Anemia and Pregnancy

Blood Volume Changes

During pregnancy, there is normally a 40%–45% increase in blood volume, the maximum being reached at 34 weeks’ gestation. ^, The plasma volume increases by 47%, but the RBC mass increases only by 17%; the latter reaches its maximum at term. As shown in Fig. 55.1 , this disparity produces a relative hemodilution throughout pregnancy, which reaches its maximum between 28 and 34 weeks. Although this dilutional effect lowers the Hb, hematocrit (Hct), and RBC count, it causes no change in the MCV or in the mean corpuscular Hb concentration (MCHC). Therefore serial evaluation of these two indices is useful in differentiating dilutional anemia from progressive IDA during pregnancy. In the former the indices do not change, and in the latter they decrease progressively.

Iron Kinetics

The classic study by Scott and Pritchard showed that iron stores in healthy women are marginal at best. These authors evaluated iron stores in the bone marrow of healthy, White college students who had never been pregnant and had never donated blood. Approximately two-thirds had minimal iron stores. In another study, almost 50% of healthy primigravidas had minimal iron stores in the marrow during the first trimester. Other reports confirm continued high rates of iron deficiency. ^, In a prospective report of more than 400 women in early pregnancy, one-third had a ferritin level of less than 20 μg/L, and 15% of them had severe iron depletion with ferritin value less than 12 μg/L. In addition, despite the high rate of iron depletion, only 6% of the women with a ferritin level of less than 20 μg/L also had anemia with a Hb level of less than 11 mg/L, suggesting that measuring only Hb is an inadequate screen for iron deficiency. The incidence of iron deficiency as measured by total-body iron, which considers body weight, was 18% in the first trimester and rose to 29% by the third trimester in US women in NHANES for 1999 to 2006.

The major reason for poor iron stores in women is likely menstrual loss. Data from Hallberg and associates indicated that typical menstrual blood loss is 28 to 36 mL per cycle. This is equivalent to 14 to 18 mg of elemental iron, because each milliliter of blood contains 0.5 mg of iron. To meet the iron loss accruing with menses alone, a woman must absorb 1.5 to 2.0 mg of elemental iron from her diet each day. Because only 10% of dietary iron is usually absorbed and the average diet contains only 6 mg/1000 kcal, a woman’s iron balance is precarious at best.

Pregnancy presents substantial demands on iron balance, exceeding that saved by 9 months of amenorrhea. Table 55.2 lists the iron requirements for pregnancy. If available iron stores are insufficient to meet the demands of pregnancy, iron-deficient erythropoiesis results. In a prospective study of 35 nonanemic women, ferritin levels were measured before and during pregnancy to determine the relationship of iron stores to developing anemia. Approximately 60% of the women with a ferritin concentration of less than 20 μg/L before pregnancy were anemic by 20 weeks’ gestation, compared with 25% of women with normal prepregnancy ferritin levels. Fenton and colleagues used serum ferritin levels to evaluate iron stores in pregnant women and found significantly higher ferritin levels in women who were receiving iron supplementation than in those who were not. The usual sequence of iron deficiency occurs in three stages. In the first stage, or prelatent iron deficiency, there is a reduction in marrow storage iron as detected by a decreased serum ferritin. During the second stage, or latent iron deficiency, abnormalities in iron studies are detected (decreased iron, increased TIBC, decreased percentage saturation), but the Hb level remains normal. In the final, third stage, anemia becomes apparent with a decreased Hb and, finally, decreased MCV.

As noted, most women enter pregnancy with marginal iron stores. Further, although the estimated average requirement of daily iron intake in pregnant women between 14 and 18 years of age is 23 mg/d of iron and for pregnant women between 19 and 50 years it is 22 mg, the National Academy of Medicine reported the median intake in pregnancy was only 15 mg. Thus pregnancy places a large demand on iron balance that cannot be met with the usual diet. In the absence of supplementation, iron deficiency will develop, and in many women anemia will also develop. Although supplementation with 60 mg of elemental iron per day during the second and third trimesters meets the daily requirement, a prospective study reported that despite a mean supplementation of 49 mg/d of iron, iron deficiency increased from 8% in the first trimester to 62% by the third trimester. However, iron supplementation reduces the incidence of anemia by as much as 73%. ^, The National Academy of Medicine recommends that supplementation be offered only to women whose serum ferritin level is less than 20 μg/L. Although this is a valid recommendation scientifically, the high cost of the screening limits its applicability.

