Life-course associations of early-life risk factors, modifiable adult lifestyles, and transitions of cardiometabolic disease and multimorbidity: A prospective cohort study

Background Whether associations of early-life risk factors with cardiometabolic disease (CMD) transitions vary by adult lifestyles remains unclear. Objectives We aimed to examine the associations between early-life risk factors and CMD transitions, and to assess whether adult lifestyles can modify these associations. Methods We analyzed data from 174,718 adults participating in the United Kingdom Biobank prospective cohort study. We defined 5 CMD transitions using a multistate model: from CMD-free to first CMD (FCMD; including stroke, ischemic heart disease, and type 2 diabetes), from FCMD to cardiometabolic multimorbidity (CMM), and from CMD-free, FCMD, and CMM to death. An early-life risk score (ERS; 0-3) summed low birth weight, maternal smoking around birth, and absence of human milk feeding in infancy. Adult lifestyle was quantified using an adult lifestyle score (ALS) adapted from 4 behavioral metrics of the Life's Essential 8 framework, and data were collected at study enrollment when participants had a median age of 55 y. Results During a median follow-up of 14.6 y, individuals with both high early-life risk (ERS ≥2) and an unhealthy adult lifestyle (ALS: 0-49) had the highest risks for most adverse transitions, including CMD-free to FCMD [hazard ratio (HR): 2.04; 95% confidence interval (CI): 1.89, 2.21], FCMD to CMM (HR: 1.46; 95% CI: 1.27, 1.69), CMD-free to death (HR: 2.31; 95% CI: 1.95, 2.72), and FCMD to death (HR: 1.64; 95% CI: 1.34, 2.01). The associations of ERS with the risk of most CMD transitions were less pronounced among participants with a healthy adult lifestyle than among those with an unhealthy adult lifestyle. Conclusions Joint exposure to adverse early-life experiences and an unhealthy adult lifestyle was associated with elevated risks of CMD progression and mortality. Notably, the detrimental associations of early-life risk factors with specific CMD transitions were less pronounced among individuals with healthier adult lifestyles.