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Hematologic Disorders

Anemia

Anemia is a significant maternal problem during pregnancy. A hemoglobin of less than 11 g/dL or a hematocrit of less than 33% should be investigated and treated to avoid blood transfusion and its related complications. A pregnant woman will lose blood during delivery and the puerperium, and an anemic woman is therefore at increased jeopardy. During pregnancy, the blood volume increases by about 50% and the red blood cell mass by about 25%. This physiologic hydremia of pregnancy will lower the hematocrit but does not truly represent anemia.

Nutritional anemia is the most common form. It results from deficiency of iron, folic acid, or vitamin B12. Pernicious anemia due to vitamin B12 deficiency almost never occurs during pregnancy. Other anemias occurring during pregnancy are aplastic anemia and drug-induced hemolytic anemia.

Iron Deficiency Anemia

Iron deficiency is responsible for about 95% of the anemias during pregnancy, reflecting the increased demands for iron. The total body iron consists mostly of (1) iron in hemoglobin (about 70% of total iron; about 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 (about 300 mg). Small amounts of iron exist in myoglobin, plasma, and various enzymes. Hemosiderin contains 37% more iron than does ferritin. Absence of hemosiderin in the bone marrow indicates that iron stores are exhausted. This is both diagnostic of anemia and one of the earliest signs of iron deficiency. This will be followed by a decrease in serum iron and 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 from food (10–15 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 about 500 mg of iron. The iron needs of the fetus average 300 mg. Thus, the total amount of iron necessary over the course of a normal pregnancy is approximately 800 mg; this cannot be supplied in the diet, and iron supplementation must be given. 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 can be met by iron supplements exceeding 40 mg/d of elemental iron.

Iron deficiency anemia normally does not endanger the pregnancy unless it is severe, in which case intrauterine growth retardation and preterm labor may result.

Clinical Findings

Symptoms and Signs

The symptoms may be vague and nonspecific, including pallor, easy fatigability, palpitations, tachycardia, and dyspnea. Angular stomatitis, glossitis, and koilonychia may be present in long-standing severe anemia.

Laboratory Findings

The hemoglobin may fall as low as 3 g/dL, but the red cell count is rarely below 2.5 x 106/mm3. The red cells are usually microcytic, with mean corpuscular volumes of less than 79 fL, and hypochromic. The reticulocyte count is low for the degree of anemia. Platelet counts are frequently increased, but white cell counts are normal. Occasional hypersegmented neutrophils are seen. Serum iron levels are usually less than 60 g/dL. The total iron-binding capacity is elevated to 350–500 g/dL, transferrin saturation is less than 16%, and the serum ferritin concentration is less than 10 g/dL. The amount of stainable iron (hemosiderin) in the marrow aspirate is a reasonably accurate indication of stored iron.

Differential Diagnosis

Anemia due to chronic disease or an inflammatory process (eg, rheumatoid arthritis) may be hypochromic and microcytic. A similar type of anemia in thalassemia trait can be differentiated from iron deficiency anemia by normal serum iron levels, the presence of stainable iron in the marrow, and elevated levels of hemoglobin A2.

Complications

Angina pectoris or congestive heart failure may develop as a result of marked iron deficiency anemia. Sideropenic dysphagia (Paterson-Kelly syndrome, Plummer-Vinson syndrome) due to long-standing severe iron deficiency anemia is rare in women of childbearing age.

Prevention

During the course of pregnancy and the puerperium, at least 60 mg/d of elemental iron should be prescribed to prevent anemia.

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 about 10% is absorbed), should be given 3 times a day. If this is not tolerated, ferrous fumarate or gluconate should be prescribed. Therapy should be continued for about 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.

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.

Imferon is a mixture of ferric hydroxide in a 0.9%sodium chloride solution for injection. It contains the equivalent of 50 mg/mL of elemental iron as an iron dextran complex. Imferon may be given intramuscularly or intravenously. Intramuscular injection must always be given into the muscle mass of the upper outer quadrant of the buttock with a 2-inch, 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). A test dose of 0.5 mL is administered and the patient watched carefully for anaphylactic reactions. After an hour or longer, 2.5 mL of dextran is given in each buttock for a total of 5 mL (total dose of 250 mg of elemental iron). This should be repeated every week until the total dosage has been given. Imferon may also be given intravenously after testing for anaphylaxis has been done with 0.5 mL of dextran. Excessive dosage must be avoided to prevent hemosiderosis.

Folic Acid Deficiency Anemia (Megaloblastic Anemia of Pregnancy)

Megaloblastic anemia of pregnancy is caused by folic acid deficiency and is common where nutrition is inadequate. Based on bone marrow studies, the incidence is 25–60%, depending upon the population studied; peripheral blood examination shows a much lower incidence. The incidence of folate deficiency in the United States is 0.5–15%, depending on the population studied and the diagnostic methods used.

