The Centers for Disease Control and Prevention's definition of anemia in pregnancy is hemoglobin (Hb) or hematocrit (Hct) value less than the fifth percentile in a healthy reference population at the same stage of pregnancy. Using this definition, anemia is diagnosed when Hb <11.0 g/dL in the first and third trimesters and <10.5 g/dL in the second trimester.
Racial differences have been noted, with lower Hb and Hct levels seen in African American women compared with white women. The Institute of Medicine suggests lowering the normal value for Hb by 0.8 g/dL and Hct by 2% in African Americans.
Anemia is commonly classified according to mean corpuscular volume (MCV) as normocytic (80-100 fL), microcytic (<80 fL), and macrocytic (>100 fL), as the differential diagnosis differs according to MCV (Table 20-1). Anemia can be further classified as hypochromic (low mean corpuscular Hb or hypochromia on peripheral smear) or normochromic.
Common types of anemia that are encountered during pregnancy include physiologic anemia of pregnancy, iron deficiency anemia, and, less often, megaloblastic anemia (Table 20-2). Iron studies can aid in differentiating various types of anemia (Table 20-3).
Hemoglobinopathies are genetic abnormalities in the globin portion of the Hb molecule that can either be qualitative, resulting in structural abnormalities like sickle cell anemia, or quantitative, resulting in a decreased number of normal globin chains as in the thalassemias. Normal adult Hb is composed of two α-globin chains and two β-chains (HbA, 96%-97%), two δ-chains (HbA2, 2%-3%), or two γ-chains (HbF, <1%). African, Southeast Asian, and Mediterranean ancestries are associated with a higher risk of being a hemoglobinopathy carrier, and carrier screening should be offered or an Hb electrophoresis obtained at the onset of pregnancy if not previously done.
Sickle cell disease (SCD) describes a group of autosomal recessive hemoglobinopathies resulting from abnormal sickle hemoglobin (HbS) that includes homozygous sickle hemoglobin (HbSS, often called “sickle cell anemia”), sickle cell–hemoglobin C (HbSC), and sickle/β-thalassemia hemoglobin (HbS/β-Thal). The HbS differs from HbA by a substitution of valine for glutamic acid at the sixth position of the β-globin chain. Sickle cell anemia (HbSS) is the most common phenotype, occurring primarily among people from sub-Saharan Africa, South and Central America, Saudi Arabia, India, and Mediterranean countries. Approximately 1 in 12 African Americans has sickle cell trait (HbAS) and 1 in 300 African American newborns have some form of SCD. When deoxygenated, HbS is less soluble and tends to polymerize into rigid aggregates that distort red blood cells (RBCs) into a sickle shape. These sickled cells undergo extravascular hemolysis and affected patients may experience hemolytic anemia, recurrent pain or vasoocclusive crises due to microvascular obstruction by sickled cells, infarction of multiple organ systems, and infection due to being functionally asplenic. Vasoocclusive crises may be triggered by infection, hypoxia, acidosis, dehydration, or psychological stress and can result in severe pain, fever, organ dysfunction, and tissue necrosis. A serious complication is acute chest syndrome, one of the leading causes of hospitalization and death in patients with SCD. Acute chest syndrome is characterized by a combination of respiratory symptoms with hypoxemia, noninfectious lung infiltrates, and fever.
Diagnosis. Diagnosis is confirmed by Hb electrophoresis, which typically shows 80% to 95% HbS, absent HbA, normal HbA2, and moderately elevated HbF (usually <15%). The anemia is normocytic and normochromic with an Hb concentration of 6 to 10 g/dL and Hct of 18% to 30%. The reticulocyte count is increased to 3% to 15%. Lactate dehydrogenase is elevated, and haptoglobin is decreased. The peripheral blood smear may show sickle cells, target cells, and Howell-Jolly bodies. Jaundice may result from RBC destruction, leading to unconjugated hyperbilirubinemia.
Treatment. Hydroxyurea may be used to reduce intracellular sickling and frequency of painful crises but is not recommended in pregnancy because it is teratogenic in animal studies, although case reports in humans do not suggest a comparable increase in risk. Infections are treated aggressively with antibiotics. Severe anemia is treated with blood transfusion. Pain crises are managed with oxygen, hydration, and analgesia. Controversy surrounds prophylactic exchange transfusion and is reserved for the most severe cases. Additionally, the risks involved with transfusions must be taken into account, such as the risk of maternal alloimmunization, infection, iron overload, and acute and delayed transfusion reactions. Advantages of transfusion are an increase in HbA level, which improves oxygen-carrying capacity and a decrease in HbS-carrying erythrocytes. If a transfusion is given, leukocyte-depleted packed red cells, phenotyped for major and minor antigens, should be used.
