Mortality Trends and Causes of Death in Individuals with Thalassemia: A Population-Based Retrospective Study in the United States from 1999 to 2020
Authors: Tan Jia Yi , Yeo Yong Hao , Chan Kok Hoe , Shaaban Hamid , Guron Gunwant 
Published: December 2023

Background
Thalassemia is a hereditary hemoglobinopathy that results in ineffective erythropoiesis. Patients with thalassemia have varying degrees of severity ranging from mild anemia to severe complications due to iron overload. Despite its clinical significance, the study on the mortality rate among patients with thalassemia in the United States (US) remains scarce.
Objective
This study aimed to analyze the trends in thalassemia-related mortality rate and the underlying causes of death among individuals with thalassemia.
Methods
We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database and performed serial cross-sectional analyses of national death certificate data for thalassemia-related mortality among patients of all ages. Thalassemia (International Classification of Diseases, Tenth Revision [ICD-10] D56) was listed as the contributing cause of death. We calculated age-adjusted mortality rates (AAMRs) per 1,000,000 individuals and examined the trends over time by estimating the average annual percent change (AAPC) using the Joinpoint Regression Program. Subgroup analyses were performed by sex, age, race, census region, and urbanization level.
Results
From 1999 to 2020, there were 2,797 deaths related to thalassemia. Among these deaths, beta thalassemia accounted for 24.87%, alpha thalassemia accounted for 6.00%, thalassemia trait accounted for 2.52%, dominant thalassemia, hemoglobin C thalassemia, mixed thalassemia, or thalassemia with other hemoglobinopathies accounted for 1.92%, and unspecified thalassemia accounted for 64.37%. The baseline demographics of patients who met the inclusion criteria are shown in Table 1. Thalassemia-related mortality rate showed an overall decline in trend from 0.50 (95% CI, 0.41 - 0.58) per 1,000,000 individuals in 1999 to 0.34 (95% CI, 0.28 - 0.40) per 1,000,000 individuals in 2019, but increased to 0.48 (95% CI, 0.41 - 0.55) per 1,000,000 individuals in 2020 (Figure 1). The highest AAMR was observed among Asians (1.34 [95% CI, 1.20 - 1.47] per 1,000,000 individuals), followed by non-Hispanic Blacks (0.65 [95% CI, 0.59 - 0.71] per 1,000,000 individuals), non-Hispanic Whites (0.32 [95% CI, 0.30 - 0.33] per 1,000,000 individuals), and Hispanics (0.11 [95% CI, 0.08 - 0.14] per 1,000,000 individuals). The most common underlying causes of death among individuals with thalassemia were cardiovascular causes (26.0%), followed by hematological causes (20.7%), malignancy (17.8%), endocrine disorders (6.3%), respiratory causes (6.2%), disorders of the nervous system (5.0%), gastrointestinal diseases (4.9%), psychiatric disorders (3.3%), infection (3.0%), and other causes (6.7%). Among the cardiovascular causes, ischemic heart disease (11.0%) was the most common cause, followed by hypertensive disease (3.0%), cerebrovascular disease (1.7%), aortic valve disease (1.1%), cardiomyopathy (0.79%), and atrial fibrillation and flutter (0.79%). The urban population had a higher AAMR compared to the rural population (0.43 [95% CI, 0.41 - 0.45] per 1,000,000 individuals vs. 0.29 [95% CI, 0.26 - 0.32] per 1,000,000 individuals). Nevertheless, the rural areas exhibited an increasing trend in the AAMR (+6.90%) while the urban areas exhibited a decreasing trend in the AAMR (-11.36%) during the study period.
Conclusion
While there has been an overall decline in the thalassemia-related mortality rate, variations exist among different races, geographic regions, and urbanization levels. Our study emphasizes the need for targeted interventions to address these disparities.