Chapter 42Anemia and Pregnancy Sarah J. Kilpatrick, MD, PhDAnemia is deﬁned as a hemoglobin (Hb) value less than the lower limit tion of anemia provides an exhaustive catalog of diagnoses, it does notof normal that is not explained by the state of hydration. This deﬁni- lend itself to a systematic investigation of an individual patient. Rather,tion has physiologic validity, in that it is the amount of Hb per unit when the patient is anemic one wants to know (1) the morphology ofvolume of blood that determines the oxygen-carrying capacity of the anemia and (2) the reticulocyte count. Determining the answersblood. The normal Hb level for the adult female is 14.0 ± 2.0 g/dL.1 to these questions allows one to make a ﬁrst approximation of a spe-Based on this normal value, 20% to 60% of prenatal patients will be ciﬁc diagnosis and to answer the following questions:found to be anemic at some time during their pregnancy. In one study,32% of women presenting at less than 7 weeks’ gestation had an Hb 1. What is the mechanism of the anemia?value lower than 12 g/dL, suggesting that the prevalence of anemia is 2. Is there an underlying disease?high.2 Because of the normal hemodilution that occurs during preg- 3. What is appropriate treatment?nancy, the Centers for Disease Control and Prevention deﬁnes anemiain pregnancy as an Hb concentration lower than 11 g/dL in the ﬁrst The CBC and the reticulocyte count provide the answers to theand third trimesters, or lower than 10.5 g/dL in the second trimester.3 ﬁrst two questions. These data allow a morphologic classiﬁcation ofSome women with mild anemia will be missed using this deﬁnition. the anemia and indicate whether the marrow is hyperproliferative or hypoproliferative. The patient’s Hb value is determined by converting the pigment to cyanmethemoglobin and quantitating the amountClinical Presentation spectrophotometrically. The remainder of the values are obtained by ﬂow cytometry with an electronic cell counter.Symptoms caused by anemia are those resulting from tissue hypoxia, Based on the size of the red blood cells (RBCs), anemia can bethe cardiovascular system’s attempts to compensate for the anemia, or classiﬁed as microcytic, normocytic, or macrocytic. The appearance ofan underlying disease. Tissue hypoxia produces fatigue, lightheaded- the RBCs may also provide a clue to the mechanism of the anemia. Forness, weakness, and exertional dyspnea. Cardiovascular compensation example, hypochromic microcytic cells associated with a low reticulo-leads to a hyperdynamic circulation, with attendant symptoms of pal- cyte count suggests iron deﬁciency, thalassemia trait, sideroblasticpitations and tachycardia. Clinical conditions commonly associated anemia, or lead poisoning. Oval macrocytes combined with a lowwith anemia in pregnancy include multiple pregnancy, trophoblastic reticulocyte count and hypersegmented polymorphonuclear leuko-disease, chronic renal disease, chronic liver disease, and chronic infec- cytes suggest megaloblastic anemia (vitamin B12 or folate deﬁciency).tion. In obstetric patients, however, anemia is most commonly discov- Oval microcytes and an elevated reticulocyte count are characteristicered not because of symptoms but because a complete blood count of hereditary spherocytosis. Various poikilocytes, such as sickle cells,(CBC) is obtained as part of routine laboratory evaluation, either at acanthocytes, target cells, and schistocytes, suggest sickle cell disease,the initial prenatal visit or at repeat screening at 24 to 28 weeks’ acanthocytosis, Hb C disease, and mechanical RBC destruction,gestation. respectively. Although the CBC is an excellent ﬁrst step in the approxi- mate diagnosis of anemia, additional studies are usually necessary to conﬁrm the diagnosis. Table 42-2 lists laboratory studies frequentlyEvaluation of Anemia used in the evaluation of an anemic patient. Serum Hb and serum haptoglobin levels are useful in deﬁningAnemia is not a diagnosis; rather, like fever or edema, it is a sign. The intravascular hemolysis. If serum haptoglobin is absent or low in con-key issue in the evaluation of anemia is to deﬁne the underlying mech- junction with an elevated serum Hb, the presence of intravascularanism or pathologic process. Although a mild anemia caused by iron hemolysis is established. Further studies are necessary to rule in ordeﬁciency during pregnancy is of little consequence to either the rule out speciﬁc causes of intravascular hemolysis, such as severemother or the fetus, a similarly mild anemia caused by carcinoma of autoimmune hemolytic anemia (direct Coombs test), paroxysmalthe colon has grave implications. One must also keep in mind the nocturnal hemoglobinuria (PNH) (osmotic fragility), and hemoglo-genetic implications of many anemias, such as the hemoglobinopathies binopathies including sickle cell disease and thalassemia major (Hband hereditary spherocytosis. electrophoresis). Table 42-1 presents a classiﬁcation of anemia based on the patho- Total bilirubin is elevated modestly in hemolytic anemia (rarely inphysiologic mechanism involved. Although a mechanistic classiﬁca- excess of 4 mg/dL). The increase results predominantly from an
870 CHAPTER 42 Anemia and Pregnancy TABLE 42-1 ANEMIA CLASSIFIED BY TABLE 42-2 LABORATORY STUDIES USEFUL IN PATHOPHYSIOLOGIC MECHANISM EVALUATION OF ANEMIA I. Dilutional (expansion of the plasma volume) Laboratory Study Reference Range A. Pregnancy B. Hyperglobulinemia Red blood cell (RBC) count 4.0-5.2 × 1012/L C. Massive splenomegaly Mean corpuscular volume (MCV) 80-100 μm3 II. Decreased RBC production Mean corpuscular hemoglobin 31-36 g/dL A. Bone marrow failure concentration (MCHC) 1. Decreased building blocks or stimulation Reticulocyte count 48-152 × 109/L (0.5-1.5%) a. Iron, protein Serum (free) hemoglobin 1.0-5 mg/dL b. Chronic infection, chronic renal disease Serum haptoglobin 30-200 mg/dL 2. Decreased erythron Total bilirubin 0.1-1.2 mg/dL a. Hypoplasia (hereditary, drugs, radiation, toxins) Direct Coombs test Negative b. Marrow replacement (tumor, ﬁbrosis, infection) Hb electrophoresis >98% A B. Ineffective production <3.5% A2 1. Megaloblastic (vitamin B12 and folate deﬁciency, <2% F myelodysplasia, erythroleukemia) Serum ferritin >20 μg/L 2. Normoblastic (refractory anemia, thalassemia) Plasma iron 33-102 μg/dL III. Increased RBC loss Plasma total iron-binding capacity 194-372 μg/dL A. Acute hemorrhage Transferrin saturation 16-60% B. Hemolysis Folate level 1. Intrinsic RBC disorders Serum >20 μg/L a. Hereditary Red blood cells 165 ng/mL (1) Hemoglobinopathies Serum vitamin B12 190-950 ng/L (2) RBC enzyme deﬁciency Anti-intrinsic factor antibody (AIF) Negative (3) Membrane defects (4) Porphyrias b. Acquired (1) Paroxysmal nocturnal hemoglobinuria (2) Lead poisoning must be discontinued for 24 to 48 hours before these studies are carried 2. Extrinsic RBC disorders out. In iron deﬁciency, the FEP increases approximately ﬁvefold. Iron a. Immune is transported in the plasma bound to transferrin. In the iron-deﬁcient b. Mechanical state, the plasma iron decreases, the TIBC increases, and the percent c. Infection of iron saturation decreases. In contrast, with chronic infection, both d. Chemical agents the plasma iron and the TIBC are decreased, but the percent saturation e. Burns remains normal. f. Hypersplenism Serum folate, RBC folate, and serum vitamin B12 levels are useful g. Liver disease in deﬁning the cause of macrocytic anemia. Because the RBC folate RBC, red blood cell. more accurately reﬂects the body’s folate stores, many laboratories no longer offer the serum folate determination. The presence of serum intrinsic factor antibodies is speciﬁc for pernicious anemia. However,increase in the indirect fraction. However, signiﬁcant hemolysis can they are undetectable in approximately 40% of cases, so the absenceoccur without an elevation in the bilirubin. Therefore, the bilirubin of these antibodies does not rule out a diagnosis of perniciouslevel is helpful only when it is elevated. anemia. The direct Coombs test uses anti-human immunoglobulin to detect Although a bone marrow aspiration or biopsy can add much usefulimmunoglobulins attached to the surface of RBCs. A positive test information, it is rarely done today in pregnant anemic women. Inindicates an immune cause for a hemolytic anemia. In such cases, it is addition to providing a ratio of myeloid to erythroid productionimportant to search for underlying causes for autoimmunity, such as (normal, approximately 3 : 1), it provides a measure of iron stores,connective tissue disease, lymphoma, carcinoma, and sarcoidosis. The allows a differential count of myeloid and erythroid precursors, pro-diagnosis and management of glucose-6-phosphate dehydrogenase vides evidence of inﬁltration with neoplasm, and allows histologic and(G6PD) deﬁciency and of the various hemoglobinopathies are dis- bacteriologic conﬁrmation of infection.cussed later in this chapter. The free erythrocyte protoporphyrin (FEP),4 plasma iron, plasmatotal iron-binding capacity (TIBC),5 and serum ferritin level6,7 areuseful in establishing a diagnosis of iron deﬁciency. Protoporphyrin is Normal Hematologic Eventsgenerated in the penultimate step of heme synthesis, with iron subse-quently incorporated into protoporphyrin to create heme. Iron deﬁ- Associated with Pregnancyciency causes elevated FEP. Serum ferritin correlates closely with bodyiron stores, and many investigators support the use of serum ferritin Blood Volume Changesas the best single test in patients with anemia to make a diagnosis of During pregnancy, there is normally a 36% increase in the bloodiron deﬁciency anemia.6,8 A ferritin level of 12 μg/L or lower is consis- volume, the maximum being reached at 34 weeks’ gestation.11 Thetent with iron deﬁciency anemia. Plasma iron and serum ferritin levels plasma volume increases by 47%, but the RBC mass increases only byare both increased after ingestion of iron.9,10 Therefore, iron therapy 17%; the latter reaches its maximum at term. As shown in Figure 42-1,