The minimum daily intake of folate necessary to maintain stores and adequate hematopoiesis is 50 g. This is increased during pregnancy (National Academy of Sciences recommendation) to 800 g. Folic acid deficiency anemia is more common in multiple pregnancy and in multigravid patients. It may recur in subsequent pregnancies.

Folic acid absorption or metabolism may be impaired during use of oral contraceptives, pyrimethamine, trimethoprim-sulfamethoxazole, primidone, phenytoin, or barbiturates. Jejunal bypass surgery for obesity or the malabsorption syndrome (sprue) may also impair folic acid absorption. Folic acid is necessary for the deoxyribonucleic acid (DNA) synthesis of erythropoiesis; thus, sickle cell anemia, a chronic hemolytic state, requires increased folate. Other hemolytic states are also commonly complicated by folic acid deficiency, including hereditary spherocytosis and malarial infestation. Alcohol consumption has been known to interfere with folate metabolism.

Megaloblastic anemia should be suspected if iron deficiency anemia fails to respond to iron therapy. Diagnosis of folic acid deficiency anemia is usually made late in pregnancy or in the puerperium. Low birthweight as well as fetal neural tube defects are known to be associated with maternal folic acid deficiency; however, an association with placental abruption, spontaneous abortion, and preeclampsia-eclampsia is not universally accepted.

Clinical Findings

Symptoms and 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 may be present. An accompanying urinary tract infection is common. Occasionally, purpura may be a clinical manifestation.

Laboratory Findings

Folic acid deficiency results in a hematologic picture similar to that of true pernicious anemia (due to vitamin B12 deficiency), which is extremely rare in women of childbearing age. Indeed, megaloblastic anemia in pregnancy almost always implies folate deficiency. The hemoglobin may be as low as 4–6 g/dL, and the red cell count may be less than 2 million/L in severe cases. Extreme anemia often is associated with leukocytopenia and thrombocytopenia. The red cells are macrocytic (mean corpuscular volume usually > 100 fL), and megaloblastic changes are present in the marrow. However, in pregnancy, macrocytosis may be concealed by accompanying iron deficiency or thalassemia. Serum folate levels of less than 4 ng/mL are suggestive of folic acid depletion in nonpregnant patients, but 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% of neutrophils with 5 or more lobes, but this may also be true for 25% of normal pregnant patients.

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 will be helpful in the diagnosis, as well as a positive hematologic response to folate. Serum iron and vitamin B12 levels should be normal.

Treatment

Folic acid, 1–5 mg/d orally or parenterally, continued for several weeks after delivery or for several weeks in patients diagnosed in the puerperium, produces the maximum hematologic response, replaces body stores, and provides the minimum daily requirements. The hematocrit should rise about 1% each day beginning at day 5–6 of therapy. The reticulocyte count should become elevated after 3–4 days of therapy and is the earliest morphologic sign of remission. Iron should be administered orally or parenterally as indicated.

Prognosis

Megaloblastic anemia due to folate deficiency during pregnancy carries a good prognosis if adequately treated. The anemia is usually mild unless associated with multifetal pregnancy, systemic infection, or hemolytic disease (eg, sickle cell anemia). The disorder usually disappears after delivery and is likely to recur only when the patient becomes pregnant again. For complete hematologic response during pregnancy, both folic acid and iron must be given because 70% of folate-deficient patients also lack iron stores.

Aplastic Anemia

Aplastic anemia with primary bone marrow failure during pregnancy is fortunately rare. The anemia may be secondary to exposure to known marrow toxins such as chloramphenicol, phenylbutazone, mephenytoin, alkylating chemotherapeutic agents, and insecticides. In most cases, no obvious cause is detected. Idiopathic aplastic anemia in pregnancy may have a spontaneous remission following delivery but may recur in subsequent pregnancies. This suggests that the cause is a disorder of the immune mechanism.

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. Patients with aplastic anemia are at increased risk for infection and hemorrhage.

Complications

Aplastic anemia in pregnancy may cause increased fetal wastage, prematurity, intrauterine fetal demise, and increased maternal morbidity and death.

Treatment

The patient must avoid any toxic agents known to cause aplastic anemia. Prednisolone should be given, 10–20 mg 4 times a day. A transfusion of packed red blood cells and platelets may be needed. In some cases, termination of pregnancy may be necessary. Bone marrow transplantation is performed if remission does not occur following delivery or termination of pregnancy. Infection must be treated aggressively with appropriate antibiotics, but most authorities do not recommend giving prophylactic antibiotics.

