemia and pregnancy; An update. J Obstet Anaesth Crit Care 2021;11:59-69
|How to cite this URL:|
Gupta S, Sharma K, Sharma C, Chhabra A, Jeengar L, Sharma N. Pathophysiologic and anaesthetic considerations in iron deficiency anaemia and pregnancy; An update. J Obstet Anaesth Crit Care [serial online] 2021 [cited 2022 Jan 17];11:59-69. Available from: https://www.joacc.com/text.asp?2021/11/2/59/327411
| Introduction|| |
Anaemia in pregnancy is a common clinical entity and is increasingly recognized as an independent modifiable perioperative risk factor. Pregnant women are particularly considered to be the most vulnerable group because of the additional demands that are made on maternal stores during pregnancy. Apart from physiological anaemia, numerous factors, including nutrition (Vitamin B12 and folate deficiency), genetics (presence of a Haemoglobin variant, thalassemia and sickle cell anaemia), acute or chronic blood loss, infections (malaria and worm infestations) bone marrow suppression (drugs and aplastic anaemia) renal disease and iron deficiency can cause anaemia. The latter is considered an established risk factor for poor perioperative, maternal, foetal and neonatal outcomes., Approximately 38% of all pregnant women worldwide are found to be anaemic, with >50% found in regions such as South Asia and Central and West Africa,, while the global prevalence of iron deficiency anaemia (IDA) in pregnancy ranges from 15% to 18%. This review focuses on IDA, which is the most common cause in pregnancy.
Anaemia is defined as a qualitative or quantitative deficiency of haemoglobin or red blood cells in circulation, resulting in reduced oxygen (O2)-carrying capacity of the blood to tissues and organs. WHO defines anaemia as a haemoglobin concentration of <120 g/L for nonpregnant women and <110 g/L haemoglobin (<11 g/dl) for pregnant women, irrespective of trimester, but Hb may fall by approximately 5 g/dL during the second trimester. The current Hb thresholds defining anaemia in pregnancy is based on historical values from nonpregnant females and are currently under review as the use of a lower Hb threshold in the female and obstetric population has been challenged on the grounds that lowering the Hb threshold may have significant implications for diagnosis and management of IDA during pregnancy., Optimizing Hb stores in the pregnant population before surgery has been reflected in several obstetric specific patient blood management guidelines,, to reduce peripartum transfusion rates. Till new guidelines are finalized, the existing threshold for anaemia during pregnancy is Hb <110 g/L in the first trimester, <105 g/L in second and third trimesters and <100 g/L in the postpartum period.
Currently, serum ferritin, a stable glycoprotein, is considered the most reliable indicator of iron stores in the absence of inflammation. There is an ongoing debate on the threshold levels of serum ferritin to diagnose Fe deficiency. In April 2020, WHO recommended a serum ferritin cut-off of <15 ug/L for diagnosing iron deficiency in adults and pregnant women in the first trimester,, whereas the UK guidelines advocate a cut-off level of <30 ug/L for pregnant women. However, ferritin is also an acute phase protein and may be elevated as a result of inflammatory pathologies, surgery and even pregnancy itself; therefore, a normal level does not exclude iron deficiency. A serum ferritin level of <30 ng/ml indicates a high risk for developing IDA due to insufficient Fe reserves, whereas levels of <12 ng/ml indicate established IDA at all levels of pregnancy.
Another important marker of iron status is transferrin saturation, and WHO recommends a threshold of <16% for iron deficiency or <20% for coexisting inflammation. Currently, active research is looking at more novel markers of iron status, such as, hepcidin, soluble transferrin receptor and erythroferrone.,,
Pathophysiology of anaemia
During pregnancy, there are complex interactions among the renal, hematologic and endocrine systems to compensate for the expected blood loss occurring at the time of delivery. Increase in foetal and maternal production of oestrogen and progesterone causes activation of renin angiotensin system and changes in osmotic set point. There is a physiological expansion of plasma volume beginning in the first trimester and plateauing by the third trimester in response to these renal homeostatic changes which exceed the increased production of red blood cells by elevated erythropoietin concentration and effects of progesterone, prolactin and placental lactogen. The free body water can be retained rapidly by the kidneys, but the production of red cells cannot occur as quickly, resulting in haemodilution, which contributes to the fall in Hb and physiological anaemia during pregnancy.
In case of anaemia, due to acute blood loss secondary to obstetric haemorrhage, sympathetic activation leads to vasoconstriction, increase in stroke volume and venous return, causing increased velocity of blood flow and cardiac output. Second, constriction of capillary bed in skin and splanchnic circulation redistributes blood to the vital organs. The physiologic response to chronic anaemia is a compensatory increase in cardiac output in order to maintain adequate oxygen delivery and increased oxygen extraction in the tissues facilitated by increased 2,3-diphosphoglycerate (2,3-DPG). This causes a rightward shift in the oxygen dissociation curve, allowing oxygen to be released to the tissues more readily. Cardiac output increases to maintain a constant arterial-venous O2 content difference and increase in O2 extraction ratio. The relative reduction in oxygen content is detected by tissue chemoreceptors, leading to further compensation and an increase in minute ventilation. Patients may be asymptomatic with mild anaemia, but poor tissue perfusion can manifest as tiredness and easy fatigability. Dyspnoea, palpitations, angina and signs of high CO, such as tachycardia, wide pulse pressure and systolic ejection murmur, may occur when anaemia is further aggravated in moderate to severe anaemia., Long-standing hyperdynamic circulation increases the cardiac load, causing hypoxia, ventricular dysfunction and eventually heart failure in severe anaemia. It has been reported that myocardial contractility decreases when Hb levels fall below 7 g/dL, and chronic anaemia can lead to an increase in LV end-diastolic pressure as well as decrease in functional reserve.