CHAPTER 42 Anemia and Pregnancy 871 6 TABLE 42-3 IRON REQUIREMENTS FOR PREGNANCY 5 Required for Average (mg) Range (mg) Volume (I) 4 External iron loss 170 150-200 3 Expansion of red blood cell 450 200-600 2 mass Fetal iron 270 200-370 1 Iron in placenta and cord 90 30-170 Blood loss at delivery 150 90-310 0 Total requirement 980 580-1340 0 10 20 30 40 50 Gestational age Requirement less red blood 840 440-1050 cell expansion Blood volume RBC volume Plasma volume HematocritFIGURE 42-1 Hematologic changes during pregnancy. RBC, red were receiving iron supplementation than in those who were not.16 Theblood cell. (Redrawn from Peck TM, Arias F: Hematologic changes usual sequence of events in regard to iron deﬁciency is an absence ofassociated with pregnancy. Clin Obstet 22:785, 1979.) iron in the marrow followed by the development of abnormal plasma iron studies (transferrin, ferritin, or FEP). The RBCs ﬁrst become microcytic, then hypochromic. Finally, anemia develops.this disparity produces a relative hemodilution throughout pregnancy, Most women enter pregnancy with marginal iron stores. Pregnancywhich reaches its maximum between 28 and 34 weeks. Although this places a large demand on iron balance that cannot be met with thedilutional effect lowers the Hb, hematocrit (Hct), and RBC count, it usual diet. In the absence of supplementation, iron deﬁciency develops.causes no change in the mean corpuscular volume or in the mean Supplementation with 60 mg of elemental iron per day during thecorpuscular Hb concentration. Therefore, serial evaluation of these second and third trimesters meets the daily requirement. The Institutetwo indices is useful in differentiating dilutional anemia from progres- of Medicine recommends that supplementation be offered only tosive iron deﬁciency anemia during pregnancy: In the former, the women whose serum ferritin level is less than 20 μg/L.17 Although thisindices do not change; in the latter, they decrease progressively. is a valid recommendation scientiﬁcally, the high cost of the screening limits its applicability. The fetal compartment preferentially obtains iron, folate, andIron Kinetics vitamin B12 from—and at the expense of—the mother.18-20 MaternalThe classic study by Scott and Pritchard shows that iron stores in iron is transferred to the fetus via serum transferrin. Transferrin bindshealthy women are marginal at best.12 These authors evaluated iron to receptors in placental syncytiotrophoblast, where the iron is releasedstores in the bone marrow of healthy, white college students who and subsequently binds to ferritin in placenta cells. It is then trans-had never been pregnant and had never donated blood. Approximately ferred to apotransferrin, which enters into the fetal circulation as holo-two thirds had minimal iron stores. In another study, Pritchard transferrin. If maternal iron status is low, placental transferrin receptorsand colleagues demonstrated that almost 50% of healthy primigra- increase to facilitate more uptake of iron by the placenta.21vidas had minimal iron stores in the marrow during the ﬁrsttrimester.13 The major reason for poor iron stores is thought to be menstrual Folateloss. Data from Monsen and associates indicated that the usual men- Folic acid, a water-soluble vitamin, is widely available in the diet.strual loss is 25 to 30 mL of whole blood.14 This is equivalent to 12 to Dietary folates are, in fact, a family of compounds that appear as poly-15 mg of elemental iron, because each milliliter of blood contains glutamates. In humans, the only source of folate is the diet, and absorp-0.5 mg of iron. To meet the iron loss for menses alone, a woman must tion occurs primarily in the proximal jejunum. Before folate can beabsorb 1.5 to 2.0 mg of elemental iron from her diet each day. Because absorbed, it must be reduced to the monoglutamate form.22 Pancreaticonly 10% of dietary iron is usually absorbed, and the average diet conjugases within the intestine are responsible for this process. Thecontains only 6 mg/1000 kilocalories, a woman’s iron balance is pre- activity of conjugase is decreased by use of anticonvulsants, oral con-carious at best. traceptives, alcohol, or sulfa drugs.23 Therefore, in addition to an abso- Pregnancy presents substantial demands on iron balance, exceeding lute diminution in dietary intake, the combination of increased needthat saved by 9 months of amenorrhea.13 Table 42-3 lists the iron (e.g., multiple pregnancy, hemolytic anemia) and decreased absorptionrequirements for pregnancy. If available iron stores are insufﬁcient to can lead to folate deﬁciency.20,24,25meet the demands of pregnancy, iron-deﬁcient erythropoiesis results. The folate requirement of 50 μg/day for a nonpregnant womanIn a prospective study of 35 nonanemic women, ferritin levels were increases to 300 to 500 μg/day during pregnancy.13,26 Because adequatemeasured before and during pregnancy to determine the relationship folate intake before and during the ﬁrst weeks of pregnancy reducesof iron stores to developing anemia.15 Approximately 60% of the the occurrence of neural tube defects, all women considering preg-women with a ferritin concentration less than 20 μg/L before preg- nancy should consume 400 μg of folate per day.27 One study estimatednancy were anemic by 20 weeks’ gestation, compared with 25% of that a folate supplementation of 400 μg/day would reduce the risk ofwomen with normal prepregnancy ferritin levels. Fenton and col- neural tube defects by 36%, and that 5 mg/day would reduce the riskleagues used serum ferritin levels to evaluate iron stores in pregnant by 85%.28 If a previous pregnancy was complicated by a neural tubewomen and found signiﬁcantly higher ferritin levels in women who defect, the mother’s intake of folate should be 4 mg/day in the next
872 CHAPTER 42 Anemia and Pregnancypregnancy, starting at least 4 weeks before conception and continuing (hemolysis, elevated liver enzymes, low platelets) and thromboticthrough the ﬁrst 3 months of pregnancy.27,29 When folate depletion thrombocytopenic purpura—and in association with prosthetic heartoccurs, the usual sequence of events is a decreased serum folate, hyper- valves. Other types of poikilocytes identiﬁed include sickle cells, targetsegmentation of polymorphonuclear leukocytes, a decrease in RBC cells, stomatocytes, ovalocytes, spherocytes, elliptocytes, andfolate, the appearance of ovalocytes in the blood, development of an acanthocytes.abnormal marrow, and, ﬁnally, anemia.22 The Coombs test differentiates immune from nonimmune causes of hemolysis. Immune hemolysis is related to alloantibodies, drug- induced antibodies, and autoantibodies. Nonimmune causes of he-Vitamin B12 molysis include various hemoglobinopathies, hereditary disorders ofVitamin B12, also abundantly available in the diet, is bound to animal the RBC membrane (spherocytosis and elliptocytosis), hereditary deﬁ-protein. Absorption requires hydrochloric acid and pepsin to free the ciency of an RBC enzyme, and the porphyrias. Acquired nonimmunecobalamin molecule from protein. Intrinsic factor is also essential for hemolysis is caused by either PNH or lead poisoning.absorption. After absorption, transport occurs via binding to transco- Bone marrow examination is essential for the evaluation of patientsbalamin II. Most of the vitamin B12 is stored in the liver, and individuals who have hypoproliferative anemias with normal iron studies. If eryth-typically have a 2- to 3-year store available.5 ropoiesis is megaloblastic, folate or vitamin B12 deﬁciency is a likely cause. If it is sideroblastic, both acquired and hereditary forms of sid- eroblastic anemia must be considered. Finally, if erythropoiesis is normoblastic, etiologic mechanisms fallMorphologic Classiﬁcation into two major categories. The ﬁrst category has myeloid-to-erythroid production ratios greater than 4 : 1 and includes aplasia, bone marrowof Anemia inﬁltration, effects of chronic diseases, and endocrine disorders such as hypothyroidism and hypopituitarism. In the second category, thereMicrocytic Anemia is ineffective erythropoiesis, usually associated with a myeloid to ery-The microcytic anemias are characterized by abnormal Hb synthesis throid production ratio lower than 2 : 1.with normal RBC production. A logical progression of diagnostic stepsrequires, ﬁrst, that iron deﬁciency anemia be ruled out. If iron deﬁ-ciency anemia is diagnosed rather than ruled out, it is important to Macrocytic Anemiaconsider gastrointestinal bleeding as the cause, although it is rare in Macrocytic anemia is associated with either (1) an increased rate ofpregnant women. This can be accomplished by testing the stool for the RBC production and release of less than fully mature RBCs or (2)presence of occult blood with guaiac or other equally sensitive reagent. disorders of impaired DNA synthesis. Early use of a bone marrowIf a microcytic anemia is not the result of iron deﬁciency, one