IRON DEFICIENCY ANEMIA
ANEMIA ASSOCIATED WITH CHRONIC DISEASE
APLASTIC AND HYPOPLASTIC ANEMIA
INHERITED COAGULATION DEFECTS
VON WILLEBRAND DISEASE
Pregnant women are susceptible to hematological abnormalities that may affect any woman of childbearing age. These include chronic disorders such as hereditary anemias, immunological thrombocytopenia, and malignancies such as leukemias and lymphomas. Other disorders arise during pregnancy because of pregnancy-induced demands. Two examples are iron deficiency and megaloblastic anemias. Pregnancy may also unmask underlying hematological disorders such as compensated hemolytic anemias caused by hemoglobinopathies or red cell membrane defects. Finally, any hematological disease may first arise during pregnancy. Importantly, pregnancy induces physiological changes that often confuse the diagnosis of these hematological disorders and assessment of their treatment. Several pregnancy-induced hematological changes are discussed in detail in Chapter 4 (p. 55).
Extensive hematological measurements have been made in healthy nonpregnant women. Concentrations of many cellular elements that are normal during pregnancy are listed in the Appendix (p. 1287). The Centers for Disease Control and Prevention (CDC) (1998) defined anemia in iron-supplemented pregnant women using a cutoff of the 5th percentile—11 g/dL in the first and third trimesters, and 10.5 g/dL in the second trimester (Fig. 56-1). An ongoing study of 278 women is currently evaluating the accuracy of an erythrogram and serum ferritin levels for anemia diagnosis and prediction of responsiveness to oral iron (Bresani, 2013).
FIGURE 56-1 Mean hemoglobin concentrations (black line) and 5th and 95th percentiles (blue lines) for healthy pregnant women taking iron supplements. (Data from the Centers for Disease Control and Prevention, 1989.)
The modest fall in hemoglobin levels during pregnancy is caused by a relatively greater expansion of plasma volume compared with the increase in red cell volume (Chap. 4, p. 55). The disproportion between the rates at which plasma and erythrocytes are added to the maternal circulation is greatest during the second trimester. Late in pregnancy, plasma expansion essentially ceases, while hemoglobin mass continues to increase.
The causes of anemia in pregnancy and their frequency are dependent on multiple factors such as geography, ethnicity, nutritional status, preexisting iron status, and prenatal iron supplementation. Other factors are socioeconomic, and anemia is more prevalent among indigent women (American College of Obstetricians and Gynecologists, 2013a). Approximately 25 percent of almost 48,000 Israeli pregnant women had a hemoglobin level < 10 g/dL (Kessous, 2013). Ren and colleagues (2007) found that 22 percent of 88,149 Chinese women were anemic in the first trimester. Of 1000 Indian women, half were anemic at some point, and 40 percent were throughout pregnancy (Kumar, 2013). The importance of prenatal iron therapy is illustrated by the study of Taylor and associates (1982), who reported that hemoglobin levels at term averaged 12.7 g/dL among women who took supplemental iron compared with 11.2 g/dL for those who did not. Bodnar and coworkers (2001) studied a cohort of 59,248 pregnancies and found a postpartum anemia prevalence of 27 percent that correlated both with prenatal anemia and hemorrhage at delivery.
The etiologies of the more common anemias encountered in pregnancy are listed in Table 56-1. The specific cause of anemia is important when evaluating effects on pregnancy outcome. For example, maternal and perinatal outcomes are seldom affected by moderate iron deficiency anemia, yet they are altered markedly in women with sickle-cell anemia.
TABLE 56-1. Causes of Anemia During Pregnancy
Iron deficiency anemia
Anemia caused by acute blood loss
Anemia of inflammation or malignancy
Acquired hemolytic anemia
Aplastic or hypoplastic anemia
Hereditary hemolytic anemias
Effects on Pregnancy Outcomes
Most studies of anemia during pregnancy describe large populations. As indicated, these likely deal with nutritional anemias, specifically those due to iron deficiency. Klebanoff and associates (1991) studied nearly 27,000 women and found a slightly increased risk of preterm birth with midtrimester anemia. Ren and colleagues (2007) found that a low first-trimester hemoglobin concentration increased the risk of low birthweight, preterm birth, and small-for-gestational age infants. In a study from Tanzania, Kidanto and coworkers (2009) reported that the incidence of preterm delivery and low birthweight was increased as the severity of anemia increased. They did not, however, take into account the cause(s) of anemia, which was diagnosed in almost 80 percent of their obstetrical population. Kumar and colleagues (2013) studied 1000 Indian women and also found that second- and third-trimester anemia was associated with preterm birth and low birthweight. Chang and associates (2013) followed 850 children born to women classified as iron deficient in the third trimester. Children without iron supplementation had lower mental development at 12, 18, and 24 months of age, suggesting that prenatal iron deficiency is associated with mental development. Tran and associates (2014) reported similar findings from a Vietnamese study.
A seemingly paradoxical finding is that healthy pregnant women with a higher hemoglobin concentration are also at increased risk for adverse perinatal outcomes (von Tempelhoff, 2008). This may result from lower than average plasma volume expansion of pregnancy concurrent with normal red cell mass increase. Murphy and coworkers (1986) described more than 54,000 singleton pregnancies in the Cardiff Birth Survey and reported excessive perinatal morbidity with high maternal hemoglobin concentrations. Scanlon and associates (2000) studied the relationship between maternal hemoglobin levels and preterm or growth-restricted infants in 173,031 pregnancies. Women whose hemoglobin concentration was three standard deviations above the mean at 12 or 18 weeks’ gestation had 1.3- to 1.8-fold increases in the incidence of fetal-growth restriction. These findings have led some to the illogical conclusion that withholding iron supplementation to cause iron deficiency anemia will improve pregnancy outcomes (Ziaei, 2007).
Iron Deficiency Anemia
The two most common causes of anemia during pregnancy and the puerperium are iron deficiency and acute blood loss. The CDC (1989) estimated that as many as 8 million American women of childbearing age were iron deficient. In a study of more than 1300 women, 21 percent had third-trimester anemia with 16 percent due to iron deficiency anemia (Vandevijvere, 2013). In a typical singleton gestation, the maternal need for iron averages close to 1000 mg. Of this, 300 mg is for the fetus and placenta; 500 mg for maternal hemoglobin mass expansion; and 200 mg that is shed normally through the gut, urine, and skin. The total amount of 1000 mg considerably exceeds the iron stores of most women and results in iron deficiency anemia unless iron supplementation is given.
Iron deficiency is often manifested by an appreciable drop in hemoglobin concentration. In the third trimester, additional iron is needed to augment maternal hemoglobin and for transport to the fetus. Because the amount of iron diverted to the fetus is similar in a normal and in an iron-deficient mother, the newborn infant of a severely anemic mother does not suffer from iron deficiency anemia. As discussed in Chapter 33 (p. 643), neonatal iron stores are related to maternal iron status and to timing of cord clamping.
Classic morphological evidence of iron deficiency anemia—erythrocyte hypochromia and microcytosis—is less prominent in the pregnant woman compared with that in the nonpregnant woman. Moderate iron deficiency anemia during pregnancy usually is not accompanied by obvious morphological changes in erythrocytes. Serum ferritin levels, however, are lower than normal, and there is no stainable bone marrow iron. Iron deficiency anemia during pregnancy is the consequence primarily of expansion of plasma volume without normal expansion of maternal hemoglobin mass.
The initial evaluation of a pregnant woman with moderate anemia should include measurements of hemoglobin, hematocrit, and red cell indices; careful examination of a peripheral blood smear; a sickle-cell preparation if the woman is of African origin; and measurement of serum iron or ferritin levels, or both. Expected values in pregnancy are found in the Appendix (p. 1287). Serum ferritin levels normally decline during pregnancy (Goldenberg, 1996). Levels less than 10 to 15 mg/L confirm iron deficiency anemia (American College of Obstetricians and Gynecologists, 2013a). Pragmatically, the diagnosis of iron deficiency in moderately anemic pregnant women usually is presumptive and based largely on exclusion.
When pregnant women with moderate iron deficiency anemia are given adequate iron therapy, a hematological response is detected by an elevated reticulocyte count. The rate of increase of hemoglobin concentration or hematocrit is typically slower than in nonpregnant women due to the increasing and larger blood volumes during pregnancy.
Regardless of anemia status, daily oral supplementation with 30 to 60 mg of elemental iron and 400 μg of folic acid is recommended in pregnancy (Peña-Rosas, 2012; World Health Organization, 2012). Anemia resolution and restitution of iron stores can be accomplished with simple iron compounds—ferrous sulfate, fumarate, or gluconate—that provide about 200 mg daily of elemental iron. If a woman cannot or will not take oral iron preparations, then parenteral therapy is given. Although both are administered intravenously, ferrous sucrose has been shown to be safer than iron-dextran (American College of Obstetricians and Gynecologists, 2013a). There are equivalent increases in hemoglobin levels in women treated with either oral or parenteral iron therapy (Bayouneu, 2002; Sharma, 2004).
Anemia from Acute Blood Loss
In early pregnancy, anemia caused by acute blood loss is common with abortion, ectopic pregnancy, and hydatidiform mole. Anemia is much more common postpartum from obstetrical hemorrhage. Massive hemorrhage demands immediate treatment as described in Chapter 41 (p. 814). If a moderately anemic woman—defined by a hemoglobin value of approximately 7 g/dL—is hemodynamically stable, is able to ambulate without adverse symptoms, and is not septic, then blood transfusions are not indicated. Instead, iron therapy is given for at least 3 months (Krafft, 2005). In a randomized trial, Van Wyck and colleagues (2007) reported that intravenous ferric carboxymaltose given weekly was as effective as thrice-daily oral ferrous sulfate tablets for hemoglobin regeneration for postpartum anemia.
Anemia Associated with Chronic Disease
Weakness, weight loss, and pallor have been recognized since antiquity as characteristics of chronic disease. Various disorders, such as chronic renal failure, cancer and chemotherapy, human immunodeficiency virus (HIV) infection, and chronic inflammation, result in moderate and sometimes severe anemia, usually with slightly hypochromic and microcytic erythrocytes. It is the second most common form of anemia worldwide (Weiss, 2005).
In nonpregnant patients with chronic inflammatory diseases, the hemoglobin concentration is rarely < 7 g/dL; bone marrow cellular morphology is not altered; and serum iron concentrations are decreased. However, ferritin levels usually are elevated. The low levels of iron are mediated by hepcidin, a polypeptide produced in the liver that participates in iron balance and transport (Weiss, 2005). These anemias share similar features that include alterations in reticuloendothelial function, iron metabolism, and decreased erythropoiesis (Cullis, 2013).
Women with chronic disorders may develop anemia for the first time during pregnancy. In those with preexisting anemia, it may be intensified as plasma volume expands disproportionately to red cell mass expansion. Causes include chronic renal insufficiency, inflammatory bowel disease, and connective-tissue disorders. Others are granulomatous infections, malignant neoplasms, rheumatoid arthritis, and chronic suppurative conditions.
Of these, chronic renal insufficiency is the most common disorder that we have encountered as a cause of anemia during pregnancy. Some cases are accompanied by erythropoietin deficiency. As discussed in Chapter 53 (p. 1060), during pregnancy in women with mild chronic renal insufficiency, the degree of red cell mass expansion is inversely related to renal impairment. At the same time, plasma volume expansion usually is normal, and thus anemia is intensified (Cunningham, 1990). Anemia often accompanies acute pyelonephritis but is due to acute endotoxin-mediated erythrocyte destruction. With normal erythropoietin production, red cell mass is restored as pregnancy progresses (Cavenee, 1994; Dotters-Katz, 2013).
