What is the recommended first‑line therapy and overall management strategy for iron‑deficiency anemia, including oral iron dosing, monitoring parameters, indications for intravenous iron or blood transfusion, and evaluation of underlying causes?

Management of Iron Deficiency Anemia

First-Line Treatment: Oral Iron

Start ferrous sulfate 200 mg (65 mg elemental iron) once daily immediately upon diagnosis—this is the preferred first-line treatment due to superior cost-effectiveness with equivalent efficacy to all other oral formulations. 1, 2

Optimal Dosing Strategy

• Once-daily dosing is superior to multiple daily doses because hepcidin levels remain elevated for 48 hours after iron intake, blocking further absorption and increasing side effects without improving efficacy 1, 2
• Take on an empty stomach for optimal absorption, though taking with food is acceptable if gastrointestinal side effects occur 1, 2
• Add vitamin C (ascorbic acid) 500 mg with each iron dose to enhance absorption, particularly critical when transferrin saturation is severely low 1, 2
• Avoid tea and coffee within 1 hour of taking iron as these powerfully inhibit absorption 1
• Alternative formulations (ferrous fumarate 106 mg elemental iron or ferrous gluconate 27-38 mg elemental iron) are equally effective if ferrous sulfate is not tolerated, though typically more expensive 1, 2

Expected Response and Monitoring

• Check hemoglobin at 2-4 weeks, expecting a rise of at least 10 g/L (1 g/dL) 1, 2
• Absence of hemoglobin rise of at least 10 g/L after 2 weeks strongly predicts subsequent treatment failure (sensitivity 90.1%, specificity 79.3%) 1
• Continue oral iron for 3 months after hemoglobin normalizes to fully replenish iron stores—total treatment duration typically 6-7 months 1, 2
• Monitor hemoglobin and red cell indices every 3 months for the first year, then again after another year 1, 2

Indications for Intravenous Iron

Switch to IV iron if any of the following criteria are met:

Absolute Indications

• Active inflammatory bowel disease with hemoglobin <10 g/dL—inflammation-induced hepcidin elevation severely impairs oral iron absorption, making IV iron first-line therapy 1, 2
• Intolerance to at least two different oral iron preparations (e.g., ferrous sulfate, ferrous fumarate, ferrous gluconate) 1, 2
• Failure of ferritin levels to improve after 4 weeks of compliant oral therapy 1, 2
• Post-bariatric surgery patients—disrupted duodenal absorption mechanisms make oral iron ineffective 1, 2

Relative Indications

• Celiac disease with inadequate response to oral iron despite strict gluten-free diet adherence 1, 2
• Ongoing gastrointestinal blood loss exceeding oral replacement capacity 1, 2
• Chronic kidney disease with functional iron deficiency (ferritin 100-300 ng/mL with transferrin saturation <20%) 2
• Chronic heart failure with iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL with transferrin saturation <20%) to improve exercise capacity 2, 3

Intravenous Iron Formulations

Prefer IV iron preparations that replace iron deficits with 1-2 infusions rather than multiple infusions to minimize risk and improve convenience 1, 2

Recommended Options

• Ferric carboxymaltose: 750-1000 mg per dose, can be administered over 15 minutes; give two doses separated by at least 7 days for total 1,500 mg per course 1, 3
• Ferric derisomaltose: 1000 mg as single dose 1
• Avoid iron dextran as first choice due to higher risk of anaphylaxis requiring test doses, though true anaphylaxis with any IV iron is very rare (0.6-0.7%) 1, 2

Safety Considerations

• Most reactions are complement activation-related pseudo-allergy (infusion reactions) rather than true anaphylaxis—stop infusion and restart 15 minutes later at slower rate for mild reactions 1
• Monitor serum phosphate levels in patients requiring repeat courses within 3 months, as ferric carboxymaltose carries risk of hypophosphatemia 3, 4
• Administer in medical facilities with resuscitation equipment available 1, 3