must examination is helpful in pointing the investigation in the correctseek another cause, such as hemoglobinopathy, chronic infection, or direction. If maturation is megaloblastic, abnormal serum vitamin B12one of the sideroblastic anemias. For this purpose, the following tests and RBC folate levels allow a diagnosis of vitamin B12 or folate deﬁ-should be considered: ciency. If a diagnosis of folate deﬁciency is conﬁrmed, the various causes of decreased deconjugation of the polyglutamate and malab- Hb electrophoresis sorption must be considered. If anti-intrinsic factor antibodies are Plasma iron and TIBC present, a diagnosis of pernicious anemia is ensured. If anti-intrinsic FEP factor antibodies are absent, a Schilling test is required to differentiate DNA probing for α-genes between pernicious anemia and a small-bowel malabsorption syn- Bone marrow examination drome. The Schilling test is performed by oral loading with cobalt 58—labeled cobalamin. Urinary excretion of cobalamin measured As noted, iron deﬁciency anemia is associated with decreased serum over 24 hours is then assessed. If abnormal excretion is noted (<10%),iron, increased TIBC (>400 μg/dL), reduced serum ferritin concentra- the test is repeated with 58Co-labeled cobalamin bound to intrinsiction (<30 μg/L), and elevated FEP. Anemia of chronic disorders is factor. If pernicious anemia is present, excretion will normalize; ifassociated with decreased serum iron and elevated FEP but paradoxi- malabsorption is the cause, excretion will remain reduced.cally normal or increased ferritin and decreased TIBC. If the serumiron and TIBC are normal or increased and FEP is normal, the patientusually has thalassemia or a sideroblastic anemia. Hb electrophoresisand DNA probes are used to deﬁne the thalassemias, and ring sidero- Anemia and Perinatalblasts are present in the bone marrow of individuals with hereditaryor acquired sideroblastic anemia. Morbidity and Mortality Fetal Effects of Maternal AnemiaNormocytic Anemia Although it has been traditionally taught that signiﬁcant maternalBecause of the diverse nature of normocytic anemia, it is the most anemia is associated with suboptimal fetal outcome, data supportingdifﬁcult type to evaluate. The reticulocyte count varies according to this concept are scarce. Most recent studies, including a meta-analysis,whether RBC production is increased, normal, or decreased. If eryth- reported a signiﬁcant relationship between anemia early in pregnancyropoiesis is increased, one must differentiate between hemorrhage and and preterm delivery but no signiﬁcant association with small-for-an increased rate of destruction. The blood smear may reveal a type gestational-age (SGA) neonates.30-33 Earlier studies reporting on mater-of RBC shape that can be virtually diagnostic. Fragmented cells are nal anemia and poor fetal outcome produced conﬂicting data.34-37seen in microangiopathic hemolysis—as in the HELLP syndrome Studies in sheep showed that fetal oxygen consumption is maintained
CHAPTER 42 Anemia and Pregnancy 873until the maternal Hct was reduced by more than 50%.38 Therefore,maternal anemia needs to be severe to affect the fetus. Elevated Hb early in pregnancy has also been associated with poor Speciﬁc Anemiasperinatal outcome, including stillbirth and SGA neonates.39,40 In a case-control study, women with stillbirths had a signiﬁcantly higher inci- Space does not allow a detailed discussion of the diagnosis and treat-dence of Hb higher than 14.5 g/dL than did control women without ment of literally hundreds of different anemias. Instead, a scheme ofstillbirths.40 Although the mechanism for this association is unknown, diagnostic studies that are useful in evaluating any anemia and a dis-the authors hypothesized that high Hb may be a marker of inadequate cussion of speciﬁc anemias that are commonly seen during pregnancyplasma-volume expansion and hence reduced blood ﬂow to the are presented.intervillous space. An alternate hypothesis was offered by Sagen andassociates, who believed that these data were evidence of chronichypoxia.39 Iron Deﬁciency Anemia In Africa, Asia, and Latin America, the relative risk of maternal Iron deﬁciency is the cause of 75% of all anemias in pregnancy, andmortality with severe anemia (Hb < 4.7 g/dL) was signiﬁcantly elevated its prevalence may be as high as 47%.48-50 Clinical symptoms includeat 3.5.41 In a case series of 130 women with a Hb less than 5 g/dL in easy fatigue, lethargy, and headache. Pica, which may involve the inges-the third trimester in India, more than half had a preterm delivery, tion of clay, dirt, ice, or starch, is a classic manifestation of iron deﬁ-and more than 25% had postpartum hemorrhage, sepsis, or a stillbirth. ciency and was signiﬁcantly associated in one study with lower maternalFurther, eight women died.42 However, these studies and others are Hb but not with adverse pregnancy outcomes.51 Clinical ﬁndingsfraught with confounders, including hemorrhage at delivery and lack include pallor, glossitis, and cheilitis. Koilonychia has been associatedof access to care, so it is difﬁcult to know whether the key factor associ- with iron deﬁciency anemia but is a rare ﬁnding. The laboratory char-ated with these deaths was the baseline anemia. Therefore, although acteristics of iron deﬁciency anemia are a microcytic, hypochromicprofound maternal anemia can have adverse effects on the fetus, the anemia with evidence of depleted iron stores, low plasma iron, highmargin of safety appears to be large. It may be that the prevalence of TIBC, low serum ferritin, and/or elevated FEP. If a bone marrowsevere anemia is too low in industrialized countries to see consistent examination is performed, stainable iron is found to be markedlyassociations with poor fetal or maternal outcomes. depleted or absent. Although iron supplementation has not been Although there is no association between maternal third-trimester shown to alter perinatal outcome, the Centers for Disease Control andHb and cord-blood Hb, maternal Hb and/or ferritin were signiﬁcantly Prevention strongly recommends screening and treatment of iron deﬁ-associated with cord-blood ferritin.21,43 In several studies, the umbilical ciency anemia in pregnancy.6,52,53 The rationale is that treatment main-cord-blood ferritin levels of infants whose mothers were iron deﬁcient tains maternal iron stores and may be beneﬁcial for neonatal ironwere reduced, compared with those of infants whose mothers were not stores.6iron deﬁcient.16,44 Yet, infants whose ferritin levels were low were not The speciﬁc treatment is oral iron, most commonly ferrous sulfate,anemic and had normal iron kinetics, and their serum ferritin values 325 mg one to three times daily. Other iron preparations are morewere not in the iron-deﬁcient range. In a study of newborns of women expensive and do not offer any advantage over ferrous sulfate if equalwith severe folate deﬁciency, Pritchard and colleagues found normal amounts of elemental iron are given. Reticulocytosis should be observedneonatal levels of folate.13 Even more interesting, Colomer found that after 7 to 10 days of therapy, and the Hb can rise by as much as 1 g/wk1-year-old infants had a 5.7-fold increased risk of anemia if their in severely anemic individuals. Absorption from the gastrointestinalmothers were anemic at delivery, compared with nonanemic mothers, tract can be enhanced by the administration of 500 mg of ascorbic acideven after the data were controlled for feeding practices and socioeco- with each dose of iron. Gastrointestinal side effects associated with ironnomic status.45 In another interesting trial, iron supplementation in therapy include nausea, vomiting, abdominal cramps, diarrhea, andwomen who were not anemic in the ﬁrst trimester was associated with constipation. These symptoms correspond to the dose of elementala signiﬁcant reduction in the incidence of birth weight less than 2500 g iron ingested; if symptoms are troublesome, the dose of iron shouldand in incidence of SGA neonates.46 This trial randomized nonanemic be reduced. Ferrous sulfate syrup (300 mg/5 mL) is an effective way ofwomen to receive 30 mg ferrous sulfate or placebo by 20 weeks’ gesta- tailoring the dose to the patient’s tolerance. Once the anemia hastion. Almost 17% of the placebo-treated women but only 4% of the resolved, the patient should continue to receive iron therapy for aniron-treated women had low-birth-weight neonates, and 18% and 7%, additional 6 months to replace iron stores.respectively, had babies that were SGA. These provocative results, indi- Parenteral administration of iron is rarely indicated and should becating that improved iron reserves enhance fetal growth independent reserved for patients with a malabsorption syndrome and those whoof anemia status, may be generalizable only to populations with a high refuse to take oral iron and are signiﬁcantly anemic (Hb < 8.5 g/dL).54incidence of smoking, because 36% to 40% of the women in each There are currently three parenteral forms of iron approved for use ingroup smoked. However, another randomized trial of routine versus the United States: iron dextran, sodium ferric gluconate, and ironindicated (Hb < 10 g/dL) treatment with iron revealed no difference sucrose.55 These are usually given intramuscularly or intravascularly,in perinatal outcome or long-term outcome, including subsequent and, because severe anaphylaxis can occur in 1% of patients, a test dosepregnancies.47 should be administered ﬁrst. In the absence of any reaction, daily injec- tions of 2 mL (100 mg) can be administered until the full dose is reached. Iron dextran contains 50 mg of iron per milliliter and comesGenetic Implications in 2-mL ampules. The required dose of iron dextran needed to correctMany of the hemolytic anemias are inherited as either autosomal- anemia and replenish stores can be calculated as follows56:dominant or recessive traits. Therefore, once the correct diagnosis hasbeen made, the genetic implications should be thoroughly discussed 1. Milligrams of Fe needed = Hb deﬁcit (in g/dL) × lean body wtwith the patient and her partner. If appropriate, the discussion should (lb) + 1000, where the Hb deﬁcit is calculated for women as 12include antenatal diagnosis. minus the patient’s Hb value
