Hematologic Disease and Pregnancy

ANEMIA @

With normal pregnancy, an increase in blood volume is observed, which results in a concomitant hemodilution. This results in a physiologically lowered hemoglobin (Hb), hematocrit (Hct), and red blood cell (RBC) count, but it has no effect on the mean corpuscular volume (MCV). Many centers define anemia in a patient who is pregnant as Hb less than 10.5 g/dL, as opposed to the reference range of 14.0 g/dL in a patient who is not pregnant.

Iron deficiency anemia

A woman who is pregnant often has insufficient iron stores to meet the demands of pregnancy. Encourage women who are pregnant to supplement their diet with 60 mg/day of elemental iron. An MCV less than 80 mg/dL and hypochromia of the RBCs should prompt further studies, including total iron-binding capacity, ferritin levels, and Hb electrophoresis if iron deficiency is excluded. Clinical symptoms of iron deficiency anemia include fatigue, headache, and pica in extreme situations. Treatment is additional supplementation with oral iron (320 mg, 1-3 times daily).

Folate and vitamin B-12 deficiency

Folate deficiency is much less common than iron deficiency; however, taking 0.4 mg a day to reduce the risk of neural tube defects is recommended to all women contemplating pregnancy. Patients with a history of neural tube defect should take 4.0 mg a day. An increased MCV can be suggestive of folate deficiency; in this case, determine serum levels of vitamin B-12 and folate. If the levels are low, the patient may require oral folate at a dose of 1.0 mg 3 times daily. Patients with vitamin B-12 deficiency need further workup to determine the level of intrinsic factor to exclude pernicious anemia. The Schilling test is not recommended during pregnancy because of the use of a radionuclide. Treatment of vitamin B-12 deficiency includes 0.1 mg/day for 1 week, followed by 6 weeks of continued therapy to reach a total administration of 2.0 mg.

SICKLE CELL HEMOGLOBINOPATHIES @

Sickle cell hemoglobinopathies include those abnormalities resulting from an alteration in structure, function, or production of Hb. Hemoglobin S (HbS) results from substitution of the neutral amino acid valine for negatively charged glutamic acid at the sixth position from the N terminus in the B chain. Hemoglobin C (HbC) results from a lysine substitution for glutamic acid.

Major sickle disorders with severe clinical symptoms include sickle cell anemia (HbSS), sickle cell hemoglobin C disease (HbSC), and sickle cell beta-thalassemia (HbS beta-Thal).

Minor disorders include hemoglobin C disease (HbAC), hemoglobin SE (HbSE), hemoglobin SD (HbSD), and hemoglobin S-Memphis (HbS-Memphis). Heterozygosity for hemoglobin A and hemoglobin S (HbAS) is the most common disorder, occurring in 1 in 12 African-Americans. HbSS is the most common major sickle cell disorder, occurring in 1 in 625 African Americans.

Anemia occurs as a result of the sickle hemoglobinopathies. Deoxygenation of the abnormal RBCs results in sickling. These permanently damaged RBCs are then removed by the reticuloendothelial system, with the average RBC lifespan reduced to 17 days. The result is a chronic compensated anemia, with Hb typically measured between 6.5 and 9.5 g/dL.

The sickle shape also results in altered motion through the microvasculature. This altered motion can predispose the patient to vascular stasis, hypoxia, acidosis, and increased 2,3 diphosphoglycerate, which perpetuates the cycle by resulting in further deoxygenation and, thus, more sickling. The microvascular injury can result in ischemic necrosis and end-organ infarction.

Maternal morbidity

In general, managing the treatment of a woman who is pregnant and has sickle cell disease requires close observation. Frequently obtain the blood cell counts of the patient because anemia can worsen quickly. Folic acid supplementation is recommended because of the quick turnover of erythrocytes. Monitor the pregnancy with serial ultrasounds for fetal growth, and implement weekly nonstress testing at 32 weeks. Offer the patient a pneumococcal vaccine before pregnancy, if possible.

