Discussion

This study was performed to construct a synthetic risk score to assess reproductive status quantitatively, and then test and verify the association between RRS and CVD. Each RRS increment was associated with a 22% higher risk of CVD, 23% higher risk of IHD and 19% higher risk of stroke. About 16% of CVD, 15% of IHD and 18% of stroke cases were attributed to the low-intermediate RRS group and above, indicating that these cases of CVD, IHD and stroke could be prevented if they were in the low-risk RRS groups. Our findings indicated that healthy lifestyle factors can decrease the risk of RRS-induced CVD and IHD.
Previous studies have identified associations between CVD and factors related to reproductive health. Early menarche (age < 12 years) was associated with a risk of morbidity from CVD, especially IHD[22, 23]; early menopause (age 40–44 years) was also associated with higher risk of CVD [24]; and use of hormonal contraceptives can increase the risk of stroke[25]. A previous study [26]suggested that a history of adverse pregnancy outcomes was related to a higher risk of IHD but not stroke, which was consistent with our results. Another study [27] suggested that ovariectomy may reduce the risk of cancer, but increase the risk of heart disease due to loss of oestrogen, which was also consistent with our results. Advanced maternal age may be related to increased risk of heart arrhythmia during pregnancy [28]. However, we found no significant associations of advanced maternal age (> 35 years at the time of last birth) with CVD, IHD or stroke.
We found a positive interaction between age and RRS for CVD. Several possible mechanisms may account for this observation. A lack of protection from oestrogen may contribute to an increased risk of heart disease. Among premenopausal women, oestradiol is the chief hormone rather than oestrone, which is more prevalent in the postmenopausal period [29]. Hormones may influence the development of CVD by affecting blood pressure[30]. A large cross-sectional study of 18 326 women aged 46–59 years indicated that menopause status was associated with significantly elevated blood pressure [31], which suggests that natural menopause is a risk factor for hypertension regardless of age or BMI. Older participants suffered from impairments in the circulatory system due to hormone deficiency and, therefore, probably had increased risk of developing CVD, independently of time. Animal studies have shown that oestrogen and the G protein-coupled oestrogen receptor (GPER) agonist G-1 decreased vasodilation in aging mice. The increased GPER mRNA expression levels in the heart and kidney may cause cardiovascular abnormalities [32].
A healthy lifestyle has been shown to be effective in reducing the risk of CVD associated with reproductive risk. Our results indicated a positive association between reproductive risk assessed by RRS and the risk of CVD reduced by a healthy lifestyle. Several biological mechanisms support our findings. Women with a history of reproductive complications also have an increased risk of CVD, and this susceptibility can be reduced by lifestyle [33]. Weight gain, decreased insulin sensitivity and abnormal lipid metabolism are not only common risk factors caused by unhealthy lifestyles but also metabolic disorders associated with CVD risks in the female population[34, 35]. A healthier lifestyle neutralised hormonal imbalances of women’s physical condition[36].
We also found a significant attributable proportion (AP) due to additive interaction in CVD (AP interaction: −0.14, 95% CI: −0.22 to −0.07 for CVD and AP interaction: −0.15, 95% CI: −0.23 to −0.09 for IHD) between RRS and HLS. These observations showed that healthy lifestyle habits were indispensable for preventing CVD and IHD, especially in individuals with high reproductive risk. Joint associations implied that HLS could neutralise the threat of CVD and IHD brought by suboptimal reproductive status. Studies have shown that adherence to a healthy lifestyle can significantly reduce the burden of CVD and the risk of death in middle-aged and older women[37]. Exercise is associated with weight loss, an important link in the causal chain from a healthy lifestyle to reduced CVD in older women. This suggests that maintaining a healthy lifestyle is an essential prerequisite for reducing the risk of CVD.
The present study had several limitations. First, data on reproductive indicators were available for only 31.2% of all women in the UK Biobank. To explore the size of the difference, we examined the baseline characteristics of participants with or without RRS and found that there were no marked differences in other indicators except age. We adjusted for age in the analysis to reduce this discrepancy. Second, we did not include diseases associated with reproductive risk (e.g. pregnancy-induced hypertension, gestational diabetes, etc.) in the analysis, which may have led to bias in the reproductive risk assessment. These reproductive risk diseases are also caused by adverse reproductive risk factors. To avoid collinearity and ensure an adequate sample size, reproductive risk diseases were excluded from RRS. The advantage of this is that the RRS constructed here can be easily repeated in future studies due to the convenient approach to data assessment using the touchscreen questionnaire. Third, we used the baseline data as proxies for long-term lifestyle behaviour and, thus, had potential information bias. Further research is needed to explore the availability of data for risk stratification of younger adults.
The results of this large prospective cohort study indicated that RRS was strongly associated with CVD, IHD and stroke. Healthy lifestyle factors can attenuate the risk of cardiovascular risk caused by reproductive risk factors. The identification of individuals at reproductive risk may provide evidence for governments and policymakers to design suitable interventions and extend healthy active life expectancy.