Adequate iron stores must be ensured. Recombinant erythropoietin has been used successfully to treat chronic anemia (Weiss, 2005). In pregnancies complicated by chronic renal insufficiency, recombinant erythropoietin is usually considered when the hematocrit approximates 20 percent (Ramin, 2006). Cyganek and coworkers (2011) described good results in five pregnant renal transplant recipients treated with human recombinant erythropoietin. One worrisome side effect is hypertension, which is already prevalent in women with renal disease. In addition, Casadevall and colleagues (2002) reported pure red cell aplasia and antierythropoietin antibodies in 13 nonpregnant patients given recombinant human erythropoietin. Numerous additional cases have been reported. However, because of changes in manufacturing and new regulations, it is an infrequent toxicity today (McKoy, 2008).
These anemias are characterized by blood and bone-marrow abnormalities from impaired DNA synthesis. Worldwide, the prevalence of megaloblastic anemia during pregnancy varies considerably. In the United States, it is rare.
Folic Acid Deficiency
In the United States, megaloblastic anemia beginning during pregnancy almost always results from folic acid deficiency. In the past, this condition was referred to as pernicious anemia of pregnancy. It usually is found in women who do not consume fresh green leafy vegetables, legumes, or animal protein. As folate deficiency and anemia worsen, anorexia often becomes intense and further aggravates the dietary deficiency. In some instances, excessive ethanol ingestion either causes or contributes to folate deficiency.
In nonpregnant women, the folic acid requirement is 50 to 100 μg/day. During pregnancy, requirements are increased, and 400 μg/day is recommended (Chap. 9, p. 181). The earliest biochemical evidence is low plasma folic acid concentrations (Appendix, p. 1287). Early morphological changes usually include neutrophils that are hypersegmented and newly formed erythrocytes that are macrocytic. With preexisting iron deficiency, macrocytic erythrocytes cannot be detected by measurement of the mean corpuscular volume. Careful examination of a peripheral blood smear, however, usually demonstrates some macrocytes. As the anemia becomes more intense, peripheral nucleated erythrocytes appear, and bone marrow examination discloses megaloblastic erythropoiesis. Anemia may then become severe, and thrombocytopenia, leukopenia, or both may develop. The fetus and placenta extract folate from maternal circulation so effectively that the fetus is not anemic despite severe maternal anemia. There have been instances in which newborn hemoglobin levels were 18 g/dL or more, whereas maternal values were as low as 3.6 g/dL (Pritchard, 1970). A Cochrane review by Lassi and associates (2013) evaluated the effectiveness of oral prenatal folic acid supplementation alone or with other micronutrients versus no folic acid. There was no conclusive evidence of supplement benefit for pregnancy outcomes that included preterm birth and perinatal mortality. There was, however, increased mean birthweight and a significant reduction in the incidence of megaloblastic anemia.
Treatment. Folic acid is given along with iron, and a nutritious diet is encouraged. As little as 1 mg of folic acid administered orally once daily produces a striking hematological response. By 4 to 7 days after beginning folic acid treatment, the reticulocyte count is increased, and leukopenia and thrombocytopenia are corrected.
Prevention. A diet sufficient in folic acid prevents megaloblastic anemia. The role of folate deficiency in the genesis of neural-tube defects has been well studied (Chap. 14, p. 283). Since the early 1990s, nutritional experts and the American College of Obstetricians and Gynecologists (2013c) have recommended that all women of childbearing age consume at least 400 μg of folic acid daily. More folic acid is given in circumstances in which requirements are increased. These include multifetal pregnancy, hemolytic anemia, Crohn disease, alcoholism, and inflammatory skin disorders. There is evidence that women who previously have had infants with neural-tube defects have a lower recurrence rate if a daily 4-mg folic acid supplement is given preconceptionally and throughout early pregnancy.
Vitamin B12 Deficiency
During pregnancy, vitamin B12 levels are lower than nonpregnant values because of decreased levels of binding proteins that include haptocorrin—transcobalamins I and III—and transcobalamin II (Morkbak, 2007). During pregnancy, megaloblastic anemia is rare from deficiency of vitamin B12, that is, cyanocobalamin. The typical example is Addisonian pernicious anemia, which results from absent intrinsic factor that is requisite for dietary vitamin B12 absorption. This autoimmune disorder usually has its onset after age 40 years (Stabler, 2013).
In our limited experience, vitamin B12 deficiency in pregnancy is more likely encountered following gastric resection. Those who have undergone total gastrectomy require 1000 μg of vitamin B12 given intramuscularly each month. Those with a partial gastrectomy usually do not need supplementation, but adequate serum vitamin B12 levels should be ensured during pregnancy (Appendix, p. 1290). Other causes of megaloblastic anemia from vitamin B12deficiency include Crohn disease, ileal resection, and bacterial overgrowth in the small bowel (Stabler, 2013).
There are several conditions in which accelerated erythrocyte destruction is stimulated by a congenital red cell abnormality or by antibodies directed against red cell membrane proteins. The cause may also go unproven. In some cases, hemolysis may be the primary disorder—some examples include sickle-cell disease and hereditary spherocytosis. In other cases, hemolysis develops secondary to an underlying disorder—examples include lupus erythematosus and the preeclampsia syndrome.
The cause of aberrant antibody production in this uncommon condition is unknown. Typically, both the direct and indirect antiglobulin (Coombs) tests are positive. Anemias caused by these factors may be due to warm-active autoantibodies (80 to 90 percent), cold-active antibodies, or a combination. These syndromes also may be classified as primary (idiopathic) or secondary due to underlying diseases or other factors. Examples of the latter include lymphomas and leukemias, connective-tissue diseases, infections, chronic inflammatory diseases, and drug-induced antibodies (Provan, 2000). Cold-agglutinin diseasemay be induced by infectious etiologies such as Mycoplasma pneumoniae or Epstein-Barr viral mononucleosis (Dhingra, 2007). Hemolysis and positive antiglobulin test results may be the consequence of either IgM or IgG antierythrocyte antibodies. Spherocytosis and reticulocytosis are characteristic of the peripheral blood smear. When there is concomitant thrombocytopenia, it is termed Evans syndrome(Wright, 2013).
During pregnancy, there may be marked acceleration of hemolysis. This usually responds to glucocorticoids, and treatment is given with prednisone, 1 mg/kg given orally each day, or its equivalent. Coincidental thrombocytopenia usually is corrected by therapy. Transfusion of red cells is complicated by antierythrocyte antibodies, but warming the donor cells to body temperature may decrease their destruction by cold agglutinins.
These hemolytic anemias must be differentiated from other causes of autoimmune hemolysis. In most cases, hemolysis is mild, it resolves with drug withdrawal, and recurrence is prevented by avoidance of the drug. One mechanism is by hemolysis induced through drug-mediated immunological injury to red cells. The drug may act as a high-affinity hapten when bound to a red cell protein to which antidrug antibodies attach—for example, IgM antipenicillin or anticephalosporin antibodies. Some other drugs act as low-affinity haptens and adhere to cell membrane proteins—examples include probenecid, quinidine, rifampin, and thiopental. A more common mechanism for drug-induced hemolysis is related to a congenital erythrocyte enzymatic defect. An example is glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is common in African American women (p. 1106).
Drug-induced hemolysis is usually chronic and mild to moderate, but occasionally there is severe acute hemolysis. For example, Garratty and coworkers (1999) described seven women with severe Coombs-positive hemolysis stimulated by cefotetan given as prophylaxis for obstetrical procedures. Alpha-methyldopa can cause similar hemolysis (Grigoriadis, 2013). Moreover, maternal hemolysis has been reported after intravenous immune globulin (IVIG) given for fetal and neonatal alloimmune thrombocytopenia (Rink, 2013). As treatment, response to glucocorticoids may be suboptimal, but withdrawal of the offending drug frequently halts the hemolysis.
In some cases, unexplained severe hemolytic anemia develops during early pregnancy and resolves within months postpartum. There is no evidence of an immune mechanism or intraerythrocytic or extraerythrocytic defects (Starksen, 1983). Because the fetus-infant also may demonstrate transient hemolysis, an immunological cause is suspected. Maternal corticosteroid treatment is often—but not always—effective (Kumar, 2001). We have cared for a woman who during each pregnancy developed intense severe hemolysis with anemia that was controlled by prednisone. Her fetuses were not affected, and in all instances, hemolysis abated spontaneously after delivery.
Paroxysmal Nocturnal Hemoglobinuria
Although commonly regarded as a hemolytic anemia, this hemopoietic stem cell disorder is characterized by formation of defective platelets, granulocytes, and erythrocytes. Paroxysmal nocturnal hemoglobinuria is acquired and arises from one abnormal clone of cells, much like a neoplasm (Nguyen, 2006). One mutated X-linked gene responsible for this condition is termed PIG-A because it codes for phosphatidylinositol glycan protein A. Resultant abnormal anchor proteins of the erythrocyte and granulocyte membrane make these cells unusually susceptible to lysis by complement (Provan, 2000). The most serious complication is thrombosis, which is heightened in the hypercoagulable state of pregnancy.
Chronic hemolysis has an insidious onset, and its severity ranges from mild to lethal. Hemoglobinuria develops at irregular intervals and is not necessarily nocturnal. Hemolysis may be initiated by transfusions, infections, or surgery. Almost 40 percent of patients suffer venous thromboses and may also experience renal failure, hypertension, and Budd-Chiari syndrome. Because of the thrombotic risk, prophylactic anticoagulation is recommended (Parker, 2005). Median survival after diagnosis is 10 years, and bone marrow transplantation is the definitive treatment. Successful treatment of nonpregnant patients has been reported with eculizumab, an antibody that inhibits complement activation (Hillmen, 2006; Parker, 2009). Kelly and colleagues (2010) described seven pregnant women exposed to eculizumab with successful outcomes.
During pregnancy, paroxysmal nocturnal hemoglobinuria can be serious and unpredictable. Complications have been reported in up to three fourths of affected women, and the maternal mortality rate is 10 to 20 percent (De Gramont, 1987). Complications more often develop postpartum, and half of affected women develop venous thrombosis during the puerperium (Fieni, 2006; Greene, 1983; Ray, 2000). In one report of 27 pregnancies in 22 women, the maternal mortality rate was 8 percent and related to postpartum thrombosis (de Guibert, 2011).
Severe Preeclampsia and Eclampsia
Fragmentation or microangiopathic hemolysis with thrombocytopenia is relatively common with severe preeclampsia and eclampsia (Kenny, 2014; Pritchard, 1976). Mild degrees are likely present in most cases of severe preeclampsia and may be referred to as HELLP syndrome—hemolysis, elevated liver enzymes, and low platelet count (Chap. 40, p. 742).
Acute Fatty Liver of Pregnancy
This syndrome is associated with moderate to severe hemolytic anemia (Nelson, 2013). It is discussed further in Chapter 55 (p. 1086).
The most fulminant acquired hemolytic anemia encountered during pregnancy is caused by the exotoxin of Clostridium perfringens or by group A β-hemolytic streptococcus (Chap. 47, p. 949). Endotoxin of gram-negative bacteria, that is, lipopolysaccharide—especially with bacteremia from severe pyelonephritis—may be accompanied by hemolysis and mild to moderate anemia (Cox, 1991).
Inherited Erythrocyte Membrane Defects
The normal erythrocyte is a biconcave disc. Its shape allows numerous cycles of reversible deformations as the erythrocyte withstands arterial shearing forces and negotiates through splenic slits half the width of its cross-sectional diameter. Several genes encode expression of erythrocyte structural membrane proteins or intraerythrocytic enzymes. Various mutations of these genes may result in inherited membrane defects or enzyme deficiencies that destabilize the lipid bilayer. The loss of lipids from the erythrocyte membrane causes a surface area deficiency and poorly deformable cells that undergo hemolysis. Anemia severity depends on the degree of rigidity or decreased distensibility. Erythrocyte morphology similarly is dependent on these factors, and these disorders are usually named after the most dominant red-cell shape characteristic of the disorder. Three examples are hereditary spherocytosis, pyropoikilocytosis, and ovalocytosis.