The fetal compartment preferentially obtains iron, folate, and vitamin B ₁₂ from—and at the expense of—the mother. Maternal iron is transferred to the fetus via serum transferrin. Transferrin binds to receptors on the apical surface of placental syncytiotrophoblast, where the iron is released and subsequently binds to ferritin in placenta cells. It is then transferred to apotransferrin, which enters into the fetal circulation as holotransferrin. If maternal iron status is low, expression of placental transferrin receptors increase to facilitate enhanced uptake.

Folate

Folic acid, a water-soluble vitamin, is widely available in the diet. Dietary folates are a family of compounds that appear as polyglutamates. In humans, the only source of folate is the diet, and absorption occurs primarily in the proximal jejunum, facilitated by pancreatic conjugases in the intestine. The activity of conjugase is decreased by use of anticonvulsants, oral contraceptives, alcohol, or sulfa drugs. Therefore, in addition to an absolute diminution in dietary intake, the combination of increased need (e.g., multiple pregnancy, hemolytic anemia) and decreased absorption can lead to folate deficiency. ^{, ,} Folate deficiency is defined as a serum level of less than 2.5 to 3 ng/mL.

The folate requirement of 400 μg/d for a nonpregnant woman increases to 600 μg/d during pregnancy. ^, Because adequate folate intake before and during the first weeks of pregnancy reduces the occurrence of neural tube defects, all women considering pregnancy should consume 600 μg of folate per day, which can be achieved by the combination of a nutritious diet plus a supplement containing 400 μg/d. One study estimated that a folate supplementation of 400 μg/d would reduce the risk for neural tube defects by 36% and that 5 mg/d would reduce the risk by 85%. If a previous pregnancy was complicated by a neural tube defect, the mother’s intake of folate should be 4 mg/d in the next pregnancy, starting at least 4 weeks before conception and continuing through the first 3 months of pregnancy. ^, When folate depletion occurs, blood abnormalities such as decreased serum folate, individual macroovalocytes then increased MCV, hypersegmentation of neutrophil nuclei, and decreased RBC folate may be detected before the development of anemia.

Vitamin B ₁₂

Vitamin B ₁₂ , also abundantly available in the diet, is bound to animal protein. Absorption requires hydrochloric acid and pepsin to free the cobalamin molecule from protein. Intrinsic factor is also essential for absorption. After absorption, transport occurs via binding to transcobalamin II, and most of the vitamin B ₁₂ is stored in the liver. The recommended daily intake of vitamin B ₁₂ is 2.4 μg. Vitamin B ₁₂ deficiency is defined by a serum level of less than 160 to 200 pg/mL.

Microcytic Anemia

The microcytic anemias are characterized by abnormal Hb synthesis with normal RBC production. A logical progression of diagnostic steps requires, first, that IDA be ruled out (see Iron Deficiency Anemia, later). If iron deficiency anemia is diagnosed rather than ruled out, it is important to consider gastrointestinal bleeding as the cause, although it is rare in pregnant women. This can be accomplished by performing a fecal occult blood test. If a microcytic anemia is not the result of iron deficiency, another cause should be sought, such as hemoglobinopathy including thalassemia, chronic infection, or inflammatory disorder, or one of the sideroblastic anemias. For this purpose, the following tests should be considered:

• 1.

  Peripheral blood smear examination

• 2.

  Serum iron studies (iron, TIBC, percentage saturation) and ferritin

• 3.

  HPLC

• 4.

  Whole blood lead level

• 5.

  Molecular testing for α- and β-thalassemias

• 6.

  Bone marrow examination

As noted, iron deficiency anemia is associated with decreased serum iron, increased TIBC (>400 μg/dL), decreased percentage saturation, and decreased ferritin concentration (<20 μg/L). Because iron deficiency is the most common anemia in pregnancy, it is reasonable and cost-effective to screen all women with microcytic anemia with ferritin initially. A ferritin level of less than 20 μg/L is generally diagnostic of IDA. However, IDA may still be present when the serum ferritin level is greater than 20 μg/L, particularly in the setting of other conditions including chronic disease. Additional tests to confirm iron deficiency may be warranted in such settings. Anemia of chronic disorders is associated with decreased serum iron level but paradoxically normal or increased ferritin and decreased TIBC. If iron studies and ferritin are normal, the patient should be evaluated for thalassemia or a sideroblastic anemia. Hb evaluation by high-performance liquid chromatography (HPLC) can help diagnose thalassemias and hemoglobinopathies; however, concurrent iron deficiency may mask HPLC abnormalities seen in thalassemia, and therefore iron deficiency should be evaluated first and treated before performing HPLC. Molecular testing for thalassemia confirmation may also be considered. Ring sideroblasts are present in the bone marrow of individuals with hereditary or acquired sideroblastic anemia (e.g., lead poisoning, alcohol abuse, arsenic, excess dietary zinc).