Drug-Induced Hemolytic Anemia

Drug-induced hemolytic anemia often occurs in individuals with inborn errors of metabolism. In the United States, blacks are frequently affected. Glucose-6-phosphate dehydrogenase reduced (G6PD) deficiency in erythrocytes is the most common cause, but catalase and glutathione deficiency may also be associated with this disorder. The traits are X-linked. About 12% of black males and 3% of black females are affected.

Clinical Findings

There is decreased G6PD activity in one-third of patients in the third trimester, causing an increased risk of hemolytic episodes. About two-thirds of pregnant patients with this disorder will have a hematocrit of less than 30%. Urinary tract infections are more common in these patients; use of sulfonamides will precipitate hemolysis. Overexposure of the G6PD-deficient fetus to maternally ingested oxidant drugs (eg, sulfonamides) may produce fetal hemolysis, hydrops fetalis, and fetal death. A black pregnant woman should probably be screened for G6PD deficiency before starting sulfonamide therapy for urinary tract infection.

The red blood cell count and morphology are normal until challenged by noxious drugs. Over 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.

Treatment

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

Sickle Cell Disease

Sickle cell disease is a genetic disorder almost always occurring in blacks. It is characterized by an abnormal hemoglobin molecule, hemoglobin S, which causes red blood cells to become sickle-shaped. Sickle cell hemoglobin results from a genetic substitution of valine for glutamic acid in the sixth position from the N-terminal end of beta chains. The autosomal recessive sickle cell gene is passed to both sexes. Patients homozygous for the hemoglobin S gene have sickle cell anemia, and those who are heterozygous have sickle cell trait. About 10% of blacks in the United States carry sickle cell trait, and 1 in 500 has sickle cell anemia. Women who are heterozygous for both the S and C genes have hemoglobin S/C disease; maternal mortality rates are as high as 2–3%. Hemoglobin S/C disease is peculiarly associated with embolization of necrotic fat and cellular bone marrow with resultant respiratory insufficiency. Neurologic symptoms from fat embolism have also 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 trait.

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. Restrictive nuclease techniques using DNA isolated from amniotic fluid cells are most useful for prenatal diagnosis of hemoglobinopathy in cases at risk.

Clinical Findings

Sickle cell disease is characterized by chronic hemolytic anemia and intermittent crises of variable frequency and severity. While persons with sickle cell trait are not anemic and are usually asymptomatic, they have twice as many urinary tract infections as normal women. Additionally, their red blood cells tend to sickle when oxygen tension is significantly lowered; thus, hypoventilation during general anesthesia may be fatal.

Symptoms and 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. These are usually precipitated by dehydration, acidosis, or infection. An aplastic crisis is characterized by rapidly developing anemia. The hemoglobin is 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, segmental bronchopneumonia, 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 vasoocclusion). Ophthalmologic abnormalities include anoxic retinal damage, retinal detachments, vitreous hemorrhages, and proliferative retinopathy. Hepatosplenomegaly or cholelithiasis may also occur.

Laboratory Findings

Sickle cell anemia is associated with high risks for mother and fetus. Screening for abnormal hemoglobin is imperative in the population at risk. Two screening tests are in common use. The sodium metabisulfite test uses 1 drop of fresh 2% reagent mixed on a slide with 1 drop of blood. Sickling of most red cells will occur in a few minutes with both sickle cell trait and sickle cell disease. The Sickledex test is a simple solubility test that uses 20 L of blood mixed with 2 mL of sodium dithionite reagent. Clouding of the solution indicates the presence of hemoglobin S. If the test is positive, the homozygous and heterozygous states must be differentiated by hemoglobin electrophoresis.

Effects on Pregnancy

Pregnancy has deleterious effects on sickle cell disease. There are 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 the maternal mortality has decreased to 1% since 1972. There is an increased incidence of early fetal wastage, stillbirth, preterm delivery, and intrauterine growth restriction.

Treatment

Good prenatal care, avoidance of complications, and prompt effective treatment for complications are necessary for a good outcome of pregnancy. Folic acid, 1 mg/d, will prevent megaloblastic anemia. Ultrasonic evaluations adequately assess fetal growth, but biophysical monitoring is necessary for antepartum fetal surveillance. Adequate pain relief must be given during labor. Close intrapartum electronic monitoring of labor is indicated. Prevent hypoxia during general anesthesia by maintaining adequate oxygenation and ventilation. Cesarean section should be done at the earliest sign of fetal compromise for the best perinatal outcome.

In the management of crises, predisposing factors should be searched for and eliminated, if possible. Symptomatic treatment for pain crisis consists of intravenous fluid and adequate analgesics (eg, meperidine or codeine). Bacterial pneumonia or pyelonephritis must be treated rigorously with blood culture and intravenous antibiotics. Streptococcal pneumonia is common and is an ominous complication. Pneumococcal polyvalent vaccine has been shown to reduce the incidence of pneumococcal infection in adults with sickle disease, and therefore it is highly recommended. This vaccine is not contraindicated in pregnancy. In all cases, adequate oxygenation must be maintained by face mask as necessary.

