Friday, February 18, 2022

Anemia in Pregnancy (Thalassemia Trait) Case File

Posted By: Medical Group - 2/18/2022 Post Author : Medical Group Post Date : Friday, February 18, 2022 Post Time : 2/18/2022
Anemia in Pregnancy (Thalassemia Trait) Case File
Eugene C. Toy, MD, Patti Jayne Ross, MD, Benton Baker III, MD, John C. Jennings, MD

A 29-year-old G2P1 woman at 20 weeks’ gestation is seen for her second prenatal visit. Her antenatal history is unremarkable except for a urinary tract infection treated with an antibiotic 2 weeks ago. The patient was noted to be anemic on her prenatal screen with a hemoglobin level of 9.5 g/dL and a mean corpuscular volume (MCV) of 70 fL. On examination, her blood pressure (BP) is 100/60 mm Hg, heart rate (HR) 80 beats per minute (bpm), and she is afebrile. The thyroid gland appears normal on palpation. The heart and lung examinations are unremarkable. The fundus is at the umbilicus. The fetal heart tones are in the 140- to 150-bpm range. The evaluation of the anemia includes: ferritin level: 90 mcg/L (normal 30-100); serum iron: 140 mcg/dL (normal 50-150); hemoglobin electrophoresis: Hb A1 of 95% and Hb A2 of 5.5% (normal 2.2%-3.5%).

» What is the most likely diagnosis?
» What is the underlying mechanism?
» What is the significance of the anemia to the pregnancy?

Anemia in Pregnancy (Thalassemia Trait)                                                

Summary: A 29-year-old G2P1 woman at 20 weeks’ gestation is being seen for prenatal care. On examination, her BP is 100/ 60, HR 80 bpm, and temperature is normal. Her hemoglobin level is 9.5 g/ dL, with an elevated Hb A2 level.
  • Most likely diagnosis: Anemia due to β-thalassemia minor.
  • Underlying mechanism: Decreased β-globin chain production.
  • Significance of the anemia to pregnancy: Although there is a small risk of intrauterine growth restriction, the pregnancy is usually uncomplicated. Because there is risk of the baby developing thalassemia major, genetic testing and evaluation of the father of the baby should be offered.

  1. Know that iron deficiency and thalassemia are common causes of microcytic anemia.
  2. Understand that deficiency of folate and vitamin B12 are causes of macrocytic anemia.
  3. Know the diagnostic approach to anemia in pregnancy.


This pregnant patient has a mild anemia, since the hemoglobin level is less than 10.5 g/ dL. The red blood cell (RBC) indices give an indication of the etiology. In this case, the MCV is low, microcytic. The most common cause of microcytic anemia is iron deficiency. Typically, with a mild microcytic anemia in the absence of risk factors for thalassemia (such as Southeast Asian ethnicity), a trial of iron supplementation and recheck of the hemoglobin in 3 weeks would be the next step. This is called a therapeutic trial of iron. If the hemoglobin level improves, the evidence supports iron deficiency. If the hemoglobin level does not improve, iron studies and a hemoglobin electrophoresis would be the next step. In this case, iron studies were performed which were normal/ high normal, thus eliminating iron deficiency as a cause. The hemoglobin electrophoresis studies strongly suggest β-thalassemia trait (heterozygous for β-thalassemia) with the elevated A2 hemoglobin. If the patient had β-thalassemia homozygous disease, there would have been complications and clinical manifestations since childhood. The patient should now be counseled about her laboratory findings, and referred for genetic counseling, and instructed that her baby has a one in four risk for β-thalassemia disease if the father of the baby also has β-thalassemia trait. Extra iron should not be given, since these patients can be prone to iron overload.

Anemia in Pregnancy Thalassemia                                                      


ANEMIA: A hemoglobin level of less than 10.5 g/ dL in the pregnant woman.
IRON DEFICIENCY ANEMIA: A fall in hemoglobin level that is due to insufficient iron to meet the increased iron requirements in pregnancy.
THALASSEMIA: A decreased production of one or more of the peptide chains (most common are the α and β chains) that make up the globin molecule. This process may result in ineffective erythropoiesis, hemolysis, and varying degrees of anemia.
HEMOLYTIC ANEMIA: An abnormally low hemoglobin level due to red blood cell destruction, which may be divided into congenital causes and acquired causes.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY: An X-linked condition whereby the red blood cells may have a decreased capacity for anaerobic glucose metabolism. Certain oxidizing agents, such as nitrofurantoin, can lead to hemolysis.


