STUDY TO EVALUATE THE EFFICACY OF FERRIC CARBOXYMALTOSE VS IRON SUCROSE IN POSTPARTUM CASES WITH IRON DEFICIENCY ANEMIA
Dissertation submitted to THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY in partial fulfillment of the regulations for the award of the degree of
M.S. BRANCH II OBSTETRICS AND GYNAECOLOGY REG.NO.221616103
MADURAI MEDICAL COLLEGE MADURAI MAY 2020
CERTIFICATE
This is to certify that the dissertation entitled “STUDY TO
EVALUATE THE EFFICACY OF FERRIC CARBOXYMALTOSE
VS IRON SUCROSE IN POSTPARTUM CASES WITH
IRON DEFICIENCYANEMIA” is a bonafide work done by
Dr. A.NARMADHAPRIYA in the institute of Madurai Medical College,
Madurai in partial fulfillment of the university rules and regulations for ward of MS degree in Obstetrics and Gynaecology under my guidance and supervision during the academic year 2018-2019.
GUIDE HEAD OF THE DEPARTMENT Prof.DR.M.GAYATHRI.M.D.DGO Prof. DR.N.SUMATHI.M.D.DGO. Dept. of Obstetrics & Gynecology, Dept. of Obstetrics & Gynecology, Madurai medical college, Madurai medical College, Madurai. Madurai.
CERTIFICATE FROM DEAN
This is to certify that the dissertation entitled “STUDY TO
EVALUATE THE EFFICACY OF FERRIC CARBOXYMALTOSE
VS IRON SUCROSE IN POSTPARTUM CASES WITH
IRON DEFICIENCYANEMIA” bonafide work done by
Dr.A.NARMADHAPRIYA in the institute of Madurai medical college,
Madurai in partial fulfillment of the university rules and regulations for ward of MS degree in Obstetrics and Gynaecology under my guidance and supervision during the academic year 2018-2019.
DEAN
Prof DR.J.SANGUMANI, M.D,
GENERAL MEDICINE
Govt Rajaji Hospital,
Madurai Medical College,
Madurai.
DECLARATION
I solemnly declare that this dissertation entitled “STUDY TO
EVALUATE THE EFFICACY OF FERRIC CARBOXYMALTOSE
VS IRON SUCROSE IN POSTPARTUM CASES WITH IRON
DEFICIENCYANEMIA ” was done by me at the Department of
Obstetrics and Gynaecology, Govt. Rajaji Hospital, Madurai medical college, Madurai during 2018-2019 under the guidance and supervision of Prof. DR.M.GAYATHIRI M.D, DGO., This dissertation is submitted to the TamilNadu Dr. M.G.R Medical
University towards the partial fulfillment of requirements for the award of M.S Degree in Obstetrics and Gynaecology (Branch II)
Place : Madurai Signature of candidate Date: Dr.A.NARMADHAPRIYA, MS, Post Graduate, Dept of Obstetrics and Gynecology, Madurai Medical College
ACKNOWLEDGEMENT
I would like to thank Prof Dr.J.SANGUMANI, M.D, Dean of Madurai Medical College for having permitted me to do this dissertation work. I would like to express my deep gratitude and regards to Prof. N. SUMATHI MD. DGO, Head of Department of Obstetrics & Gynecology, Madurai medical college for her keen acumen and suggestions I am deeply indebted to my guide, Prof. Dr.M.GAYATHIRI, MD, DGO., PROF of department, Department of Obstetrics & Gynaecology, Madurai medical college for her valuable guidance, interest and encouragement in his study. I take this opportunity to express my deep sense of gratitude and humble regards for her timely guidance, suggestion and constant inspiration which enabled me to complete this dissertation. I would like to thank all my Assistant Professors for their support. I thank all my patients for their co-operation & hence for success of this study. I thank my family & friends for their inspiration and support given to me.
CONTENT
S.NO TITLE PAGE NO
1. INTRODUCTION 1
2. REVIEW OF LITERATURE 3
3 OBJECTIVES OF THE STUDY 65
4. MATERIALS AND METHOD 66
5. RESULT AND ANALYSIS 71
6. DISCUSSION 84
7. CONCLUSION 87
8. BIBLIOGRAPHY 88
9. PROFORMA 91
10. MASTER CHART 94
11. ETHICAL CLEARANCE 96
CERTIFICATE
12. PLAGIARISM CERTIFICATE 98
INTRODUCTION
INTRODUCTION
ANEMIA
Anaemia is defined as decrease in oxygen carrying capacity of the red blood cell . WHO defines anaemia as haemoglobin less than <
12g% in women and < 13g% in men . There are different types of anaemia of which anaemia due to nutritional deficiency being most common. Among the nutritional deficiency anaemia, IRON
DEFICIENCY is most common type of anaemia.
Anaemia is the most common nutritional deficiency in the world.
Globally, anaemia affects 1.62 billion people which constitute to
24.8% of the total population and the group with the greatest number of individuals affected being pregnant women (41.8%).
The causes of anemia in pregnancy and their frequency are dependent on multiple factors such as geography, ethnicity, nutritional status, preexisting iron status, and prenatal iron supplementation. Other factors are socioeconomic, and anemia is more prevalent among indigent women
1
In pregnancy it is associated with increased maternal and neonatal morbidity and mortality. It is a leading cause for preterm labour,
Infections, poorly tolerated postpartum haemorrhage, cardiac failure in the mother and in the new born it is the main cause for prematurity, infection and poor neurological and cognitive functions of new born.
In mother during postnatal period there will be poor wound healing, postpartum depression, lactation failure .
In India anaemia antedates pregnancy, it is aggravated during pregnancy by increased requirements and blood loss at delivery ,
Infection during antenatal , postnatal period and early advent of next pregnancy .
In order to prevent this vicious cycle of anaemia carrying over to next pregnancy it is mandatory to correct anaemia during the pregnancy by iron supplementation but due to its poor compliance among the mothers it mandates a definitive correction of anaemia during the postnatal period with parental iron preparation or blood depending on the severity of anaemia.
2
REVIEW OF LITERATURE
REVIEW OF LITERATURES
Comparison of ferric Carboxymaltose and iron sucrose complex for treatment of iron deficiency anaemia in pregnancy- randomised controlled trial
A randomized clinical trial was conducted from (January 2016-
August 2017). at a tertiary hospital. Pregnant women diagnosed with moderate to severe iron deficiency anaemia were screened for the study. One hundred patients were randomized to receive either intravenous FCM or ISC. Primary outcome was rise in haemoglobin
(Hb) from baseline after 12 weeks. Secondary outcomes were change in RBC indices, serum iron studies, improvement in fatigue scores, number of visits and perinatal outcome.
Mean rise in Hb at 12 weeks was significantly higher in FCM group (29 g/L vs 22 g/L; p value < 0.01). FCM was associated with greater improvement in fatigue scores. Number of visits were significantly less in FCM group. No serious adverse events were noted in either group.
3
Iron Sucrose vs Ferric Carboxymaltose: In Search of Better
Treatment Option in Cases of Post-Partum Iron Deficiency
Anemia
Ferric carboxymaltose is an efficient and better alternative to
Iron Sucrose in treating postpartum anaemia. It has an added advantage of single dose regime with lower side effects.
Comparative study of safety and efficacy of intravenous iron sucrose and ferric carboxymaltose in the treatment of postpartum iron deficiency anaemia
Ferric carboxymaltose has a greater safety profile (p) and offers faster elevation of haemoglobin and iron stores with lesser hospital stay as compared to iron sucrose.
ANAEMIA
Definition - Anaemia is defined as decrease in oxygen carrying capacity of the red blood cell . WHO defines anaemia as haemoglobin less than < 12g% in women and < 13g% in men. Postnatal anaemia is defined as HB less than 11 % .
4
HISTORY OF ANAEMIA
Anaemia is the cause for poor maternal and foetal outcome from time immemorial. A disease believed to be iron deficiency anaemia is described in about 1500 B.C. in the Egyptian Ebers Papyrus. It was termed as chlorosis or green sickness in medieval Europe and iron salts were used for treatment in France by the mid- 17 th century.
THOMAS SYNDENHAM recommended iron salts as treatment for cholorosis but treatment with iron was controversial until the 20 th century , when its mechanism of action was more fully elucidated
As described by Hartford , conn. In 1973 , the gray look is typical of hypochromic anaemia , the so called “ primary” anaemia of women who are fortyish, the anaemia which has taken the place of chlorosis
Chlorosis was first described by Lange in the 16th century as an anaemia often found in adolescent girls and young women. despite the recommendation by Sydenham in the 17th century that the condition be treated with iron supplemtation , chlorosis was classified among the hysterical diseases
5
By the end of 16th century , the incidence of chlorosis apparently increased. It became an important subject in medical literature, but the true nature of the disease remained unknown. Many physicians believed that it was a result of a nervous disorder affecting various organ system including the blood forming organs. Iron medication became popular because of its therapeutic value, but its mode of action was controversial .