The concentration of hemoglobin S should be less than 50% of the total hemoglobin to prevent crisis. Blood transfusion should be considered in cases of a fall in hematocrit to less than 25%; repeated crisis; symptoms of tachycardia, palpitation, dyspnea, or fatigue; or evidence of inadequate or retarded intrauterine growth.

The immediate risk of transfusion (eg, congestive cardiac failure) must be avoided. Prophylactic hypertransfusion or exchange transfusion to prevent maternal complications, improve uteroplacental perfusion, and achieve a better perinatal outcome has been advocated by some, but these methods are not universally accepted. Transfusion always carries a risk of allergic reaction, delayed hemolytic reaction with rapid fall in hemoglobin A, and transmission of hepatitis virus or the AIDS virus. Isoimmunization may also occur. The antibodies most commonly found are Rh, Kell, Duffy, and Kidd; all pregnant patients with sickle cell trait or disease should be tested for these antigens plus ABO type. Hemolytic disease of the newborn or transfusion reactions due to improper cross-matching of blood may occur if careful blood typing is not done. The use of fresh buffy coat–poor washed packed cells for exchange transfusion will help in avoiding transfusion reactions. (See also Chapter 15: Late Pregnancy Complications.) Induction of nonsickling red blood cells (RBCs) from bone marrow has been considered. The use of erythropoietin was found to increase production of hemoglobin F in baboons; however, it stimulated hemoglobin S production in humans. Hemoglobin F synthesis by stimulating Y-chain production appears to be a promising form of therapy for the sickle cell disease and thalassemia syndrome. Y-chains of hemoglobin F inhibit polymerization of hemoglobin S and therefore inhibit sickling. Recombinant erythropoietin and hydroxyurea have been used together recently with elevation of hemoglobin F. More recently intravenous arginine butyrate has been used with the increase in fetal globin synthesis, production of F reticulocytes, and the level of Y-globin. Bone marrow transplant has been limited by the complications of infection and graft-versus-host disease. Prenatal diagnosis of sickle cell disease might encourage in utero stem cell therapy with normal hemoglobin stem cells.

Sterilization should be considered if maternal complications are too threatening. Oral contraceptives are avoided because of the risk of thromboembolism.

Thalassemia

The thalassemias are genetically determined disorders of reduced synthesis of one or more of the structurally normal globin chains in hemoglobin. 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 alpha and 2 beta chains. The severity of the anemia varies with the type of hemoglobin abnormality. In beta thalassemia, the beta hemoglobin chains are defective, but the alpha chains are normal; in alpha thalassemia, the reverse is true. The unbalanced synthesis results in precipitation of the normal chains. If the beta chains are impaired, the alpha chains are produced at a normal rate but in relative excess. The alpha 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.

The most severe form of alpha thalassemia compatible with extrauterine life is hemoglobin H (beta4) disease, which results from deletion of 3 genes. In patients with this disease, abnormal quantities of both hemoglobin H and hemoglobin B accumulate. In alpha thalassemia minor, 2 genes are deleted, causing a mild hypochromic, microcytic anemia that must be differentiated from iron deficiency anemia.

In beta thalassemia, no gene deletions have been demonstrated. There are 2 forms of beta thalassemia, beta+ and beta0, depending on whether beta chain production is reduced or entirely absent. Beta thalassemia major is the homozygous state, in which there is little or no production of beta chains. 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 hypochromic microcytic anemia, with increased red blood cell count, elevated hemoglobin A2 concentrations, increased serum iron levels, and iron saturation greater than 20%.

The fetus is protected from severe disease because fetal hemoglobin (alpha22) contains no beta globin chain. However, this protection disappears at birth, when fetal hemoglobin production terminates. At about 1 year of age, a baby with defective beta globin production usually begins to show signs of thalassemia (anemia, hepatosplenomegaly) and requires frequent blood transfusions. Victims of severe thalassemia often die in their late teens or early twenties because of congestive heart failure, often related to myocardial hemosiderosis, liver failure, or diabetes mellitus. During pregnancy, iron supplementation should be given only following assessment of iron stores to prevent hemosiderosis. Suspected cases of thalassemia must be diagnosed by means of hemoglobin electrophoresis.

Antenatal diagnosis of thalassemia is now possible. A technique known as molecular hybridization measures the number of intact alpha globin structural genes in fetal cells obtained by amniocentesis. In antepartum diagnosis of beta thalassemia, hemoglobin A is measured in fetal blood obtained via fetoscopy or sonographically directed placental aspiration of fetal blood.

