Chronic Hydroxyurea Therapy in Pediatric Sickle Cell Anemia: Efficacy, Mechanisms, and Safety

In children with sickle cell anemia, chronic hydroxyurea reduces vaso-occlusive events and improves systemic outcomes. Trial-level reductions in painful crises, acute chest syndrome, and transfusion requirements are consistently reported alongside predictable rises in fetal hemoglobin (HbF). Hematologic responses are durable across pediatric cohorts and translate into fewer hospitalizations and measurable quality-of-life gains. Overall, hydroxyurea offers clear disease-modifying benefit in pediatric sickle cell anemia.

HbF induction is the dominant mechanism: therapy increases HbF fraction and dilutes intracellular HbS, improving red blood cell deformability and lifespan. Typical pediatric responses show HbF increases into the mid‑teens to low‑30s percent range with a parallel mean corpuscular volume (MCV) rise of roughly 8–15 fL; reticulocyte counts fall as hemolysis declines. Reduced HbS polymerization lowers sickling, and hydroxyurea also modulates adhesive and inflammatory pathways, including enhanced nitric oxide–related signaling—together explaining the fall in vaso‑occlusive events.

Begin at a low dose and escalate to the maximum tolerated dose, using routine CBCs to detect marrow suppression and guide titration. Common practice uses CBCs every 4 weeks during escalation until counts stabilize, then every 8–12 weeks thereafter, with annual renal and hepatic screening; MCV and reticulocyte trends are practical pharmacodynamic markers and HbF guides. Precision-dosing strategies increasingly incorporate individualized HbF targets and clinical endpoints to pace escalation. The monitoring approach therefore balances achieving clinical effect with hematologic safety.

Long-term follow-up has not identified an increased malignancy risk and supports normal somatic growth and pubertal progression in treated children. Fertility data remain limited but generally reassuring: reversible semen abnormalities have been reported without consistent evidence of permanent gonadal failure. Surveillance priorities include tracking pubertal milestones and documenting reproductive counseling as patients near adolescence. Improved hematologic control also correlates with fewer stroke‑related complications and more stable neurocognitive trajectories in several cohorts, supporting a favorable long-term safety profile.

Mechanistic efficacy, pragmatic monitoring pathways, and reassuring long-term data position chronic hydroxyurea as foundational therapy in pediatric sickle cell anemia. Routine CBC- and organ-function–based surveillance facilitates safe up‑titration to clinical effect, and wider adoption of precision dosing plus registry-based follow-up will strengthen outcomes across practice settings. Emphasis on implementation and ongoing surveillance remains central to maximizing population‑level benefit.