Hematological Disorders of Pregnancy

Mae-Lan Winchester

Carl P. Weiner

Introduction

Multiple physiologic adaptations occur to help women cope with the added demands of pregnancy. Blood volume increases by up to 50% during pregnancy (approximately 1250 mL) while the red blood cell (RBC) mass expands some 25%. This discordance results in a physiologic hemodilution, with decreased hemoglobin (Hb) and hematocrit (HCT) levels. The rise in blood volume begins as early as 7 weeks’ gestation and peaks at 30 to 34 weeks.¹ There is increased renal secretion of erythropoietin which stimulates RBC production. Maternal iron requirements also increase due to a combination of elevated erythropoiesis and fetal demand. Because of these rapid changes, pregnancy increases a woman’s risk of developing any number of hematologic disorders. This chapter summarizes the most commonly encountered conditions: anemia, coagulation disorders, thrombocytopenia and other platelet disorders, inherited bleeding disorders, disseminated intravascular coagulation (DIC), and thrombophilias in pregnancy.

Anemia

Etiology

The Centers for Disease Control and Prevention (CDC) defines anemia as an Hb or HCT < 5th percentile for a healthy reference population.² The specific values of Hb and HCT change during pregnancy, with cutoffs of Hb 11 g/dL and HCT 33% in the first trimester, 10.5 g/dL and 32% in the second trimester, and 11 g/dL and 33% in the third trimester considered normal. Anemia is considered moderate when the Hb is <10 g/dL and severe when it is <7 g/dL at any point during pregnancy.³

Anemia is traditionally classified by etiology (impaired production, increased destruction) and/or by morphology (using the mean corpuscular volume [MCV]). For the purposes of the discussion in this chapter, we will describe anemic conditions using the morphological classification system, as a complete blood count is routinely obtained in most countries at the first prenatal visit and includes the MCV.

Incidence and Risk Factors

Data from the National Health and Nutrition Examination Surveys (NHANES) reveal that 5.6% of the United States population meets the criteria for anemia.⁴ When the sample is confined to pregnancy, the incidence of anemia is 8.8%. African American women have the highest proportion of anemia, with 24.2% affected. Other risk factors for anemia in pregnancy include younger age, iron-poor diet, short-interval pregnancy, and heavy menses. Anemia due to iron deficiency in pregnancy accounts for at least 85% of all cases.⁵

Effects of Anemia on Pregnancy

The impact of anemia on the pregnancy depends upon the severity and cause of the condition. Although many studies have been inconclusive, a systematic review and meta-analysis by Scholl et al,⁶ showed a significant association between prenatal anemia and increased rates of low birth weight and preterm birth, compared to no anemia or anemias due to other causes.⁶ However, there is no clear evidence, at least from studies in developed countries, that treatment of anemia alters these complication rates. Increasing severity of maternal anemia in animal studies has been associated with neurodevelopmental delay outcomes in offspring.⁷^,⁸ In humans, maternal iron deficiency has been noted to correlate with a smaller hippocampus and decreased volume of brain-derived neurotrophic factor in the neonate.⁹ Longitudinal studies, however, are lacking. There is no significant association
of mild or even moderate maternal anemia with perinatal mortality. However, severe maternal anemia, as defined in one study as a hemoglobin < 6 mg/dL, has been correlated with redistribution of fetal cardiac output and a reduction in amniotic fluid.¹⁰ Associations between severe maternal anemia and small for gestational age infants have also been described.¹¹

Clinical Assessment of Anemia in Pregnancy

All pregnant women should be screened for anemia at the first prenatal visit according to CDC and American College of Obstetricians and Gynecologists (ACOG) guidelines.¹²

An immediate and comprehensive laboratory investigation into the cause of anemia is not cost-effective, given that the vast majority of pregnant women will have iron deficiency anemia. If a woman has mild anemia, a trial of iron replacement therapy should be initiated if it is not already included in her prenatal vitamin. A repeat complete blood count should be obtained 4 to 6 weeks later to look for improvement.

