In women several reproductive factors early in life affect disease risks late in life. The reproductive patterns of women in China differ importantly from those in Western countries, especially among Chinese women born before the 1970s. In general, Chinese women tend to start their periods later, their menopause earlier, and rarely use hormone replacement treatment. Childbearing and breastfeeding are almost universal. A decade of research in CKB has generated important results about the patterns and health effects of reproductive factors on diseases among Chinese women.
Patterns and inter generational changes
Among the 0.3 million women in CKB, the self-reported mean age at menarche was 15.4 years and mean age at menopause was 48.5 years, compared with under 13 and over 50 years typically seen in Western populations. Nearly all women gave birth and breastfed their children. On average, each women had 2.2 live births with the mean age at first birth of 23.4 years and duration of breastfeeding of 12 months per child. The proportions of women who reported having a history of miscarriage, induced abortion, and stillbirth were 10%, 53%, and 6%, respectively. However, there were striking differences between women born in different decades, for example the mean age at menarche decreased from 16.1 for women born in the 1930s to 14.3 years for women born in the 1970s but the mean age at menopause increased from 47.9 to 49.3 years. Similar inter-generational changes were also evident, with women born in recent decades less likely to have given birth, more likely to have had their first child later and breastfed each baby for a shorter time, particularly in urban areas (Int J Epidemiol 2014). The large intergenerational changes on reproductive factors reflect in part the major socio-economic changes that have occurred in China, such as increased urbanisation, better education and improved nutrition (Chin J Epidemiol 2016).
Associations with adiposity and other disease risk factors
In CKB women, the mean baseline BMI was 23.7 kg/m2. Both general and central adiposity showed inverse associations with age at menarche and age at first birth, but positive associations with age at menopause and reproductive years among post-menopausal women. Overall, each one-year earlier menarche was associated with 0.19 kg/m2 higher BMI, while each one-year earlier menopause was associated with 0.05 kg/m2 lower BMI. Adiposity also had a non-linear positive association with parity, but no association with breastfeeding duration (Int J Epidemiol 2017). Women who were better educated tended to have earlier age at menarche (Int J Epidemiol 2014). and later age at menopause (Menopause 2021).
Prospective associations with disease risks
Our detailed prospective analyses provided new evidence about the health effects of reproductive factors on several major diseases in Chinese women. For cardio vascular disease (CVD), the observed association with age at menarche appeared to differ by birth cohort. We found no association in older generations but U-shaped or weak positive associations in younger women, especially those born after the 1960s (Int J Cardiology 2017). For diabetes, there was a log-linear inverse association with age at menarche, which was somewhat stronger in younger than older generations (Am J Epidemiology 2018). Given age, post-menopausal women were at higher risks of CVD (Circ Cardiovasc Qual Outcomes 2017), diabetes (Nutrition & Metabolism 2022) and hip fracture (Menopause 2020) than pre-menopausal women. Among post-menopausal women younger age at menopause, longer time since menopause, and shorter total reproductive years were associated with higher risks of cardio-metabolic and bone diseases. Furthermore, women with surgical menopause from hysterectomy or bilateral oophorectomy (removal of ovaries) had 10-20% higher risks of ischemic stroke and heart disease than naturally menopausal women, particularly when operated at a young age (Stroke 2022(revision). These study findings are consistent with the protective effects of oestrogen on development of cardio-metabolic diseases.
Apart from the reproductive timing, other reproductive factors such as pregnancy consequences and breastfeeding also determine the duration and level of endogenous exposure to oestrogen. Among ever-pregnant women, each pregnancy loss, depending on the nature, was associated with 2-7% higher risks of CVD (BMC Med 2017) and diabetes (Eur J Epidemiol 2020), with greater risk among those with multiple pregnancy loss. Further large-scale genetic investigation involving data from CKB and many other studies found miscarriage is related to genetic variants affecting placental biology (Nat Commun. 2020).
Compared with those with only one child, women who were childless or had more than one child had a higher risk of CVD (Int J Epidemiol 2017). and diabetes (Diabetologia 2016) but a lower risk of hip fracture (Osteoporos Int 2020). However, similar associations were also found among men, suggesting that these associations are not biological but reflect differences in socio-economic and lifestyle factors associated with childrearing.
Breastfeeding benefits child health and also affects the maternal cardio-metabolic system. CKB showed that compared to women who had given birth but never breastfed, women who had ever breastfed had about 10% lower risk of major CVD diseases (e.g. stroke or coronary heart disease) later in life (J Am Heart Assoc 2017). Moreover, there appeared to be a dose-response relationship with duration of breastfeeding, with each additional six months of breastfeeding per child associated with about 4% lower risk of CVD.
As in many other previous studies, CKB found that one year longer of total reproductive years was associated with 5% higher risk of breast cancer, while each additional live birth was associated with 17% lower risk.
Impact of research
The CKB findings have greatly improved our understanding of the relevance of several reproductive factors for health later in life, including many that cannot be properly investigated in the Western populations. As China is moving towards more contemporary reproductive patterns that are associated with higher risks of many chronic diseases, CKB findings are likely to have far reaching implications especially as China changed the one-child family planning policy to two in 2016 then three children per couple after a steep decline in birth rates in the 2020 national census. Further research on reproductive factors in CKB will cover a wider range of health outcomes and will also assess more genetic determinants of reproductive traits and long-term biological changes associated with reproductive factors.