ANEMIA IN PREGNANCY IDA: CHANGING CONCEPT

Dr Veena Agrawal
M.S., MICOG, WHO Fellow (USA) Professor & HOD, Obst. & Gynecology, G. R. Medical College Core faculty of human Genetics, Jiwaji University Gwalior, M.P.

Dr Sonali Agrawal
DGO Consultant Agrawal Hospital & Research Centre Gwalior, M.P. India

Anemia is a sign, not a disease of dynamic process

World Health Organization

y Anemia a major killer y Incidence is about 50% in general population, (in

India 80%).
y Iron deficiency anemia is the most common

medical disorder during pregnancy.

y In pregnancy, it is one of the leading causes of

maternal mortality in developing countries.

y It affects both mother and fetus.

PREVALENCE OF anemia in India

Available studies on prevalence of nutritional anemia show that:
65% infant and toddlers, 60% 1-6 years of age, 88% adolescent girls (3.3% has hemoglobin <7 gm./dl; severe anemia) and 85% pregnant women (9.9% having severe anemia) prevalence higher in lactating than pregnant women

The most common is iron deficiency anemia.

Causes:
y Physiological - disproportionate se of plasma

volume apparent reduction of RBC, Hb & Hct. Picture is normochromic normocytic. y Acquired:
y Nutritional y Iron deficiency anemia (60%), y Macrocytic anemia (10%) due to def of folic acid

and/or vitamin B12 y Dimorphic and protein deficiency anemia (30%) in extreme malnutrition

Causes of Anemia
y Hemorrhagic y acute blood loss, y chronic (hook worm, bleeding piles) y Infections
y Acute (e.g., malaria) y Chronic (e.g., tuberculosis)

y Genetic conditions (e.g., thalassemia, sickle cell) y Enzyme disorders (e.g., sideroblastic anemia) y Anemia of chronic disease (e.g., malignancy, chronic renal failure

Criteria for Physiologic Anemia

y Hb: 10gm% y RBC: 3.2 million/mm3 y PCV: 30% y Peripheral smear showing normal morphology of

RBC with central pallor

Significance of Hypervolemia
1. To meet the demands of the enlarged uterus with its greatly hypertrophied vascular system. 2. To protect the mother, and in turn the fetus, against the deleterious effects of impaired venous return in the supine and erect positions. 3. To safeguard the mother against the adverse effects of blood loss associated with parturition.

IDA
y 12th most important risk factor for all mortality

globally. y 9th most important risk factor for the global burden of disease. y associated with 115,000 of the 510,000 maternal deaths (22%) and 591,000 of the 2,464,000 perinatal deaths (24%) occurring annually around the world.

Mason, Rivers and Helwig Food and Nutrition Bulletin 26: 57-162, 2005..

y 1/3 world s population suffers from anemia, mostly iron

deficiency anemia.
y India continues to have a very high prevalence. y National Family Health Survey (NFHS-3) reveals the

prevalence of anemia to be 70-80% in children, 70% in pregnant women and 24% in adult men.

Definition of Anemia in Pregnancy

y WHO-Hb conc <11gm/dl & Hct < 33% y CDC definition-Hb con <11gm/dl & Hct < 33% during

the 1st trimester & < 10.5 gm/dl Hct < 32% during the 2nd trimester

y Absolute iron deficiency is defined as ferritin <200

g/L with or without iron saturation <20%,

CDC definition:
Pregnancy Trimester First Second Third Hemoglobin 11.0 10.5 11.0 Hematocrit 33.0 32.0 33.0

Factors required for erythropoiesis

Proteins (erythropoietin) Minerals (iron) Trace elements: (Zinc, Cobalt, Copper etc) Vitamins: Folic acid, Cyanocobalamin (B12), Vitamin C, Pyridoxine
(B6), Riboflavin, Vitamin A

Hormones: Androgens & Thryoxine

Letsky E. 1995 Prasad AS. J. Am. Coll. Nutr. 1996

Anemia
y Acc to ICMR y Mild

10-11mg% y Moderate 7-10.9mg% y Severe 4 - 6.9mg% y Very severe <4mg%

Normal Storage iron Transport iron Erythorin iron

Iron depletion

Iron deficient erythropoiesis

Iron deficiency anemia

Marrow iron Plasma ferritin (g/l) Transferrin saturation(%) Iron absorption

2-3+ 10060 3515

0 trace < 20 Normal

0 10 Normal

0 <10 Microcytic hypochromic +

Normal

+

Normal Levels
Hb R.B.C. Serum Iron TIBC Transferrin saturation S. Ferritin level Red Cell protoporphyrin Erythropoietin MCV MCH MCHC PCV 13.5 14 gm % 4.5 4.7 million/cu mm 50 150 gm / dL 300 360 gm / dL 25 50 % 30 g / Lit 30 g / dL 15.20 U / Lit 76 100 L 27 33 pg 33.37 gm / dL 32 40 %

