INTRODUCTION
Anemia is a major global public health problem, especially among the developing countries like India, and other southeast countries. It is estimated that 20-50% of the world population is suffering from iron deficiency anemia. The influence of maternal nutrition on outcome of pregnancy is of great concern as it is closely linked with economical, social and environmental factors that relates with planning of Public Health Anemia antedates conception, aggravated by increasing demands of pregnancy and perpetuated by blood loss, infections during labor and postnatal period. Anemia is responsible for 20% maternal deaths directly and in another 20-40%, acts as a predisposing factor. Significant loss due to premature and preterm labor is due to anemia.
DEFINITION
Anemia is defined as reduction in oxygen carrying capacity of blood due to hemoglobin below normal levels.
Nonpregnant values: | <12 gm%, hematocrit <36% |
Pregnancy: | WHO—Hb% < 11 gm% India (ICMR) Hb% <10 gm% |
Majority of women undergo pregnancy without any apparent problems with mild anemia. Obvious complications occur when Hb% goes below 8.5 gm%.
INCIDENCE
33-88% in India (WHO 1992).
10-20% in. West
Severe anemia in 5-10%, moderate in 10-20%, mild in 70-80%.
Incidence is more in rural area due to poor socio-economic status, infections and infestations.
Seasonal higher incidence is found in summer due lack of availability of green and leafy vegetables. 30-50% of women are anemic before pregnancy.
CLASSIFICATION
Physiological: Hypervolemia of pregnancy.
Clinical: | |||
Hb% (WHO) | Hb% (ICMR) India | ||
Mild | 8-11 gm% | 7.5-10 gm% | |
Moderate | 6.5-8 gm% | 5-7.5 gm% | |
Severe | <6.5 gm% | <5 gm% | |
Morphological: | |||
Microcytic hypochromic | |||
Normocytic normochromic | |||
Macrocytic normochromic | |||
Classification: | |||
A. Deficiency: |
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B. Hemorrhagic: |
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C. Hemolytic disease: | |||
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D. Aplastic/Hypoplastic (due to bone marrow depression): Drug induced—due to analgesics, antipyretics aspirin, and indomethacin. Exposure to radiation. | |||
Physiological Hypervolemia of Pregnancy
There is disproportionate increase in plasma volume (40-45%), RBC volume, hemoglobin mass (17-25%), especially during 28-32 weeks of gestation. This also called as hydremic plethora. The Hb% decreases by 2 grams. It occurs in well nourished women also. It is not eliminated by administration of iron. This causes fall in Hb%, increase in iron binding capacity, peripheral smear is normocytic, normochromic and there is an increased rate of iron absorption. Blood volume starts increasing from 8-10 weeks of gestation reaches peak at the end of 2nd trimester. In late pregnancy, volume expansion ceases but hemoglobin mass continues to increase.
Advantages of Hypervolemia
- To meet increasing demands of pregnancy
- To protect mother from deleterious effects of impaired venous return in supine and standing position
- To safeguard against blood loss in 3rd stage of labor and puerperium.
Disadvantages of Hypervolemia
- Increased circulatory burden decompensate underlying heart disease.
- There is a decrease in oxygen carrying capacity.
Increase in erythropoiesis during pregnancy is controlled by various factors such as:
- Increase in erythropoietin levels
- Placental lactogen stimulates secretion of erythropoietin.
Many studies have shown that supplementation of iron during pregnancy can keep hemoglobin level above 10 gm% despite changes in blood and volume.
Erythropoiesis
Erythropoiesis is confined to bone marrow in adults.
Stages of RBC formation are: Pronormoblast—normoblast—reticulocyte—mature non-nucleated erythrocyte.
It needs minerals—iron, copper, zinc, cobalt; vitamins—B12, Folic acid, vitamin C; protein, hormone— erythropoietin.
