Anemia is a significant maternal problem during pregnancy. The Centers for Disease Control and Prevention defines anemia as a hemoglobin concentration of <11 g/dL (hematocrit of <33%) in the first or third trimester or a hemoglobin concentration of <10.5 g/dL (hematocrit <32%) in the second trimester. A pregnant woman will lose blood during delivery and the puerperium, and an anemic woman is at increased jeopardy of blood transfusion and its related complications.
During pregnancy, the blood volume increases by approximately 50% and the red blood cell mass by approximately 33%. This relatively greater increase in plasma volume results in a lower hematocrit but does not truly represent anemia.
Anemia in pregnancy most commonly results from a nutritional deficiency in either iron or folate. Pernicious anemia due to vitamin B12 deficiency almost never occurs during pregnancy. Other anemias occurring during pregnancy include anemia of chronic disease; anemia due to hemoglobinopathy; immune, chronic (eg, hereditary spherocytosis or paroxysmal nocturnal hemoglobinuria), or drug-induced hemolytic anemia; and aplastic anemia.
- Hypochromic and microcytic anemia with evidence of depleted iron stores
Iron deficiency is responsible for approximately 95% of the anemias during pregnancy, reflecting the increased demands for iron. The total body iron consists mostly of (1) iron in hemoglobin (approximately 70% of total iron; approximately 1700 mg in a 56-kg woman) and (2) iron stored as ferritin and hemosiderin in reticuloendothelial cells in bone marrow, the spleen, and parenchymal cells of the liver (approximately 300 mg). Small amounts of iron exist in myoglobin, plasma, and various enzymes. The absence of hemosiderin in the bone marrow indicates that iron stores are depleted. This finding is both diagnostic of anemia and an early sign of iron deficiency. Subsequent events are a decrease in serum iron, an increase in serum total iron-binding capacity, and anemia.
During the first half of pregnancy, iron requirements may not be increased significantly, and iron absorbed from food (approximately 1 mg/d) is sufficient to cover the basal loss of 1 mg/d. However, in the second half of pregnancy, iron requirements increase due to expansion of red blood cell mass and rapid growth of the fetus. Increased numbers of red blood cells and a greater hemoglobin mass require approximately 500 mg of iron. The iron needs of the fetus average 300 mg. Thus, the additional amount of iron needed due to the pregnancy is approximately 800 mg. Data published by the Food and Nutrition Board of the National Academy of Sciences show that pregnancy increases a woman's iron requirements to approximately 3.5 mg/d. This need outstrips the 1 mg/d of iron available from the normal diet.
It is unclear whether the well-nourished, nonanemic woman benefits from routine iron supplementation during pregnancy. However, for women with a history of iron deficiency anemia, at least 60 mg/d of elemental iron should be prescribed to prevent anemia during the course of pregnancy and the puerperium.
The symptoms may be vague and nonspecific, including pallor, easy fatigability, headache, palpitations, tachycardia, and dyspnea. Angular stomatitis, glossitis, and koilonychia (spoon nails) may be present in longstanding severe anemia.
The hematocrit is <33% in the first or third trimesters or <32% in the second trimester. The hemoglobin may fall as low as 3 g/dL, but the red cell count is rarely below 2.5 × 106/mm3. The red cells usually are hypochromic and microcytic, with mean corpuscular volumes of <79 fL. Serum ferritin concentrations fall to <15 μg/dL and transferrin saturation to <16%. Serum iron levels usually are <60 μg/dL. The total iron-binding capacity is elevated in both normal pregnancies and pregnancies affected by iron deficiency anemia and, therefore, is of little diagnostic value by itself. The reticulocyte count is low for the degree of anemia. Platelet counts are frequently increased, but white cell counts are normal. Bone marrow biopsy demonstrates lack of stainable iron in marrow macrophages and erythroid precursors but usually is unnecessary in uncomplicated iron deficiency anemia.