Requirement of Iron
IRON in mg THAT SHOULD be ABSORBED DAILY ADULT FEMALES MENSTRUATION PREGNANCY(1st HALF) (2nd HALF) LACTATION POSTMENOPAUSE 2.8 0.8 3.5 2.4 0.7

Iron Requirements in Pregnancy

Amount mg Total cost of pregnancy Fetus Placenta Expansion of red blood cell mass Obligatory basal losses Sum Maternal blood loss at delivery Total cost Net cost of pregnancy Contraction of maternal red blood cell mass Absence of menstruation during pregnancy Subtotal Net cost -450 -160 -610 580 270 90 450 230 1040 150 1190

Normal Iron Requirements

y Iron requirement for normal pregnancy is 1gm 200 mg is excreted 300 mg is transferred to fetus 500 mg is need for mother y Total volume of RBC inc is 450 ml

1 ml of RBCs contains 1.1 mg of iron 450 ml X 1.1 mg/ml = 500 mg

y Daily average is 6-7 mg/day

Early Pregnancy 2.5 mg. / day

20 32 weeks 5.5 mg. / day

32 40 weeks 6.8 mg / day

y Overall needs are about 2 to 4.8 mg iron/day. y Must consume 20 to 48 mg of dietary iron to absorb

this quantity of iron daily. y Average vegetarian diet provide 10-15 mg iron/day. y Amount of iron absorbed from diet+iron mobilized from stores, is usually insufficient to meet the demands. y Therefore, iron supplementation during pregnancy is recommended universally even in non anemic women.

Maternal Anemia: A Preventable Killer

Increased requirements

Decreased absorption

Causes of IDA

Poor diet

Increased blood loss

Anemia: Etiologies
y Inadequate dietary intake y Poor nutrition y Chronic alcoholism y Decreased consumption of animal protein and ascorbic acid y Increased iron demands y Multiparity y Diarrhea, HIV/ AIDS and y UTI y Recurrent InfectionsTuberculosis, Amoebiasis , Giardiasis, Roundworm y other infectious diseases y Inadequate GIT absorption y Malabsorption syndromes y Certain drugs/foods y Blood loss y Hookworm infestation y Malaria y Bleeding piles &gums y Surgery y Gastrointestinal bleeding y Trauma y Dialysis

Low Iron Intake or Low Iron Absorption Haemolysis due to malaria worm infestations (hookworm) Multiparity

Effects of Anemia on Pregnancy

Pathophysiology - Fetus

Fetal Effects

y Mild and moderate anemia may not show significant effects. y Iron is actively transported across the placenta. y Fetal iron and ferritin levels > maternal levels 3 times

Effects of Anemia on Fetus

PROM, IUGR, IUFD, Prematurity, Abnormal trophoblast invasion Fetal programming & disease of newborn: behavioral abnormalities, poor performance on Bayley Mental Development Index, decreased cognitive function. Neonatal anemia Adult HT associated with low birth weight & high ratio of placenta to birth weight. (Barker DJP, Bull AR, et all BMJ 1990; 301:259-262)

 If maternal oxygenation is 98 100 %, The fetus gets around 70 % of O2, with fetal Hb.

Fetus can compensate. As the maternal Hb. drops, fetal hypoxia develops, which leads to stimulation of fetal erythropoiesis Increased viscosity of blood due to raised PCV. sluggish circulation End artery thrombosis Failure of the organs, supplied by these vessels.

y Increased PCV y Brain damage y Necrotising enterocolitis y Hypoglycemia y Hypocalcemia y Hyperbilirubinimia y RDS

At Birth Hb 18 to 20 gms %, PCV 55 to 60 %

Severe Anemia

Fetal hypoxia Prolonged period Neurological deficit Short duration

IQ less, slow learner

Fetal hypoxia leads to an increase in the cord blood EPO. Cord blood EPO correlates with perinatal brain damage.

