Reproductive Factors and Cardiovascular Risk in Postmenopausal Women by Obesity Status

Introduction: Early menarche (<12 years), menopause (<40 years), and a short reproductive lifespan (<35 years), have been associated with increased CVD risk. It is unclear whether these reproductive factors are independently associated with CVD risk or if associations are modified by adiposity. Purpose: Examine whether early menarche, menopause, and a short reproductive lifespan are independently associated with incident CVD and examine heterogeneity by obesity status. Methods: Postmenopausal women enrolled into the WHI observational study or trials with ages at menarche and menopause recalled at baseline were included. Reproductive lifespan was defined as the difference between age at menopause and menarche. Obesity was defined as either a waist circumference (WC) of ≥88 cm or a body mass index (BMI) of ≥30 kg/m 2 at enrollment. Incident CVD was a composite outcome including incidence of coronary artery disease, heart failure, peripheral artery disease, and stroke. Multivariable cox regression models assessed associations of reproductive characteristics and incident CVD, adjusting for lifestyle, demographic, and clinical factors. Interactions of reproductive factors, WC, and BMI were also examined. Results: At enrollment, participants (N=119182) were on average 68.2±7.1 years with a WC of 85.9±13.6 cm and BMI of 27.7±5.8 kg/m 2 . Over a median follow-up of 12.6 years, there were 12,731 (10.7%) incident CVD cases. Mean ages at menarche and menopause were 12.6±1.5 and 48.2±6.3 years, yielding an average reproductive lifespan of 35.6±6.4 years. Early menarche (HR: 1.15, 95% CI: 1.07-1.23), menopause (HR: 1.24, 95% CI: 1.12-1.38), and a short reproductive lifespan (HR: 1.15, 95% CI: 1.08-1.23) were significantly associated with increased risk of incident CVD. Excess menopausal adiposity significantly modified association of early menarche and CVD only ( Table ). Conclusions: Among postmenopausal women, age at reproductive transitions and duration of reproductive lifespan were independently associated with incident CVD. Future research should examine whether prioritizing weight management earlier in the life course, especially among those with menarche before age 12, impacts CVD risk and can inform public health strategies.