Discussion
This large study in China provides the most comprehensive assessment to date of the relationships of pregnancy and pregnancy loss and the risk of diabetes in later life. Among women who had ever been pregnant, each additional pregnancy was associated with a 4% higher risk of diabetes. Moreover, a history of pregnancy loss was associated with a 7% higher risk of diabetes and the relationships became stronger with recurrent pregnancy loss, irrespective of the number of livebirths. These findings were directionally similar for different types of pregnancy loss, were robust to adjustment for potential confounders, and were broadly consistent across major subgroups.
Previous studies on the association between pregnancy and the risk of diabetes have provided conflicting results [
8,
16‐
20]. The US Nurses’ Health study of 114,000 women and 2300 cases of diabetes did find an association between parity and incident diabetes before, but not after, adjustment for BMI [
17]. The ARIC study of 7000 women and 750 cases of diabetes also demonstrated that a substantial part of the relationship between parity and diabetes was explained by obesity; after adjustment, only women with five or more live births had a significantly higher risk of diabetes than nulliparous women [
20]. Similarly, the Singapore Chinese Health Study among 25,000 Chinese women and 1300 cases of diabetes showed that the association between parity and diabetes was attenuated, but remained significant, after adjustment for BMI and other demographic, lifestyle, and reproductive health factors. [
18] In the EPIC-Heidelberg cohort, among 14,000 women and 900 cases of diabetes, each additional pregnancy increased the risk of diabetes before, but not after adjustment for possible confounders. [
8] In the present study, which included more cases of diabetes than all previous studies combined, the association between the number of pregnancies and the onset of diabetes was attenuated, yet remained statistically significant, after adjustment for a raft of potential confounders and mediators. However, we recently found that the association between the number of children and the risk of diabetes and cardiovascular disease was largely similar between women and men [
21,
22]. Hence, the relationship between pregnancy and the risk of diabetes observed in the present study is likely to be explained by lifestyle and socioeconomic factors related to parenthood and raising offspring, rather than by the direct biological effects of childbearing.
Few studies have examined the relationship between pregnancy loss and new onset of diabetes [
8,
9]. The EPIC-Heidelberg study found that a history of miscarriage was associated with a 30% greater risk of diabetes; recurrent miscarriage was associated with a two-fold increased risk of diabetes. [
8] No significant associations were found between induced abortion and stillbirth and the risk of diabetes, albeit the small proportion of women who had experienced at least one stillbirth might have hampered the analyses. A study among 3851 women with gestational diabetes and 11,553 women with normal glucose tolerance indicated that stillbirth increased the risk of diabetes by about two-fold, irrespective of gestational diabetes status. [
9] This study included a much larger number of well-characterised incident cases of diabetes and provides robust evidence for the implications of different types of pregnancy on the risk of diabetes in a contemporary population of Chinese women.
Pregnancy loss is characterised by multifactorial and polygenic aetiologies that may also be implicated in the onset of diabetes. However, the mechanisms underpinning the association between pregnancy loss and the onset of diabetes in later life are uncertain. We previously reported that women with a history of miscarriage, induced abortion, and stillbirth were at a substantially higher risk of cardiovascular disease, with stronger associations among those with recurrent pregnancy loss. [
23] Since diabetes is a strong risk factor for cardiovascular disease, similar pathological mechanisms may be involved. Autoimmune disorders and subclinical inflammatory processes are involved in the pathophysiology of pregnancy loss and there is growing evidence that inflammatory processes also play a role in the development of diabetes. [
24‐
27] Moreover, women with a history of gestational diabetes are at substantially higher risk of type 2 diabetes and previous studies have reported that a history of spontaneous abortion was associated with a higher risk of impaired glucose tolerance or gestational diabetes in later pregnancies. [
28] For instance, in a study among 16,000 pregnant women in China, a history of spontaneous abortion was associated with a 50% increased risk of gestational diabetes. [
7] A lower socioeconomic status is also associated with a higher risk of spontaneous abortion, indicating that behavioural and environmental exposures more dominant in those with lower socioeconomic status could be involved. [
29] In this study, however, the relationships between pregnancy loss and the risk of diabetes were similar in women with different levels of educational achievement. Further studies are needed to elucidate the mechanisms involved by which pregnancy loss might be involved in the pathophysiology of diabetes.
The strengths of the present study include its large sample size, prospective design, and ability to study different types of pregnancy loss simultaneously and to adjust for a range of potential confounders. The generalisability of our findings was enhanced by the inclusion of women from 10 diverse areas in China. While our findings were robust and consistent across a range of analyses, we cannot exclude the possibility that the observed associations have been subject to residual confounding by biomarkers, such as inflammatory variables, and physiological, cultural, or socioeconomic factors underlying the number of pregnancies and/or pregnancy losses not included in our analyses. In particular, information on risk factors before pregnancy or pregnancy-induced conditions, such as polycystic ovary syndrome, preeclampsia, and gestational diabetes, were not available. We were therefore not able to examine to what extent maternal conditions before or during pregnancy have affected the observed relationships between pregnancy loss and diabetes. The number of pregnancies and pregnancy losses were self-reported and may have been subject to recall and reporting bias, resulting in misclassification of the exposure status. However, any misclassification is unlikely to be related to the risk of diabetes in later life, which would have led to conservative estimates.