Pregnancy considerations. Patients with SCD are at increased risk for sickling during pregnancy because of increased metabolic requirements, vascular stasis, and a relative hypercoagulable state. Complications during pregnancy in women with SCD include an increased risk of spontaneous abortion, intrauterine growth restriction (IUGR), fetal death in utero, low birth weight, preeclampsia, and premature birth. Women with SCD also experience greater risk of urinary tract infection (UTI), bacteriuria, pulmonary infections and infarction, and, possibly, more painful crises. A multidisciplinary approach involving hematology and anesthesia is recommended to optimize patient care during pregnancy. Due to elevated risk of UTI, a urine culture should be evaluated at minimum in every trimester and treated correspondingly. Women with SCD should receive the pneumococcal vaccine before pregnancy and folate supplementation of 1 to 4 mg/d. Iron supplements should be prescribed only if iron is deficient to avoid iron overload. The intensity of fetal surveillance varies according to the clinical severity of the disease. In severe cases, assessment of fetal well-being should begin at 32 weeks' gestation, and monthly sonography should be performed to evaluate fetal growth. All African American patients should undergo an Hb electrophoresis to assess carrier status. If both the patient and the father of the baby are found to be hemoglobinopathy carriers, genetic counseling is indicated. Amniocentesis or chorionic villus sampling (CVS) may be offered for prenatal diagnosis. Mode of delivery is dictated by usual obstetric indications. After delivery, patients should practice early ambulation and wear thromboembolic deterrent stockings to prevent thromboembolism.
Regarding contraception, the levonorgestrel-containing intrauterine device (IUD) and progestin-only implants are considered excellent contraceptive options for patients with SCD. No well-controlled studies have evaluated oral contraceptives in SCD; however, low-dose combined contraceptives appear to be a good choice in some women with SCD. The benefits of copper-containing IUDs are debated due to a potential for increased blood loss, but copper-containing IUDs are generally considered a safe and effective method of contraception for women with SCD. Progestin-only pills, depot medroxyprogesterone, and barrier devices are also safe for contraception. Medroxyprogesterone acetate (Depo-Provera) injections may decrease the number of pain crises.
Women with sickle cell trait (HbAS) have approximately twice the frequency of UTIs compared to the general population, especially during pregnancy, and should be screened each trimester. No direct fetal compromise exists from maternal sickle cell trait. Partners should be screened because the risk of having a child with SCD becomes one in four if the father is also a carrier.
The thalassemias encompass a group of inherited blood disorders that can cause severe microcytic, hypochromic anemia. α-Thalassemia and β-thalassemia result from absent or decreased production of structurally normal α- and β-globulin chains, respectively, generating an abnormal ratio of α to non-α chains (Table 20-4). The excess chains form aggregates that lead to ineffective erythropoiesis and/or hemolysis. A broad spectrum of syndromes is possible, ranging from no symptoms to transfusion-dependent anemia and death. Both diseases are inherited in an autosomal recessive fashion.
α-Thalassemia is associated with Southeast Asian, African, Caribbean, or Mediterranean origin and results from a deletion of one to all four α-globin genes, located on chromosome 16. Individuals of Southeast Asian origin are more likely to carry two α-globin gene deletions in cis or on the same chromosome (- -/αα). Their offspring are more likely to be affected by the deletion of three α-globin genes (HbH, - -/-α) or four α-globin genes (Hb Barts, - -/- -). A fetus would be affected because fetal Hb also requires α chains. Individuals of African origin are more likely to carry two α-globin gene deletions in trans or on each chromosome (α-/α-), and their offspring generally do not develop Hb Barts.
β-Thalassemia is associated with Mediterranean, Asian, Middle Eastern, Caribbean, and Hispanic origin. More than 200 alterations (mostly point mutations) in β-globin genes, located on chromosome 11, have been reported. The two consequences of these gene defects are the following: β 0, which is the complete absence of the β chain, and β+, which is decreased synthesis of the β chain. These conditions result in an absence of HbA.
Diagnosis. Thalassemia is usually microcytic and hypochromic with an MCV of <80 fL, similar to iron deficiency anemia but with important differences in clinical presentation and laboratory testing.
Laboratory findings. In general, thalassemias, especially the traits, are often misdiagnosed as iron deficiency anemia. However, the anemia is not corrected with iron repletion. A microcytic anemia in the absence of iron deficiency suggests thalassemia and additional testing including electrophoresis and iron studies are warranted. Suspicion for the presence of α-thalassemia is raised by the finding of microcytosis and a normal red cell distribution width with minimal or no anemia in the absence of iron deficiency or β-thalassemia. Pedigree studies are often helpful during workup of patients with α-thalassemia. Molecular genetic testing, such as quantitative polymerase chain reaction, is needed for diagnosis. Quantitative Hb electrophoresis is required for the diagnosis of β-thalassemia and should be suspected in cases of elevated HbA2 (>3.5%) and HbF.
Pregnancy considerations. Women diagnosed with or at high risk for thalassemia should be offered preconception counseling and information about the availability of prenatal diagnosis. First-trimester, DNA-based prenatal testing (CVS) is available if both members of the couple are carriers. Preimplantation genetic diagnosis may also be an option for affected parents.