874 CHAPTER 42 Anemia and Pregnancy 2. Milliliters of iron dextran needed = mg of Fe needed ÷ The most common causes of vitamin B12 deﬁciency are autoim- 50 mg/mL mune inhibition of intrinsic factor production (pernicious anemia), inadequate production of intrinsic factor after gastrectomy, and the Iron sucrose and sodium ferric gluconate preparations appear to presence of a malabsorption syndrome. The morphologic features ofhave fewer adverse events, including anaphylaxis, in part because of B12 deﬁciency are similar to those of folate deﬁciency. In this instance,lower molecular weights.55-57 In a recent study, oral iron was compared the serum vitamin B12 level is low and the folate level is normal.with intravenous iron sucrose in a randomized trial of pregnant Because ineffective erythropoiesis is a prominent feature, evidence ofwomen with Hb values of 8 to 10 g/dL.58 The increase in Hb (2 g/dL) low-grade hemolysis may be present (increased bilirubin and decreasedwas the same in both groups at day 30. In another, partially random- haptoglobin). The measurement of anti-intrinsic factor antibodies isized study comparing oral iron with intramuscular iron dextran in useful. Treatment consists of an intramuscular dose of 1000 μg (1 mg)anemic women, there was no signiﬁcant difference in term Hb levels of vitamin B12 every day for 1 week, then 1 mg every week for 4 weeks,but a signiﬁcant increase in ferritin in the group treated with intra- and then 1 mg every month for the remainder of the patient’s life inmuscular iron, compared with orally treated women.59 In contrast, cases of pernicious anemia. A prompt reticulocyte response is antici-another randomized trial comparing oral to intravenous iron sucrose pated after 3 to 5 days of therapy.found that the latter was associated with a signiﬁcantly larger increasein Hb at 2 and 4 weeks and at delivery.60 However, at delivery, therewas less than 1 mg/dL difference between the mean Hb values in the Hereditary Spherocytosistwo groups. The authors reported no serious side effects in either and Elliptocytosisgroup. Spherocytosis is the most common form of inherited hemolytic Subcutaneous erythropoietin with or without oral iron therapy or anemia. The inheritance is autosomal-dominant with variable pene-intravenous iron sucrose has been used successfully to treat severe iron trance. Hereditary spherocytosis (HS) is characterized by a structuraldeﬁciency anemia in pregnancy, with no signiﬁcant risks to the defect in the erythrocyte membrane caused by several different molec-mother.61-63 In one study in women for whom oral iron therapy had ular defects in the membrane proteins, including spectrin deﬁciencyfailed and who had an Hb value lower than 8.5 g/dL, the addition of and ankyrin deﬁcinecy.66 The classic characteristic is an increased RBCerythropoietin to oral iron was associated with normalization of Hb osmotic fragility. The prevalence of the disorder is 2-3/10,000, whichin 2 weeks in 73% of the women.62 Darbepoetin alfa, which has a longer implies around 1000 pregnancies annually in women with spherocy-half-life than erythropoietin, has also been used to successfully treat tosis. A hemolytic crisis can be precipitated by many conditions, suchanemia after renal transplantation in a pregnant patient.64 as infection, trauma, and pregnancy itself.67 A relationship between increased hemolysis and increased maternal blood volume and splenic blood ﬂow has been proposed. An alternative suggestionMegaloblastic Anemia is an increased osmotic fragility during the third trimester ofMegaloblastic anemia is the second most common nutritional anemia pregnancy.68seen during pregnancy. Most commonly, folate deﬁciency is the cause, The diagnosis is suspected on the basis of family history and ﬁnd-but a deﬁciency in vitamin B12 must also be considered. The etiology ings in the CBC and reticulocyte count that suggest a hyperprolifera-of these anemias are poor nutrition and or decreased absorption. With tive anemia. Conﬁrmation is obtained with the osmotic fragility test.the increase in pregnancies occurring after bariatric surgery, it is pos- Prenatal care of women with hereditary spherocytosis who have notsible that bariatric surgery may become a common cause of folate or had a splenectomy requires vigilance for hemolytic crisis and folateB12 deﬁciency in pregnancy in the United States.65 supplementation to ensure adequate marrow function.69 A hemolytic Patients with folate deﬁciency present with the typical symptoms crisis can be treated conservatively with replacement transfusions orof anemia plus roughness of the skin and glossitis. The CBC reveals a with splenectomy. Because splenectomy is mechanically difﬁcult tomacrocytic or normocytic, normochromic anemia with hypersegmen- accomplish during the third trimester of pregnancy, it is sometimestation of the polymorphonuclear leukocytes. The reticulocyte count is preceded by delivery. In the absence of severe, untreated anemia, sphe-normal or low, and the white blood cell and platelet counts are fre- rocytosis does not contribute to perinatal morbidity or mortality.quently decreased. Bone marrow examination is not usually necessary Hereditary elliptocytosis, also inherited as an autosomal-dominantfor diagnosis, but if it is done, megaloblastic erythropoiesis is noted. trait, is a milder hemolytic state also caused by a structural defect inThe RBC folate level is decreased to less than 165 ng/mL (serum folate the RBC wall. The signs and symptoms are similar to those of sphero-to less than 2 μg/L), and the vitamin B12 level is normal. Treatment cytosis but are not as severe. Most cases detected during pregnancyconsists of oral folic acid administered in a dose of 1 mg/day. Parenteral have been successfully treated with supportive therapy alone.70folic acid may be indicated for individuals with malabsorption. Areticulocyte response should be seen in 48 to 72 hours, and the plateletcount should normalize within a few days. The neutrophils normalize Autoimmune Hemolytic Anemiaafter 1 to 2 weeks. There are two major types of antibodies responsible for autoimmune In addition to anemia, women with vitamin B12 deﬁciency may also hemolytic anemia: warm-reactive and cold-reactive. Most warm-manifest neurologic defects relating to damage to the posterior columns reactive antibodies are of the immunoglobulin G (IgG) class and areof the spinal cord. It is critical that individuals with vitamin B12 deﬁ- directed against some component of the Rh system on the surface ofciency not be treated with folic acid alone. Such treatment may well the RBC. In contrast, most cold-reactive antibodies are IgM; they areimprove the anemia but has absolutely no salutary effect on the neu- usually anti-I or anti-i. Autoimmune hemolytic anemia with warm-ropathy and, in fact, may make it worse. As with folate deﬁciency, reactive antibodies is frequently seen in association with various hema-vitamin B12 deﬁciency is associated with dietary deﬁciency, an increased tologic malignancies (chronic lymphocytic leukemia, lymphoma),requirement, or both. Except in strict vegetarians who avoid all animal lupus erythematosus, viral infections, and drug ingestion. Penicillinproducts, dietary deﬁciency is rare. and α-methyldopa have been reported to cause autoimmune hemo-
