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M.S., MICOG, WHO Fellow (USA) Professor & HOD, Obst. & Gynecology, G. R. Medical College Core faculty of human Genetics, Jiwaji University Gwalior, M.P. DGO Consultant Agrawal Hospital & Research Centre Gwalior, M.P. India
Dr Veena Agrawal
Dr Sonali Agrawal
India 80%).
Iron deficiency anemia is the most common
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:
Physiological - disproportionate se of plasma
volume apparent reduction of RBC, Hb & Hct. Picture is normochromic normocytic. Acquired:
Nutritional Iron deficiency anemia (60%),
and/or vitamin B12 Dimorphic and protein deficiency anemia (30%) in extreme malnutrition
Causes of Anemia
Hemorrhagic
acute blood loss, chronic (hook worm, bleeding piles) Infections
Acute (e.g., malaria) Chronic (e.g., tuberculosis)
renal failure
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
12th most important risk factor for all mortality
globally. 9th most important risk factor for the global burden of disease. 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..
prevalence of anemia to be 70-80% in children, 70% in pregnant women and 24% in adult men.
the 1st trimester & < 10.5 gm/dl Hct < 32% during the 2nd trimester
Absolute iron deficiency is defined as ferritin <200
CDC definition:
Pregnancy Trimester First Second Third Hemoglobin 11.0 10.5 11.0 Hematocrit 33.0 32.0 33.0
Minerals (iron)
Trace elements: (Zinc, Cobalt, Copper etc) Vitamins: Folic acid, Cyanocobalamin (B12), Vitamin C, Pyridoxine
(B6), Riboflavin, Vitamin A
Anemia
Acc to ICMR
Mild
Iron depletion
0 10 Normal +
Normal Levels
Hb R.B.C. Serum Iron TIBC Transferrin saturation 13.5 14 gm % 4.5 4.7 million/cu mm 50 150 gm / dL 300 360 gm / dL 25 50 %
S. Ferritin level
Red Cell protoporphyrin
30 g / Lit
30 g / dL
Erythropoietin
MCV
15.20 U / Lit
76 100 L
MCH
MCHC PCV
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
-450
-160 -610 580
20 32 weeks
32 40 weeks
6.8 mg / day
Overall needs are about 2 to 4.8 mg iron/day. Must consume 20 to 48 mg of dietary iron to absorb
this quantity of iron daily. Average vegetarian diet provide 10-15 mg iron/day. Amount of iron absorbed from diet+iron mobilized from stores, is usually insufficient to meet the demands. Therefore, iron supplementation during pregnancy is recommended universally even in non anemic women.
Increased requirements
Decreased absorption
Causes of IDA
Poor diet
Anemia: Etiologies
Inadequate dietary intake
Poor nutrition Chronic alcoholism Decreased consumption of
UTI
Recurrent Infections-
Low Iron Intake or Low Iron Absorption Haemolysis due to malaria worm infestations (hookworm) Multiparity
Pathophysiology - Fetus
Fetal Effects
effects. Iron is actively transported across the placenta. Fetal iron and ferritin levels > maternal levels 3 times
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)
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.
Increased PCV Brain damage Necrotising enterocolitis Hypoglycemia Hypocalcemia Hyperbilirubinimia RDS
Severe Anemia
Fetal hypoxia
Prolonged period
Neurological deficit
Short duration
Fetal hypoxia leads to an increase in the cord blood EPO. Cord blood EPO correlates with perinatal brain damage.
Production of uterine contraction stimulating hormones (estrogen, connexin) and inhibition of IGF, an anabolic hormone
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.
- infection, ante-partum and puerperal sepsis. Negative thermoregulation Increased risk of blood transfusion Preterm Labor Sub involution Failing lactation Pulmonary Venous: thrombosis & embolism, due to thrombophlebitis.
postpartum Early cord clamping No methergin Cut shirt 2nd stage labor IV Diuretic Antibiotics
Postpartum Management
Monitor patient for sign of CCF
Antibiotics Otherwise same
appetite, indigestion, giddiness, breathlessness Severe anemia-palpitation, tachycardia, breathlessness, Increased cardiac output, CHF, general anasarca, pulmonary edema
Sharma J.B. Progress in Obst. & Gynae. (Studd) 2003.
What is level
Type
cause
Anemia?
Production?
Survival/Destruction?
bl loss and hemolytic processes, although up to 25% of hemolytic anemia's will present with a normal count.