Basic physiology of O2 delivery and function of Hb
The three key components for delivery of oxygen to the tissues involves a good pumping mechanism (the heart), an efficient distributor of O2 (the circulatory system) and an efficient O2 reservoir (the Hb). O2 is carried in the blood as a physical solution in plasma (dissolved form) and reversible chemical combination with haemoglobin (oxyhaemoglobin). Arterial blood contains only 0.3 mL of O2 in each 100 mL of blood at a pO2 of 100 mm Hg and temperature of 37°C. This small quantity reflects tension of O2 in the blood and acts as a pathway for the supply of O2 to Hb and for the transfer of O2 to cells. The total quantity of O2 in arterial blood delivered to tissues is a function of the cardiac output (CO). Thus, RBCs with the constituent Hb is the principle transporter of oxygen and hence oxygen delivery to tissues is significantly reduced in anaemia. [Figure 1]
Haemoglobin is a tetramer of 2 alpha and 2 beta subunits; each subunit can carry one molecule of oxygen, and a complete haemoglobin tetramer can carry four molecules. In the completely unbound state, Hb predominates in the T (tense) form, which requires a higher PO2 to bind an oxygen atom, while the O2 rich Hb in the systemic circulation is in the R (relaxed) form, which does not require high PO2 to allow oxygen binding. A conformational change is induced in the other subunits due to O2 binding to one Hb subunit, which disrupts the interdimer bonds in the R form and increases the O2 affinity of the remaining subunits (co-operativity). In the T form, the H and ionic bonds limit the movement of monomers; thus, the subunits have a low affinity for O2. Oxygen–haemoglobin dissociation curve (ODC) relates to the partial pressure of oxygen in the blood to the per cent saturation of Hb with oxygen. [Figure 2] shows the ODC with the T and R forms of Hb.
|Figure 2: Shift of oxygen dissociation curve and oxy (r) and deoxy (t) forms of Hb|
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Adaptations to enhance O2 delivery to tissues
The majority of oxygen is carried by haemoglobin, and along with a functioning cardiovascular system, they are both central to the efficient delivery of oxygen to the tissues. Thus, the risk of anaemia depends both on the magnitude of fall in tissue O2 content and on the nature and severity of co-existing medical diseases. Further insights into the adaptive mechanisms that ensure oxygen delivery to tissues include the following:
- Oxygen sensors exist at the level of organs (kidneys), tissues (aortic and carotid body chemoreceptors) and cells [hypoxia-inducible factor (HIF)]. Adaptive physiological responses occur to compensate for anaemia-induced tissue hypoxia, which supports cellular (and ultimately organism) survival during anaemia.
- The Respiratory adaptations during anaemia lead to an increase in minute ventilation due to stimulation of respiration. The partial pressure of O2 in arterial blood (PaO2) and Hb O2 saturation (SaO2) are increased following NO-mediated mechanisms, which improve the ventilation-perfusion matching. This ensures that optimal SaO2 is maintained in the presence of reduced Hb.
- Cardiovascular adaptations are observed as an increase in CO and reduction in systemic vascular resistance (SVR) during anaemia as the hypoxia-sensing cells activate the sympathetic nervous system along with other mechanisms. A reduction in blood viscosity, systemic vasodilation and increased venous return can help to maintain an adequate CO and reduced SVR in anaemia.
- An increase in systemic O2 extraction helps to some extent in maintaining the global and tissue-specific O2 delivery. Three mechanisms are deemed to come into play to facilitate oxygen diffusion from microcirculation to tissues and thus sustain mitochondrial oxidative phosphorylation (aerobic respiration): a) a right shift of the oxygen dissociation curve facilitating unloading of O2 to the tissues,, b) increased tissue blood flow helping to increase oxygen diffusion from microcirculation to the tissues, and (c) increased capillary recruitment and density helping in reducing the diffusion distance to the cells during anaemia. These adaptations allow the mitochondria to generate ATP under aerobic conditions and function as a primary oxygen sensor.
- The HIF-mediated metabolic cellular adaptations, along with other mechanisms, are activated to strike an overall balance between systemic oxygen delivery and consumption, promoting survival during acute anaemia.,, HIF has been described as a master regulator of hypoxia sensing,, and hypoxic cell signalling.
Fetoplacental unit and oxygen delivery
The foetal–placental unit towards the end of the first trimester requires an increase in oxygenation, which is vital to support the energy demands of foetal growth. The foetal haemoglobin (α2, γ2) has a lower affinity for 2,3-diphosphoglycerate as compared to adult haemoglobin (α2, β2), which promotes a leftward shift in the haemoglobin–O2 dissociation curve, providing a greater arterial oxygen saturation (SaO2) in foetal blood vs maternal blood for any given arterial oxygen pressure (PaO2). Thus, the placenta acts as a pathway for oxygen transport to foetal circulation and provides oxygen to support its own metabolism. A fine balance between these two demands becomes more important, particularly when the oxygen resources are limited. Thus, chronic hypoxia following anaemia in pregnancy can lead to intrauterine growth restriction because of low arterial oxygen content as the oxygen carrying capacity is decreased. To compensate for such changes, there is a dramatic increase in placental vascularity along with increase in placental villous surface. Furthermore, the maternal uterine vessels receive an enhanced blood supply, increasing the maternal cardiac output, which is shared between both the foetal–placental unit and other maternal organs.
Research shows that approximately 45% of women enter pregnancy with low or absent iron stores. Requirement of iron increases from 0.8 mg/day in the first trimester to 7.5 mg/day in the third trimester while the daily absorption of iron is only 1–5 mg. During pregnancy, an additional 1 g of Fe is required for increase in red cell mass (450 mg), foetal growth (225 mg), placental development (80 mg) and blood loss through normal vaginal delivery (250 mg). In the postpartum period, breastfeeding necessitates an additional 1 g/day.