Abnormal trophoblast invasion and release of hypoxic inducible factor

Early anaemia during gestation

Release of placental stress hormones (CRH,Nor epinephrine)

Fetal release of ACTH and cortisol

Production of uterine contraction stimulating hormones (estrogen, connexin) and inhibition of IGF, an anabolic hormone

Maternal Effects of Anemia

Behavioral changes, irritability. Loss of appetite, indigestion, etc. due low performance of each organ. Increased morbidity and mortality due to PIH, APH, PPH, if associated. C CF at 30-32 wks, intrapartum & post-partum. y Reduced immune function - infection, ante-partum and puerperal sepsis. y Negative thermoregulation y Increased risk of blood transfusion Preterm Labor Sub involution Failing lactation Pulmonary Venous: thrombosis & embolism, due to thrombophlebitis.

ANTENATAL CARE As a routine - No difference

Registration Counseling Regular check up weight, B.P., Hb%, urine Prevention of complications Immunizations

Care in addition to routine ANC

y H & P of Anemia y Investigate for y Grade of anemia y Type y Severity of IDA y cause y Tx of anemia y Tx the cause of anemia ie. deworming, Antimalarial

Intrapartum Management if patient comes in labor

y Individuals who MUST present in labor room y Skilled Birth attendant's y Anesthesiologist y Pediatrician y Nursing Staff y Extra Hands y Informed consent

Things that should be available:

y US Machine y Cardiotocographic machine y Blood transfusion facility y Neonatal resuscitative measures

Things that should be done:

y IV Line should be patent y Bl arranged - PCV y Monitor pt for sign of CCF esp. immediately

postpartum y Early cord clamping y No methergin y Cut shirt 2nd stage labor y IV Diuretic y Antibiotics

Postpartum Management
y Monitor patient for sign of CCF y Antibiotics y Otherwise same

Clinical Feature of Anemia

Symptoms:
y Mild anemia; usually asymptomatic y Moderate anemia - weakness, fatigue, exhaustion, loss of appetite, indigestion, giddiness, breathlessness y Severe anemia-palpitation, tachycardia, breathlessness, Increased cardiac output, CHF, general anasarca, pulmonary edema
Sharma J.B. Progress in Obst. & Gynae. (Studd) 2003.

Clinical Features of Anemia

Signs:
y Pallor y Nail changes Koilonychia y Angular cheilosis, Glossitis, Stomatitis y Oedema y Hyperdynamic circulation (short and soft systolic murmur) y Fine crepts
Sharma J.B. Progress in Obst. & Gynae. (Studd) 2003.

y What is level

y Type

y cause

Anemia?

Production?

Survival/Destruction?

The key test is the ..

The Reticulocyte Count (Kinetic Approach)

y

reticulocytes (>2-3% or 100,000/mm3 total) are seen in bl loss and hemolytic processes, although up to 25% of hemolytic anemia's will present with a normal count.

y Hb Measurement & Haematocrit y Peripheral smear will often reveal many diagnostic clues y Reticulocyte count y Serum ferritin most sensitive tool. Values < 10mcg/L indicate

absence of stored iron, <20 or <15 g/L indicate depleted iron stores y Transferrin saturation (TSAT), should be above 16% with normal being 30% y Soluble serum transferrin receptors (sTfR) (>45 nM/Ldenote IDA),

TSAT <20%, serum ferritin <100 ng/mL & % of hypochromic RBCs >10% indicate absolute ID,

y RBC indices - little diagnostic value unless the MCV is below 70fl y Serum iron - decreased in a variety of states including iron deficiency, inflammation & stress. Varies tremendously from morning to evening and from day to day. value < 0.5mg/L indicate anemia, normal range :0.80 to 1.80 mg/L y Total iron binding capacity is very specific for iron deficiency (near 100%) but has poor sensitivity (<30%). y Iron saturation (Fe/TIBC x 100) can be decreased below 16% in both anemia of chronic disease and iron deficiency

Tests used in Diagnosing Iron Deficiency Anemia (IDA)

Test *Blood smear hypochromia *MCV RDW Serum iro Iro bi di g capacity (IBC) Iro /IBC (% saturatio ) *Ferriti Stool for occult blood Bo e marrow for iro stores Limitations Subjectivity I se sitivity No -specificity Markedly lowered by fever or i flammatio Moderately lowered by fever; i creased by preg a cy Like serum iro , lowered by fever Mildly raised by fever or i flammatio Bleedi g may be i termitte t Expe sive a d i vasive; iro depletio does ot prove IDA

Specific tests for etiology of the anemia Urine & stool examination Test for malaria Rarely- Endoscopic or barium studies of the GI tract, bone marrow examination Exclude other causes of hypochromic microcytic anemia Anemia of chronic disease Thalassaemia trait Sideroblastic anemia

Lab Testing for Iron Deficiency Anemia (IDA)