Stockman in 1895 proposed that chlorosis was the result of a nutritional iron defiency , but his view was largely ignored for decades
After the world war 1 the incidence of chlorosis declined, and the disease ceased to be reported in the 1930 . the role of blood in the delivery of oxygen has been known for centuries, and deficiencies in the bloods ability to transport oxygen were recognized as a clinical entity in the early 1800 by Thomas Addison, who described pernicious anaemia
The oxygen carrying protein haemoglobin was discovered by hunefeld in 1840. Haemoglobin reversible oxygenation was described a few year later by Felix Hoppe Seyeler.
6
IN 1959 Max Perutz determined the molecular structure of haemoglobin by X-ray crystallography. This work resulted in his sharing with John Kendrew the 1962 Nobel prize in chemistry
The role of haemoglobin in the blood was elucidated by physiologist Claude BERNARD. The name haemoglobin is the portmanteau of HEAM & GLOBIN, reflecting the fact that each subunit of haemoglobin is a globular protein with an embedded heme group.
Each heme group contains one iron atom that can bind one oxygen molecule through ion induced dipole forces. In human haemoglobin contains four such subunits .
IRON METABOLISM :
Iron is a critical element in the function of all cells, although the amount of iron required by individual tissues varies during development. At the same time, the body must protect itself from free iron, which is highly toxic in that it participates in chemical reactions that
7 generate free radicals such as singlet O2 or OH- . Consequently, elaborate mechanisms have evolved that allow iron to be made available for
physiologic functions while at the same time conserving this element and handling it in such a way that toxicity is avoided.
Iron is a critical element in iron-containing enzymes, including the cytochrome system in mitochondria.
Iron distribution in the body is as shown below table 1.
Adult male , 80kg Adult female ,60 kg
Haemoglobin 2500 1700
Myoglobin 500 300
Transferrin iron 3 3
Iron stores 600-1000 0-300
Tab 1 : Iron distribution in males and females
Without iron, cells lose their capacity for electron transport and energy metabolism. In erythroid cells, hemoglobin synthesis is impaired, resulting in anemia and reduced O2 delivery to tissue.
8
THE IRON CYCLE IN HUMANS
Fig 1 : The Iron cycle
Iron absorbed from the diet or released from stores circulates in the plasma bound to transferrin, the iron transport protein.
Transferrin is a bilobed glycoprotein with two iron binding sites.
Transferrin that carries iron exists in two forms—monoferric (one iron atom) or diferric (two iron atoms). The turnover (half-clearance time) of transferrin-bound iron is very rapid—typically 60–90 min. Because
9 almost all of the iron transported by transferrin is delivered to the erythroid marrow, the clearance time of transferrin-bound iron from the circulation is affected most by the plasma iron level and the erythroid marrow activity. When erythropoiesis is markedly stimulated, the pool of erythroid cells requiring iron increases and the clearance time of iron from the circulation decreases. The half- clearance time of iron in the presence of iron deficiency is as short as
10–15 min. With suppression of erythropoiesis, the plasma iron level typically increases and the half-clearance time may be prolonged to several hours. Normally, the iron bound to transferrin turns over 6–8 times per day. Assuming a normal plasma iron level of 80–100 μg/dL, the amount of iron passing.
The iron-transferrin complex circulates in the plasma until it interacts with specific transferrin receptors on the surface of marrow erythroid cells. Diferric transferrin has the highest affinity for transferrin receptors; apotransferrin (not carrying iron) has very little affinity.
Although transferrin receptors are found on cells in many tissues within the body—and all cells at some time during development will display transferrin receptors—the cell having the
10 greatest number of receptors (300,000–400,000/cell) is the developing erythroblast.
Once the iron-bearing transferrin interacts with its receptor, the complex is internalized via clathrin-coated pits and transported to an acidic endosome, where the iron is released at the low pH. The iron is then made available for heme synthesis while the transferrin-receptor complex is recycled to the surface of the cell, where the bulk of the transferrin is released back into circulation and the transferrin receptor reanchors into the cell membrane. At this point a certain amount of the transferrin receptor protein may be released into circulation and can be measured as soluble transferrin receptor protein. Within the erythroid cell, iron in excess of the amount needed for hemoglobin synthesis binds to a storage protein, apoferritin, forming ferritin. This mechanism of iron exchange also takes place in other cells of the body expressing transferrin receptors, especially liver parenchymal cells
Where the iron can be incorporated into heme -containing enzymes or
Stored. The iron incorporated into haemoglobin subsequently enters
The circulation as new red cells are released from the bone marrow.
11
The Iron is then part of the red cell mass and will not become available for Reutilization until the red cell dies. In a normal individual, the average red cell life span is 120 days.
Thus, 0.8–1% of red cells are replaced each day. At the end of its life span, the red cell is recognized as senescent by the cells of the reticuloendothelial (RE) system, and the red cell undergoes phagocytosis. Once within the RE cell, the ingested hemoglobin is broken down, the globin and other proteins are returned to the amino acid pool, and the iron is shuttled back to the surface of the RE cell, where it is presented to circulating transferrin. It is the efficient and highly conserved recycling of iron from senescent red cells that supports steady-state (and even mildly accelerated) erythropoiesis.
Because each millilitre of red cells contains 1 mg of elemental iron,
The amount of iron needed to replace those red cells lost through senescence amounts to 20 mg/d (assuming an adult with a red cell mass of 2 L). Any additional iron required for daily red cell production comes From the diet. Normally, an adult male will need to absorb at least 1 mg of elemental iron daily to meet needs, while females in the childbearing years will need to absorb an average of 1.4 mg/d.
12
However, to achieve a maximum proliferative erythroid marrow response to anaemia, additional iron must be available. With markedly stimulated Erythropoiesis, demands for iron are increased by as much as six- to eightfold. With extravascular hemolytic anemia, the rate of red cell destruction is increased, but the iron recovered from the red cells is efficiently reutilized for hemoglobin synthesis. In contrast, with intravascular hemolysis or blood loss anemia, the rate of red cell production is limited by the amount of iron that can be mobilized from stores.
Typically, the rate of mobilization under these circumstances will not support red cell production more than 2.5 times normal. If the delivery of iron to the stimulated marrow is suboptimal, the marrow’s proliferative response is blunted, and hemoglobin synthesis is impaired. The result is a hypoproliferative marrow accompanied by microcytic, hypochromic anemia.
Whereas blood loss or hemolysis places a demand on the iron supply, inflammatory conditions interfere with iron release from stores and can result in a rapid decrease in the serum iron.
13
NUTRITIONAL IRON BALANCE
The balance of iron in humans is tightly controlled and designed to conserve iron for reutilization. There is no regulated excretory pathway for iron, and the only mechanisms by which iron is lost are blood loss (via gastrointestinal bleeding, menses, or other forms of bleeding) and the loss of epithelial cells from the skin, gut, and genitourinary tract. Normally, the only route by which iron comes into the body is via absorption from food or from medicinal iron taken orally. Iron may also enter the body through red cell transfusions or injection of iron complexes. The margin between the amount of iron available for absorption and the requirement for iron in growing infants and the adult female is narrow; this accounts for the great prevalence of iron deficiency worldwide—currently estimated at onehalf billion people.
14
Fig 2 : Nutritional Iron Balance
The amount of iron required from the diet to replace losses averages approximately 10% of body iron content a year in men and 15% in women of childbearing age. Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories). Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed . An individual with iron deficiency can increase iron absorption to
15 approximately 20% of the iron present in a meat containing diet but only 5–10% of the iron in a vegetarian diet. As a result, one-third of the female population has virtually no iron stores. Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates reduce iron absorption by approximately
50%. When ionizable iron salts are given together with food, the amount of iron absorbed is reduced.
When the percentage of iron absorbed from individual food items is compared with the percentage for an equivalent amount of ferrous salt,iron in vegetables is only about one-twentieth as available, egg iron one-eighth, liver iron one-half, and heme iron one-half to two-thirds. During the last two trimesters of pregnancy, daily iron requirements increase to 5–6 mg, and iron supplements are strongly recommended for pregnant women in developed countries.
IRON ABSORPTION
Iron absorption takes place largely in the proximal small intestine and is a carefully regulated process. For absorption, iron must be taken up by the luminal cell. That process is facilitated by the acidic contents
16 of the stomach, which maintains the iron in solution. At the brush border of the absorptive cell, the ferric iron is converted to the ferrous form by a ferrireductase. Transport across the membrane is accomplished by divalent metal transporter type 1 (DMT-1, also known as natural resistance macrophage-associated protein type 2
[Nramp 2] or DCT-1). DMT-1 is a general cation transporter. Once inside the gut cell, iron may be stored as ferritin or transported through the cell to be released at the basolateral surface to plasma transferrin through the membrane-embedded iron exporter, ferroportin. The function of ferroportin is negatively regulated by hepcidin, the principal iron regulatory hormone. In the process of release, iron interacts with another ferroxidase, hephaestin, which oxidizes the iron to the ferric form for transferrin binding. Hephaestin is similar to ceruloplasmin, the copper-carrying protein.
17
Fig 3 : Iron Metabolism
18
Iron absorption is influenced by a number of physiologic states.
Erythroid hyperplasia stimulates iron absorption even in the face of normal or increased iron stores, and hepcidin levels are inappropriately low. Thus, patients with anemias associated with high levels of ineffective erythropoiesis absorb excess amounts of dietary iron. The molecular mechanism underlying this relationship is not know . In iron deficiency, hepcidin levels are also low and iron is much more efficiently absorbed; the contrary is true in states of secondary iron overload.