In cases when moderate or severe anemia is suspected on routine compete blood count, a comprehensive laboratory evaluation may reveal a diagnosis with implications for the mother, fetus, and future children. This evaluation begins with a complete medical history and physical examination. Potentially important questions to be addressed include onset and duration of symptoms (such as fatigue, shortness of breath, palpitations), medical history, family history, diet, occupational exposures, transfusion history, and drug history. Physical signs, such as fever, bruising, jaundice, hepatomegaly, and splenomegaly, will also direct the clinician to consider more serious causes of anemia.

The laboratory evaluation begins with testing for iron deficiency, which entails measuring serum ferritin, total iron-binding capacity (TIBC), and/or plasma iron levels. Measuring transferrin, the major iron transport protein, is rarely useful for the evaluation of anemia because transferrin levels fluctuate daily.¹³ Ferritin and plasma iron are both reduced in anemia due to iron deficiency, whereas TIBC may be elevated. However, TIBC and plasma iron are less helpful tests, and in practice, measuring serum ferritin is all that is necessary. Importantly, iron supplementation should be withheld for 24 to 48 hours before testing.

Further testing may be necessary based on findings in the maternal history, from laboratory tests that suggest another condition, or if testing for iron deficiency is negative. For example, hemoglobin electrophoresis provides the identity and concentrations of the different types of hemoglobin present and is useful for the differential diagnosis of thalassemia. If a reticulocyte count, a measurement of RBC production, is elevated, this suggests RBC loss via blood loss (acute or chronic) or hemolysis; a low reticulocyte count may reveal anemia secondary to decreased RBC production.

Measuring the MCV helps narrow the potential etiology. In general, the MCV is lower in patients with hemoglobinopathies than in those with iron deficiency anemia. It is important to note that microcytosis is a late finding in iron deficiency anemia. The Mentzer Index (MCV/RBC count [M/µL]) is a quick calculation helpful in differentiating iron deficiency anemia from thalassemia. Iron deficiency is more likely if the Mentzer Index is greater than 13.

Other laboratory studies that may be useful in specific settings include measuring haptoglobin or performing a peripheral blood smear. Haptoglobin is a glycoprotein that binds free serum hemoglobin, and its concentration declines when bound to hemoglobin and cleared by the liver. Schistocytes on a peripheral smear can suggest hemolysis, whereas abnormal RBC shapes point to a hereditary disorder of RBC morphology (such as sickle cell anemia or hereditary spherocytosis) (ie, sickle cell anemia).

Microcytic Anemias

Microcytosis is defined by an MCV < 80 fL. Causes of microcytic anemia include iron deficiency, anemia of chronic inflammation, thalassemias, and sideroblastic anemia.

Iron Deficiency

Iron deficiency is the most common cause of anemia during pregnancy and is the diagnosis when the ferritin is low and the MCV mildly decreased (usually 70-80 fL). Iron requirements increase throughout pregnancy, and most menstruating women have low iron stores. Current CDC guidelines recommend 30 mg of elemental iron daily during pregnancy for women who do not begin pregnancy with anemia.¹⁴ Most over-the-counter and prescription prenatal vitamins contain 27 to 29 mg elemental iron (Table 38.1).

Table 38.1 Amount of Iron in the Various Oral Iron Supplements

	Dose	Average Amount of Elemental Iron Per Tablet
Ferrous sulfate	325 mg orally, two to three times a day	65 mg
Ferrous gluconate	300 mg orally, two to three times a day	36 mg

The effects of iron deficiency (or its supplementation) on pregnancy outcomes are unclear. Iron supplementation of deficient women clearly raises both their hemoglobin and iron stores, but may not change perinatal outcomes especially for women in medium- to high-resource countries.¹⁵ Although several studies suggest an increase in low birth weight and preterm birth when the mother is iron deficient,⁶^,¹⁶ it is not clear whether there is a cause and effect relationship. Fetal iron stores are typically not affected by maternal iron deficiency anemia.¹⁷^,¹⁸

Although elemental iron is best absorbed on an empty stomach, it may trigger maternal nausea and vomiting. Many practitioners recommend taking iron or iron-containing supplements during or after meals, assuming that any decrease in absorption is offset by the excessive dose given. Constipation is common. Many over-the-counter formulations seek to minimize constipation by including stool softeners.