Hereditary Spherocytosis. Hemolytic anemias that comprise this group of inherited membrane defects are probably the most common identified in pregnant women. Mutations are usually an autosomally dominant, variably penetrant spectrin deficiency. Others are autosomally recessive or de novo gene mutations that result from deficiency of ankyrin, protein 4.2, moderate band 3, or combinations of these (Gallagher, 2010; Yawata, 2000). Clinically, varying degrees of anemia and jaundice result from hemolysis. Diagnosis is confirmed by identification of spherocytes on peripheral smear, reticulocytosis, and increased osmotic fragility (Fig. 56-2).
FIGURE 56-2 Scanning electron micrograph showing (A) normal-appearing erythrocytes from a heterozygous carrier of recessive spherocytosis, and (B) from her daughter, a homozygote with severe anemia. (From Agre, 1989, with permission.)
Spherocytic anemias may be associated with the so-called crisis that is characterized by severe anemia from accelerated hemolysis, and it develops in patients with an enlarged spleen. Infection can also accelerate hemolysis or suppress erythropoiesis to worsen anemia. An example of the latter is infection with parvovirus B19 (Chap. 64, p. 1244). In severe cases, splenectomy reduces hemolysis, anemia, and jaundice.
Pregnancy. In general, women with inherited red-cell membrane defects do well during pregnancy. Folic acid supplementation is given to sustain erythropoiesis. Pregnancy outcomes in women with hereditary spherocytosis cared for at Parkland Hospital were reported by Maberry and associates (1992). Twenty-three women with 50 pregnancies were described. In late pregnancy, these women had hematocrits ranging from 23 to 41 volume percent—mean 31. Their reticulocyte count ranged from 1 to 23 percent. Eight women miscarried. Four of 42 infants were born preterm, but none were growth restricted. Infection in four women intensified hemolysis, and three of these required transfusions. Similar results were reported by Pajor and coworkers (1993) in 19 pregnancies in eight women.
Because these disorders are inherited, the newborn may be affected. Celkan and Alhaj (2008) report prenatal diagnosis via cordocentesis at 18 weeks’ gestation and testing for osmotic fragility. Those with hereditary spherocytosis may manifest hyperbilirubinemia and anemia shortly after birth.
Erythrocyte Enzyme Deficiencies
An intraerythrocytic deficiency of enzymes that permit anaerobic glucose metabolism may cause hereditary nonspherocytic anemia. Most of these mutations are autosomal recessive traits, and pyruvate kinase deficiency is probably the most clinically significant. Another is X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency (Puig, 2013). Other rare enzyme abnormalities may cause varying degrees of chronic hemolysis. As discussed on page 1105, most episodes of severe anemia with enzyme deficiencies are induced by drugs or infections. During pregnancy, oxidant drugs are avoided, infections are treated promptly, and iron and folic acid are given.
Pyruvate kinase deficiency is associated with variable anemia and hypertensive complications (Wax, 2007). Due to recurrent transfusions in homozygous carriers, iron overload is frequent, and associated myocardial dysfunction should be monitored (Dolan, 2002). The fetus that is homozygous for this mutation may develop hydrops fetalis from anemia and heart failure (Chap. 15, p. 315). Gilsanz and colleagues (1993) used funipuncture to diagnose fetal anemia and pyruvate kinase deficiency.
Glucose-6-phosphate dehydrogenase deficiency is complex because there are more than 400 known enzyme variants. The most common are caused by a base substitution that leads to an amino acid replacement and a broad range of phenotypic severity (Beutler, 1991; Puig, 2013)). In the homozygous or A variant, both X chromosomes are affected, and erythrocytes are markedly deficient in G6PD activity. Approximately 2 percent of African American women are affected. The heterozygous variant that is found in 10 to 15 percent of African American women may confer some degree of protection against malaria (Mockenhaupt, 2003). In both instances, random X-chromosome inactivation—lyonization—results in a variable deficiency of enzyme activity.
During pregnancy, infections or drugs can induce hemolysis in both heterozygous and homozygous women, and the severity is related to enzyme activity. Anemia is usually episodic, although some variants induce chronic nonspherocytic hemolysis. Because young erythrocytes contain more enzyme activity than older erythrocytes, in the absence of bone marrow depression, anemia ultimately stabilizes and is corrected soon after the inciting cause is eliminated. Newborn screening for G6PD deficiency is not recommended by the American College of Medical Genetics (2013) as discussed in Chapter 32 (Table 32-3, p. 632).
Aplastic and Hypoplastic Anemia
Although rarely encountered during pregnancy, aplastic anemia is a grave complication. It is characterized by pancytopenia and markedly hypocellular bone marrow (Young, 2008). There are multiple etiologies, and at least one is linked to autoimmune diseases (Stalder, 2009). The inciting cause can be identified in approximately a third of cases. These include drugs and other chemicals, infection, irradiation, leukemia, immunological disorders, and inherited conditions such as Fanconi anemia and Diamond-Blackfan syndrome (Green, 2009; Lipton, 2009). The functional defect appears to be a marked decrease in committed marrow stem cells.
Hematopoietic stem-cell transplantation is optimal therapy in a young patient (Young, 2008). Immunosuppressive therapy is given. In some nonresponders, eltrombopag has been used successfully (Olnes, 2012). Definitive treatment is bone marrow transplantation, and approximately three fourths of patients have a good response with long-term survival when treated with antithymocyte globulin and cyclosporine (Rosenfeld, 2003). There is a potential for transplantation with umbilical cord blood-derived stem cells (Moise, 2005; Pinto, 2008). Previous blood transfusions and even pregnancy enhance the risk of graft rejection, which is the most common serious complication, causing two thirds of deaths within the first 2 years (Socié, 1999).
Hypoplastic or aplastic anemia complicating pregnancy is rare. In most cases, the diagnosis precedes conception, or the condition develops during pregnancy as a chance occurrence. That said, there are a few well-documented cases of pregnancy-induced hypoplastic anemia (Bourantas, 1997; Choudhry, 2002). We have cared for a few such women in whom hypoplastic anemia was first identified during a pregnancy. Anemia and other cytopenias improved or remitted following delivery or pregnancy termination. In some cases, recurrence in a subsequent pregnancy was documented.
Diamond-Blackfan anemia is a rare form of pure red-cell hypoplasia, and approximately 40 percent are familial and have autosomal dominant inheritance (Orfali, 2004). There is usually a good response to glucocorticoid therapy. However, continuous treatment is necessary, and most become at least partially transfusion dependent (Vlachos, 2008). In 64 pregnancies complicated by this syndrome, Faivre and associates (2006) reported that two thirds had complications related to placental vascular etiologies that included miscarriage, preeclampsia, preterm birth, stillbirth, or growth-restricted newborn.
Gaucher disease is an autosomally recessive lysosomal enzyme deficiency characterized by deficient acid β-glucosidase activity. It involves multiple systems, including bone marrow. Affected women have anemia and thrombocytopenia that is usually worsened by pregnancy (Granovsky-Grisaru, 1995). Elstein and colleagues (1997) described six pregnant women whose disease improved when they were given alglucerase enzyme replacement. Imiglucerase therapy, which is human recombinant enzyme replacement therapy, has been available since 1994. European guidelines recommend treatment in pregnancy, whereas the Food and Drug Administration states it may be given in pregnancy with “clear indications” (Granovsky-Grisaru, 2011).
The major risks to pregnant woman with hypoplastic anemia are hemorrhage and infection. Management depends on gestational age, disease severity, and whether treatment has been given. Supportive care includes continuous infection surveillance and prompt antimicrobial therapy. Granulocyte transfusions are given only during infections. Red cells are transfused to improve symptomatic anemia and routinely to maintain the hematocrit at or above 20 volume percent. Platelet transfusions may be needed to control hemorrhage. Even when thrombocytopenia is intense, the risk of severe hemorrhage can be minimized by vaginal rather than cesarean delivery. Maternal mortality rates reported since 1960 have averaged nearly 50 percent (Choudhry, 2002). Better outcomes are reported with more recent series (Kwon, 2006).
Pregnancy after Bone Marrow Transplantation
There have been several reports of successful pregnancies in women who have undergone bone marrow transplantation (Borgna-Pignatti, 1996; Eliyahu, 1994). In their review, Sanders and coworkers (1996) reported 72 pregnancies in 41 women who had undergone transplantation. In the 52 pregnancies resulting in a liveborn infant, almost half were complicated by preterm delivery or hypertension. Our experiences with a few of these women indicate that they have normal pregnancy-augmented erythropoiesis and total blood volume expansion.
Excessive erythrocytosis during pregnancy is usually related to chronic hypoxia from maternal congenital cardiac disease or a chronic pulmonary disorder. Unusually heavy cigarette smoking can cause polycythemia. We have encountered otherwise healthy pregnant women who were heavy smokers, had chronic bronchitis, and had hematocrits ranging from 55 to 60 volume percent! Brewer and colleagues (1992) described a woman with persistent erythrocytosis associated with a placental site tumor. If polycythemia is severe, the probability of a successful pregnancy outcome is low.
This is a primary myeloproliferative hemopoietic stem cell disorder characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic precursors. It is uncommon and likely an acquired genetic disorder of stem cells (Spivak, 2008). Virtually all patients have either a JAK2V617F or a JAK2 exon 12 gene mutation (Harrison, 2009). Serum erythropoietin level measurement is helpful to differentiate polycythemia vera—low values—from secondary erythrocytosis—high values. Symptoms are related to increased blood viscosity, and thrombotic complications are common. Fetal loss has been reported to be high in women with polycythemia vera, and pregnancy outcome may be improved with aspirin therapy (Griesshammer, 2006; Robinson, 2005; Tefferi, 2000).
Hemoglobin A is the most common hemoglobin tetramer and consists of two α- and two β-chains. In contrast, sickle hemoglobin (hemoglobin S) originates from a single β-chain substitution of glutamic acid by valine, which stems from an A-for-T substitution at codon 6 of the β-globin gene. Hemoglobinopathies that can result in clinical features of the sickle-cell syndrome include sickle-cell anemia—Hb SS; sickle cell-hemoglobin C disease—Hb SC; sickle cell-β-thalassemia disease—either Hb S/B0 or Hb S/B+; and sickle-cell E disease—Hb SE (Stuart, 2004). All are also associated with increased maternal and perinatal morbidity and mortality.
Sickle-cell anemia originates from the inheritance of the gene for S hemoglobin from each parent. In the United States, 1 of 12 African Americans has sickle-cell trait, which results from inheritance of one gene for hemoglobin S and one for normal hemoglobin A. The computed incidence of sickle-cell anemia among African Americans is 1 in 576 (1/12 × 1/12 × 1/4 = 1/576). But, the disease is less common in adults and therefore during pregnancy because of earlier mortality, especially during early childhood.
Hemoglobin C originates from a single β-chain substitution of glutamic acid by lysine at codon 6 of the β-globin gene. Approximately 1 in 40 African Americans has the gene for hemoglobin C. Thus, the theoretical incidence for coinheritance of the gene for hemoglobin S and an allelic gene for hemoglobin C in an African American child is about 1 in 2000 (1/12 × 1/40 × 1/4). β-Thalassemia minor is approximately 1 in 40, thus S-β-thalassemia also is found in approximately 1 in 2000 (1/12 × 1/40 × 1/4).
Red cells with hemoglobin S undergo sickling when they are deoxygenated, and the hemoglobin aggregates. Constant sickling and unsickling cause membrane damage, and the cell may become irreversibly sickled. Events that slow erythrocyte transit through the microcirculation contribute to vasoocclusion. These include endothelial cell adhesion, erythrocytic dehydration, and vasomotor dysregulation. Clinically, the hallmarks of sickling episodes are periods during which there is ischemia and infarction in various organs. These produce clinical symptoms, predominately pain, which is often severe—the sickle-cell crisis. There may be aplastic, megaloblastic, sequestration, and hemolytic crises.
