SUMMARY:

Anemia is the most common hematologic abnormality with adverse maternal-fetal consequences if left untreated. The most common causes of microcytic anemia include iron-deficiency anemia and hemoglobinopathies whereas macrocytic anemia is commonly caused by folate or B12 deficiency

Definition and Classification

CDC Definition of Anemia

• Hemoglobin or hematocrit <5th percentile based on trimester of pregnancy

Thresholds

• First trimester
  • Hemoglobin <11 g/dL or Hematocrit <33%
• Second trimester
  • Hemoglobin <10.5 g/dL or Hematocrit <32%
• Third trimester
  • Hemoglobin <11 g/dL or Hematocrit <33%

Classification

• Cell size volume used to distinguish etiology
  • Mean corpuscular volume (MCV) <80 fl: Microcytic anemia
  • MCV >100 fL: Macrocytic anemia

Physiologic Changes in Pregnancy

• Hemodilution
  • Plasma volume expands by 40 to 50% | Erythrocyte mass expands 15 to 25%
• Larger volume expansion vs RBC mass leads to a hemodilution and consequent decrease in hemoglobin and hematocrit values
• Iron requirements
  • At baseline approximately 2.3 g stored
  • Stores increase during pregnancy due to erythrocyte expansion, placental and fetal growth in anticipation of blood loss during delivery
• Approximately 1g of additional iron is needed during pregnancy
  • 70% classified as “functional iron” and the remainder stored
  • Majority of functional iron stored in red blood cell mass (80%)

Screening Recommendations

• CDC recommends
  • Universal screening for iron-deficiency anemia in pregnant women and universal iron supplementation except in presence of certain genetic disorders (i.e. hemochromatosis)
    • Recommended daily dietary allowance is 27mg daily during pregnancy and 9mg daily during lactation
    • Typical diet only confers approximately 15mg of daily iron
• CDC and ACOG recommends screening for iron-deficiency anemia with CBC twice in pregnancy
  • First trimester
  • Between 24w0d to 28w6d
• Initial evaluation may include
  • RBC indices | Serum iron levels | Ferritin
  • Empiric treatment with iron is reasonable | Expect reticulocytosis within 7 to 10 days and subsequent improvement in hemoglobin and hematocrit afterwards
• Race-based adjustment for anemia are no longer recommended due to possibility of perpetuating disparities in maternal and neonatal outcomes

Iron Deficiency Anemia

Prevalence

• Prevalence of iron-deficiency anemia during pregnancy varies based on trimester with an increasing prevalence as the pregnancy continues, but overall at 16% for all pregnant women in the US
• Rates of iron-deficiency anemia
  • First trimester; 7%
  • Second trimester: 14%
  • Third trimester: 29.5%

Risk Factors

• Race and parity
  • Pregnant teenagers | Mexican American | Non-Hispanic Black | Parity >2
• Diet
  • Poor in iron-rich foods: Clams, oysters, liver, beef, shrimp turkey, enriched breakfast cereals, beans, and lentils
  • Poor in food that enhance iron absorption: Orange juice, grapefruit, strawberries, broccoli, and peppers
  • Rich in foods that diminish iron absorption: Dairy products, soy products, spinach, coffee, and tea
• GI disease affecting absorption (e.g., Crohn’s disease or previous gastric bypass surgery)
• Short interval pregnancy <6 months

Screening

• Best screening test is measurement of serum hemoglobin or hematocrit, but non-specific for identification of iron deficiency
• Characteristic findings for iron-deficiency anemia include
  • Low serum ferritin levels | Note: Highest sensitivity and specificity for diagnosis
  • Microcytic hypochromic anemia
  • Low plasma iron levels (indicating depleted iron stores)
  • High total iron-binding capacity
  • Increased levels of free erythrocyte protoporphyrin

Diagnosis of Iron-Deficiency Anemia

• Diagnosis can be made multiple ways
  • Microcytic anemia with MCV <80 and anemia seen on CBC
  • Increase in Hemoglobin >1 g/dl after iron treatment
  • Absent bone marrow iron stores or bone marrow iron smear
  • Ferritin levels <30 microgram/L confirmatory
• ACOG recommends follow investigations for
  • Hematocrit <33% in the first and third trimesters
  • Hematocrit <32% in the second trimester