Intravenous (IV) iron therapy may help women who either fail to respond adequately or cannot tolerate oral therapy. Although unstudied in the first trimester, IV iron is safe and effective during the second and third trimesters. In one systematic review of six randomized controlled trials, Shi and colleagues concluded that intravenous iron was more effective and better tolerated than oral iron therapy in pregnant women who either cannot tolerate oral therapy or who required rapid correction.¹⁹

One example of an IV iron protocol (iron dextran) is listed in Table 38.2. The major risk associated with iron dextran is anaphylaxis, estimated to occur at a rate of 68 per 100,000 persons following the first exposure. The risk drops to 24 per 100,000 for all nondextran IV iron products (iron sucrose, gluconate, and ferumoxytol).²⁰ A firm diagnosis of severe iron deficiency should be made before administering IV iron because of this risk.

Table 38.2 Iron Dextran Protocol.

Indications: Treatment of iron deficiency anemia in patients unable to absorb oral iron
Contraindications/precautions:
Hypersensitivity to iron dextran complex
Use caution in patients with asthma, hepatic impairment, and rheumatoid arthritis
Dosing recommendations:
Test dose:
	Administer 0.5 mL IV/IM prior to starting therapy
	For the IV dose, dilute 25 mg/0.5 mL in 50 mL of NSS and infuse over 15 min
	Have epinephrine at the bedside. Watch patient for 30 min after test dose for anaphylactic reactions
Dose (mL):
	0.0476 × weight (kg) × (14.8-observed Hgb) + (1 mL/5 kg to maximum of 14 mL for iron stores)
	Maximum IVIV dose = 3000 mg (60 mL)
	Dilute total dose in 250-1000 mL of NSS. Usual volume 500 mL
	Maximum concentration = 50 mg/mL
	Infuse over 1-6 h (no faster than 50 mg/min). Common infusion time over 2-3 h. Watch patient closely during first 25 mL for allergic reactions
	Do not add iron dextran to TPN
Adverse effects:
	CV	flushing, hypotension, cardiovascular collapse (<1%)
	CNS	dizziness, fever, headache (>10%), chills (<1%)
	DERM	urticaria, phlebitis (<1%), staining of skin at IM site
	GI	nausea, vomiting, metallic taste, discoloration of urine (1%-10%)
	RESP	diaphoresis (>10%)
Note: Diaphoresis, urticaria, fever, chills, and dizziness may be delayed 24-48 h after IV administration and 3-4 d after IM administration. Anaphylactic reactions occur generally in the first few minutes after administration
Pregnancy category: C
Monitoring: Check blood pressure every 5 min during the test dose. Watch for allergic reactions and side effects for 3-4 d. Monitor Hgb and reticulocyte count
CNS, central nervous system; CV, cardiovascular; DERM, dermatologic; GI, gastrointestinal; Hgb, hemoglobin; IM, intramuscularly; IVIV intravenously; NSS, normal saline solution; RESP, respiratory; TPN, total parenteral nutrition.

Megaloblastic Anemia

Megaloblastic anemia reflects impaired DNA synthesis secondary to a cofactor deficiency, usually either folic acid or vitamin B12. The diagnosis of megaloblastic anemia is suggested when the MCV is greater than 100. Microscopically, there is hypersegmentation of the polymorphonuclear leukocytes. The diagnosis is confirmed by serum testing. Folate supplementation with 2 to 4 mg daily should correct a folate deficiency. However, B12 deficiency requires parenteral therapy for 6 weeks or until the deficiency has corrected. A prolonged period of vitamin B12 deficiency can lead to neuropathy and pernicious anemia. Isolated deficiency of either folic acid or B12 is rare: an extreme diet or malabsorption are potential etiologies.

