Chapter 34. Hematologic Disorders in Pregnancy

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.

Iron Deficiency Anemia

Essentials of Diagnosis

• Hypochromic and microcytic anemia with evidence of depleted iron stores

Pathogenesis

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.

Prevention

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.

Clinical Findings

Symptoms & Signs

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.

Laboratory Findings

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.

Differential Diagnosis

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.

Complications

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.

Treatment

In an established case of anemia, prompt adequate treatment is necessary.

Oral Iron Therapy

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.

Parenteral Iron Therapy

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.

Erythropoietin

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

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

Essentials of Diagnosis

• Macrocytic anemia with low serum levels of folate or vitamin B12

Pathogenesis

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.

Clinical Findings

Symptoms & Signs

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.

Laboratory Findings

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.

Treatment

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.

Prognosis

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.

Aplastic Anemia

Essentials of Diagnosis

• Pancytopenia
• Empty bone marrow on biopsy

Pathogenesis

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.

Clinical Findings

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.

Complications

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.

Treatment

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.

Prognosis

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

Essentials of Diagnosis

• Anemia with evidence of hemolysis

Pathogenesis

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.

Clinical Findings

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.

Complications

Exposure of the G6PD-deficient fetus to maternally ingested oxidant drugs (eg, sulfonamides) may produce fetal hemolysis, hydrops fetalis, and fetal death.

Treatment

Management includes immediate discontinuation of any suspected medications, treatment of intercurrent illness, and blood transfusion where indicated.

Essentials of Diagnosis

• Abnormal hemoglobin (hemoglobin S) leads to sickling of erythrocytes in the setting of decreased oxygen tension.
• Hemoglobin electrophoresis demonstrates hemoglobin S.
• Pregnancy in women with sickle cell disease is associated with an increased risk of obstetrical complications.

Pathogenesis

Sickle cell hemoglobin (hemoglobin S) results from a genetic substitution of valine for glutamic acid at codon 6 of the β-globin chains. Decreased oxygen tension causes hemoglobin S to form insoluble polymers in curvilinear strands. These polymers deform the normal biconcave structure of the erythrocyte. The process is reversible but eventually leads to cell membrane damage and permanent sickling.

Patients homozygous for the hemoglobin S gene have sickle cell anemia (SS disease), and those who are heterozygous have sickle cell trait. Approximately 8–10% of African-Americans carry the sickle cell trait, whereas approximately 1 in 500 has sickle cell anemia.

Other sickling syndromes exist when the gene for hemoglobin S is inherited along with the gene for another abnormal hemoglobin, such as hemoglobin C or thalassemia. Hemoglobin C, also caused by β-globin chain mutation, is less soluble than normal hemoglobin A and has a propensity to form hexagonal crystals. Women who are heterozygous for both the S and C genes have hemoglobin SC disease. Maternal mortality rates are as high as 2–3%. Hemoglobin SC disease is peculiarly associated with embolization of necrotic fat and cellular bone marrow with resultant respiratory insufficiency. Neurologic symptoms from fat embolism have been reported with sickle cell disease.

In hemoglobin S/beta-thalassemia disease, the patient is heterozygous for both hemoglobin S and beta-thalassemia. The severity of complications during pregnancy is related to hemoglobin S concentrations in this particular disease.

Sickle cell disease is characterized by chronic hemolytic anemia and intermittent crises of variable frequency and severity. Although persons with sickle cell trait are not anemic and usually are asymptomatic, they are at increased risk of developing urinary tract infections during pregnancy and are at higher risk for preeclampsia. Additionally, their red blood cells tend to sickle when oxygen tension is significantly lowered.

Clinical Findings

Symptoms & Signs

Chronic Anemia

Chronic anemia results from the shortened survival time of the homozygous S red blood cells due to circulation trauma and intravascular hemolysis or phagocytosis by reticuloendothelial cells in the spleen and liver.