CHAPTER 42 Anemia and Pregnancy 875lytic anemia. Cold-reacting antibodies can be seen in association with enced metabolic disturbances or infections that precipitate an acutemycoplasmal infections, infectious mononucleosis, and lymphoreticu- hemolytic episode. Most affected African Americans carry a variantlar neoplasms. with these properties. Their hemolytic episodes are relatively mild. In a large number of cases, no speciﬁc inciting event can be identi- Greeks, Sardinians, and Sephardic Jews are more likely to carry G6PDﬁed.71 The diagnosis is suspected when a hyperproliferative, macro- Mediterranean, in which hemolysis is characteristically more severecytic anemia is identiﬁed. The stained smear of peripheral blood often and favism (hemolysis induced by ingestion of fava beans) occurs. Thereveals microcytes, polychromatophilia, poikilocytosis, and the pres- G6PD-deﬁcient African-American population has not been reportedence of normoblasts. Leukocytosis is frequently seen and is a result of to experience favism.marrow hyperactivity. The critical study to conﬁrm the diagnosis is a It is relatively unusual for a pregnant woman to experience severepositive direct Coombs test. There are several case reports in the litera- sequelae of G6PD deﬁciency. However, Silverstein and associatesture describing pregnancy-induced hemolytic anemia in which no reported Hct levels lower than 30% in 62% of 180 G6PD-deﬁcientetiology could be discerned, the disease was diagnosed during preg- women.75 Prudence would argue against exposure of a known carriernancy, and spontaneous remission occurred after delivery.72,73 The to precipitants of hemolysis. Sulfonamides, sulfones, some antimalari-most recent report described a woman who had hemolytic anemia als, nitrofurans, naphthalene, probenecid, para-aminosalicylic acid–diagnosed in three separate pregnancies that was not responsive to isoniazid, and nalidixic acid are among the medications and commonlyeither steroids or intravenous IgG therapy but resolved after delivery occurring environmental chemicals known to precipitate RBC destruc-in all pregnancies.72 tion in at-risk individuals. Treatment of autoimmune hemolytic anemia is directed toward One report suggested an increased incidence of low-birth-weightboth the hemolytic process and the underlying disease. Blood trans- infants born to G6PD-deﬁcient mothers, but no correction for thefusion, corticosteroid therapy, immunosuppression, and splenectomy effects of anemia or urinary tract infection was employed.76 Affectedare the most frequently used measures. In cases with warm-reactive male infants born of carrier females have a higher incidence of neona-antibodies, corticosteroid should be tried initially, because approxi- tal hyperbilirubinemia, sometimes severe, than normal infants, andmately 80% of patients respond dramatically. Splenectomy is an careful observation of those at risk is strongly advised.77 The incidenceeffective form of treatment in approximately 60% of patients with of severe jaundice in G6PD-deﬁcient newborn males is approximatelywarm-reactive antibodies. If the disease is refractory to both cortico- 5%, rising to 50% if there is a history of an icteric sibling.steroid therapy and splenectomy, a trial of immunosuppression If a hemolytic episode occurs during pregnancy because of G6PDis warranted. The treatment of cold-reactive antibodies depends on deﬁciency in a female heterozygote or the very rare homozygote, man-the severity of the hemolytic process. In patients with mild anemia, agement should include prompt discontinuation of any medication oravoidance of cold temperatures is all that is required. Corticosteroid other agent that may be responsible, treatment of any intercurrenttherapy and splenectomy are usually not effective if the majority illness, and, if clinically indicated, transfusion support. In patients withof the RBC breakdown is intravascular. In patients with severe the variant common among African Americans, even in the male hemi-anemia, a trial of immunosuppression or plasmapheresis should be zygote, the G6PD activity of young RBCs is much higher than in RBCsconsidered. that have circulated for weeks and months. Old cells may be totally devoid of activity. Hence, the hemolytic episode, recognized early, is generally relatively mild and can be limited to the oldest population ofGluose-6-Phosphate circulating RBCs if the inciting agent is eliminated. A comprehensiveDehydrogenase Deﬁciency review of G6PD deﬁciency was published by Beutler.74More than 20 different hereditary RBC enzyme defects have beendescribed, most with an associated hemolytic anemia. Of these, onlyG6PD deﬁciency occurs with more than occasional frequency. The Aplastic and Hypoplastic Anemiagenetic locus controlling G6PD synthesis is on the X chromosome, and Aplastic anemia is characterized by pancytopenia in the presence of amales with an abnormal gene may suffer hemolysis, especially if they hypocellular bone marrow. If it is left untreated, patients usually dieare exposed to oxidant drugs that stress the pentose phosphate pathway from infection or bleeding. Three mechanisms have been postulatedof the erythrocyte. Female heterozygotes are generally clinically unaf- to explain the development of aplastic anemia: (1) insufﬁcient stemfected by similar exposure. The G6PD activity of the RBCs in hetero- cells resulting from an intrinsic defect or a reduction in number afterzygous females is usually intermediate between the activity in exposure to a noxious agent, (2) the presence of a suppressor substancehemizygous males and that in normal subjects. However, some female that inhibits the maturation of the myeloid precursors, and (3) devel-carriers have normal G6PD activity, whereas others have activity that opment of an autoimmune reaction that causes death of the stemfalls within the range seen in affected males. It has been proposed that cells.this is consistent with the Lyon hypothesis, that one of the two X Agents such as benzene, ionizing radiation, nitrogen mustard, anti-chromosomes of every female cell is randomly inactivated in early metabolites, antimitotic agents, certain antibiotics, and toxic chemicalsembryonic life and continues to be inactive throughout all cell divi- predictably lead to marrow aplasia. In another category are agents suchsions.74 Therefore, a few heterozygous women may be severely deﬁ- as chloramphenicol, anticonvulsants, analgesics, and gold salts, whichcient in G6PD activity, but most have sufﬁcient activity to withstand induce aplasia only occasionally. Finally, hundreds of agents of variousadded stress on this critical metabolic pathway in erythrocytes. types have been implicated in several cases as causes of aplastic anemia. The ethnic groups in which variants of the deﬁciency occur with In about 50% of the cases, however, careful search does not reveal anygreatest frequency are blacks, Mediterranean populations, Sephardic causative agent.and Asiatic Jews, and selected Asian populations. Of African-American Holly described eight patients with hypoplastic anemia detectedmales in the United States, 12% are reported to be deﬁcient in G6PD during pregnancy that remitted spontaneously after delivery.78 Theactivity. Most affected individuals are hematologically normal unless bone marrow was described as hypocellular with an increase in mega-they have been exposed to certain drugs or chemicals or have experi- karyocytes. There are now many case reports and series of pregnancy-
876 CHAPTER 42 Anemia and Pregnancyassociated aplastic anemia, although they present a spectrum of clinical also been widely used with some beneﬁt. However, the remission rateand bone marrow ﬁndings that makes it difﬁcult to substantiate the with steroids is only 12%.existence of an aplastic anemia speciﬁcally related to pregnancy.79-84 Because of anecdotal reports of complete remission after pregnancyMany papers used the criteria delineated by Snyder and coworkers84 termination, it is tempting to consider therapeutic abortion. However,as evidence that the disease was pregnancy related: identiﬁcation of the thorough examination of the available literature indicates that abor-disease after the onset of pregnancy; no other etiology of aplastic tion or premature termination of pregnancy is not associated with aanemia; decrease in all blood cell counts and in Hb; and hypoplastic more favorable outcome. The only reason to terminate pregnancybone marrow. However, recovery from the aplastic anemia was not prematurely is inability to treat the patient satisfactorily during preg-universally documented after delivery, which raises the question of nancy with transfusion alone and a consequent need to proceed towhether it is truly pregnancy related.80,82 marrow transplantation. Patients with aplastic anemia seek medical attention because ofsymptoms related to profound anemia, bleeding, or infection. TheCBC reveals pancytopenia with a hypoproliferative reticulocyte count. Paroxysmal Nocturnal HemoglobinuriaExamination of the bone marrow reveals hypoplasia with normoblas- PNH was named for its characteristic nighttime hemolysis with darktic erythropoiesis. Severe aplastic anemia is fatal for more than 50% of early-morning urine. Hemolysis in PNH occurs as a result of a somaticaffected patients.85 mutation in the phosphatidylinositol glycan class A (PIGA) gene on Bone marrow transplantation is now the treatment of choice, and the X chromosome. This enzyme mediates formation of phosphati-long-term survival of 50% to 70% of patients can be expected. Alterna- dylinositol anchors for various transmembrane proteins, includingtives include antithymocyte globulin, immunosuppressive therapy, inhibitors of the complement proteins.93 These latter proteins nor-and other supportive therapy described later in this section.86 Survivors mally are present in the RBC and protect against complement activa-have had successful pregnancies after bone marrow transplantation.87-90 tion. Their reduction renders RBCs susceptible to intravascularThe largest series examined pregnancy outcomes in 146 pregnancies hemolysis by complement. PNH usually begins insidiously, and thereoccurring after treatment for aplastic anemia in 41 women.89 The out- is no familial tendency. Considerable variability exists in severity of thecomes in cases treated with total-body irradiation and bone marrow disease, and the classic presentation of hemoglobinuria is seen in onlytransplantation were compared with those in cases treated with high- 25% of patients. Exacerbations of the hemolytic process are precipi-dose chemotherapy and bone marrow transplantation. The data dem- tated by infection, menstruation, transfusion, surgery, and ingestiononstrated no increase in the incidence of congenital anomalies in of iron.infants. However, total-body irradiation was associated with an The most serious complications are marrow