Thalassemias

Adult hemoglobin consists of two α-chains and two β-chains (Hgb A), while fetal hemoglobin consists of two α-chains and two γ-chains (Hgb F). Mutations, whether they cause decreased hemoglobin synthesis (eg, the thalassemias) or altered hemoglobin structure (structural hemoglobinopathies), can cause a wide range of problems. Hundreds of hemoglobin variants are recognized. A description of hemoglobin nomenclature and the various hemoglobinopathies can be found in Table 38.3.

The thalassemias are a group of disorders caused by an imbalance in the ratio of α- and β-hemoglobin chains. They are classified by the abnormal chain, and the specific diagnosis is made using DNA probes.

α-Thalassemias

The α-chain is encoded by four gene copies with two copies on each chromosome 16 (αα/αα). The severity of α-thalassemia depends on the number of gene copies that are deleted or defective. There is no clinical impact if one gene is missing. A mild microcytic anemia results if two genes are lost (α-thalassemia minor). A three-gene deletion results in a β-globulin tetramer called hemoglobin H (Hgb H) and is called hemoglobin H disease. Hemoglobin H disease is compatible with life but is associated with profound hemolytic anemia. The loss of all four α-globin genes results in hemoglobin Bart disease. Affected fetuses cannot synthesize either fetal or adult hemoglobin, resulting in heart failure and hydrops fetalis. Bart disease was previously thought to be incompatible with life, with most fetal deaths occurring in the late-second through mid-third trimester. However, neonatal survival is documented with intrauterine transfusion, followed by serial transfusion and iron chelation therapy as a bridge to bone marrow transplantation.²¹

In Africans, α-thalassemia minor usually results from the loss of one gene from each chromosome (α−/α−). In Asians, two gene deletions are more likely to occur on one chromosome (αα/—). In Southeast Asia, where hemoglobin Bart disease is the most common cause of fetal hydrops, there were only nine living survivors as of 2018.²² Nearly half of survivors had various degrees of transient or permanent neurodevelopmental impairment. Affected infants frequently have congenital malformations, the most common of which are genitourinary or musculoskeletal. Mothers of affected infants are at risk for several obstetrical complications, especially severe, early-onset preeclampsia (mirror syndrome).

β-Thalassemias

The β-thalassemias result from an underproduction of the β-globulin chains. Although less common than α-thalassemia, abnormalities of the β-globulin chain are transmitted in an autosomal-dominant fashion.²³ β-thalassemias occur in many parts of the world including the Mediterranean, Africa, southern China, the Malay Peninsula, and Indonesia. Over 150 mutations affecting the promoter region of the β-globulin gene have been identified.²⁴

The severity of the β-thalassemias is determined by the quantity of β-globulin produced. β⁺ indicates that some β-chains are being produced, whereas β⁰ means no chains are being produced. Homozygote patients for a defective β-thalassemia gene (thalassemia major or Cooley anemia) have markedly ineffective erythropoiesis and severe hemolysis. The disease first manifests postnatally, as the fetus produces hemoglobin F, which does not use the β-globulin chain. Postnatally, the hemoglobin type switches from hemoglobin F to adult type and β-thalassemia appears.

Couples who are heterozygotic for β-thalassemia require prenatal counseling, and antenatal diagnosis should be offered. Screening programs are effective in areas where β-thalassemia is prevalent. Although the β-thalassemia heterozygosity on its own does not increase the rate of adverse maternal outcomes, a combination of
β-thalassemia heterozygosity with another abnormal hemoglobin variant can cause hemolytic and sickling anemias associated with higher rates of maternal and fetal morbidities.