HEPCIDIN
Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in humans . During conditions in which the hepcidin level is abnormally high, such as inflammation, serum iron falls due to iron trapping within macrophages and liver cells and decreased gut iron absorption. This typically leads to anemia due to an inadequate amount of serum iron being available for developing red blood cells.
When the hepcidin level is abnormally low such as in hemochromatosis, iron overload occurs due to increased ferroportin mediated iron efflux from storage and increased gut iron absorption.
19
Functions of Hepcidin
Hepcidin is a regulator of iron metabolism. Hepcidin inhibits iron transport by binding to the iron export channel ferroportin which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). Hepcidin ultimately breaks down the transporter protein in the lysosome.
Inhibiting ferroportin prevents iron from being exported and the iron is sequestered in the cells. By inhibiting ferroportin, hepcidin prevents enterocytes from allowing iron into the hepatic portal system, thereby reducing dietary iron absorption. The iron release from macrophages is also reduced by ferroportin inhibition. Increased hepcidin activity is partially responsible for reduced iron availability seen in anaemia of chronic inflammation, such as renal failure.
Any one of several mutations in hepcidin result in juvenile hemochromatosis. The majority of juvenile hemochromatosis cases are due to mutations in hemojuvelin. Mutations in TMPRSS6 can cause anaemia through dysregulation of Hepcidin.
Hepcidin has strong antimicrobial activity against E.coli
ML35P and weaker antimicrobial activity against S.epidermidis,
20
S.aureus and Group B streptococcus bacteria. Active against the fungus C.albicans. No activity against P.aeruginosa.
REGULATION
Hepcidin synthesis and secretion by the liver is controlled by iron stores within macrophages, inflammation, hypoxia, and erythropoiesis. Macrophages communicate with the hepatocyte to regulate hepcidin release into the circulation via eight different proteins: hemojuvelin, hereditary hemochromatosis protein, transferrin receptor 2, bone morphogenic protein 6 (BMP6), matriptase-2, neogenin, BMP receptors, and transferrin.
Erythroferrone, produced in erythroblasts, has been identified as inhibiting hepcidin and so providing more iron for hemoglobin synthesis in situations such as stress erythropoiesis.
Vitamin D has been shown to decrease hepcidin, in cell models looking at transcription and when given in big doses to human volunteers. Optimal function of hepcidin may be predicated upon the
21 adequate presence OF vitamin D in the blood.
FIG 4. HEPCIDIN REGULATION
DISTRIBUTION OF IRON
Functionally iron is found in 3 main compartments in the body
1. Hemoglobin
2. Storage iron – ferrtin , hemosidirin
3. Tissue iron – myoglobin
22
Hemoglobin
Hemoglobin (Hb) is synthesized in a complex series of steps.
The heme part is synthesized in a series of steps in the in a series of steps in the mitochondria mitochondria and the and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol. Heme synthesized by mitochondria, fixed with iron Heme then surrounded by “globin” proteins that surround and “protect” the heme Each single
Hemoglobin molecule has two globin chains, each with its Each single
Hemoglobin molecule has two globin chains, each with its own heme protein attached One globin chain is alpha One is “non-alpha” Two hemoglobin molecules combine to produce functional hgb Tetramer.
23
FIG 5 HEMOGLOBIN STRUCTURE
FIG 6 : MOLECULAR STRUCTURE OF HEME
24
- Alpha globin genes coded on Chrom 16 Each Chrom 16 has 2 alpha gene loci four total per cell four total per cell - Non alpha globin genes on Chrom 11 Arranged from embryonic expression to adult expression (epsilon, gamma, delta, beta ) Adult chromosome has one copy of beta gene. Several hundred abnormal forms of hemoglobin
(variants) have been identified, but only a few are common and clinically significant.
Common hemoglobin variants
Some normal hemoglobin types are; Hemoglobin A (Hb A), which is 95-98% of hemoglobin found in adults, Hemoglobin A2 (Hb
A2), which is 2-3% of hemoglobin found in adults, and Hemoglobin
F (Hb F), which is found in adults up to 2.5% and is the primary hemoglobin that is produced by the fetus during pregnancy
Hemoglobin F: Hb F is the primary hemoglobin produced by the fetus, and its role is to transport oxygen efficiently in a low oxygen environment. Production of Hb F decreases sharply after birth and reaches adult levels by 1-2 years of age. Hb F may be elevated in several congenital disorders. Levels can be normal to significantly increased in beta thalassemia and are frequently increased in individuals with sickle cell anemia and in sickle cell-beta thalassemia.
25
Individuals with sickle cell disease and increased Hb F often have a milder disease, as the F hemoglobin inhibits sickling of the red cells.
Hb F levels are also increased in a rare condition called hereditary persistence of fetal hemoglobin (HPFH). This is a group of inherited disorders in which Hb F levels are increased without the signs or clinical features of thalassemia. Different ethnic groups have different mutations causing HPFH. Hb F can also be increased in some acquired conditions involving impaired red blood cell production.
Some leukemias and other myeloproliferative neoplasms are also associated with mild elevation in Hb F.
Hemoglobin H: Hb H is an abnormal hemoglobin that occurs in some cases of alpha thalassemia. It is composed of four beta (β) globin chains and is produced due to a severe shortage of alpha (α) chains.
Although each of the beta (β) globin chains is normal, the tetramer of
4 beta chains does not function normally. It has an increased affinity for oxygen, holding onto it instead of releasing it to the tissues and cells. Hemoglobin H is also associated with significant breakdown of red blood cells (hemolysis) as it is unstable and tends to form solid structures within red blood cells. Serious medical problems are not
26 common in people with hemoglobin H disease, though they often have anemia.
Hemoglobin Barts: Hb Barts develops in fetuses with alpha thalassemia. It is formed of four gamma (γ) protein chains when there is a shortage of alpha chains, in a manner similar to the formation of
Hemoglobin H. If a small amount of Hb Barts is detected, it usually disappears shortly after birth due to dwindling gamma chain production. These children have one or two alpha gene deletions and are silent carriers or have the alpha thalassemia trait. If a child has a large amount of Hb Barts, he or she usually has hemoglobin H disease and a three-gene deletion. Fetuses with four-gene deletions have hydrops fetalis and usually do not survive without blood
Hemoglobin S: this is the primary hemoglobin in people with sickle cell disease (also known as sickle cell anemia). Approximately
1 in 375 African American babies are born with sickle cell disease, and about 100,000 Americans live with the disorder, according to the
Centers for Disease Control and Prevention. Those with Hb S disease have two abnormal beta chains and two normal alpha chains. The presence of hemoglobin S causes the red blood cell to deform and
27 assume a sickle shape when exposed to decreased amounts of oxygen
(such as might happen when someone exercises or has infection in the lungs). Sickled red blood cells are rigid and can block small blood vessels, causing pain, impaired circulation, and decreased oxygen delivery, as well as shortened red cell survival. A single beta (βS) copy (known as sickle cell trait, which is present in approximately 8% of African Americans) typically does not cause significant symptoms unless it is combined with another hemoglobin mutation, such as that causing Hb C or beta thalassemia.
Hemoglobin C: About 2-3% of African Americans in the United
States are heterozygotes for hemoglobin C (have one copy, known as hemoglobin C trait) and are often asymptomatic. Hemoglobin C disease (seen in homozygotes, those with two copies) is rare (0.02% of African Americans) and relatively mild. It usually causes a minor amount of hemolytic anemia and a mild to moderate enlargement of the spleen.
Hemoglobin E:
Hemoglobin E is one of the most common beta chain hemoglobin variants in the world. It is very prevalent in Southeast
Asia, especially in Cambodia, Laos, and Thailand, and in individuals
28 of Southeast Asian descent. People who are homozygous for Hb E
(have two copies of βE) generally have a mild hemolytic anemia, microcytic red blood cells, and a mild enlargement of the spleen. A single copy of the hemoglobin E gene does not cause symptoms unless it is combined with another mutation, such as the one for beta thalassemia trait.
FERRITIN
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including algae, bacteria, higher plants, and animals. In humans, it acts as a buffer against iron deficiency and iron overload.Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where it functions as an iron carrier. Plasma ferritin is also an indirect marker of the total amount of iron stored in the body, hence serum ferritin is used as a diagnostic test for iron-deficiency anemia.
29
HEMOSIDERIN
Hemosiderin or haemosiderin is an iron-storage complex. The breakdown of heme gives rise to biliverdin and iron. The body then traps the released iron and stores it as hemosiderin in tissues.
Hemosiderin is also generated from the abnormal metabolic pathway of ferritin.
It is only found within cells (as opposed to circulating in blood) and appears to be a complex of ferritin, denatured ferritin and other material.The iron within deposits of hemosiderin is very poorly available to supply iron when needed. Hemosiderin can be identified histologically with Perls' Prussian blue stain; iron in hemosiderin turns blue to black when exposed to potassium ferrocyanide.
Hemosiderin often forms after bleeding (haemorrhage).When blood leaves a ruptured blood vessel, the red blood cell dies, and the hemoglobin of the cell is released into the extracellular space.