Iron is an important component for the synthesis of Hb, mitochondrial energy metabolism for cell growth and differentiation, neurotransmitter production, immunity and cardiopulmonary function.,, Iron homeostasis in the human body at the systemic and cellular level includes absorption, transport and intracellular storage of iron as ferritin. Iron is absorbed from the proximal duodenum in three forms:
- Inorganic or free iron (non-heme iron)
- Heme-bound iron
- Iron incorporated in ferritin.
Once iron passes absorptive enterocytes and crosses the apical and basolateral membranes, it is oxidized back to ferric iron by ferroxidases to enter the circulation and is bound to plasma proteins. Heme iron is absorbed by heme carrier protein 1 and transported into the enterocyte, where iron is liberated by heme oxygenase from protoporphyrin. Inorganic non-heme iron is mainly found in the oxidized ferric (Fe+++) form for absorption, which is first reduced to ferrous (Fe++) iron by brush border ferrireductase. The iron incorporated in ferritin makes up only a small contribution to the total iron intake.
The intracellular storage form of iron is called ferritin, and each mol of ferritin contains 4000 mol of iron and is mainly stored in the liver. All circulating iron is carried by transferrin, which can bind one or two ferric iron molecules. The iron-binding transferrin-receptor complex remains as an endosome in the cell till iron is released, reduced to its ferrous state (Fe++) and used by the mitochondria to form Hb and iron–sulphur crystals. The majority of iron is transported to the bone marrow for production of mature red blood cells. Senescent 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 stored in the storage molecule ferritin. The regulation of iron occurs through iron regulatory proteins (IRPs), which bind to mRNA structures called iron-responsive elements. When iron levels are low, iron–sulphur complexes within IRPs act as iron sensors within the cell. These units then become unable to bind to mRNA, further reducing the iron influx through a reduction in transferrin receptor protein synthesis and increasing the intracellular storage through ferritin.,
The majority of iron regulation at a systemic level is under the control of hepcidin, which is primarily produced by hepatocytes in the liver but is also produced in the heart, pancreas and hematopoietic cells. Hepcidin inhibits the movement of iron into the circulation by blocking ferroportin-dependent iron efflux out of macrophages, hepatocytes and enterocytes. Ferroportin is the sole exporter of iron and delivers stored, dietary or recycled iron to the plasma. Hepcidin levels are decreased in IDA, which allows increased absorption of iron through ferroportin. During pregnancy, hepcidin levels increase in the first trimester and decrease in the second and third trimesters, thus facilitating increased absorption of dietary iron and promoting the release of iron from stores., Iron is also essential for invading microbes, and hepcidin has an important role in host defence against infection.
As iron deficiency develops, iron is initially utilized from ferritin in the liver and subsequently from iron enzymes and iron proteins in tissues in an attempt to preserve erythropoiesis., [Figure 3] shows the major hepcidin–ferroportin and iron pathways.
Maternal and neonatal effects of IDA
It is important to understand that symptomatic Fe deficiency can occur without anaemia. Symptoms relating to Fe deficiency can be diverse, which relate to the depletion of cellular Fe function in different tissue organs and may exist long before Fe deficiency restricts erythropoiesis and anaemia develops., In a multinational observational study in 312,000 women from 29 countries with Hb levels of <70 g/L, there has been a 2–4-fold increased odds of death (adjusted odds ratio: 2.4; 95% CI: 1.6–3.5). Maternal complications also include pulmonary embolism, congestive heart failure and increased risk of obstetric haemorrhage, puerperal sepsis and poor wound healing., Depression, fatigue, lactation failure and impaired cognition are significant maternal co-morbidities in the postpartum period, which negatively impacts maternal–child bonding.
Systematic reviews of low- and middle-income countries have shown higher rates of perinatal and neonatal mortality, increased risk of premature delivery and low birthweight. Observational studies have also shown a lower APGAR score, and impaired neonatal cognition, which have been attributed to a potential risk to the developing brain structures, neurotransmitter systems and myelination.
Management of IDA during pregnancy
A detailed history and examination during the antenatal visit should help identify women who are at risk of developing iron deficiency with or without anaemia. Healthcare professionals should be aware of certain risk factors such as multiple gestations, previous history of anaemia, teenage pregnancy, short inter-pregnancy interval and history of vegetarian or vegan diets. There is an overlap in the common symptoms of iron deficiency, pregnancy and anaemia, such as fatigue, lethargy, dizziness and shortness of breath, but loss of concentration, headaches and easy bruising are more specific to iron deficiency. Hair loss, restless leg syndrome and pica (inexplicable eating of ice, paper or dirt) are highly specific to IDA.,
The NATA consensus statement has recommended the management for pregnant women with IDA both for prevention and as treatment in established cases. Wherever there is a high prevalence of anaemia in pregnancy, daily oral iron (30–60 mg) and folic acid (400 μg) supplementation should be routinely given as antenatal care to reduce the risks of maternal anaemia and its effects on the infant. In areas with a low prevalence of anaemia in pregnancy, non-anaemic women who may have an increased risk of ID should be given oral supplements (30–60 mg/day) if their serum ferritin is <30 ng mL−1. A trial of oral Fe++100 mg (elemental Fe/day) has been considered a first-line diagnostic test for IDA,, and if the Hb levels improve within 2–4 weeks, then it is considered a positive response and confirms IDA. In early pregnancy, women diagnosed with mild to moderate IDA (Hb ≥80 g L−1) should be treated with oral ferrous iron (80–100 mg/day elemental iron) and folic acid (400 μg/day).