Physiology of Pregnancy
Anemia is a common complication in the pregnant woman. It is most often due to iron deficiency, partially because of decreased iron stores prior to pregnancy and increased demands for iron (due to fetus need and expanded maternal blood volume). A hemoglobin level below 10.5 g/ dL is usually considered a sign of anemia in the pregnant woman, with a mild anemia between 8 and 10 g/dL and severe as less than 7g/dL.

Iron Deficiency
A gravid woman who presents with mild anemia and no risk factors for hemoglobinopathies (African-American, Southeast Asian, or Mediterranean descent) may be treated with supplemental iron and the hemoglobin level reassessed in 3 to 4 weeks. Persistent anemia necessitates an evaluation for iron stores, such as ferritin level (low with iron deficiency) and hemoglobin electrophoresis.

The size of the red blood cell may give a clue about the etiology. A microcytic anemia is most commonly due to iron deficiency, although thalassemia may also be causative. Results from a hemoglobin electrophoresis can differentiate between the two, and may also indicate the presence of sickle cell trait or sickle cell anemia. The different types of thalassemias are classified according to the deficient peptide chain. In β-thalassemia minor, for example, there is a decreased production of the β-globin chain. This particular thalassemia during pregnancy is usually safe for both the mother and fetus, and there is no specific therapy given other than prophylactic folic acid. Patients may be asymptomatic and go their whole life without being aware that they have β-thalassemia minor. Genetic counseling in a patient with a known hemoglobinopathy is important because if the baby inherits a recessive trait from both parents, it will typically be born with a more serious or fatal disease (ie, β-thalassemia major). A neonate born with β-thalassemia major may appear healthy at birth, but as the hemoglobin F level falls (and no β-chains are able to replace the diminishing γ-chains of the fetal hemoglobin), the infant may become severely anemic and fail to thrive if not adequately transfused. The life expectancy with transfusions is somewhere in the third decade.

Whereas the thalassemias are quantitative defects in a hemoglobin chain production, sickle cell disease involves a qualitative defect that results in a sickle-shaped and rigid hemoglobin molecule. Sickle cell anemia is a recessive disorder caused by a point mutation in the β-globin chain in which the amino acid glutamic acid is replaced with valine. This causes improper folding of the hemoglobin molecule, which results in either sickle cell disease (HbSS) or sickle cell trait (HbS), when only the sickle cell trait is inherited. A patient with sickle cell trait should not be discouraged to get pregnant as far as risk to her is concerned; however, her baby has a 1:4 chance of inheriting sickle cell disease if the father also has the sickle cell trait. Infants born with sickle cell disease typically do not show signs of being affected until about 4 months. Patients with sickle cell disease usually deal with symptoms related to anemia (ie, fatigue and shortness of breath) and pain. In pregnancy, women with sickle cell disease often have a more intense anemia, more frequent bouts of sickle cell crisis (painful vaso-occlusive episodes), and more frequent infections and pulmonary complications. Careful attention must be taken when a pregnant sickle cell patient presents in crisis because some of the symptoms may mimic other common occurrences during pregnancy (ectopic pregnancy, placental abruption, pyelonephritis, appendicitis, or cholecystitis), and they may be missed. All causes of fever, pain, and low Hg laboratory value should be considered before attributing it to a pain crisis. Also, these patients have a higher incidence of fetal growth retardation and perinatal mortality; therefore, serial ultrasonography is recommended.

Macrocytic Anemia
Macrocytic anemias may be due to vitamin B12 and folate deficiency. Because vitamin B12 stores last for many years, megaloblastic anemias in pregnancy are much more likely to be caused by folate deficiency.

Other Conditions
Less commonly, a woman with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop hemolytic anemia triggered by various medications such as sulfonamides, nitrofurantoin, and antimalarial agents. Nitrofurantoin is a common medication utilized for uncomplicated urinary tract infections. Affected women usually have dark-colored urine due to bilirubinuria, jaundice, and fatigue due to anemia. G6PD deficiency is more commonly seen in the African-American population.

In the pregnant woman with anemia, jaundice, and thrombocytopenia, the examiner must also consider other hemolytic processes, such as HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, which is a life-threatening condition best treated by delivery. In evaluating anemia, if other hematologic cell lines are also decreased, such as the white blood cell (WBC) count or platelet count, a bone marrow process, such as leukemia or tuberculosis infection of the marrow, should be considered. Bone marrow biopsy may be indicated in these circumstances.