Anemia due to chronic disease or an inflammatory process (eg, rheumatoid arthritis) may be hypochromic and microcytic. Anemia due to thalassemia trait can be differentiated from iron deficiency anemia by normal serum iron levels and ferritin levels, the presence of stainable iron in the marrow, and elevated levels of hemoglobin A2. Other less common causes of microcytic, hypochromic anemia include sideroblastic anemia and anemia due to lead poisoning.
Iron deficiency anemia may be associated with intrauterine growth retardation and preterm birth. There also appears to be an association between iron deficiency anemia and an increased risk of postpartum depression.
Angina pectoris or congestive heart failure may develop as a result of marked iron deficiency anemia. Sideropenic dysphagia (Paterson-Kelly syndrome, Plummer-Vinson syndrome) is a rare condition characterized by dysphagia, esophageal web, and atrophic glossitis due to long-standing severe iron deficiency anemia.
Severe anemia with hemoglobin <6–7 g/dL has been associated with reduced fetal oxygenation, abnormal fetal heart tracing, low amniotic fluid volume, and intrauterine fetal demise.
In an established case of anemia, prompt adequate treatment is necessary.
Ferrous sulfate 300 mg (containing 60 mg of elemental iron, of which approximately 10% is absorbed) should be given 3 times per day. If this agent is not tolerated, ferrous fumarate or gluconate should be prescribed. Therapy should be continued for approximately 3 months after hemoglobin values return to normal in order to replenish iron stores. Hemoglobin levels should increase by at least 0.3 g/dL/wk if the patient is responding to therapy.
Iron is best absorbed in the ferrous or reduced form from an empty stomach. Administering ascorbic acid via supplement or citrus juice at the time of iron supplementation creates a mildly acidic environment that aids the absorption of iron.
The indication for parenteral iron is intolerance of, or refractoriness to, oral iron. In most cases of moderate iron deficiency anemia, the total iron requirements equal the amount of iron needed to restore hemoglobin levels to normal or near normal plus 50% of that amount to replenish iron stores.
Iron dextran is the most widely available parenteral iron preparation in the United States. While it may be given intramuscularly, it is preferable to administer it intravenously (IV). Each 2-mL vial provides 100 mg of elemental iron. After a 0.5-mL test dose, iron dextran can be administered intramuscularly or IV at a rate not to exceed 100 mg/d of elemental iron. Intramuscular injection must always be given into the muscle mass of the upper outer quadrant of the buttock with a 2-in, 20-gauge needle, using the Z technique (ie, pulling the skin and superficial musculature to one side before inserting the needle to prevent leakage of the solution and subsequent tattooing of the skin). Intramuscular iron raises hemoglobin concentration only slightly faster than oral iron administration due to slow and occasionally incomplete mobilization of iron from the muscle. Risks of parenteral iron administration include anaphylactic reaction (approximately 1% risk), muscle necrosis, fever, and phlebitis.
Other forms of IV iron such as ferric gluconate complex may also be administered IV. Ferric gluconate complex is associated with a lower incidence of adverse reactions.
Few studies have evaluated the role of erythropoietin in pregnant women with iron deficiency anemia. Although the data are conflicting, erythropoietin administered in conjunction with IV iron may be associated with a shorter time to targeted hematologic indices than IV iron alone. The addition of erythropoietin to iron therapy may be considered in women for whom rapid correction of anemia is desired, particularly women in the third trimester of pregnancy.
Blood transfusion is generally reserved for women with coexisting issues such as operative deliver or postpartum hemorrhage or women with evidence of active bleeding. It may also be considered for women with hemoglobin <6–7 g/dL due to the increased risk of obstetrical and fetal complications in women with anemia of this severity.
Megaloblastic Anemia of Pregnancy
- Macrocytic anemia with low serum levels of folate or vitamin B12
Megaloblastic anemia of pregnancy is most commonly caused by folic acid deficiency and is common where nutrition is inadequate. In the United States, access to fresh vegetables and the fortification of grains makes folate deficiency much less common than in the developing world.