Prophylactic RBC transfusion was once standard in patients who were pregnant and had sickle cell disease; however, it is no longer routinely advised. In 1988, a National Institutes of Health (NIH)-sponsored multicenter randomized controlled trial of 72 patients with HbSS disease showed no significant difference in overall maternal or perinatal outcome of patients who received transfusions and those who did not, except for a lower incidence of painful crises in patients who received transfusions. The risks incurred with multiple blood transfusions include infection and alloimmunization, which have their own implications for pregnancy. Similar findings have been reported in a more heterogenous group of patients from the United Kingdom (including patients with HbSS, HbSC, and HbS beta-Thal), though there is some evidence that the subset of women with sickle hemoglobinopathies carrying twins or higher order multiples may benefit from prophylactic transfusion.

A woman who is pregnant is at risk of developing sickle cell crisis (SCC). These crises typically are vasoocclusive and may be precipitated by infection. They may be associated with thrombophlebitis or preeclampsia. Commonly, a pattern of sudden recurrent attacks of pain involving the abdomen, chest, vertebrae, or extremities occurs. These crises are somewhat more common in HbSS disease than HbSC and HbS beta-Thal disease.

Laboratory tests that may be helpful to distinguish between SCC and other possible etiologies of pain include white blood cell count with differential and lactic dehydrogenase (LDH). An elevated WBC count may be seen in cases of SCC, but a left shift should not be seen. Patients with SCC have elevated LDH. Other laboratory tests that should be ordered upon patient admission include CBC, type and cross match, and arterial blood gas as indicated.

Therapeutic measures for SCC mainly are supportive, with institution of intravenous (IV) fluids to decrease blood viscosity and pain control as standard pillars of care. If a sudden drop in Hct occurs, therapeutic transfusion may be advisable. It is of paramount importance to identify and treat any underlying infections. If the fetus is viable, continuous fetal heart rate monitoring is necessary if maternal oxygenation is compromised. The mother and fetus may benefit from supplemental oxygen. Remember that fetal heart rate tracings may be nonreactive and the blood pressure and pulse (BP&P) may be abnormal during crisis; BP&P typically revert to normal when the crisis resolves. Umbilical artery Doppler studies also have been noted as frequently being normal during crisis, even in the setting of abnormal uterine artery Doppler studies.

Overall, great improvement in maternal and fetal outcome in sickle cell disease has occurred. A widely quoted study from West Africa in the early 1970s reports 11.5% mortality in mothers who are homozygous. Other investigators noted a decrease in maternal death rates at Los Angeles County Hospital from 4.1% in the era before 1972 to 1.7% from 1972-1982, with all deaths occurring in patients with HbSS or HbS beta-Thal disease. A decade later, the NIH-sponsored Cooperative Study of Sickle Cell Disease reported 2 deaths in 445 (0.6%) pregnancies. Both of these deaths occurred in patients with HbSS. Few reported maternal deaths have been associated with HbSC disease in the last 2 decades. The Cooperative Study also found earlier gestational ages at delivery, smaller birthweights, and an increased rate of stillbirths (0.9%) in the HbSS group, as well as a greater rate of painful crises (50%). No difference in the rates of preeclampsia existed among the different genotypes, and surprisingly, little pyelonephritis occurred (<1%). Most likely, an increase in first trimester fetal wastage occurs; however, it is difficult to correctly ascertain this rate in the modern era because many women with this disease electively terminate their pregnancies. Despite the improvement in survival of both mother and fetus, remember that patients with the sickle hemoglobinopathies remain at risk for renal insufficiency, cerebrovascular accident, cardiac dysfunction, leg ulcers, and sepsis, particularly from encapsulated organisms.

THALASSEMIA @

Thalassemia is a disease with many forms, all of which are characterized by impaired production of one of the normal globin peptide chains found in Hb. Healthy adults should have over 95% HbA, consisting of 2 alpha and 2 beta peptide chains. The 2 major thalassemias, alpha-thalassemia and beta-thalassemia, result from decreased production of 1 or more of these peptide chains. The clinical consequences can be ineffective erythropoiesis, hemolysis, and anemia of varying degrees.