Patient with anemia, Check ferritin, Iron, IBC level
Ferritin > 100 Ferritin 20-100 Ferritin < 20, or Iron < 50 and IBC > 450 sTR >45 Ferritin > 20, or Iron > 50 and IBC < 450

sTR <45

IDA Iron therapy

Look for source of blood loss

Workup for other causes of anemia

Prevention
y Dietary modification y Iron supplementation of adolescent & non pregnant female y Tx of Hookworm infestation y Control of malaria y Iron supplementation in pregnant Women y Food fortification y Antenatal care for early recognition y Optimal birth spacing

Eat foods that are:

y Rich in iron - liver, beef, whole-grain breads y cereals, eggs, dark green vegetables and dried fruit. y High in folic acid, such as wheat germ, beans,

peanut butter, oatmeal, mushrooms, collards, broccoli, beef liver and asparagus. y High in vitamin C, such as citrus fruits and fresh, raw vegetables. Vitamin C makes iron absorption more efficient. y Take prenatal vitamin and mineral supplements, especially folic acid.

Diet
Low Bioavailability Rice, Wheat Maize Potato High Bioavailability Eggs Fish Meat

Dietary Components and Absorption of Iron

Diet r c m nents cts) Abs r ti n

Calci m (Dair pr

Meat, fis , poultr , sea-food P tate (grain products)

Pol phenols (Tea, spices, vegeta les) Vitamin

Depends upon severity and gestation

Which Iron Compound?

Inorganic 1. Ferrous
sulfate, fumarate, gluconate, ascorbate, succinate, glutamate, dextran, carbonyl iron, and lactate bis-glycinate chelate. 2. Ferric Salts iron (III)-hydroxide polymaltose complex

Organic - Heme

Ferrous vs. Ferric iron

y y

Ferrous iron is absorbed three times more than ferric iron. Ferric iron absorption is dependent on duodenal ferric reductase.

Availability of duodenal ferric reductase is dependent on ascorbic acid.

Supplementation of ascorbic acid may increase ferric iron absorption.

First iron pills were commonly known as Blaud's pills, which were named after P. Blaud of Beaucaire. He is a French physician who introduced and started the use of these medications as a treatment for patients with anemia.

Goal:
y Hgb 11-12g/dL y Hct 33 36%

Iron Preparations
y Available with various amounts of iron, iron salts,

complexes, combinations, and dosing regimens. y Available in tablets and capsules, liquid and drops, coated and extended release tablets and capsules.

 Different oral preparations exhibit different safety profiles. Greater oxidative stress is observed with oral iron (II) salts than with iron (III) complexes Iron salts are selected based on compliance of the tolerance, side effects, clinical situation of the pt and availability of a particular salt. Fe sulphate is cheapest, best absorbed, and most commonly prescribed, showing a rapid rise in both serum iron concentrate and NTBI (Non transperrin bound iron) & greatest frequency of adverse events If not tolerated, then ferrous gluconate, fumarate and others are the next choice. Oral iron must be continued for 3-6 mon after Hb has come to normal levels for building iron stores.

In small intestine ferric iron is precipitated as ferric hydroxide which is basically RUST The difficulty of absorbing rust is the main reason for the prevalence of iron deficiency anemia in the world The most readily available and cheapest natural reducing agent is ascorbic acid

Iron metabolism

Iron Supplementation During Pregnancy

In developed countries like U.K., routine Iron supplementation is not recommended. However, it is mandatory in non-industrialized countries. WHO - 60 mg elemental iron with 250 Qg folic acid for 6 months in pregnancy and additional 3 months postpartum. NNACP in India - 100 mg of elemental iron and 500 mcg of folic acid for 100 days after the first trimester

Ferrous Salts or Bivalent Iron Salts

y

Good bioavailability however, decreases in the presence of dietary inhibitors like phytates, tannic acid, etc. Efficacious and cheap Several disadvantages: y High incidence of GI Tract side effects (~23 %). y Teeth staining with liquid preparations y Salty astringent taste which is not palatable for most children

y y

Side Effects of Oral Iron

Nausea Vomiting Constipation Abdominal cramping Diarrhea The tab can be given with meals or different brands may be tried.

Ways to Minimize Adverse Effects of Oral Iron

y Recommend half the dose and gradually se to the

full dose. y Take the supplement in divided doses. y Take with food to alleviate GIT distress ( se iron absorption by as much as 40-66%). y Change to a different iron preparation. y Concomitant use of a stool softener, such as docusate, may help alleviate constipation.