aplasia, thrombosis,increased risk of spontaneous abortion. Twenty-ﬁve percent of the and infection. Thrombosis accounts for 50% of deaths in nonpregnantpregnancies ended with a preterm delivery or delivery of a low-birth- patients and often involves intra-abdominal vessels, including Budd-weight infant. A more recent paper described pregnancy outcomes of Chiari syndrome resulting from hepatic vein thrombosis.94,95 Although36 women with aplastic anemia who had been treated with immuno- anemia is the most prominent hematologic feature of PNH, leukope-suppression before their pregnancy.91 Only 11 of these women had nia and thrombocytopenia also occur frequently. The diagnosis iscomplete remission before they became pregnant, and 19% of the total based on tests including the sucrose hemolysis and acidiﬁed serumgroup had a relapse of their aplastic anemia during pregnancy that lysis tests, which demonstrate the sensitivity of the patient’s RBCs torequired transfusion. Two women died, one of whom also had PNH, complement.and two women had eclampsia. The majority of the pregnancies There are two excellent reviews of PNH in pregnancy.93,96 A reviewresulted in live births, with a 14% prematurity rate. Several patients of 20 case reports and series encompassing 33 pregnancies in 24 womenwere treated with cyclosporine or corticosteroids during their revealed several interesting features. One third of these cases werepregnancy. diagnosed for the ﬁrst time during pregnancy, and 12% of the preg- During pregnancy, supportive therapy remains the major objective, nancies were complicated by thromboembolism with three fourths ofbecause bone marrow transplantation is still relatively contraindicated the patients having Budd-Chiari syndrome or hepatic vein thrombus.96in pregnancy. In recent years, with modern supportive therapy, the Half of these women died. In addition, there were two maternal deathsmaternal mortality rate has been 15% or less, and more than 90% of from infection, which means that the maternal mortality rate in thispatients survive in remission.80,82 Treatment consists of maintenance summary of 24 women with PNH was 17%. In addition, 73% hadof Hb levels through periodic transfusion, prevention and treatment anemia or hemolysis during pregnancy, and 27% developed thrombo-of infection, stimulation of hematopoiesis with androgens, splenec- cytopenia. In another review, the most common complication wastomy, intravenous immune globulin (IVIG), and intravenous ste- venous thrombosis.93 Although at least two pregnant or puerperalroids.92 Two case reports described successful pregnancies with a women developed a thromboembolism despite receiving thrombopro-combination of RBC and platelet transfusions, cyclosporine, human phylaxis, experts continue to recommend thromboprophylaxis.93,96granulocyte colony-stimulating factor, high-dose intravenous predni- This may be particularly challenging if the patient develops thrombo-sone, and intravenous immunoglobulin.79,83 In a series of 14 women cytopenia. There is one case report of a successful labor epidural place-diagnosed during pregnancy, all of whom were treated with transfu- ment in a woman with PNH and a platelet count of 64,000/mL.97sions only, there were no deaths, and 10 of the women had normal The optimal treatment of PNH is replacement of the abnormalpregnancy outcomes.82 The four abnormal outcomes were spontane- stem cells with cells capable of producing the normal cellular compo-ous abortion, preterm delivery, preeclampsia, and intrauterine growth nents. This has been accomplished by bone marrow transplantation.restriction (IUGR). Androgen therapy can be effective at stimulating The major therapeutic modalities during pregnancy are iron therapy,erythropoiesis; however, androgens are contraindicated during preg- transfusions, corticosteroids, and androgen treatment (if the fetusnancy unless the fetus is demonstrated to be male. Androgenic agents is male).93,98,99 Iron can be administered orally to replace the consider-commonly used include the anabolic steroids, oxymetholone, nandro- able amount lost in the urine. However, in patients with signiﬁcantlone decanoate, or testosterone enanthate. Adrenocorticosteroids have iron deﬁciency, such treatment may lead to a burst of erythropoiesis,
CHAPTER 42 Anemia and Pregnancy 877with delivery of a cohort of cells susceptible to the lytic action of Genotypecomplement. If a hemolytic episode follows iron therapy, it should betreated with either suppression of erythropoiesis by transfusion or Asian Africansuppression of hemolysis with corticosteroids. When acute hemolytic Phenotype Pattern Patternepisodes occur, treatment is aimed at diminishing hemolysis and pre-venting complications. α α α α NormalHemoglobinopathies α α α αThe hemoglobinopathies can be broadly divided into two generaltypes. In the thalassemia syndromes, normal Hb is synthesized at anabnormally slow rate. In contrast, the structural hemoglobinopathies α αoccur because of a speciﬁc change in the amino acid content of Hb. HeterozygousThese structural changes may have either no effect or profound effects α-thalassemia 2on the function of Hb, including instability of the molecule, reduced α α α αsolubility, methemoglobinemia, and increased or decreased oxygenafﬁnity. αThalassemia SyndromesThe thalassemia syndromes are named and classiﬁed by the type of α-Thalassemia 1chain that is inadequately produced. The two most common types are α α αα-thalassemia and β-thalassemia, both of which affect the synthesis ofHb A. Reduced synthesis of γ or δ chains and combinations in whichtwo or more globin chains are affected are relatively rare. In eachinstance, the thalassemia is a quantitative disorder of globin synthesis. Hb H diseasea-Thalassemia αIn patients with α-thalassemia, one or more structural genes are physi-cally absent from the genome. The various α-thalassemia genotypesare summarized in Figure 42-2. In blacks, the most common two-genedeletion state consists of one gene missing on each chromosome. InAsians, most often both genes are missing from the same chromosome. HomozygousIn the homozygous stage, all four genes are deleted and no chains are hydrops fetalisproduced. In such cases, the fetus is unable to synthesize normal HbF or any adult hemoglobins. This deﬁciency results in high-outputcardiac failure, hydrops fetalis, and stillbirth.100 The most severe form of α-thalassemia compatible with extrauter- FIGURE 42-2 Genotypes of the various α-thalassemiaine life is Hb H disease, which results from deletion of three α genes. syndromes. Hb H, hemoglobin H.In these patients, abnormally high quantities of both Hb H (β4) andHb Barts (γ4) accumulate. Because Hb H precipitates within the RBC,the cell is removed by the reticuloendothelial system, leading to a β-globin gene is on chromosome 11. In homozygous β-thalassemia,moderately severe hemolytic anemia. In α-thalassemia minor (also α-chain production is unimpeded, and these highly unstable chainscalled α-thalassemia-1), two genes are deleted, resulting in a mild accumulate and eventually precipitate; markedly ineffective erythro-hypochromic, microcytic anemia that must be differentiated from iron poiesis and severe hemolysis result in a condition known as β-deﬁciency. A single gene deletion (α-thalassemia 2) is clinically unde- thalassemia major or Cooley anemia. There is variation in severitytectable and is called the “silent carrier” state. depending on whether homozygous for reduced (β+) or absent (β0) The diagnosis of α-thalassemia is presumptive by exclusion of iron β-globin synthesis (see Table 42-4). The fetus is protected from severedeﬁciency and β-thalassemia. Although α-thalassemia-1 minor does disease by α-chain production. However, this protection disappearsnot present a hazard to the adult, there are serious genetic implications rapidly after birth, with the affected infant becoming anemic by 3 to 6when a mating of two individuals with the trait occurs. Under these months of age. The infant has splenomegaly and requires blood trans-circumstances, one must make a speciﬁc diagnosis by using restriction fusions every 3 to 4 weeks. Death typically occurs by the third decadeendonuclease techniques or a DNA probe before undertaking antenatal of life and is usually secondary to myocardial hemochromatosis.diagnosis.101 Female infants surviving until puberty are usually amenorrheic and have severely impaired fertility.103,104b-Thalassemia β-Thalassemia minor (also called β-thalassemia trait) results in aβ-Thalassemia is autosomal-recessive and is more common in people variable degree of illness, depending on the rate of β-chain production.of Mediterranean, Middle Eastern, and Asian descent. The underpro- The characteristic ﬁndings include a relatively high RBC membraneduction of β-globulin chains is caused by point mutations with single rigidity, moderate to marked microcytosis, and a peripheral smearnucleotide substitution or oligonucleotide addition or deletion.102 The resembling that observed in iron deﬁciency. Hb electrophoresis char-