Table 38.3 Hemoglobin Nomenclature

Normal hemoglobin (Hgb)

Hgb A(A/A): Normal adult hemoglobin. Composed of two α-chains and two β-chains.

Hgb A2 (note: not the same as A/A): A less common, but normal form of adult hemoglobin. Composed of two α-chains and two δ-chains. Will be increased, typically >3.5% in β-thalassemia.

Hgb F: Normal fetal hemoglobin. May be elevated in patients with β-thalassemias. Has a different oxygen dissociation curve than Hgb A.

Hemoglobinopathies

Hgb SA: Sickle cell trait. Defect in the β-chain. Little maternal clinical significance other than an increased risk of urinary tract infections. Obvious genetic implications.

Hgb SS: Sickle cell anemia. Characterized by painful crises. Both maternal and fetal implications for poor outcome. Genetic implications.

Hgb CA: Hemoglobin C trait. Defect in the β-chain on one chromosome. No maternal clinical significance, mild microcytic anemia. Genetic implications for fetus if parent has child with partner with SA or SS or β-thalassemia.

Hgb CC: Hemoglobin C disease. Homozygous for Hgb C. No maternal clinical significance. More microcytic anemia compared with Hgb CA. Genetic implications for fetus if parent has child with partner with SA or SS or β-thalassemia.

Hgb SC: Hemoglobin SC disease. Milder form of sickle cell anemia, less crises when nonpregnant. Debatable whether maternal and fetal outcomes are worse, the same, or better than Hgb SS. Spleen is more functional, and hemolytic crises may be made worse because of acute splenic sequestration.

Hgb EA: Hemoglobin E trait. Defect in the β-globulin chain. Like Hgb C, no maternal clinical significance, mild microcytic anemia. Genetic implications for fetus if parent has child with partner with SA or SS or β-thalassemia. Found primarily in South-east Asians.

Hgb EE: Hemoglobin E disease. No maternal clinical significance. More microcytic anemia compared with Hgb EA. Genetic implications for fetus if parent has child with partner with SA or SS or β-thalassemia.

Thalassemia disorders

α-Thalassemia minor: Deletion of one or two α-globulin genes. No maternal clinical significance, mild microcytic anemia. Genetic implications for fetus if parent has child with partner also with α-thalassemia minor.

Hgb H: Hemoglobin H. Composed of four β-globulin chains because of little α-chain. Hgb H disease patients have a three-gene deletion, and will have a mixture of Hgb H, Hgb A, and Hgb Bart. Severe hemolytic anemia, compatible with extrauterine life. Note that Hgb H disease is separate from Hgb H.

Hgb Bart: Hemoglobin Bart. Composed of four γ-globulin chains. Hgb Bart disease patients have no α-chain production at all because of a four-gene deletion. Not compatible with extrauterine life. No α-chain production at all.

β-Thalassemia: Decreased production of β-globulin usually because of a defect in the promoter region of the β-globulin gene. β⁰ means that no β-chain is produced. β⁺ means that little chain is produced. There are hundreds of mutations, and there is a spectrum of clinical findings and severity.

β-Thalassemia major or Cooley anemia: No fetal significance because Hgb F produced; however, after birth, neonates will fail to thrive and become anemic. Little maternal significance because females do not get pregnant often because of the severity of disease.

β-Thalassemia minor: Heterozygote for β-thalassemia gene. Diagnosed because of elevated Hgb A2 levels (>3.5%). Hgb A2 has no β-chains.

β-Thalassemia intermedia: Applied to patients in between minor and major thalassemia in terms of clinical significance and severity.

Combined abnormalities

Because the defects in hemoglobinopathies can combine with thalassemias, especially with β-thalassemias, a combined abnormality will be found on occasion, which may cause a hemolytic anemia (such as Hgb C/β-thalassemia or Hgb E/β-thalassemia). If β-thalassemia combines with Hgb S, a sickling hemoglobinopathy will result.

