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.