The disease is found throughout the world, but its highest prevalence is in areas endemic for malaria, where it may confirm a heterozygote advantage. These regions include the Mediterranean, central Africa, and parts of Asia.

Inheritance is autosomal recessive. A lethal homozygous state results when an individual inherits genes for both alpha or beta chains. Various defects that may be responsible for the different thalassemia syndromes have been implicated on a molecular level. In most populations, the gene loci for the alpha globin chains are located on chromosome 16. Geographical variation exists with the various syndromes. HbBart and hemoglobin B (HbB) afflict people of Asian descent principally.

Alpha thalassemia

Four clinical syndromes have been described. The homozygous condition results when all 4 genes for the alpha globin chain are deleted and the fetus is unable to synthesize fetal hemoglobin (HbF) or any adult hemoglobins. This condition results in HbBart as the predominant Hb. Because of its high oxygen affinity, little oxygen is released to the tissues. The fetus suffers from nonimmune hydrops and typically dies in utero or shortly after birth.

Hemoglobin H (HbH) disease is a compound heterozygous state that results in the deletion of 3 out of 4 alpha-globin genes. The abnormal red cells at birth consist of both HbH and HbBart. The neonate appears well at birth but then develops hemolytic anemia. Ultimately, the HbBart is replaced with HbH. The result is anemia, which varies in severity and can worsen significantly during pregnancy. Alpha-thalassemia minor is the heterozygous state, which results from a deletion of 2 genes and results in a mild-to-moderate hypochromic microcytic anemia. Patients with this condition typically do well during pregnancy.

Beta-thalassemia

The beta-thalassemias are the consequence of one of many point mutations that cause absence of or reduction in beta-chain production. Homozygous beta-thalassemia major or Cooley anemia is characterized by precipitation of the excessive alpha chains that results in ineffective erythropoiesis and hemolysis. The fetus is protected from this, but after birth as HbF levels fall, the infant becomes anemic. Though transfusion can prolong life, especially when combined with iron chelation therapy, females with this disorder historically have been infertile. However, the number of successful pregnancies in these patients has been increasing. These patients require frequent transfusions and desferrioxamine chelation therapy throughout pregnancy.

Beta-thalassemia minor has variable clinical effects, depending on the rate of beta-chain production. It may be unmasked during pregnancy or uncovered after a patient has delivered a homozygous infant. Hb electrophoresis characteristically shows a minor fraction of adult hemoglobin (HbA2), which consists of 2 alpha and 2 delta chains, to be increased to greater than 3.5%. These patients do not have impaired fertility or pregnancy outcome; however, they may become disproportionately anemic and require iron or folate supplementation during pregnancy. The obstetric emphasis with these patients who are heterozygous is on prenatal diagnosis.

SCREENING AND GENETIC TESTING FOR THE HEMOGLOBINOPATHIES @

Advances in genetic research that allow precise identification of mutations of the Hb genes make it increasingly important for the obstetrician-gynecologist to identify couples at risk for having offspring with the hemoglobinopathies. Although universal screening is not recommended, send in CBC with RBC indices for all pregnant women at the initiation of prenatal care. Pay particular attention to patients of Southeast Asian, Mediterranean, or African descent. Refer patients of African descent for Hb electrophoresis to look for the sickle hemoglobinopathies. Also refer patients who are from Southeast Asia or the Mediterranean and have anemia and reduced MCV (<80m3) and normal iron studies for Hb electrophoresis.

If Hb is normal in patients who are Southeast Asian, specifically evaluate for alpha-thalassemia. Offer to test the partner of any carrier of sickle hemoglobinopathies and any patient with elevated HbA2 (>3.5%) to assess the risk to the fetus. If both partners are identified as carriers, offer DNA-based tests of the fetus.

