Association of Female Reproductive Factors with Incident Cardiometabolic Disease: Finding from a European Population-Based Study

Abstract

Background: Cardiometabolic diseases (CMD), including ischemic heart disease, stroke, and type 2 diabetes, have caused an enormous global healthcare burden. Beyond traditional risk factors, female reproductive factors may also be associated with CMD. However, comprehensive evaluations of female reproductive factors related CMD is limited.

Methods: A total of 189,411 women with no prior CMD from the UK Biobank cohort from 2007 to 2010 were included and followed until December 2022. Associations between reproductive factors and CMD were analyzed using Cox proportional hazards models with adjustment for potential confounders based on the directed acyclic graph (DAG).

Results: During a median follow-up of 13.2 years, 17,251 incident CMD events occurred. Compared to menarche at age 12-13 years, <12 years and >13 years had a higher risk of CMD (HR <12 year (y) vs 12-13 y: 1.04 [95% CI, 1.01-1.08]; >13 y vs 12-13 y: 1.08 [1.04-1.13]). Earlier age at menopause was related to a higher risk of CMD (HR <46 y vs 50-51 y: 1.22 [1.15-1.29]; 46-49 y vs 50-51 y: 1.08 [1.03-1.14]), and a short reproductive lifespan (HR <33 y vs 36-38 y: 1.19 [1.13-1.25]; 33-35 y vs 36-38 y: 1.08 [1.03-1.14]). Younger age at first live birth (HR <22 y vs 24-26 y: 1.18 [1.12-1.24]; 22-23 y vs 24-26 y: 1.06 [1.00-1.12]) and last live birth (HR <26 y vs 29-30 y: 1.12 [1.06-1.18]) were associated with higher risk. Women with three or four children (HR 3-4 children: 1.21 [1.15-1.28]) and those with more than four children (HR >4 children: 1.27 [1.07-1.52]) were associated with higher risk of CMD. Recurrent pregnancy loss was associated with a 39% and 14% higher risk of CMD, respectively.

Conclusion: Female reproductive factors are associated with CMD, independent of traditional risk factors. These reproductive factors could inform clinical screening and improve cardiometabolic risk assessment in women.

Keywords: cardiometabolic disease; female reproductive factors; metabolic health; reproductive health.

Figure 1

The RCS curve of the association between (a) age at menarche, (b) age at menopause, (c) reproductive lifespan, (d) age at first live birth, (e) age at last live birth, (f) number of live births and cardiometabolic disease in women in the UK Biobank. HR and 95% CI. Abbreviations: HR, hazard ratio; CI, confidence interval; CMD, cardiometabolic disease; AFB, age at first live birth; ALB, age at last live birth. Adjusted for age, Townsend deprived index, qualifications, ethnicity, smoking status, drinking status, body mass index, systolic blood pressure, C-reactive protein, cholesterol, high-density lipoprotein, triglyceride-glucose index, hormone replacement therapy and use of oral contraceptives.

Figure 2

Forest plot of hazard ratios and 95% CIs for the association of reproductive factors and cardiometabolic disease stratified by age. Abbreviations: HR, hazard ratio; CI, confidence interval. Adjusted for Townsend deprived index, qualifications, ethnicity, smoking status, drinking status, body mass index, systolic blood pressure, C-reactive protein, cholesterol, high-density lipoprotein, triglyceride-glucose index, hormone replacement therapy and use of oral contraceptives.

Figure 3

Forest plot of hazard ratios and 95% CIs for the association of reproductive factors and cardiometabolic disease stratified by BMI. Abbreviations: HR, hazard ratio; CI, confidence interval. Adjusted for age, Townsend deprived index, qualifications, ethnicity, smoking status, drinking status, systolic blood pressure, C-reactive protein, cholesterol, high-density lipoprotein, triglyceride-glucose index, hormone replacement therapy and use of oral contraceptives.