Sickling of Red Blood Cells

Intravascular sickling leads to vaso-occlusion and infarction. Small blood vessels supplying various organs and tissues can be partially or completely blocked by sickled erythrocytes, resulting in ischemia, pain, necrosis, and organ damage.

Crises

Crises of variable frequency and severity occur. Pain crises involve the bones and joints. They usually are precipitated by dehydration, acidosis, or infection. An aplastic crisis is characterized by rapidly developing anemia. The hemoglobin may be as low as 2–3 g/dL due to cessation of red blood cell production. An acute splenic sequestration crisis is associated with severe anemia and hypovolemic shock, resulting from sudden massive trapping of red blood cells within the splenic sinusoids.

Other Manifestations

Other manifestations include increased susceptibility to bacterial infection; bacterial pneumonia and pulmonary infarction; myocardial damage and cardiomegaly; and functional and anatomic renal abnormalities in the form of sickle cell nephropathy or papillary renal necrosis, resulting in hematuria. Central nervous system manifestations include headache, convulsions, hemorrhage, or thrombosis (from vaso-occlusion). Ophthalmologic abnormalities include anoxic retinal damage, retinal detachments, vitreous hemorrhages, and proliferative retinopathy. Hepatosplenomegaly or cholelithiasis may occur.

Laboratory Findings

Screening for abnormal hemoglobin is imperative in the population at risk. Hemoglobin electrophoresis ascertains the diagnosis and can differentiate between homozygous and heterozygous states.

Complications

Sickle cell anemia is associated with serious risks for mother and fetus. Pregnant women with sickle cell disease face increased rates of maternal mortality and morbidity from hemolytic and folic acid deficiency anemias, frequent crises, pulmonary complications, congestive heart failure, infection, and preeclampsia–eclampsia. It is encouraging, however, that maternal mortality has decreased to 1% since 1972. There is an increased incidence of early fetal wastage, stillbirth, preterm delivery, and fetal growth restriction. The course of pregnancy is generally more benign in women with hemoglobin SC disease than women with sickle cell disease.

Treatment

Preconception counseling is essential in women with sickle cell disease to optimize the patient's health prior to conception. Many women with sickle cell disease are treated with hydroxyurea. Hydroxyurea use in pregnancy has been associated with fetal structural malformations in animals and is poorly studied in humans. Therefore, it should be discontinued prior to conception. Assessment of preconception health includes maternal echocardiogram to evaluate ejection fraction and to look for signs of pulmonary hypertension. Type and screen should also be tested for any sign of alloimmunization. Many women with sickle cell disease have a history of multiple blood transfusions, which puts them at risk of development of alloantibodies that could affect the fetus.

Additionally, preconception or prenatal genetic counseling is of great importance. If both partners have the gene for S hemoglobin, their offspring have a 1 in 4 chance of having sickle cell anemia. If it is determined that a fetus is at risk of hemoglobinopathy, chorionic villus sampling or amniocentesis can diagnose these disorders in the fetus. Preimplantation genetic diagnosis using single-blastomere DNA analysis prior to in vitro fertilization has allowed for the successful transfer of unaffected embryos.

Optimal prenatal care, including prevention or rapid treatment of complications, is necessary to increase the chance for a good outcome. Pneumococcal polyvalent vaccine has been shown to reduce the incidence of pneumococcal infection in adults with sickle disease and therefore is highly recommended. This vaccine is not contraindicated in pregnancy. Similarly, influenza vaccine should be administered annually. Folic acid 1 mg/d will prevent megaloblastic anemia, which can result from intense hematopoiesis. Serial ultrasonic evaluations are essential to assess fetal growth. Antepartum testing should begin at 32–34 weeks' gestation. Careful surveillance for asymptomatic bacteriuria and demonstration of cure is important for preventing pyelonephritis. Regional anesthesia can be safely administered to patients with sickle cell disease while they are in labor.