Iron Metabolism
Iron in human body is bound to transferrin (transport form), ferritin (storage form 20-30%) or Heme (such as hemoglobin (65-70%), myoglobin or iron containing enzymes). The iron necessary for synthesis of hemoglobin is carried as transferrin. In patients with nutritional iron deficiency, the iron stores become depleted to maintain the production of erythrocytes and to satisfy the needs of pregnancy.
Non-heme iron is in ferric (Fe+++) form after reduction to ferrous (Fe++) iron by a membrane associated cytochrome-B, divalent metal transporter 1(DMT1) first moves non-heme iron across the apical membrane. At least 2 proteins then required for the basolateral transfer of iron to transferring in the plasma: ferroprotein, a transporter and hephaestin, an iron oxidase. Both DMT1 and ferroprotein are widely distributed in body suggesting their involvement in iron transport in other tissues. After absorption both Heme and non-heme iron enter the common pool in mucosal cell. Normally a fraction of iron that enters the cell is rapidly delivered to plasma transferrin. Most is deposited as ferritin, some to be transferred to plasma transferrin and some to be lost in exfoliation of mucosal cells. The extent to which mucosal iron is distributed along these various pathways depends on the body's iron requirement. When the body is replete with iron, formation of ferritin within the mucosal cell is maximal, whereas transport to plasma is enhanced in iron difficiency.
Iron Balance During Pregnancy
The demand of iron arises from the need for
- Basal iron requirement—900 mg; (range 700-1400 mg) of which about 300-650 mg goes to the uterus and its contents.
- Expansion of red cell mass—500 mg.
- Iron transferred to fetus—200-350 mg.
- Iron content of placenta and cord 100-170 mg.
- Blood loss at delivery—150-250 mg.
- Breastfeeding over six months may result in loss of another 100-180 mg of iron.
Amount of iron conserved during amenorrhea of 15 months may range between 240-480 mg. So, overall 500-600 mg of additional iron is required during pregnancy. Therefore, requirement is 4-6 mg/day in second trimester and 6-8 mg/day in third trimester. Iron absorption is increased from 7.3% in first trimester to 66.1% in third trimester.
Total Body Iron
It varies with body size, age and sex of individual. Average pregnant adult total body iron is about 2-5 gm.
Iron Sources and Balance During Pregnancy
- Total 5-10% dietary iron is absorbed from diet during pregnancy. Minimum 4-6 mg of iron daily should be absorbed during pregnancy to maintain an iron balance. The level of iron can be derived only from 40-60 mg of dietary iron. Even the best of diets do not contain this amount of iron. Absorption of medicinal iron is higher than dietary ironincreased erythropoiesis which is stimulated by placental lactogen result 4in increase in hemoglobin mass and decrease in iron stores
- Absorption increases in presence of glucose, fructose, and ascorbic acid
- Phytates, bicarbonates, phosphates, tannin, caffeine reduces absorption of iron
- Heme and myoglobin is absorbed easily than elemental iron.
When iron stores are depleted, molecules of transferrin become less than 15% saturated with iron and erythropoiesis is impaired leading to microcytosis and hypochromia, so the production of red cells by marrow decreases.
Causes of Increased Prevalence in Pregnancy
- Increased demand of iron
- Diminished intake of iron due to loss of appetite, nausea, vomiting
- Infections: Asymptomatic bacteriuria and presence of other infections markedly interferes with erythropoietic function in bone marrow
- Prepregnant iron deficiency aggravated during pregnancy
- Increased demand during pregnancy
- Blood loss: Blood loss during pregnancy (APH)increases severity of Anemia
- Over intake of antacids leading to hypochorhydria and less absorption of iron.
Increased Prevalence in Tropical Developing Countries
- Diet: Rich in carbohydrates, phytates decrease absorption, vegetarian diet which is less in iron content. Deficiency of ascorbic acid, calcium and proteins tend to lower iron absorption
- Depleted iron stores before pregnancy
- Infections: Increased prevalence of malaria, hookworm, round worm and other infections
- Low socioeconomic status, lack of education and nonavailability of medical aid
- Iron loss: Sweating causes iron loss to extent of 15 mg per month
- Repeated pregnancies, teenage and multiple pregnancies, prolonged lactation.