Women with trait status for either thalassemia require no special care.
Pregnancy may exacerbate the anemia, necessitating transfusions, and place women at an increased risk for congestive heart failure and premature delivery.
Thalassemia may confer an increased risk of neural tube defects (NTDs) secondary to folic acid deficiency, so up to 4 mg/d periconceptional folic acid supplementation is recommended. Iron supplements should be prescribed only if iron deficiency is present; otherwise, iron overload can result.
Women with HbH may have successful pregnancies, with maternal outcome related to the severity of anemia.
Pregnancies affected by a fetus with Hb Barts are associated with hydrops fetalis, intrauterine death, and preeclampsia.
Information on pregnancy in women with β-thalassemia major or intermedia is more limited, although successful pregnancies have been reported. These women require close medical evaluation and follow-up.
If asplenic (HbS/β-Thal), vaccinations for pneumococcus, Haemophilus influenzae, and meningococcus need to be up-to-date.
Periodic fetal sonography to assess fetal growth in thalassemia patients is recommended. Antepartum fetal testing should be considered in anemic thalassemia patients, especially in cases in which fetal growth is lagging.
Ultrasonography is also useful to detect hydrops fetalis but usually at a later gestational age. Intrauterine blood transfusions have shown good success in fetuses with hydrops fetalis.
Thrombocytopenia, defined as a platelet count <150 000/μL, is caused by increased platelet destruction or decreased platelet production and occurs in about 10% of pregnancies. Clinical signs, such as petechiae, easy bruising, epistaxis, gingival bleeding, and hematuria, are usually not seen until platelets are <50 000/μL. Counts below 50 000/μL may also increase surgical bleeding. The risk of spontaneous bleeding increases only when platelet counts fall below 20 000/μL, and significant bleeding may occur with platelet counts <10 000/μL. Thrombocytopenia, depending on the severity and etiology, may or may not be associated with serious maternal and/or fetal morbidity and mortality. Many conditions can cause thrombocytopenia during pregnancy.
Gestational thrombocytopenia, also referred to as incidental thrombocytopenia of pregnancy or essential thrombocytopenia, affects up to 8% of pregnancies and accounts for 80% of cases of mild thrombocytopenia during pregnancy. It generally occurs late in gestation and the incidence of fetal or neonatal thrombocytopenia is low. The decreased platelet count is likely due to hemodilution and increased physiologic platelet turnover. Platelet counts usually return to normal within 2 to 12 weeks after delivery. Gestational thrombocytopenia can recur in subsequent pregnancies, although the recurrence rate is unknown.
Diagnosis. Gestational thrombocytopenia is a diagnosis of exclusion; therefore, the first step is to take a careful history to rule out other causes. Platelet counts obtained before pregnancy and any laboratory data available from prior pregnancies should be reviewed.
Four criteria should be present: (1) mild thrombocytopenia (75 000-150 000/μL); (2) no previous history of thrombocytopenia, except during pregnancy; (3) no bleeding symptoms; and (4) platelet counts should return to normal within 2 to 12 weeks postpartum.
There are no specific diagnostic tests to distinguish gestational thrombocytopenia from mild idiopathic thrombocytopenic purpura (ITP). In fact, many women with gestational thrombocytopenia have platelet-associated immunoglobulin G (IgG) and serum antiplatelet IgG, making it difficult to distinguish from ITP using platelet antibody testing.
Management. In gestational thrombocytopenia, no intervention is necessary. Women with gestational thrombocytopenia are not at risk for maternal or fetal hemorrhage or bleeding complications.
Monitor platelets closely to detect decreases below 50 000/μL.
Document normal neonatal platelet count. Approximately 2% of the offspring of mothers with gestational thrombocytopenia have mild thrombocytopenia (<50 000/μL). However, infants generally do not suffer from severe platelet deficiency.
Reevaluate platelet count in the postpartum period to ensure it returns to normal. If thrombocytopenia persists, consider referring patient for evaluation by a hematologist.
Hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome is the most common pathologic cause of maternal thrombocytopenia. It occurs in approximately 10% to 20% of women who have preeclampsia with severe features, with a platelet count less than 100 000/μL being a hematologic diagnostic criterion for preeclampsia. Platelets usually reach a nadir at 24 to 48 hours after delivery but typically do not drop below 20 000/μL. Clinical hemorrhage rarely occurs unless the patient develops disseminated intravascular coagulopathy, but it is important to note that platelet function may be impaired even if the platelet count is normal. Delivery is recommended following maternal stabilization. Although rare, thrombocytopenia may continue for a prolonged period. Treatment with corticosteroids, however, has not resulted in decreased maternal mortality or morbidity.