878 CHAPTER 42 Anemia and Pregnancy TABLE 42-4 HEMATOLOGIC AND CLINICAL ASPECTS OF THE THALASSEMIA SYNDROMES Hemoglobin (Hb) Pattern* Condition Hb Level Hb A2 HB F Other Hb Clinical Severity Homozygotes α-Thalassemia ↓↓↓↓ 0 0 80% Hb Barts, remainder Hb Hydrops fetalis H and H Portland, some Hb A β+-Thalassemia ↓↓↓ Variable ↑↑ Some Hb A Moderately severe Cooley anemia β0-Thalassemia ↓↓↓↓ Variable ↑↑↑ No Hb A Severe Cooley anemia δβ0-Thalassemia ↓↓ 0 100% No Hb A Thalassemia intermedia Heterozygotes α-Thalassemia silent carrier N N N 1-2% Hb Barts in cord blood at birth N α-Thalassemia trait ↓ N N 5% Hb Barts in cord blood at birth Very mild Hb H disease ↓↓ N N 4-30% Hb H in adults; 25% Hb Barts in Thalassemia intermedia cord blood β+-Thalassemia ↓ to ↓↓ ↑ ↑ None Mild β0-Thalassemia ↓ to ↓↓ ↓ ↑↑↑ None Mild *Number of arrows indicates relative intensity of increase or decrease. ≠, increased; Ø, decreased; b+, reduced b-globin synthesis; b0, absent b-globin synthesis; db0, both d- and b-globin synthesis reduced or absent; N, normal.acteristically shows an elevation of Hb A2. β-Thalassemia trait does not TABLE 42-5 FREQUENCY OF THE MOSTimpair fertility, and the incidence of prematurity, low-birth-weight COMMON HEMOGLOBINOPATHIESinfants, and infants of abnormal size for gestational age is identical to IN ADULT AFRICAN AMERICANSthat in normal women.105,106 Nineteen women with β-thalassemiamajor or intermedia (e.g., the compound heterozygous state) were Hemoglobinopathy Abbreviated Name Frequencyfollowed through 22 pregnancies; 21 viable infants were delivered.107These patients all had intensive treatment, including transfusions and Sickle cell trait Hb SA 1 : 122 Sickle cell anemia Hb SS 1 : 708iron-chelating agents, if necessary, before pregnancy or if their Hb Sickle cell–hemoglobin C Hb SC 1 : 757concentration was greater than 7 g/dL. In addition, all women had a diseaseprepregnancy cardiac echocardiogram showing a left ventricular ejec- Hemoglobin C disease Hb CC 1 : 4790tion fraction greater than 55%. These results suggest that women with Hemoglobin C trait Hb CA 1 : 41well-managed, stable β-thalassemia can do very well during preg- Hemoglobin S–β-thalassemia Hb S-β-thal 1 : 1672nancy.107 The clinical characteristics and hematologic ﬁndings of the Hemoglobin S-high F Hb S-HPFH 1 : 3412various thalassemias are summarized in Table 42-4. Because of increased Asian immigration, the number of β-thalassemia cases in the United States has risen, so maternal screen-ing of appropriate women is important.108 In California, cases of The nomenclature and frequency of the most common hemoglobin-β-thalassemia major, Hb E/β-thalassemia, and other combined struc- opathies among African Americans are depicted in Table 42-5.114 Con-tural Hb abnormalities are more common than phenylketonuria or ﬁrmation of a diagnosis of a speciﬁc hemoglobinopathy requiresgalactosemia.108 A suggestion for easy antenatal maternal screening for identiﬁcation of the abnormal Hb by means of Hb electrophoresis.α- and β-thalassemia is shown in Figure 42-3.105,109 Prenatal diagnosis,including preimplantation genetic diagnosis, is now available for β- Sickle Cell Traitthalassemia by polymerase chain reaction techniques of mutation Traditionally, women with sickle cell trait have been thought to do welldetection on fetal blood or fetal DNA obtained from amniocentesis or during pregnancy and labor. However, new studies have reported con-chorionic villus sampling.102,110-113 ﬂicting results about increased morbidities in women with sickle trait.115-117 A case-control study from Mississippi, in which women with or without the trait were matched for race, reported a signiﬁcantStructural Hemoglobinopathies decrease in gestational age at birth (33 versus 35 weeks), lower meanTo date, several hundred variants of α, β, γ, and δ chains have been birth weight, and an increased rate of fetal death (9.7% versus 3.5%)identiﬁed. Most differ from normal chains by only one amino acid. in the women with sickle cell trait.116 Of interest, 42% of the fetal
CHAPTER 42 Anemia and Pregnancy 879 CBC with RBC indices MCV 80 μm3 MCV 80 μm3 No thalassemia Hb electrophoresis, Fe studies* Hb A2 3.5% Hb A2 3.5% Hb A2 3.5% and Low Fe studies and NI Fe studies† NI Fe studies Probable -thalassemia Fe deficiency -Thalassemia Father evaluated Father evaluated MCV 80 μm3 MCV 80 μm3 Hb A2 3.5% Hb A2 3.5% No -thalassemia -Thalassemia -Thalassemia No -thalassemia Cord blood for Counseling Hb electrophoresis Hb Barts prenatal Dx when infant 1 yr FIGURE 42-3 Maternal screening for a- and b-thalassemia. *May be serum Fe, total Fe binding capacity. †Percent transferrin saturation >15 or ferritin >12 μg/L. CBC, complete blood count; Dx, diagnosis; Fe, iron; Hb, hemoglobin; NI, normal; MCV, mean corpuscular volume; RBC, red blood cell.deaths in the sickle cell trait group were early deaths (16 to 20 weeks). Sickle Cell AnemiaIn contrast, in a large cohort study of all African-American deliveries Patients with sickle cell anemia (SCA) suffer from lifelong complica-at one institution that compared those with and without maternal tions, in part as a result of the markedly shortened life span of theirsickle cell trait, the trait was found to have a signiﬁcant protective effect RBCs. Virtually all signs and symptoms of SCA are secondary to hemol-for preterm delivery at less than 32 weeks (0.9% versus 4.5%).115 This ysis, vaso-occlusive disease, or an increased susceptibility to infectionprotective effect was even more apparent in women with multiple (Table 42-6). Clinical manifestations may affect growth and develop-gestations, with 0% versus 22% delivering before 32 weeks. ment, with growth restriction and skeletal changes secondary to expan- Because there is an increased rate of urinary tract infection among sion of the marrow cavity. Painful crises may occur in the long bones,women with sickle cell trait, pregnant patients should be repeatedly abdomen, chest, or back. The cardiovascular manifestations are thosescreened for asymptomatic bacteriuria.118-120 Recently, in a large case- of a hyperdynamic circulation, and pulmonary signs may be secondarycontrol study of women with or without sickle cell trait who were to either infection or vaso-occlusion. In addition to painful vaso-occlu-matched for race, age, gestational age, and entry into prenatal care, sive episodes, patients may exhibit hepatomegaly, signs and symptomsthere was no signiﬁcant difference in the incidence of positive urine of hepatitis, cholecystitis, and painful splenic infarcts. Genitourinarycultures (22% versus 19%).117 However, pyelonephritis was signiﬁ- signs include an impairment in concentrating ability (hyposthenuria),cantly more common in the women with sickle cell trait (2.4% versus hematuria, and pyelonephritis.0.7%). Another study suggested that the risk of preeclampsia Whether pregnancy in women with SCA is associated with morewas increased to 25% in those with the trait, compared with 10% maternal complications is controversial. One comparison of pregnancyin a sickle-negative control group.121 These patients may become outcomes between women with and without SCA revealed no signiﬁ-iron deﬁcient, and iron supplementation during pregnancy is cant differences. Rates of maternal morbidity from SCA were theindicated. same during pregnancy as in the nonpregnant state.122 However,
880 CHAPTER 42 Anemia and Pregnancy TABLE 42-6 CLINICAL MANIFESTATIONS OF cated.129,130 The goal of partial exchange transfusions is to keep the Hb SICKLE CELL ANEMIA A level higher than 50% and the Hct greater than 25%.131 A prospective, randomized study of 72 patients with SCA showed no signiﬁcant dif- I. Growth and development ference in perinatal outcome between women who were treated with A. Retarded growth prophylactic transfusions and those who received transfusions only if B. Skeletal changes their Hb level fell to less than 6 g/dL or the Hct to less than 18%.127 C. Decreased life span However, this study did report a signiﬁcant decrease in crises during II. Sickle cell crisis pregnancy, from 50% to 14%, in the group receiving prophylactic trans- A. Painful vaso-occlusive episodes: bones, abdomen, chest, and back fusions. Sixty-six patients with sickle cell–Hb C disease and 23 with III. Cardiovascular manifestations of hyperdynamic circulation sickle cell–β-thalassemia received transfusions for hematologic reasons A. Cardiomegaly only and experienced similar perinatal outcomes.127 However, the ben- B. Systolic murmurs eﬁts attained must be balanced against a 25% incidence of alloimmu- C. Failure nization and 20% occurrence of delayed transfusion reaction. IV. Pulmonary signs Several studies documented no relationship between maternal A. Infection: pneumococcus, mycoplasma, hemophilus, anemia and risk for IUGR or perinatal death in women with SCA.124,132 salmonella The use of prophylactic transfusions should be individualized. An B. Vascular occlusion excellent review of SCA in nonpregnant individuals suggested that V. Abdominal involvement transfusion is indicated for symptomatic acute anemia, severe symp- A. Painful vaso-occlusive episodes B. Hepatomegaly tomatic chronic anemia, acute chest syndrome with hypoxia, and C. Hepatitis surgery with general anesthesia and may be useful for severe protracted D. Cholecystitis pain episodes.133 Most observers believe that the prepregnancy course E. Splenic infarction of a woman is a good index of how she will fare during pregnancy. VI. Bone and joint changes Although fetal outcomes are generally good in pregnancies compli- A. Bone marrow infarction cated by SCA, there continues to be an increased risk of prematurity B. Osteomyelitis: salmonella and IUGR.122,123,134,135 The most recent series showed an incidence of C. Arthritis IUGR and preterm delivery of 45% each, and both were signiﬁcantly VII. Genitourinary signs more common in women with SCA than in the control group without