Hydroxyurea to decrease stroke risk in children with sickle cell anemia: a systematic review and meta-analysis

Sickle cell anemia (SCA) is an inherited hemolytic anemia that causes stroke in children. Transcranial Doppler ultrasound (TCD) of the intracerebral arteries quantifies primary stroke risk. Chronic blood transfusions reduce risk but are not always feasible in lower resource settings. Hydroxyurea decreases TCD velocities in SCA, but the effect size and duration are unclear. We conducted a systematic review to understand hydroxyurea's effectiveness in children. We searched 5 major medical databases (CINAHL, EMBASE, Trip Medical Database, Scopus, and PubMed) and identified prospective clinical trials that enrolled children with SCA, performed TCD screening before hydroxyurea treatment, and collected serial measurements of TCD velocities and stroke incidence during hydroxyurea treatment. Citations were screened for inclusion, eligible citations selected, and data extracted. A total of 104 reports describing 13 clinical trials with 592 participants were included in the review. Hydroxyurea decreased TCD with a mean decline of -30 cm/s (95% confidence interval, -41 to -19) over 0.5 to 2.6 years of therapy. The TCD velocity normalized in most children. Stroke was reported in 3 trials, only occurred in those with persistent abnormal TCD values (>200 cm/s), and had lower incidence than expected (0.52-1.92 per 100 patient-years). Hydroxyurea is an effective strategy for reducing TCD velocities and stroke risk in children with SCA and is a feasible alternative when transfusions are unavailable, especially in resource-limited settings. Additional research is needed to clarify the effect on stroke incidence and optimal dosing strategies for durable treatment effect, long-term safety, and comprehensive benefits in diverse health care settings.