Sickle Cell Disease

Sickle cell disease (SCD) is caused by an abnormal β-globulin resulting from a point mutation replacement of glutamic acid with valine at the
sixth position (hemoglobin S). In times of stress (eg, hypoxemia or infection), the abnormal β-globulin chain undergoes a conformational change causing sickling of the RBCs. The sickled RBCs have reduced deformability, causing microvascular occlusion, hemolysis, and increased susceptibility to infection.

A patient homozygous for hemoglobin S (hemoglobin SS) has sickle cell anemia. Heterozygous individuals (hemoglobin SA) have sickle cell trait. Other sickling hemoglobinopathies of importance during pregnancy include hemoglobin SCD and hemoglobin S/β-thalassemia. Patients with hemoglobin SCD are double heterozygotes. Hemoglobin C is a β-globulin chain that does not confer as much protection from sickling during pregnancy as does hemoglobin A. Hemoglobin S/β-thalassemia is a “mild” form of sickle cell anemia that is managed similarly to hemoglobin SCD.

Sickle cell crises characterized by splenic infarction and vaso-occlusive disease occur especially in the third trimester with hemoglobin SCD and are uncommon outside of pregnancy. As their spleens function normally, patients with hemoglobin SCD can experience a more rapid and severe anemia than expected with hemoglobin SS because of acute splenic sequestration. The management of SC crisis remains similar to the patient with SS crisis. Individuals with sickle cell trait are not at risk for splenic sequestration crises, nor are they at risk of excess obstetric complications except for urinary tract infections.²⁴

Pregnancy in women with one of the three sickling disorders exposes the mother and fetus to increased complications due to vaso-occlusive disease, such as intrauterine growth restriction (IUGR), preterm labor, preeclampsia, and perinatal and maternal mortality.²⁵^,²⁶^,²⁷^,²⁸ Mortality among women with SCD is due to complications of the preexisting disease rather than obstetrical issues.²⁹

The hallmark of SCD is sickle cell crisis during which the main complaint is severe pain in the back, chest, abdomen, and long bones. Pain crises are more frequent in the third trimester. The treatment of sickle cell crisis has changed very little over the past decade and consists of hydration, oxygenation, and pain relief. Pulmonary and urinary infections are common triggers and must be diagnosed and treated aggressively. Regular antepartum fetal testing for fetal well-being and growth is strongly recommended.

Symptomatic patients may benefit from transfusion therapy. General indications for transfusion are hemoglobin < 5 g/dL, a hemoglobin drop of 30% or more, acute chest syndrome (ACS), and hypoxemia. The goal of therapy is to keep the hemoglobin S concentration below 40% of the total hemoglobin. For acute disease, attaining an Hb of 10 g/dL is desired.³⁰

Transfusion therapy for acute disease is uncontroversial, and must be differentiated from prophylaxis, which is controversial. The goal of prophylactic transfusion therapy is to maintain the hematocrit above 25% and the hemoglobin S concentration below 60%. A meta-analysis of 12 studies involving 1291 patients found that prophylactic transfusion was associated with a reduction in maternal mortality, vaso-occlusive pain episodes, pulmonary complications, preterm birth, perinatal mortality, and neonatal death.³¹ However, prophylactic partial exchange and exchange transfusion are associated with a 5.3% and 16.6% rates of new alloimmunization, respectively.³²

There are two complications of SCD that may be misdiagnosed during pregnancy. First, patients with SCD have a higher likelihood of a seizure disorder. Neurologic events secondary to SCD must be separated from pregnancy-associated events such as eclampsia. SCD associated neurologic events may be due to thrombosis, hemorrhage, hypoxia, or meperidine use. Imaging studies and other clinical findings may help to differentiate neurologic events from complications of SCD and pregnancy.