Leukemia & Lymphoma

Leukemia is a neoplastic process affecting the leukopoietic tissues of the body. Acute leukemia has a short and fulminant clinical course, whereas chronic leukemia may have a prolonged course lasting several years. Depending on the type of leukocyte affected, leukemia may be lymphatic, myeloid, or monocytic. Lymphomas result from proliferation of cells of the lymphoreticular system. Two types are known: Hodgkin's disease and non-Hodgkin's lymphoma. Fortunately, these diseases are uncommon in pregnancy. The peak incidence of chronic lymphocytic leukemia and non-Hodgkin's lymphoma occurs after childbearing age, so the association of pregnancy with these diseases is extremely rare.

Clinical Findings

Pregnancy does not affect the course of these diseases, but several complications should be anticipated. Chemotherapy may cause fetal death or malformation or intrauterine growth restriction. The teratogenic and mutagenic effects of ionizing radiation in the first trimester have long been known. More than 10 rads of irradiation to the pelvis during the first trimester in Hodgkin's disease can have deleterious effects on the fetus. The carcinogenic potential and alteration in intelligence and behavior in fetuses exposed to chemotherapy and radiation in utero are uncertain. Intrauterine growth restriction and preterm labor, both iatrogenic and spontaneous, are not uncommon in maternal leukemia. Perinatal mortality rates are increased considerably. Several cases of possible transfer of leukemia and Hodgkin's disease to offspring have been reported.

Splenomegaly, a common manifestation, may cause abdominal discomfort. Severe anemia may cause marked weakness and heart failure. The patient may need multiple blood transfusions. Thrombocytopenia may lead to bruising of the skin and bleeding from the mucous membranes, necessitating platelet transfusion. Postpartum hemorrhage occurs in about 20% of cases. In acute leukemia, severe infection with organisms of usually low virulence is common. Patients with Hodgkin's disease may have complications of irradiation, including pneumonitis causing restrictive lung disease, pericarditis leading to congestive heart failure, various neurologic symptoms, nephritis, and ovarian failure. The risk of a second cancer is substantially increased in patients with Hodgkin's disease. The risk for leukemia has been reported to have increased almost 100-fold if chemotherapy has been given.

Treatment

Management is difficult. Therapy must be individualized if pregnancy is allowed to continue. The obstetrician and a hematologic oncologist should work together. Treatment will require chemotherapy, correction of anemia, and prevention of, or aggressive therapy for, infection. Induced abortion should be considered if chemotherapy is given early in pregnancy.

Effective agents in acute leukemia include prednisone, vincristine, asparaginase, daunorubicin, doxorubicin, mercaptopurine, methotrexate, cyclophosphamide, and cytarabine. Major drugs for chronic leukemia include busulfan, hydroxyurea, and cyclophosphamide. Although chemotherapy entails a risk to the fetus, it often cannot be deferred. In acute leukemia, the median maternal survival rate is only 2.5 months without chemotherapy.

Termination of pregnancy does not seem to affect the course of Hodgkin's disease or the length of survival. Interruption of the pregnancy is recommended if irradiation or chemotherapy is given early in pregnancy. However, neither chemotherapy during second and third trimesters nor irradiation to the mediastinum and neck appears to adversely affect the fetus or neonate. The chemotherapeutic agents normally used in Hodgkin's disease include mechlorethamine, vincristine, procarbazine, and prednisone. If local radiation therapy to the liver, spleen, or lymph nodes is indicated, the uterus should be shielded. Agents used in non-Hodgkin's lymphoma include cyclophosphamide, doxorubicin, vincristine, and prednisone.

Fetal status should be monitored with periodic ultrasonic examination and biophysical monitoring. Delivery should be accomplished when fetal lung maturation is evident on amniotic fluid phospholipid study, and ideally, when the mother is in complete remission.

Prognosis

The prognosis of pregnant patients with these disorders is not significantly different from that for nonpregnant patients. However, since 85% of relapses in Hodgkin's disease occur within 2 years, it is generally accepted that pregnancy should be deferred for 2 years following remission.

The newborn should be carefully evaluated periodically to note any immediate or delayed toxic effects of maternal chemotherapy.

Hemorrhagic Disorders

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

Immune Thrombocytopenic Purpura

In immune thrombocytopenic purpura, platelet destruction is secondary to a circulating IgG antibody that crosses the placenta and may also affect fetal platelets. The maternal clinical picture varies from asymptomatic to minor bruises or petechiae, bleeding from mucosal sites, or fatal intracranial bleeding. There may be splenomegaly. The marrow aspirate demonstrates hyperplasia of megakaryocytes. In the peripheral circulation, the platelet count will be 80,000–160,000/L.

