Approximately 54% of the deaths in our study were considered premature. In each category—NCDs, CMPN conditions, and injuries—more than half of the deaths occurred prematurely. Among these premature deaths, 79% were attributed to NCDs, with vascular diseases such as IHD and stroke being the most common causes. The identified risk factors for premature death included older age, tobacco and opium consumption, hypertension, and increased waist circumference. Conversely, protective factors included being female, having higher education levels, being married, engaging in high physical activity, possessing a greater hip circumference, and having a greater wealth score. Socioeconomic variables, including education and wealth score, and behavioral variables, including alcohol, opium, and tobacco use and physical activity, exhibited the highest PAF, respectively. By effectively managing these modifiable risk factors, substantial reductions of 61% and 48% in premature deaths can be achieved, respectively.
Globally, some studies have investigated the prevalence of premature death. For example, in the Golestan Cohort Study (GCS) conducted in northeastern Iran, the rate of premature death among participants aged 40–70 years was 63.3% (9). In our current investigation, a comparable 54% of deaths were deemed premature. In contrast, this rate was reported to be 4.5% in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study conducted among nine European countries with the same age range. According to the EPIC cohort study, 50% of premature deaths were attributed to cancer and 22% to CVDs (10). However, in the GCS, almost 50% of premature deaths are due to CVDs (9). Factors contributing to the elevated rates of premature deaths in this demographic may include both country-level and individual-level socioeconomic status; for example, rural residents with low levels of education (76% of participants had less than five years of education) and wealth score (52% falling within the first two quartiles of the wealth score) composed most of the participants in our study. Environmental factors, such as access to healthy food and venues for physical activity, and healthcare system factors are other important factors that affect premature mortality.
The most common causes of premature death in PCS participants were IHD, stroke, RTIs, lower respiratory infections, and COVID-19. Our findings align with the Global Burden of Disease (GBD) study, underscoring IHD, stroke, and RTIs as the primary contributors to premature mortality in Iran, mirroring patterns observed in upper-middle-income countries. The GBD study demonstrated that the specific causes contributing to premature death varied globally (27, 28). Premature deaths in the EPIC cohort study were primarily attributed to cancer (50%) and circulatory diseases (22%). In contrast, cohort studies conducted in Iran, including the PCS, GCS, and Tehran Lipid and Glucose Study, indicated that CVDs are the leading cause of death, with RTIs ranking among the top 5 causes of premature death. The leading causes of premature death in GCS participants are IHD, stroke, RTIs, stomach cancer, and esophageal cancer (9). The Tehran Lipid and Glucose Study cohort in Iran identified CVD, cancer, RTIs, sepsis, and pneumonia as the underlying causes of premature deaths (6, 11). In this study, RTIs were the third leading cause of premature death. According to the Global Status Report on Road Safety 2018, 93% of the 1.35 million global road traffic deaths occurred in low- and middle-income countries in 2016 (29). RTIs remain a public health concern in Iran, despite evidence of a decline in RTIs across all countries (30).
This study revealed that premature mortality due to the COVID-19 pandemic was one of the main causes of premature death, although only the first year of the pandemic was included in our analysis. The COVID-19 pandemic has had a significant impact on mortality worldwide. The Global Burden of Disease study revealed that while age-standardized mortality rates globally declined between 1950 and 2019 (a 62.8% decline), they increased considerably during the COVID-19 pandemic period (2020–21; by 5.1%) (31). Unprecedented reversals in adult mortality and life expectancy trends at the global and national levels during the pandemic highlighted the importance of paying comprehensive attention to both communicable and noncommunicable diseases simultaneously.