In the management of crises, the most common predisposing factors—infection, dehydration, and hypoxia—should be evaluated and treated. Symptomatic treatment of pain crisis consists of IV fluid, oxygen supplementation, and adequate analgesics (eg, morphine). Bacterial pneumonia or pyelonephritis must be treated vigorously with IV antibiotics. Streptococcal pneumonia is common and is a serious complication. In all cases, adequate oxygenation must be maintained by face mask as necessary.

The concentration of hemoglobin S should be <50% of the total hemoglobin to prevent crisis. Blood transfusion should be considered in cases of a fall in hematocrit to <25%, but this decision must be guided by the individual patient history and her status during pregnancy. Important considerations are repeated crisis; symptoms of tachycardia, palpitation, dyspnea, or fatigue; and evidence of inadequate or retarded intrauterine growth.

Randomized controlled trials have shown that administration of prophylactic hypertransfusion or exchange transfusion is not necessary to prevent maternal and fetal complications, except in well-defined circumstances. Transfusion carries the risks of allergic reaction, delayed hemolytic reaction, isoimmunization, and transmission of infection.

Bone marrow transplant has been limited by the complications of infection and graft-versus-host disease but shows promise as a potential long-term solution to sickle cell anemia. In utero stem cell therapy with normal hemoglobin stem cells is a potential future treatment for affected fetuses.

Essentials of Diagnosis

• The thalassemias are genetically determined disorders of reduced synthesis of 1 or more of the structurally normal globin chains in hemoglobin.
• Thalassemia is associated with varying degrees of anemia, depending on the type and number of globin chains that are reduced or absent.

Pathogenesis

Thalassemia is found throughout the world but is concentrated in the Mediterranean coastal areas, central Africa, and parts of Asia. The high incidence in these regions may represent a balanced polymorphism due to heterozygous advantage.

All thalassemias are inherited as an autosomal recessive trait. The 2 major groups are the alpha- and beta-thalassemias, both of which affect the synthesis of hemoglobin A, which contains 2 α and 2 β chains. The severity of the anemia varies with the type of hemoglobin abnormality.

Alpha-thalassemia is due to defective production of α-globin chains, resulting in a relative excess of β-globin chains. In beta-thalassemia, hemoglobin β-chain synthesis is defective, but the α chains are produced normally. In both cases, the unbalanced synthesis results in a relative excess of the normally produced chain. The normal globin chains then form tetramers that precipitate within red blood cell precursors in the bone marrow, resulting in ineffective erythropoiesis, red cell sequestration and destruction, and hypochromic anemia. The most severe forms of this disorder may cause intrauterine or childhood death. A person who is heterozygous, or a carrier, for a thalassemia trait may be asymptomatic.

Clinical Findings

Alpha-Thalassemia

Normally, a patient has 4 functional α-globin genes. Disease severity with alpha-thalassemia varies depending on how many genes are absent or mutated.

1. Alpha-thalassemia-2 trait is seen when 1 of the 4 genes is absent. These patients are not anemic, do not have microcytic red cells, and have a normal hemoglobin electrophoresis.

2. Alpha-thalassemia-1 trait, or alpha-thalassemia minor, is seen when 2 of the 4 genes are absent. These patients may have mild anemia with microcytic red cells, but their hemoglobin electrophoresis is normal.

3. Hemoglobin H (β4) disease results from deletion of 3 of the 4 α-globin genes. In patients with this disease, some normal hemoglobin A (α2β2) is produced because one of the α-globin genes is present, but the excess of β-globin changes causes the formation of hemoglobin H (β4) as well. Anemia of variable degree results that usually is worsened in pregnancy. Hemoglobin electrophoresis demonstrates 5–30% hemoglobin H.

4. Hemoglobin Barts is seen with loss of all 4 α-globin genes. This condition is not compatible with extrauterine life. It is associated with fetal hydrops and intrauterine fetal demise.

