What laboratory tests and clinical parameters should be monitored in a patient receiving iron therapy for restless‑legs syndrome?

Monitoring Requirements for Iron Therapy in Restless Legs Syndrome

All patients receiving iron therapy for RLS must have serum ferritin and transferrin saturation monitored every 6–12 months during ongoing treatment, with blood drawn in the morning after avoiding all iron-containing supplements and foods for at least 24 hours. 1, 2

Pre-Treatment Laboratory Assessment

Before initiating any iron therapy, the following baseline measurements are mandatory:

• Serum ferritin and transferrin saturation must be checked in all patients with clinically significant RLS, drawn in the morning after a ≥24-hour iron-free interval (American Academy of Sleep Medicine good practice statement, strong recommendation). 3, 1, 2
• Complete blood count (CBC) is reasonable to assess for iron-deficiency anemia, which is a well-established secondary cause of RLS with significantly higher prevalence in affected patients. 4
• Electrolytes and renal function are essential to identify chronic kidney disease, which requires different treatment algorithms (higher ferritin threshold of <200 ng/mL for iron supplementation in end-stage renal disease). 3, 4
• Thyroid function (TSH), calcium, and HbA1c should be obtained as part of the standard endocrine and metabolic screening to identify secondary causes of RLS. 4

The timing and preparation for iron studies is critical because ferritin has diurnal variation and recent iron intake can falsely elevate results, while inflammation can raise ferritin independent of true iron stores. 4

During-Treatment Monitoring

For Intravenous Ferric Carboxymaltose

• Clinical response typically requires up to 12 weeks to achieve full benefit; significant improvement is usually observed by week 12. 1
• Laboratory assays may overestimate serum iron and transferrin-bound iron in the 24 hours following administration by also measuring the iron in the infusion product itself (FDA label warning). 5
• Serum phosphate levels should be checked in patients requiring repeat courses of IV iron, especially if within 3 months, to monitor for hypophosphatemia—a known adverse effect occurring in 27% of patients in clinical trials and 13% in pediatric patients. 1, 5
• Transient decreases in laboratory blood phosphorus levels (<2 mg/dL) have been observed in 27% of patients receiving ferric carboxymaltose. 5

For Oral Iron (Ferrous Sulfate)

• Reassess symptoms and repeat iron studies after 3 months of oral therapy; if ineffective or not tolerated, switch to IV ferric carboxymaltose. 1
• Monitor for constipation, which is the most common side effect of oral iron and may limit tolerability, particularly in pediatric patients. 1, 2

Ongoing Surveillance

• Ferritin and transferrin saturation every 6–12 months during maintenance therapy, as RLS symptoms may recur if iron stores decline below therapeutic thresholds (ferritin ≤75 ng/mL or transferrin saturation <20% in adults; ferritin <50 ng/mL in children). 1, 2
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) at each follow-up visit. 2
• Monitor for side effects of concomitant alpha-2-delta ligands (gabapentin, pregabalin), including dizziness and somnolence, which may influence treatment decisions. 2

Special Population Considerations

End-Stage Renal Disease (ESRD)

• Use higher ferritin cutoff (<200 ng/mL) and transferrin saturation (<20%) to guide iron supplementation decisions, reflecting altered iron metabolism in ESRD. 3, 1
• IV iron sucrose (not ferric carboxymaltose) is the recommended formulation for ESRD patients meeting these criteria. 3, 1

Pregnancy

• Oral iron formulations are preferred throughout gestation due to favorable safety profile; continue monitoring ferritin and transferrin saturation given pregnancy-specific RLS prevalence. 1, 2

Pediatric Patients

• Monitor for constipation as the primary side effect of oral ferrous sulfate. 1, 2
• Use lower ferritin threshold (<50 ng/mL) for treatment decisions. 3, 1

Critical Pitfalls to Avoid

• Do not perform iron studies while the patient is taking iron supplements; wait ≥24 hours after the last iron-containing product to ensure accurate results. 1, 4
• Do not use general population ferritin cutoffs (<15–30 ng/mL) for RLS; higher thresholds (≤75 ng/mL in adults, <50 ng/mL in children) are required because brain iron deficiency plays a key role in RLS pathophysiology even when serum iron appears normal. 1, 2
• Do not assume symptom resolution means iron stores are adequate; maintenance surveillance with iron studies every 6–12 months is necessary, as brain iron deficiency may persist despite normal serum parameters. 1, 2
• Do not forget to check serum phosphate after repeat IV iron courses, particularly with ferric carboxymaltose, to detect hypophosphatemia. 1, 5