Effects of Anemia on Pregnancy
Antenatal
- Increased chances of abortion
- Increased chances of pre-eclampsia/eclampsia abruption (due to folic acid deficiency and pre-eclampsia) placenta previa
- Preterm labor, PROM
Intranatal
- Dysfunctional labor, cardiac failure, anesthesia complications due to hypoxia
- More chances of PPH, hemorrhagic shock even with less amount of blood loss.
Puerperium
- Sepsis
- Chances of infection double when Hb% is less than 8 gm%, higher chances of UTI, vulvovaginitis.
- Subinvolution, secondary PPH
- Embolism, cardiac failure, shock after labor
- Lactation failure
- Psychological disturbances, postpartum blues.
Effects on Fetus
- There is significant correlation between Hb percent less than 8 gm/dl and preterm labor and premature rupture of membrane.
- IUGR: Due to poor oxygenation hypoproteinemia folic acid and other deficiencies
- IUGR leading to adult cardiovascular diseases and hypertension according to Barker's hypothesis
- Neonatal anemia
- In severe cases of anemia, CCF in fetus and IUFD.
There is usually a two to threefold increase in perinatal mortality, when maternal hemoglobin level falls below 8 g/dl and eight to ten fold when these levels are below 5 g/dl.
Effects on Placenta
Increased size for extracting more oxygen but less perfused.
Effects of Pregnancy on Anemia
- Anemia is precipitated in latent iron deficiency.
- Higher incidence of cardiac failure in pregnancy anemia: Due to hypervolemia of pregnancy there is high output failure around 28-32 weeks of gestation, labor and puerperium.
- Maternal morbidity and mortality rate are higher in women with hemoglobin below 8 g/dl and it shows steep rise to 20% when hemoglobin falls to less than 5 gm/dl.
Daily Iron Requirement
- Adult female nonpregnant requires 2.0 mg/day enough for daily loss and menstruation
- Pregnant women require 3-5 mg/day enough for normal pregnancy requirements.
Clinical Features
Depends on degree of anemia.
Symptoms: Tiredness, easy fatiguability, generalized weakness, lethargy, headache, palpitation, breathlessness.
Signs:
General examination: Pallor: Mucous membrane, conjunctiva, skin palmer creases nail bed. Koilonychia, platynychia, spotted nails, cheilosis, glossitis, edema.
Cardiovascular examination (Due to hyperdynamic circulation):
Tachycardia, collapsing pulse, postural hypotension Grade III systolic murmur, cardiomegaly, and signs of congestive cardiac failure, pulmonary edema.
CNS: Giddiness, headache, numbness and tingling in extremities.
Gastrointestinal tract: Anorexia, nausea, diarrhea, constipation, weight loss.
Investigations
Basic aim of investigation is to know:
- Degree of anemia
- Type of anemia
- Cause of anemia.
Degree of Anemia
- Hb%: Preferably by colorimetric method (direct, indirect by spectrophotometric method), it is done during the first visit, repeated subsequently at least at 28 weeks and 36 weeks of gestation.
- Hematological indices:(Refer Table 1.1 for values) Total red cell count, packed cell volume, mean corpuscular volume, reticulocyte count, mean corpuscular hemoglobin concentration. MCHC is the most sensitive index of iron deficiency anemia.
- Blood investigations like serum iron, serum transferritin, total iron binding capacity, percentage saturation, serum ferritin, serum bilirubin, red cell protoporphyrin, hemoglobin electrophoresis.