2.1 A 30-year-old G1P0 woman complains of nausea and vomiting for the first 3 months of her pregnancy. She is noted to have a hemoglobin level of 9.0 g/ dL and a mean corpuscular volume of 110 fL (normal 90-105 fL). Which of the following is the most likely etiology of the anemia?
A. Iron deficiency
B. Folate deficiency
C. Vitamin B12 deficiency
D. Physiologic anemia of pregnancy

2.2 A 29-year-old G2P1 woman at 28 weeks’ gestation, who had normal hemoglobin level 4 weeks ago at her first prenatal visit, complains of 1 week of fatigue and now has a hemoglobin level of 7.0 g/ dL. She noted dark-colored urine after taking an antibiotic for a urinary tract infection. Which of the following is the most likely diagnosis?
A. Iron deficiency anemia
B. Thalassemia
C. Hemolysis
D. Folate deficiency
E. Vitamin B12 deficiency

2.3 A 33-year-old African-American G1P0 woman at 16 weeks’ gestation is diagnosed with sickle cell trait. Her husband also is a carrier for the sickle cell gene. Which of the following best describes the likelihood that their unborn baby will have sickle cell disease?
A. 1/ 100
B. 1/ 50
C. 1/ 10
D. 1/ 4

2.4 A 36-year-old G2P1 woman at 24 weeks’ gestation is noted to have fatigue of 4 weeks’ duration. Her hemoglobin level is 8.0 g/ dL, leukocyte count is 2.0 cells/ μL, and platelet count is 20 000/ μL. Which of the following is the most likely diagnosis?
A. Iron deficiency anemia
B. HELLP syndrome
C. Preeclampsia with severe features
D. Acute leukemia

2.5 A 31-year-old G3P2 woman at 34 weeks’ gestation presents to the OB Triage Unit due to nausea and “not feeling well.” The BP is 110/82. The fetal heart rate pattern is category 1. The hemoglobin level is 9.0 g/dL leukocyte count of 8000 cells/mL and platelet count is 84 000/fL, ALT of 500 IU/ L, AST 550 IU/L, and bilirubin of 2.5 mg/ dL. Which of the following is the most likely diagnosis?
A. Acute leukemia
B. HELLP syndrome
C. Hepatitis infection
D. Preeclampsia with severe features
E. Viral illness

2.6 A 28-year-old G1P0 woman who is at 32 weeks’ gestation with sickle cell anemia is admitted to the hospital for vaso-oclusive pain crisis due to severe pain of the back and hands. She is treated with intravenous fluids and oxygen and pain control. On hospital day 2, she develops acute dyspnea, and has an oxygen saturation level of 85% on room air. Her vital signs are: T 98.2°F, BP 130/80 mm Hg, HR 100 bpm, and RR 36/minute and labored. A chest x-ray shows a new left lower lobe infiltrate. A computed tomography (CT) angiography study is negative. Which of the following is the best treatment for this patient?
A. Anticoagulation
B. Antibiotic therapy
C. Beta-agonist respiratory therapy
D. Diuretic therapy
E. Exchange transfusion


2.1 B. This is a macrocytic anemia because the mean corpuscular volume is above normal. Macrocytic anemias include folate deficiency and vitamin B12 deficiency; however, folate deficiency is more commonly seen in pregnancy than vitamin B12 deficiency. Iron deficiency is a microcytic anemia (MCV below normal), and it is the most common cause of anemia in pregnancy. Physiologic anemia of pregnancy is a result of the physiologic hemodilution that occurs in the vasculature. There is a disproportionate increase in plasma volume over the increased RBC volume, and this “diluted state” also gives the appearance of a fall in the laboratory values of hemoglobin and hematocrit.

2.2 C. This 29-year-old woman at 28 weeks’ gestation complains of fatigue. She took an antibiotic for a urinary tract infection and then developed dark-colored urine. She was also probably icteric. Currently, her hemoglobin level is low, reflecting anemia. This constellation of symptoms likely reflects a hemolytic process probably due to G6PD deficiency. The dark urine suggests bilirubinuria. Other causes of hemolysis could include malaria, HELLP syndrome, autoimmune hemolytic anemia, or sickle cell crisis. In this case, the woman ingested an antibiotic, which likely was nitrofurantoin, a commonly prescribed medication for pregnant women. She does not have hypertension, symptoms of systemic lupus erythematosus or other autoimmune diseases, or pain suggestive of sickle cell disease.

