Knowledge Synthesis: Cardiovascular Disease

Women and Healthcare Professionals:

Our work demonstrates that if women have experienced adverse reproductive conditions (i.e., early puberty, recurrent pregnancy loss, early natural or surgical menopause, short reproductive lifespan, or severe vasomotor symptoms) they are at an increased risk of cardiovascular disesease (CVD). Therefore, general practitioners (GPs) should take thorough patient histories and monitor women for other CVD risk changes, such as the development of hypertension, diabetes, and dyslipidaemia.

Early menarche and heavy menstrual bleeding may also be indicative of a higher risk profile for CVD in young women. GPs should consider screening young women with early puberty and menstrual abnormalities more regularly for elevated blood pressure and metabolic syndrome. Ethnicity may play an important role in determining a woman’s risk factors for CVD after menopause, such as type 2 diabetes.

Policymakers:

These robust results from large, pooled analyses could inform clinical guidelines and policy to coordinate sex-specific risk factors in screening and prevention of CVD in women. Targeted programs that support girls and women to maintain a healthy lifestyle (especially smoking cessation and maintaining a healthy weight) may reduce their risk of both adverse reproductive conditions and future risk of CVD. Findings from InterLACE that included women from diverse ethnic backgrounds could help inform ethnic-specific initiatives to present CVD risk factors in women globally.

Reproductive History and CVD

Robust evidence from InterLACE pooled analyses and systematic reviews showed that several reproductive histories across the life course are associated with an increased risk of CVD in later life, including early menarche (≤11 years), premature and early natural menopause (<45 years), premature and early surgical menopause (bilateral oophorectomy <45 years), short reproductive lifespan (<33 years), and severe vasomotor symptoms (hot flushes and night sweats) [1-6]. 

On the other hand, premenopausal women who experienced a first CVD event before age 35 had a substantially increased risk of early menopause before age 45, indicating cardiovascular damage itself could also be a driving factor in the process of ovarian ageing [7].   

In terms of CVD risk factors among young women, earlier age at menarche was associated with higher BMI and metabolic syndrome in young adulthood [10], and heavy menstrual bleeding was associated with an increased risk of chronic hypertension but not with hypertensive disorder during pregnancy [11].

Pregnancy Loss and Stroke

Large meta-analyses and InterLACE pooled analyses conclusively showed a link between pregnancy loss and stroke, the more miscarriages or stillbirths, the greater the risk of stroke, both fatal and non-fatal stroke [8,9]. 

Type 2 Diabetes

A systematic review and ALSHW data demonstrated that short reproductive lifespan (<35 years) was associated with an increased risk of both type 2 diabetes and hypertension [12,13].  InterLACE pooled data showed that premature and early natural menopause (<45 years) was associated with an increased risk of type 2 diabetes, with considerable variation across ethnic groups [14].

Our systematic review and pooled analysis on pregnancy loss and stroke risk (published in Stroke and BMJ) was selected for the American Heart Association’s Go Red For Women collection, which is a platform designed to increase women’s heart health awareness and was accompanied by a Conversation article and an op-ed for Insight+, the MJAs free news service for GPs and other health professionals.  

Our definitive findings on early menopause and CVD risk (published in Lancet Public Health, JAMA Cardiology, Human Reproduction) have informed 10 clinical practice guidelines and consensus statements (PMIDs: 35666723, 33281418, 32951056, 35118808, 33495787, 32439010, 33251828, 32896176, 35797481, 35569270) that provided clinical recommendations for premature menopause and CVD prevention in women, as well as the Lancet Commission for reducing the global burden of CVD in women by 2023 (PMID: 34010613).

Current evidence on sex-specific risk factors for CVD was largely based on data derived from high-income countries, more research is needed to include women from low-and-middle-income countries, diverse ethnic backgrounds, and socioeconomically deprived groups. Prioritising sex-specific research focuses on identifying biological mechanisms linking these reproductive conditions and their roles in the pathophysiology and progression of CVD in women, especially hormone changes across the reproductive lifespan. As the burden of CVD is increasing among young women, further research is needed to investigate sex-specific and other under-recognised CVD risk factors (e.g., early life, psychosocial, and socioeconomic factors) in young women to improve CVD risk assessment and prevention.

1. Age at natural menopause and risk of incident cardiovascular disease: A pooled analysis of 15 studies. 
2. Type of menopause, age of menopause and variations in the risk of incident cardiovascular disease: pooled analysis of individual data from 10 international studies. 
3. Vasomotor menopausal symptoms and risk of cardiovascular disease: a pooled analysis of six prospective studies. 
4. Duration of estrogen exposure during reproductive years, age at menarche and age at menopause, and risk of cardiovascular disease events, all-cause and cardiovascular mortality: a systematic review and meta-analysis. 
5. Association between reproductive life span and incident nonfatal cardiovascular disease: a pooled analysis of individual patient data from 12 studies. 
6. Association of the length of oestrogen exposure with risk of incident stroke in postmenopausal women: insights from a 20-year prospective study. 
7. Premenopausal cardiovascular disease and age at natural menopause: a pooled analysis of over 170,000 women. 
8. Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women: A Systematic Review and Meta-Analysis.  
9. Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women.  
10. Age at menarche and childhood body mass index as predictors of cardio-metabolic risk in young adulthood: A prospective cohort study. 
11. The association between menstrual symptoms and hypertension among young women: a prospective longitudinal study. 
12. Epidemiological studies of the association between reproductive lifespan characteristics and risk of type 2 diabetes and hypertension: a systematic review. 
13. Association between reproductive lifespan and risk of incident type 2 diabetes and hypertension in postmenopausal women: findings from a 20-year prospective study. 
14. Ethnic differences in the association between age at natural menopause and risk of type 2 diabetes mellitus among postmenopausal women: a pooled analysis of individual data from 13 cohort studies.