Type of Anemia
Peripheral blood smear: (Well-spread smear stained with Leishmann stain to study the morphology of red cells, Fig. 1.1). RBC shows anisocytosis (variation in size), poikilocytosis (variation in shape). RBC are reduced in size (microcytic). Few tear drop cells, Pencil cells are also seen. Chromacity—RBC are hypochromic, it varies according to degree of anemia. Reticulocyte count is raised slightly.
The RBC's here are smaller than normal and have an increased zone of central pallor. This is indicative of a hypochromic (less hemoglobin in each RBC) microcytic (smaller size of each RBC) anemia. There is also increased anisocytosis (variation in size) and poikilocytosis (variation in shape).
Other Investigations
- Total and differential WBC count for underlying infection, leukemia.
- Urine exam—Routine and microscopic examination, culture and sensitivity for detection of UTI, asymptomatic bacteriuria.
- Stool exam—Routine and microscopy for detection especially for detection hook worm infestation and occult blood.
- Koch's disease—PPD, chest X-ray, sputum AFB, ESR, PCR.
- LFT, RFT, serum proteins.
- Bone marrow biopsy/aspiration rarely needed.
Indications
- Patient not responding to treatment
- Pancytopenia
- Presence of nucleated red cells or immature white cells in smear
- Refractory anemia
- Blood smear suggestive of leukemia
- Anemia with very low reticulocyte count.
Bone marrow: Hypercellular marrow with Erythroid hyperplasia. Erythropoiesis is micronormoblastic (cytoplasmic maturation lags behind nuclear maturation.) Predominant cells are polychromatic normoblast, which are smaller than normal. Granulopoietic cells and megakaryocytes are present in normal numbers and are normal appearance.
Examination of films of aspirates and sections of trephine biopsies stained with potassium ferrocyanide shows reticuloendothelial iron is absent and sideroblast are diminished.
Diagnosis
Iron deficiency anemia can be fairly diagnosed by serum iron, serum ferritin, transferrin and TIBC.
Treatment of Anemia
It depends on degree, type and cause of anemia. It also depends on period of gestation, whether patient is in antenatal period or in labor, and whether any associated condition or complications.
Dietary Prescription
Balanced, nutritious, high protein diet should be designed, iron rich foodstuff like green leafy vegetables, dry fruits, cereals, pulses jaggery, beetroot, legume, meat, liver, eggs and fish advised. Vitamin C rich foodstuff like amla, lemon facilitates iron absorption.
Fortification of salt with iron and double fortification with iron and iodine is under consideration of Government of India. Use of iron utensils should be encouraged.
Use of antacids should be avoided.
Deworming: Single dose of Albendazol 400 mg is useful for deworming.
Prophylactic Treatment
It is advisable to keep iron stores optimal right from adolescence or at least before pregnancy. Following things are advised for the same.
- Routine screening for anemia in adolescent girls
- Education and encouragement about inexpensive iron rich food
- Fortification of salt with iron
- Supplementation of iron to adolescent girl
- Screening of those with risk factors.
National Anemia Control Program in tenth five year plan of Government of India again emphasized on need for operationalization of universal screening for anemia in pregnant women, early detection and appropriate managements based on supplementation of iron and folic acid tablet to prevent mild and moderate anemia. A pack of 100 tabs containing each tab of 60 mg elemental iron with 500 µg folic acid is given antenatally and 1-packet postnatally. For optimal benefits of iron supplementation, it should be started by 20-24 weeks of gestation.
Curative Treatment
Anemia is a sign of underlying disorder and not a disease. So cause of anemia should be investigated and treated basically along with supplementation.
Hospitalization: Patients of severe type of anemia should be hospitalized. Moderate anemia along with obstetrical complication should be hospitalized. Blood transfusion, IV infusion of iron necessitates hospitalization.
Specific therapy: Aim of therapy is to raise hemoglobin level to normal and to restore the iron reserves.
Choice of therapy depends upon severity of anemia, period of gestation and association complicating factors (Table 1.2).