Phagocytic cells (of the mononuclear phagocyte system) called macrophages engulf (phagocytose) the hemoglobin to degrade it, producing hemosiderin and biliverdin. Excessive systemic accumulations of hemosiderin may occur in macrophages in the liver, lungs, spleen, kidneys, lymph nodes, and bone marrow. These
30 accumulations may be caused by excessive red blood cell destruction
(haemolysis), excessive iron uptake/hyperferraemia, or decreased iron utilization (e.g., anaemia of copper toxicity) uptake hypoferraemia
(which often leads to iron deficiency anemia).
TISSUE IRON
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is distantly related to hemoglobin which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. In humans, myoglobin is only found in the bloodstream after muscle injury. It is an abnormal finding, and can be diagnostically relevant when found in blood.
Myoglobin is the primary oxygen-carrying pigment of muscle tissues.High concentrations of myoglobin in muscle cells allow organisms to hold their breath for a longer period of time. Diving mammals such as whales and seals have muscles with particularly high abundance of myoglobin. Myoglobin is found in Type I muscle,
Type II A and Type II B.
Myoglobin can take the forms oxymyoglobin (MbO2), carboxymyoglobin (MbCO), and metmyoglobin (met-Mb),
31 analogously to hemoglobin taking the forms oxyhemoglobin (HbO2), carboxyhemoglobin (HbCO), and methemoglobin (met-Hb).
HEMATOLOGICAL CHANGES DURING PREGNANCY
The well-known hypervolemia associated with normal pregnancy averages 40 to 45 percent above the nonpregnant blood volume after 32 to 34 weeks. Pregnancy-induced hypervolemia has several important functions. First, it meets the metabolic demands of the enlarged uterus and its greatly hypertrophied vascular system.
Second, it provides abundant nutrients and elements to support the rapidly growing placenta and fetus. Increased intravascular volume also protects the mother, and in turn the fetus, against the deleterious effects of impaired venous return in the supine and erect positions.
Last, it safeguards the mother against the adverse effects of parturition-associated blood loss.
32
Fig 7 : Hematological changes during pregnancy
Maternal blood volume begins to increase during the first trimester.
By 12 menstrual weeks, plasma volume expands by approximately 15 percent compared with that of prepregnancy maternal blood volume expands most rapidly during the second trimester. It then rises at a much slower rate during the third trimester to plateau during the last several weeks of pregnancy.
33
Fig 8 : Changes in blood volume and plasma volume
Blood volume expansion results from an increase in both plasma and erythrocytes. Although more plasma than erythrocytes is usually added to the maternal circulation, the increase in erythrocyte volume is considerable and averages 450 mL . Moderate erythroid hyperplasia is present in the bone marrow, and the reticulocyte count is elevated slightly during normal pregnancy, these changes are almost certainly related to an elevated maternal plasma erythropoietin level. This peaks early during the third trimester and corresponds to maximal erythrocyte production.
34
Haemoglobin Concentration and Haematocrit
Because of great plasma augmentation, haemoglobin concentration and haematocrit decrease slightly during pregnancy .
As a result, whole blood viscosity decreases. Haemoglobin concentration at term averages 12.5 g/dL, and in approximately 5 percent of women, it is below 11.0 g/dL . Thus, a haemoglobin concentration below 11.0 g/dL, especially late in pregnancy, should be considered abnormal and usually due to iron deficiency rather than pregnancy hypervolemia.
FIG 9 : Haemoglobin and Haematocrit changes during pregnancy
35
Iron Requirements
Of the approximate 1000 mg of iron required for normal pregnancy, about 300 mg are actively transferred to the fetus and placenta, and another 200 mg are lost through various normal excretion routes, primarily the gastrointestinal tract.
FIG 10: Iron requirement in pregnancy
These are obligatory losses and accrue even when the mother is iron deficient. The average increase in the total circulating erythrocyte volume—about 450 mL—requires another 500 mg. Recall that each
1 mL of erythrocytes contains 1.1 mg of iron. Because most iron is
36 used during the latter half of pregnancy, the iron requirement becomes large after midpregnancy and averages 6 to 7 mg/day . In most women, this amount is usually not available from iron stores. Thus, without supplemental iron, the optimal increase in maternal erythrocyte volume will not develop, and the haemoglobin concentration and haematocrit will fall appreciably as plasma volume increases. At the same time, foetal red cell production is not impaired because the placenta transfers iron even if the mother has severe iron deficiency anaemia.
It follows that the amount of dietary iron, together with that mobilized from stores, will be insufficient to meet the average demands imposed by pregnancy. If the nonanemic pregnant woman is not given Supplemental iron, then serum iron and ferritin concentrations Decline after midpregnancy. The early pregnancy increases in Serum iron and ferritin are likely due to minimal early iron demands combined with the positive iron balance from amenorrhea.
The Puerperium
Generally, not all the maternal iron added in the form of hemoglobin is lost with normal delivery. During vaginal delivery and
37 the first postpartum days, only approximately half of the added erythrocytes are lost from most women. These normal losses are from the placental implantation site, episiotomy or lacerations and lochia.
On average, maternal erythrocytes corresponding to approximately 500 to 600 mL of pre delivery whole blood are lost with vaginal delivery of a single foetus. The average blood loss associated with caesarean delivery or with the vaginal delivery of twins is approximately 1000 Ml.
IRON DEFIENCY ANEMIA
The two most common causes of anemia during pregnancy and the puerperium are iron deficiency and acute blood loss . In a typical singleton gestation, the maternal need for iron averages close to 1000 mg. Of this, 300 mg is for the fetus and placenta; 500 mg for maternal hemoglobin mass expansion; and 200 mg that is shed normally through the gut, urine, and skin. The total amount of 1000 mg considerably exceeds the iron stores of most women and results in iron deficiency anemia unless iron supplementation is given.
Iron deficiency is often manifested by an appreciable drop in hemoglobin concentration. In the third trimester, additional iron is
38 needed to augment maternal hemoglobin and for transport to the fetus.
Because the amount of iron diverted to the fetus is similar in a normal and in an iron-deficient mother, the newborn infant of a severely anemic mother does not suffer from iron deficiency anemia.
STAGES OF IRON DEFICIENCY
The progression to iron deficiency can be divided into three stages . The first stage is negative iron balance, in which the demands for (or losses of) iron exceed the body’s ability to absorb iron from the diet. This stage results from a number of physiologic mechanisms, including blood loss, pregnancy (in which the demands for red cell production by the fetus outstrip the mother’s ability to provide iron).
Blood loss in excess of 10–20 mL of red cells per day is greater than the amount of iron that the gut can absorb from a normal diet. Under these circumstances, the iron deficit must be made up by mobilization of iron from RE storage sites. During this period, iron stores— reflected by the serum ferritin level or the appearance of stainable iron on bone marrow aspirations—decrease. As long as iron stores are present and can be mobilized, the serum iron, total iron-binding capacity (TIBC), and red cell protoporphyrin levels remain within normal limits. At this stage, red cell morphology and indices are
39 normal. When iron stores become depleted, the serum iron begins to fall. Gradually, the TIBC increases, as do red cell protoporphyrin levels. By definition, marrow iron stores are absent when the serum ferritin level is <15 μg/L. As long as the serum iron remains within the normal range, hemoglobin synthesis is unaffected despite the dwindling iron stores. Once the transferrin saturation falls to 15–20%, hemoglobin synthesis becomes impaired. This is a period of iron- deficient erythropoiesis. Careful evaluation of the peripheral blood smear reveals the first appearance of microcytic cells, and if the laboratory technology is available, one finds hypochromic reticulocytes in circulation.
40
Fig 11 : microcytic with central pallor
Gradually, the hemoglobin and hematocrit begin to fall, reflecting iron deficiency anemia. The transferrin saturation at this point is 10–15%.
When moderate anemia is present (hemoglobin 10–13 g/dL), the bone marrow remains hypoproliferative. With more severe anemia
(hemoglobin 7–8 g/dL), hypochromia and microcytosis become more prominent, target cells and misshapen red cells (poikilocytes) appear on the blood smear as cigar- or pencil-shaped forms, and the erythroid marrow becomes increasingly ineffective.
41
Fig 12 : Peripheral smear with Hypochromic Microcytic Anemia
Consequently, with severe prolonged iron-deficiency anemia, erythroid hyperplasia of the marrow develops, rather than hypoproliferation.
42
Fig 13 : Erythroid Hyperplasia of Bone Marrow .
CAUSES OF IRON DEFIENCY
• Pre-pregnancy poor nutrition very important
• Besides Iron, folate and B12 deficiency also important
• Chronic blood loss due to parasitic infections – Hookworm &
malaria
• Multiparity
• Multiple pregnancy
43
• Acute blood loss in APH, PPH
• Recurrent infections (UTI) - anemia due to impaired
erythropoiesis
• Hemolytic anemia in PIH
• Hemoglobinopathies like Thalassemia, sickle cell anemia
• Aplastic anemia is rare.