Maternal hemoglobin H is generally diagnosed prior to pregnancy. Alpha-thalassemia-2 trait and alpha-thalassemia minor may not be diagnosed prior to pregnancy and are relevant in that if the father is a carrier of thalassemia or another hemoglobinopathy, the fetus at risk for significant disease. If the fetus is at risk for thalassemia, prenatal diagnosis is available via DNA testing of fetal cells obtained from amniocentesis or chorionic villus sampling. Preimplantation genetic diagnosis is also available for couples at risk of having a fetus with severe alpha-thalassemia who are undergoing in vitro fertilization.

Beta-Thalassemia

Beta-thalassemia results from impaired β-globin chain production. Beta-thalassemia major is the homozygous state, in which there is little or no production of β-chains. At birth, the neonate usually is asymptomatic because fetal hemoglobin F (α2γ2) contains no β-globin chain. However, this protection disappears at birth, when fetal hemoglobin production terminates. At approximately 1 year of age, a baby with defective β-globin production usually begins to show signs of thalassemia (anemia, hepatosplenomegaly) and requires frequent blood transfusions. Affected individuals often die in their late teens or early 20s because of congestive heart failure, often related to myocardial hemosiderosis and liver failure. However, improved treatment with transfusion and iron chelation has led to overall improved survival and even to successful pregnancies in women with beta-thalassemia major.

Beta-thalassemia minor, the heterozygous state, is frequently diagnosed only after the patient fails to respond to iron therapy or delivers a baby with homozygous disease. Such patients usually suffer from mild to moderate hypochromic microcytic anemia, with increased red blood cell count, elevated hemoglobin A2 (α2δ2) concentrations, increased serum iron levels, and iron saturation >20%, although hemoglobin electrophoresis may miss a small percentage of patients with beta-thalassemia minor.

Suspected adult cases of thalassemia are diagnosed by hemoglobin electrophoresis. As with alpha-thalassemia, antenatal diagnosis of beta-thalassemia is possible. Molecular hybridization measures the number of intact α-globin structural genes in fetal cells obtained by amniocentesis. Preimplantation genetic diagnosis allows for the transfer of unaffected embryos after in vitro fertilization.

Hodgkin's Lymphoma

Hodgkin's lymphoma (previously known as Hodgkin's disease) is the most common lymphoma to affect women of childbearing age. Even so, it is uncommon during pregnancy, affecting only approximately 1 in 6000 pregnancies.

Clinical Findings

Patients may be asymptomatic or have fever, weight loss, and pruritus. The most common finding is peripheral lymphadenopathy. Histologic evaluation of the affected nodes establishes the diagnosis.

Careful staging is essential prior to the initiation of treatment with radiotherapy or chemotherapy. Modifications of standard staging modalities, such as the use of magnetic resonance imaging (MRI), can allow for adequate staging during pregnancy. However, some procedures, such as staging laparotomy, after the first trimester impose risks to the pregnancy.

Complications

Complications associated with Hodgkin's lymphoma during pregnancy are related to treatment of the disease, not the disease itself. Chemotherapy during the first trimester is associated with an increased risk of fetal structural malformation. During the second and third trimesters, chemotherapy is associated with intrauterine growth restriction, preterm birth, stillbirth, and adverse fetal neurodevelopmental outcomes such as mental retardation and learning disabilities. Children exposed to chemotherapy in utero appear to be at increased risk of cancer themselves.

Treatment

Treatment is tailored to the individual based on the extent of disease and the gestational age. Radiotherapy is an effective treatment option if radiation scatter to the fetus can be minimized. Chemotherapy is relatively safe later in gestation but best avoided in the first trimester if the clinical situation allows. Pregnancy termination is an alternative if Hodgkin's lymphoma is diagnosed early in gestation. Although pregnancy itself does not appear to adversely affect the lymphoma, pregnancy termination permits the aggressive radiotherapy and chemotherapy often necessary. Conversely, if the diagnosis is made later in gestation and the patient is asymptomatic, delaying therapy until fetal lung maturity is established may be reasonable.

