To our knowledge, this large study of almost 300,000 women in China is among the first to evaluate the relationships between pregnancy loss and cardiometabolic multimorbidity. Our findings suggest that pregnancy loss, in particular, spontaneous or induced abortions, were associated with higher risk of cardiometabolic multimorbidity. However, the association was not significant for pregnancy loss due to stillbirth. Our findings also suggest that increased number of pregnancy losses, in particular induced abortion, were associated with elevated risk of cardiometabolic multimorbidity.
Much of the evidence on the role of pregnancy loss for health comes from studies on individual CMDs, rather than cardiometabolic multimorbidity. These studies have yielded conflicting results on the association of pregnancy loss with cardiovascular disease and diabetes. A meta-analysis of ten studies reported that a history or recurrent spontaneous abortion was associated with a greater risk of CHD and stroke, although the association was weaker for stroke[7]. Similarly, two studies using data from the CKB database and the Nurses’ Health Study II (NHSII) reported that spontaneous abortion and induced abortion was associated with increased risk of CHD and stroke[9, 18]. Data from the NHSII also demonstrated greater rates of hypertension in women with a history of spontaneous abortion and stillbirth. However, interestingly, the study also found reduced rates of hypertension in women with a history of induced abortion[10]. Another population-based cohort in Denmark of more than one million women found that a history of spontaneous abortion and stillbirth was associated with higher risks of stroke and hypertension, with reports of stronger associations in women with repeated spontaneous abortions[20]. Moreover, a prior study conducted in the United States on 77,701 women reported that a history of 1 and 2 or more spontaneous abortion, and a history of 1 or more stillbirth was associated with a greater risk of CHD but not stroke[15]. Similarly, a Scottish study on 60,105 female participants demonstrated that women who had a history of two or more spontaneous abortion had an increased risk of CHD but not stroke[17] and a study using data from the UK Biobank on 267,440 women reported that a history of spontaneous abortion was associated with an increased risk of CHD, but not stroke. Interestingly, however, the study reported that a history of stillbirth was associated with an increased risk of stroke, but not CHD[14].
Few studies have examined the relationship between pregnancy loss and the onset of diabetes, with inconsistent findings. The EPIC-Heidelberg study on 13,612 women found that a history or recurrent spontaneous abortions was associated with a greater risk of diabetes. In contrast, no significant associations were observed between induced abortion and stillbirth with the risk of diabetes[21]. A study using data from the NHSII on 60,651 women reported that spontaneous abortion and stillbirth was associated with increased risk of type 2 diabetes, whereas induced abortion was associated with lower risk of type 2 diabetes[10]. An Italian study on 15,404 women reported that stillbirth increased the risk of diabetes by approximately two-fold[22] and a recent study utilizing data from the CKB database reported that pregnancy loss, particularly induced abortion, was associated with an increased risk of diabetes, although the association were not significant for spontaneous abortion and stillbirth[11].
Our analyses extend upon the study of a single CMD in existing literature to cardiometabolic multimorbidity, demonstrating that a history of pregnancy loss is associated with increased risk of cardiometabolic multimorbidity. Similar to most studies, we found that pregnancy loss, particularly recurrent pregnancy loss, is not only associated with increased risk of a single CMD, but also higher risk of cardiometabolic multimorbidity. The findings of this study suggest that women with a history of pregnancy loss may benefit from early screening for risk factors of cardiometabolic multimorbidity. In addition, our findings demonstrate that the association between pregnancy loss and cardiometabolic multimorbidity is more apparent in older women. This is as expected as metabolic processes deteriorate with age due to factors such as cumulative oxidative stress, contributing to the occurrence of CMDs [25–27].
There are several possible explanations for the mechanisms underlying the link between pregnancy loss and cardiometabolic multimorbidity. We postulate that both pregnancy loss and cardiometabolic multimorbidity may be due to endothelial dysfunction, which results in placental dysfunction, pregnancy loss, and the development of both single CMD and cardiometabolic multimorbidity[28, 29]. Studies have demonstrated that women who experienced recurrent pregnancy loss have higher rate of endothelial dysfunction compared to those with uncomplicated pregnancies[28]. Autoimmune disorders and consequently, systemic inflammation are involved in the occurrence of pregnancy loss[30, 31] and, there is growing evidence to indicate that inflammatory processes play a role in the development of cardiometabolic multimorbidity[20, 32, 33]. However, further studies are necessary to verify our results and elucidate the mechanisms implicated by which pregnancy loss might be involved in the pathophysiology of cardiometabolic multimorbidity.
The present study has several strengths. First, the analysis was based on a large representative population sample from ten diverse areas in China, which strengthened the generalizability of our findings. Second, the comprehensive collection of data allowed for the analysis of the correlations between various types of pregnancy losses and combinations of CMDs, as well as the control of a variety of potential confounders, which contributed to the emerging literature on associations that were limited to a single disease.
However, the study has several limitations. First, the cross-sectional nature of this study does not allow for investigation of the temporal relationship between pregnancy loss and cardiometabolic multimorbidity. Second, pregnancy loss and CMDs were self-reported, which may lead to recall bias. Last, although we adjusted for a wide range of covariates, residual confounding may still remain.