Idiopathic thrombocytopenic purpura occurs in approximately 1 in 1000 pregnancies and accounts for 5% of pregnancy-associated thrombocytopenia. The ITP is the most common cause of thrombocytopenia in the first trimester. Antiplatelet antibodies are directed at platelet surface glycoproteins, leading to increased destruction of platelets by the reticuloendothelial system (primarily the spleen) that exceeds the rate of platelet synthesis by the bone marrow. The ITP can be a primary acquired disorder in which no underlying etiology is identified or can be secondary to an underlying disease or drug exposure. The course of ITP is not typically affected by pregnancy.
Diagnosis. Diagnosis is based on the history, physical exam, complete blood count, and peripheral smear. Women with ITP may report symptoms of easy bruising, petechiae, epistaxis, or gingival bleeding predating pregnancy. The ITP is a diagnosis of exclusion, and there is no diagnostic test. If thrombocytopenia is mild, it is difficult to distinguish ITP from gestational thrombocytopenia; however, a platelet count less than 100 000/μL is more suggestive of ITP. Detection of platelet-associated antibodies is consistent with, but not diagnostic of, ITP because they may also be present in women with gestational thrombocytopenia and preeclampsia. Platelet antibody testing has a fairly low sensitivity (49%-66%). However, the absence of platelet-associated IgG makes the diagnosis of ITP less likely. The ITP is more likely if the platelet count is <50 000/μL or in the presence of an underlying autoimmune disease or history of previous thrombocytopenia. In contrast to gestational thrombocytopenia, ITP-associated thrombocytopenia is typically evident early in pregnancy. Findings include the following:
Persistent thrombocytopenia (platelet count <100 000/μL with or without accompanying megathrombocytes on the peripheral smear).
Normal or increased megakaryocytes determined from bone marrow.
Secondary causes of maternal thrombocytopenia should be excluded (eg, preeclampsia, human immunodeficiency virus [HIV] infection, systemic lupus erythematosus, and drugs).
Absence of splenomegaly
Antenatal management. According to the American Society of Hematology, any adult with a new diagnosis of ITP requires testing for HIV and hepatitis C. Therapy is considered if the platelet counts are below 30 000 to 50 000 μL, or if the patient demonstrates bleeding symptoms, treatment is required. Corticosteroids, intravenous immunoglobulin (IVIG), or both are the first-line treatments for ITP.
Glucocorticoids suppress antibody production, inhibit sequestration of antibody-coated platelets and interfere with the interaction between platelets and antibodies. Oral prednisone is started at 0.5 to 2 mg/kg/d and is tapered to the lowest dose supporting an acceptable platelet count (usually over 50 000/μL) and tolerable side effect profile. An initial response usually occurs within 4 to 14 days and reaches peak response within 1 to 4 weeks. One-fourth of patients may achieve complete remission. High-dose glucocorticoids, such as methylprednisolone, may be administered at 1 to 1.5 mg/kg IV in divided doses. Very little crosses the placenta. Response is usually seen in 2 to 10 days. Maternal side effects of long-term glucocorticoid treatment include increased risk of hypertension, preeclampsia, weight gain, hyperglycemia, immunosuppression, and gastrointestinal ulceration. Fetal effects include prelabor rupture of membranes and IUGR.
The IVIG is another therapeutic option, but it is typically reserved for cases refractory to corticosteroids or when a more rapid platelet increase is necessary. The IVIG should be given initially at 1 g/kg as a one-time dose but may be repeated. Initial response usually occurs within 1 to 3 days and peak response is reached within 2 to 7 days. The proposed mechanism of action of IVIG is prolongation of the clearance time of IgG-coated platelets by the maternal reticuloendothelial system.
Splenectomy is an option in the second trimester in women who fail glucocorticoid and IVIG therapy and are experiencing bleeding associated with platelet counts <10 000/μL. Splenectomy remains the only therapy that provides prolonged remission at 1 year and longer. With splenectomy, remission occurs in 75% of women; however, data in pregnancy are limited. Splenectomy can be performed safely during pregnancy, ideally in the second trimester. Individuals with splenectomies should be immunized against pneumococcus, H influenzae, and meningococcus.
Intrapartum management. As pregnancy approaches term, more aggressive measures to increase maternal platelet counts may be indicated to allow for adequate hemostasis during delivery and epidural anesthesia. Platelet counts over 50 000/μL are usually adequate for either vaginal or cesarean delivery. Epidural or spinal anesthesia is considered safe in patients with platelet counts of at least 80 000/μL. Prophylactic platelet transfusion may be appropriate with a maternal platelet count <10 000 to 20 000/μL before vaginal delivery or <50 000/μL before a cesarean delivery or if bleeding is present. For vaginal delivery, the transfusion should begin as close to the timing of delivery as reasonably possible. For cesarean delivery, the transfusion should begin at the time of incision. One “pack” of platelets will increase the platelet count by 5000 to 10 000/μL. Transfused platelets will have a shorter half-life because of circulating antibodies.
Thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) can manifest during pregnancy, most often in the third trimester or postpartum, and because of clinical similarities must be differentiated from preeclampsia/HELLP syndrome. Common features of TTP/HUS include hemolytic anemia, marked thrombocytopenia, and severe acute kidney injury. Fever and neurologic impairment can also be seen with TTP. The TTP is marked by an inherited or acquired deficiency in the protease ADAMTS13 that is responsible for cleavage of von Willebrand factor (vWF) multimers to prevent platelet thrombi formation. Atypical HUS resulting from complement dysregulation can be inherited or acquired and is more common in pregnancy than cases of typical HUS that result from the production of Shiga-like toxin in the setting of a diarrheal illness due to Escherichia coli. Unlike preeclampsia/HELLP syndrome, TTP/HUS is not definitively treated with delivery and more directed therapy is required. Treatment of these conditions involves appropriate supportive care and therapies directed at the underlying cause. The TTP is treated with plasma exchange (PEX) to remove autoantibodies to ADAMTS13 and restore functional ADAMTS13. Atypical HUS is treated with PEX and anticomplement therapy aimed at blocking the complement cascade.
Thromboembolic disease is linked with both adverse maternal and fetal/neonatal outcomes. The term venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). Approximately 80% of VTEs in pregnancy are DVT and 20% are PE. Pregnant women are 4 to 5 times more likely to experience a VTE than age-matched nonpregnant women. Approximately half of all DVT/VTEs occur in the antepartum period and appear to be evenly divided among the three trimesters. Cesarean delivery imparts a 3 to 5 times greater risk than a vaginal delivery. The risk of VTE is greater postpartum.
Pregnancy is considered a hypercoagulable state. Fibrinogen, coagulation factors, and plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 levels are increased; free protein S levels are decreased, and fibrinolytic activity is decreased. Additionally, VTE risk is increased by anatomic changes in pregnancy including increased venous stasis and compression of the inferior vena cava and pelvic veins by the enlarging uterus.
One of the most significant risk factors is a personal history of VTE. Maternal medical conditions including heart disease, SCD, lupus, obesity, diabetes, and hypertension increase risk. Other risk factors include recent surgery, family history of VTE, bed rest or prolonged immobilization, smoking, older than 35 years, multiple gestation, preeclampsia, and postpartum infection.
Thrombophilias may be inherited or acquired. Pregnancy may trigger an event in women with an underlying thrombophilia. Fetal death in utero, severe fetal growth restriction, abruption, and severe early-onset preeclampsia have been correlated with underlying thrombophilias that affect uteroplacental circulation; however, this is controversial, and recent studies fail to reliably establish causal links between thrombophilias and these adverse pregnancy outcomes.
Inherited thrombophilias (Table 20-5) increase the risk of a maternal thromboembolic event. They are present in up to half of all maternal thrombotic events. Antithrombin deficiency, homozygosity for factor V Leiden mutation, homozygosity for prothrombin G20219A mutation, and compound heterozygosity for both factor V Leiden and prothrombin G20219A are the most potent of the inherited thrombophilias.
Acquired thrombophilias include persistent antiphospholipid antibody syndromes (lupus anticoagulants, anticardiolipin, or β2 glycoprotein 1 antibodies). Antiphospholipid antibodies have been associated with arterial and venous thrombosis, autoimmune thrombocytopenia, and obstetric complications that include preeclampsia, IUGR, placental insufficiency, and preterm birth.
Routine screening for thrombophilias is not recommended in all pregnant women, and screening indications are controversial. American College of Obstetricians and Gynecologists no longer recommends thrombophilia testing in women with recurrent fetal loss, placental abruption, fetal growth restriction, or preeclampsia. A thrombophilia workup (Table 20-6) should be considered for the following:
Personal history of VTE associated with a nonrecurrent risk factor such as prolonged immobilization.
First-degree relative with a history of high-risk thrombophilia
Antiphospholipid antibody syndromes screening may be appropriate for women with one or more unexplained fetal deaths at or greater than 10 weeks' gestation of a morphologically normal fetus; one or more premature births of a morphologically normal neonate before 34 weeks due to eclampsia, preeclampsia, or placental insufficiency; or three or more unexplained consecutive spontaneous losses before the 10th week.
Manifestations and diagnosis of VTE in pregnancy
DVT
Over 70% of DVTs in pregnancy develop in the iliofemoral veins, from which they are more likely to embolize, and the majority are on the left side. Diagnosis of DVT is difficult in pregnancy because expected changes in pregnancy may mimic the symptoms of DVT. Additionally, many patients are asymptomatic. If symptoms exist, the most common include calf or lower extremity swelling, pain or tenderness, warmth, and erythema. Homan sign (calf pain with passive dorsiflexion of the foot) is present in <15% of cases, and a palpable cord is present in <10% of cases. Symptoms of an iliac DVT include abdominal pain, back pain, and swelling of the entire leg. In pregnant women with clinical suspicion of DVT, diagnosis is confirmed in <10%.