In the nonpregnant woman, the minimum daily intake of folate necessary for adequate hematopoiesis and to maintain stores is 50 mg. However, this requirement increases during pregnancy. In order to meet this need and to decrease the neural tube defects associated with folate deficiency, a dietary supplement of at least 400 mg/d of folic acid is recommended.
Additional folic acid may be required in states of heightened DNA synthesis, such as multifetal gestation. Similarly, patients with a chronic hemolytic anemia such as sickle cell anemia require additional folate supplementation in order to meet the demand imposed by increased hematopoiesis. Other hemolytic states are also commonly complicated by folic acid deficiency, including hereditary spherocytosis and malaria.
Folic acid absorption or metabolism may be impaired by the use of oral contraceptives, pyrimethamine, trimethoprim-sulfamethoxazole, primidone, phenytoin, or barbiturates. Alcohol consumption also interferes with folate metabolism. Jejunal bypass surgery for obesity or the malabsorption syndrome (sprue) may impair folic acid absorption.
Megaloblastic anemia may also be caused by vitamin B12 deficiency. Women with a history of partial or total gastrectomy or Crohn's disease are at risk of vitamin B12 deficiency.
The symptoms are nonspecific (eg, lassitude, anorexia, nausea and vomiting, diarrhea, and depression). Pallor often is not marked. Rarely, a sore mouth or tongue is present. Occasionally, purpura may be a clinical manifestation. Megaloblastic anemia should be suspected if iron deficiency anemia fails to respond to iron therapy.
Folic acid deficiency results in a hematologic picture similar to that of true pernicious anemia (autoimmune disease that leads to vitamin B12 deficiency), which is extremely rare in women of childbearing age.
The hemoglobin may be as low as 4–6 g/dL, and the red cell count may be <2 million/μL in severe cases. Extreme anemia often is associated with leukocytopenia and thrombocytopenia.
The red cells are macrocytic (mean corpuscular volume usually >100 fL) and appear as macro-ovalocytes on peripheral blood smear. However, in pregnancy, macrocytosis may be concealed by accompanying iron deficiency or thalassemia. Up to 70% of folate-deficient patients also lack iron stores.
Serum folate levels <4 ng/mL are suggestive of folic acid depletion in nonpregnant patients. However, in otherwise normal pregnant patients, folate tends to fall slowly to low levels (3–6 ng/mL) with advancing gestation. The red cell folate level in megaloblastic patients is lower, but in 30% of patients, the values overlap. The peripheral white blood cells are hypersegmented. Seventy-five percent of folate-deficient patients have more than 5% neutrophils with 5 or more lobes, but this also may be true for 25% of normal pregnant patients.
The urinary excretion of formiminoglutamic acid (FIGLU) has been used to diagnose folate deficiency, but levels are abnormal only in severe megaloblastic anemia. Bone marrow aspirate demonstrates megaloblastic erythropoiesis but usually is not necessary for diagnosis. Serum iron and vitamin B12 levels should be normal.
In women with vitamin B12 deficiency, low serum levels of vitamin B12 are seen.
If the megaloblastic anemia is due to folate deficiency, folic acid 1–5 mg/d orally is initiated. This therapy produces the maximum hematologic response, replaces body stores, and provides the minimum daily requirements. The hematocrit should rise approximately 1% each day, beginning on day 5–6 of therapy. The reticulocyte count should become elevated after 3–4 days of therapy and is the earliest morphologic sign of response. Iron supplementation should be administered as indicated.
For women with vitamin B12 deficiency, 1000 μg of vitamin B12 should be administered intramuscularly or subcutaneously monthly.
Megaloblastic anemia due to folate deficiency during pregnancy carries a good prognosis if adequately treated.