Normocytic Anemia

Because of the diverse nature of normocytic anemia, it is the most difficult type to evaluate. The reticulocyte count varies according to whether RBC production is increased, normal, or decreased. If erythropoiesis is increased, one must differentiate between hemorrhage and an increased rate of destruction. The blood smear may reveal a type of RBC shape that can be virtually diagnostic. Schistocytes are seen in microangiopathic hemolysis—as in the HELLP syndrome ( h emolysis, e levated l iver enzymes, l ow p latelets) and thrombotic thrombocytopenic purpura—and in association with prosthetic heart valves. Other types of poikilocytes that may be encountered on peripheral blood smear examination and that may suggest an etiology include sickle cells, target cells, stomatocytes, ovalocytes, spherocytes, elliptocytes, and acanthocytes and should warrant further evaluation by a hematologist.

The Coombs test differentiates immune from nonimmune causes of hemolysis. Immune hemolysis is related to alloantibodies, drug-induced antibodies, and autoantibodies. Nonimmune causes of hemolysis include various hereditary disorders such as hemoglobinopathies, disorders of the RBC membrane (hereditary spherocytosis and hereditary elliptocytosis), or deficiency of an RBC enzyme, and acquired nonimmune hemolytic anemias may be caused by PNH or lead poisoning.

Bone marrow examination can be helpful for evaluation of patients who have hypoproliferative anemias with normal iron studies and folate and vitamin B ₁₂ levels. If increased ring sideroblasts are identified, both acquired and hereditary forms of sideroblastic anemia must be considered. If erythropoiesis is normoblastic, etiologic mechanisms fall into two major categories. The first category has myeloid-to-erythroid production ratios greater than 4:1 and includes red cell aplasia, primary marrow-based disorder (e.g., chronic myeloid leukemia), effects of chronic diseases, infection (e.g., parvovirus), and endocrine disorders such as hypothyroidism and hypopituitarism. In contrast, the myeloid-to-erythroid ratio is decreased (e.g., 2:1 or less) when erythroid hyperplasia is present, as with relatively acute hemolysis or myelodysplastic syndrome (MDS) if in conjunction with significant dysplasia. If there is megaloblastic erythropoiesis and erythroid hyperplasia, considerations include nutritional deficiencies such as folate and vitamin B ₁₂ deficiencies, MDS, drugs, particularly those that interfere with nucleotide synthesis, and toxins (benzene, arsenic).

Macrocytic Anemia

Macrocytic anemia is associated with either (1) an increased rate of RBC production and release of less than fully mature RBCs or (2) disorders of impaired DNA synthesis. Abnormal serum vitamin B ₁₂ or serum and RBC folate levels allow a diagnosis of vitamin B ₁₂ or folate deficiency. If a diagnosis of folate deficiency is confirmed, the various causes of decreased deconjugation of the polyglutamate and malabsorption must be considered. Folic acid, the polyglutamate present in food, must be deconjugated by intestinal enzymes such as dihydrofolate reductase for absorption. Causes of decreased deconjugation and hence poor absorption of folate include alcoholism and folate antagonists (methotrexate, pyrimethamine, trimethoprim), which inhibit dihydrofolate reductase. Additional causes of malabsorption causing folate deficiency are celiac sprue, inflammatory bowel disease, and gastric bypass surgery. If vitamin B ₁₂ deficiency is diagnosed, causes of malabsorption such as pernicious anemia or small bowel malabsorption should be considered. Pernicious anemia, the most common cause of B ₁₂ deficiency, is diagnosed when anti–intrinsic factor antibodies are present. These antibodies bind intrinsic factor produced in the stomach and thus inhibit B ₁₂ absorption. If anti–intrinsic factor antibodies are negative, referral to gastroenterology for appropriate evaluation for small bowel malabsorption is appropriate.