Treatment

• All women should be initiated on low-dose iron supplementation at the beginning of pregnancy due to low dietary iron intake regardless of presence of anemia
• If there is no reason to suspect other causes of anemia, “it may be reasonable to empirically initiate iron therapy without first obtaining iron test results”
• Oral therapy
  • The mainstay of treatment relies on oral iron therapy, typically initiated with 325mg (65 mg of elemental iron) BID with evaluation of hemoglobin levels after 2 weeks
  • After two weeks, if hemoglobin rises by more than 1 g/dL then continue supplementation
  • If hemoglobin does not rise more than 1 g/dL consider IV iron therapy
• Dosing of Oral Therapy
  • Traditionally, oral iron was given BID with vitamin C or with meals | No evidence has shown that Vitamin C supplementation improves absorption of iron
  • Note: Newer research (‘Clinical Expert Series’) shows that absorption of iron was optimal when 40 to 80mg of elemental iron was given on alternate days with reduced GI distress and improved compliance
• Parenteral iron (IV)
  •  Consistently associated with higher maternal hemoglobin at delivery with fewer medication reactions
  • Consider for patients who have difficulty tolerating oral iron or with severe iron deficiency later in pregnancy
  • Role of erythropoietin and iron versus iron alone is unclear and is without obvious benefits
• Transfusion
  • Consider for severe anemia (hemoglobin levels <6 g/dL) for fetal indications
  • Severe anemia associated with abnormal fetal oxygenation, non-reassuring fetal heart rate patterns, reduced amniotic fluid, fetal cerebral vasodilation, and fetal death

Macrocytic Anemia

• Characterized as megaloblastic (abnormally large immature RBC) or non-megaloblastic
  • MCV >115 fL almost always seen in folic acid or Vitamin B12 (cyanocobalamin) deficiencies

Megaloblastic Anemia

• Causes
  • Folate deficiency is typically the cause during pregnancy | Majority of cases due to diet poor of fresh leafy vegetables, legumes, or animal proteins
  • Rarely due to vitamin B12 deficiency | Can be seen after partial or total gastric resection, Crohn disease, or pernicious anemia (low vitamin B12 due to autoimmune disease)
• Folic acid requirements during pregnancy
  • Increase from 50 micrograms daily to 400 micrograms daily | Typically found in fresh leafy vegetables, legumes, and animal proteins
• Tests to confirm etiology
  • Folic acid and vitamin B12 levels can be measured
• Folate deficiency treatment
  • 1mg of folic acid daily
• Vitamin B12 deficiency treatment
  • 1,000 microgram IM monthly

Non-Megaloblastic Anemia

• Causes include
  • Alcoholism | Liver disease | Myelodysplasia | Aplastic anemia | Hypothyroidism

KEY POINTS: 

• Low-dose iron supplementation is recommended beginning in the first trimester for all pregnant patients except in presence of certain genetic disorders (i.e. hemochromatosis)
  • Recommended daily dietary allowance is 27 mg daily during pregnancy and 9 mg daily during lactation
  • Typical diet only confers approximately 15mg of daily iron
• Screening for anemia should include a complete blood count at least twice during pregnancy
  • During the first trimester and again between 24w0d to 28w6d
• Iron deficiency anemia should be treated with iron supplementation due to increased risk for
  • Low birth weight | Preterm delivery | Perinatal mortality
  • Parental iron is an effective alternative to oral iron supplementation
• Iron supplementation for anemia should be evaluated approximately two weeks after initiation to confirm appropriate rise in Hemoglobin levels
• Iron supplementation every other day is just as effective as daily or BID dosing with improved side effect profile and better tolerability and adherence
• Severe anemia (Hemoglobin < 6 g/dL)
  • Affects fetal oxygenation
  • Consider maternal transfusion for fetal benefit
• Intraoperative cell salvage is feasible and safe during pregnancy
  • Potentially effective at avoiding transfusion
  • Particularly useful for situations where significant blood loss is anticipated, such as placenta previa or accreta

Learn More – Primary Sources:

ACOG Practice Bulletin Number 233: Anemia in Pregnancy

ASH: How I treat anemia in pregnancy: iron, cobalamin, and folate

Clinical Expert Series: Iron Deficiency Anemia in Pregnancy