In 2015, Catalonia introduced sickle cell disease (SCD) screening in its newborn screening (NBS) program along with standard-of-care treatments like penicillin, hydroxyurea, and anti-pneumococcal vaccination. Few studies have assessed the clinical impact of introducing NBS programs on SCD patients. We analyzed the incidence of SCD and related hemoglobinopathies in Catalonia and the change in clinical events occurring after introducing NBS. Screening 506,996 newborns from 2015 to 2022, we conducted a retrospective multicenter study including 100 screened (SG) and 95 unscreened (UG) SCD patients and analyzed SCD-related clinical events over the first six years of life. We diagnosed 160 cases of SCD, with an incidence of 1 in 3169 newborns. The SG had a significantly lower median age at diagnosis (0.1 y vs. 1.68 y, p < 0.0001), and initiated penicillin prophylaxis (0.12 y vs. 1.86 y, p < 0.0001) and hydroxyurea treatment earlier (1.42 y vs. 4.5 y, p < 0.0001). The SG experienced fewer median SCD-related clinical events (vaso-occlusive crisis, acute chest syndrome, infections of probable bacterial origin, acute anemia requiring transfusion, acute splenic sequestration, and pathological transcranial Doppler echography) per year of follow-up (0.19 vs. 0.77, p < 0.0001), a reduced number of annual emergency department visits (0.37 vs. 0.76, p < 0.0001), and fewer hospitalizations (0.33 vs. 0.72, p < 0.0001). SCD screening in Catalonia’s NBS program has effectively reduced morbidity and improved affected children’s quality of life.

Sickle cell disease (SCD) has large phenotypic variability. Systematic metabolomic profiling may provide insights into phenotypes and treatment responses. We conducted a scoping review on associations between blood metabolites, SCD-related complications, and therapies in studies analyzing ≥10 metabolites in red blood cells, whole blood, and plasma. Lipidomics-focused studies were excluded. Fifteen studies were included, focusing on metabolic profiling, clinical outcomes, or therapies (hydroxyurea, transfusion, and mitapivat). Metabolic profiling differentiated SCD from healthy controls and patients with HbSS and HbSC genotypes. Associations with hemolysis, vaso-occlusive events, nephropathy, TRV, and mortality were identified. Overall, metabolites were involved in arginine, tryptophan, glutamate metabolism, glycolysis, pentose phosphate pathway, and the Lands cycle. Some metabolites showed opposite correlations across complications or sample types. Despite growing interest, gaps remain in study designs, metabolite selection, genotype representation, and underexplored complications and therapies. Standardized, large-scale metabolomics studies are needed to advance personalized treatment in SCD.

Hydroxyurea (HU) is the most widely prescribed disease‐modifying treatment in sickle cell disease (SCD), though treatment responses vary due to metabolism and adherence. We examined HU blood levels and treatment response in patients with homozygous sickle cell disease (HbSS). We measured HU in whole blood of 955 SCD patients enrolled in GenoMed4All using mass spectrometry. HU detection was defined as Z‐score > 2.5 relative to untreated healthy controls. Among HbSS patients not receiving recent transfusion therapy ( n = 539), HU was detected in 39% (143/369) of HU‐prescribed patients ≥ 10 years (median age 31.8 [10.0–69.9]). In only 24% (23/109) of young patients (< 10 years, median age 5.9 [1.2–9.9]), HU was detected, despite comparable HU dosing (18.8 vs. 20.3 mg/kg/day). Detectable HU was associated with increased MCV ( p < 0.001), and in patients ≥ 10 years also with increased HbF, despite low HbF (< 10%) in 25%. Neutropenia occurred in 8.0% of patients with detectable HU, 4.5% with undetected HU. Only one patient had severe neutropenia (< 0.5 × 10e9/l). In young patients, neutropenia occurred in 1.4% with undetected HU, and in 8.7% with detected HU. This is the largest study to date that reports data on HU levels in HbSS patients. Most HU‐prescribed patients, particularly young patients, had undetectable HU levels. Low MCV, HbF, and absent toxicity in children and limited toxicity in adults suggest that treatment for patients with undetectable HU is suboptimal. These findings warrant the need to optimize dosing and adherence to improve treatment in SCD, especially in young patients.