Sustained neurocognitive improvement with hydroxyurea in Ugandan children with sickle cell anemia

Abstract: Neurocognitive impairment is common in sickle cell anemia (SCA) and worsens with age. We determined effects of multiyear, dose-intensified hydroxyurea therapy on neurocognitive functioning in children aged 3 to 9 years in a 2.5-year, single-arm, open-label trial in Uganda. We compared age- and sex-normalized neurocognitive scores at trial completion vs enrollment. Primary outcomes were age-adjusted neurocognitive z scores and the proportion with neurocognitive impairment at completion compared with at entry. Overall, 264 participants, mean age of 5.6 ± 1.7 years, were enrolled. Four died, 4 sustained overt strokes, and 4 withdrew or were lost to follow-up. Of 252 participants who completed the trial, the proportion with any neurocognitive impairment decreased from 18 (9.0%) to 5 (2.5%) (n = 199; P = .005). In specific domains, mean overall cognition z scores improved from −0.53 ± 1.10 to 0.15 ± 1.10 ( P < .001), and the number with impaired overall cognition decreased from 16 (8%) to 4 (2%) (n = 199; P < .001). For attention, mean z scores improved from −0.08 ± 1.01 to 0.51 ± 0.91 ( P < .001) and the number with impaired attention decreased from 3 (2.1%) to 1 (0.7%) (n = 146; P < .001). Improved cognition and attention were each strongly associated with higher baseline scores, better weight-for-age z scores, hemoglobin level and socioeconomic status but these were not associated with either test of executive function. These novel findings support the use of hydroxyurea for neurocognitive function protection and emphasize the importance of increased access for all children with SCA in sub-Saharan Africa. This trial was registered at www.clinicaltrials.gov as NCT04750707 .