The second SCD complication commonly misdiagnosed during pregnancy is ACS. ACS is the leading cause of death in SCD patients and the second most common cause of hospitalization.³³ Some 7% to 20% of pregnant patients with SCD develop ACS during pregnancy.²⁹ The presentation resembles pneumonia, consisting of fever, cough, chest pain, pulmonary infiltrates, hypoxemia, and leukocytosis. Differentiation between the two diseases may be impossible. Pneumonia is a potential cause of ACS and is diagnosed concomitantly in 20% of ACS patients. The exact role of infection, thrombosis, or embolism in the development of ACS remains unclear. Exchange transfusion and antibiotic therapy are recommended should a patient with SCD present with severe respiratory symptoms; consultation with a pulmonologist and/or a hematologist would be wise. General anesthesia increases the risk of ACS and, as such, should be avoided during delivery when possible.³⁴

At-risk women should be offered counseling and screening for sickle cell trait (via hemoglobin electrophoresis). If a woman is found to have sickle cell trait, her partner should be offered testing to determine whether the fetus is at risk of SCD. Prenatal diagnosis can be accomplished by amniocentesis or by chorionic villus sampling (CVS). Many locales of high prevalence have effective postnatal screening programs in place.

Hemoglobin C and E

Hemoglobin C and E are both variants that cause microcytic anemia. Hemoglobin C is common in Africans, whereas hemoglobin E is more prevalent in Southeast Asia. Patients may either have a trait form (hemoglobin CA and hemoglobin EA) or a “disease” form (hemoglobin CC and hemoglobin EE). However, this form of microcytic anemia is mild even in homozygous states and is of little clinical significance. No additional maternal treatment or fetal testing is required. However, pregnant women are at higher risk for morbidity if they have compound heterozygosity. Hemoglobin E/β-thalassemia and hemoglobin SE are each reported to cause a hemolytic anemia.³⁵

Normocytic Anemias

Normocytic anemia is diagnosed by an MCV between 80 and 100 fL and describes a group of structural, immunologic, and enzymopathic hemolytic anemias which can be exacerbated by pregnancy.

Structural hemolytic anemias include hereditary spherocytosis (HS), hereditary elliptocytosis (HE), hereditary pyropoikilocytosis (HPP), Southeast Asian ovalocytosis (SAO), hereditary and acquired acanthocytosis, and hereditary and acquired stomatocytosis. These diseases are distinguished by the morphology of the erythrocyte and result from defective erythrocyte membrane skeleton proteins that deform the erythrocytes such that they are selectively sequestered and destroyed in the spleen.

Over 50 mutations affecting various membrane proteins, such as spectrin and ankyrin, have been identified. They may be inherited in an autosomal-dominant or recessive manner. Anemia can present at any age with varying degrees of severity, ranging from hydrops fetalis to disease in the latter half of adult life. The symptomatology is varied and, in milder cases, may not be identified until pregnancy. The diagnosis should be considered when unexplained splenomegaly, anemia, hemolysis, and unconjugated bilirubinemia present during pregnancy.

