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Summary Table

Category	Details
Risk Factors	Multigravida, short interpregnancy interval, adolescent pregnancy, poor nutritional intake, vegetarian/vegan diet, twin/multiple gestation, history of menorrhagia prior to conception, low socioeconomic status, endemic areas for malaria or hookworm
Etiology	Most common: iron deficiency anemia (IDA) due to increased iron demands of pregnancy. Second most common: folate deficiency. Less common: B12 deficiency, thalassemia trait, anemia of chronic disease, sickle cell disease
Patient Presentation	Fatigue, exercise intolerance, dyspnea on exertion, pallor, pica (craving for ice/dirt/starch), dizziness, palpitations. Many patients are asymptomatic and detected only on routine prenatal labs
Classic Physical Exam	Conjunctival pallor, pale nail beds, tachycardia, koilonychia (spoon nails) in chronic IDA, glossitis and angular cheilitis in B12/folate deficiency, jaundice in hemolytic anemias
Key Diagnostic Results	Hemoglobin < 11 g/dL in 1st and 3rd trimesters, < 10.5 g/dL in 2nd trimester. IDA: low ferritin (< 30 ng/mL), low serum iron, elevated TIBC, low MCV (microcytic). Folate deficiency: low serum folate, elevated MCV (macrocytic), hypersegmented neutrophils on smear
Management	IDA: oral ferrous sulfate 325 mg (65 mg elemental iron) PO 1-3 times daily. Folate deficiency: folic acid 1 mg PO daily (higher dose 4-5 mg if history of neural tube defect). IV iron if oral therapy fails or intolerance. Transfusion for severe symptomatic anemia or hemoglobin < 7 g/dL
Keywords	"Physiologic anemia of pregnancy," "dilutional anemia," "pica," "low ferritin," "microcytic hypochromic," "neural tube defect prevention," "koilonychia"

1. Pathophysiology

Understanding anemia in pregnancy requires first understanding the normal physiologic changes of pregnancy. During pregnancy, maternal blood volume increases by approximately 40-50%, with plasma volume expanding by about 50% while red blood cell mass increases by only about 25-30%. This disproportionate expansion creates a dilutional effect, lowering the hematocrit and hemoglobin concentration even in healthy women. This phenomenon is called physiologic (dilutional) anemia of pregnancy and typically becomes most pronounced during the late second trimester (around 28-34 weeks). It is not a pathologic state and does not require treatment, but it is the reason pregnancy-adjusted hemoglobin thresholds exist.

True pathologic anemia in pregnancy, however, occurs when hemoglobin drops below these adjusted thresholds. The most common cause by far is iron deficiency anemia, accounting for approximately 75% of all anemia in pregnancy. The mechanism is straightforward: the developing fetus, placenta, and expanding maternal red cell mass together demand roughly 1,000 mg of additional iron over the course of pregnancy. Most women enter pregnancy with iron stores of only 300-500 mg, and dietary intake alone cannot bridge this gap. When stores are depleted, erythropoiesis becomes iron-limited, producing microcytic, hypochromic red blood cells that carry less hemoglobin per cell. This is why the MCV falls and the peripheral smear shows small, pale erythrocytes.

Folate deficiency is the second most common cause and is particularly important because of its dual consequence: it causes megaloblastic anemia (macrocytic RBCs with hypersegmented neutrophils) and independently increases the risk of neural tube defects (anencephaly, spina bifida) in the fetus. Folate demand rises during pregnancy due to rapid cell division in both the fetus and the maternal erythropoietic system. Unlike iron, folate stores are limited (lasting only a few months), so deficiency develops relatively quickly in the absence of supplementation. This is the pathophysiologic basis for universal periconceptional folic acid supplementation.

Vitamin B12 deficiency is uncommon in pregnancy but should be considered in vegan patients or those with malabsorption syndromes. Like folate deficiency, it produces a macrocytic anemia, but it additionally causes neurologic damage (subacute combined degeneration of the spinal cord) that folate supplementation alone cannot prevent or reverse. This distinction is tested: giving folate to a B12-deficient patient will correct the anemia but will mask ongoing neurologic deterioration.

In certain populations, inherited hemoglobinopathies and thalassemia traits are important considerations. Thalassemia trait (alpha or beta) produces a microcytic anemia that can mimic iron deficiency, but it does not respond to iron supplementation. Sickle cell disease patients face heightened risks in pregnancy including vaso-occlusive crises, acute chest syndrome, and increased fetal loss. These are not caused by pregnancy itself but are exacerbated by the increased metabolic and hemodynamic demands.

