Anemia in Pregnancy

Anemia is one of the general and dangerous maternal problem during pregnancy if
left untreated. The Centers for Disease Control and Prevention defines anemia as a
hemoglobin concentration of <11 g/dL (hematocrit of <33%) in the first or third trimester or a
hemoglobin concentration of <10.5 g/dL (hematocrit <32%) in the second trimester. A
pregnant woman will lose blood during delivery and the puerperium, and an anemic woman
is at increased jeopardy of blood transfusion and its related complications.
During pregnancy, the blood volume increases by approximately 50% and the red
blood cell mass by approximately 33%. This relatively greater increase in plasma volume
results in a lower hematocrit but does not truly represent anemia.
Anemia in pregnancy most commonly results from a nutritional deficiency in either
iron orfolate. Pernicious anemia due to vitamin B12 deficiency almost never occurs during
pregnancy. Other anemias occurring during pregnancy include anemia of chronic disease;
anemia due to hemoglobinopathy; immune, chronic (eg, hereditary spherocytosis or
paroxysmal nocturnal hemoglobinuria), or drug-induced hemolytic anemia; and aplastic
anemia.
1.Iron Deficiency Anemia
Iron deficiency is responsible for approximately 95% of the anemias during pregnancy,
reflecting the increased demands for iron. The total body iron consists mostly of (1) iron in
hemoglobin (approximately 70% of total iron; approximately 1700 mg in a 56-kg woman)
and (2) iron stored as ferritin and hemosiderin in reticuloendothelial cells in bone marrow, the
spleen, and parenchymal cells of the liver (approximately 300 mg). Small amounts of iron
exist in myoglobin, plasma, and various enzymes. The absence of hemosiderin in the bone
marrow indicates that iron stores are depleted. This finding is both diagnostic of anemia and
an early sign of iron deficiency. Subsequent events are a decrease in serum iron, an increase
in serum total iron-binding capacity, and anemia.
During the first half of pregnancy, iron requirements may not be increased significantly, and
iron absorbed from food (approximately 1 mg/d) is sufficient to cover the basal loss of 1
mg/d. However, in the second half of pregnancy, iron requirements increase due to expansion
of red blood cell mass and rapid growth of the fetus. Increased numbers of red blood cells and
a greater hemoglobin mass require approximately 500 mg of iron. The iron needs of the fetus
average 300 mg. Thus, the additional amount of iron needed due to the pregnancy is
approximately 800 mg. Data published by the Food and Nutrition Board of the National
Academy of Sciences show that pregnancy increases a woman's iron requirements to
approximately 3.5 mg/d. This need outstrips the 1 mg/d of iron available from the normal
diet.
Prevention

It is unclear whether the well-nourished, nonanemic woman benefits from routine iron
supplementation during pregnancy. However, for women with a history of iron deficiency
anemia, at least 60 mg/d of elemental iron should be prescribed to prevent anemia during the
course of pregnancy and the puerperium.
Clinical Findings
Symptoms and Signs
The symptoms may be vague and nonspecific, including pallor, easy fatigability, headache,
palpitations, tachycardia, and dyspnea. Angular stomatitis, glossitis, and koilonychia (spoon
nails) may be present in long-standing severe anemia.
Laboratory Findings
The hemoglobin may fall as low as 3 g/dL, but the red cell count is rarely below 2.5 x
106/mm3. The red cells usually are hypochromic and microcytic, with mean corpuscular
volumes of less than 79 fL. Serum ferritin concentrations fall to less than 15
g/dL

and transferrin saturation to less than 16%. Serum iron levels usually are less than 60
g/dL. The total iron-binding capacity is elevated in both normal pregnancies and

pregnancies affected by iron deficiency anemia and therefore is of little diagnostic value by
itself. The reticulocyte count is low for the degree of anemia. Platelet counts are frequently
increased, but white cell counts are normal. Bone marrow biopsy demonstrates lack of
stainable iron in marrow macrophages and erythroid precursors but usually is unnecessary in
uncomplicated iron deficiency anemia.
Differential Diagnosis
Anemia due to chronic disease or an inflammatory process (eg, rheumatoid arthritis) may be
hypochromic and microcytic. Anemia due to thalassemia trait can be differentiated from iron
deficiency anemia by normal serum iron levels, the presence of stainable iron in the marrow,
and elevated levels of hemoglobin A2. Other less common causes of microcytic, hypochromic
anemia include sideroblastic anemia and anemia due to lead poisoning.
Complications
Iron deficiency anemia normally does not endanger the pregnancy unless it is severe, in
which case intrauterine growth retardation and preterm labor may result.
Angina pectoris or congestive heart failure may develop as a result of marked iron deficiency
anemia. Sideropenic dysphagia (Paterson-Kelly syndrome, Plummer-Vinson syndrome)
is a rare condition characterized by dysphagia, esophageal web, and atrophic glossitis due to
long-standing severe iron deficiency anemia.
Prevention
During the course of pregnancy and the puerperium, at least 60 mg/d of elemental iron should

be prescribed to prevent anemia.