A rise in haemoglobin by 1 g/dl is expected at the end of 2 weeks and by 2 g/dl by the end of 4 weeks in the absence of other micronutrient deficiencies and ongoing blood loss for patients on oral iron., Checking compliance, reconfirmation of diagnosis and switching to parenteral iron therapy should be considered if there is a suboptimal rise in Hb levels. Once the Hb is in normal range, 100–200 mg/day of iron should be continued for at least 3 months during pregnancy and at least 6 weeks postpartum to replenish the stores, and 60–100 mg/day oral iron should be continued for at least 3–6 months postpartum.
Oral therapy has several limitations despite its low cost, ease of access and relative safety. The major limitation is gastrointestinal side effects, which drive adherence rates to <50%. It is best absorbed from an acidic environment and hence is advised to be taken on an empty stomach between meals. Gastrointestinal adverse effects such as nausea, abdominal pain, diarrhoea, constipation and black or tarry stools may be particularly problematic in the pregnant population and may require switching to a parenteral route of administration in severe cases.
Treatment should be shifted to parenteral iron after the first trimester of pregnancy if there is inability to tolerate oral Fe (hyperemesis gravidarum; gastrointestinal pathology limiting iron absorption, e.g. inflammatory bowel disease; and previous bypass surgery). Women who are on haemodialysis or have donated large amounts of blood for an auto-transfusion programme or have presented late in pregnancy with severe IDA should also receive parenteral Fe.
All those patients who are diagnosed as IDA and are intolerant to oral Fe after >14 weeks gestation or fail to respond to correct administration of oral therapy or are newly diagnosed with severe IDA (<80 g/dL) beyond 34 weeks of gestation should receive parenteral Fe therapy.
Calculation of dose of parenteral Fe:
Administration of IV iron preparation is based on the total iron deficit (Ganzoni's equation)
Total dose in mg = Body Wt. × (Target Hb − Actual Hb) ×2.4 followed by 10 mg/kg body weight to replenish the iron stores. Formulations with very low labile iron content (low molecular weight iron dextran, ferumoxytol, ferric carboxymaltose and iron isomaltoside) allow for rapid administration of large single doses or total dose infusion (TDI). Haemoglobin responses to IV iron are rapid (50% response by 1 week and 75% by 2 weeks), and levels should be rechecked approximately 2–3 weeks after the infusion.
While hypersensitivity reactions are possible with all IV iron formulations, the incidence of serious adverse events with iron infusion is estimated to be <1:250,000. Severe acute hypersensitivity reactions are likely complement mediated, resulting in pseudo-anaphylaxis, termed complement activation-related pseudo allergy (CARPA). Some minor infusion reactions are more common (1:200) and usually consist of chest or back tightness; arthralgias, myalgias and/or flushing without associated hypotension; respiratory distress; or periorbital oedema.
In women with moderate to severe anaemia not responding adequately to IV iron due to inappropriate synthesis of, and/or response to, endogenous erythropoietin levels, erythropoiesis-stimulating agents (ESA) are prescribed. The co-administration of intravenous iron enhances the response to ESA, allowing dose reduction and reduction of platelet counts, thus diminishing thrombotic risk. Thus, to safeguard the efficacy and safety of ESA therapy, namely recombinant human erythropoietin (rHuEPO), within the approved indications, an individually tailored dose is advised along with adjuvant i.v. iron and deep venous thrombosis prophylaxis.
In situations where dangerously low Hb levels need to be quickly raised, RBC transfusions remain the mainstay of management in severely anaemic patients. Standard protocols must be available in every obstetric unit for optimal use of blood and blood products. Patient blood management guidelines are yet to be implemented universally and some good practice points include the following:,
- If Hb is >7 gm/dL, transfusion is not indicated unless there is a significant risk of rebleed/cardiac compromise; however, for Hb levels of <6 gm/dL, it is almost always indicated. A healthy myocardium compensates for levels of 7–8 gm/dL of Hb or 21%–24% haematocrit to optimize O2 delivery.
- Transfusion should be decided on an individual basis below 7 gm/dL by considering the clinical and haematological parameters. Thus, when the patient does not respond to either oral or parenteral iron or when there is severe bleeding, blood transfusion is required. If the patient is not bleeding, the patient should be reassessed for further requirement of blood or blood products following a single transfusion.
- Referral to a tertiary centre should be considered if there are significant symptoms of anaemia and/or severe anaemia (Hb <70 gL− 1) or late gestation (>34 weeks).
Large randomized trials have demonstrated restrictive transfusion to be non-inferior to most liberal transfusions. NICE guidelines on blood transfusion recommend transfusion triggers of 7 or 8 gm/dl in those with underlying cardiovascular disease. There is little evidence of the benefit of blood transfusion in asymptomatic parturients. Benefits from replenishing O2-carrying capacity by transfusion must always be balanced against transfusion-associated risks such as pulmonary oedema, immune suppression etc.
Managing anaesthesia in pregnancy with anaemia is a great challenge and has a significant role in maternal and foetal outcomes. Meticulous management of perioperative anaemia not only reduces the length of hospital stay and overall cost but also significantly reduces the maternal and foetal complications in the intra- and post-operative period.