Chronic and acute changes from sickling include bony abnormalities such as osteonecrosis of femoral and humeral heads, renal medullary damage, autosplenectomy in homozygous SS patients and splenomegaly in other variants, hepatomegaly, ventricular hypertrophy, pulmonary infarctions, pulmonary hypertension, cerebrovascular accidents, leg ulcers, and a propensity for infection and sepsis (Driscoll, 2003; Gladwin, 2004; Stuart, 2004). Of increasing importance is acquisition of pulmonary hypertension, which can be demonstrated in 20 percent of adults with SS hemoglobin (Gladwin, 2008). Depending on its severity, this complication increases the relative risk for death from four- to 11-fold. Another emerging problem with improved survival is chronic sickle-cell disease nephropathy (Maigne, 2010). The median age at death for women is 48 years. Even so, Serjeant and associates (2009) described a cohort of 102 patients followed since birth in which 40 were still alive at 60 to 87 years!
Good supportive care is essential to prevent mortality in patients with sickle-cell syndromes. Specific therapies are evolving, and many are still experimental (Stuart, 2004). One treatment is hemoglobin F induction given for both sickling and thalassemia syndromes. These drugs stimulate gamma-chain synthesis. This increases hemoglobin F (fetal hemoglobin), which inhibits hemoglobin S polymerization. One inducing agent, hydroxyurea, when given to patients with moderate to severe disease, increases hemoglobin F production and mitigates erythrocyte membrane damage. This reduces the number of clinical sickling episodes (Platt, 2008). It is not known yet if hydroxyurea increases long-term patient survival (Brawley, 2008). Hydroxyurea is teratogenic in animals, although a preliminary 17-year surveillance of antenatally exposed children was reassuring (Ballas, 2009; Briggs, 2011; Italia, 2010).
Various forms of hemopoietic cell transplantation are emerging as “cures” for sickle-cell syndromes and severe thalassemias (Hsieh, 2009). Oringanje and coworkers (2009) performed a Cochrane Review and found that only observational studies have been reported. Bone marrow transplantation, as discussed on page 1107, has 5-year survival rates that exceed 90 percent (Dalle, 2013). Cord-blood stem-cell transplantation from related donors has also shown great promise (Shenoy, 2013). One intriguing treatment uses cells taken for prenatal diagnosis from a fetus destined to have sickle-cell anemia. Research suggests these cells can be conditioned to produce hemoglobin A and used for replacement after birth (Ye, 2009).
Pregnancy and Sickle-Cell Syndromes
Pregnancy is a serious burden to women with any of the major sickle hemoglobinopathies, particularly those with hemoglobin SS disease. Two large studies define this relationship. The first, by Villers and colleagues (2008), included 17,952 births delivered of women with sickle-cell syndromes from 2000 through 2003. The second study, by Chakravarty and associates (2008), was from 2002 through 2004 and included 4352 pregnancies. A more recent cohort study of 1526 women was reported by Boulet and coworkers (2013). Common obstetrical and medical complications and their relative risks from these studies are shown in Table 56-2. Added to these are findings of Chakravarty and associates (2008), who reported significantly increased risks for renal failure, gestational hypertension, and fetal-growth restriction.
TABLE 56-2. Increased Rates for Maternal Complications in Pregnancies Complicated by Sickle-Cell Syndromes
Maternal morbidity common in pregnancy includes ischemic necrosis of multiple organs, especially bone marrow, that causes episodes of severe pain. Pyelonephritis, pneumonia, and other pulmonary complications are frequent. The acute chest syndrome is manifest by the radiological appearance of a new pulmonary infiltrate accompanied by fever and respiratory symptoms. There are four precipitants of this—infection, marrow emboli, thromboembolism, and atelectasis (Medoff, 2005). Of these, infection causes approximately half of cases and results from typical bacteria and viruses. When the chest syndrome develops, the mean duration of hospitalization is 10.5 days. Mechanical ventilation is required in approximately 15 percent, and the mortality rate is about 3 percent (Gladwin, 2008).
Despite these complications, the maternal mortality rate has decreased. And although improved, perinatal morbidity and mortality rates remain formidable (Yu, 2009). Some perinatal outcomes reported since 2000 are shown in Table 56-3. In addition to increased risks for preterm birth shown in Table 56-2, the frequency of fetal-growth restriction and perinatal mortality are daunting.
TABLE 56-3. Perinatal Outcomes in Women with Hemoglobin SS and SC Disease
In nonpregnant women, morbidity and mortality rates from SC disease are appreciably lower than those from sickle-cell anemia. Indeed, fewer than half of women with SC disease have symptoms before pregnancy. In our experiences, affected pregnant and puerperal women suffer attacks of severe bone pain and episodes of pulmonary infarction and embolization—acute chest syndrome—more commonly compared with when they are not pregnant (Cunningham, 1983). It is arguable whether SC disease has a maternal mortality rate equivalent to that of hemoglobin SS disease (Pritchard, 1973; Serjeant, 2005). In the reports shown in Table 56-3, the perinatal mortality rate is somewhat greater than that of the general obstetrical population, but nowhere as great as with sickle-cell anemia (Tita, 2007).
Management During Pregnancy
Women with sickle-cell hemoglobinopathies require close prenatal observation. These women maintain hemoglobin mass by intense hemopoiesis to compensate for the markedly shortened erythrocyte life span. Thus, any factor that impairs erythropoiesis or increases red cell destruction or both aggravates the anemia. Prenatal folic acid supplementation with 4 mg daily is needed to support the rapid red blood cell turnover (American College of Obstetricians and Gynecologists, 2013b).
One danger is that a symptomatic woman may categorically be considered to be suffering from a sickle-cell crisis. As a result, serious obstetrical or medical problems that cause pain, anemia, or both may be overlooked. Some examples are ectopic pregnancy, placental abruption, pyelonephritis, or appendicitis. Thus, the term “sickle-cell crisis” importantly should be applied only after all other possible causes of pain or fever or worsening anemia have been excluded. Pain with sickle-cell syndromes is caused by intense sequestration of sickled erythrocytes and infarction in various organs. These episodes may develop acutely, especially late in pregnancy, during labor and delivery, and early in the puerperium. Because bone marrow is frequently involved, intense bone pain is common.
A system for care of these women has been appropriately stressed by Rees and colleagues (2003). Marti-Carvajal and coworkers (2009) performed a Cochrane review and reported that no randomized trials have evaluated treatment during pregnancy. At minimum, intravenous fluids are given and opioids administered promptly for severe pain. Oxygen via nasal cannula may decrease the intensity of sickling at the capillary level. We have found that red cell transfusions after the onset of severe pain do not dramatically improve the intensity of the current pain crisis and may not shorten its duration. Conversely, as discussed later, prophylactic transfusions almost always prevent further vasoocclusive episodes and pain crises. Recent reports suggest benefits from epidural analgesia used for severe sickle-cell crisis in nonlaboring obstetrical patients (Verstraete, 2012; Winder, 2011). During the past few years, we have encountered several affected women who apparently are habituated to narcotics given chronically to alleviate sickle-cell pain. It is problematic that such women complain of “sickling pain” even when they have effectively undergone exchange transfusion with normal AA-hemoglobin-containing donor red cells.
Rates of covert bacteriuria and acute pyelonephritis are increased substantively, and screening and treatment for bacteriuria are essential. If pyelonephritis develops, sickle cells are extremely susceptible to bacterial endotoxin, which can cause dramatic and rapid red cell destruction while simultaneously suppressing erythropoiesis. Pneumonia, especially due to Streptococcus pneumoniae, is common. The CDC (2013a) recommends the following vaccines for those with sickle-cell disease and all asplenic patients: polyvalent pneumococcal, Haemophilus influenzae type B, and meningococcal vaccines.
Pulmonary complications are often encountered. Acute chest syndrome is characterized by pleuritic chest pain, fever, cough, lung infiltrates, and hypoxia, and usually also by bone and joint pain (Vichinsky, 2000). The spectrum of its pathology includes infection, infarction, pulmonary sequestration, and fat embolization from bone marrow. At least for nonpregnant adults, some recommend rapid simple or exchange transfusions to remove the “trigger” for acute chest syndromes (Gladwin, 2008). In a cohort study of nonpregnant patients, Turner and colleagues (2009) reported that there were no increased benefits of exchange versus simple transfusions, and the former were associated with fourfold increased blood usage. Recurrent episodes of acute chest syndrome may lead to restrictive chronic lung disease or arteriolar vasculopathy and pulmonary hypertension.
Pregnant women with sickle-cell anemia usually have some degree of cardiac dysfunction from ventricular hypertrophy. There is increased preload, decreased afterload, normal ejection fraction, and a high cardiac output. Chronic hypertension worsens this pattern (Gandhi, 2000). During pregnancy, the basal hemodynamic state characterized by high cardiac output and increased blood volume is augmented (Veille, 1994). Although most women tolerate pregnancy without problems, complications such as severe preeclampsia or serious infections may result in ventricular failure (Cunningham, 1986). As discussed in Chapter 49 (p. 986), heart failure caused by pulmonary hypertension must also be considered (Chakravarty, 2008; Stuart, 2004).
In the review of 4352 pregnancies in women with sickle-cell syndromes noted earlier, Chakravarty and associates (2008) reported significantly increased pregnancy complications compared with the total population of 11.2 million women. Compared with controls, women with sickling disorders had a 63-percent rate of nondelivery-related admissions. They had a 1.8-fold increased incidence of hypertensive disorders—19 percent; a 2.9-fold increased rate of fetal-growth restriction—6 percent; and a 1.7-fold increased cesarean delivery rate—45 percent.
Prophylactic Red Cell Transfusions. There are several clinical situations for which prophylactic transfusions have been shown to decrease morbidity from sickle-cell syndromes. For example, chronic transfusion therapy prevents strokes in high-risk children. However, there are no randomized trials of such therapy to prevent pulmonary hypertension and chronic sickle-cell lung disease (Cho, 2014). Preoperative transfusions improved some postoperative outcomes (Howard, 2013). During pregnancy, the most dramatic impact of prophylactic transfusions has been on maternal morbidity. In an observational 10-year prospective study at Parkland Hospital, we offered prophylactic transfusions to all pregnant women with sickle-cell syndromes. Transfusions were given throughout pregnancy to maintain the hematocrit above 25 volume percent and the portion of hemoglobin S below 60 percent (Cunningham, 1979). There was minimal maternal morbidity, and erythropoiesis suppression was not problematic. Their outcomes were compared with historical controls who were not routinely transfused. Morbidity and hospitalizations were significantly reduced in the transfused group (Cunningham, 1983). Others have reported similar data (Grossetti, 2009; Howard, 1995). Still, adverse perinatal outcomes are prevalent (Ngô, 2010).
In a multicenter trial, Koshy and coworkers (1988) randomly assigned 72 pregnant women with sickle-cell syndrome to prophylactic or indicated transfusions. They reported a significant decline in the incidence of painful sickle-cell crises with prophylactic transfusions but no differences in perinatal outcomes. Because of risks inherent with blood administration, they concluded that prophylactic transfusions were not necessary.
There is no doubt that morbidity from multiple transfusions is significant. Up to 10 percent of women had a delayed hemolytic transfusion reaction, and infections are major concerns (Garratty, 1997). From our experiences from Parkland Hospital cited above, we found the incidence of red cell alloimmunization to be 3 percent per unit of blood transfused (Cox, 1988). Similarly, in 12 studies reviewed by Garratty (1997), alloimmunization developed in a fourth of women undergoing chronic transfusions. According to Kacker and colleagues (2014), it not cost effective to extensively match blood donors for these women. Finally, although worrisome, we found no evidence of transfusional iron overload, hemochromatosis, or chronic hepatitis in liver biopsies performed in 40 women transfused during pregnancy (Yeomans, 1990).
Because of what some consider marginal benefits, routine prophylactic transfusions during pregnancy remain controversial (American College of Obstetricians and Gynecologists, 2013b). Similar conclusions were reached after a Cochrane Database analysis (Okusayna, 2013). Current consensus is that their use should be individualized. For example, some clinicians recommend prophylactic transfusions for women with either frequent vasoocclusive episodes or poor obstetrical outcomes (Castro, 2003).