Tab 2 : Classification of Anemia
44
EFFECT OF ANEMIA ON PREGNANCY
1. Higher incidence of pregnancy complications
2. PET, abruption placentae, preterm labour
3. Predisposed to infections like – UTI, puerperal sepsis
4. Increased risk to PPH
5. Sub involution of uterus
6. Lactation failure
7. Maternal mortality – due to
8. CHF,
9. Cerebral anoxia,
10. Sepsis,
11. Thrombo-embolism.
EFFECT OF ANEMIA ON FETUS
1. Higher incidence of abortions, preterm birth, IUGR
2. IUD
3. Low APGAR at birth
4. Neonate more susceptible for anemia & infections
5. Higher Perinatal morbidity & mortality
6. Anemic infant with cognitive & affective dysfunction
45
CLINICAL FEATURES
Depends on severity of anemia
Mild anemic - asymptomatic
Symptoms – pallor, weakness, fatigue, dyspnoea, palpitation, swelling over feet & body
Signs – pallor, facial puffiness, raised JVP, tachycardia, tachypnea, crepts in lung bases, hepato-splenomegaly, pitting oedema over abdominal wall & legs. Haemic murmur, cardiac failure. Glossitis, stomatitis, chelosis, brittle hair.
Fig 14: PALLOR
46
Fig 15: CLINICAL FEATURES OF ANAEMIA
47
Diagnosis - Basic Investigation
CBC,
CHG WITH PS,
RBC INDICES,
RETICULOCYTE COUNT
URINE ROUTINE & CULTURE AND SENSITIVITY
STOOL FOR OVA AND CYST
Classic morphological evidence of iron deficiency anaemia— erythrocyte hypochromic and microcytosis—is less prominent in the pregnant woman compared with that in the nonpregnant woman.
RBC INDICES
RBC count – decreases in anemia (N 3.2 million/cu mm)
PCV - < 32%, (N37-47%)
MCV – low in iron defiency anemia, microcytic
MCH - decreases
MCHC – decreases, one of the most sensitive indices (N26-30%)
48
SPECIAL INVESTIGATIONS
Serum Ferritin – abnormal if < 20 ng/ml (N 40-160 ng/dl), assess iron stores
Serum Iron – N 65-165 ug/dl, decreases in Fe def anemia
Serum Iron binding capacity – 300-360 ug/dl, increases with severity of anemia
Percentage saturation of transferrin – 35-50%, decreases to less than
20% in Iron def anemia
RBC Protoporphyrin – 30ug/dl, it doubles or triples in iron defiency anemia ( substrate to bind with Fe, cannot be converted into Hb in iron defiency anemia )
Bone marrow studies can be done in those patients with refractory anemia .
Treatment of IDA – GENERAL CONSIDRATIONS
Improving diet rich in iron & fruits & leafy vegetables
Treat worm infections, maintain general hygiene
Food fortification with iron & genetic modification of food
Iron & folic acid supplementation in young girls & during
pregnancy
49
Heme iron better, present in animal food & is better absorbed
Iron absorption enhanced by citrous fruits, Vit C
Avoid tea, coffee, Ca, phytates, phosphates, oxalates, egg, cereals
with iron
Green leafy vegetables-chana sag, sarson ka sag, chauli. Sowa,
salgam
Cereals - wheat, ragi, jowar, bajra
Pulses-sprouted pulses
Jaggery
Animal flesh food - meat, liver
Vit C - lemon, orange, guava, amla, green mango etc
Fig. 16. Iron rich food
50
Supplementation- Interventions as suggested by Ministry of
Health and Family Welfare Government of India:
(i) At 14-16 weeks - First Hb estimation should be done at 14-16th week pregnancy during antenatal visit:
• If the Hb is more than 11 gms, prophylactic doses of IFA tablets are given.
• If the Hb is 7.1-10.9 gms%, therapeutic doses of IFA tablets are given.
• If the Hb is less than 7 gms%, she has to be referred to CEmONC centres (Comprehensive Emergency Obstetric and New Born Care
Services) for blood transfusion and further management.
51
(Prophylactic dose: Tab.IFA (100 mg of iron with 0.5mg of folic acid) once daily for 100 days.
Therapeutic dosage: Tab.IFA twice daily for 100 days.
(ii) At 20-24 weeks- Second Hb estimation has to be done between 20 and 24 weeks of gestation for all pregnant mothers.
• If the Hb is more than 11 gms, give prophylactic dose of IFA tablets.
• If the Hb is 9-10.9 gms%, give therapeutic dose of IFA tablets.
• If haemoglobin level is between 7.1 to 8.9 gm/dl. Intravenous (IV)
Iron sucrose infusion should be given.
• If the Hb is less than 7 gms%, she has to be referred to CEmONC centres for blood transfusion and further management.
(iii) At 26-30 weeks- Third Hb estimation has to be done between 26 and 30 weeks of gestation for all pregnant mothers. For ante-natal mothers infused with iron sucrose infusion during 20-24 weeks, Hb estimation has to be done after one month. • If the Hb is more than 11 gms, assure and counsel to continue with prophylactic dose of IFA tablets.
52
• If the Hb is 9-10.9 gms%, assure and counsel the mother for further improvement of Hb% and continue with therapeutic dose of IFA tablets.
• If the Hb is 7.1 -8.9 gms%
For mothers who received iron sucrose infusion, give two top up doses of 100 mgs of Iron sucrose infusion with 2-4 days’ interval between each infusion.
For mothers who had not received injection iron sucrose earlier during current pregnancy, give four doses of iron sucrose injection (100 mg in 100 ml of normal saline infused over 20 -30 minutes once a day x
4 days over a period of 2 weeks with 2-4 days of interval between each infusion)
• If the Hb is less than 7 gms%, she has to be referred to CEmONC centres for blood transfusion and further management.
ORAL IRON
60 mg elemental iron & 400 ug of folic acid daily during pregnancy and 3 months there after.In anemia therapeutic doses are 180-200 mg
/d
53
Route of administration depends on, severity of anemia, Gest age, compliance & tolerability of iron.
Various preparations – fumarate, gluconate, succinate, sulfate, ascorbate
Carbonyl iron better tolerated
Oral iron can have side effects like nausea, vomiting, gastritis, diarrhoea, constipation.
Fig 17. TABLET FERROUS SULFATE
54
Contraindication to Oral Iron Therapy
Intolerance to oral iron
Severe anemia in advanced pregnancy
Non compliant
Failure to Respond
Inaccurate diagnosis
Faulty absorption
Continuous blood loss
Co-existant infection
Concomitant folate deficiency
INDICATORS FOR IRON RESPONSE
Feeling of well being
Improved look of patient
Better appetite
Rise in Hb .5-.7 gm/dl per week (starts after 3 weeks)
Reticulocytosis in 7-10 days
55
PARENTRAL IRON THERAPY
INDICATONS
IV iron administration is indicated in four situations: a. In acquired or hereditary decreased intestinal iron absorption and/or liberation of iron from macrophages. Cases with high hepcidin levels secondary to any kind of inflammation represent the most common acquired cause of this setting . The newly described IRIDA disease is the best example of hereditary iron malabsorption associated with decreased iron release from the macrophages .This category also includes cases where, because of surgery, intestinal iron absorption is abolished, e.g. post gastrectomy. b. In cases with true severe iron deficiency because of continuous severe bleeding or because of increased iron needs(pregnancy) or combination of both previous situations (post-partum anaemia). c. In cases of functional iron deficiency particularly when an erythropoietin stimulating agent (ESA) is used such as in renal anaemia, anaemia of cancer patients and autologous blood donation before elective surgery.
56 d. Finally in case of intolerance or non compliance to oral iron treatment main indications
1. Cancer related anemia
2. Postpartum anemia
3. Anemia in pregnancy
4. Anemia in chronic kidney diseases
5. Anemia in inflammatory bowel disease
6. In malabsorption.
Available intravenous iron preparations
1. High molecular weight iron dextran, was for years considered to be the reference iron preparation for IV administration. The main advantage was the possibility to give the totality of the calculated iron dose. However, because of the antigenicity of the dextran macromolecule allergic reactions are the main severe complications which obliged clinicians to greatly limit its use . Currently high molecular weight dextran is only used in a few countries where the new IV iron preparations are not yet available.
2. Low molecular weight iron dextran was recently introduced as an improved form of IV iron with a negligible risk of allergic reactions.
57
Studies in pregnancy and in chronic kidney disease demonstrated its efficacy and its safety.
Fig 18. IRON DEXTRAN
3. Iron sucrose is one of the most popular IV iron preparations particularly in the treatment of renal anaemia. It was also studied in gynaecology, particularly in post-partum anaemia, in anaemia of inflammatory bowel disease and in elective orthopedic surgery. It is administrated in doses varying from 50 to 300 mg/perfusion with a
58 maximum dosage of 900 mg/week (= 3 x 300 mg). It is diluted in 1 mL 0.9% NaCl per mg of iron and it is given as an infusion over 15 to 45 minutes. The product is extremely safe, allergic reactions being
< than 1/100.000 infusions.
FIG 19 IRON SUCROSE
59
4. Ferric gluconate is another IV iron preparation used in haemodialysis patients, in anaemia of cancer as well as in anaemia of patients treated in intensive care units. Because of stability of the molecule only small quantities of iron can be infused without risk of serious side effects .
FIG.20 IRON GLUCONATE
60
5. Ferric carboxymaltose is the most recently registred iron preparation . its use in chronic kidney disease, in the treatment of post-partum anaemia and in inflammatory bowel disease have proved its efficacy and its safety. The most important advantages of this preparation are the possibility to infuse up to 1000 mg of iron, with almost no risk of side effects and in a small perfusion time (15 min).