Venous duplex imaging, including compression ultrasound, color, and spectral Doppler sonography, has replaced contrast venography as the gold standard and is the most commonly available noninvasive diagnostic method, with a sensitivity of 97% and specificity of 94% in symptomatic proximal DVT. If the deep venous system is normal, the presence of a clinically significant thrombus is unlikely. Limitations include poor sensitivity for asymptomatic disease and difficulty in detecting iliac vein thromboses.
Magnetic resonance imaging is recommended when compression ultrasound results are negative or equivocal and iliac vein thrombosis is suspected. Studies in nonpregnant patients show a sensitivity of 100% and specificity of 98% to 99% for pelvic and proximal DVTs while maintaining a high accuracy in detecting below-the-knee DVTs.
D-dimer test is a sensitive but nonspecific test for DVT; however, D-dimer normally increases with gestational age. A normal D-dimer result may be reassuring if clinical suspicion is low, but even a high D-dimer level does not predict VTE in pregnancy.
The PE remains one of the leading causes of maternal mortality in developed countries, accounting for approximately 20% of deaths. The risk of PE is greatest immediately postpartum, particularly after cesarean delivery, with a fatality rate of nearly 15%. A PE most commonly originates from DVT in the lower extremities, occurring in nearly 50% of patients with proximal DVT. Symptoms typically associated with PE are all common in pregnancy, such as sudden shortness of breath, chest pain, and cough, or signs of tachypnea and tachycardia. Because of the serious potential consequences of PE and the increased incidence in pregnancy, clinicians must have a low threshold for evaluation.
Diagnosis starts with a careful history and physical examination, followed by diagnostic tests to rule out other possible etiologies, such as asthma, pneumonia, or pulmonary edema.
An arterial blood gas, electrocardiogram, and chest x-ray should be performed. Arterial blood gas values are altered in pregnancy and must be interpreted using pregnancy-adjusted normal values. More than half of pregnant women with a documented PE have a normal alveolar-arterial gradient.
A chest x-ray helps rule out other disease processes and enhances interpretation of the ventilation-perfusion (/) scan. The risks associated with various radiologic tests indicated for PE workup are minimal compared with the consequences of a missed PE.
Pulmonary angiography is the gold standard for PE diagnosis, but it is expensive and invasive.
Computed tomographic (pulmonary) angiography (CTA) is becoming the recommended imaging test in pregnant women with suspected PE. The CTA is easier to perform, more readily available, and more cost-effective and provides a lower dose of radiation to the fetus than a / scan. The CTA is also useful in detecting other abnormalities that may be contributing to the patient's symptoms (eg, pneumonia, aortic dissection). Newer technology, multidetector CTA, allows visualization of finer pulmonary vascular detail and provides greater diagnostic accuracy.
Historically, the / scan has been the primary diagnostic test for PE. It is interpreted as low, intermediate, or high probability for PE. High-probability scans (ie, segmental perfusion defect with normal ventilation) confirm PE, with a positive predictive value over 90% when pretest likelihood is high. The / scans are limited in their usefulness because of the large proportion of indeterminate results. Most fetal radiation exposure occurs when radioactive tracers are excreted in the maternal bladder. Therefore, exposure can be limited by prompt and frequent voiding after the procedure. If patient is postpartum and breastfeeding, breast milk should not be used for 2 days after a / scan.
If a pregnant woman has a nondiagnostic lung scan, bilateral venous duplex imaging of the lower extremities is recommended to evaluate for DVT. If DVT is found, PE can be diagnosed. If no DVT is seen, arteriography may be performed for further evaluation before a commitment to long-term anticoagulation is made, or a repeat venous duplex imaging may be repeated in 1 week.
According to the Centers for Disease Control and Prevention, in all stages of gestation, a dose of <5 rads (0.05 Gy) represents no measurable noncancer health effects. After 16 weeks' gestation, congenital effects are unlikely below 50 rads. The risk for childhood cancer from prenatal radiation exposure is 0.3% to 1% for 0 to 5 rads. Any of the proposed modalities for diagnosis of PE are well below the dose levels that increase congenital abnormalities. Radiation exposure from a two-view chest radiograph is <0.001 rad. A higher dose of fetal radiation is provided with / scan (0.064-0.08 rad) compared with CTA (0.0003-0.0131 rad). Pulmonary angiography provides approximately 0.2 to 0.4 rad with the femoral approach and <0.05 rad with the brachial approach. Maternal radiation dose is higher with CTA than / scan.
Treatment of VTE in pregnancy
When VTE is suspected, anticoagulation with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) should be initiated until the diagnosis is excluded. Neither of these heparin anticoagulants crosses the placenta or is secreted into breast milk. Although UFH has been standard treatment for the prevention and treatment of VTE during pregnancy, recent evidence-based clinical practice guidelines now recommend LMWH. Table 20-7 lists dosing regimens. Thromboembolic deterrent compression stockings and leg elevation should be used for DVT.