Factors that Affect Absorption

y y y

y y y

as doses get larger - supplement in 2 or 3 divided doses. Enteric-coated and long-acting supplements may be ineffective. not dissolve in the stomach hence not absorbed in duodenum or upper jejunum Ascorbic acid is enhanced absorption by forming a chelate with ferric iron at acid pH that remains soluble at the alkaline pH of the duodenum. & reverse the inhibiting effects of substances such as tea and calcium. Taken with food decreased absorption by as much as 40-66%. Food absorption- Tannins from foods, such as tea Iron forms an insoluble complex with several other drugs - decreased absorption of both iron and the other drugs, e.g. tetracycline, pencillamine, methyldopa, levodopa, bisphosphonates quinolones, calcium and antacids, phosphates, etc.

Effectiveness of Iron Supplementation

y Clinical improvement y laboratory indices y Reticulocyte count y Hemoglobin y Ferritin levels y TAST y Newer measurements:
y y y

Reticulocyte hemoglobin content Percent hypochromic RBCs Soluble transferrin receptors (sTfR)

y Reticulocytosis occurs within 7-10 days after

initiation of iron therapy. y Hb usually es within 2-3 wks of starting Iron y Therapeutic doses should se Hb 0.7-1.0 g/dL / wk. y Serum ferritin level is a more accurate measure of total body iron stores. y Adequate iron replacement has typically occurred when the serum ferritin level reaches 50 g/L.

Reasons for Failure to Respond

1. Non compliance 2. Concomitant folate deficiency 3. Continuous loss of blood through hookworm infestation or bleeding hemorrhoids 4. Co-existing infection 5. Faulty iron absorption 6. Inaccurate diagnosis Non iron deficiency microcytic anemia
a. Thalassaemia b. Pyridoxine deficiency c. Lead poisoning d. Sideroblastic anemia e. Atransferrinemia

Prema K. Obst. & Gynaecol 1992 Sharma JB, In Progress in Obst. & Gynaec, 2002

Foods and Drugs that Impair Oral Iron Absorption

y Taking oral iron with food reduces absorption y Caffeinated beverages, (especially tea) y Calcium containing foods and beverages y Calcium supplements y Antacids y H-2 receptor blockers y Proton pump inhibitors

3 months postpartum to replenish the iron stores

Follow up:
y Iron status (ferritin, TIBC, & TSAT) and RBC indices

must be checked periodically to re-evaluate the pt's need for additional iron supplementation. y Parenteral iron should not be administered to patients with ferritin > 800 ng/mL or transferrin saturation > 50%.

Parenteral Iron Therapy

Indicated: y when unable to take iron due to side effects y Non compliant y Suffers from inflammatory bowel disease y Near term y With chronic renal disease y Postpartum, especially in those who have had significant blood loss at delivery y Pre post operative anemia can also be cured Its main advantage is certainty of administration Rise in Hb is similar to oral iron (up to 1gm per wk)

Postpartum
y High EPO state in postpartum anemia y IV iron supplementation in such period es the

erythropoiesis 5 times
y The Hb rise will be evident in as early as 5 days
Harrisons principles of medicine

Contraindications:
y Hypersensitivity to any of the Parenteral iron

products y Liver disease or acute renal failure, Nephritis, y Cardio respiratory disease y Pts with ferritin > 800 ng/mL or transferrin saturation > 50%.

Disadvantages
y y y y y y y y

Pain Nausea vomiting, headache Skin discoloration Abscess formation Fever Lymphadenopathy Allergic reaction Anaphylaxis

Precaution
y Oral Iron to be suspended 48 hours before parenteral therapy. y Emergency measures like injection hydrocortisone adrenaline, oxygen cylinder etc., should be kept ready. y Look for a reaction while giving infusion.

Parenteral Iron Preparations

y Iron- sorbitol -citric acid complex (jectofer (1.5ml) 75mg Available in Europe, Asia & Canada. It is not yet approved by US FDA. IM use only y HMW Iron Dextran both IM & IV use y LMW Iron Dextran - both IM & IV use y Sodium ferric gluconate IV use only y Iron sucrose - IV use only y Ferric carboxymaltose - IV use only y Newer y Iron isomaltoside 1000 - IV use only y Ferumoxytol - IV dose of 510 mg, followed by 2nd dose 38 days later. (Undiluted, at a rate of 1 ml/second (30 mg/sec)).