Women with Hodgkin's lymphoma are extremely susceptible to infection and sepsis. Sequelae of treatment include radiation pneumonitis causing restrictive lung disease, pericarditis leading to congestive heart failure, hypothyroidism, and ovarian failure. Given that 85% of relapses in Hodgkin's lymphoma occur within 2 years, it is generally accepted that pregnancy should be deferred for 2 years following remission. The risk of second malignancies, especially leukemia, is dramatically increased.

Non-Hodgkin's Lymphoma

Until recently, non-Hodgkin's lymphomas were encountered infrequently in pregnancy. However, because 5–10% of individuals infected with the human immunodeficiency virus (HIV) will develop a lymphoma, the incidence of non-Hodgkin's lymphomas is rising. Similar to Hodgkin's lymphoma, extensive staging is essential. Treatment with radiotherapy is indicated for localized disease, whereas chemotherapy is used for more extensive disease. Care of the pregnant patient with lymphoma requires a multidisciplinary approach by obstetrician-gynecologists, hematologic oncologists, perinatologists, and neonatologists. With careful treatment, the fetuses of affected women appear to tolerate treatment of lymphoma quite well.

Leukemia

Leukemias are malignant proliferations of cells of the hematopoietic system. Acute leukemias are derived from primitive progenitor cells of either the myeloid lineage (acute myelogenous leukemia [AML]) or the lymphocytic lineage (acute lymphocytic leukemia [ALL]). Chronic leukemias are also derived from either myeloid cells (chronic myelogenous leukemia [CML]) or lymphocytic cells (chronic lymphocytic leukemia [CLL]). All leukemias are rare before age 40 years with the exception of ALL, a childhood disease with a median age at diagnosis of 10 years.

Clinical Findings

Affected individuals often present with the symptoms of anemia (fatigue, weakness), thrombocytopenia (bleeding, bruising), or neutropenia (infection) caused by the replacement of normal hematopoietic cells with leukemia cells in the bone marrow. White blood cell count in the serum can be low, normal, or extremely elevated. Diagnosis is made by cytochemical, genetic, and immunochemical evaluations of the cells of a bone marrow biopsy or aspirate.

Treatment

Treatment of acute leukemia is based on immediate initiation of chemotherapy. For example, the median survival time of untreated patients with AML is 3 months or less. Exposure to chemotherapy during organogenesis frequently results in fetal death. However, most authorities consider chemotherapy safe in the second and third trimesters. A period of pancytopenia following chemotherapy can be complicated by infection and hemorrhage. Patients often require erythrocyte and platelet transfusions, as well as antibiotic medications.

Acute leukemia during pregnancy is associated with premature delivery, fetal growth restriction, and fetal loss, but these findings are more likely due to chemotherapy and its complications rather than the leukemia itself.

Although hemorrhagic disorders (eg, immune thrombocytopenic purpura [ITP], disseminated intravascular coagulation, circulating anticoagulants) are not common during pregnancy, these conditions could cause significant risks for both mother and fetus.

Gestational Thrombocytopenia

Incidental thrombocytopenia of pregnancy, also termed gestational thrombocytopenia, affects 5% of pregnancies. It is characterized by mild, asymptomatic thrombocytopenia with platelet levels usually >70,000/μL. It usually occurs late in gestation and resolves spontaneously after delivery. Gestational thrombocytopenia has no association with fetal thrombocytopenia. Its etiology is unclear, although some authorities suspect that gestational thrombocytopenia represents a very mild form of ITP. Antiplatelet antibodies are isolated from patients in both groups and therefore do not aid in diagnosis. Routine obstetric management is appropriate.

