The first step in recognizing the etiology of any anemia is to obtain the appropriate history, physical examination, and laboratory tests. This initial step will aid in the formulation of the differential diagnosis to distinguish between an acquired and inherited anemia. While pregnant patients with anemia are often asymptomatic, in part because of the increase in blood volume, clinical findings can be identified, such as glossitis (nutritional deficiencies), jaundice (hemolytic problems), petechiae (coagulopathies) or skeletal abnormalities (hemoglobin sickle cell anemias), which suggest the presence of anemia.

The basic laboratory work-up includes a complete blood count, peripheral blood smear, iron studies, and urinalysis. Patients at risk for sickle cell anemia or thalassemia should also have a hemoglobin electrophoresis.

Iron deficiency anemia

The most common cause of anemia in pregnancy is iron deficiency – it accounts for about 95% of anemia seen during pregnancy. The ideal body iron content in the adult woman is 3.5–4 g with approximately 60–70% contained in circulating hemoglobin and the remainder stored as ferritin and hemosiderin in the liver, spleen, and bone marrow. Absence of hemosiderin in the bone marrow indicates that iron stores are exhausted.

The World Health Organization and most experts recommend prevention of iron deficiency anemia with prophylactic iron supplementation in pregnancy. Pregnancy requires an additional 700–1200 mg of iron. Of this, 200–300 mg is transferred to the fetus. Most of the iron requirements of pregnancy are in the second half of pregnancy, and they are approximately 5–6 mg/day. An average balanced diet will supply only 1–2 mg/day. Daily supplementation with 300 mg ferrous sulfate (which contains 60 mg elemental iron) will satisfy the pregnancy requirements; it is recognized that only 10–15% of the ingested iron is being absorbed.

The consequence of iron deficiency is a microcytic, hypochromic anemia with red cells showing a mean corpuscular volume (MCV) of less than 80 femtoliters (fL). Serum iron studies typically demonstrate a decrease in serum iron, low serum ferritin, and an increase in serum total iron-binding capacity.

When iron deficiency anemia is identified, the treatment requires the administration of 900 mg of oral ferrous sulfate daily. On occasion, some women will require parenteral iron therapy given as iron dextran. Each 2 mL vial of iron dextran provides 100 mg of elemental iron. The rapidity of response of parenteral therapy is the same as for oral iron.

A rise in hemoglobin concentration of 0.2 g/dL associated with an increase in reticulocyte count indicates that the patient is responding to treatment. Blood transfusion is seldom required, and the potential risks for blood-borne infections (hepatitis, cytomegalovirus, HIV) must be weighed carefully before transfusion is recommended. At hemoglobin levels of 4–6 g/dL there is some risk for high-output cardiac failure in the mother and somewhat less of a risk for fetal hypoxia.

Vitamin deficiency megaloblastic anemias

The two most common megaloblastic conditions acquired in pregnancy are caused by folate deficiency and vitamin B12 deficiency. Both vitamin B12 and folate deficiency delay DNA synthesis and can result in megaloblastic anemias. Megaloblastic anemia is a nonspecific term utilized to describe hypoproliferative disorders that have characteristic hematocytopathic features, evidence of inadequate erythropoiesis, and/or hemolysis of red blood cells. The most prominent clinical features of severe megaloblastic anemias are roughness of the skin and glossitis. Folic acid deficiency is the most common cause for megaloblastic anemia, while vitamin B12 deficiency is extremely uncommon during pregnancy.

The diagnosis of folic acid deficiency anemia is usually made late in pregnancy or in the puerperium. Diagnostic laboratory tests show a macrocytic anemia (MCV above 100 fL) with hypersegmentation of the polymorphonuclear leukocytes, decreased reticulocyte count, and a decreased serum folate (normal folate values in pregnancy are 5–10 mg/μL). The natural history of folate deficiency is such that the sequential events usually observed are: decrease in serum folate in 3 weeks, appearance of hypersegmented neutrophils in 7 weeks, a decrease in red cell folate in 18 weeks, a megaloblastic bone marrow in 19 weeks, with clinical anemia presenting in 20 weeks. Among the late fetal effects of folate deficiency are low birthweight and fetal growth restriction. An association with placental abruption and pre-eclampsia/eclampsia has been reported but not definitively established.

A variety of factors contribute to folic acid deficiency in pregnancy: multiple pregnancy, inadequate diet, excessive hyperemesis, chronic infection, ethanol, drugs (nitrofurantoin, hydantoin), and inherited defects in folate metabolism.

The recommended daily allowance of folate during pregnancy is 800 μg/day. Dietary intake of up to 400 μg of folate can be achieved with a well-rounded diet. An additional 400 μg of synthetic folate from fortified foods or supplements is recommended. The treatment of anemia caused by folate deficiency is 4 mg of folate PO per day as soon as the condition is recognized.

Vitamin B12 deficiency (pernicious anemia) is primarily caused by deficiency in oral absorption. The most common type is that caused by autoimmune atrophic gastritis, which occurs most frequently in patients of Scandinavian and Northern European ancestry as well as those of Hispanic origins. This condition usually presents in women between 30 and 40 years of age. Rare causes of vitamin B12 deficiency, which should be considered, include infection by the fish tapeworm Diphyllobothrium latum, and chronic conditions such as Crohn’s disease. The diagnosis is made in patients demonstrating a macrocytic anemia with an abnormally low serum vitamin B12 level.

Treatment of patients with pernicious anemia is undertaken with parenteral therapy because oral absorption of vitamin B12 is deficient. Daily injections of 200 μg are given for the first week followed by weekly injections for 3 weeks and then once a month thereafter. Importantly, therapy must continue for life to prevent recurrence of anemia. Response to therapy is usually manifested by a brisk production of reticulocytes within the first few days of therapy.

Sickle cell disease