The consequences of untreated anemia in pregnancy are both maternal and fetal. Maternal risks include heart failure (from chronic high-output state as the heart compensates for reduced oxygen-carrying capacity), increased susceptibility to infection, poor wound healing, and increased transfusion risk at delivery. Fetal risks include intrauterine growth restriction (IUGR), preterm delivery, low birth weight, and in severe cases, fetal demise. The placenta has some ability to preferentially extract iron for the fetus even when the mother is deficient, but this compensatory mechanism fails when maternal stores are profoundly depleted.

2. Classification and Clinical Manifestation

Classification by MCV

Category	MCV	Causes in Pregnancy	Peripheral Smear Findings
Microcytic (MCV < 80 fL)	Low	Iron deficiency anemia, thalassemia trait, anemia of chronic disease (some cases), sideroblastic anemia (rare)	Microcytic hypochromic RBCs, target cells (thalassemia), pencil cells (IDA)
Normocytic (MCV 80-100 fL)	Normal	Physiologic anemia of pregnancy, acute blood loss, anemia of chronic disease, hemolytic anemias (sickle cell, autoimmune), mixed deficiency (iron + folate)	Normal morphology, sickle cells, spherocytes (autoimmune hemolysis)
Macrocytic (MCV > 100 fL)	High	Folate deficiency, B12 deficiency, hypothyroidism, medications (e.g., anticonvulsants like phenytoin, valproate)	Megaloblastic changes: macro-ovalocytes, hypersegmented neutrophils (5+ lobes)

Classification by Severity (WHO Criteria, Pregnancy-Adjusted)

Severity	Hemoglobin Level	Clinical Implications
Mild	10-10.9 g/dL (1st/3rd trimester) or 10-10.4 g/dL (2nd trimester)	Usually asymptomatic; respond well to oral supplementation
Moderate	7-9.9 g/dL	Symptomatic (fatigue, dyspnea, tachycardia); oral or IV iron depending on gestational age and tolerance
Severe	< 7 g/dL	High risk for maternal and fetal complications; likely requires parenteral iron or blood transfusion

Clinical Manifestation by Etiology

Etiology	Distinctive Clinical Features
Iron Deficiency	Pica (pagophagia = ice craving is most common), koilonychia, brittle nails, restless leg syndrome, Plummer-Vinson syndrome (esophageal web + dysphagia + IDA, rare but tested)
Folate Deficiency	Glossitis, diarrhea, no neurologic findings; history of poor vegetable/fruit intake or anticonvulsant use
B12 Deficiency	Glossitis, peripheral neuropathy, ataxia, loss of proprioception/vibratory sense (neurologic findings distinguish from folate); strict vegan diet, history of gastrectomy or ileal disease
Thalassemia Trait	Often asymptomatic with only mild microcytic anemia; family history from Mediterranean, Southeast Asian, or African descent; does not worsen proportionally despite iron-replete state
Sickle Cell Disease	Episodic pain crises, history of recurrent infections, functional asplenia, avascular necrosis; pregnancy increases crisis frequency

3. Diagnostic Workup

Test	Role	Expected Findings
CBC with indices	Best initial test; part of routine prenatal screening	Low Hb, low Hct, MCV guides differential (micro vs. normo vs. macro)
Peripheral blood smear	Morphologic evaluation	Microcytic hypochromic (IDA), target cells (thalassemia), macro-ovalocytes + hypersegmented neutrophils (B12/folate deficiency)
Serum ferritin	Best single test for iron deficiency; reflects total body iron stores	< 30 ng/mL confirms iron deficiency; < 15 ng/mL is diagnostic. Note: ferritin is an acute-phase reactant and may be falsely elevated in infection/inflammation
Serum iron, TIBC, transferrin saturation	Supports IDA diagnosis when ferritin is equivocal	IDA: low serum iron, elevated TIBC, low transferrin saturation (< 20%)
Reticulocyte count	Assesses bone marrow response	Low in production-failure anemias (IDA, B12, folate). Elevated in hemolytic anemias and after treatment response
Serum folate	Evaluates folate stores	Low in folate deficiency; RBC folate is more accurate for chronic deficiency but less commonly tested
Serum B12 (cobalamin)	Evaluates B12 stores	Low in B12 deficiency; methylmalonic acid (MMA) and homocysteine are elevated (MMA is more distinguishing from folate deficiency, where only homocysteine rises)
Hemoglobin electrophoresis	Gold standard for hemoglobinopathy diagnosis	Elevated HbA2 (> 3.5%) in beta-thalassemia trait; HbS in sickle cell disease; normal in alpha-thalassemia trait (requires genetic testing for confirmation)
Soluble transferrin receptor (sTfR)	Distinguishes IDA from anemia of chronic disease when ferritin is unreliable	Elevated in true iron deficiency; normal in anemia of chronic disease