Blood Transfusion Indications

Blood transfusion is rarely required and should be reserved for severe symptomatic anemia with circulatory compromise 1, 2

• Target hemoglobin 70-90 g/L (80-100 g/L in unstable coronary artery disease) 1
• Since one unit of packed red cells contains only 200 mg elemental iron, follow restrictive transfusion with adequate iron replacement (preferably IV) to replenish stores 1
• Parenteral iron reliably produces clinically meaningful hemoglobin response within one week, making it preferable to transfusion in most cases 1

Evaluation of Underlying Causes

Premenopausal Women

• Assess menstrual blood loss first—menorrhagia, pregnancy, and breastfeeding account for iron deficiency in 5-10% of menstruating women 2
• Consider pictorial blood loss assessment charts (80% sensitivity and specificity for detecting menorrhagia) 2
• Screen for celiac disease with antiendomysial antibody and IgA measurement before pursuing endoscopy 2
• Gastrointestinal endoscopy not indicated in women under 45 years without upper GI symptoms, alarm features, or family history of colon cancer 2

Men and Postmenopausal Women

• Perform bidirectional endoscopy (upper endoscopy and colonoscopy) as recurrent blood loss is responsible for 94% of cases 5
• Test for Helicobacter pylori infection and celiac disease noninvasively—both are common causes 5

Special Population Considerations

Inflammatory Bowel Disease

• Treat active inflammation first to enhance iron absorption and reduce iron depletion 1, 2
• Use IV iron as first-line when hemoglobin <10 g/dL with active inflammation—IV iron is more effective (odds ratio 1.57 for achieving 2.0 g/dL hemoglobin increase) and better tolerated than oral iron 1, 2
• For mild anemia (hemoglobin >10 g/dL) with clinically inactive disease, oral iron may be appropriate if disease is truly quiescent 2

Pregnancy

• Start oral low-dose iron 30 mg/day at first prenatal visit for prevention 2
• Treat anemia with 60-120 mg/day elemental iron 2
• Refer pregnant women with hemoglobin <9.0 g/dL for further medical evaluation 2
• IV iron indicated during second and third trimesters if oral iron fails 2

Celiac Disease

• Ensure strict adherence to gluten-free diet to improve iron absorption 1, 2
• Progress to IV iron if iron stores do not improve with oral supplementation despite dietary compliance 1, 2

Critical Pitfalls to Avoid

• Do not prescribe multiple daily doses—this increases side effects without improving efficacy due to hepcidin-mediated absorption blockade 1, 2
• Do not stop iron therapy when hemoglobin normalizes—continue for 3 months to replenish stores 1, 2
• Do not continue oral iron indefinitely without response—reassess after 4 weeks and switch to IV iron if hemoglobin fails to rise 1, 2
• Do not prescribe oral iron to patients with active inflammatory bowel disease and hemoglobin <10 g/dL—this is ineffective and IV iron is first-line 1, 2
• Do not overlook vitamin C supplementation when oral iron response is suboptimal 1, 2
• Do not fail to identify and treat the underlying cause while supplementing iron 1, 2
• Do not defer iron replacement while awaiting investigations unless colonoscopy is imminent (iron can interfere with visualization) 2

Failure to Respond Algorithm

If no hemoglobin rise after 4 weeks of compliant oral therapy:

1. Assess for non-adherence to therapy 1, 2
2. Evaluate for continued blood loss 1, 2
3. Consider malabsorption syndromes (celiac disease, inflammatory bowel disease, post-bariatric surgery) 1, 2
4. Check for concurrent vitamin B12 or folate deficiency 1, 2
5. Evaluate for systemic disease, bone marrow pathology, or hemolysis 1
6. Switch to IV iron if oral iron failure confirmed 1, 2

If anemia does not resolve within 6 months despite appropriate therapy:

• Reassess for ongoing blood loss 2
• Consider further gastrointestinal investigation 2
• Consider hematology consultation for complex cases 2