The American Society of Hematology cerebrovascular guidelines for sickle cell disease (SCD) recommend surveillance using signaling questions to screen for neurocognitive difficulties, although the clinical utility of these signaling questions has yet to be established. This study aimed to determine the clinical utility of caregiver signaling questions for detecting significant neurocognitive impairment (defined as >
1.5 standard deviation [SD] below the normative mean on ≥2 measures) and domain-specific impairment (defined as >
1.5 SD below the normative mean) in children and adolescents with SCD. A total of 421 caregivers of children with SCD aged 8 to 17 years (62% hemoglobin SS (HbSS) or hemoglobin S-beta zero (HbSβ0) thalassemia) were asked 7 signaling questions. Children completed performance-based neurocognitive and academic measures. Children who were reported to have repeated a grade, did not obtain primarily A/B grades in school, had a history of learning difficulties, or whose caregiver reported concern for their learning were more likely to have significant neurocognitive impairment and obtained lower scores across all measures (all q <
0.05). History of learning difficulties emerged as the most sensitive and specific signaling question for detecting significant neurocognitive impairment (sensitivity, 0.64
specificity, 0.77) and domain-specific impairment (sensitivity range, 0.56-0.77
specificity range, 0.63-0.72). Cumulative caregiver report improved prediction of neurocognitive impairment beyond demographic/clinical factors alone. Although performance-based screening for all patients with SCD is the most effective means to identify those with neurocognitive or academic impairment, use of caregiver signaling questions represents a brief and low-cost method to improve the detection of patients with SCD in need of support.