Weight-adjusted LMWH should be used for the treatment of VTE (see Table 20-7). Advantages of LMWH include fewer bleeding complications, lower risk of heparin-induced thrombocytopenia (HIT) and osteoporosis, longer plasma half-life, and more predictable dose-response relationships. Theoretical concerns have been raised regarding once-daily dosing compared to twice-daily dosing (ie, prophylactic or therapeutic) secondary to the increased renal clearance in pregnancy possibly prolonging trough LMWH levels. However, no comparison data of the two regimens are available. Additionally, recent data suggest daily dosing in the treatment of acute VTE is effective. Monitoring of LMWH levels remains controversial. The LMWH cannot be monitored using activated partial thromboplastin time (aPTT) because aPTT will likely be normal. Peak anti-factor Xa activity levels may be measured 4 hours after subcutaneous (SC) injection, with a therapeutic peak goal of 0.6 to 1.0 U/mL (slightly higher if once-daily dosing is used); however, frequent monitoring is not typically recommended, except at extremes of body weight. If trough levels are evaluated with therapeutic dosing (ie, 12 h after dosing), goal level is 0.2 to 0.4 IU/mL. Current guidelines do not provide definitive monitoring recommendations; however, some researchers advocate checking levels periodically (every 1-3 mo).
The UFH is administered either IV or SC. The IV UFH may be a better initial therapeutic option in unstable patients (eg, large PE with hypoxia or extensive iliofemoral disease) or patients with significant renal impairment (ie, creatinine clearance <30 mL/min). The goal of the initial bolus dose (typically 80 U/kg) and subsequent maintenance dosing (typically 18 U/kg/h) is to achieve a therapeutic aPTT of 1.5 to 2.5 times normal. Many facilities have standard protocols for heparin titration. The IV treatment should be maintained in the therapeutic range for at least 5 days, after which therapy may be continued with either adjusted-dose SC heparin injections or LMWH. If maintained on UFH, a midinterval (6 h postinjection) aPTT should be monitored every 1 to 2 weeks. Measuring anti-factor Xa heparin levels may assist in evaluating heparin dosing (target level 0.3-0.7 IU/mL). The aPTT response to heparin in pregnant women is often attenuated secondary to elevated heparin-binding proteins and increased factor VIII and fibrinogen. The therapeutic dose may need to be adjusted. Thus, it may be difficult to achieve target aPTT levels late in pregnancy. The major concerns with UFH use during pregnancy are bleeding, osteopenia, and thrombocytopenia. The risk of major bleeding with UFH is approximately 2%. Bone density reductions have been reported in 30% of patients on heparin for over 1 month. The HIT occurs in up to 3% of nonpregnant patients and should be suspected when platelet count decreases to <100 000/μL or <50% of baseline value 5 to 15 days after beginning heparin or sooner with recent heparin exposure. In 25% to 30% of patients who develop HIT, onset occurs rapidly (within 24 h) after starting heparin and is related to recent exposure to heparin. After obtaining a starting platelet level, American College of Obstetricians and Gynecologists recommends checking platelets again on day 5 and then periodically for the first 2 weeks of therapy. Others suggest platelets be monitored at 24 hours and then every 2 to 3 days for the first 2 weeks or weekly for the first 3 weeks. If HIT is acquired and ongoing anticoagulant therapy is required, fondaparinux (Factor Xa inhibitor) or argatroban (direct thrombin inhibitor) can be used. The use of new or direct oral anticoagulants, such as dabigatran, rivaroxaban, apixaban, or edoxaban, is not recommended during pregnancy or during the immediate postpartum period.
Warfarin sodium crosses the placenta and, therefore, is a potential teratogen and may cause fetal bleeding. Warfarin is likely safe during the first 6 weeks' gestation, but between 6 and 12 weeks' gestation, a risk of skeletal embryopathy exists, consisting of stippled epiphyses and nasal and limb hypoplasia. One-third of fetuses exposed to warfarin late in pregnancy develop central nervous system injuries, hemorrhage, or ophthalmologic abnormalities. Warfarin may be used postpartum and may be given to nursing mothers because it does not enter breast milk. Antepartum use can be considered for women with mechanical heart valves, for which neither LMWH nor heparin provide adequate anticoagulation in the antepartum period.
Temporary inferior vena cava filters are indicated in women in whom anticoagulants are contraindicated. They may be inserted within a week of elective induction or cesarean delivery and removed at least 6 weeks (for DVT) or up to 4 to 6 months (for PE) postpartum.
Prophylaxis for VTE in pregnancy
Antepartum. Limited data exist regarding the use of prophylactic anticoagulation for VTE during pregnancy. Women need to be stratified by risk, and clinical judgment applied when making recommendations for prophylaxis. Although recommendations vary, women at very increased for VTE probably benefit from prophylactic or intermediate dosing of UFH or LMWH throughout pregnancy and postpartum. At a minimum, postpartum prophylaxis is usually recommended in women at elevated risk for VTE.
