Paradoxical urban mortality penalty in sickle cell disease: A 20-year national analysis revealing age-dependent disparities

Abstract Background: Advancements in sickle-cell disease (SCD) management have improved care for ~100,000 affected Americans. However, mortality disparities between urban and rural populations, especially when considering age and sex, are still not well understood in the modern treatment era. While rural penalties exist for most chronic diseases, SCD patterns remain unknown. Methods: We used the CDC's WONDER database to identify all SCD-related deaths (ICD-10 D57 as underlying cause of death) from 2000 to 2020. Age-adjusted mortality rates were calculated and standardized to the 2000 US census data. We applied the 2013 NCHS metro–non-metro hierarchy. Then we stratified by sex and age (<24, 25–44, ≥45 years). Incidence rate ratios (IRRs) were computed using Poisson regression. Absolute risk differences per one million residents were calculated. Results: Contrary to expectations, a significant urban mortality penalty was observed. The study identified 10,647 SCD deaths; age-adjusted mortality peaked in large-central metros (0.37/100 000 in 2000; 0.30 in 2020) and declined step-wise with rurality. Mortality was 37% lower in rural counties (IRRs, 0.63; 95% CI 0.49–0.82) and 21% lower in large fringe metros (IRRs, 0.79; 95% CI 0.66–0.94) than in large central metros. This translates to an absolute risk difference of 1.1 deaths per million residents per year. This urban-rural mortality gradient was consistent across both sexes (males: IRR 0.71; females: 0.66, both p<0.001). Crucially, this urban-rural gap intensified dramatically with age (p-trend <0.001), IRRs were 0.79 (ages <25), 0.67 (ages 25-44), and 0.55 (ages ≥45). Among adults ≥45, urban residents faced nearly double the mortality risk of their rural counterparts. A concerning geographic shift occurred, with mortality rates rising 33% (2000-2010 vs 2011-2020) in suburban areas while declining 6% in large central metros, driven primarily by adults aged 25-44. Conclusion: This study, the largest to examine the spatial distribution of SCD mortality in relation to urban residency, reveals an unexpected urban disadvantage that worsens with age and an emerging mortality gap is centered in the suburbs. Fragmented care, emergency department reliance, and concentrated poverty in urban cores likely contribute. There is an imperative need for targeted resource investment in urban and suburban adult sickle cell disease care, including the implementation of mobile hydroxyurea clinics and community-based outreach programs.