When should iron and folic acid supplements be started in a patient with a febrile illness?

Timing of Iron and Folic Acid Supplementation in Febrile Illness

Defer iron supplementation until the febrile illness has resolved and inflammation has subsided, but folic acid can generally be continued or started during acute illness.

Key Principle: Inflammation Affects Iron Interpretation and Safety

• Serum ferritin and other iron markers are acute phase reactants that rise during inflammation and fever, making accurate assessment of true iron deficiency impossible during active illness 1
• Many micronutrient serum levels change as part of the inflammatory response—ferritin and copper increase, while folate, selenium, and zinc decrease during inflammation 1
• Do not administer intravenous iron in cases of active infection or uncontrolled severe inflammation, as recommended by multiple societies 2

Specific Timing Recommendations

For Iron Supplementation:

• Wait until clinical disease is inactive before starting oral iron therapy 1
• Oral iron should be considered first-line only in patients with mild anemia whose disease is clinically inactive and who have not been previously intolerant to oral iron 1
• Intravenous iron should be considered as first-line treatment in patients with clinically active inflammatory bowel disease (as a model for active inflammation), but this applies to chronic inflammatory conditions, not acute febrile illnesses 1
• The rationale is that active inflammation can exacerbate disease through generation of reactive oxygen species via the Fenton reaction from non-absorbed iron 1

For Folic Acid Supplementation:

• Folic acid supplementation can be initiated or continued during febrile illness, as there is no contraindication related to active infection 1
• Folic acid levels actually decrease during inflammation, making supplementation potentially beneficial during acute illness 1
• Selected patients on medications like sulfasalazine and methotrexate should continue folic acid supplementation regardless of illness status 1

Practical Algorithm for Clinical Decision-Making

Step 1: Assess for active fever/infection

• If fever present or acute infection suspected → defer iron supplementation
• Folic acid may be started or continued

Step 2: Once fever resolves (typically 48-72 hours afebrile)

• Reassess hemoglobin and ferritin levels
• Wait 8-10 weeks after any acute illness before measuring ferritin to evaluate true iron status, as early measurement may give falsely elevated results 2

Step 3: Initiate iron based on disease activity

• For clinically inactive disease with mild anemia → oral iron acceptable 1
• For active disease or hemoglobin <100 g/L → consider intravenous iron once inflammation controlled 1

Critical Caveats

• In malaria-endemic areas, there is evidence that routine iron-folic acid supplementation in children with febrile illness (potential malaria) may increase risk of severe illness and death 3
• In one large trial in Zanzibar, children receiving iron and folic acid were 12% more likely to die or need hospital treatment and 11% more likely to be admitted to hospital 3
• However, iron-deficient and anemic children can benefit from supplementation when there is an active program to detect and treat malaria and other infections 3

Special Populations

Pregnant Women:

• Iron status and folate levels should be monitored regularly, and supplementation provided when deficiencies are identified 1
• The consequences of anemia and neural tube defects warrant regular screening during pregnancy 1

Patients on Antifolate Antimalarials:

• There is theoretical concern about folic acid interfering with antifolate antimalarial efficacy, though evidence is limited 4
• Clinical judgment should guide whether to defer folic acid during acute antimalarial treatment