Hb Measurement & Haematocrit Peripheral smear will often reveal many diagnostic clues
Reticulocyte count
Serum ferritin most sensitive tool. Values < 10mcg/L indicate
absence of stored iron, <20 or <15 g/L indicate depleted iron stores Transferrin saturation (TSAT), should be above 16% with normal being 30% Soluble serum transferrin receptors (sTfR) (>45 nM/Ldenote IDA),
TSAT <20%, serum ferritin <100 ng/mL & % of hypochromic RBCs >10% indicate absolute ID,
below 70fl 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 Total iron binding capacity is very specific for iron deficiency (near 100%) but has poor sensitivity (<30%). Iron saturation (Fe/TIBC x 100) can be decreased below 16% in both anemia of chronic disease and iron deficiency
*MCV
RDW Serum iron Iron binding capacity (IBC) Iron/IBC (% saturation) *Ferritin Stool for occult blood Bone marrow for iron stores
Insensitivity
Non-specificity Markedly lowered by fever or inflammation Moderately lowered by fever; increased by pregnancy Like serum iron, lowered by fever Mildly raised by fever or inflammation Bleeding may be intermittent Expensive and invasive; iron depletion does not prove IDA
sTR <45
IDA
Iron therapy
Prevention
Dietary modification
female Tx of Hookworm infestation Control of malaria Iron supplementation in pregnant Women Food fortification Antenatal care for early recognition Optimal birth spacing
peanut butter, oatmeal, mushrooms, collards, broccoli, beef liver and asparagus. High in vitamin C, such as citrus fruits and fresh, raw vegetables. Vitamin C makes iron absorption more efficient. Take prenatal vitamin and mineral supplements, especially folic acid.
Diet
Low Bioavailability Rice, Wheat Maize
Potato
High Bioavailability Eggs Fish
Meat
Absorption
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
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:
Hgb 11-12g/dL
Hct 33 36%
Iron Preparations
Available with various amounts of iron, iron salts,
complexes, combinations, and dosing regimens. Available in tablets and capsules, liquid and drops, coated and extended release tablets and capsules.
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
Good bioavailability however, decreases in the presence of dietary inhibitors like phytates, tannic acid, etc.
Efficacious and cheap Several disadvantages: High incidence of GI Tract side effects (~23 %). Teeth staining with liquid preparations Salty astringent taste which is not palatable for most children
full dose. Take the supplement in divided doses. Take with food to alleviate GIT distress (se iron absorption by as much as 40-66%). Change to a different iron preparation. Concomitant use of a stool softener, such as docusate, may help alleviate constipation.
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.
Reticulocyte hemoglobin content Percent hypochromic RBCs Soluble transferrin receptors (sTfR)
initiation of iron therapy. Hb usually es within 2-3 wks of starting Iron Therapeutic doses should se Hb 0.7-1.0 g/dL / wk. Serum ferritin level is a more accurate measure of total body iron stores. Adequate iron replacement has typically occurred when the serum ferritin level reaches 50 g/L.
2002
Follow up:
Iron status (ferritin, TIBC, & TSAT) and RBC indices
must be checked periodically to re-evaluate the pt's need for additional iron supplementation. Parenteral iron should not be administered to patients with ferritin > 800 ng/mL or transferrin saturation > 50%.
Postpartum
High EPO state in postpartum anemia
IV iron supplementation in such period es the
erythropoiesis 5 times
The Hb rise will be evident in as early as 5 days
Harrisons principles of medicine
Contraindications:
Hypersensitivity to any of the Parenteral iron
products Liver disease or acute renal failure, Nephritis, Cardio respiratory disease Pts with ferritin > 800 ng/mL or transferrin saturation > 50%.
Disadvantages
Pain Nausea vomiting, headache Skin discoloration Abscess formation Fever Lymphadenopathy Allergic reaction Anaphylaxis
Precaution
Oral Iron to be suspended 48 hours before parenteral
therapy. Emergency measures like injection hydrocortisone adrenaline, oxygen cylinder etc., should be kept ready. Look for a reaction while giving infusion.
Available in Europe, Asia & Canada. It is not yet approved by US FDA. IM use only HMW Iron Dextran both IM & IV use LMW Iron Dextran - both IM & IV use Sodium ferric gluconate IV use only Iron sucrose - IV use only Ferric carboxymaltose - IV use only Newer
Iron isomaltoside 1000 - IV use only Ferumoxytol - IV dose of 510 mg, followed by 2nd dose 38
HMW ID
LMW ID
Iron Saccharate
Ferric Gluconate IronIIIgluconate in sucrose 12.5 mg/ml Yes, 9 mg of benzyl alcohol per ml Weak/labile
IronIIIdextran
50 mg/ml No Robust/ strong
IronIIIdextran
50 mg/ml No Robust/ strong
IronIIIsucrose
20 mg/ml No Half robust/ medium strong
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
125 mg 10 min
100 mg
200 mg
125 mg
Infusion 2 min time/Injection undil. adm. time. TDI adm. possible Yes
Complex stability: Iron dextran > iron sucrose > iron gluconate
Strongest iron complexes allow for the largest dose
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.
Iron-transferrin-transferrin receptor complex supplies Fe for Hb synthesis & maturation of the red cell
Safety Profile
Most of the iron is deposited in the Reticulo-endothelial
Practically no liver injuries occur as confirmed by Iron dextran has the highest incidence of modest and
Hypersensitivity Reactions:
Anaphylactic reactions Almost exclusively with iron dextran, independent of dose - 0.6 to 0.7% Mechanism is unknown but some possibilities are: Dextran itself is immunogenic, cause allergic reactions including anaphylaxis & anaphylactoid reactions, Availability of free iron after administration. Antidextran antibody mediated mast cell activation Alternate pathway complement activation Direct stimulation of mast cell degranulation
Conditions associated with low ironbinding capacity of parentral iron- More reaction
Malnutrition & previous or simultaneous oral iron
therapy Folic acid def - likely mechanism - disturbance of iron utilization. (Side Effects of Drugs, Annual 9, 516). 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).
