Growth and puberty in African children with sickle cell anemia treated with hydroxyurea.

Children with sickle cell anemia (SCA) have poor growth and pubertal development. REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731) is a prospective trial evaluating the feasibility, safety, and benefits of hydroxyurea at maximum tolerated dose (MTD) for children with SCA in sub-Saharan Africa. Children 1-10 years old at 4 sites received open-label hydroxyurea with longitudinal follow-up. Height, weight, and pubertal (Tanner) staging were collected at enrollment and sequentially over 7 years of treatment. Biomarkers included insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3), luteinizing hormone (LH), follicle stimulating hormone (FSH), and anti-Mullerian hormone (AMH). Hydroxyurea commenced at an average (mean±1SD) age of 5.9±2.4 years (range 1.6-10.2) for girls (n=296) and 5.4±2.4 years (range 1.3-10.1) for boys (n=310). Using natural history SCA-specific reference curves, the mean weight-for-age Z-score improved from 0.47±0.90 at enrollment to 0.69±1.00 on hydroxyurea treatment. Height increased from 0.26±0.90 to 0.42±1.00 on treatment, and BMI from 0.46±1.00 to 0.85±1.20. IGF-I remained low in many participants: mean IGF-I was -1.5 SD at baseline and -1.4 SD at follow-up in girls, and -2.3 at baseline and -2.2 at follow-up in boys. Pubertal onset was delayed in 25-30% of children, with gradual progress on treatment. AMH was low (<2.5th percentile) in 4% of girls, while 52% of boys had low AMH at baseline and 28% at follow-up. Long-term hydroxyurea treatment at MTD is associated with beneficial effects on growth with improved weight and height, and does not negatively impact pubertal development in children with SCA in sub-Saharan Africa.