A detailed history and evaluation of symptoms and signs of anaemia, along with looking for signs of high CO, is essential and helps in planning the technique of anaesthesia., History of increased or acute blood loss from GIT, female genital tract and any history of chronic diseases that may be associated with anaemia should be recorded. History of prior transfusion, drug/alcohol intake, nutritional habits and history of anaemia or worm infestations should also be sought.,
Iron deficiency anaemia shows a typical blood picture of microcytic and hypochromic anaemia with elliptocytes; decrease in MCV, MCH and MCHC values; and variation in RBC volume as seen by red cell distribution width, which is pathognomonic. [Table 1] Assessment of iron status, storage, and synthetic capacity should be performed using commonly available tests, such as serum iron level, ferritin level, transferrin saturation, total iron-binding capacity (TIBC), and reticulocyte haemoglobin content (CHr), to help differentiate between anaemia states., CHr provides useful information on iron availability and adequacy for haematopoiesis. Many studies, have found levels of CHr <28–30 pg as a strong indicator of iron-restricted erythropoiesis (due to true or functional iron deficiency) and thus justifies iron supplementation. When iron, ferritin, or CHr levels are reduced, the patient should be treated for iron deficiency including identification of the source of iron loss. [Table 2]
|Table 1: Normal reference range of various haematological parameters in the adult female population|
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A decision for normal vaginal delivery should be considered if there is no history of previous caesarean section or any other obstetric indication for caesarean delivery. Labour epidural analgesia is beneficial in the first stage of labour along with supplemental oxygen. Steroids, antibiotics and digitalization should be considered if signs of pulmonary oedema exist. The second stage of labour should be curtailed by assisted vaginal delivery, and active management of third stage with uterotonics and tranexamic acid should be considered to prevent PPH.
Caesarean section is mostly performed for obstetric indications rather than anaemia but anaemia per se is also associated with increased risk of caesarean section.,
To assess the adequacy of perfusion and oxygenation, non-invasive monitoring should include ECG, NIBP, EtCO2, temperature monitoring, pulse oximetry and urine output. Serial Hb, haematocrit to monitor expected and ongoing blood loss, invasive monitoring (e.g. CVP), invasive arterial blood pressure monitoring, ABG analysis and measurement of mixed venous PvO2 should be planned, especially wherein major blood losses are anticipated, such as in placenta previa or acccreta.
The main anaesthetic goals during surgical intervention include avoidance of hypoxemia and adequate oxygenation, minimal time in securing definitive airway during GA, maintenance of stable hemodynamics and avoidance of hypothermia and hyperventilation.
The anaesthetic technique in parturients with severe anaemia depends upon a multitude of factors such as severity and type of anaemia, co-morbid diseases, extent of physiological compensation, and type and nature of anticipated haemorrhagic loss.,, The main concern while choosing anaesthetic technique is to avoid hypoxia, maintain cardiac output and prevent a left shift of ODC. Both regional and general anaesthesia can be administered for caesarean sections as both the techniques have their relative advantages and disadvantages; selection depends upon the patient's physical status and the circumstances at the time of surgery. Anaemic patients with a Hb concentration of <7.5 gm/dl, who already have a 50% decrease in O2 carrying capacity, risk a further decrease due to surgical stress and pain, which causes tachycardia and increases the oxygen demand. Adverse incidents such as hypotension, hypoxia, hypercarbia, respiratory depression and hypoglycaemia further increase the O2 demand.
Regional anaesthesia or central neuraxial block includes low-dose spinal anaesthesia along with adjuvants, epidural anaesthesia with intermittent/continuous catheter dosing and combined spinal-epidural anaesthesia (CSE). The latter has the added advantage of providing a dense blockade and allows titratability of drug with stable hemodynamic along with post-operative analgesia. Supplemental oxygen by face mask or nasal cannula to avoid hypoxia, left uterine displacement to prevent supine hypotension, and restricted fluid infusions to maintain euvolemia and avoid fluid overload should be ensured. Mild anxiolytics may be desirable but over-sedation should be avoided. Advantages of regional anaesthesia are that it provides good analgesia, ability to provide supplemental O2, and decreased blood loss with stable hemodynamics,, along with psychological benefit for the mother as she is aware of her childbirth. Sudden hypotension due to sympathetic blockade extending above T4 compromises the cardiovascular system with impairment of tissue oxygenation, which is a major disadvantage of central neuraxial blockade. Extra precautions should be taken to avoid hypotension, hemodilution and subsequent heart failure or pulmonary oedema, which may occur on the return of vascular tone once the effect of spinal anaesthesia wears off.
GA is the anaesthesia of choice in severely anaemic or moderately anaemic patients with cardiac decompensation. The major advantages of general anaesthesia are rapid induction, better cardiovascular stability, control of airway and ventilation, and less hemodynamic changes, thus allaying anxiety and preventing associated cardiovascular changes. Disadvantages of general anaesthesia include chances of aspiration, hypoxemia during induction, failed intubation, awareness to the mother and adverse neonatal effects.
Intra- and post-operative optimization of cardiac output and oxygenation helps to improve the patient's tolerance for anaemia, which can be achieved by reducing the oxygen demand, supplementing oxygen and early use of vasopressors to maintain adequate perfusion and tissue oxygen delivery. Appropriate measures should be taken to prevent pain and infection to reduce oxygen requirement.
Measures taken to prevent hypoxia include pre-oxygenation with 100% O2 and supplementing oxygen in the peri-operative period. Measures and expertise to secure a definitive airway should be available to prevent any delay in addressing an unexpected difficult airway. Adequate FiO2, monitoring of ABG and ventilatory parameters, will prevent any undesirable decrease in O2 flux. Intravenous anaesthetic agents should be slowly titrated to prevent any precipitous fall in CO, and patients should be carefully positioned to minimize position associated volume shifts. Similarly, a high concentration of volatile agents depresses both the myocardium as well as ventilation and may lead to hemodynamic instability. Uterotonics and antifibrinolytics such as tranexamic acid should be administered to manage blood loss. Transfusion practices for blood and blood products should be guided by laboratory testing and point-of-care viscoelastic assays, where available. Care should be taken to anticipate and treat any adverse events, such as fever, shivering and acute massive blood loss, which lead to an increase in the tissue O2 demand. Mild tachycardia and wide pulse pressure may be physiological and should not be confused with light anaesthesia. Temperature monitoring and measures to prevent hypothermia to maintain normal core body temperatures, including warming the IV fluids and blood products, should be ensured.,,
Anaemia may be further aggravated in the postoperative period in patients with pre-operative anaemia, peri-operative blood loss, poor nutritional intake post-operatively and frequent blood sampling for laboratory investigations. Further aggravation of anaemia can occur as there is a rise in hepcidin levels due to inflammatory response to surgery, which can lead to inhibition of intestinal Fe absorption and reduce the Fe release from stores.