Maternal morbidity and mortality rates are low, but the perinatal mortality rate is around 20%, mostly related to intracranial bleeding. Differences of opinion exist regarding antepartum and intrapartum management of the pregnant woman. Steroids should be given. In refractory cases, splenectomy should be performed in the second trimester, if possible. Immunosuppressive agents should be used with great caution and only in extraordinary cases of immune thrombocytopenic purpura 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). More recently, maternal infusion of gamma globulin during pregnancy has been used in an attempt to block placental transfer of maternal IgG.

Fifty percent of thrombocytopenic mothers have babies with low platelet counts during the first week of neonatal life. Maternal levels of circulating IgG correlate well with the presence of neonatal thrombocytopenia.

Intrapartum management includes avoidance of traumatic vaginal delivery and maternal soft tissue injury. However, delivery by cesarean section is not universally accepted. Fetal scalp blood sampling to determine the fetal platelet count has been recommended in the past to determine the mode of delivery. However, fetal scalp sampling is fraught with technical difficulties and inaccuracies. Furthermore, there is overall a very low incidence of neonatal morbidity and neonatal outcome does not seem to differ between vaginal and cesarean deliveries. Therefore it is the general opinion that fetal scalp blood sampling is not warranted in the setting of immune thrombocytopenic purpura. However, a small minority still recommend assessment of fetal platelet counts (either through cordocentesis or fetal scalp sampling) to identify the small percentage of fetuses with severe thrombocytopenia.

Circulating Anticoagulants

Circulating anticoagulants, mainly inhibitors of factor VIII, an IgG immunoglobulin, can cause minor to severe bleeding from various sites. Bleeding may be spontaneous or due to trauma, surgery, or sometimes delivery. Treatment may include exchange transfusion with replacement of specific factors or use of corticosteroids or immunosuppressive agents.

Thromboembolization

Thromboembolization denotes all vascular occlusive processes, including thrombophlebitis, phlebothrombosis, septic pelvic thrombophlebitis, and embolization of venous clots to the lungs. The incidence of thromboembolism is 0.2% in the antepartum period and 0.6% in the postpartum period. Cesarean section increases the incidence to 1–2%. Pulmonary embolism, with a mortality rate of 15%, occurs in 50% of patients with documented deep vein thromboses; only 5–10% of these are symptomatic. Early diagnosis and adequate treatment drastically reduce the incidence of pulmonary embolism and death.

Pathophysiology

Vascular clotting develops mainly due to circulatory stasis, infection, vascular damage, or increased coagulability of blood. All the elements of Virchow's triad (circulatory stasis, vascular damage, and hypercoagulability of blood) are present during pregnancy. Increase in caliber of capacitance vessels produces vascular stasis, and blood hypercoagulability is due to increased amounts of factors VII, VIII, and X. Thrombin-mediated fibrin generation is increased many times during pregnancy. Significant vascular damage occurs during delivery. Venous return from the lower extremities is reduced by the pressure of the gravid uterus on both the iliac veins and the inferior vena cava. Other important predisposing factors include heavy cigarette smoking, obesity, previous thromboembolism, anemia, hemorrhage, heart disease, hypertensive disorders, prolonged labor, operative delivery, and postpartum endomyometritis.

The venous thrombi may develop first in the relatively small veins of the calf muscle and extend proximally as far as the femoral or iliac veins or, rarely, even into the inferior vena cava. Another common site of postpartum thrombosis is the pelvic veins due to diminished blood flow in the hypertrophied uterine veins. Thrombi may extend into the iliac veins and may produce pelvic venous thrombosis. Fatal pulmonary embolism may follow. Septic emboli are usually from the uterine, ovarian, or iliac veins. Partial liquefaction of the infected thrombus creates showers of bacteria-laden emboli. Although the lungs are almost always involved, secondary abscesses may occur in the brain or the heart, or a mycotic aneurysm may develop in one of the great vessels.

Phlebothrombosis is coagulation of blood in the veins without apparent antecedent inflammation. The clot is usually loosely adherent and causes incomplete occlusion. When thrombosis of a vein is secondary to inflammation of the wall of the vein, the condition is known as thrombophlebitis. This pathologic difference has little significance so far as the management is concerned because both disorders can cause pulmonary embolism. Superficial thrombophlebitis is the most common venous thrombosis associated with pregnancy. It usually occurs in varicose veins in the calf and is most frequent after delivery. Deep vein thrombophlebitis may be a sequela of the superficial form; this is an ominous condition. It is more common during the third trimester and the first few days of the puerperium.