A. Hyposthenuria B. Hematuria SCA.123 C. Pyelonephritis Serial ultrasound studies should be done throughout pregnancy to VIII. Neurologic manifestations conﬁrm normal fetal growth. There are no prospective studies on the A. Vascular occlusion use of antepartum fetal testing in women with SCA, so this should be B. Convulsions instituted at the discretion of the physician. In addition, preimplanta- C. Hemorrhage tion genetic diagnosis with polymerase chain reaction assays is avail- D. Visual disturbances able for SCA.110 IX. Ocular manifestations In general, prenatal vitamins without iron should be given to A. Conjunctival vessel changes women who are receiving multiple transfusions. But all women with B. Vitreous hemorrhage SCA should have an additional folic acid supplement of 1.0 mg/day prescribed. The pneumococcal vaccine should be given if the patient has not had the vaccine within the past year. During labor and delivery,another study showed a signiﬁcant increase in antepartum admissions, the patient must remain well oxygenated and hydrated. If an exchangepreterm labor or preterm premature rupture of membranes, and post- transfusion protocol has been used and the Hb A level is greater thanpartum infection in women with versus those without SCA.123 In two 40%, painful crises are distinctly unusual.136 Finally, a recent retrospec-studies, there was no difference in the incidence of preeclampsia in tive study of 40 women with SCA reported that the initial prenatalwomen with and without SCA.123,124 Series examining maternal deaths white blood cell count was signiﬁcantly higher in those women whohave been too small to determine whether there is an increased risk subsequently developed SCA-related complications (11.2 × 109/L)with SCA; however, pulmonary embolus or acute chest syndrome or during their pregnancy than in those who did not develop complica-both was the cause in 5 of 7 deaths.125 tions (8 × 109/L).137 It is not known whether the frequency of painful crises in womenwith SCA changes with pregnancy. In one large study, the average Hemoglobin Sickle C Diseasenumber of crises per patient per pregnancy was 1 to 2, and other studies Women who are doubly heterozygous for both the Hb S and the Hbhave suggested that 20% to 50% of affected pregnant women had C genes are said to have Hb SC disease. Hb electrophoresis revealscrises.122,124,126,127 Treatment is largely symptomatic, with the major approximately 60% Hb C and 40% Hb S. Patients with Hb SC diseaseobjectives being to end a painful crisis and to combat infection. Hydra- typically have a normal habitus, a healthy childhood, and a normal lifetion, oxygen therapy, and pain management are the cornerstones of span. If a systematic screening program has not been used, the condi-managing a pain crisis. Acute chest syndrome is one of the most severe tion may ﬁrst be detected in many women during the latter part ofcomplications of SCA and can be very difﬁcult to treat. It has been pregnancy, when a complication occurs. At the beginning of preg-reported to occur in up to 20% of pregnancies.122,124,128 Urinary tract nancy, most women are mildly anemic and splenomegaly is present.and pulmonary infections should be diagnosed promptly and treated Examination of a peripheral blood smear shows numerous target cells.vigorously with appropriate antibiotics. Transfusion therapy has been Hb electrophoresis ensures the correct diagnosis.138,139used widely for years in the treatment of symptomatic patients. Partial During pregnancy, 40% to 60% of patients with Hb SC diseaseexchange transfusions or prophylactic transfusions have been advo- present as if they had SCA. In contrast to patients with SCA, those with
CHAPTER 42 Anemia and Pregnancy 881Hb SC disease frequently experience rapid and severe anemic crises usually is discovered during a medical evaluation. Mild hemolyticresulting from splenic sequestration. These patients also have a greater anemia with an Hct in the range of 25% to 35% is characteristic. Thetendency to experience bone marrow necrosis with the release of fat- RBCs show microspherocytes and characteristic targeting. No increasedforming marrow emboli. The clinical manifestations of Hb SC disease morbidity or mortality is associated with pregnancy, and no speciﬁcare otherwise similar to those of SCA but milder, and the general therapy is indicated.management of symptomatic patients is identical. Considerations forthe management of labor are the same as with SCA. In a recent report, Hemoglobin E Diseasewomen with Hb SC disease had a signiﬁcantly increased risk of ante- The recent immigration of Southeast Asians to the United States haspartum admission, IUGR, and postpartum infection compared to resulted in an increase in the number of individuals with Hb E traitwomen without sickle disease, but these risks were only half as great and disease. The clinical and laboratory manifestations of the variousas those of the women with SCA.123 Similarly, Serjeant and associates Hb E syndromes are outlined in Table 42-7.142,143 Most individuals havereported that the rates of miscarriage, live-born delivery, and newborn a mild microcytic anemia that is of no clinical signiﬁcance, and noweight less than 2500 g in women with Hb SC disease were similar to treatment is necessary. However, patients who are homozygous for Hbthose in women with normal Hb and signiﬁcantly better than those in E have a greater degree of microcytosis and are frequently anemic.women with SCA.140 Rates of pain crises, acute chest syndrome, and Target cells are prominent. As with Hb C trait and disease, no speciﬁcurinary tract infections were similar in women with Hb SC disease and therapy is required, and reproductive outcome is normal.those with SCA.140Hemoglobin S-b-ThalassemiaPatients with Hb S-β-thalassemia are heterozygous for the sickle cell Anemias Associated withand the β-thalassemia genes, and in general about 10% of sickle cell Systemic Diseasedisease is caused by Hb S-β-thalassemia.111 In addition to decreasedβ-chain production, there is a variably increased production of Hb F The normal bone marrow has the capacity to increase its RBC produc-and Hb A2. Because of this variable production rate, Hb electrophoresis tion sixfold to eightfold in response to anemia. This compensatoryreveals a spectrum of Hb concentrations. Hb S may account for 70% mechanism, which is responsible also for the increase in RBC mass into 95% of the Hb present, with Hb F rarely exceeding 20%.141 Because normal pregnancy, is triggered by tissue hypoxia and mediated byof the thalassemia inﬂuence, the Hb S concentration exceeds the Hb A erythropoietin. The response may be absent or blunted in some cir-concentration. This is in sharp contrast to patients with sickle cell trait, cumstances, most commonly in chronic disorders. Chronic infections,in whom Hb A levels exceed the concentration of Hb S. rheumatoid arthritis, and other inﬂammatory states are characterized The diagnosis is made in an anemic patient by demonstrating by a mild normocytic, normochromic anemia (or sometimes a hypo-increased Hb A2 and Hb F levels in association with a level of Hb S chromic, microcytic anemia) with low serum iron concentration, lowexceeding that of Hb A. The peripheral smear reveals hypochromia and transferrin level, inappropriately low reticulocyte count, and generousmicrocytosis with anisocytosis, poikilocytosis, basophilic stippling, and but poorly utilized stores of reticuloendothelial iron. Although thetarget cells. The clinical manifestations of this disorder parallel those of bone marrow is normally cellular, it does not respond appropriatelySCA but are generally milder. Painful crises may occur; however, these to the mildly accelerated RBC destruction typical of chronic inﬂam-patients have a normal body habitus and frequently enjoy an uncom- mation. Studies thus far have not determined whether the defect inpromised life span. The role of exchange transfusion should be similar erythropoiesis can be attributed to inadequate erythropoietin secre-to that in patients with SCA; that is, exchange transfusion should be tion. In the absence of pregnancy, the Hb concentration in thesereserved for the woman who experiences painful crises or whose anemia chronic states is frequently 9 to 10 g/dL, and the Hct concentration isleads to an Hct lower than 25%. approximately 30%. The hydremia of pregnancy may lower these values somewhat.Hemoglobin C Trait and Disease A similar but frequently more complicated anemia accompaniesHb C trait is an asymptomatic trait without reproductive consequences. renal failure. Here, more often perhaps than in chronic inﬂammatoryTarget cells are found in the peripheral smear, but anemia is not states, blood loss and hemolysis are contributory factors, and thepresent. Hb C disease, the homozygous state, is a mild disorder that serum iron and transferrin changes noted earlier are less regular. In TABLE 42-7 VARIOUS GENOTYPES OF HEMOGLOBIN E AND THEIR PHENOTYPIC EXPRESSION* Hb Electrophoresis (%) Genotype Degree of Anemia MCV† A + A2 E F S Phenotype Expression A/E 0 ↓ 68 30 <2 0 None E/E 0 to + ↓↓ <4 94 <2 0 None E/α-thal + to ++ ↓ 50 15 35 0 None S/E ++ ↓ 0 40 0 60 None E/β+-thal ++ ↓↓ 10 60 30 0 Splenomegaly E/β0-thal +++ ↓↓ 0 60 40 0 Splenomegaly *Number of + symbols indicates relative severity of anemia. † Number of arrows indicates relative amount of decrease. Hb, hemoglobin; MCV, mean corpuscular volume.
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