What is the differential diagnosis for severe anemia in a pregnant woman?

Differential Diagnosis of Severe Anemia in Pregnancy

Iron deficiency anemia is by far the most common cause of severe anemia in pregnancy, accounting for the vast majority of cases, but you must systematically exclude other important etiologies including folate deficiency, vitamin B12 deficiency, hemoglobinopathies, and hemolytic anemias. 1, 2, 3

Primary Differential Diagnoses

Iron Deficiency Anemia (Most Common)

• This is the most prevalent cause, affecting up to 29.5% of women in the third trimester 4
• Suspect when hemoglobin <7.0 g/dL with microcytic indices (low MCV) 5
• Confirm with low serum ferritin, though remember ferritin is an acute phase reactant and may be falsely elevated during inflammation 6, 4
• Consider elevated serum soluble transferrin receptor and low transferrin saturation as supporting evidence 1

Folate Deficiency

• More common than B12 deficiency in pregnancy due to increased folate uptake and faster depletion of stores 7
• Presents with macrocytic anemia (elevated MCV) 3
• Critical to identify as folate deficiency can mimic HELLP syndrome with proteinuria and thrombocytopenia 7
• Serum folate levels <3 μg/L are diagnostic 7
• Associated with neural tube defects if present early in pregnancy 3

Vitamin B12 (Cobalamin) Deficiency

• Less common than folate deficiency but increasing in prevalence with rising rates of obesity and bariatric surgery 3
• Also presents with macrocytic anemia 3
• May be associated with fetal growth retardation, fetal insulin resistance, and excess adiposity 3
• Takes longer to develop than folate deficiency due to larger body stores 7

Hemoglobinopathies

• In women of African, Mediterranean, or Southeast Asian ancestry, consider thalassemia minor or sickle cell trait, especially if anemia is unresponsive to iron therapy 6, 5
• These conditions present with mild anemia that does not respond to standard iron supplementation 6
• Hemoglobin electrophoresis is diagnostic 5
• Must be identified to avoid unnecessary iron therapy and guide genetic counseling 1

Hemolytic Anemias

• Rare in pregnancy but can be life-threatening if not diagnosed promptly 8
• Consider thrombotic thrombocytopenic purpura (TTP), pregnancy-associated atypical hemolytic-uremic syndrome, or immune thrombocytopenia 2
• Peripheral blood smear showing schistocytes or spherocytes is key to diagnosis 5
• May present with thrombocytopenia and can mimic HELLP syndrome 7

Diagnostic Algorithm for Severe Anemia

Initial Laboratory Evaluation

• Confirm severe anemia with repeat hemoglobin/hematocrit (Hb <7.0 g/dL or Hct <27.0%) 6
• Obtain complete blood count with MCV and RDW 6, 9
• Check serum ferritin to assess iron stores 6, 9

Based on MCV Results

If Microcytic (Low MCV):

• Iron deficiency anemia is most likely 1
• Check transferrin saturation and serum soluble transferrin receptor if ferritin is equivocal 1
• Consider thalassemia if patient is of appropriate ethnic background and unresponsive to iron 6

If Macrocytic (High MCV):

• Check serum folate and vitamin B12 levels 3, 7
• Folate <3 μg/L confirms folate deficiency 7
• Low B12 confirms cobalamin deficiency 3

If Normocytic (Normal MCV):

• Obtain peripheral blood smear to evaluate for hemolysis 5
• Consider hemolytic anemia, chronic disease, or combined deficiencies 2, 8

Ethnicity-Specific Considerations

• For African, Mediterranean, or Southeast Asian ancestry: obtain hemoglobin electrophoresis if anemia is unresponsive to iron therapy after 4 weeks 6, 5
• This identifies thalassemia minor or sickle cell trait that would not respond to iron supplementation 6

Critical Pitfalls to Avoid

Physiologic Hemodilution vs. True Anemia

• Normal pregnancy causes hemodilution, lowering hemoglobin and hematocrit 5, 8
• Use trimester-specific cutoffs: <11.0 g/dL in first trimester, <10.5 g/dL in second/third trimester 5
• Severe anemia (Hb <7.0 g/dL) is never physiologic and requires urgent evaluation 5

HELLP Syndrome Mimics

• Severe folate/B12 deficiency can present with proteinuria and thrombocytopenia, mimicking HELLP syndrome 7
• Check folate and B12 levels in any pregnant woman with anemia plus proteinuria or thrombocytopenia 7
• This distinction is critical as treatment differs dramatically 7

Ferritin Interpretation

• Ferritin is an acute phase reactant and may be falsely elevated during inflammation or infection 6, 4
• A "normal" ferritin in the setting of inflammation may still represent iron deficiency 6
• Consider serum soluble transferrin receptor as a more reliable marker in inflammatory states 1

Combined Deficiencies

• Multiple nutritional deficiencies often coexist, particularly in women with poor dietary intake or malabsorption 3, 8
• Check for both iron and vitamin deficiencies simultaneously in severe anemia 3
• Combined deficiencies result in more severe anemia and worse outcomes 3