In summary, we observed graded and positive relationships of pregnancy and pregnancy loss with the risk of diabetes in a contemporary population of Chinese women. Further studies will be needed to examine which physiological, behavioural, and socioeconomic factors might be involved and how these could be mediated to delay or prevent the onset of diabetes among affected women.
Acknowledgments
The chief acknowledgment is to the participants, the project staff, and the China National Centre for Disease Control and Prevention (CDC) and its regional offices for access to death and disease registries. The Chinese National Health Insurance scheme provides electronic linkage to all hospital admission data. Baseline survey: Kadoorie Charitable Foundation, Hong Kong. Long-term continuation: UK Wellcome Trust (088,158/Z/09/Z, 104,085/Z/14/Z), Chinese Ministry of Science and Technology (2011BAI09B01, 2012-14), Chinese National Natural Science Foundation (81390541). The British Heart Foundation, UK Medical Research Council and Cancer Research UK provide core funding to the Oxford CTSU. This work was also supported by grants from the National Natural Science Foundation of China (No. 81390541, No. 81390544).
Members of the China Kadoorie Biobank collaborative group: International Steering Committee: Junshi Chen, Zhengming Chen (PI), Rory Collins, Liming Li (PI), Richard Peto. International Co-ordinating Centre, Oxford: Daniel Avery, Derrick Bennett, Yumei Chang, Yiping Chen, Zhengming Chen, Robert Clarke, Huaidong Du, Xuejuan Fan, Simon Gilbert, Alex Hacker, Michael Holmes, Andri Iona, Christiana Kartsonaki; Rene Kerosi, Ling Kong, Om Kurmi, Garry Lancaster, Sarah Lewington, John McDonnell, Iona Millwood, Qunhua Nie, Jayakrishnan Radhakrishnan, Sajjad Rafiq, Paul Ryder, Sam Sansome, Dan Schmidt, Paul Sherliker, Rajani Sohoni, Iain Turnbull, Robin Walters, Jenny Wang, Lin Wang, Ling Yang, Xiaoming Yang. National Co-ordinating Centre, Beijing: Zheng Bian, Ge Chen, Yu Guo, Bingyang Han, Can Hou, Jun Lv, Pei Pei, Shuzhen Qu, Yunlong Tan, Canqing Yu, Huiyan Zhou. 10 Regional Co-ordinating Centres: Qingdao Qingdao CDC: Zengchang Pang, Ruqin Gao, Shaojie Wang, Yongmei Liu, Ranran Du, Yajing Zang, Liang Cheng, Xiaocao Tian, Hua Zhang. Licang CDC: Silu Lv, Junzheng Wang, Wei Hou. Heilongjiang Provincial CDC: Jiyuan Yin, Ge Jiang, Shumei Liu, Zhigang Pang, Xue Zhou. Nangang CDC: Liqiu Yang, Hui He, Bo Yu, Yanjie Li, Huaiyi Mu, Qinai Xu, Meiling Dou, Jiaojiao Ren. Hainan Provincial CDC: Jianwei Du, Shanqing Wang, Ximin Hu, Hongmei Wang, Jinyan Chen, Yan Fu, Zhenwang Fu, Xiaohuan Wang, Hua Dong. Meilan CDC: Min Weng, Xiangyang Zheng, Yijun Li, Huimei Li, Chenglong Li. Jiangsu Provincial CDC: Ming Wu, Jinyi Zhou, Ran Tao, Jie Yang. Suzhou CDC: Jie Shen, Yihe Hu, Yan Lu, Yan Gao, Liangcai Ma, Renxian Zhou, Aiyu Tang, Shuo Zhang, Jianrong Jin. Guangxi Provincial CDC: Zhenzhu Tang, Naying Chen, Ying Huang. Liuzhou CDC: Mingqiang Li, Jinhuai Meng, Rong Pan, Qilian Jiang, Jingxin Qing, Weiyuan Zhang, Yun Liu, Liuping Wei, Liyuan Zhou, Ningyu Chen, Jun Yang, Hairong Guan. Sichuan Provincial CDC: Xianping Wu, Ningmei Zhang, Xiaofang Chen, Xuefeng Tang. Pengzhou CDC: Guojin Luo, Jianguo Li, Xiaofang Chen, Jian Wang, Jiaqiu Liu, Qiang Sun. Gansu Provincial CDC: Pengfei Ge, Xiaolan Ren, Caixia Dong. Maiji CDC: Hui Zhang, Enke Mao, Xiaoping Wang, Tao Wang. Henan Provincial CDC: Guohua Liu, Baoyu Zhu, Gang Zhou, Shixian Feng, Liang Chang, Lei Fan. Huixian CDC: Yulian Gao, Tianyou He, Li Jiang, Huarong Sun, Pan He, Chen Hu, Qiannan Lv, Xukui Zhang. Zhejiang Provincial CDC: Min Yu, Ruying Hu, Le Fang, Hao Wang. Tongxiang CDC: Yijian Qian, Chunmei Wang, Kaixue Xie, Lingli Chen, Yaxing Pan, Dongxia Pan. Hunan Provincial CDC: Yuelong Huang, Biyun Chen, Donghui Jin, Huilin Liu, Zhongxi Fu, Qiaohua Xu. Liuyang CDC: Xin Xu, Youping Xiong, Weifang Jia, Xianzhi Li, Libo Zhang, Zhe Qiu.