Risk Factors for Cerebral Vasculopathy in a Sickle Cell Disease Neonatal Cohort: A Prospective Study

Children with sickle cell disease have a significant vascular morbidity, specifically cerebral vasculopathy (CV) that can be detected by transcranial Doppler. The aim of this study was to identify CV risk factors using longitudinal biological and clinical data including upper and lower respiratory tract evaluation in the newborn cohort of Robert Debre Pediatric Sickle Cell Referral Center. 375 patients with sickle cell anemia with a total of 2677 patient-years and a 7 years median follow-up were evaluated. Among the 59 children presenting CV, seven had a stroke. Overall, the incidence rate of CV was 2.20/100 patient-years (95% CI 1.64-2.76) and the incidence rate of stroke was 0.26/100 patient-years (95% CI 0.07-0.46). The cumulative risk of CV by the age of 11.3 years was 26.0% (95% CI 20.0%-33.3%). CV risk factors were assessed by a Cox model encompassing linear multivariable modelling of longitudinal quantitative variables. The final model retained four variables. Years with upper airways obstruction (HR=1.47, 95%CI 1.05-2.06), bronchial obstruction (HR=1.76, 95%CI 1.49-2.08), fetal hemoglobin level (HR=0.68 per 5% increase 95%CI 0.48-0.96) and reticulocyte count (HR=1.82 per 50000/mm³ increase 95%CI 1.10-3.01) were independent risk factors. An ancillary analysis performed for the 209 patients with α-thalassemia data (29 patients with CV and 180 without) found that α-thalassemia was protective in bivariate analysis but was not retained in multivariable analysis. The final Cox multivariable analysis for CV in this subgroup retained three variables. Years with upper airways obstruction and bronchial obstruction were significant risk factors for CV (with respectively HR=1.57 IC95% [1.05-2.32] and HR=1.73 IC95% [1.37-2.17]) whereas fetal hemoglobin was protective (HR=0.54 per 5% increase IC95% [0.31-0.94]). Reticulocyte count was no more retained as risk factor for CV after introducing α-thalassemia in the final multivariable model. Early evaluation and specific treatment for symptoms of asthma or nocturnal respiratory abnormalities could potentially reduce the risk of CV and stroke. They are currently under evaluation in a multicenter clinical trial with systematic nocturnal polysomnography.