Fetal Assessment. Because of the high incidence of fetal-growth restriction and perinatal mortality, serial fetal assessment is necessary. According to the American College of Obstetricians and Gynecologists (2013b), a plan for serial sonographic examinations and antepartum fetal surveillance is reasonable. Anyaegbunam and colleagues (1991) evaluated fetal well-being during 39 sickling crises in 24 women. Almost 60 percent had nonreactive stress tests, which became reactive with crisis resolution, and all had an increased uterine artery systolic-diastolic (S/D) ratio. At the same time, there were no changes in umbilical artery S/D ratios (Chap. 10, p. 219). These investigators concluded that transient effects of sickle-cell crisis do not compromise umbilical, and hence fetal, blood flow. At Parkland Hospital, we serially assess these women with sonography for fetal growth and amnionic fluid volume changes. Nonstress or contraction stress tests are not done routinely unless complications such as fetal-growth restriction develop or fetal movement is reported to be diminished.
Labor and Delivery. Management is essentially identical to that for women with cardiac disease (Chap. 49, p. 978). Women should be kept comfortable but not oversedated. Labor epidural analgesia is ideal, and conduction analgesia seems preferable for operative delivery (Camous, 2008). Compatible blood should be available. If a difficult vaginal or cesarean delivery is contemplated, and the hematocrit is < 20 volume percent, then packed erythrocyte transfusions are administered. There is no categorical contraindication to vaginal delivery, and cesarean delivery is reserved for obstetrical indications (Rogers, 2010). Circulatory overload and pulmonary edema from ventricular failure should be avoided.
Contraception and Sterilization
Because of chronic debility, complications caused by pregnancy, and the predictably shortened life span of women with sickle-cell anemia, contraception and possibly sterilization are important considerations. Many clinicians do not recommend combined hormonal pills because of potential adverse vascular and thrombotic effects. After a systematic review, however, it was concluded that there was no increase in complications with their use in women with sickle-cell syndromes (Haddad, 2012). The CDC (2013b) regards the contraceptive pill, patch, and ring along with the copper intrauterine device (IUD) as having “advantages that generally outweigh theoretical or proven risks.” All progestin-only methods may be used without restrictions. Because progesterone has been long known to prevent painful sickle-cell crises, low-dose oral progestins or progesterone injections or implants seem ideal. In one study, de Abood and associates (1997) reported significantly fewer and less intense pain crises in women given depot medroxyprogesterone intramuscularly.
The heterozygous inheritance of the gene for hemoglobin S results in sickle-cell trait, or AS hemoglobin. Hemoglobin A is most abundant, and the amount of hemoglobin S averages approximately 30 percent in each red cell. The frequency of sickle-cell trait among African Americans averages 8 percent. There is evidence that carriers have occasional hematuria, renal papillary necrosis, and hyposthenuria (Tsaras, 2009). And although controversial, we believe that sickle-cell trait is not associated with increased rates of abortion, perinatal mortality, low birthweight, or pregnancy-induced hypertension (Pritchard, 1973; Tita, 2007; Tuck, 1983). One unquestioned relationship is the twofold increased incidence of asymptomatic bacteriuria and urinary infection. Sickle-cell trait therefore should not be considered a deterrent to pregnancy on the basis of increased maternal risks.
Preliminary findings from a cohort study by Austin and coworkers (2009) suggested that African American women with sickle trait may have a higher incidence of venous thromboembolism when using hormonal contraceptives compared with women without the trait. However, more data are needed before these effective contraceptive methods are withheld from trait-positive women.
Inheritance is a concern for the infant of a mother with sickle-cell trait whenever the father carries a gene for abnormal hemoglobins that include S, C, and D or for β-thalassemia trait. Prenatal diagnosis through amniocentesis, chorionic villus sampling (CVS), or preimplantation genetic evaluation is available (Chap. 14, p. 297).
Hemoglobin C and C-β-Thalassemia
Approximately 2 percent of African Americans are heterozygous for hemoglobin C, but even if homozygous, hemoglobin C is innocuous (Nagel, 2003). Neither cause severe anemia or adverse pregnancy outcomes. However, when coinherited with sickle-cell trait, hemoglobin SC is the second most common serious sickle-cell syndrome.
Pregnancy and homozygous hemoglobin CC disease or hemoglobin C-β-thalassemia are relatively benign associations. Maberry and colleagues (1990) reported our experiences from Parkland Hospital as shown in Table 56-4. Other than mild to moderate anemia, pregnancy outcomes were not different compared with those of the general obstetrical population. When severe anemia is identified, iron or folic acid deficiency or some other superimposed cause should be suspected. Supplementation with folic acid and iron is indicated.
TABLE 56-4. Outcomes in 72 Pregnancies Complicated by Hemoglobin CC and C-β-Thalassemia
Although it is uncommon in the United States, hemoglobin E is the second most frequent hemoglobin variant worldwide. Hemoglobin E results from a single β-chain substitution of lysine for glutamic acid at codon 26. The hemoglobin is particularly susceptible to oxidative stress. The heterozygous E trait is common in Southeast Asia. Hurst and coworkers (1983) identified homozygous hemoglobin E, hemoglobin E plus β-thalassemia, or hemoglobin E trait in 36 percent of Cambodians and 25 percent of Laotians. In addition, α- and β-thalassemia traits were prevalent in all groups.
Homozygous hemoglobin EE is associated with little or no anemia, hypochromia, marked microcytosis, or erythrocyte targeting. In our limited experience, pregnant women do not appear to be at increased risk. Conversely, doubly heterozygous hemoglobin E-β-thalassemia is a common cause of childhood anemia in Southeast Asia (Fucharoen, 2000). In a cohort study of 54 women with singleton pregnancies, Luewan and associates (2009) reported a threefold increased risk of preterm birth and fetal-growth restriction in affected women. It is unclear if hemoglobin SE disease is as ominous during pregnancy as hemoglobin SC or S-β-thalassemia disease (Ramahi, 1988).
Hemoglobinopathy in the Newborn
Infants with homozygous SS, SC, and CC disease can be identified accurately at birth by cord blood electrophoresis. The United States Preventive Services Task Force recommends that all newborn infants be tested for sickle-cell disease (Lin, 2007). In most states, such screening is mandated by law and performed routinely (Chap. 32, p. 632). Screening for sickle hemoglobinopathies leads to clearly decreased mortality rates in children with sickle-cell disease identified at birth.
There are many tests to detect sickle-cell disease prenatally. Most are DNA based and use CVS samples or amnionic fluid specimens (American College of Obstetricians and Gynecologists, 2013b). Several mutations that encode hemoglobin S and other abnormal hemoglobins can be detected by targeted mutation analysis as well as polymerase chain reaction-based techniques (Chap. 13, p. 277).
Hundreds of mutations have been described for genes that control production of the normal hemoglobins. Some of these mutations impair synthesis of one or more of the normal globin peptide chains and may result in a clinical syndrome characterized by varying degrees of ineffective erythropoiesis, hemolysis, and anemia. Thalassemias are classified according to the globin chain that is deficient. The two major forms involve impaired production or instability of α-peptide chains—causing α-thalassemia, or of β-chains—causing β-thalassemia. These may form from point mutations, deletions, or translocations involving the α- or non-α-globin gene. The estimated prevalence for thalassemia trait is 16 percent in Southern European, 10 percent in Thai, and 3 to 8 percent in Indian and Chinese populations (Leung, 2012).
Because there are four α-globin genes, the inheritance of α-thalassemia is more complicated than for β-thalassemia (Weatherall, 2010). Possible genotypes and phenotypes arising from these mutations are shown in Table 56-5. For each, a close correlation has been established between clinical severity and the degree of α-globin chains synthesis impairment. In most populations, the α-globin chain “cluster” or gene loci are doubled on chromosome 16. Thus, the normal genotype for diploid cells can be expressed as αα/αα. There are two main groups of α-thalassemia determinants: α0-thalassemia is characterized by the deletion of both loci from one chromosome (––/αα), whereas α+-thalassemia is characterized by the loss of a single locus from one allele (–α/αα heterozygote) or a loss from each allele alleles (–α/–α homozygote).
TABLE 56-5. Genotypes and Phenotypes of α-Thalassemia Syndromes
There are two major phenotypes. The deletion of all four α-globin chain genes (––/––) characterizes homozygous α-thalassemia. Because α-chains are contained in fetal hemoglobin, the fetus is affected. With none of the four genes expressed, there are no α-globin chains, and instead, hemoglobin Bart (γ4) and hemoglobin H (β4) are formed as abnormal tetramers (Chap. 7, p. 137).
The relative frequency of α-thalassemia minor, hemoglobin H disease, and hemoglobin Bart disease varies remarkably among racial groups. All of these variants are encountered in Asians. In those of African descent, although α-thalassemia minor has a frequency of approximately 2 percent, hemoglobin H disease is rare and hemoglobin Bart disease is unreported. This is because Asians usually have α0-thalassemia minor inherited with both gene deletions typically from the same chromosome (––/αα), whereas blacks usually have a+-thalassemia minor in which one gene is deleted from each chromosome (–α/–α). The α-thalassemia syndromes appear sporadically in other racial and ethnic groups. Diagnosis of β-thalassemia minor and α-thalassemia major in the fetus can be accomplished by DNA analysis using molecular techniques (American College of Obstetricians and Gynecologists, 2013b). Fetal diagnosis of hemoglobin Bart has been described using capillary electrophoresis or high-performance liquid chromatography (HPLC) techniques (Sirichotiyakul, 2009; Srivorakun, 2009). Molecular genetic testing for HBA1 and HBA2identifies 90 percent of deletions and 10 percent of point mutations in affected individuals (Galanello, 2011b).
Important obstetrical aspects of some α-thalassemia syndromes depend on the number of gene deletions in a given woman. The silent carrier state with one gene deletion is of no consequence. Deletion of two genes resulting in α-thalassemia minor is characterized by minimal to moderate hypochromic microcytic anemia. This is due to either the α0- or the α+-thalassemia trait, and thus genotypes may be –α/–α or ––/αα. Differentiation is possible only by DNA analysis (Weatherall, 2000a,b). Because there are no other clinical abnormalities with either α-thalassemia minor, it often goes unrecognized and is usually of no maternal consequence. The fetus with these forms of thalassemia minor will have hemoglobin Bart at birth, but as its levels drop, it is not replaced by hemoglobin H. Red cells are hypochromic and microcytic, and the hemoglobin concentration is normal to slightly depressed.
Hemoglobin H disease (β4) results from the compound heterozygous state for α0- plus α+-thalassemia with deletion of three of four alpha genes (––/–α). With only one functional α-globin gene per diploid genome, the newborn will have abnormal red cells containing a mixture of hemoglobin Bart (γ4), hemoglobin H (β4), and hemoglobin A. The neonate appears normal but soon develops hemolytic anemia as most of the hemoglobin Bart is replaced by hemoglobin H. Anemia is moderate to severe, and it usually worsens during pregnancy.
Inheritance of all four abnormal alpha genes causes homozygous α-thalassemia with predominant production of hemoglobin Bart, which has an appreciably increased affinity for oxygen. This is incompatible with extended survival, and stillbirths caused by the homozygous condition are especially common in Southeast Asia. Hsieh and colleagues (1989) reported that blood obtained by funipuncture from 20 hydropic fetuses contained 65 to 98 percent Bart hemoglobin. Either these fetuses are stillborn, or they die very soon after birth and have the typical features of nonimmune hydrops fetalis shown in Figure 16-4 (p. 330).