FIG 21 FERRIC CARBOXYMALTOSE
61
THE PHARMACOKINETICS OF FCM – The important pharmacokinetic aspect of the drug is that, this drug has the maximum transferrin saturation, unlike the other drugs of the group , by this method the amount of iron available for absorption is more and the amount of free iron is less there by costing less adverse reaction .
6.Ferumoxytol is an iron oxide nanoparticle with polyglucose sorbitol carboxymethylether coating designed to minimise immunological sensitivity so that large doses may be given .One phase 3 trial demonstrated the efficacy of this new agent in anaemic patients with chronic kidney disease.
ADVERSE EFFECTS
Intramuscular: – Local pain at site , pigmentation of skin , sterile abcess – Systemic: headache, fever, arthralgia, backache, tachycardia, flushing hemolysis and collapse these effects are probably due to excessive amount of free iron in plasma
Adverse effects
Intravenous – Systemic reaction of more severe form –
Anaphylactoid reaction can occur within minutes – Severe chest pain, respiratory distress circulatory collapse.
62
BLOOD TRANSFUSION
INDICATIONS
Severe anemia first seen after 36 weeks of pregnancy and in postnatal period
Anemia due to acute blood Loss – APH & PPH
Associated Infection
Patient not responding to oral or parenteral therapy
The quality and quantity of blood: The blood to be transfused should be relatively fresh, properly typed, grouped and cross matched. Only packed cells are transfused. The quantity should be between
80 mL and 100 ml at a time. To allow time for circulatory readjustment, transfusion should not be repeated within 24 hours.
Advantages of blood transfusion:
(1) Increases oxygen carrying capacity of the blood
(2) Hemoglobin from the hemolyzed red cells may be utilized for the formation of new red cells
(3) Stimulates erythropoiesis.
(4) Supplies the natural constituents of blood like proteins, antibodies, e
(5) Improvement is expected after 3 days.
63
Precautions:
Utmost precautions are to be taken to minimize reaction and over loading of the heart.
(1) Antihistaminic (Phenergan 25 mg) is given intramuscularly
(2) Diuretics (Frusemide 20 mg) is given intramuscularly at least 2 hours prior to transfusion to produce negative fluid balance
(3) The drip rate should be about 10 drops per minute
(4) To observe carefully the pulse, respiration and crepitations in the base
of lungs.
Drawbacks:
(1) Premature labor may start which is more related to blood reaction. (2)
There is increased chance of cardiac failure with pulmonary edema because
of overloading of the heart.
(3) Features of transfusion reaction, if occur, are often exaggerated.
64
OBJECTIVES OF THE STUDY
OBJECTIVES OF THE STUDY
To evaluate the efficacy and safety of ferric carboxymaltose injection in improving Hemoglobin levels and comparing it with iron sucrose in postpartum iron defiency anemia
65
MATERIALS AND METHOD
MATERIALS AND METHODS
STUDY PLACE : MADURAI MEDICAL COLLEGE
STUDY DESIGN : PROSPECTIVE, OBSERVATIONAL &
COMPARETIVE STUDY
STUDY PERIOD : 3 MONTHS
( JANUARY 2019 TO MARCH 2019 )
SAMPLE SIZE : 100 CASES
ETHICAL CLEARANCE : OBTAINED
PARTICIPANTS :
The study population included all women who delivered at GRH ,
MADURAI during the study period
Inclusion criteria :
• All normal delivered and caesarean delivered patients with
Iron defiency anemia ( HB < 10g %)
66
• All primi and multi parous women
Exclusion criteria :
• Patients with hemoglobin levels less than 7gm%.
• Patients with history of allergic reactions to previous iron therapy.
• Severe asthma/allergy
• Patients with other causes of anaemia like: Liver diseases
Renal disease.
METHODOLOGY :
The study comprises of 100 cases who are to be randomly distributed into two groups consisting of 50 cases each.
• Group - A: 50 cases in this group will receive intravenous iron
Carboxymaltose therapy.
• Group - B: 50 cases in this group will receive intravenous iron sucrose therapy.
The participants consent were sought and obtained after adequate information about all aspects covered by the study.
Voluntary participation including the right to decline, being in the
67 study or to withdraw their participation at any time they wish to do so was emphasized. They were ensured of receiving the same care whether they agree to participate or not. A signed consent form was mandatory since there is a chance of severe drug reaction. All the women informed that obtained data is confidential and only for research purpose. Ethical clearance was obtained from the Human
Ethics Committee of the Government Medical College MADURAI.
The mother who voulentered for the study a basic workup for anemia was done which included complete blood count , and a complete hemogram with peripheral smear , this was done to identify the type of anemia
GANZONI ‘ S FORMULA:
• Calculation of total iron requirement Iron deficit
• calculated by the formula:
• Total iron deficit = Iron deficit + amount of iron
• Hb deficit = Target Hb - Initially measured Hb
• Target Hb concentration = 11 gm%
• Iron required to replenish = Body weight (kg) × 10 stores
(mg)
68
• Total iron dose required (mg) = 2.4 × Body weight (kg) ×
(Target Hb - Actual Hb in g/dl) + 500 mg.
After calculating the iron dose required for each patient in both the groups the required amount of drug was administered in the following way
IRON THERAPY
GROUP A : Intravenous injections (Iron carboxymaltose
Complex)They are available as ampules of 20 ml containing 1000 mg of elemental iron. Total 1000 mg/20 ml in 250 ml of 0.9% normal saline infused over 15-20 min at a rate of 2ml to 4 ml per min. single dose was only administered for all mothers of the group . there was no need for second dose .
GROUP B : Intravenous injections (iron sucrose complex) Iron sucrose complex was given as 200 mg elemental Iron (2 ampules of 5 ml) in 100 ml of 0.9% normal saline and infused over 30 min. every alternate days up to 5dose. ALL women in this group had 5 doses of iron sucrose on the alternate day .
AFTER been administered with the drug the mothers who were administered inj. Ferric carboxy maltose were discharged on the next
69 day and was adviced not to take any other form of oral iron and those patients were reviewed after 2 weeks and 4th week .
Those mothers who were on inj . iron sucrose were discharged on the 10th day after completion of course of the dosing , they were asked not to take any other form of iron and to review after 2nd week and 4th week
70
RESULT AND ANALYSIS
RESULTS AND ANALYSIS
This study was done in hundred patients with postnatal anaemia who delivered at government Rajaji hospital, irrespective of mode of delivery.
The initial assessment of the mother was to look for clinical wellbeing, the intial assessment was done two weeks after the administration of the drug , the final outcome was assessed by estimating the haemoglobin values , and a peripheral smear picture done after 4 weeks .
Statistical Analysis:
To calculate the mean +- SD, descriptive analysis was used. means of the parameters of both the groups were compared using independent student to test. A p value of 0.05 was considered significant. Statically analysis was performed using the SPSS software package.
