An earlier first birth, a higher number of live births, and starting periods at a younger age are all linked to a higher risk of cardiovascular problems in women, according to research, which provides evidence for a causal relationship between sex-specific factors and CVD disease in women, and identifies potential ways to mediate this risk.
The study, led by a team from Imperial College London, is the most comprehensive analysis to date of reproductive factors specific to women and their links to a range of cardiovascular diseases, including atrial fibrillation, coronary heart disease, heart failure, and stroke. The researchers hope it will help doctors to better understand and monitor women’s risk factors and intervene where appropriate.
Researchers from Imperial’s National Heart & Lung Institute, University of Cambridge and Yale School of Public Health analysed genetic data linked to women’s age at first birth, their number of live births, their age at their first period (menarche), and at menopause. They also looked at previous studies involving more than 100 000 women.
Observational research has previously identified that some reproductive factors are associated with cardiovascular disease for women in later life, but such studies are limited as they have been unable to support a causal relationship.
By using a statistical technique called Mendelian Randomisation, the researchers were able to show a link between the genes that predict reproductive factors and the risk of multiple cardiovascular diseases. This enables researchers to cut through factors like diet, economic background and physical activity levels that can otherwise complicate the overall picture, and so it points to causal links.
The analysis showed that first birth, a higher number of live births, and earlier menarche was linked to a higher risk of atrial fibrillation, coronary artery disease, heart failure and stroke. However, it did not find an association between the age of menopause and cardiovascular disease.
They also found that much of the increased risk for earlier menarche resulted from this factor being associated with women having a higher BMI – so lowering their BMI could help reduce this risk. The increased risk for earlier first birth could be partly limited by acting on traditional cardiometabolic risk factors, such as BMI, high cholesterol and high blood pressure.
Dr Maddalena Ardissino, lead author of the study, from the National Heart and Lung Institute at Imperial College London, said:
“Women are often mischaracterised as being at low risk for cardiovascular disease, leading to delays in diagnosis. Even when they are diagnosed, they tend to receive less targeted treatment than men.
“This study shows a clear link between reproductive factors and cardiovascular disease, but doesn’t mean women should worry if they started their period at a young age, or had an early first birth. Our research shows that the additional risk of CVD can be minimised if traditional risk factors like BMI and blood pressure are well-controlled. These findings highlight the need for doctors to monitor these risk factors closely and intervene where needed.”
Dr Fu Siong Ng, senior author for the study and also from the National Heart and Lung Institute, said: “Many previous studies have focused on men, but our research shows that there are sex-specific factors influencing the risk for women.
“While we cannot say exactly how much these increase the risk of cardiovascular disease, our study shows that reproductive history is important and it points towards a causal impact. We need to understand more about these factors to make sure women get the best possible care.”
Further research is needed to understand the extent of the relationship between reproductive factors and cardiovascular disease risk, such as whether there is a linear or non-linear relationship between a factor and increased risk.
Cardiovascular disease has often been thought of as a man’s disease, as men are more likely to develop it at an earlier age than women. However, this group of diseases is a serious problem for women.
Research by the British Heart Foundation has shown that coronary heart disease kills more than twice as many British women as breast cancer annually, with more than 800 000 women in the UK living with the disease. It is also estimated that around 380 000 women alive in Britain today have survived a heart attack.
Dr Sonya Babu-Narayan, associate medical director at the British Heart Foundation and consultant cardiologist, said: “The misconception that cardiovascular disease mostly affects men is costing women their health, and even their lives.
“It’s critical that women are empowered with the knowledge of what could put them at higher risk of developing heart disease or stroke in the future. This includes the well-known risks that affect everyone – but for women, there may be additional risk factors from their reproductive years to add to the list.
“If we’re going to save more women’s lives, asking about periods and pregnancy must be routine when assessing every woman’s risk of heart disease and stroke.”
Study details
Sex‐Specific Reproductive Factors Augment Cardiovascular Disease Risk in Women: A Mendelian Randomization Study.
Maddalena Ardissino, Eric Slob, Paul Carter, Tormod Rogne, Joanna Girling, Stephen Burgess, Fu Siong Ng.
Published in the Journal of the American Heart Association (JAHA) on 23 February 2023.
Abstract
Background
Observational studies suggest that reproductive factors are associated with cardiovascular disease, but these are liable to influence by residual confounding. This study explores the causal relevance of reproductive factors on cardiovascular disease in women using Mendelian randomization.
Methods and Results
Uncorrelated (r2<0.001), genome‐wide significant (P<5×10−8) single‐nucleotide polymorphisms were extracted from sex‐specific genome‐wide association studies of age at first birth, number of live births, age at menarche, and age at menopause. Inverse‐variance weighted Mendelian randomization was used for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischemic stroke, and stroke. Earlier genetically predicted age at first birth increased risk of coronary artery disease (odds ratio [OR] per year, 1.49 [95% CI, 1.28–1.74], P=3.72×10−7) heart failure (OR, 1.27 [95% CI, 1.06–1.53], P=0.009), and stroke (OR, 1.25 [95% CI, 1.00–1.56], P=0.048), with partial mediation through body mass index, type 2 diabetes, blood pressure, and cholesterol traits. Higher genetically predicted number of live births increased risk of atrial fibrillation (OR for <2, versus 2, versus >2 live births, 2.91 [95% CI, 1.16–7.29], P=0.023), heart failure (OR, 1.90 [95% CI, 1.28–2.82], P=0.001), ischemic stroke (OR, 1.86 [95% CI, 1.03–3.37], P=0.039), and stroke (OR, 2.07 [95% CI, 1.22–3.52], P=0.007). Earlier genetically predicted age at menarche increased risk of coronary artery disease (OR per year, 1.10 [95% CI, 1.06–1.14], P=1.68×10−6) and heart failure (OR, 1.12 [95% CI, 1.07–1.17], P=5.06×10−7); both associations were at least partly mediated by body mass index.
Conclusions
These results support a causal role of a number of reproductive factors on cardiovascular disease in women and identify multiple modifiable mediators amenable to clinical intervention.
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