Lam and associates (1999) reported that sonographic measurement of the fetal cardiothoracic ratio at 12 to 13 weeks’ gestation was 100-percent sensitive and specific for identifying affected fetuses. Sonographic evaluation of the myocardial performance index—the Tei index—in the first half of pregnancy has been evaluated. Changes predating hydrops are seen in affected fetuses (Luewan, 2013). Severe anemia can be detected using Doppler velocimetry of the middle cerebral artery (Chap. 10, p. 221). Although a successful case of hemopoietic cell transplantation with a fetal “cure” has been described, this remains experimental (Galanello, 2011a; Yi, 2009).
The β-thalassemias are the consequences of impaired β-globin chain production or α-chain instability. Genes that encode control of β-globin synthesis are in the δγβ-gene “cluster” located on chromosome 11 (Fig. 7-10, p. 138). More than 150 point mutations in the β-globin gene have been described (Weatherall, 2010). Most are single-nucleotide substitutions that produce transcriptional or translational defects, RNA splicing or modification, or frameshifts that result in highly unstable hemoglobins. Thus, deletional and nondeletional mutations affect β-globin RNA. In β-thalassemia, there is decreased β-chain production, and excess α-chains precipitate to cause cell membrane damage. Other forms of β-thalassemias are caused by α-chain instability (Kihm, 2002). Because of the variety of genetic defects and their combinations with genes that code for globin chain synthesis, these are collectively referred to as thalassemia syndromes (Weatherall, 2010).
The heterozygous trait is β-thalassemia minor, and those most commonly encountered have elevated hemoglobin A2 levels. This hemoglobin is composed of two α- and two δ-globin chains, and concentrations are usually more than 3.5 percent. Hemoglobin F—composed of two α- and two γ-globin chains—also usually has increased concentrations of more than 2 percent. Some patients with heterozygous β-thalassemia minor do not have anemia, and others have mild to moderate anemia characterized by hypochromia and microcytosis.
Homozygous β-thalassemia—also called β-thalassemia major or Cooley anemia—is a serious and frequently fatal disorder. There is intense hemolysis and severe anemia. Many patients become transfusion dependent, and the subsequent iron load, along with abnormally increased gastrointestinal iron absorption, leads to hemochromatosis, which is fatal in many cases. A heterozygous form of β-thalassemia that clinically manifests as thalassemia intermedia produces moderate anemia.
There are few problems that arise during pregnancy in women with β-thalassemia minor who have mild anemia. Iron and folate supplements are given. In some women, anemia will worsen because normal plasma volume expansion may be accompanied by slightly subnormal erythropoiesis.
Thalassemia major and some of the other severe forms were uncommonly encountered during pregnancy before the advent of transfusion and iron chelation therapy. With such management, there were 63 pregnancies reported without serious complications (Aessopos, 1999; Daskalakis, 1998; Kumar, 1997). Pregnancy is considered advisable if there is normal maternal cardiac function. Transfusions are given throughout pregnancy to maintain the hemoglobin concentration at 10 g/dL. This is coupled with surveillance of fetal growth (American College of Obstetricians and Gynecologists, 2013b; Sheiner, 2004).
Because β-thalassemia major is caused by numerous mutations, prenatal diagnosis is difficult. For a given individual, targeted mutation analysis is done that requires prior identification of that familial mutation. These are done using CVS and other techniques discussed in Chapter 14 (p. 300). Noninvasive testing of circulating fetal nucleic acids in maternal plasma for the diagnosis of β-thalassemia has been described (Galbiati, 2012; Leung, 2012).
Various platelet abnormalities may precede pregnancy, may develop during pregnancy coincidentally, or may be induced by pregnancy. Abnormally low platelet counts are relatively common in the pregnant woman and have various causes. These disorders may be inherited or idiopathic, acute or chronic in onset, and either primary or associated with other disorders. For example, thrombocytopenia in obstetrics is seen often with severe preeclampsia syndrome; massive hemorrhage with transfusions; consumptive coagulopathy from placental abruption, sepsis syndrome, or amnionic-fluid embolism; hemolytic anemias; systemic lupus erythematosus and antiphospholipid antibody syndrome; or hypoplastic or aplastic anemia. Other causes include viral infections, exposure to various drugs, and allergic reactions (Aster, 2007; Diz-Küçükkāya, 2010). Thrombocytopenia defined as < 150,000/μL platelets occurs in 6 to 15 percent of pregnant women, and 75 percent of these cases stem from gestational thrombocytopenia (Boehlen, 2006).
Burrows and Kelton (1993) reported that 6.6 percent of 15,471 pregnant women had a platelet count < 150,000/μL, and in 1.2 percent, it was < 100,000/μL. They reported that almost 75 percent of 1027 women whose platelet counts were < 150,000/μL were found to have normal-variant incidental thrombocytopenia. Of the remainder, 21 percent had a hypertensive disorder of pregnancy, and 4 percent had an immunological disorder. A platelet count of < 80,000/μL should trigger an evaluation for etiologies other than incidental or gestational thrombocytopenia, which is unlikely to have a platelet count of < 50,000/μL (Gernsheimer, 2013).
Normal pregnancy may be accompanied by a physiological decrease in platelet concentration (Appendix, p. 1287). This is usually evident in the third trimester and is thought to be predominantly due to hemodilution. However, the increased splenic mass characteristic of normal pregnancy may be contributory (Maymon, 2006). Most evidence shows that platelet life span is unchanged in normal pregnancy (Kenny, 2014). Thus, some degree of gestational thrombocytopenia is considered normal. Obviously, the definition used for thrombocytopenia is important. In their review, Rouse and coworkers (1998) cited an incidence of 4 to 7 percent for gestational thrombocytopenia, defined by platelet counts < 150,000/μL.
The Bernard-Soulier syndrome is characterized by lack of platelet membrane glycoprotein (GPIb/IX), which causes severe dysfunction. Maternal antibodies against fetal GPIb/IX antigen can cause alloimmune fetal thrombocytopenia. Peng and colleagues (1991) described an affected woman who during four pregnancies had episodes of postpartum hemorrhage, gastrointestinal hemorrhage, and fetal thrombocytopenia. Fujimori and associates (1999) described a similarly affected woman whose neonate died from thrombocytopenic intracranial hemorrhage. A systematic review of 30 pregnancies in 18 women reported a 33-percent rate of primary postpartum hemorrhage, and half of women with bleeding required blood transfusion. The reviewers also noted six cases of neonatal alloimmune thrombocytopenia and two perinatal deaths (Peitsidis, 2010). Close monitoring through pregnancy and 6 weeks postpartum is critical due to the possibility of life-threatening hemorrhage (Prabu, 2006).
Chatwani and coworkers (1992) reported a woman with autosomally dominant May-Hegglin anomaly whose infant was not affected. This condition is characterized by thrombocytopenia, giant platelets, and leukocyte inclusions. Urato and Repke (1998) also described such a woman who was delivered vaginally. Despite a platelet count of 16,000/μL, she did not bleed excessively. The neonate inherited the anomaly, but also had no bleeding despite a platelet count of 35,000/μL. Fayyad and colleagues (2002) managed three pregnancies in a woman with May-Hegglin anomaly. In the first, the mother had a term cesarean delivery of an unaffected infant; in the second, she had a fetal demise with multiple placental infarcts; and in the third, she received low-dose aspirin (75 mg/d) and gave birth to an unaffected infant.
Immune Thrombocytopenic Purpura
The primary form—also termed idiopathic thrombocytopenic purpura (ITP)—is usually caused by a cluster of IgG antibodies directed against one or more platelet glycoproteins (Schwartz, 2007). Antibody-coated platelets are destroyed prematurely in the reticuloendothelial system, especially the spleen. Although this is not proven, the disorder is probably mediated by autoantibodies directed at platelet-associated immunoglobulins—PAIgG, PAIgM, and PAIgA. In adults, ITP most often is a chronic disease that rarely resolves spontaneously.
Secondary forms of chronic thrombocytopenia appear in association with systemic lupus erythematosus, lymphomas, leukemias, and several systemic diseases. Approximately 2 percent of thrombocytopenic patients have positive serological tests for lupus, and in some cases there are high levels of anticardiolipin antibodies. Perhaps 10 percent of HIV-positive patients will have associated thrombocytopenia (Scaradavou, 2002).
Diagnosis and Management. Only a few adults with primary ITP recover spontaneously, and for those who do not, platelet counts usually range from 10,000 to 100,000/μL (George, 2010). There is no irrefutable evidence that pregnancy increases the risk of relapse in women with previously diagnosed ITP or worsens thrombocytopenia in women with active disease. That said, it is certainly not unusual for women who have been in clinical remission for several years to have recurrent thrombocytopenia during pregnancy. Although this may be from closer surveillance, hyperestrogenemia has also been suggested as a cause.
Therapy is considered if the platelet count is less than 30,000 to 50,000/μL (George, 2010). Primary treatment includes IVIG or corticosteroids (Neunert, 2011). Prednisone, 1 mg/kg daily, is given to suppress the phagocytic activity of the splenic monocyte-macrophage system. IVIG given in a total dose of 2 g/kg during 2 to 5 days is also usually effective.
In pregnant women with no response to corticosteroid or IVIG therapy, open or laparoscopic splenectomy may be effective. In late pregnancy, surgery is technically more difficult, and cesarean delivery may be necessary for exposure. Intravenous anti-D IgG, 50 to 75 μg/kg, has been described for treatment of resistant ITP in D-positive patients with a spleen (Konkle, 2008). There usually is improvement by 1 to 3 days, with a peak at approximately 8 days (Sieunarine, 2007). Cytotoxic agents are typically avoided in pregnancy due to teratogenicity risks. Azathioprine and rituximab, however, which are used in nonpregnant ITP, have been used for other conditions in pregnancy. Finally, the thrombopoietin agonist romiplostim has improved responses (Imbach, 2011; Kuter, 2010).
Fetal and Neonatal Effects. Platelet-associated IgG antibodies cross the placenta and may cause thrombocytopenia in the fetus-neonate. Fetal death from hemorrhage occurs occasionally (Webert, 2003). The severely thrombocytopenic fetus is at increased risk for intracranial hemorrhage with labor and delivery. This fortunately is unusual. Payne and associates (1997) reviewed studies of maternal ITP published since 1973 and added their experiences with 55 cases. Of 601 newborns, 12 percent had severe thrombocytopenia defined as a platelet count < 50,000/μL. Six infants had intracranial hemorrhage, and in three, their initial platelet count was > 50,000/μL. This is consistent with a study of 127 pregnancies in women with ITP in which 10 to 15 percent of neonates were found to have transient ITP (Koyama, 2012).
Considerable attention has been directed at identifying the fetus with potentially dangerous thrombocytopenia. All investigators have concurred that there is not a strong correlation between fetal and maternal platelet counts (George, 2009; Payne, 1997). Because of this, there have been attempts to quantify the relationships among maternal IgG free platelet antibody levels, platelet-associated antibody levels, and fetal platelet count. Again, however, there is little concurrence with these.
Investigators have also examined the association between the specific maternal cause of thrombocytopenia and risk of a thrombocytopenic fetus. Four causes investigated include gestational thrombocytopenia, hypertension-associated thrombocytopenia, ITP, and alloimmune thrombocytopenia. Burrows and Kelton (1993) reported neonatal umbilical cord platelet counts of < 50,000/μL in 19 of 15,932 consecutive newborns (0.12 percent). Of all of these pregnancies, only one of 756 mothers with gestational thrombocytopenia had an affected infant. Of 1414 hypertensive women with thrombocytopenia, five infants had thrombocytopenia. In contrast, of 46 mothers with ITP, four infants had thrombocytopenia. Finally, alloimmune thrombocytopenia was associated with profound thrombocytopenia and cord platelet counts < 20,000/μL. One of these fetuses died, and two others had intracranial hemorrhage.