Clinical Findings

Symptoms and Signs

Superficial thrombophlebitis is suspected when an erythematous tender, firm cordlike superficial vein is palpated. Clinical diagnosis of deep vein thrombophlebitis is neither sensitive nor specific; the false-positive rate is as high as 50%. Most deep vein thrombi are completely asymptomatic. Symptoms may be subtle or classic, depending upon the site and extent of the thrombus and the status of the collateral venous circulation. Classic features include swelling of the affected site of the legs, pain, tenderness, local cyanosis, and fever. These features are common if the proximal veins are involved. Pain in the calf muscle with dorsiflexion of the foot on the affected leg (Homans' sign) has little value in diagnosis. Moreover, embolic risk cannot be correlated with the severity of the pain. Most patients with pulmonary emboli do not have prior evidence of venous thrombosis. Iliofemoral venous thrombophlebitis causes acute swelling in the leg, pain above the hip, tenderness over the femoral triangle, and vaginal bleeding.

Diagnostic Studies

Ideally, the diagnosis should be objectively confirmed prior to initiation of treatment. Objective tests may be noninvasive (eg, Doppler ultrasound) or invasive (eg, venography). There are limitations to both the performance and interpretation of the objective tests, eg, an antepartum venogram exposes the fetus to radiation. The safest method of diagnosing venous thrombosis in pregnancy is use of impedance plethysmography, Doppler ultrasonography, and limited venography.

Impedance Plethysmography

Impedance plethysmography measures the volume changes within the veins of the leg. Thrombotic and nonthrombotic occlusions cannot be differentiated by this method. The pressure by the gravid uterus on the common iliac vein or inferior vena cava (particularly after 20 weeks' gestation) can produce false-positive results. A normal result excludes proximal venous thrombosis but does not exclude calf vein thrombosis.

Directional Doppler Ultrasound

Directional Doppler ultrasound can detect the presence or absence of venous flow. Damping of pulsatile flow is consistent with nonocclusive thrombus. This test is also insensitive to calf vein thrombosis and could be influenced by the pressure of the gravid uterus on the pelvic veins. Real-time sonography coupled with duplex and color Doppler ultrasound have been found to be useful in the diagnosis of deep venous thrombosis of the lower extremities, but its role in the evaluation of pelvic vein thrombosis is less clear. During pregnancy thrombosis frequently originates in the iliac veins. Magnetic resonance imaging allows for excellent delineation of anatomic detail above the inguinal ligaments, and phase images can be used to diagnose the presence or absence of flow in the pelvic veins. Computed tomographic scanning requires contrast agent and ionizing radiation, and is therefore avoided in favor of magnetic resonance imaging.

Venography

Venography allows the entire lower extremity, including the external and common iliac veins, to be evaluated. It is the most definitive method for diagnosis of venous thrombosis. Unfortunately, 1–2% of patients develop clinically significant phlebitis following venography. This risk can be minimized by flushing the dye with saline and elevating the legs. If the pelvic veins are not well visualized by ascending venography, femoral venography should be done. The abdomen must be shielded during venography.

125I-Fibrinogen Scanning

125I-fibrinogen is absorbed by the thrombus following intravenous injection. A hand-held probe is placed over the affected area. Unbound 125I-fibrinogen scanning is contraindicated during pregnancy and breastfeeding. Leg scanning should not be used when proximal vein thrombosis (iliac or femoral vein) is suspected.

Prevention

The indications for preventive therapy include previous documented deep vein thrombosis or pulmonary embolism or antithrombin III deficiency. Heparin is the drug of choice; give 5000–7500 U subcutaneously twice a day during the first and second trimesters. Around the beginning of the third trimester, increase the dosage by approximately one-third to provide additional anticoagulation for the increased coagulation factors in late pregnancy. Prophylaxis should be stopped with the onset of labor and started again following delivery and continued for at least 2 weeks.

Treatment

Superficial Venous Thrombophlebitis

Treatment of superficial venous thrombophlebitis consists of elevation of the involved leg and local application of moist heat. In resistant cases in nonpregnant patients, nonsteroidal anti-inflammatory agents may be used, but these should be avoided in pregnant women after 30 weeks' gestation because they may cause premature closure of the ductus arteriosus in the fetus. In high-risk patients with varicose veins, custom-made support panty hose should be worn.

Deep Vein Thrombosis

Heparin

Heparin is the drug of choice. It is a naturally occurring, negatively charged polysaccharide with an average molecular weight of 16,000 found in the mast cells of most mammals. It is effective intravenously or subcutaneously. It exerts its anticoagulant effect in the presence of a plasma cofactor, antithrombin III. The activity of antithrombin III is markedly increased by heparin.

