Anemia Update in Pregnancy1

The relative prevalence of mild, moderate, and severe anemia is 13%, 57% and 12% respectively in India (ICMR data) Table 1-2.

According to WHO, hemoglobin level below 11 g/dl in pregnant women constitutes anemia and hemoglobin below 7 g/dl is severe anemia. The Center for Disease Control and Prevention (1990) defines anemia as less than 11 g/dl in the first and third trimester and less than 10.5 g/dl in second trimester. ^4,16 Serum ferritin level of 15 μg/L is associated with iron deficiency anemia.^8,16

In addition to the common deficiencies of iron and folate, there is a growing body of evidence to implicate vitamin A (important for cell growth and differentiation, maintenance of epithelial integrity and normal immune function) and zinc (important in protein synthesis and nucleic acid metabolism) in nutritional anemias.^6,8

Anemia is a condition of low circulating hemoglobin (Hb) in which concentration has fallen below a threshold lying at two standard 5deviations below the median of a healthy population of the same age, sex and stage of pregnancy. The WHO definition for diagnosis of anemia in pregnancy is a Hb concentration of less than 11 g/dl (7.45 mmol/L) and a hematocrit of less than 33%.⁹

Iron deficiency anemia (IDA) is the commonest type of anemia in pregnancy.¹² Iron nutritional status depends on long-term iron balance and is favored by ingestion of adequate amounts of iron in the diet (native or fortified) or through iron supplementation as shown in Table 1-3. The balance is adversely affected by the loss of iron through intestinal mucosal turnover and excretion, skin desquamation, menstruation and lactation.¹³ Iron absorption which is 15—30% (heme iron) and up to 50% in the iron deficiency state reduces to 5—8% with an excessive haem diet. Its absorption is usually not affected by inhibitors. The non-heme iron pool is made of all other sources of iron such as cereals, seeds, vegetables, milk and eggs. Its absorption can be increased by enhancers (heme, proteins, ascorbic acid and fermentation) and decreased by inhibitors (phytic acid, fibers, calcium, tannins, tea, coffee, chocolate and herbal infusion).^8,14 The factors affecting the iron status of a pregnant woman are shown in Table 1-3.

Peripheral blood film is another bedside indicator for diagnosis of anemia which will also differentiate between iron deficiency anemia, megaloblastic anemia and hemolytic anemia. In iron deficiency anemia, there is microcytosis, hypochromia anisocytosis, poikilocytosis and target cells in the blood film. Iron deficiency anemia must be differentiated from thalassemia as shown in Table 1-4.

Serum ferritin level below 12 μg/L is taken to indicate iron deficiency. It is stable, unaffected by recent iron intake, reflects iron stores accurately, and is the first abnormal laboratory test in iron deficiency.

Serum iron varies from 60—120 μg/dl while TIBC is 300—350 μg/dl, (increased to 300—400 μg/dl in pregnancy). Serum iron of less than 60 μg/dl, TIBC of more than 350 μg/dl and transferrin saturation of less than 15% indicates deficiency of iron during pregnancy (Table 1-5).11

Free erythrocyte protoporphyrin (FEP) is the third estimation of Iron status rising with defective iron supply to the developing red cells and takes 2–3 weeks to become abnormal after depletion of iron stores. It also helps in differentiation between iron deficiency anemia and thalassemia.²³

Serum transferrin receptor appears to be specific and sensitive marker of iron deficiency in pregnancy. Its levels are increased in iron deficiency anemia. Bone marrow examination by staining with potassium ferrocyanate to see characteristic blue granules of stainable iron in erythroblasts is the most accurate method for iron stores, but is not practical in most cases as the test is invasive. Bone marrow examination is only indicated in cases where there is no response to iron therapy after 4 weeks or for diagnosis of kala azar or in suspected aplastic anemia.¹¹ As worm infestations are common causes of anemia, stool examination for ova and cysts should be done consecutively for 3 days in all cases. In areas where schistosomiasis is prevalent, urine examination for occult blood and schistosomes should be performed. As malaria is an important cause of anemia, peripheral blood should be examined for malarial parasites. Significant bacteriuria should also be ruled out. If the clinical scenario demands, other tests can be done, such as sputum examination and chest X-ray for pulmonary tuberculosis (abdominal shielding should be done), renal function tests in suspected renal disease and serum proteins in hypoproteinemia.²²