The osmotic fragility test is the classic method of diagnosis. However, a normal test does not rule-out the possibility of a membrane defect as 10% to 20% have a falsely normal test.³⁶ Additionally, the test is time-consuming, labor intensive, and expensive. Newer tests employing flow cytometry have replaced osmotic fragility testing. Splenectomy is the treatment of choice for the more severe forms of structural hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is caused by the production of antierythrocyte autoantibodies. Three forms of AIHA have been described: IgM-mediated (cold-reactive) AIHA; IgG-mediated (warm-reactive) AIHA; and IgG Donath-Landsteiner antibody-mediated (paroxysmal cold-reactive). AIHA may occur as the primary disease, a secondary disease (often associated with an existing hematological malignancy), or following the administration of various drugs. Penicillin, cephalosporins, and methyldopa are implicated as causes of hemolytic episodes.³⁷^,³⁸ Infection is another known trigger, but often no trigger is found. The prevalence of autoantibody production against RBCs increases during pregnancy compared to age-matched, nonpregnant subjects.³⁹ As a result, hemolytic episodes may worsen during pregnancy and then improve after delivery. The diagnosis of AIHA is made after documentation of a hemolytic anemia associated with a positive direct Coomb test. The treatment includes corticosteroid and IV immunoglobulin (IVIG) administration. RBC transfusion should be performed if indicated, although the autoantibodies often make crossmatching difficult.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency causes hemolytic anemia when the erythrocyte is exposed to oxidative stress, as G6PD aids the synthesis of reduced glutathione (GSH), which protects the erythrocyte from oxidative damage. G6PD is often associated with certain drugs, such as nitrofurantoin and trimethoprim-sulfa, commonly used to treat urinary tract infections. The inheritance of G6PD mutations is X-linked recessive. Up to 20% of African American women are heterozygous and 1% are homozygous.⁴⁰ Although rare, hemolytic episodes have been reported through “vertical” transmission.⁴¹ Thus, pregnant and nursing women should avoid taking certain drugs where possible in case their fetus/neonate is
either an affected male or a homozygous female. The primary treatment during a hemolytic episode is discontinuation of the offending drugs and transfusion if necessary.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder in which the abnormal erythrocytes undergo intravascular complement-mediated hemolysis. The abnormal stem cells also produce abnormal leukocytes and platelets. The degree of hemolysis reflects the size of the abnormal clone, the degree of erythrocyte abnormality, and the amount of complement fixation. These patients are at increased risk for thrombotic events and for bone marrow failure. Prophylactic heparin should be considered beginning in the first trimester. One report described a 5-year mortality rate of 35% in patients with PNH, primarily due to Budd-Chiari syndrome (thrombosis of the mesenteric vessels) or other thrombosis.⁴² The diagnosis is made after a positive Ham test which demonstrates RBC vulnerability to complement. Referral to a hematologist is appropriate.

Macrocytic Anemias

Macrocytic anemia may be secondary to folate and/or vitamin B12 deficiency, or drugs that interfere with DNA synthesis. Blood levels of these nutrients should be obtained in cases of macrocytic anemia, as determined by MCV > 100 fL.

Folate deficiency was once one of the most common causes of macrocytic anemia during pregnancy. Although folate fortification of foods and supplementation has drastically decreased the incidence of folate deficiency in the United States, some 1% to 4% of pregnancies are still affected.⁴³ Risk factors include low socioeconomic status, short-interval pregnancy, and malabsorptive conditions (ie, inflammatory bowel disease). As pregnancy progresses, fetal need for folate increases and may worsen a preexisting deficiency. The diagnosis of folate deficiency is confirmed by low RBC folate levels (under 2-4 ng/mL). Treatment is with oral folic acid (1-5 mg daily) and may take months before there is laboratory evidence of improvement.

B12 deficiency is much less common than folate deficiency, but certain conditions confer an increased risk. These include a vegetarian or vegan diet, gastric/bariatric surgery, other malabsorptive disorders (B12 is predominantly absorbed in the terminal ileum), and certain autoimmune conditions. The prevalence of vitamin B12 deficiency is 11% and of folate deficiency is 12% in patients with prior bariatric or gastric surgery.⁴⁴ Women who report such a history should be tested for nutrient deficiencies at the beginning of pregnancy. Supplementation, typically in the form of a weekly intramuscular injection is necessary should a diagnosis be made.

Coagulation Disorders in Pregnancy

Pregnancy Changes in Coagulation Factors

Coagulation is a complex process requiring a delicate balance between prothrombotic factors and thrombolytic factors. Pregnancy tips the balance between thrombotic and thrombolytic factors toward a hypercoagulable state. The concentrations of both thrombotic and thrombolytic factors change during pregnancy, and most changes are estrogen dependent (Table 38.4).

Table 38.4 Relative Changes in Coagulation Factors During Pregnancy

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