In the immediate post-operative period, supplementation of oxygen is required to keep the available haemoglobin saturated. Repeat assessment of Hb and correction should be done with blood transfusion if necessary. Transfused RBC contains hem Fe (200–250 mg per unit) with a small amount of labile iron that is immediately available for erythropoiesis depending on the storage time of RBC. Close monitoring of vital parameters is required to detect decompensation and early intervention. Good postoperative analgesia helps in preventing tachycardia and further load on the CVS. The patient's physiological parameters should be optimized by ensuring euvolemia, normothermia and normalizing the acid-base status.
During the postpartum period, management of Fe deficiency in patients with mild to moderate postpartum anaemia (PPA) who are hemodynamically stable, asymptomatic or mildly symptomatic should be managed with oral Fe for 3 months. They can be switched to parenteral Fe (if response with oral therapy is not adequate) with a single dose of up to 1000 mg of ferric carboxymaltose, which provides a faster and higher replenishment of iron stores and correction of Hb levels as compared to Fe sucrose. Early ambulation and physical therapy to prevent venous thromboembolism should be ensured in the postpartum period.
Covid-19 infection and IDA during pregnancy
During pregnancy, women become more susceptible to respiratory and viral diseases, including novel coronavirus infection (COVID-19). Pregnancy exacerbates the acute inflammation typical to COVID-19, increasing the risk of developing a cytokine storm. There exists a pathophysiological link between anaemia and severe COVID-19 during pregnancy, which can lead to a poor maternal and neonatal outcome.
Serum levels of ferritin are found to be elevated in acute inflammatory conditions and hyperferritinemia, an acute-phase reaction that is used by clinicians to map the therapeutic response. Recently, an increase in serum ferritin levels has also been adjudged to play a critical role in the development of the cytokine storm. Iron metabolism plays an important role in supporting the immune system to fight against invading microorganisms. As viral replication requires adequate iron levels within the host cells to support enhanced cellular metabolism,, the immune system reacts by decreasing the bioavailability of iron during the acute phase. The increase in serum ferritin levels is mediated by hepcidin, a master regulator of iron homeostasis, which blocks the activity of ferroportin, causing cellular sequestration of iron in macrophages, hepatocytes and enterocytes. There is an upregulation of cytosolic ferritin, and the increased retention of iron within the ferritin in macrophages leads to a fall in serum iron concentrations and an increase in serum ferritin., This leads to decrease in availability of iron for erythropoiesis and thus aggravates iron deficiency anaemia. The low Hb levels further disrupt the transport of O2, causing hypoxia and eventually resulting in multiorgan dysfunction syndrome in pregnant COVID-19 patients.
Apart from this, SARS-CoV-2 can interact with haemoglobin molecules on the erythrocyte through ACE2, CD147 and CD26 receptors and cause the virus to attack the heme on the 1-beta chain of haemoglobin and cause haemolysis. Patients with anaemia should hence be advised to take extra precautions to minimize the risk of exposure to the virus.
| Conclusions|| |
The anaesthetic implications of anaemia in pregnancy are based on the understanding of the normal and compensatory mechanisms that optimize tissue oxygenation and iron homeostasis. The main aim is to maintain a fine balance between the compensatory mechanisms and adequate tissue oxygenation in these parturients. Both regional and general anaesthesia can be used judiciously. Monitoring should aim at assessing the adequacy of perfusion and oxygenation and the magnitude of ongoing losses. Deleterious effects of chronic tissue hypoxemia along with threat of major blood losses in the perioperative period need to be anticipated and treated adequately.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Rahman MM, Abe SK, Rahman MS, Kanda M, Narita S, Bilano V, et al
. Maternal anemia and risk of adverse birth and health outcomes in low- and middle-income countries: Systematic review and metaanalysis. Am J Clin Nutr 2016;103:495–504.
Young MF. Maternal anemia and risk of mortality: A call for action. Lancet Global Health 2018;6:e479–80.
Butwick AJ, McDonnell N. Antepartum and postpartum anemia: A narrative review. Int J Obstet Anesth 2021;47:102985.
Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron deficiency anemia. Lancet 2016;387:907–16.
Pavord S, Daru J, Prasannan N, Robinson S, Stanworth S, Girling J, et al
. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2020;188:819-30.
Pasricha SR, Colman K, Centeno-Tablante E, Garcia-Casal MN, Peña-Rosas JP. Revisiting WHO hemoglobin thresholds to define anemia in clinical medicine and public health. Lancet Haematol 2018;5:e60-2.
Butcher A, Richards T, Stanworth SJ, Klein AA. Diagnostic criteria for pre-operative anemia – time to end sex discrimination. Anesthesia 2017;72:811–4.
Ferguson MT, Dennis AT. Defining peri-operative anaemia in pregnant women-challenging the status quo. Anaesthesia 2019;74:237-45.
Munoz M, Peña-Rosas JP, Robinson S, Milman N, Holzgreve W, Breymann F, et al
. Patient blood management in obstetrics: Management of anemia and haematinic deficiencies in pregnancy and in the post-partum period: NATA consensus statement. Transfus Med 2018;28:22–39.