For treatment, Government of India, Ministry of Health recommends 100 mg of elemental iron with 0.5 mg folic acid twice a day or elemental iron of 180 mg. This may cause increased incidence of side-effects thus some recommend 120 mg elemental iron per day. Ferrous ascorbate is the most favorable iron for Indian diet which his high content of inhibitors for iron absorption.¹² One needs to change a brand only when the patient cannot tolerate it. Addition of folic acid, but not vitamin B₁₂ helps in improving the results in supervised supplementation. Up to 10% of women may have side-effects with oral iron in the form of gastrointestinal symptoms such as nausea, vomiting, constipation, abdominal cramping and diarrhea which are dose-related. The treatment of choice is to reduce the dose. If this does not work, another preparation (carbonyl) iron or hemoglobin preparations may be better tolerated.

Reasons for failure to respond to oral therapy are inaccurate diagnosis (non-iron deficiency, microcytic anemia, such as thalassemia, pyridoxine deficiency and lead poisoning), non-compliance, continuous loss of blood through hook worm infestation or bleeding hemorrhoids, co-existing infection, faulty iron absorption and concomitant folate deficiency. Iron content in different salts is shown in Table 1-6.

Deficit is calculated as:

Elemental iron needed (mg) = (Normal Hb — Patient's Hb) × Weight (kg)× 2.21 + 1000

Here, normal hemoglobin is taken as 14% and 2.21 is standard coefficient. To the value calculated by above formula, 1000 mg is added for the stores.

Iron dextran (Imferon) is diluted in normal saline or 5% dextrose and given slowly initially.²² If there is no reaction, it can be given faster. If the calculated dose is more than 2500 mg, it should be even in 2 doses on two consecutive days. One should look for any reaction in the form of chest pain, rigor, chills, fall in blood pressure, dyspnea and anaphylactic reaction.²² For any such reaction, infusion should stopped and antihistaminic, corticoids and epinephrine given.

We have performed studies on role of parenteral iron (iron sucrose) alone or in combination with erythropoietin at AIIMS and found a rise in Hb of 1.5 g with parenteral iron alone as compared to 3.0 g in combination with parenteral iron and erythropoietin.

Inj. iron sucrose plus inj. erythropoietin (Epofer) 4000–6000 unit subcutaneously every other day for 3 doses (total about 18000 units).

Dose should be given after subcutaneous sensitivity test. Adrenaline, hydrocortisone and oxygen to be kept ready.

In megaloblstic anemia, DNA replication is affected. There is derangement of red cell maturation with production of abnormal precursors known as megaloblasts which can be due to deficiency of folate or vit B₁₂.^22,23

Usually, it has an insidious onset with gradually progressive symptoms and signs of anemia, i.e. weakness, easy fatigability, tiredness, etc. Gastrointestinal symptoms like anorexia, nausea, vomiting, diarrhea and glossitis are more common. Hyperpigmentation of skin and oral mucosa, palpable liver and spleen, petechial rash due to thrombocytopenia may be present and in such cases, leukemia and aplastic anemia should be ruled out.

Nail changes do not occur in megaloblastic anemia. If occurs more commonly in multiple pregnancies, develops late in pregnancy around 20–28 weeks, develops immediately postpartum or up to fifth month, in OC pill users or in antiepileptic drug users.

The cause of megaloblastic anemia in pregnancy is nearly always due to the deficiency of folate which leads to wasting and hematological symptoms. If post-delivery hemoglobin level falls rapidly and there is no history of excessive blood loss then suspicion of folic acid deficiency is aroused first. Folic acid in pregnancy is not always accompanied by significant hematological changes. In the absence of changes, megaloblastic hematopoiesis is suspected when expected response to adequate iron therapy is not achieved. Ultimately diagnosis is dependent on marrow examination and the finding of large erythroblasts and giant abnormally shaped metamyelocytes.

As such vitamin B₁₂ deficiency takes years to develop anemia and its deficiency causes infertility thus megaloblastic anemia due to B₁₂ deficiency is very rare in pregnancy. Neurological features are more pronounced and if any autoimmune disease exists in the body with anemia then suspicion of B₁₂ megaloblastic anemia arises.

