Hydroxyurea promotes brain development in children with sickle cell anemia.

Sickle cell anemia (SCA) is associated with chronic anemia and cerebrovascular dysfunction, leading to progressive brain atrophy. Hydroxyurea (HU), a disease-modifying therapy, improves hematologic parameters and reduces stroke risk, but its long-term effects on brain development remain unclear. Even though clinician guidelines recommend initiation of HU in infancy, there is a persistent underuse of HU. We examined whether HU use initiated during childhood and long-term HU use can mitigate the changes in gray matter volume (GMV), white matter volume (WMV), total brain volume, and cortical thickness in children with SCA. We used FreeSurfer derived volumetrics to conduct historical longitudinal analyses on 330 MRI scans (2004-2024) from participants with SCA and healthy controls to understand the effects of HU on brain development. Linear mixed-effects models showed that SCA participants who started using HU before the age of 9 (+HU<9yo) and those who did not (-HU<9yo) showed reduced total brain volume, GMV, and WMV compared to healthy controls. However, specifically for GMV, the + HU< 9yo group exhibited higher values than -HU< 9yo group, which suggests that early HU initiation might have a neuroprotective effect. Also, compared to the controls, only the -HU< 9yo group showed a decrease in cortical thickness. Furthermore, participants who used HU for at least 1 year prior to scan (+HU>1 yr) had higher total brain volume and GMV compared to those who did not (-HU>1 yr). An interaction between age and long-term HU treatment indicated that long-term HU treatment may be more advantageous at early ages with effects diminishing across development.