Cohort studies play a pivotal role in uncovering modifiable risk factors for premature deaths. In the GCS, noteworthy protective factors included wealth score, physical activity, education, and fruit/vegetable consumption. Conversely, significant risk factors included opium use, tobacco consumption, diabetes, and hypertension. The cumulative impact of these factors accounted for 73% of the PAF. The factors associated with the highest PAF were wealth score, physical activity, and hypertension (9). In our study, modifiable factors played a pivotal role, contributing to 83% of premature deaths. The Tehran Lipid and Glucose Study identified hypertension, diabetes, and current smoking as significant risk factors for premature mortality. Controlling these risk factors, particularly diabetes, hypertension, and smoking, has the potential to reduce mortality by more than 40% (11). In the PCS, opium use, hypertension, and tobacco consumption were considered among the most important modifiable risk factors.
Globally, some studies have sought to assess premature deaths, revealing regional variations in the significance of risk factors. These disparities arise from differences in the strength of associations and variations in the prevalence of these factors across diverse regions. The EPIC cohort study conducted on middle-aged individuals in Western Europe focused on evaluating modifiable causes of premature death (10). While smoking remains the primary contributor to premature mortality in Europe, other notable factors such as suboptimal dietary habits, overweight and obesity, hypertension, insufficient physical activity, and excessive alcohol consumption also play significant roles. The collective attributable fraction (AF) for these six risk factors was determined to be 57%.
In the PCS, the predominant cause of death was vascular disease, which included IHD and stroke. CVD accounts for a substantial proportion of global deaths, accounting for 31% annually, a trend partially attributed to population growth and aging (32). Findings from the PURE cohort study indicated that a substantial 70% of CVD and associated deaths can be attributed to a limited set of modifiable factors (33). Certain factors, such as high blood pressure and education, exert a widespread influence globally, while others, such as household air pollution and unhealthy eating habits, exhibit variability based on a country's economic status. Metabolic elements emerged as the primary contributors to the risk of CVD, constituting 41.2% of the PAF, with hypertension representing the most significant portion at 22.3% of the PAF. The INTERSTROKE case-control study identified various factors associated with all strokes, including a history of hypertension or elevated blood pressure, regular physical activity, apolipoprotein (Apo)B/ApoA1 ratio, dietary habits, waist-to-hip ratio, psychosocial factors, current smoking status, cardiac causes, alcohol consumption, and diabetes mellitus. Together, these factors contributed to 90.7% of the Population attributable risk (PAR) for all strokes globally (34). A case-control study known as the INTERHEART study revealed that abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruits, vegetables, alcohol, and regular physical activity are the primary contributors to the risk of myocardial infarction globally. Together, these nine risk factors were responsible for 90.4% of the total PAR (35).
In our study, opium exhibited the highest HR among the variables. Opium consumption notably correlated with elevated risks of death from diverse causes, including circulatory diseases and cancer (36). In the GCS study, long-term opiate consumption was related to increased cardiovascular death, independent of other known risk factors (37). Opium consumption was also associated with an increased likelihood of developing various cancers (38).
This study possesses notable strengths attributable to its prospective design, extensive and precise follow-up data, meticulous death ascertainment, and the incorporation of objective measurements alongside self-reported data. A comprehensive evaluation was conducted, including wealth score, eGFR, and non-HDL. Noteworthy strengths of this investigation included the availability of data for confounder adjustment and a less than 1% loss to follow-up rate. Several limitations characterize our study, including the limited sample size and the fact that the participants were solely from rural districts. The infrequent occurrence of premature death within our cohort may compromise the statistical power of our study, potentially impeding the detection of risk factors within specific subgroups. Furthermore, the absence of data on urban populations and individuals younger than 40 years can limit the generalizability of our findings. The impact of alcohol consumption could not be analyzed due to its low prevalence for religious reasons and absence from social habits. We recommend conducting further cohort studies on this subject to obtain comprehensive results and implement necessary interventions and policies based on the outcomes.
To decrease premature death several measures can be taken. The PolyPars study which was conducted in the PCS to assess the effectiveness of polypill (two antihypertensive agents, a statin and aspirin) for primary and secondary prevention of CVD demonstrated that it can safely halve the risk of major CVDs (39). Also, paying simultaneous attention to socioeconomic and behavioral factors is recommended. Because opium and road traffic have impressive negative effects, new policies and public awareness on these topics are suggested.