Heparin may be given by continuous intravenous infusion; an initial loading dose of 5000 U is followed by 25,000–30,000 U given over a 24-hour period. Heparin may also be given subcutaneously, 15,000 U twice daily. With intermittent intravenous infusion, 5000 U is given every 4 hours. For prevention of postoperative thrombosis, 5000 U of heparin is given subcutaneously 2 hours before surgery; this dose should be repeated 12 hours after operation and then twice daily until the patient is ambulatory. The anticoagulant action of heparin occurs within 10–15 minutes of injection, but the effect disappears in about 2 hours.

Tests used to monitor heparin therapy include coagulation time, activated partial thromboplastin time, thrombin clotting time, and heparin assay. Heparin should not be given if the platelet count is below 50,000/L. The partial thromboplastin time should be 1.5–2 times the control value during heparin therapy.

The major side effect is bleeding in about 5% of cases. Other complications include thrombocytopenia, osteoporosis, and fat necrosis. Protamine sulfate is the antidote for heparin. Protamine, 1 mg per 100 U of heparin, will quickly shorten the partial thromboplastin time. Care must be taken not to give too much protamine, since it can induce bleeding.

The more recent availability of low-molecular-weight heparin has provided an attractive alternative to traditional unfractionated heparin for thromboprophylaxis and treatment of venous thrombosis and thromboembolism. Low molecular weight heparin does not cross the placenta and in not teratogenic, similarly to unfractionated heparin. However, it has a longer half-life and bioavailability, a more predictable dose-response relationship, and decreased risk of thrombocytopenia and hemorrhagic complications when compared to traditional heparin. Because of these characteristics, low-molecular-weight heparin may be administered subcutaneously once or twice daily without laboratory monitoring. Widespread use of low-molecular-weight heparin may be limited, however, by its cost, which exceeds that of unfractionated heparin by about 4–6 times.

Oral Anticoagulants

Oral anticoagulants such as warfarin, a coumarin derivative, are usually contraindicated during pregnancy and breastfeeding. The teratogenic effects of warfarin (warfarin embryopathy) include nasal hypoplasia, skeletal abnormalities, and multiple central nervous system abnormalities. Fetal and placental bleeding leading to intrauterine fetal demise has been described with the use of warfarin. Its therapeutic effect depends on its ability to inhibit the action of vitamin K. The usual dose of warfarin is 10–15 mg/d until the therapeutic level of prothrombin time is achieved (1.5–2.5 times the control value). Thereafter, a maintenance dose is given based on prothrombin time, which should be checked twice daily. Vitamin K1 (phytonadione), 5 mg given intravenously, is the specific antidote for warfarin.

Septic Pelvic Thrombophlebitis

Septic pelvic thrombophlebitis is clotting in the veins of the pelvis due to infection. This may occur following vaginal or cesarean delivery. Predisposing factors include cesarean section after a long labor, premature rupture of the membranes, difficult delivery, anemia, malnourishment, and systemic disease. Septic pelvic thrombophlebitis occurs in 1 in 2000 deliveries. The pathologic process involves bacterial invasion of the intimal lining of the veins. The clotting process is initiated by the damaged intima, and the clot is invaded by microorganisms. Suppuration follows, with liquefaction, fragmentation, and finally, septic embolization. Thirty to 40% of untreated patients will have septic pulmonary emboli.

Clinical Findings

Both the uterine and ovarian veins are involved, as well as the common iliac, hypogastric, and vaginal veins and the inferior vena cava. The ovarian vein is the most common site (40% of cases). The onset may be as early as 2–3 days postpartum or as late as 6 weeks following delivery. The condition is suspected when fever persists in the puerperium in spite of adequate antibiotic therapy for aerobic and anaerobic organisms and there is no other discernible cause of fever. A picket-fence fever curve with wide swings from normal to as high as 41 °C (105.8 °F) is seen in 90% of cases. The pulse rate is rapid and sustained in most cases. The respiratory rate is increased, but there is no indication of pulmonary disease. There are no typical x-ray signs, because the emboli are small, multiple, and infected, but around 46% of cases show some x-ray abnormality due to abscess or infarct. The pelvic examination may be normal; however, hard, tender, wormlike thrombosed veins are palpable in the vaginal fornices or in one or both parametrial areas in about 30% of cases. Abdominal examination may occasionally reveal thrombosed ovarian veins. A temperature spike may be noted following examination because of disturbance of infected pelvic veins; this may be considered one diagnostic indication. Resolution of fever with heparin anticoagulation will help in the presumptive diagnosis. Blood for culture should be drawn during fever spikes; cultures are positive more than 35% of the time.

Differential Diagnosis

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

Treatment

Heparin and broad-spectrum antibiotics should be given (eg, penicillin and gentamicin with clindamycin or metronidazole; ampicillin may be added to clindamycin and gentamicin to cover enterococci). Within 48–72 hours of initiation of heparin therapy, fever should resolve. Heparin should be continued for 7–10 days.

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