Classification of IV Iron Carbohydrate Complex Preparations (Geisser )

TYPE I Example Ferric carboxymalt ose Iron dextran TYPE II Iron sucrose TYPE III Sodium ferric gluconat e TYPE IV Iron(III)-citrate Iron(III)-sorbitol Iron(III)-citrate + iron(III)sorbitol + iron dextrin Sodium ferric gluconate + iron sucrose

HMW ID Type of iron complex Mg iron per ml Preservative Relative stability of iron complex IronIIIdextran 50 mg/ml No Robust/ strong

LMW ID IronIIIdextran 50 mg/ml No Robust/ strong

Iron Saccharate IronIIIsucrose 20 mg/ml No Half robust/ medium strong

Ferric Gluconate IronIIIgluconate in sucrose 12.5 mg/ml Yes, 9 mg of benzyl alcohol per ml Weak/labile

HMW ID = high molecular wt iron dextran;,LMW ID = low molecular wt iron dextran; TDI = total dose infusion.

HMW ID pH T Standard dosage 4.5 - 7.0 9.4 - 87.4 hr. (average 58.9 hr.) 100 mg

LMW ID 5.2 - 6.5 5-20 hr. 100 - 200 mg

Iron Saccharate 10.5 - 11.1 6 hr.

Ferric Gluconate 7.7 - 9.7 1 hr.

100 - 200 mg 2 min or 10 min 5-10 min 200 mg

125 mg 10 min 125 mg

Injection time 2 min for undil. adm. Maximum single dose 100 mg

20 mg/kg body weight 4-6 hrs. adm. Yes

Infusion 2 min time/Injection undil. adm. time. TDI adm. possible Yes

10 min undil. adm. No

10 min undil. adm. No

y Complex stability: y Iron dextran > iron sucrose > iron gluconate y Strongest iron complexes allow for the largest dose

of iron in one infusion.

y Toxicological potential y Iron sucrose > iron gluconate >> low Mw iron dextran

Fe-carbohydrate agents mix with plasma, enter the RES directly from intravascular fluid compartment

Within Phagocytes of RES,Fe released from the iron-carbohydrate compound into an LMW iron pool

LMWFe either is incorporated by ferritin into intracellular iron stores or released from the cell to be taken up by the extracellular iron-binding protein transferrin.

Transferrin delivers iron to transferrin receptors on the surface of erythroid precursors.

Transferrin delivers iron to transferrin receptors on the surface of erythroid precursors.

Iron-transferrin-transferrin receptor complex supplies Fe for Hb synthesis & maturation of the red cell

Safety Profile
y Most of the iron is deposited in the Reticulo-endothelial system than in parenchyma. y This gives the advantage of not having free-radical induced lipid peroxidation which takes place within parenchyma only. y Practically no liver injuries occur as confirmed by experimental histological results. y Iron dextran has the highest incidence of modest and

severe life-threatening side effects.

Hypersensitivity Reactions:
y Anaphylactic reactions y Almost exclusively with iron dextran, independent of dose - 0.6 to 0.7% y Mechanism is unknown but some possibilities are: y Dextran itself is immunogenic, cause allergic reactions including anaphylaxis & anaphylactoid reactions, y Availability of free iron after administration. y Antidextran antibody mediated mast cell activation y Alternate pathway complement activation y Direct stimulation of mast cell degranulation

y.

Controversies severe adverse allergic reactions with iron dextran

y component but other formulations are also not safe y Pts with a h/o of allergy may be at risk of developing undesired immunological reactions such as asthma (Meyler 14th edition, page 701). y Iron toxicity is more if amount of free iron released into plasma exceeds plasma iron-binding capacity (more likely to occur when using iron sorbitol citric acid complex, since the iron is less firmly bound than with iron dextran (Meyler 14th edition, page 701).

Conditions associated with low ironbinding capacity of parentral iron- More reaction
y Malnutrition & previous or simultaneous oral iron

therapy y Folic acid def - likely mechanism - disturbance of iron utilization. (Side Effects of Drugs, Annual 9, 516). y Different parenteral iron differ experimentally in their comparative toxicity related to free radical generation & severe ATP depletion. Iron sucrose has greater potential for this than iron dextran (Zager et al, 2002).

y Both Iron gluconate & sucrose are associated

with anaphylactoid type reactions, dose related. y Reactions were due to over saturation of the transferrin molecule resulting in the circulation of free iron. y This theory is still uncertain.

y Iron sucrose is also associated with

anaphylactoid type reactions, but these seem to be dose related y Reactions that occur are due to over saturation of the transferrin molecule resulting in the circulation of free iron y This theory is still uncertain

How to give
y IM y Intravenous Iron Therapy
y

IV PUSH in divided doses y Diluted y Undiluted TDI

y Parenteral Iron Therapy (IM or IV) with recombinant

human erythropoietin (rHuEPO)