Treatment
In an established case of anemia, prompt adequate treatment is necessary.
Oral Iron Therapy
Ferrous sulfate 300 mg (containing 60 mg of elemental iron, of which approximately 10% is
absorbed) should be given 3 times per day. If this agent is not tolerated, ferrous fumarate or
gluconate should be prescribed. Therapy should be continued for approximately 3 months
after hemoglobin values return to normal in order to replenish iron stores. Hemoglobin levels
should increase by at least 0.3 g/dL/wk if the patient is responding to therapy.
Iron is best absorbed in the ferrous or reduced form from an empty stomach. Administering
ascorbic acid at the time of iron supplementation creates a mildly acidic environment that
aids the absorption of iron.
Parenteral Iron Therapy
The indication for parenteral iron is intolerance of, or refractoriness to, oral iron. In most
cases of moderate iron deficiency anemia, the total iron requirements equal the amount of
iron needed to restore hemoglobin levels to normal or near normal plus 50% of that amount
to replenish iron stores.
Iron dextran is the most widely available parenteral iron preparation in the United States.
Each 2-mL vial provides 100 mg of elemental iron. After a 0.5-mL test dose, iron dextran can
be administered intramuscularly or intravenously at a rate not to exceed 100 mg/d of
elemental iron. Intramuscular injection must always be given into the muscle mass of the
upper outer quadrant of the buttock with a 2-inch, 20-gauge needle, using the Z technique (ie,
pulling the skin and superficial musculature to one side before inserting the needle to prevent
leakage of the solution and subsequent tattooing of the skin). Intramuscular iron raises
hemoglobin concentration only slightly faster than oral iron administration due to slow and
occasionally incomplete mobilization of iron from the muscle. Risks of parenteral iron
administration include anaphylactic reaction, muscle necrosis, and phlebitis.
2. Folic Acid Deficiency Anemia (Megaloblastic Anemia of Pregnancy)
Megaloblastic anemia of pregnancy is almost exclusively caused by folic acid deficiency and
is common where nutrition is inadequate. In the United States, access to fresh vegetables and
the fortification of grains makes folate deficiency much less common than in the developing
world.
In the nonpregnant woman, the minimum daily intake of folate necessary for adequate
hematopoiesis and to maintain stores is 50 mg. However, this requirement increases during
pregnancy. In order to meet this need and to decrease the neural tube defects associated with
folate deficiency, a dietary supplement of at least 400 mg/d of folic acid is recommended.
Additional folic acid may be required in states of heightened DNA synthesis, such as
multifetal gestation. Similarly, patients with a chronic hemolytic anemia such as sickle cell

anemia require additional folate supplementation in order to meet the demand imposed by
increased hematopoiesis. Other hemolytic states are also commonly complicated by folic acid
deficiency, including hereditary spherocytosis and malaria.
Folic acid absorption or metabolism may be impaired by the use of oral contraceptives,
pyrimethamine, trimethoprim-sulfamethoxazole, primidone, phenytoin, or barbiturates.
Alcohol consumption also interferes with folate metabolism. Jejunal bypass surgery for
obesity or the malabsorption syndrome (sprue) may impair folic acid absorption.
Clinical Findings
Symptoms and Signs
The symptoms are nonspecific (eg, lassitude, anorexia, nausea and vomiting, diarrhea, and
depression). Pallor often is not marked. Rarely, a sore mouth or tongue is present.
Occasionally, purpura may be a clinical manifestation. Megaloblastic anemia should be
suspected if iron deficiency anemia fails to respond to iron therapy.
Laboratory Findings
Folic acid deficiency results in a hematologic picture similar to that of true pernicious anemia
(due to vitamin B12 deficiency), which is extremely rare in women of childbearing age.
The hemoglobin may be as low as 46 g/dL, and the red cell count may be less than 2
million/
L in severe cases. Extreme anemia often is associated with leukocytopenia

and thrombocytopenia.
The red cells are macrocytic (mean corpuscular volume usually > 100 fL) and appear as
macroovalocytes on peripheral blood smear. However, in pregnancy macrocytosis may be
concealed by accompanying iron deficiency or thalassemia. Up to 70% of folate-deficient
patients also lack iron stores.
Serum folate levels less than 4 ng/mL are suggestive of folic acid depletion in nonpregnant
patients. However, in otherwise normal pregnant patients, folate tends to fall slowly to low
levels (36 ng/mL) with advancing gestation. The red cell folate level in megaloblastic
patients is lower, but in 30% of patients the values overlap. The peripheral white blood cells
are hypersegmented. Seventy-five percent of folate-deficient patients have more than 5%
neutrophils with 5 or more lobes, but this also may be true for 25% of normal pregnant
patients.
The urinary excretion of formiminoglutamic acid (FIGLU) has been used to diagnose folate
deficiency, but levels are abnormal only in severe megaloblastic anemia. Bone marrow
aspirate demonstrates megaloblastic erythropoiesis but usually is not necessary for diagnosis.
Serum iron and vitamin B12 levels should be normal.
Treatment
Folic acid 15 mg/d orally is continued for several weeks after delivery or for several weeks