2.3 D. With autosomal recessive disorders, when both parents are heterozygous for the gene (gene carriers), then there is a 1:4 chance that the offspring will be affected by the disease or will be homozygous for the gene. It is important for expectant mothers, who are at high risk for having sickle cell disease or trait, to get a hemoglobin electrophoresis in addition to other prenatal laboratory tests. They need to know what risks they may have during pregnancy and be counseled on how to have a healthy pregnancy with sickle cell disease. They should also know what kinds of risks they may have in either passing the disease or trait to their children and may seek genetic counseling for this reason. During pregnancy, pain crisis may be more severe, so it is especially important for these women to stay well hydrated and avoid dehydration. There is an increased rate of preterm labor and having a low-birthweight baby in a sickle cell patient, but with proper prenatal care, these women can have perfectly normal pregnancies.

2.4 D. Pancytopenia, a reduction in the number of RBCs, WBCs, and platelets circulating throughout the body, suggests a bone marrow process. None of the other answer choices involve low leukocyte counts (leucopenia). Low platelets (thrombocytopenia) may also be a manifestation of severe preeclampsia, and is part of the criteria for HELLP syndrome as well. Iron deficiency anemia involves low hemoglobin levels and is common in pregnancy due to decreased iron stored prior to pregnancy, and increased demands for iron during pregnancy. Since this patient’s blood work showed low WBCs, a bone marrow biopsy should be done. A pregnant woman with leukemia may require chemotherapy, which poses a risk of intrauterine growth retardation to the developing fetus. Acute leukemia itself carries a risk for preterm labor, spontaneous abortion, and stillbirth.

2.5 B. This patient likely has HELLP syndrome, which is hemolysis, elevated liver enzymes, and low platelets. An elevated serum LDH or evidence of fragmented erythrocytes would “clinch” the diagnosis. It is unlikely to be preeclampsia with normal blood pressure. There is no urine protein given, which would be elevated in preeclampsia. The leukocyte count is normal, speaking against leukemia. A viral illness can lead to mildly low platelets (100 000-120 000/ fL), and slightly elevated liver function tests (ALT 100-150 UI/mL), but not to this extent. Acute hepatitis should not affect the platelet count, and usually leads to ALT levels above 1500 IU/mL.

2.6 E. This patient likely has acute chest syndrome, which is vaso-occlusive disease of the lungs, leading to a new pulmonary infiltrate, acute dyspnea, and hypoxia. Pneumonia is a possibility but the patient does not have a fever or cough. Pulmonary embolism is less likely due to the negative CT angiography examination, which is treated with anticoagulation. There is no history of asthma or report of wheezing on examination, which would be treated with beta-agonist therapy. Acute chest syndrome that is severe is usually treated with a partial exchange transfusion. Antibiotics are also administered in case pneumonia is present.


» The most common cause of anemia in pregnancy is iron deficiency.
» The two most common causes of microcytic anemia are iron deficiency and thalassemia.
» An elevated A2 hemoglobin level is suggestive of β-thalassemia disorder, whereas an elevated hemoglobin F level is suggestive of α-thalassemia.
» For mild anemias, it is acceptable to initiate a trial of iron supplementation and reassess the hemoglobin level.
» The most common cause of megaloblastic anemia in pregnancy is folate deficiency.
» Hemolysis in individuals with glucose-6-phosphate dehydrogenase deficiency may be triggered by sulfonamides, nitrofurantoin, or antimalarial agents.
» Patients with sickle cell anemia may develop vaso-occlusive crisis. Acute chest syndrome affects the lungs and is diagnosed by a new pulmonary infiltrate, dyspnea, hypoxia after ruling out pulmonary embolism or pneumonia.
» Acute chest syndrome, a complication of sickle cell disease, when severe is best treated with partial exchange transfusion.


American College of Obstetricians and Gynecologists. Anemia in pregnancy. ACOG Practice Bulletin 95. Washington, DC; 2008. 

Castro LC, Ognyemi D. Common medical and surgical conditions complicating pregnancy. In: H acker NF, Gambone JC, Hobel CJ, eds. Essentials of Obstetrics and Gynecology. 5th ed. Philadelphia, PA: Saunders; 2009:191-218. 

Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap LC III, Wenstrom KD. Hematological disorders. In: Williams Obstetrics. 23rd ed. New York, NY: McGraw-Hill Education; 2010:1043-1167. 

Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap LC III, Wenstrom KD. Teratology, drugs, and medications. In: Williams Obstetrics. 24th ed. New York, NY: McGraw-Hill Education; 2014:1021.


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