Syphilis-related mortality in the United States, 2021-2025: trends, demographic disparities, and clinical...

Syphilis-related mortality in the United States remains incompletely characterized in the post-pandemic period. This study aimed to quantify trends, demographic disparities, and geographic distribution of syphilis-related mortality from 2021 to 2025 using multiple causes of death data, with attention to their clinical implications.

A retrospective cross-sectional analysis was conducted using the CDC WONDER Multiple Cause-of-Death database. Decedents with ICD-10 codes A50-A53, listed as contributing causes, were included. Age-adjusted mortality rates (AAMRs) were calculated per 100,000 population using the 2000 US Standard Population. Poisson regression was used to estimate the annual percent change (APC) for temporal trends and rate ratios (RRs) for demographic comparisons. Eight pre-specified sensitivity analyses were performed, including restriction to the underlying cause of death only and assessment of HIV and COVID-19 co-occurrence.

A total of 1,148 syphilis-related deaths were identified, yielding an overall AAMR of 0.06 per 100,000 (95% CI: 0.06-0.07). No significant temporal trend was identified (APC: -1.24%, p = 0.550). Late-stage syphilis was recorded in 51.4% of deaths. The mortality rate among men was 2.5 times that of women (RR: 2.50; 95% CI: 2.20-2.83). The mortality among non-Hispanic Black individuals was 4.8 times that of non-Hispanic White individuals (RR: 4.81; 95% CI: 4.20-5.50). The South accounted for 50.3% of all deaths. HIV was co-listed in 27.5% of deaths, with a borderline increasing trend (APC: +8.25%; p = 0.047). More than half of the deaths occurred outside inpatient hospital settings.

Syphilis-related mortality remained stable but was concentrated in identifiable high-risk groups and geographical areas. The predominance of late-stage disease, high HIV co-occurrence, and substantial proportion of deaths in community and long-term care settings may reflect gaps in early detection and treatment retention, although death certificate data cannot directly establish these mechanisms. These findings have implications for clinical practice, public health screening programs, and targeted interventions in high-burden populations.

Not Applicable.