Detection of Fetal Thrombocytopenia. Because there are no clinical characteristics or laboratory tests that accurately predict fetal platelet count, direct fetal blood sampling is necessary. Scott and coworkers (1983) obtained intrapartum scalp blood samples and recommended cesarean delivery for fetuses with platelet counts < 50,000/μL. Daffos and colleagues (1985) reported that percutaneous umbilical cord blood sampling (PUBS) had a high complication rate (Chap. 14, p. 300). Conversely, using PUBS, Berry and associates (1997) reported no complications but found a high negative predictive value of low platelet counts. Payne and coworkers (1997) summarized six studies in which fetal blood sampling was done for platelet estimation. Of the total of 195 fetuses, severe neonatal thrombocytopenia—defined as < 50,000/μL—was found in 7 percent. However, there were serious complications from cordocentesis in 4.6 percent. Because of the low incidence of severe neonatal thrombocytopenia and morbidity, fetal platelet determinations and cesarean delivery are not recommended for women with ITP (Neunert, 2011).
Neonatal Alloimmune Thrombocytopenia (NAIT). Disparity between maternal and fetal platelet antigens can stimulate maternal production of antiplatelet antibodies. Such platelet alloimmunization is identical to that caused by red cell antigens (Chap. 15, p. 313).
Also called thrombocythemia, thrombocytosis generally is defined as persistent platelet counts > 450,000/μL. Common causes of secondary or reactive thrombocytosis are iron deficiency, infection, inflammatory diseases, and malignant tumors (Deutsch, 2013). Platelet counts seldom exceed 800,000/μL in these secondary disorders, and prognosis depends on the underlying disease. On the other hand, primary or essential thrombocytosis accounts for most cases in which platelet counts exceed 1 million/μL. It is a clonal disorder frequently due to an acquired mutation in the JAK2 gene (Beer, 2010). Thrombocytosis usually is asymptomatic, but arterial and venous thromboses may develop (Rabinerson, 2007). These cases must be differentiated from the sticky platelet syndrome, which is also associated with thromboses (Rac, 2011). Cortelazzo and colleagues (1995) reported that myelosuppression with hydroxyurea for nonpregnant patients with essential thrombocytosis decreased thrombotic episodes from 24 to 4 percent compared with rates in untreated controls.
Normal pregnancies have been described in women whose mean platelet counts were > 1.25 million/μL (Beard, 1991; Randi, 1994). Others report more adverse outcomes. Niittyvuopio and associates (2004) described 40 pregnancies in 16 women with essential thrombocythemia. Almost half had a spontaneous abortion, fetal demise, or preeclampsia. In 63 pregnancies in 36 women cared for at the Mayo Clinic, a third had a spontaneous miscarriage, but other pregnancy complications were uncommon (Gangat, 2009). In this observational study, aspirin therapy was associated with a significantly lower abortion rate than that in untreated women—1 versus 75 percent, respectively.
Suggested treatments for thrombocytosis during pregnancy include aspirin, low-molecular-weight heparin, and interferon-α (Finazzi, 2012). Interferon-α therapy during pregnancy was successful in 11 women in the review by Delage and coworkers (1996). One of these women had transient blindness at midpregnancy when her platelet count was 2.3 million/μL. Thrombocytapheresis and interferon-α were used to maintain platelet counts at approximately 1 million/μL until delivery.
Although not a proven primary platelet disorder, there almost always is some degree of thrombocytopenia with the thrombotic microangiopathies. Their similarities to the HELLP syndrome allude to their obstetrical ramifications (George, 2013). Moschcowitz (1925) originally described thrombotic thrombocytopenic purpura (TTP) by the pentad of thrombocytopenia, fever, neurological abnormalities, renal impairment, and hemolytic anemia. Gasser and colleagues (1955) later described the similar hemolytic uremic syndrome (HUS), which had more profound renal involvement and fewer neurological aberrations. Scully and associates (2012) provided guidelines for the diagnosis and management of thrombotic microangiopathic hemolytic anemias. The syndromes have an incidence of 2 to 6 per million persons per year (Miller, 2004).
Different causes likely account for the variable findings within these syndromes. Clinically, however, they frequently are indistinguishable in adults. Most cases of TTP are thought to be caused by a plasma deficiency of or antibodies to a von Willebrand factor-cleaving protease termed ADAMTS-13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13) (Ganesan, 2011; Sadler, 2010). Conversely, HUS is usually due to endothelial damage incited by viral or bacterial infections and is seen primarily in children (Ardissino, 2013; George, 2013).
The general consensus is that intravascular platelet aggregation stimulates a cascade of events leading to end-organ failure. Although there is endothelial activation and damage, it is unclear whether this is a consequence or a cause. Elevated levels of unusually large multimers of von Willebrand factor are identified with active TTP. The ADAMTS13 gene encodes the endothelium-derived protease responsible for cleaving von Willebrand factor—vWF (Sadler, 2010). Defects in this gene result in various clinical presentations of thrombotic microangiopathy (Camilleri, 2007; Moake, 2002, 2004). In another scheme, antibodies raised against ADAMTS-13 neutralize its action to cleave vWF multimers during an acute episode. The end result is microthrombi of hyaline material consisting of platelets and small amounts of fibrin develop within arterioles and capillaries. When sufficient in number or size, these aggregates produce ischemia or infarctions in various organs.
Clinical and Laboratory Manifestations
Thrombotic microangiopathies are characterized by thrombocytopenia, fragmentation hemolysis, and variable organ dysfunction. Neurological symptoms develop in up to 50 percent and include headache, altered consciousness, convulsions, fever, or stroke. Because renal involvement is common, TTP and HUS are difficult to separate clinically. Renal failure is thought to be more severe with the HUS, and in half of the cases, dialysis is required.
Thrombocytopenia is usually severe, but fortunately, even with very low platelet counts, spontaneous severe hemorrhage is uncommon. Microangiopathic hemolysis is associated with moderate to marked anemia, and erythrocyte transfusions are frequently necessary. The blood smear is characterized by erythrocyte fragmentation with schizocytosis. Reticulocytes and nucleated red blood cells are increased, lactate dehydrogenase (LDH) levels are high, and haptoglobin concentrations are decreased. Consumptive coagulopathy, although common, is usually subtle and clinically insignificant.
The cornerstone of treatment is plasmapheresis with fresh-frozen plasma replacement. Plasma exchange removes inhibitors and replaces the ADAMTS-13 enzyme (George, 2010; Michael, 2009; Sadler, 2010). This has remarkably improved outcomes with these formerly fatal syndromes. Red cell transfusions are imperative for life-threatening anemia. If there are neurological abnormalities or rapid clinical deterioration, then plasmapheresis and plasma exchange can be performed twice daily. These are usually continued until the platelet count is > 150,000/μL. Unfortunately, relapses are common (Sadler, 2010). Additionally, there may be long-term sequelae such as renal impairment (Dashe, 1998).
As shown in the Appendix (p. 1288), ADAMTS-13 enzyme activity decreases across pregnancy by as much as 50 percent (Sánchez-Luceros, 2004). Levels are decreased even further with the preeclampsia syndrome (Chap. 40, p. 731). This is consonant with prevailing opinions that TTP is more commonly seen during pregnancy. The Parkland Hospital experiences were described by Dashe and coworkers (1998), who identified 11 pregnancies complicated by these syndromes among nearly 275,000 obstetrical patients—a frequency of 1 in 25,000.
It seems likely that the disparately higher incidence in pregnancy reported by others is because of inclusion of women with severe preeclampsia and eclampsia (Hsu, 1995; Magann, 1994). There are differences that allow appropriate diagnosis (Table 56-6). For example, moderate to severe hemolysis is a rather constant feature of thrombotic microangiopathies. This is seldom severe with the preeclampsia syndrome, even when complicated by HELLP syndrome (Chap. 40, p. 742). And, although there is deposition of hyaline microthrombi within the liver with thrombotic microangiopathy, hepatocellular necrosis with elevated serum hepatic aminotransferase levels characteristic of preeclampsia is not a common feature (Ganesan, 2011; Sadler, 2010). Importantly, whereas delivery is imperative to reverse the preeclampsia syndrome in women with the HELLP syndrome, there is no evidence that thrombotic microangiopathy is improved by delivery (Dashe, 1998; Letsky, 2000). Finally, microangiopathic syndromes are usually recurrent and unassociated with pregnancy. For example, seven of 11 women described by Dashe and colleagues (1998) had recurrent disease either when not pregnant or within the first trimester of a subsequent pregnancy. George (2009) reported recurrent TTP in only five of 36 subsequent pregnancies.
TABLE 56-6. Some Differential Factors between HELLP Syndrome and Thrombotic Microangiopathiesa
Unless the diagnosis is unequivocally one of these thrombotic microangiopathies, rather than severe preeclampsia, the response to pregnancy termination should be evaluated before resorting to plasmapheresis and exchange transfusion, massive-dose glucocorticoid therapy, or other therapy. Unfortunately, recall that determination of ADAMTS-13 enzyme activity may be difficult to interpret if not within the already lower range for normal pregnancy. With HELLP syndrome, enzyme activity levels are much lower and similar to those reported with microangiopathies (Franchini, 2007). It cannot be overemphasized that plasmapheresis is not indicated for preeclampsia-eclampsia complicated by hemolysis and thrombocytopenia.
During the past two decades, and coincidental with plasmapheresis and plasma exchange, maternal survival rates from thrombotic microangiopathy have improved dramatically (Dashe, 1998). Although previously fatal in up to half of mothers, with such treatment, Egerman and coworkers (1996) reported two maternal and three fetal deaths in 11 pregnancies. Hunt and associates (2013) reported that TTP accounted for 1 percent of maternal deaths in the United Kingdom from 2003 to 2008. Finally, a case of sudden maternal death from TTP has been described (Yamamoto, 2013).
Women who are diagnosed with thrombotic microangiopathy during pregnancy are at risk for serious long-term complications. The Parkland experiences included a mean 9-year surveillance period (Dashe, 1998). These women had multiple recurrences; renal disease requiring dialysis, transplantation, or both; severe hypertension; and transfusion-acquired infectious diseases. Two women died remote from pregnancy—one from dialysis complications and one from transfusion-acquired HIV infection. Similar observations were reported by Egerman and colleagues (1996).
There have been reports of persistent cognitive defects and physical disabilities in nonpregnant women who have recovered from thrombotic microangiopathies (Kennedy, 2009; Lewis, 2009). Interestingly, these cognitive defects are very similar to those found in long-term surveillance studies of women who had eclampsia. Aukes (2009, 2012) and Wiegman (2012) and their associates from The Netherlands have documented cognitive and visual defects years following an eclamptic episode as further discussed in Chapter 40 (p. 770).
INHERITED COAGULATION DEFECTS
Hemophilias A and B
Obstetrical hemorrhage may infrequently be the consequence of an inherited defect of a protein that controls coagulation. As examples, both types of hemophilia may be involved. These are dependent on plasma factor levels and are categorized as mild—levels of 6 to 30 percent; moderate—2 to 5 percent; or severe—less than 1 percent (Mannucci, 2001).
Hemophilia A is an X-linked recessively transmitted disease characterized by a marked deficiency of small component antihemophilic factor (factor VIII). It is rare among women compared with men, in whom the heterozygous state is responsible for the disease. Heterozygous women have diminished factor VIII levels, but almost invariably, the homozygous state is the requisite for hemophilia A. In a few instances, it appears in women spontaneously from a newly mutant gene. Pregnancy-associated acquired hemophilia A from antibodies may result in severe morbidity from bleeding (Tengborn, 2012).
Christmas disease or hemophilia B is caused by severe deficiency of factor IX and has genetic and clinical features similar to those of hemophilia A.
The obstetrical bleeding risk with these is directly related to factor VIII or factor IX levels. Affected women have a range of activity that is determined by random X-chromosome inactivation—lyonization—although activity is expected to average 50 percent (Letsky, 2000). If levels fall below 10 to 20 percent, there is a risk of hemorrhage. If levels fall to near zero, the risks are substantial. Pregnancy does afford some protection, however, because both of these clotting factors increase appreciably during normal pregnancy (Appendix, p. 1288). Treatment with desmopressin may also stimulate factor VIII release. Risks are further reduced by avoiding lacerations, minimizing episiotomy use, and maximizing postpartum uterine contractions. Operative vaginal deliveries should be avoided (Ljung, 1994).