Muñoz M, Acheson AG, Auerbach M, Besser M, Habler O, Kehlet H, et al
. International consensus statement on the peri-operative management of anemia and iron deficiency. Anesthesia 2017;72:233–47.
National Blood Authority (NBA). Patient Blood Management Guidelines: Module 5 – Obstetrics and Maternity. Canberra, Australia: NBA; 2015.
Flores CJ, Sethna F, Stephens B, Saxon B, Hong FS, Roberts T, et al
. Improving patient blood management in obstetrics: Snapshots of a practice improvement partnership. BMJ Qual Improv Rep 2017;23:e000009.
World Health Organization. WHO Guideline on use of Ferritin Concentrations to Assess Iron Status in Individuals and Populations. Geneva: WHO; 2020.
Munoz M, Garcia-Erce JA, Remacha AF. Disorders of Fe metabolism. Part II: Iron deficiency and iron overload. J Clin Path 2011;64:287-96.
Bah A, Muhammad AK, Wegmuller R, Verhoef H, Goheen MM, Sanyang S, et al
. Hepcidin-guided screen-and-treat interventions against iron-deficiency anemia in pregnancy: A randomised controlled trial in the Gambia. Lancet Global Health 2019;7:e1564-74.
Benson CS, Shah A, Stanworth SJ, Frise CJ, Spiby H, Lax SJ, et al
. The effect of iron deficiency and anaemia on women's health. Anaesthesia 2021;76:84-95
Grewal A. Anemia and pregnancy: Anesthetic implications. Indian J Anaesth 2010;54:380-6.
] [Full text]
Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, Filipescu DC, et al
. Management of severe perioperative bleeding: Guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol 2017;34:332-95.
Basu SM. Anemia and pregnancy. In: Gupta S, editor. Obstetric Anesthesia. 1st
ed. Delhi: Arya Publications; 2004. p. 433-56.
Oprea AD. Hematologic Disorders. In: Hines RL, Marschall KE, editors. Stoelting's Anesthesia and Co-Existing Disease, 7th
Ed. Philadelphia : Elsevier Saunders, 2018. p. 477-506.
Silverberg DS, Wexler D, Iaina A. The role of anemia in the progression of congestive heart failure. Is there a place for erythropoietin and intravenous iron? J Nephrol 2004;17:749-61.
Shander A, Javidroozi M, Ozawa S, Hare GMT. What is really dangerous: Anemia or transfusion? Br J Anaesth 2011;107:i41–59.
Dunn OC, Mythen MG, Grocott MP. Physiology of oxygen transport. BJA Educ 2016;17:341–8.
Doctor A, Platt R, Sheram ML, Eischeid A, McMahon T, Maxey T, et al
. Hemoglobin conformation couples erythrocyte S-nitrosothiol content to O2 gradients. Proc Natl Acad Sci USA 2005;102:5709–14.
Sladen RN. The oxyhemoglobin dissociation curve. Int Anesthesiol Clin 1981;19:39–70.
El Hasnaoui-Saadani R, Pichon A, Marchant D, Olivier P, Launay T, Quidu P, et al
. Cerebral adaptations to chronic anemia in a model of erythropoietin deficient mice exposed to hypoxia. Am J Physiol Regul Integr Comp Physiol 2009;296:R801–11.
Wilson DF. Quantifying the role of oxygen pressure in tissue function. Am J Physiol Heart Circ Physiol 2008;294:H11–3.
Semenza GL. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J 2007;405:1–9.
Ickx BE, Rigolet M, Van Der Linden PJ. Cardiovascular and metabolic response to acute normovolemic anemia. Effects of anesthesia. Anesthesiology 2000;93:1011–6.
Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: The central role of the HIF hydroxylase pathway. Mol Cell 2008;30:393–402.
Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007:cm8. doi: 10.1126/stke. 4072007cm8.
Murray AJ. Oxygen delivery and fetal-placental growth: Beyond a question of supply and demand? Placenta 2012;33:16-22.
Kadyrov M, Kosanke G, Kingdom J, Kaufmann P. Increased fetoplacental angiogenesis during first trimester in anaemic women. Lancet 1998;352:1747-9.
Milman N. Iron in pregnancy: How do we secure an appropriate iron status in the mother and child? Ann Nutr Metab 2011;59:50–4.
Fisher AL, Nemeth E. Iron homeostasis during pregnancy. Am J Clin Nutr 2017;106:1567S–74S.
Frise MC, Robbins PA. Iron, oxygen, and the pulmonary circulation. J Appl Physiol 1985;2015:1421–31.
Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science 2012;338:768–72.
Litton E, Lim J. Iron metabolism: An emerging therapeutic target in critical illness. In: Vincent JL, editors. Annual update in Intensive Care and Emergency Medicine.[e book] Springer, Chem; 2019: 573-584. Available from: https://doi.org/10.1007/978-3-030-06067-1-44.23:81
Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J 2011;434:365–81.
Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: Regulation of mammalian iron metabolism. Cell 2010;142:24–38.
Cleland SR, Thomas W. Iron homeostasis and perioperative management of iron deficiency. BJA Educ 2019;19:390-7.
Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al
. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090–3.
Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell 2017;168:344–61.
Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr 2001;131:568S-79S; discussion 580S.
Zaritsky J, Young B, Wang HJ, Westerman M, Olbina G, Nemeth E, et al
. Hepcidin--A potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1051-6.
Tandon R, Jain A, Malhotra P. Management of iron deficiency anemia in pregnancy in India. Ind J Hematol Blood Transfus 2018;34:204-15.