How to Calculate TDI:

y Total dose of infusion of iron is calculated as: y (15- pt s Hb%) x body wt in Kg x3 = Fe in mg.

y Ganzoni Equation

Total Iron Deficit = Weight {kg} x (Target Hb Actual Hb) {g/l} x 2.4 + Iron stores {mg}
y

{ 500 if W > 35kg } { 15 mg/kg if W < 35kg }

Dosage Intramuscular Iron

y

100mg/d, Max 200mg/d can be given on D 1, 3 & 5 Z shaped deep IM to avoid skin staining. 2 High doses of IM injection 250mg each at monthly with injection T.T has been recommended in moderate anemia of pregnancy.

Dosage IV Iron
y Divided doses (IV Push) - dosing frequency y Iron dextran agents, plasma half-lives - 30 to 60 hrs, every 2 to 7 days, (once to thrice weekly). y Ferric gluconate and iron sucrose, with 1- & 8-h halflives, respectively, could be given as frequently as every 24 hours. y Total Dose infusion

INTRAVENOUS IRON THERAPY

y Iron Dextran y Test dose (25 mg Fe) is required. Diluted in 50-100 mL of NS and infused over 15-20 minutes. y Monitor HR, RR, & BP q15 min for 1-2 hrs after test dose. y Total Fe (dose) administered
y

as one large dose (diluted in 500-1000 mL NS and infused over 4 to 8 hrs, or divided into many smaller doses given 1-3 times per week. Each 100-mg dose may be administered undiluted as iv push or 100-mg dose is diluted in 250 mL NS and infused over 30-60 min.

Adverse Reactions
y Increased incidence with TDI. y Onset is 24-48 hrs after administration. y Effects subside within 3-4 days. y Dose related: y arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, N/V. y Non-dose related: y Hypersensitivity reactions characterized by anaphylactic shock, CV collapse, cardiac arrest, bronchospasm, oral or pharyngeal edema, or dyspnea.

Iron Sucrose and Iron Gluconate

y 0.3% side effects with iron gluconate very low y Pts who had a reaction to iron dextran are more likely to have a reaction to iron gluconate than to iron sucrose. y Adverse reactions with iron sucrose or gluconate seen at higher doses only. y No anaphylactic death from either preparation in 35 yrs. y used in similar total doses per course of therapy, generally 1 gm/course. y Iron sucrose may be given at 500 mg/4 hours; iron gluconate can only be given at 300 mg/4 hours.

Iron Sucrose
y No test dose is required. y May be administered y as iv push undiluted at the rate of 1 mL/min. 100 mg. 200 mg over 10 min. y Or 5-mL vial diluted in a max 100 mL NS (final conc = 1mg/mL) and administered over at least 20 min. y 200-300 mg infused over 2 hrs have been used

safely. y Doses as 500 mg have been infused in a single 2hour session. This rate was associated with higher incidence of side effects such as nausea, hypotension, dizziness, and lower-back pain.

Adverse Reactions
y Experienced in > 5% of patients: y Hypotension y Cramps/leg cramps y Nausea y Headache y Vomiting y Diarrhea

Precautions
y Iron overload or infusing too rapidly can cause: y hypotension, headache, N/V, dizziness, joint aches, paresthesia, abdominal & muscle pain, edema, & CV collapse y Tx - IV fluids, hydrocortisone, or antihistamines y or slow down rate of infusion

Iron gluconate
y No test dose is required. y Administered in: y Small installments of 125 mg Fe or less diluted in 100 mL of NS and infused over 60 min. y Or undiluted as a slow IV injection at a rate not exceeding 12.5 mg/min (1 mL/min).

Adverse Reactions
y Hypotension/flushing y Associated with rapid administration y Not associated with hypersensitivity reactions y Resolves within 1-2 hours

Precautions
y Iron overload due to accumulation of iron in storage

sites. y Serum iron > 300mcg/dl with transferrin saturation may indicate overload. y Symptoms: abdominal pain, diarrhea, vomiting leading to pallor or cyanosis, lassitude, drowsiness, hyperventilation due to acidosis, and CV collapse.