71
Age
AGE FCM % Iron Sucrose % 18 - 20 1 2 12 24 21 - 25 24 48 20 40 26 - 30 16 32 12 24 > 30 9 18 6 12 TOTAL 50 100 50 100
CHART -1
AGE
25 24 20 20 16 15 12 12 9 10 6 5 1 0 18 - 20 21 - 25 26 - 30 > 30
FCM Iron Sukrose
AGE
72
Parity
PARITY FCM % Iron Sukrose % P1 22 44 20 40 P2 19 38 18 36 P3 9 18 11 22 P4 0 0 1 2 TOTAL 50 100 50 100
CHART 2
73
SOCIO ECONOMIC STATUS
SOCIO FCM IRON SUCROSE
ECONOMIC
UPPER MIDDLE 2 1
LOWER MIDDLE 10 12
POOR 38 34
TOTAL 50 50
CHART 3
SOCIO ECONOMIC STATUS
74
PRE TRANSFUSION HB
PRE FCM HB FCM % Iron Sucrose % < 8 28 56 32 64 > 8 22 44 18 36 TOTAL 50 100 50 100
Mean 7.864 7.734
CHART 4
PRE TRANSFUSION HB
PRE HB 30 28 22 20 10 0 < 8 > 8
75
HEMATOCRIT
PRE FCM PCV FCM % Iron Sucrose % < 25 22 44 25 50 > 25 28 56 25 50 TOTAL 50 100 50 100
CHART 5
HEMATOCRIT
PRE PCV FCM
25 > 25 28
25 < 25 22
0 5 10 15 20 25 30
76
PALLOR
5PALLORFCMIron Sukrose Pallor + 41 48 no pallor 9 2 TOTAL 50 50
CHART 6
PALLOR
PALLOR
48 60 41 40 9 20 2 0 Pallor + no pallor
FCM
77
PERIPERAL SMEAR
PERIPERAL SMEAR 1 FCM % Iron Sucrose % Hypochromic microcytic 41 82 50 100 normochromic normocytic 9 18 0 0
TOTAL 50 100 50 100
CHART 7
PERIPHERAL SMEAR
50 50 41 40 30 20 9 10 0 0 Hypochromic microcytic normochromic normocytic
FCM Iron Sucrose
78
POST TRANSFUSION HB
POST FCM HB FCM % Iron Sukrose % < 10.5 18 36 49 98 > 10.5 32 64 1 2 TOTAL 50 100 50 100 Mean 10.762 9.442
SD 0.605 0.589
CHART 8
POST TRANSFUSION HB
POST HB
50 49
40 32 30 18 20
10 1 0 < 10.5 > 10.5
FCM
79
POST TRANSFUSION HAEMATOCRIT
POST FCM PCV FCM % Iron Sucrose % < 35 8 16 40 80 >35 42 84 10 20
TOTAL 50 100 50 100
CHART 9
POST TRANSFUSION HAEMATOCRIT
POST PCV
42 45 40 40 35 30 25 20 15 10 10 8 5 0 < 35 >35
FCM
80
CHART 10
POST TRANSFUSION PEROPHERAL SMEAR
PERIPHERAL SMEAR 2 FCM % Iron Sucrose % hypochromic microcytic 2 4 49 98 normochromic normocytic 48 96 1 2
TOTAL 50 100 50 100
POST TRANSFUSION PEROPHERAL SMEAR
PERIPHERAL SMEAR 2
49 48 50
40
30
20
10 2 1 0 hypochromicnormochromic microcytic normocytic
FCM
81
CHART 11
ALLERGIC REACTION
Complications FCM % Iron Sukrose % allergic rection 2 4 0 0 Allergic rashes 1 2 0 0 breathlessness 0 0 1 2 flushing 0 0 1 2 skin rashes 0 0 4 8 Nil 47 94 44 88 TOTAL 50 100 50 100
ALLERGIC REACTION
Complications
47 50 44
40
30
20
10 4 2001 00011 0 allergicAlleergic rectionbreathlessness rashesflushingskin rashesNil
FCM
82
CHART 12
PRE FCM HB VS POST FCM HB
12 10.762 10 7.864 8 6 4 2 0 PRE FCM HB POST FCM HB
PRE FCM HB
pre iron sucrose Hb VS post iron sucrose hb
10 9.442 9 7.734 8 7 6 5 4 3 2 1 0 PRE IRON SUCROSE POST IRON SUCROSE
PRE IRON SUCROSE
83
DISCUSSION
DISCUSSION
We as a nation have been battling against anaemia since many years. Iron is one of the most abundant minerals in nature and most life forms require it. Ironically, it is also the most common nutrient deficiency in the world leading to anemia, which has now become a serious global healthconcern. It is alarming to know that the prevalence of anaemia in India is as high as 62% and it is projected that India has the utmost prevalence among the South Asian countries.
Anaemia in pregnancy is associated with unfavorable consequences both for the mother and the fetus and is a major cause of maternal and perinatal mortality and morbidity. The detection of anaemia in pregnancy and its effective management is available, affordable and possible.
The search for an ideal parenteral iron preparation has led to the introduction of Ferric carboxymaltose. This study was conducted with the aim to compare the efficacy and safety of intravenous Ferric
Carboxymaltose with Iron Sucrose in Iron deficiency anaemia of pregnancy. There was a statistically significant rise in Hb in FCM group as compared to that of Iron Sucrose .
84
The Group A mothers where those who were given inj. Ferric carboxymaltose and group B mothers where those who were given inj. Iron sucrose .
According to age distribution most of the anemic mothers where between the age of 25 to 30 years , and found to be statiscally significant with a p value of <0.025 .
Then when classified according to b.j Prasad classification of socio economic status , most of the women belong to class v ie poor and few women belong to class iv ie lower middle class. And this was found to be statiscally significant and was found similar to other studies .
The pre transfusion haemoglobin and haematocrit was less than
7 and 22 respectively most of the women had clinical pallor , and more than 60 % of mothers had clinical pallor , and the peripheral smear of the women in both the group was hypochromic microcytic picture
When parity was taken in to account most of the anemic mothers where primiparous women , but the overall incidence of anemia was found high among multiparous women , hence this was not satiscally significant .
85
Post transfusion status of the mothers of both the group the average increase in haemoglobin and haematocrit values was significantly high with those mothers on inj. Ferric carboxymaltose than those mothers on iron sucrose . the initial clinical assessment of those mothers during the first follow up visit nearly 85 % of the women had clinical improvement .
The mean hemoglobin level before starting therapy in group A was 7.8 gm/dl and in group B was 7.76 gm/dl , there was an increase of 3 gm/dl in hemoglobin level after 4 weeks of therapy and mean hemoglobin level was 10.7 gm/dl in group A and in group B there was an increase of 2.4 gm/dl in hemoglobin level and the hemoglobin level was 9.4 gm/dl .
And this was found to be statically significant with a p value of
<0.001. Adverse event were more among those mother who received iron sucrose than those mothers who received inj. Ferric carboxy maltose, only 3 women had allergic reaction with inj . FCM all were mild reaction , there was no severe allergic reaction documented in any of the groups . since the number of adverse events were few with
FCM group this turns to be more safety than iron sucrose .
86
CONCLUSION
CONCLUSION
Thus we can conclude that intravenous iron carboxymaltose therapy is safe, convenient, more effective and faster acting than intravenous iron sucrose therapy for the treatment of severe iron deficiency anemia during postpartum period.
Ferric carboxymaltose thus seems superior to Iron sucrose for definitive treatment of anaemia in pregnancy.The only limiting factor is its high cost but this is very well compensated when the number of visits/ days of admission in hospital is taken into account. Also reduced frequency of venous access reduces the risk of infection.
87
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8.Froessler B, Collingwood J, Hodyl NA, Dekker G. Intravenous ferric carboxymaltose for anaemia in pregnancy. BMC Pregnancy
Childbirth. 2014;14:115.
9.Froessler B, Gajic T, Dekker G, Hodyl NA. Treatment of iron deficiency and iron deficiency anemia with intravenous ferric carboxymaltose in pregnancy. Arch Obstet Gynaecol. 2018; https://doi.org/10.1007/s00404-018-4782-9.
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IV iron carboxymaltose compared with oral iron in the treatment of postpartum anemia. Obstet Gynecol. 2008;111(4):996.
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89 injection for iron deficiency anemia in heavy uterine bleeding; a randomized controlled trial. Transfusion. 2009;49(12):2719–28.
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2017 Sep 18
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PROFORMA
PATIENT PROFORMA
• Name
• Age
• Ip No
• Address
• Parity
• Education
• Socio economic status
• Present history
• Past history :
• Menstural history :
• Marital history:
• Antenatal history :
• Intranatal :
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GENERAL EXAMINATION
• PALLOR
• PEDAL EDEMA
• PR
• BP
• SPO2
SYSTEMIC EXAMINATION
• CVS
• RS
• P/A
• P/V
INVESTIGATIONS
• CBC
• CHG WITH PERIPHERAL SMEAR
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• RETICULOCYTE COUNT
• RBS ,RFT,LFT
• URINE ROUITNE
• STOOL FOR OVA AND CYST
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MASTER CHART
FCM MASTER CHART