Tests for prenatal diagnosis of sickle cell anemia and thalassemia now include polymerase chain reaction (PCR) of fetal DNA extracted from amniotic cells, of trophoblasts from chorionic villus sampling, and of erythroblasts obtained from cordocentesis. In many hemoglobinopathies, including sickle cell disease and most beta-thalassemias, there are point mutations for which specifically designed oligonucleotide probes can be used, especially in combination with knowledge of the patient's ethnicity. For some thalassemias, performing indirect DNA testing by linkage analysis is still necessary.

Efforts to reduce the risks to the fetus incurred with invasive tests like amniocentesis, chorionic villus sampling, and cordocentesis have been made by acquisition of fetal cells from the maternal circulation using magnetic cell sorting; however, this procedure is not standard. This technique can only work in hemoglobinopathies in which the mutation has been identified because only a small amount of fetal cells can be purified.

A fascinating advancement in prenatal diagnosis has been the development of a preimplantation genetic diagnosis. In 1999, a team of reproductive endocrinologists reported single-cell PCR and DNA analysis of embryos from a couple, both carriers for sickle cell disease, with transfer of the genetically healthy embryos and subsequent delivery of healthy twins.

THROMBOCYTOPENIA @

Thrombocytopenia in pregnancy is common and is diagnosed in about 7% of pregnancies. It typically is defined as a platelet count of less than 150,000 per mL. The most common cause of thrombocytopenia during pregnancy is gestational thrombocytopenia, which is a mild thrombocytopenia with platelet levels remaining greater than 70,000 per mL. Patients who are affected usually are asymptomatic and have no history of thrombocytopenia prior to pregnancy. Their platelet levels should return to normal within several weeks following delivery. An extremely low risk of fetal or neonatal thrombocytopenia is associated with gestational thrombocytopenia. Gestational thrombocytopenia may result from increased platelet consumption and can be associated with antiplatelet antibodies. Gestational thrombocytopenia can be hard to distinguish from immune thrombocytopenia purpura (ITP) presenting during pregnancy.

Immune thrombocytopenia purpura

Acute ITP is a disorder occurring in childhood with little implication for women who are pregnant because it resolves spontaneously. Chronic ITP may occur in the second or third decade of life, affecting females 3 times as frequently as males. This condition is characterized by immunologically mediated platelet destruction. Antiplatelet antibodies (immunoglobulin G [IgG]) attack platelet membrane glycoproteins and destroy platelets at a rate that cannot be compensated by the bone marrow. ITP usually is associated with persistent thrombocytopenia (<100,000 per mL), normal or increased megakaryocytes on bone marrow aspirate, exclusion of other disorders associated with thrombocytopenia, and the absence of splenomegaly. Patients may report a history of easy bruising and petechiae or epistaxis and gingival bleeding preceding the pregnancy.

Although worsening of the disease is not typical during pregnancy, when it occurs, the mother is at risk for bleeding complications at the time of delivery. Therapies aimed at improving maternal platelet count in anticipation of delivery include intravenous immunoglobulin (IVIg) and steroids. The patient may require platelet transfusion during delivery if the platelets drop below 20,000 per mL. Splenectomy is reserved for severe cases only.

Some controversy exists regarding the threat of intracranial hemorrhage (ICH) in neonates born to mothers with ITP. Although as many as 12-15% of infants born to mothers with ITP may develop platelet counts less than 50, 000 per mL, the risk of ICH is estimated at less than 1% in 2 recent prospective studies.

Neonatal alloimmune thrombocytopenia

In contrast to ITP, neonatal alloimmune thrombocytopenia may pose a serious risk to the newborn. It may occur in 1 in 1000 live births and often is unanticipated when it occurs in first pregnancies. The presentation may be in the setting of an unremarkable pregnancy and delivery. Clinical manifestations in the neonate include generalized petechiae, ecchymoses, hemorrhage into viscera, increased bleeding at the time of circumcision or venipuncture, or most gravely, ICH. ICH may occur in utero in as many as 25% of cases. Like Rhesus (Rh) disease, neonatal alloimmune thrombocytopenia results from maternal alloimmunization against fetal platelet antigens. The most severely affected antigen is human platelet antigen-1a, which has been described in about 50% of cases in Caucasians. A high risk of recurrence of neonatal alloimmune thrombocytopenia exists, and it tends to worsen with subsequent gestations in a manner similar to Rh disease.

