ANEMIA

With normal pregnancy, blood volume increases, which results in a concomitant hemodilution. This results in a physiologically lowered hemoglobin (Hb) level, hematocrit (Hct) value, 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 an Hb value less than 10.5 g/dL, as opposed to the reference range of 14 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/d 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/d 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 mg/d. 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 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 radionuclide used in testing. Treatment of vitamin B-12 deficiency includes 0.1 mg/d for 1 week, followed by 6 weeks of continued therapy to reach a total administration of 2 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 (HbSC) disease, 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, treating a woman who is pregnant and has sickle cell disease requires close observation. Obtain blood cell counts frequently 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' gestation. 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. 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 WBC count with differential and lactic dehydrogenase (LDH) determinations. An elevated WBC count may be observed in cases of SCC, but a left shift should not be observed. Patients with SCC have elevated LDH levels. Other laboratory tests that should be ordered upon patient admission include CBC count, type and cross match, and arterial blood gas determinations as indicated.

Therapeutic measures for SCC mainly are supportive, with institution of intravenous 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. Identification and treatment of any underlying infection is of paramount importance. 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 study findings have also been noted as frequently being normal during crisis, even in the setting of abnormal uterine artery Doppler study results.

Overall, great improvement has occurred in maternal and fetal outcome in patients with sickle cell disease. 

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 more than 95% hemoglobin A (HbA), consisting of 2 alpha and 2 beta peptide chains. The 2 major thalassemias, alpha-thalassemia and beta-thalassemia, result from decreased production of one 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 and 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) principally affect people of Asian descent.

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 Hbs. This condition results in HbBart as the predominant Hb. Because of its high oxygen affinity, little oxygen is released to the tissues. The fetus develops 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 of 4 alpha-globin genes. The abnormal red cells at birth consist of both HbH and HbBart. The neonate appears healthy 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 causes 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. Although 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 the process of identifying couples at risk for having offspring with the hemoglobinopathies increasingly important for obstetrician-gynecologists. Although universal screening is not recommended, submit CBC counts 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 evaluate for sickle hemoglobinopathies. Also, refer patients who are from Southeast Asia or the Mediterranean and have anemia and reduced MCV (<80 m3) and normal iron study findings for Hb electrophoresis.

If Hb is normal in patients who are of Southeast Asian descent, 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 for 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, point mutations exist 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 such as 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 approximately 7% of pregnancies. It typically is defined as a platelet count of less than 150,000/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/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) attack platelet membrane glycoproteins and destroy platelets at a rate that cannot be compensated by the bone marrow. ITP is usually associated with persistent thrombocytopenia (<100,000/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 the maternal platelet count in anticipation of delivery include intravenous immunoglobulin (IVIg) and steroids. The patient may require platelet transfusion during delivery if the platelet count drops below 20,000/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/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 approximately 50% of cases in white persons. 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/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 rate of 0.8-1.3%. This disorder is secondary to a decrease or defect in the von Willebrand portion of the factor VIII 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. 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, although 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.  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 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 vWF. 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. Because type I disease is autosomal dominant (although 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. The risk to a male fetus is 50%. Chorionic villus sampling can help determine if the fetus is at risk by determining fetal sex and providing tissue for DNA analysis.

Hemophilia B

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