NAME AGE IP NO PARITY PRE FCM HB PRE FCM PCV PALLOR PERIPERAL SMEAR 1 POST FCM HB DIVYA BARRATHI 23 18190 P2L2 7.1 28 Pallor + Hypochromic microcytic 10.3 kamala 28 18632 p1l1a2 7.2 26 Pallor + Hypochromic microcytic 9.8 Nandhini 27 19632 p1l1 7.4 28 Pallor + Hypochromic microcytic 10.2 kaleeshwari 25 22190 p2l2 7.7 29 Pallor + Hypochromic microcytic 11.4 palaniammal 29 14982 p2l2 9.2 32 no pallor normochromic normocytic 11.8 baby 24 14952 p1l1 9.4 30 no pallor normochromic normocytic 11.4 kamala 29 18192 p2l2 8.2 28 no pallor normochromic normocytic 11.2 veeravalli 23 17429 p2l2a1 8.7 29 no pallor normochromic normocytic 11.6 alagumeena 20 17448 p1l1 7 24 Pallor + Hypochromic microcytic 10.6 chinnaponnu 32 14517 p3l4 9.1 28 Pallor + Hypochromic microcytic 11.2 meena 24 14322 p1l1 7.7 24 Pallor + Hypochromic microcytic 10.8 lakshmi 29 17647 p2l2 8.2 28 Pallor + Hypochromic microcytic 11.2 arul vasanthi 32 14381 p1l2 8.2 28 Pallor + Hypochromic microcytic 9.2 vishitra 24 14872 p1l1 7.6 24 Pallor + Hypochromic microcytic 10.8 kulandai theresa 30 14871 p3l2 8.4 28 Pallor + Hypochromic microcytic 11.2 deepa 24 14372 p3l3 7.4 24 Pallor + Hypochromic microcytic 10.8 podialagu 21 19372 p1l1 7.2 22 Pallor + Hypochromic microcytic 9.8 premalatha 21 18810 p1l1 8.4 26 Pallor + Hypochromic microcytic 11.6 selvarani 24 19864 p3l3 7 22 Pallor + Hypochromic microcytic 10.2 sangeetha 33 19876 p3l3 7 20 Pallor + Hypochromic microcytic 10.2 shivasankari 32 14532 p3l2 8 23 Pallor + Hypochromic microcytic 9.8 geetha 30 14332 p2l2 7.6 24 Pallor + Hypochromic microcytic 10.2 perinbam 24 19865 p1l1 7.2 23 Pallor + Hypochromic microcytic 10.6 amutha 22 14657 p1l1 8.4 26 Pallor + Hypochromic microcytic 11.2 archana 24 17654 p2l2 8.8 32 Pallor + Hypochromic microcytic 11.8 sathya 23 13242 p1l1 8.2 32 Pallor + Hypochromic microcytic 11.4 saranya 32 15564 p3l3 7.6 28 Pallor + Hypochromic microcytic 10.8 meenatchi 29 16854 p3l2 7.2 24 Pallor + Hypochromic microcytic 10.3 vinitha 32 17654 p2l2 7.6 22 Pallor + Hypochromic microcytic 10.8 rajeshwari 26 19861 p1l1 7.2 24 Pallor + Hypochromic microcytic 10.2 kokila 22 19865 p3l2 7.1 22 Pallor + Hypochromic microcytic 10.4 panchavarnam 32 14567 p2l2 8.2 28 Pallor + Hypochromic microcytic 10.2 sharatha 26 14563 p1l1 7.2 22 Pallor + Hypochromic microcytic 10.2 raji 27 15482 p2l2 7.4 24 Pallor + Hypochromic microcytic 10.2 latha 23 16547 p2l2 7.7 28 Pallor + Hypochromic microcytic 10.6 radhika 25 12234 p1l1a1 7.2 24 Pallor + Hypochromic microcytic 10.6 suganthi 32 16598 p2l2 7.7 22 Pallor + Hypochromic microcytic 10.3 kalpana 30 22134 p1l1 8.2 28 Pallor + Hypochromic microcytic 11.2 indhu 27 19854 p1l1 8.4 30 Pallor + Hypochromic microcytic 11.6 meenatchi 22 15160 p2l1 8.7 32 no pallor normochromic normocytic 11.8 manikavalli 26 15551 p1l1 8.7 34 no pallor normochromic normocytic 11.2 kanathal 23 15504 p1l1 8.2 32 no pallor normochromic normocytic 11.2 raji 27 17665 p2l2 7.2 24 Pallor + Hypochromic microcytic 10.8 nithya 24 18867 p1l1 7.2 24 Pallor + Hypochromic microcytic 10.8 anitha 25 14453 p2l2 8.2 28 Pallor + Hypochromic microcytic 10.2 vijayashanthi 24 13254 p1l1 7.4 24 Pallor + Hypochromic microcytic 10.8 parameshwari 25 12234 p2l2 8.2 28 Pallor + Hypochromic microcytic 10.2 parvathy 27 15564 p1l1 7.4 22 Pallor + Hypochromic microcytic 10.8 karthiga 32 17765 p2l1 8.6 26 no pallor normochromic normocytic 11.2 seetha 21 18976 p2l2 8.4 26 no pallor normochromic normocytic 11.4
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IRON SUCROSE MASTER CHART
Name age ip no parity pre iron sucrose Hb pcv pallor peripheral smear post iron sucrose hb sivaranjani 23 19147 p1l1 7.2 28 pallor + hypochromic microcytic 9.2 shanthini 23 62074 p2l2 8.2 30 pallor + hypochromic microcytic 9.8 jenipriya 28 19251p2l2 7.6 27pallor + hypochromic microcytic 9.8 gowri madha 30 61281 p3l3 8.6 32 no pallor hypochromic microcytic 10.2 muthuramalakshmi 28 19243 p1l1 8.2 30 pallor + hypochromic microcytic 10.8 anjugam 38 17884 p1l2 7.2 24 pallor + hypochromic microcytic 9.2 bakyalakshmi 30 18369 p2l1 7.4 28 pallor + hypochromic microcytic 9.4 jeya bharathi 23 62244 p3l3 7.8 26 pallor + hypochromic microcytic 9.2 pavithra 22 62037 p1l1 7.2 22 pallor + hypochromic microcytic 7.6 radhamani 25 19311 p2l2 8.2 26 pallor + hypochromic microcytic 9.8 kartheshwari 31 19359 p3l3 7.6 24 pallor + hypochromic microcytic 9.2 Abirami 22 19354 p1l1 7.2 20 pallor + hypochromic microcytic 9.6 manimegalai 25 19150 p2l2 7.4 24 pallor + hypochromic microcytic 9.5 lakshmi 27 19391 p2l2 7.2 22 pallor + hypochromic microcytic 9.8 sudha 26 62060 p2l2 7.4 22 pallor + hypochromic microcytic 9.6 dhayanidhi 26 19485 p1l1 7.8 26 pallor + hypochromic microcytic 9.4 ayyammal 31 19476 p3l3 7.2 23 pallor + hypochromic microcytic 9.8 jothilakshmi 19 19222 p2l2 7.4 22 pallor + hypochromic microcytic 7.4 muthulakshmi 26 18690 p1l1 8.2 30 pallor + hypochromic microcytic 8.2 preetha 20 19496 p2l2 8.4 30 pallor + hypochromic microcytic 8.4 roshini 18 19566 p1l1 8.2 30 pallor + hypochromic microcytic 9.8 chitra 19 20216 p2l2 7.6 28 pallor + hypochromic microcytic 9.6 ramalakshmi 24 65527 p2l2 7.2 23 pallor + hypochromic microcytic 9.2 nithya 22 20334 p1l1 8 29 pallor + hypochromic microcytic 9.8 sangavi 27 20309 p3l3 7.4 25 pallor + hypochromic microcytic 9.2 mumtaj 21 20340 p2l2 7.6 25 pallor + hypochromic microcytic 9.6 tharani 19 19933 p1l1 8.2 27 pallor + hypochromic microcytic 10.2 roopa 18 20185 p1l1 8.4 28 pallor + hypochromic microcytic 10.2 kalpana 35 20306 p3l3 7.2 24 pallor + hypochromic microcytic 9.8 jothika 21 20947 p2l2 7 20 pallor + hypochromic microcytic 9.2 anusya 19 67573 p1l1 7.2 22 pallor + hypochromic microcytic 9.8 murugeshwari 21 20994 p2l2 8.2 26 pallor + hypochromic microcytic 10.2 suganya 18 20933 p1l1 7.6 24 pallor + hypochromic microcytic 9.6 karthika 23 67688 p2l2 7.4 22 pallor + hypochromic microcytic 9.2 thangameena 24 67570 p3l3 7.3 21 pallor + hypochromic microcytic 9.8 selvi 25 20898 p3l3 7.4 22 pallor + hypochromic microcytic 9.2 thamarai 18 21043 p1l1 7.2 21 pallor + hypochromic microcytic 9.4 nandhini 20 21004 p1l1 8.4 30 pallor + hypochromic microcytic 9.6 suryaprabha 19 68021 p1l1 8.6 32 no pallor hypochromic microcytic 9.2 ragavi 22 21336 p1l1 7.2 22 pallor + hypochromic microcytic 9.2 nagajothi 23 21201 p2l2 7.4 24 pallor + hypochromic microcytic 9 pandiselvi 19 68217 p1l1 8.2 25 pallor + hypochromic microcytic 9.4 anandhi 21 21244 p1l1 8.6 28 pallor + hypochromic microcytic 9.8 alagukanagavalli 25 21166 p1l1 7.7 29 pallor + hypochromic microcytic 9.3 kousalya 28 21195 p3l3 7.5 25 pallor + hypochromic microcytic 9.6 malarvizhi 29 68222 p3l3 7.4 25 pallor + hypochromic microcytic 9.3 pechiammal 35 68671 p4l3 8.5 30 pallor + hypochromic microcytic 9.2 pandiammal 32 68735 p2l2 8.3 29 pallor + hypochromic microcytic 9.6 kanaga 24 68739 p1l1 8.2 30 pallor + hypochromic microcytic 9.4 jeyalakshmi 26 68687 p2l2 8.2 31 pallor + hypochromic microcytic 9.8
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ETHICAL CLEARANCE CERTIFICATE
ETHICAL COMMITTEE CERTIFICATE
96
CONSENT FORM
I MRS.______W/O ------Hosp. No.______in my full senses hereby give my full consent for THERAPUTIC procedure FOR FCM/
IRON SUCROSE transfusion for anemia correction . The nature, risks and complications involved in the procedure have been explained to me in my own language and to my satisfaction.
Signature/Thumb Impression
Name of Patient/Guardian:
Guardian Relation ship
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PLAGIARISM CERTIFICATE
CERTIFICATE
This is to certify that this dissertation titled “STUDY TO EVALUATE THE
EFFICACY OF FERRIC CARBOXYMALTOSE VS IRON SUCROSE IN
POSTPARTUM CASES WITH IRON DEFICIENCY ANEMIA” of the candidate
Dr. A.NARMADHAPRIYA with registration number 221616103 for the award of
M.S. BRANCH II degree in the branch of OBSTETRICS AND GYNAECOLOGY.
I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file containing from introduction to conclusion pages and result shows 4 percentage of plagiarism in the dissertation.
Prof. DR.N.SUMATHI.M.D.DGO. HEAD OF THE DEPARTMENT Dept. of Obstetrics & Gynecology, Madurai medical College, Madurai.
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