There are few published experiences during pregnancy in women with hemophilia complications. Kadir and coworkers (1997) reported that 20 percent of carriers had postpartum hemorrhage, and in two, it was massive. Guy and associates (1992) reviewed five pregnancies in women with hemophilia B, and in all, outcomes were favorable. They recommended factor IX administration if levels are below 10 percent. Desmopressin has been shown in selected cases to reduce obstetrical bleeding complications (Trigg, 2012).
If a male fetus has hemophilia, the risk of hemorrhage increases after delivery in the neonate. This is especially true if circumcision is attempted.
If a mother has hemophilia A or B, all of her sons will have the disease, and all of her daughters will be carriers. If she is a carrier, half of her sons will inherit the disease, and half of her daughters will be carriers. Prenatal diagnosis of hemophilia is possible in some families using CVS (Chap. 14, p. 300). Preimplantation genetic diagnosis for hemophilia was reviewed by Lavery (2009).
Factor VIII or IX Inhibitors
Rarely, antibodies directed against factor VIII or IX are acquired and may lead to life-threatening hemorrhage. Patients with hemophilia A or B, because of prior treatment with factor VIII or IX, more commonly develop such antibodies. In contrast, acquisition of these antibodies in nonhemophiliacs is extraordinary. That said, this phenomenon has been identified rarely in women during the puerperium (Santoro, 2009). The prominent clinical feature is severe, protracted, repetitive hemorrhage from the reproductive tract starting a week or so after an apparently uncomplicated delivery (Reece, 1988). The activated partial thromboplastin time is markedly prolonged. Treatment has included multiple transfusions of whole blood and plasma; huge doses of cryoprecipitate; large volumes of an admixture of activated coagulation factors, including porcine factor VIII; immunosuppressive therapy; and attempts at various surgical procedures, especially curettage and hysterectomy. Another treatment involves bypassing factor VIII or IX by the use of activated forms of factors VII, IX, and X. A recombinant activated factor VII (NovoSeven) stops bleeding in up to 75 percent of patients with these inhibitors (Mannucci, 2001). As discussed in Chapter 41 (p. 817), NovoSeven has also been used in nonhemophiliac patients in cases of intractable obstetrical hemorrhage caused by uterine atony and by dilutional effects of multiple transfusions.
Von Willebrand Disease
There are at least 20 heterogeneous clinical disorders involving aberrations of factor VIII complex and platelet dysfunction—collectively termed von Willebrand disease (vWD). These abnormalities are the most commonly inherited bleeding disorders, and their prevalence is as high as 1 to 2 percent (Mannucci, 2004; Pacheco, 2010). Most von Willebrand variants are inherited as autosomal dominant traits, and types I and II are the most common. Type III, which is the most severe, is a recessive trait (Nichols, 2008).
Although far less common than inherited von Willebrand disease, acquired disorders have been described. These are stimulated by underlying conditions such as benign and malignant hematological diseases, solid tumors, autoimmune disorders, and medications such as ciprofloxacin (Shau, 2002). Although most cases of acquired vWD develop after age 50 years, some have been reported in pregnant women (Lipkind, 2005).
The von Willebrand factor is a series of large plasma multimeric glycoproteins that form part of the factor VIII complex. It is essential for normal platelet adhesion to subendothelial collagen and formation of a primary hemostatic plug at the site of blood vessel injury. It also plays a major role in stabilizing the coagulant properties of factor VIII. The procoagulant component is the antihemophilic factor or factor VIII, which is a glycoprotein synthesized by the liver. Conversely, von Willebrand precursor, which is present in platelets and plasma, is synthesized by endothelium and megakaryocytes under the control of autosomal genes on chromosome 12. The von Willebrand factor antigen (vWF:Ag) is the antigenic determinant measured by immunoassays.
Symptomatic patients usually present with bleeding suggestive of a chronic coagulation disorder. The classic autosomal dominant form usually causes symptoms in the heterozygous state. The less common but clinically more severe autosomal recessive form is manifest when inherited from both parents, who typically demonstrate little or no disease. Type I, which accounts for 75 percent of von Willebrand variants, is characterized by easy bruising; epistaxis; mucosal hemorrhage; and excessive bleeding with trauma, including surgery. Its laboratory features are usually a prolonged bleeding time, prolonged partial thromboplastin time, decreased vWF antigen levels, decreased factor VIII immunological and coagulation-promoting activity, and inability of platelets from an affected person to react to various stimuli.
During normal pregnancy, maternal levels of both factor VIII and vWF antigen increase substantively (Appendix, p. 1288). Because of this, pregnant women with vWD often develop normal levels of factor VIII coagulant activity and vWF antigen, although the bleeding time still may be prolonged. If factor VIII activity is very low or if there is bleeding, treatment is recommended. Desmopressin by infusion may transiently increase factor VIII and vWF levels, especially in patients with type I disease (Kujovich, 2005; Mannucci, 2004). With significant bleeding, 15 or 20 units of cryoprecipitate are given every 12 hours. Alternatively, factor VIII concentrates may be given that contain high-molecular-weight vWF multimers (Alfanate, Hemate-P). These concentrates are highly purified and are heat treated to destroy HIV. Lubetsky and colleagues (1999) described continuous infusion with Hemate-P in a woman during a vaginal delivery. According to Chi and coworkers (2009), conduction analgesia can be given safely if coagulation defects have normalized or if hemostatic agents are given prophylactically.
Pregnancy outcomes in women with von Willebrand disease are generally good, but postpartum hemorrhage is encountered in up to 50 percent of cases. Of 38 cases summarized by Conti and associates (1986), bleeding was reported with abortion, with delivery, or in the puerperium in a fourth. Greer and colleagues (1991) noted that eight of 14 pregnancies were complicated by postpartum hemorrhage. Kadir and coworkers (1998) reported their experiences with 84 pregnancies. They described a 20-percent incidence of immediate postpartum hemorrhage and another 20-percent incidence of late hemorrhage. Most cases were associated with low vWF levels in untreated women, and none given treatment peripartum had hemorrhage. In our experiences, levels of coagulant factors within the normal range do not always protect against such bleeding.
Although most patients with von Willebrand disease have heterozygous variants and associated minor bleeding complications, the disease can be severe. Moreover, homozygous offspring develop a serious clotting dysfunction. CVS with DNA analysis to detect the missing genes has been described. Some authorities recommend cesarean delivery to avoid trauma to a possibly affected fetus if the mother has severe disease.
Other Factor Deficiencies
In general, the activity of most procoagulant factors increases across pregnancy (Appendix, p. 1288). In addition to the hemophilias, there are other inherited deficiencies of these factors that may cause a coagulopathy.
Factor VII deficiency is a rare autosomal recessive disorder. Levels of this factor normally increase during pregnancy, but these may rise only mildly in women with factor VII deficiency (Fadel, 1989). A systematic review of 94 births found no difference in postpartum hemorrhage rates with or without prophylaxis with recombinant factor VIIa (Baumann Kreuziger, 2013).
Factor X or Stuart-Prower factor deficiency is rare and is inherited as an autosomal recessive trait. Factor X levels typically rise by 50 percent during normal pregnancy. Konje and colleagues (1994) described a woman who had 2-percent factor activity. She was given prophylactic treatment with plasma-derived factor X, which raised her plasma levels to 37 percent. Despite this, she suffered an intrapartum placental abruption. Bofill and coworkers (1996) gave intrapartum fresh-frozen plasma to a woman with less than 1-percent factor X activity. She delivered spontaneously without incident. Beksaç and associates (2010) described a woman with severe factor X deficiency who was successfully managed with prophylactic prothrombin complex concentrate. Nance and colleagues (2012) reported on 24 pregnancies, of which 18 resulted in a healthy baby. However, the authors found a 2.5-fold increased risk of preterm birth.
Factor XI—plasma thromboplastin antecedent—deficiency is inherited as an autosomal trait. It is manifest as severe disease in homozygotes but only as a minor defect in heterozygotes. It is most prevalent in Ashkenazi Jews and is rarely seen in pregnancy. Musclow and coworkers (1987) reported 41 deliveries in 17 affected women, and none required transfusion. They also described a woman who developed a spontaneous hemarthrosis at 39 weeks. Kadir and associates (1998) analyzed 29 pregnancies in 11 affected women. None of these had factor XI level increases; 15 percent had immediate postpartum hemorrhage; and another 25 percent had delayed hemorrhage. In 105 pregnancies from 33 affected women, Myers and colleagues (2007) reported an uneventful pregnancy and delivery in 70 percent. They recommended peripartum treatment with factor XI concentrate if cesarean delivery is performed and advised against epidural analgesia unless factor XI is given. From their review, Martin-Salces and associates (2010) found that there was poor correlation between factor XI levels and bleeding in women with severe deficiency.
Factor XII deficiency is another autosomal recessive disorder that rarely complicates pregnancy. An increased incidence of thromboembolism is encountered in nonpregnant patients with this deficiency. Lao and coworkers (1991) reported an affected pregnant woman in whom placental abruption developed at 26 weeks’ gestation.
Factor XIII deficiency is an autosomal recessive trait and may be associated with maternal intracranial hemorrhage (Letsky, 2000). In their review, Kadir and associates (2009) cited an increased risk of recurrent miscarriage and placental abruption. It has also been reported to cause umbilical cord bleeding (Odame, 2014). Treatment is fresh frozen plasma. Naderi and colleagues (2012) described 17 successful pregnancies in women receiving weekly prophylaxis with FXIII concentrate.
Fibrinogen abnormalities—either qualitative or quantitative—also may cause coagulation abnormalities. Autosomally inherited abnormalities usually involve the formation of a functionally defective fibrinogen—commonly referred to as dysfibrinogenemia (Edwards, 2000). Familial hypofibrinogenemia and sometimes afibrinogenemia are infrequent recessive disorders. In some cases, both are found—hypodysfibrinogenemia (Deering, 2003). Our experience suggests that hypofibrinogenemia represents a heterozygous autosomal dominant state. Typically, the thrombin-clottable protein level in these patients ranges from 80 to 110 mg/dL when nonpregnant, and this increases by 40 or 50 percent in normal pregnancy. Those pregnancy complications that give rise to acquired hypofibrinogenemia, for example, placental abruption, are more common with fibrinogen deficiency. Trehan and Fergusson (1991) and Funai and coworkers (1997) described successful outcomes in two affected women in whom fibrinogen or plasma infusions were given weekly or biweekly throughout pregnancy.
Conduction Analgesia with Bleeding Disorders
Most serious bleeding disorders would logically preclude the use of epidural or spinal analgesia for labor or delivery. If the bleeding disorder is controlled, however, conduction analgesia may be considered. Chi and colleagues (2009) reviewed intrapartum outcomes in 80 pregnancies in 63 women with an inherited bleeding disorder. These included those with factor XI deficiency, hemophilia carrier status, von Willebrand disease, platelet disorders, or a deficiency of factor VII, XI, or X. Regional block was used in 41. Of these, 35 had spontaneously normalized hemostatic dysfunction, and others were given prophylactic replacement therapy. The reviewers encountered no unusual complications and concluded that such practices were safe. Singh and associates (2009) reviewed 13 women with factor XI deficiency. Nine received neuraxial analgesia without complications, but only after fresh-frozen plasma was given to most to correct the activated partial thromboplastin time.
Several important regulatory proteins inhibit clotting. There are physiological antithrombotic proteins that act as inhibitors at strategic sites in the coagulation cascade to maintain blood fluidity. Inherited deficiencies of these inhibitory proteins are caused by gene mutations. Because they may be associated with recurrent thromboembolism, they are collectively referred to as thrombophilias. Because these deficiencies may be associated with thromboembolism, they are discussed in Chapter 52 (p. 1029), and they have been recently reviewed by the American College of Obstetricians and Gynecologists (2013d).
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