The diagnostic workup begins at the first prenatal visit with a complete blood count (CBC). This is universal screening, and the hemoglobin and MCV together are the starting point for all further evaluation. The hemoglobin cutoffs for diagnosing anemia in pregnancy are trimester-adjusted: < 11 g/dL in the first and third trimesters, and < 10.5 g/dL in the second trimester (reflecting the peak of physiologic hemodilution).

Once anemia is identified, the MCV directs the differential. A low MCV (microcytic) points primarily toward iron deficiency or thalassemia trait. A high MCV (macrocytic) suggests folate or B12 deficiency. A normal MCV can represent physiologic dilutional anemia, acute blood loss, early iron deficiency (before MCV falls), or a mixed-deficiency picture where concurrent iron and folate deficiency normalize the MCV.

For suspected iron deficiency, serum ferritin is the best initial confirmatory test. A ferritin level below 30 ng/mL in a pregnant woman is consistent with depleted iron stores, and below 15 ng/mL is definitive. However, because ferritin is an acute-phase reactant, it can be falsely normal or elevated in the setting of concurrent infection, inflammation, or preeclampsia. In these situations, the combination of low serum iron, elevated TIBC, and low transferrin saturation supports the diagnosis. The soluble transferrin receptor (sTfR) level is another adjunctive test that is elevated in true iron deficiency but is not affected by inflammation, making it useful when ferritin is unreliable.

For macrocytic anemia, the distinguishing question is whether the deficiency is folate or B12. Both produce megaloblastic changes on peripheral smear (macro-ovalocytes and hypersegmented neutrophils). Serum folate and serum B12 levels are measured directly. When levels are borderline, metabolite testing helps: both folate and B12 deficiency elevate homocysteine, but only B12 deficiency elevates methylmalonic acid (MMA). This MMA distinction is a frequently tested pearl.

Metabolite	Folate Deficiency	B12 Deficiency
Homocysteine	Elevated	Elevated
Methylmalonic acid (MMA)	Normal	Elevated

If the MCV is low and ferritin is normal or elevated, thalassemia trait should be suspected, especially in patients of Mediterranean, Southeast Asian, Middle Eastern, or African descent. The next step is hemoglobin electrophoresis. In beta-thalassemia trait, HbA2 is elevated above 3.5%. In alpha-thalassemia trait, hemoglobin electrophoresis is often normal in adults, and definitive diagnosis requires genetic (DNA) testing for alpha-globin gene deletions. A helpful clinical clue is the Mentzer index ($MCV \div RBC\ count$): a ratio < 13 favors thalassemia, while > 13 favors iron deficiency. This is not definitive but is a useful screening tool.

Repeat CBC is recommended at 24-28 weeks (when physiologic anemia peaks) and again in the third trimester to monitor response to therapy and detect late-developing anemia.

4. Management and Treatment

Clinical Scenario	Management	Details
Prophylaxis (all pregnancies)	Prenatal vitamins with iron + folic acid	Elemental iron 27-30 mg/day + folic acid 0.4-0.8 mg/day starting at first prenatal visit (ideally preconception)
Mild-moderate IDA	Oral iron supplementation	Ferrous sulfate 325 mg PO (65 mg elemental iron) 1-3 times daily; take with vitamin C to enhance absorption; avoid concurrent calcium, antacids, tea, coffee
IDA with oral intolerance or non-response	IV iron	Ferric carboxymaltose 750 mg IV, repeated once after 7 days (total 1,500 mg); or iron sucrose 200 mg IV per infusion over multiple sessions. Preferred after 2nd trimester
Severe anemia (Hb < 7 g/dL) or hemodynamic instability	Packed RBC transfusion	Transfuse to stabilize; each unit raises Hb by approximately 1 g/dL. Follow with iron supplementation to replenish stores
Folate deficiency	Therapeutic-dose folic acid	Folic acid 1 mg PO daily; increase to 4-5 mg PO daily if prior pregnancy with neural tube defect, on antiepileptic drugs, or twin gestation
B12 deficiency	Cyanocobalamin	Cyanocobalamin 1,000 mcg IM weekly for 4 weeks, then monthly; or high-dose oral B12 (1,000-2,000 mcg PO daily) if compliance is assured
Thalassemia trait	Genetic counseling; avoid unnecessary iron supplementation	If both parents carry thalassemia trait, offer prenatal genetic testing (chorionic villus sampling or amniocentesis) to evaluate for thalassemia major in the fetus
Sickle cell disease in pregnancy	Multidisciplinary management	Continue folic acid 4 mg PO daily; aggressive hydration; pain management (avoid NSAIDs in 3rd trimester); transfusion if Hb drops below 7 g/dL or for acute complications; hydroxyurea is contraindicated in pregnancy (teratogenic)