Intrapartum. The risk of maternal hemorrhage may be minimized with carefully planned delivery. If possible, induction of labor or scheduled cesarean delivery should be considered in women on therapeutic anticoagulation dosing regimens, so therapy may be discontinued at an appropriate time. When used in therapeutic doses, LMWH should be discontinued 24 hours before elective induction of labor or cesarean delivery. Epidural or spinal anesthesia should not be administered within 24 hours of the last therapeutic dose of LMWH. A common approach is to transition from LMWH to UFH at 36 to 38 weeks' gestation. If the patient goes into spontaneous labor and is receiving SC UFH, she should be able to receive regional analgesia if the aPTT is normal. If significantly prolonged, protamine sulfate may be administered at 1 mg/100 U of UFH. If the patient is at very high risk for VTE, IV UFH can be started and then discontinued 4 to 6 hours before expected delivery. When receiving LMWH once daily for prophylaxis, regional anesthesia can be administered 12 hours after the last dose. Also, LMWH should be withheld for at least 2 to 4 hours after the removal of an epidural catheter.
Postpartum. Postpartum anticoagulation may typically be resumed 6 to 12 hours after cesarean delivery and 4 to 6 hours after vaginal delivery. If at high risk of bleeding postpartum, IV UFH may be chosen initially because its effect dissipates more rapidly and may be reversed with protamine sulfate. Once adequate hemostasis is assured, warfarin can be started by initial overlap with UFH or LMWH until international normalized ratio is 2.0 for 2 consecutive days, with a target international normalized ratio of 2.0 to 3.0. Anticoagulation should be administered for at least 6 weeks postpartum for DVT and 4 to 6 months for PE.
Birth control options for women with a history of VTE or those with a high-risk thrombophilia
Due to the thrombogenic potential of estrogen-containing contraceptives, progestin-only or nonhormonal contraceptive methods are recommended. Natural family planning, condoms, progestin-only pills, levonorgestrel-releasing IUD, copper IUD, and tubal ligation/occlusion are methods that can be discussed with patients at high risk for VTE.
von Willebrand disease (vWD) is an inherited congenital bleeding disorder that involves a qualitative or quantitative deficiency of vWF. There are three main types of vWD (Table 20-8). The vWF binds to subendothelium at sites of endothelial injury and is required for proper platelet adhesion. It also serves as a protein carrier for factor VIII increasing its half-life. The vWD is the most common inherited bleeding disorder among American women, with a prevalence of approximately 1%.
Diagnosis. Clinical suspicion for a diagnosis should exist in any woman with a personal history with or without a family history of easy bruising and heavy or prolonged bleeding. Clinical findings that warrant further diagnostic evaluation include the following:
Heavy menstrual bleeding since menarche
Personal history of postpartum hemorrhage, surgery-related bleeding, or bleeding associated with dental work
Two or more of the following conditions:
Epistaxis, one to two times per month
Frequent gum bleeding
Family history of bleeding symptoms
Laboratory tests. If diagnostic workup is required following a positive clinical screen, laboratory tests for vWD should be obtained and include vWF antigen, von Willebrand-ristocetin cofactor activity, and factor VIII level. In some cases, genetic testing may be necessary to confirm certain vWD types.
Management. Treatment options for patients with vWD include desmopressin (DDAVP), replacement therapy with vWF-containing concentrates, and antifibrinolytic drugs.
The DDAVP is a synthetic analog of antidiuretic hormone that promotes the release of vWF from endothelial storage sites. It can be used in patients with type 1 and some types of type 2 vWD. Administration is IV or by intranasal spray as prophylaxis before invasive procedures or for acute bleeding episodes.
The vWF replacement therapy can be used in all types of vWD especially in cases of more serious bleeding situations, when other therapies have failed, or when prolonged treatment is necessary. Therapy is by IV infusion to control bleeding, and dosing is empiric and weight based with the goal to maintain vWF activity above 50%.
Antifibrinolytic therapy with aminocaproic acid and tranexamic acid work by inhibiting the conversion of plasminogen to plasmin, thereby preventing fibrinolysis and stabilizing clots to treat bleeding. They are administered IV or orally three to four times a day as needed to control bleeding.
Pregnancy considerations. Early referral during pregnancy to hematology to confirm diagnosis and establish a management plan is recommended. Anesthesia consultation is also recommended given an increased risk of epidural or spinal hematoma. Genetic counseling should also be offered to discuss the possibility of having an affected child. Periodic assessment of vWF and factor VIII levels can be obtained throughout pregnancy, but it is important to remember that vWF and factor VIII levels increase throughout pregnancy, so many patients with vWD may have normal levels near term. Most invasive procedures (ie, amniocentesis or CVS) are safe with vWF and factor VIII levels maintained above 50%. Invasive fetal procedures, such as fetal scalp electrode placement and operative vaginal delivery, are best avoided, if possible, if the fetal vWD status is unknown. Route of delivery is determined by the usual obstetric indications.