Both Iron gluconate & sucrose are associated with anaphylactoid type reactions, dose related.
Reactions were due to over saturation of the transferrin molecule resulting in the circulation of free iron. This theory is still uncertain.
Iron sucrose is also associated with anaphylactoid type reactions, but these seem to
be dose related Reactions that occur are due to over saturation of the transferrin molecule resulting in the circulation of free iron This theory is still uncertain
How to give
IM
Intravenous Iron Therapy
Ganzoni Equation
Total Iron Deficit = Weight {kg} x (Target Hb Actual Hb) {g/l} x 2.4 + Iron stores {mg}
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
Divided doses (IV Push) - dosing frequency Iron dextran agents, plasma half-lives - 30 to 60 hrs, every 2 to 7 days, (once to thrice weekly). Ferric gluconate and iron sucrose, with 1- & 8-h halflives, respectively, could be given as frequently as every 24 hours. Total Dose infusion
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
Increased incidence with TDI.
Onset is 24-48 hrs after administration. Effects subside within 3-4 days. Dose related: arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, N/V. Non-dose related: Hypersensitivity reactions characterized by anaphylactic shock, CV collapse, cardiac arrest, bronchospasm, oral or pharyngeal edema, or dyspnea.
have a reaction to iron gluconate than to iron sucrose. Adverse reactions with iron sucrose or gluconate seen at higher doses only. No anaphylactic death from either preparation in 35 yrs. used in similar total doses per course of therapy, generally 1 gm/course. Iron sucrose may be given at 500 mg/4 hours; iron gluconate can only be given at 300 mg/4 hours.
Iron Sucrose
No test dose is required. May be administered as iv push undiluted at the rate of 1 mL/min. 100 mg. 200 mg over 10 min. Or 5-mL vial diluted in a max 100 mL NS (final conc = 1mg/mL) and administered over at least 20 min. 200-300 mg infused over 2 hrs have been used
safely. 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
Experienced in > 5% of patients: Hypotension Cramps/leg cramps Nausea Headache Vomiting Diarrhea
Precautions
Iron overload or infusing too rapidly can cause: hypotension, headache, N/V, dizziness, joint aches, paresthesia, abdominal & muscle pain, edema, & CV collapse
Tx - IV fluids, hydrocortisone, or antihistamines or slow down rate of infusion
Iron gluconate
No test dose is required.
Administered in: Small installments of 125 mg Fe or less diluted in 100 mL of NS and infused over 60 min. Or undiluted as a slow IV injection at a rate not exceeding 12.5 mg/min (1 mL/min).
Adverse Reactions
Hypotension/flushing Associated with rapid administration Not associated with hypersensitivity reactions Resolves within 1-2 hours
Precautions
Iron overload due to accumulation of iron in storage
sites. Serum iron > 300mcg/dl with transferrin saturation may indicate overload. Symptoms: abdominal pain, diarrhea, vomiting leading to pallor or cyanosis, lassitude, drowsiness, hyperventilation due to acidosis, and CV collapse.
IV IRON POLYMALTOSE
500mg in 200mls 0.9% NS.Run at 40ml/hr for 30
Monitor reaction to medication: Headache, hypotension, joint/muscle pain, tachycardia, syncope, nausea and vomiting, circulatory collapse. Delayed reactions may include: Dizziness, syncope, stiffness (myalgia of legs/hands/face) Chest pain/back pain Rash
laboratory determination of serum iron Serum iron & transferrin saturation should be tested after most or all of the IV iron agent has been cleared.
No earlier than 7 days after administration of a 100-mg
dose of iron dextran, 2 wk after a 500-mg dose of iron dextran, and 24 to 48 hrs after a 125-mg dose of ferric gluconate or a 100-mg dose of iron sucrose. One month for ferritin or iron studies after a 500-mg dose of Polymaltose
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. First dose after subcutaneous sensitivity test. Adrenaline, hydrocortisone injection oxygen to be kept ready. 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
Used in severe anemia & renal failure for significant
increase in Hb and to avoid Blood transfusion. Gynaecological surgeries: preop use of erythropoietin and Parenteral iron has shown to avoid the need for blood transfusion later.
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. .
Intolerance or noncompliance
Intramuscular iron
Intravenous iron
Parenteral iron
Intramuscular iron
Intravenous iron
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
Proper antenatal care and awareness programmes for
prevention of anemia. Adequate iron / folic acid prophylaxis in all antenatal cases. Early detection and timely referral to tertiary centers. Management to be decided depending upon the cause of anemia, type of anemia and severity of anemia. Logical use of blood and blood components. Proper intrapartum and postpartum care. Motivation of the patient for acceptance of any contraceptive method.
Severe Anemia
Management depends on the time at hand. 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. Clinical condition Associated risk factors
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