Iron Deficiency Anemia

The cornerstone of treatment for mild-to-moderate IDA in pregnancy is oral iron supplementation. The standard regimen is ferrous sulfate 325 mg PO (containing 65 mg of elemental iron) taken one to three times daily, depending on severity. To optimize absorption, iron should be taken on an empty stomach or with a source of vitamin C (ascorbic acid), which converts ferric iron to the more absorbable ferrous form. Patients should be counseled to avoid taking iron simultaneously with calcium supplements, dairy products, antacids, tea, or coffee, all of which inhibit absorption.

Common side effects of oral iron include nausea, constipation, abdominal cramping, and dark-colored stools. These side effects are the leading reason for non-compliance. If a patient cannot tolerate the standard dose, an acceptable alternative is every-other-day dosing, which has been shown to maintain comparable absorption while reducing GI side effects. Another option is switching to ferrous gluconate (38 mg elemental iron per 325 mg tablet) or ferrous fumarate (106 mg elemental iron per 325 mg tablet), which some patients tolerate better.

Response to therapy should be assessed by checking a reticulocyte count at 1-2 weeks (an early rise confirms marrow response) and repeating hemoglobin at 4 weeks. A hemoglobin increase of at least 1 g/dL after 2-4 weeks of therapy confirms the diagnosis of IDA and adequate response. Iron supplementation should be continued for at least 3 months after hemoglobin normalizes to replenish ferritin stores to above 50 ng/mL.

If hemoglobin does not rise after 4 weeks of appropriate oral therapy, the differential includes: non-compliance, malabsorption (celiac disease, inflammatory bowel disease, H. pylori gastritis), ongoing blood loss, incorrect diagnosis (consider thalassemia trait or anemia of chronic disease), or inadequate dosing. This is the point at which IV iron becomes indicated.

IV iron is the preferred parenteral route in pregnancy. The two most commonly used formulations are:

Ferric carboxymaltose: 750 mg IV infused over 15-30 minutes, with a second dose of 750 mg given at least 7 days later (total course: 1,500 mg). This is preferred for its convenience (only 2 infusions needed).
Iron sucrose: 200 mg IV per infusion, given over multiple sessions (typically 5 infusions for a 1,000 mg total course). Considered safe throughout pregnancy.

Iron dextran carries a higher risk of anaphylaxis and is generally avoided in pregnancy when alternatives are available. A test dose is required if iron dextran must be used.

Blood transfusion is reserved for severe anemia with hemodynamic compromise (tachycardia, hypotension, dyspnea at rest) or hemoglobin below 7 g/dL approaching delivery. Transfusion is a bridge, not a cure; iron supplementation must follow to rebuild stores.

Folate and B₁₂ Deficiency Anemia

For folate deficiency, the treatment dose of folic acid 1 mg PO daily exceeds the prophylactic dose of 0.4-0.8 mg. Women with a prior neural tube defect-affected pregnancy should receive 4-5 mg PO daily, starting at least 1 month before conception and continuing through the first 12 weeks of pregnancy. This high-dose recommendation also applies to women on antiepileptic drugs (valproate, carbamazepine, phenytoin) that interfere with folate metabolism.

For B12 deficiency, replacement with cyanocobalamin 1,000 mcg IM is safe in pregnancy. The critical management pearl is to never give folate alone without first checking B12, because folate will partially correct the hematologic picture while allowing irreversible neurologic damage from B12 deficiency to progress silently.