The anemia usually is mild unless associated with multifetal pregnancy, systemic infection, or hemolytic disease (eg, sickle cell anemia). Low birthweight as well as fetal neural tube defects are known to be associated with maternal folic acid deficiency. The associations with placental abruption, spontaneous abortion, and preeclampsia–eclampsia are not universally accepted. Even without treatment, anemia due to folate deficiency usually resolves after delivery when folate demands normalize.
- Empty bone marrow on biopsy
Aplastic anemia with primary bone marrow failure during pregnancy is rare. The anemia may be secondary to exposure to known marrow toxins, such as chloramphenicol, phenylbutazone, mephenytoin, alkylating chemotherapeutic agents, or insecticides. In approximately two-thirds of cases, no obvious cause is detected. Idiopathic aplastic anemia in pregnancy may have a spontaneous remission following delivery or pregnancy termination but may recur in subsequent pregnancies. The condition likely is immunologically mediated.
The rapidly developing anemia causes pallor, fatigue, tachycardia, painful ulceration of the throat, and fever. The diagnostic criteria are pancytopenia and empty bone marrow on biopsy examination.
Aplastic anemia in pregnancy may cause increased fetal wastage, prematurity, or intrauterine fetal demise. Increased maternal morbidity and death usually are due to infection and hemorrhage.
The patient must avoid any toxic agents known to cause aplastic anemia. Blood product replacement with packed red blood cells and platelets should be used as needed. In some cases, delivery or termination of pregnancy may be necessary. Bone marrow transplantation is performed if remission does not occur following delivery or termination of pregnancy. Other possible treatments include antithymocyte antibody, corticosteroids, or immunosuppressive agents. Infection must be treated aggressively with appropriate antibiotics, but most authorities do not recommend giving prophylactic antibiotics.
Pregnancy generally does not affect the prognosis of aplastic anemia. Prognosis is dependent on degree of bone marrow cellularity and patient age.
Drug-Induced Hemolytic Anemia
- Anemia with evidence of hemolysis
Drug-induced hemolytic anemia usually occurs as a result of drug-mediated immunologic red cell injury. For example, a drug can act as a hapten with an erythrocyte protein to which an antidrug antibody attaches. Hemolysis occurs as a result of the subsequent immune response. Many drugs used in pregnancy can have such an effect, including cephalosporins, acetaminophen, and erythromycin.
In African-American women, drug-induced hemolytic anemia is more likely caused by drug-induced oxidative damage rather than a drug-mediated immune mechanism. The most common congenital erythrocyte enzymatic defect to cause this condition is glucose-6-phosphate dehydrogenase (G6PD) deficiency. This X-linked disorder causes a heterozygous state in 10–15% of African-American females, but enzyme activity is variable due to random X-chromosome inactivation.
Decreased G6PD activity in one-third of patients in the third trimester causes an increased risk of hemolytic episodes. More than 40 substances toxic to susceptible people are recognized, including sulfonamides, nitrofurans, antipyretics, some analgesics, sulfones, vitamin K analogues, uncooked fava beans, some antimalarials, naphthalene, and nalidixic acid. Specific laboratory tests to identify susceptible individuals include a glutathione stability test and cresyl blue dye reduction test.
The red blood cell count and morphology are normal until hemolysis occurs. Levels of anemia are variable depending on the degree of hemolysis. Hemolysis can be diagnosed based on examination of peripheral smear, which may demonstrate spherocytes, elliptocytes, schistocytes, or helmet cells (fragmented red blood cells). Elevated lactate dehydrogenase (LDH) is also used to diagnose hemolysis. Patients with hemolytic anemia also demonstrate an increase in reticulocyte count.
Exposure of the G6PD-deficient fetus to maternally ingested oxidant drugs (eg, sulfonamides) may produce fetal hemolysis, hydrops fetalis, and fetal death.
Management includes immediate discontinuation of any suspected medications, treatment of intercurrent illness, and blood transfusion where indicated.