in patients diagnosed in the puerperium. This therapy produces the maximum hematologic
response, replaces body stores, and provides the minimum daily requirements. The
hematocrit should rise approximately 1% each day, beginning on day 56 of therapy. The
reticulocyte count should become elevated after 34 days of therapy and is the earliest
morphologic sign of response. Iron supplementation should be administered as indicated.
Prognosis
Megaloblastic anemia due to folate deficiency during pregnancy carries a good prognosis if
adequately treated.
The anemia usually is mild unless associated with multifetal pregnancy, systemic infection, or
hemolytic disease (eg, sickle cell anemia). Low birthweight as well as fetal neural tube
defects are known to be associated with maternal folic acid deficiency. The associations with
placental abruption, spontaneous abortion, and preeclampsiaeclampsia are not universally
accepted. Even without treatment, anemia due to folate deficiency usually resolves after
delivery when folate demands normalize.
3. Aplastic Anemia
Aplastic anemia with primary bone marrow failure during pregnancy is rare. The anemia may
be secondary to exposure to known marrow toxins, such as chloramphenicol,
phenylbutazone, mephenytoin, alkylating chemotherapeutic agents, or insecticides. In
approximately two-thirds of cases, no obvious cause is detected. Idiopathic aplastic anemia in
pregnancy may have a spontaneous remission following delivery or pregnancy termination
but may recur in subsequent pregnancies. The condition likely is immunologically mediated.
Clinical Findings
The rapidly developing anemia causes pallor, fatigue, tachycardia, painful ulceration of the
throat, and fever. The diagnostic criteria are pancytopenia and empty bone marrow on biopsy
examination.
Complications
Aplastic anemia in pregnancy may cause increased fetal wastage, prematurity, or intrauterine
fetal demise. Increased maternal morbidity and death usually are due to infection and
hemorrhage.
Treatment
The patient must avoid any toxic agents known to cause aplastic anemia. Blood product
replacement with packed red blood cells and platelets should be utilized as needed. In some
cases, delivery or termination of pregnancy may be necessary. Bone marrow transplantation
is performed if remission does not occur following delivery or termination of pregnancy.
Other possible treatments include antithymocyte antibody, corticosteroids, or
immunosuppressive agents. Infection must be treated aggressively with appropriate
antibiotics, but most authorities do not recommend giving prophylactic antibiotics.
4 . Drug-Induced Hemolytic Anemia

Drug-induced hemolytic anemia usually occurs as a result of drug-mediated immunologic red

cell injury. For example, a drug can act as a hapten with an erythrocyte protein to which an
antidrug antibody attaches. Hemolysis occurs as a result of the subsequent immune response.
Many drugs used in pregnancy can have such an effect, including cephalosporins,
acetaminophen, and erythromycin.
In African-American women, drug-induced hemolytic anemia is more likely caused by druginduced oxidative damage rather than a drug-mediated immune mechanism. The most
common congenital erythrocyte enzymatic defect to cause this condition is glucose-6phosphate dehydrogenase (G6PD) deficiency. This X-linked disorder causes a
heterozygous state in 1015% of African-American females, but enzyme activity is variable
due to random X-chromosome inactivation.
Decreased G6PD activity in one-third of patients in the third trimester causes an increased
risk of hemolytic episodes. More than 40 substances toxic to susceptible people are
recognized, including sulfonamides, nitrofurans, antipyretics, some analgesics, sulfones,
vitamin K analogues, uncooked fava beans, some antimalarials, naphthalene, and nalidixic
acid. Specific laboratory tests to identify susceptible individuals include a glutathione
stability test and cresyl blue dye reduction test.
Clinical Findings
The red blood cell count and morphology are normal until hemolysis occurs. Levels of
anemia are variable depending on the degree of hemolysis.
Complications
Exposure of the G6PD-deficient fetus to maternally ingested oxidant drugs (eg,
sulfonamides) may produce fetal hemolysis, hydrops fetalis, and fetal death. A black pregnant
woman probably should be screened for G6PD deficiency before starting sulfonamide
therapy for urinary tract infection.
Treatment
Management includes immediate discontinuation of any suspected medications, treatment of
intercurrent illness, and blood transfusion where indicated.

Cunningham, F. Gary and J. Whitridge Williams. Williams

Obstetrics 24th edition. New York: McGraw-Hill Professional,

2014.
Dutta DC. Textbook of obstetrics including perinatology and
contraception. The Health Sciences Publisher: 2015.