Immune Thrombocytopenic Purpura

In ITP, also called idiopathic thrombocytopenic purpura, platelet destruction is secondary to a circulating immunoglobulin (Ig) G antiplatelet antibody that crosses the placenta and may affect fetal platelets.

Clinical Findings

The maternal clinical picture varies from asymptomatic to minor bruises or petechiae, bleeding from mucosal sites, or rarely fatal intracranial bleeding. Splenomegaly may be present. In the peripheral circulation, the platelet count often is between 80,000 and 160,000/μL, but it may be lower. The bone marrow aspirate demonstrates hyperplasia of megakaryocytes, although this test is rarely indicated. The diagnosis can be made once laboratory evaluation demonstrates an isolated thrombocytopenia and other causes, such as drug-induced or HIV-related thrombocytopenia, have been excluded. Antiplatelet antibody testing is not diagnostic.

Complications

Because maternal IgG antiplatelet antibodies cross the placenta, the fetus is at risk for severe thrombocytopenia. Fortunately, only approximately 10% of infants born to women with ITP have platelet counts less than 50,000/μL at birth. Antepartum identification of severely affected fetuses has proved difficult. Maternal and fetal platelet counts do not correlate well, nor do levels of maternal antiplatelet antibody and fetal platelet levels. Given the low incidence of severe neonatal thrombocytopenia and morbidity, most authorities do not recommend direct fetal platelet determination by fetal scalp sampling or umbilical cord blood sampling.

Treatment

The standard management is to initiate treatment when the platelet count falls to <30,000–50,000/μL, although significant bleeding does not begin until platelet levels are <10,000/μL. Glucocorticoids suppress the phagocytic activity in the splenic monocyte-macrophage system, increasing platelet levels in approximately two-thirds of patients. Patients refractory to steroid therapy are candidates for immunoglobulin infusion, which has been a great benefit to most patients who fail glucocorticoid therapy. Splenectomy usually is reserved for patients refractory to prednisone and IV immunoglobulin. Immunosuppressive agents should be used with great caution and only in extraordinary cases of ITP in pregnancy. Transfusion of platelets and whole blood may be necessary to restore losses from acute hemorrhage or to normalize low perioperative platelet counts (<50,000/mL).

Pathogenesis

Venous thromboembolism (VTE) affects approximately 1 in 1000 pregnancies. Pregnancy and the puerperium are periods of increased risk for these events because they are hypercoagulable states. Indeed, all the elements of Virchow's triad (circulatory stasis, vascular damage, and hypercoagulability of blood) are present. Increased venous capacity during pregnancy coupled with compression of large veins by the gravid uterus causes venous stasis. Endothelial damage occurs at delivery and is more extensive after caesarean delivery, contributing to the increased risk of VTE after caesarean section. Coagulation is favored during pregnancy due to estrogen stimulation of coagulation factors and decreased activity of the fibrinolytic.

Inherited thrombophilias such as activated protein C resistance (most commonly due to the factor V Leiden mutation), prothrombin gene mutation, antithrombin III deficiency, and protein C and protein S deficiency, along with acquired thrombophilias such as the antiphospholipid syndrome (APS), have emerged as important risk factors for VTE. Other risk factors include prior VTE, older age, smoking, and immobilization.

Superficial Thrombophlebitis

Patients with thrombosis of the superficial veins of the saphenous system present with tenderness, pain, or erythema along a vein. A palpable cord is sometimes present. Because of the possibility of concurrent deep vein thrombosis (DVT), compression ultrasound is reasonable to confirm the diagnosis and exclude DVT. Treatment consists of compression stockings, ambulation, leg elevation, local heat, and analgesic medications. Of note, the superficial femoral vein belongs to the deep venous system despite its name. A thrombus in this vein requires treatment for DVT.

Deep Vein Thrombosis

Approximately half of DVT in pregnancy occurs antepartum and half occurs postpartum. Previous clinical practices that contributed to thrombosis, such as prolonged postpartum bed rest, likely falsely elevated the risk of DVT in the puerperium. Greater than 80% of DVT in pregnancy occurs in the left lower extremity rather than the right, a finding attributed to compression of the left iliac vein by the right iliac artery as it branches off the aorta.