Extravascular hemolysis is the most common hemolytic anemia. The red cells are destroyed in the reticuloendothelial system, hemoglobin is converted to bilirubin. An increase in indirect bilirubin is apparent in the patient´s serum. The products of bilirubin metabolism, fecal and urinary urobilinogen, also increase. Erythropoiesis increases markedly, and reticulocytosis occurs. Thus, elevated unconjugated bilirubin, increased urinary urobilinogen, and reticulocytosis are the laboratory hallmarks of extravascular hemolysis.

Intravascular and extravascular hemolysis both cause bone marrow response characterized by marked erythroid hyperplasia and reticulocytosis. In some cases, the erythropoiesis is so active that there is passage of immature cells into the bloodstream. Also, in all cases of accelerated red cell destruction, plasma-lactic dehydro (LDH) increases as a consequence of the liberation LDH isoenzyme from the red cells.

The most common form of hemolytic anemia seen during pregnancy is the intravascular microangiopathic hemolysis, which is a part of the HELLP syndrome. More infrequently the obstetrician sees the hemolytic anemia associated with defects in hemoglobin structure, particularly sickle cell disease (SCD). The World Health Organization (WHO) estimates that globally at least 5% of adults are carriers for a hemoglobin condition: approximately 2.9% for thalassemia and 2.3% for sickle cell disease.

In SCD when HbS is oxygenated, its solubility is similar to that of normal hemoglobin (HbSS) but in the deoxy form solubility decreases and in a reduced oxygen environment the HbSS will polymerize into long tube-like fibers, which causes morphological changes characterized by sickling of the erythrocytes. The abnormal erythrocytes are removed and destroyed in the reticuloendothelial system, resulting in chronic extravascular hemolysis. HbF inhibits the polymerization of HbSS and patients with elevated levels of HbF have milder forms of the disease.

In certain situations such as increased deoxygenation, prolonged capillary transit time is increased. Concentration of corpuscular hemoglobin, and acidosis, clusters of sickle cells occlude the microvasculature, producing ischemic infarction and severe inflammatory reactions that clinically translate into a painful sickle cell crisis. Around 14.2% of all pregnancies in patients with SCD end with the delivery of stillborn infants and neonatal morality is approximately 84.5 per 100 live births. Another study shows a perinatal mortality as low as 11.0%. The frequency of infants with birth weights less than 2500 g in patients with SCD is increased.

Acute chest syndrome is the most common cause of mortality in patients with SCD. It is characterized by chest pain, respiratory distress with tachypnea, coughing and wheezing, fever, and decreased oxygen saturation.

Infection is a frequent-cause of sickle cell crisis but diagnosis is difficult because many of the signs and symptoms of a vaso-occlusive 23crisis are similar to those of infection. Fever, leukocytosis, elevated bilirubin, and LDH are also components of crises. Relief of the severe pain, reduction in HbSS concentration and increased oxygen supply to the tissues are the goals of management. Treatment usually involves pain management, oxygen, antibiotics, incentive spirometry, bronchodilators, and in most cases transfusion therapy.

Patients with SCD do not require iron supplements during pregnancy, unless laboratory evidence of iron deficiency is obtained. In contrast, they need adequate folic acid supplementation to compensate for the increased consumption of folate secondary to the active process of cell replication that takes place in their bone marrow.

The diagnosis of beta thalassemia minor should be suspected when the MCV is 75 fl or less and the RBC is greater than 4.5—5.0 million cells/μL. If still doubtful, measurements of serum ferritin and serum iron will clarify the dilemma. Also, microcytic, hypochromic anemia which does not respond to oral iron by an elevation of her hemoglobin concentration after 4 weeks of treatment should raise suspicion of thalassemia. Patients with beta thalassemia minor characteristically show hemoglobin A2 (HbA2) concentrations greater than 3.5% and normal or increased serum iron concentrations. In 90% of the cases, the HbA2 level is above 5%. Approximately 50% of women with beta thalassemia minor will exhibit a hemoglobin F concentration greater than 2%.25

The diagnosis of immune hemolytic anemia is made with the direct Coombs test. In this test, red cells of the patient are mixed with Coombs anti-human globulin antiserum, and since they are coated with IgG and complement, agglutination occurs immediately.