Daru J, Zamora J, Fernández-Félix BM, Vogel J, Oladapo OT, Morisak Ni, et al
. Risk of maternal mortality in women with severe anemia during pregnancy and postpartum: A multilevel analysis. Lancet Glob Health 2018;6:e548–54.
Cakmak BD, Turker UA, Oztas S, Aric M, Ustunyurt E. The effect of first trimester hemoglobin levels on pregnancy outcomes. Turk J Obstet Gynecol 2018;15:165-70.
Anjanappa B, Radhika BH, Nataraja HG, Ramaiah R, Sathya P. Maternal hemoglobin and perinatal outcome. Int J Reprod Contracept Obstet Gynecol 2015;4:1335-8.
McGregor SG, Ani C. A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr 2001;131:649S-66S; discussion 666S-8S.
Georgieff MK. The role of iron in neurodevelopment: Fetal iron deficiency and the developing hippocampus. Biochem Soc Trans 2008;36:1267–71.
Pasricha SR, Tye-Din J, Muckenthaler MU, Swinkels DW. Iron deficiency. Lancet 2021;397:233-48.
Dugan C, MacLean B, Cabolis K, Abeysiri S, Khong A, Sajic M, et al
. The misogyny of iron deficiency. Anaesthesia 2021;76:56-62.
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 95: Anemia in pregnancy. Obstet Gynecol 2008;112:201-7.
Pavord S, Myers B, Robinson S, Allard S, Strong J, Oppenheimer C, et al
. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 2012;156:588-600.
Krafft A, Breymann C. Iron sucrose with and without recombinant erythropoietin for the treatment of severe postpartum anemia: A prospective, randomized, open-label study. J Obstet Gynaecol Res 2011;37:119-24.
Krafft A, Bencaiova G, Breymann C. Selective use of recombinant human erythropoietin in pregnant patients with severe anemia or nonresponsive to iron sucrose alone. Fetal Diagn Ther 2009;25:239–45.
Breymann C, Vista E, Huch R, Huch A. Efficacy and safety of intravenously administered iron in sucrose with or without adjuvant recombinant erythropoietin for the treatment of resistant iron deficiency anemia during pregnancy. Am J Obstet Gynaecol 2001;184:662-7.
Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastro- intestinal side-effects in adults: A systematic review and meta-analysis. PLoS One 2015;10:e0117383.
Ganzoni AM. Intravenous iron-dextran: Therapeutic and experimental possibilities. Schweiz Med Wochenschr 1970;100:301–3.
Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood 2000;96:823–33.
Warner MA, Shore-Lesserson L, Shander A, Patel SY, Perelman SI, Guinn NR. Perioperative anemia: Prevention, diagnosis, and management throughout the spectrum of perioperative care. Anesth Analg 2020;130:1364–80.
Szebeni J, Fishbane S, Hedenus M, Howaldt S, Locatelli F, Patni S, et al
. Hypersensitivity to intravenous iron: Classification, terminology, mechanisms and management. Br J Pharmacol 2015;172:5025–36.
Fishbane S, Ungureanu VD, Maesaka JK, Kaupke CJ, Lim V, Wish J. The safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis 1996;28:529–34.
Muñoz M, Gómez-Ramírez S, Kozek-Langeneker S, Shander A, Richards T, Pavía JA, et al
. 'Fit to fly': Overcoming barriers to preoperative hemoglobin optimization in surgical patients. Br J Anaesth 2015;115:15–24.
Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al
. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409–17.
Sweitzer BJ. Preoperative Assessment and Management. 3rd
ed. Philadelphia, PA: Wolters Kluwer Health; 2018.
Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 2010;116:4754–61.
Urrechaga E, Hoffmann JJ, Bernal A, Arévalo JA, Cabriada JL. Reticulocyte hemoglobin content (MCHr) in the assessment of iron deficient erythropoiesis in inflammatory bowel disease. Dig Liver Dis 2018;50:1178–82.
Mast AE, Blinder MA, Dietzen DJ. Reticulocyte hemoglobin content. Am J Hematol 2008;83:307–10.
Practical guidelines for blood component therapy: A report by the Americal Society of Anesthesiologists Task Force on Blood Component Therapy. Anaesthesiology 1996;84:737-47.
Adam I, Kheiri S, Sharif ME, Ahmed AB, Rayis DA. Anemia is associated with an increased risk for cesarean delivery. Int J Gynaecol Obstet 2019;147:202-5.
Lertakyamanee J, Chinachoti T, Tritrakarn T, Muangkasem J, Somboonnanonda A, Kolatat T. Comparison of general and regional anesthesia for cesarean section: Success rate, blood loss and satisfaction from a randomized trial. J Med Assoc Thai 1999;82:672–80.
Rathod S, Samal SK, Mahapatra PC, Samal S. Ferric carboxymaltose: A revolution in the treatment of postpartum anemia in Indian women. Int J Appl Basic Med Res 2015;5:25–30.
Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol 2017;29:401–9.
Wessling-Resnick M. Crossing the Iron Gate: Why and how transferrin receptors mediate viral entry. Annu Rev Nutr 2018;38:431–58.
Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol 2008;6:541–52.
Shoenfeld Y. Corona (COVID-19) time musings: Our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmun Rev 2020;19:102538.
Taneri PE, Gòmez-Ochoa SA, Llanaj E, Raguindin PF, Rojas LZ, Roa-Dìaz ZM, et al
. Anemia and iron metabolism in COVID-19: A systematic review and meta-analysis. Eur J Epidemiol 2020;35:763–73.
Cavezzi A, Troiani E, Corrao S. COVID-19: Hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract 2020;10:1271.
Hariyanto TI, Anemia is associated with severe coronavirus disease 2019 (Covid-19) infection. Transfus Apher Sci 2020;59:102926.
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