IV IRON POLYMALTOSE
y 500mg in 200mls 0.9% NS.Run at 40ml/hr for 30

minutes, then 80mls/hr.

y Or 1000mg in 200mls 0.9% NS.Run at 20mls/hr for

30 minutes, then 45mls/hr.

y First 30 minutes will always be run as a test dose.

y Monitor reaction to medication: y Headache, hypotension, joint/muscle pain, tachycardia, syncope, nausea and vomiting, circulatory collapse. y Delayed reactions may include: y Dizziness, syncope, stiffness (myalgia of legs/hands/face) y Chest pain/back pain y Rash

Laboratory Testing after IV

y Iron-carbohydrate compounds interfere with clinical

laboratory determination of serum iron y Serum iron & transferrin saturation should be tested after most or all of the IV iron agent has been cleared.
y No earlier than 7 days after administration of a 100-mg

dose of iron dextran, y 2 wk after a 500-mg dose of iron dextran, and y 24 to 48 hrs after a 125-mg dose of ferric gluconate or a 100-mg dose of iron sucrose. y One month for ferritin or iron studies after a 500-mg dose of Polymaltose

Dosage regimen Erythropoetin

y Inj erythropoetin - Sc or iv 100-150 iu/kg

On day 1, 3 & 5 along with parenteral iron or day 1, 3 & 5 6000units s/c erythropoetin and iron dextran 100mg deep im daily for 5 days. y First dose after subcutaneous sensitivity test. y Adrenaline, hydrocortisone injection oxygen to be kept ready. y Produces 3gm % rise in Hb over a 2wk period

Inj erythropoietin 18000u s/c in one dose & inj low molecular dextran 500mg to be dissolved in 500ml of dextrose to be given over 2 hours, as slow iv

Indication of Erythropoetin
y Used in severe anemia & renal failure for significant increase in Hb and to avoid Blood transfusion. y Gynaecological surgeries: preop use of erythropoietin and Parenteral iron has shown to avoid the need for blood transfusion later.

World Health Organization

Transfusion should be prescribed ONLY for conditions for which there is NO OTHER TREATMENT

Blood Transfusion:
Indications Severe Anemia in third trimester, CCF in pregnancy,

Acute hemorrhage or hemolysis in pregnancy. Jehovahs Witness who refuse blood transfusion due to religious beliefs. S/E of BT HIV, Hepatitis B, C, malaria, rubella, etc. Transfusion reaction Risk of incorrect cross - matching and transfusion negative impact on immune system. .

Hazards of Blood Transfusion in USA

y Hemolytic reactions 1 in 40,000 y Non hemolytic febrile reactions 3-4% y Anaphylactic reactions 1 in 20,000 y GVHD 0.1 to 1% y TRALI 0.1-0.2% 0.1y HBV 1 in 50,000 y HCV 1 in 3000 y HIV 1 in 1,50,000

Summary Protocol of Severe Anemia in Pregnancy Pregnancy < 30 weeks

Iron deficiency anemia Folic acid deficiency

Oral iron therapy

Oral folate therapy

Intolerance or noncompliance

Intramuscular iron

Intravenous iron

Summary Protocol of Severe Anemia in Pregnancy Pregnancy 30-36 weeks

Iron deficiency Folic acid deficiency

Pregnancy >36 weeks

Blood transfusion

Parenteral iron

Oral folate therapy

Intramuscular iron

Intravenous iron

Key Points of Iron-deficiency Anemia

y IDA is an illness of low iron in the body. y Iron makes Hb and healthy RBC which are needed for oxygenation y Reasons of IDA: blood loss, either from disease or injury,

y y y y y

nutritional; defective absorption, demand such as during pregnancy. 1 in 5 women of childbearing age and > 50% pregnant women have iron-deficiency anemia. Most common symptoms are fatigue & weakness. Treated by stopping the bleeding, increasing iron in the diet, and giving iron supplements. Eating a well-balanced diet rich in iron and vitamins can prevent. Can be successfully treated

CONCLUSION
y Proper antenatal care and awareness programmes for prevention of anemia. y Adequate iron / folic acid prophylaxis in all antenatal cases. y Early detection and timely referral to tertiary centers. y Management to be decided depending upon the cause of anemia, type of anemia and severity of anemia. y Logical use of blood and blood components. y Proper intrapartum and postpartum care. y Motivation of the patient for acceptance of any contraceptive method.

Mild and Moderate

y Nutrition y Control of infestation y Control of infection y Iron and Folic acid supplement y Economic reforms y Education y Cultural reforms y Infrastructure development, etc.

Severe Anemia
y Management depends on the time at hand. y If diagnosis:  Preconception - oral, if not tolerated, parenteral  First & second trimester - oral + parenteral  Third trimester - parenteral + blood transfusion by PCV  Late in third trimester and/ labor, blood transfusion by PCV nasal O2, B T, digitalization and ICU management with team approach. y Clinical condition y Associated risk factors

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