Neurodevelopment in Infants with Sickle Cell Anemia: Baseline Data from the Baby HUG Trial
Authors: Armstrong F. Daniel , Elkin T. David , Brown R. Clark , Glass Penny , Rees Renee C. , Wang Winfred C. , Investigators The Baby HUG 
Published: October 2019

Abstract
Delays and deficits in neurodevelopment are known complications of sickle cell anemia (SCA) in young children1. Hydroxyurea is a chemotherapeutic agent that increases production of fetal hemoglobin, and has proven effective in reducing pain and other SCA-related complications in adults, adolescents, and school-age children. To determine whether treatment with hydroxyurea for 24 months would benefit infants with SCA, the NHLBI initiated a multi-center, randomized, double-blind, placebo-controlled clinical trial (NCT00006400) in 2003 (BABY HUG). After screening 233 infants for eligibility, 193 infants 9 to 17 months of age from 14 participating institutions were randomized. While the primary outcomes for BABY HUG are spleen and kidney function, neurodevelopment is an important safety assessment and a secondary outcome. Two hundred and seven (male=89, female = 117) infants were administered the Bayley Scales of Infant Development-2nd Edition (BSID-II) by qualified psychological examiners during the screening phase of the trial. The infants also completed a transcranial Doppler ultrasound (TCD) to determine flow velocity in seven ascending arteries of the brain. The analyses for this report focused on the relationships between neurodevelopmental function on the BSID-II, age at study entry and TCD flow velocities. Overall the mean neurodevelopmental function of the sample was in the average range (mean Motor Developmental Index= 96.8; mean Mental Developmental Index = 96.3). Age at study entry (continuous and categorical) was significantly correlated with the Mental Scale of the BSID-II (p=0.0042, p=0.0001, respectively). On average, a child’s Mental Developmental Index (MDI) decreased by 0.75 for every one month increase in age. Age (categorical) was also significantly associated with the Motor Scale of the BSID (p=0.0255). TCD velocity has been shown to be a sensitive indicator of existing and future risk for central nervous system (CNS) events in children with SCA. In children age 2–16 years, flow velocities over 200mm/ sec are associated with significant stroke risk; flow velocities between 170–200 mm/sec are associated with potential risk for neurodevelopmental deficits. Early associations between TCD and neurodevelopment could be considered important clinical indicators of risk for future CNS events. BSID Mental Scale scores were significantly associated with the maximum (of left or right) flow velocity in the M-1 artery (p=0.04) and the Behavior Rating Scale scores were significantly associated with the dICA velocity (p=0.008). In both of these cases, higher flow velocity was associated with poorer neurodevelopmental function. These results reflect the function of a large group of infants and toddlers with SCA prior to the initiation of any treatment targeting the CNS. Although the overall function of the group was in the average range, it is concerning to find strong relationships between increasing age at enrollment and decreasing MDI and between higher TCD flow velocity and decreased neurodevelopmental function in these very young children. The importance of early screening and perhaps sequential assessment of infants with both TCD and neurodevelopmental assessments is raised by these findings, as is the importance of continuing efforts to determine whether interventions, such as early HU therapy, might favorably impact the CNS complications of this disease that affect neurodevelopment.