Clinical Findings

The presentation of DVT is variable but frequently includes lower extremity tenderness, swelling, color changes, and a palpable cord. Homan's sign, pain elicited by passive dorsiflexion of the foot, may be present. Occasionally, the extremity is pale and cool with decreased pulses due to reflex arterial spasm.

Diagnosis

The modality of choice for diagnosis of DVT is real-time ultrasound, used with duplex and color Doppler ultrasound. Venography remains the standard but has been largely replaced by the less invasive diagnostic tests. MRI is used when there is a strong clinical suspicion of thrombus not detected by ultrasound or if the ultrasound results are equivocal. With MRI, anatomy above the inguinal ligament can be evaluated, as can pelvic blood flow.

Treatment

Anticoagulation, bed rest, and analgesia are the fundamental treatments of DVT. Ambulation with elastic stockings begins once all symptoms have abated, usually in 7–10 days. Patients are initially anticoagulated with unfractionated heparin or low-molecular-weight heparin. Low-molecular-weight heparin has a longer half-life and increased bioavailability, making administration easier and anticoagulant response more predictable. It is associated with fewer bleeding problems than unfractionated heparin and does not require laboratory monitoring. In the postpartum state, the patient can then transition to warfarin. Due to embryopathy and fetal hemorrhage, warfarin is contraindicated during pregnancy. Antepartum DVT is treated with anticoagulation for the rest of pregnancy and then for 6–12 weeks postpartum for at least a total of 3–6 months of therapy. DVT occurring postpartum should be treated with anticoagulation for 3–6 months.

Pulmonary Embolism

Pulmonary embolism accounts for approximately 20% of maternal deaths in the United States. Its antepartum and postpartum prevalence are approximately equal, although postpartum pulmonary embolism is associated with higher mortality rates. Clinical evidence of DVT often precedes pulmonary embolization. However, given the prevalence of thrombosis originating in the iliac veins during pregnancy, antecedent DVT is frequently not clinically apparent.

Prevention

Prophylactic anticoagulation should be considered for women at high risk for thromboembolism during pregnancy. Women with inherited thrombophilias that confer a high risk for thrombosis during pregnancy, such as antithrombin III deficiency, homozygosity for factor V Leiden mutation, or prothrombin gene mutation, or compound heterozygosity for factor V Leiden and prothrombin gene mutations, should be anticoagulated during pregnancy regardless of whether they have an antecedent history of thromboembolism. Women with lower risk thrombophilias, such as protein C or S deficiency and heterozygosity for prothrombin gene mutation (G20210A) or factor V Leiden mutation, and a history of thromboembolism should also receive anticoagulation during pregnancy. Women with a prior VTE that was related to a temporary risk factor (eg, prolonged immobilization after injury) do not require anticoagulation during pregnancy. However, for women with a prior thromboembolic event related to pregnancy or estrogen-containing birth control pills and no thrombophilia, consideration may be given to anticoagulation during pregnancy. For this subgroup of women, the American College of Obstetricians and Gynecologists indicates that surveillance without anticoagulation is also acceptable.

Clinical Findings

The most common presenting symptom of pulmonary embolus is dyspnea, followed by pleuritic chest pain, apprehension, cough, syncope, and hemoptysis. Associated signs include tachypnea and tachycardia.