Management of Severe Anemia
Hospitalization, intensive personalized care to ensure fetal and maternal salvage, rest, digitalization, oxygen inhalation, diuretics and pack cell transfusion to tide over crisis. Screening for associated obstetric or systemic problem should be done. Subsequently, parenteral and oral iron for correction of anemia should be given.
Management of Moderate Anemia
Screening for associated obstetric or systemic problem should be done. Oral or parenteral iron therapy is given after calculation of dose. 120-180 mg of oral iron supplemented with folic acid under supervision is necessary. Increasing dose does not improve result. Maximum response is seen after 10-12 weeks of supplementation. Regular intake should be ensured, otherwise use of parenteral iron therapy in hospital obstetric practice should be included. Starting with small dose and gradual increase improves compliance.
Management of Mild Anemia
Oral iron therapy of maximum tolerated dose is of choice if patient is compliant.
Oral Iron Therapy
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Iron salt should be selected on the basis of absorption, side effects, amount of elementalron, compliance, tolerance, availability and cost. Ferrous sulphate is the least expensive and best absorbed form of iron ferrous gluconate, and fumarate are next choice. Response starts after a week, takes 6-8 weeks for full effect. Hemoglobin rises at the rate of 0.8 gm/wk. Oral iron should be continued 3-6 months after normal hemoglobin is achieved for supplementation of stores.
A combination of vitamin A and iron helped to eradicate anemia in Indonesia, where role of vitamin A is unknown. Oral iron avoided in first trimester due to nausea and vomiting. In second trimester, oral iron is given in dose of 60-120 mg of elemental iron with 400-600 µg of folic acid in nonanemic pregnant patient.
Revised National Anemia Prophylaxis Program is aimed at distribution of iron tablet containing 100 mg of elemental iron and 500 µg of folic acid for at least 100 days. Women with mild anemia should receive daily 2-3 tablets of iron and should be continued for 100 days following delivery to replenish iron stores. This doubles the erythropoiesis. Dose more than this has no value.
Intermittent therapy: Oral iron, if given thrice a week, absorption is better than daily dose as there is time for intestinal mucosa cells to regenerate. Daily intake of oral iron causes oxidative damage to gut mucosa is shown by recent molecular studies. It forms basis of intermittent therapy. It reduces gastrointestinal side effects.
Food decreases bioavailability of iron. Hence ideally iron should be taken on empty stomach. Study carried out by National Institute of Hyderabad between 1967 to 1975 on iron supplementation during pregnancy have indicated that 95% of pregnant women are able to tolerate iron administered on empty stomach unless told about tolerance. Remaining 5% who had in tolerated had same after full stomach also. However, if patient complains gastric disturbances, it can be taken along with food. Citric acid cysteine increases absorption plant phytates, phosphates, tannic acid, and caffeine decreases absorption.
Antacids like aluminium hydroxide and magnesium hydroxide milk decrease iron absorption by neutralizing gastric pH.
Patient's response is positive when there is:
- Sense of well-being.
- Increased appetite.
- Change is reticulocyte count in 5-10 days.
- Hb increase 0.3-1.0 gm% per week on an average 0.7 gm%.
- Significant increase in hematocrit values within 2-3 weeks after initiation of treatment.
Contraindications of Oral Iron
Intolerance
Severe anemia
Side Effects
Gastrointestinal Intolerance: Nausea, vomiting diarrhea, constipation, cramping and malena, metallic taste, transient tanning of teeth and tongue, signs of hemochromatoses (iron overload after long treatment).
Causes of Failure of Oral Iron Therapy
Noncompliance, improper typing of anemia, defective absorption, diarrhea malabsorption syndrome, 9coexisting, hookworm infestation, infections like malaria, UTI, protein deficiency and folate deficiency.