Contraindications and Cautions

Agent	Contraindication/Caution in Pregnancy
Hydroxyurea	Teratogenic; must be discontinued before conception in sickle cell patients
Iron dextran	Higher anaphylaxis risk; avoid if alternatives available; requires test dose
Methotrexate	Absolutely contraindicated (category X); relevant if anemia is from a concurrent rheumatologic condition
NSAIDs	Avoid in the third trimester (premature closure of ductus arteriosus); relevant for pain management in sickle cell crises
Deferoxamine (iron chelation)	Used cautiously only in iron overload (e.g., transfusion-dependent thalassemia); potential teratogenic effects at high doses

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Looks Similar	Key Discriminator
Physiologic anemia of pregnancy	Hemoglobin is low, patient may be asymptomatic, occurs in all pregnancies	Hemoglobin typically does not drop below 10 g/dL; ferritin remains normal (> 30 ng/mL); MCV is normal. If Hb is below trimester thresholds with low ferritin, this is true IDA, not physiologic
Thalassemia trait	Microcytic anemia that mimics IDA on CBC	Ferritin is normal or elevated, RBC count is often elevated (not low as in IDA), Mentzer index < 13, hemoglobin electrophoresis shows elevated HbA2. Does not respond to iron therapy
Anemia of chronic disease	Microcytic or normocytic anemia with low serum iron, mimicking IDA	TIBC is low (not elevated as in IDA), ferritin is normal or elevated (acute-phase reactant), sTfR is normal. Underlying inflammatory or chronic condition is present
Folate deficiency vs. B12 deficiency	Both produce macrocytic, megaloblastic anemia with identical smear findings	Neurologic symptoms (paresthesias, ataxia, loss of vibratory sense) point to B12. Elevated MMA confirms B12 deficiency; MMA is normal in isolated folate deficiency
Aplastic anemia	Pancytopenia with fatigue and pallor in a pregnant woman	All three cell lines are depressed (anemia + leukopenia + thrombocytopenia); bone marrow biopsy shows hypocellular marrow. Rare but life-threatening in pregnancy
Hemolytic anemia (autoimmune)	Normocytic anemia with reticulocytosis	Elevated LDH, indirect bilirubin, low haptoglobin; positive direct Coombs test (DAT); spherocytes on smear
HELLP syndrome	Anemia with thrombocytopenia in the third trimester; can be confused with worsening pregnancy anemia	Presents with hemolysis (schistocytes), elevated liver enzymes, low platelets; associated with preeclampsia; occurs typically after 20 weeks

The distractor that catches students most often is the physiologic anemia vs. true IDA distinction. A vignette describing mild hemoglobin drop in the second trimester with normal ferritin is physiologic and requires no treatment. But if ferritin is low or MCV is reduced, it has crossed into pathologic territory. The second common trap is confusing IDA with thalassemia trait, both of which are microcytic. The ferritin level and response to iron are the discriminators: thalassemia trait will not correct with iron, and giving unnecessary iron to a thalassemia patient risks iron overload.

6. Traps and High-Yield Pearls

The most common way students get questions about anemia in pregnancy wrong is by failing to differentiate physiologic dilutional anemia from true iron deficiency. A vignette showing a mildly low hemoglobin at 28-30 weeks with a normal MCV and normal ferritin does not warrant iron therapy. Choosing to "start ferrous sulfate" in this scenario is the wrong answer; the correct response is reassurance and continued prenatal vitamins.

The second major trap is treating microcytic anemia as iron deficiency without confirming iron studies. If ferritin is normal and the patient has a family background consistent with thalassemia, the correct next step is hemoglobin electrophoresis, not iron supplementation. Giving iron to a thalassemia trait patient is not only ineffective but potentially harmful.

A third tested concept is the B12-folate masking phenomenon. A vignette may present a pregnant vegan woman with macrocytic anemia and neurologic complaints. If the student selects "folic acid supplementation" as the answer, the hematologic anemia will improve, but the neurologic damage will progress irreversibly. The correct answer is to check B12 first and replace it if deficient, before or alongside folate.

Students also lose points on the IV iron indication. The question will describe a patient who has been on oral iron for 4-6 weeks with no improvement (or who has GI intolerance preventing compliance). The next step is IV iron, not transfusion and not continued oral iron at a higher dose. Transfusion is reserved for hemodynamic instability or severe anemia near delivery.

Finally, for sickle cell disease in pregnancy, the tested trap is selecting hydroxyurea as part of management. Hydroxyurea is the mainstay of sickle cell disease treatment outside of pregnancy, but it is teratogenic and must be discontinued before conception. The correct management in pregnancy relies on folic acid supplementation, hydration, transfusion support, and close fetal monitoring.

The core competency being tested across anemia-in-pregnancy questions is the student's ability to correctly classify the anemia using MCV and iron studies, match the etiology to the appropriate treatment, and recognize when not to treat (physiologic anemia) or when standard therapy is contraindicated (hydroxyurea in sickle cell, iron in thalassemia trait).

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