For patients who have a history of the disease and are experiencing their first pregnancy, referral to a maternal-fetal medicine specialist skilled in cordocentesis may be warranted because the fetus may need to have platelet counts or a transfusion while in utero. IVIg has been shown to improve fetal thrombocytopenia. Cesarean delivery is the preferred route of delivery for infants with platelet counts less than 50,000 per mL to reduce the risk of ICH secondary to trauma incurred during labor.

COAGULATION DISORDERS @

Von Willebrand disease

This is the most common inherited bleeding abnormality, with a prevalence of 0.8-1.3%. This disorder is secondary to a decrease or defect in the von Willebrand portion of the factor 8 complex, which plays a significant role in platelet aggregation. Type I, which is inherited in an autosomal dominant fashion, is the most common subtype (>70% of cases). Patients may present with menorrhagia, easy bruising, gingival bleeding, and epistaxis or with abnormal bleeding following surgery or trauma. Laboratory findings in patients with type I disease typically show a prolonged bleeding time from decreased platelet aggregation, decreased von Willebrand factor (vWF), decreased factor VIII:C, and sometimes, a prolonged activated partial thromboplastin time (aPTT). Mild thrombocytopenia may occur. In patients with type II disease, normal amounts of abnormally functioning vWF may exist. Type III disease is very rare and is characterized by very low vWF. Type III disease tends to have a more severe course.

During pregnancy, a patient with type I disease may have improvement in the bleeding time secondary to an increase in factor VIII:C, though these beneficial effects are not seen until after the first trimester. Thus, patients are at the highest risk of bleeding problems early in pregnancy and in the puerperium. In one series from the United Kingdom, 33% of patients had first trimester bleeding, and the miscarriage rate was 21%, not unlike those rates observed in the healthy population. However, patients had increased rates of postabortal transfusion, persistent bleeding, and an increased need for repeat dilatation and curettage. Measure factor VIII:C and bleeding time in patients at their first and third trimester. Historically, cryoprecipitate has been advised when factor levels fall below 80% of the reference level (approximately 50 IU/dL) or when anything but an uncomplicated vaginal delivery is anticipated.

Because of the concern of infection risk with these products from pooled donors, deamino-8-D-arginine vasopressin (DDAVP) is now used in many patients, particularly those with type I disease. Another product that can be used at the time of anticipated bleeding is Humate-P, a concentrate of many high molecular proteins needed to replace von Willebrand factor. A woman with mild disease may not need these measures in case of an uncomplicated vaginal delivery. Avoid epidural and spinal anesthesia in all patients, except those with mild disease. In the case of cesarean delivery, transfusion generally is recommended. Patients are at increased risk of postpartum hemorrhage; monitor levels of factor VIII:C and bleeding. As type I disease is autosomal dominant (though with variable penetrance), avoid fetal scalp electrodes during labor, and evaluate the neonate before circumcision.

Hemophilia A

This is an X-linked recessive disorder characterized by a decrease in factor VIII:C. Women who are homozygous are extremely rare and require fresh frozen plasma or cryoprecipitate at the time of delivery to prevent postpartum hemorrhage. The main obstetric concern is the risk to the offspring. A 50% risk to the male fetus exists. Chorionic villus sampling (CVS) can determine if the fetus is at risk by determining fetal sex and providing tissue for DNA analysis.

Hemophilia B

This X-linked recessive disorder also is known as Christmas disease. Patients are afflicted with a deficiency in factor IX. Carriers typically have no clinical manifestations. Prenatal diagnosis is limited to determination of fetal sex.

BIBLIOGRAPHY @