Diagnosis

Initial evaluation of the symptoms associated with pulmonary embolism usually consists of arterial blood gas measurement, chest radiograph, and electrocardiogram. Ventilation–perfusion scintigraphy may be used to evaluate for perfusion defects and ventilation mismatches that suggest pulmonary embolus. The test has negligible fetal radiation exposure. High-probability scans are indicative of pulmonary embolism in 88% of cases. Conversely, in patients with normal or near-normal scans, pulmonary embolism was detected by angiography only 4% of the time. However, the usefulness of this modality is limited by that fact that the majority of results are reported as intermediate- or low-probability scans, categories without much diagnostic value. Because of these limitations, spiral computed tomographic (CT) pulmonary angiography has emerged as a useful, noninvasive modality for the detection of pulmonary embolism but is limited in the detection of small emboli. Pulmonary artery catheterization with angiography remains the gold standard but is used less frequently due to its invasive nature.

Treatment

Treatment of pulmonary embolism is anticoagulation. Guidelines such as those published by the American College of Chest Physicians (2004) should be followed. The factors influencing anticoagulant choice (heparin vs. warfarin [Coumadin]) are the same as those for DVT. First-line therapy during pregnancy is adjusted-dose unfractionated heparin or low-molecular-weight heparin. Therapeutic anticoagulation should be continued for at least 4–6 months to prevent recurrence. Vena caval filter use may be necessary should recurrent embolization occur despite anticoagulation.

Essentials of Diagnosis

• Septic pelvic thrombophlebitis is thrombosis in the veins of the pelvis due to infection.
• It is associated with abdominal pain and high fever.
• CT or MRI can confirm the diagnosis.

Pathogenesis

Septic pelvic thrombophlebitis is thrombosis in the veins of the pelvis due to infection. The most important risk factor is caesarean section, especially if complicated by infection. In fact, almost 90% of cases occur after caesarean delivery. The overall incidence is low, affecting only approximately 1 in every 2000 pregnancies.

Pelvic infection leads to infection of the vein wall and intimal damage. Thrombogenesis occurs at the site of intimal damage. The clot is then invaded by microorganisms. Suppuration follows, with liquefaction, fragmentation, and, finally, septic embolization.

Both the uterine and ovarian veins may be involved, as well as the common iliac, hypogastric, and vaginal veins and the inferior vena cava. The ovarian vein is the most common site of septic thrombosis (40% of cases). The onset of symptoms may be as early as 2–3 days postpartum or as late as 6 weeks after delivery.

Clinical Findings

The condition is suspected when fever persists in the puerperium despite adequate antibiotic therapy for aerobic and anaerobic organisms and no other discernible cause of fever. Abdominal pain and back discomfort are common presenting symptoms. A picket-fence fever curve (“hectic” fevers) with wide swings from normal to as high as 41°C (105.8°F) is seen in 90% of cases. Tachycardia and tachypnea may be present. Leukocytosis usually is present. Blood cultures drawn during fever spikes yield positive results more than 35% of the time.

Pelvic examination often is consistent with a normal postpartum examination and therefore not helpful in diagnosing this condition. However, in approximately 30% of cases, hard, tender, wormlike thrombosed veins may be palpable in the vaginal fornices or in 1 or both parametrial areas. A temperature spike may be noted after examination because of disturbance of infected pelvic veins; this may be considered a diagnostic indication of septic pelvic thrombophlebitis. Chest radiograph often reveals evidence of multiple, small septic emboli. CT or MRI may assist in the diagnosis of pelvic vein thrombosis and eliminate other pelvic causes, such as abscess.

Differential Diagnosis

The differential diagnosis includes pyelonephritis, meningitis, systemic lupus erythematosus, tuberculosis, malaria, typhoid, sickle cell crisis, appendicitis, and torsion of the adnexa.

Complications

The serious complications associated with this condition are septic pulmonary emboli, extension of the venous clot in the pelvis, renal vein thrombosis, ureteral obstruction, and death.

Treatment

The mainstays are anticoagulation with heparin and broad-spectrum antibiotics (including coverage for anaerobes and common Enterobacteriaceae). Within 48–72 hours of initiation of heparin therapy, fever should resolve. Treatment usually is empirically continued for 7–10 days, although the optimal duration of therapy is not well defined.