Parenteral Iron Therapy
Parenteral iron should ideally be given after documentation of iron deficiency. Rate of rise of hemoglobin is same for oral as well as parenteral treatment. Advantages of parenteral treatment are: It ensures iron entry in the system, iron stores are replenished faster, hemopoietic response is reliable. The expected rise in hemoglobinconcentration after parenteraltherapy is 0.7-1.0 gm% per week.
Indications for Parenteral Iron Therapy
Failure of oral iron therapy, allergic reactions, side effects of oral iron therapy, noncompliance, limited time until delivery co-existing risks (bowel disease, renal disease), pre- or postoperative period, moderate to severe anemia.
Routes
Intramuscular route, intravenous route.
Preparations
Iron dextran (IM, IV), iron sorbitol citric acid complex (IM) 50 mg elemental iron/ml iron sucrose complex (IV).
Adverse Effects
IM iron—Allergic reaction, local pain and inflammation phlebitis, skin staining, systemic reactions (headache, arthralgia, myalgia fever), tender lymphadenopathy.
IV iron—Local phlebitis, fever, chest pain, palpitation, dyspnea, cyanosis anaphylactic reaction resulting in vascular collapse injection abscess, arthralgia, myalgia, staining of skin.
Calculation of Total Iron Requirement
- Iron requirement in mg = 4.4 × body weight in kg × hemoglobin deficit in gm/dlThis includes iron required to replenish the stores. Stores can be replenished faster with parenteral therapy.
- Total iron in mg =
- Total dose in mg = (wt in pounds × Hb deficit in % × 0.3) + 50% extra supplementation for stores.
- For each gm of hemoglobin below normal, 250 mg of elemental iron to be given.
Iron should always be injected after sensitivity test.
Intramuscular
Deep intramuscular injection is given in Z technique to avoid staining of skin. Daily or alternate day injections are given in alternate gluteal region. 200 mg iron raised hemoglobin value of 1 gm/dl. A course of 10-20 injections is well tolerated by the patient.
Intravenous
Test dose of 0.5 ml IV over 5 min given and patient is observed for 1 hr.
Total dose is calculated. If it exceeds 2500 mg, it is given over 2 days.
The total dose is given in solution is diluted to 5% in normal saline or 5% dextrose. Rate of infusion should be 10 drops/min for 30 min. If no sideeffects, 150 ml/hr given vitals should be monitored strictly.
Emergency medicines should by handy or preloaded. Patient should be watched for 24 hrs.
Maximum response is seen between 4-9 weeks
Iron sucrose can be administered undiluted as a bolus or diluted (in 100-200 ml normal saline) with maximum single dose of 200 mg, biweekly with least side effects. It can be given with or without rHuEPO (recombinant human erythropoietin).
Blood Transfusion
Whole blood-packed cells are given depending on patient's condition.
Indications
Severe anemia, moderate anemia in late pregnancy, or in labor, cardiac failure due to anemia, acute blood loss, shock, aplastic anemia.
Advantages
Improves oxygen carrying capacity of blood immediately, stimulates erythropoiesis.
Management During Labor
Patient should be treated like heart disease case.
1st stage: | Rest, propped-up position, liberal sedation, epidural analgesia, oxygen Inhalation by mask, vital monitoring, monitoring for evidence of CCF and Diuretics, digitalization if needed, pulse-oxymeter monitoring Active management of third stage of labor. |
2nd stage: | To be shortened by liberal episiotomy, instrumental delivery. |
3rd stage: | Prophylactic oxytocics to avoid PPH, watch for signs of failure. |
Puerperium: Adequate rest, antibiotics, balanced diet and continue oral iron therapy.
Summary
Anemia is the major contributor to maternal mortality that varies world over from <1% to >50%. In India, anemia, majority belonging to iron deficiency, is responsible for 17% of maternal deaths and the case fatality rate of pregnancy anemia approaches to 6-17%. It is also responsible for very high perinatal morbidity and mortality. Prevention, detection and treatment of anemia during pregnancy are the primary concerns of antenatal care.