Using Pregnancy for the Identification of Future Risk of Cardiovascular Disease in Young Women
By Ravi Retnakaran MD MSc FRCPC
Photograph courtesy of Chung Ho Leung
Pregnancy has been described as a stress test for many systems in the body. This description is particularly appropriate for the pancreatic beta-cells that secrete insulin, as they must respond and compensate appropriately for the severe insulin resistance that characterizes late pregnancy. In this way, pregnancy is a natural stress test for the beta-cells.(1) As beta-cell dysfunction has emerged as the key pathophysiologic determinant of an individual’s risk of ultimately developing type 2 diabetes mellitus (T2DM), a woman’s response to the metabolic challenge of pregnancy provides a means of stratifying her future diabetic risk.
It is this concept that underlies a component of our research program at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital. Indeed, we have established a long-term prospective observational cohort study, in which women across the full range of glucose tolerance in pregnancy−from normal glucose tolerance to mildly abnormal glucose tolerance to gestational diabetes mellitus−are recruited in late second trimester and undergo cardio-metabolic characterization at that time and then serially in the years postpartum. Since each degree of gestational dysglycemia reflects a different level of underlying beta-cell dysfunction and hence a differential risk of ultimately progressing to T2DM,(1-4) longitudinal characterization of the metabolic changes that occur over time in these patient subgroups can provide insight into the early pathophysiology of diabetes.
Supported by funding from the Canadian Institutes of Health Research (CIHR), the Canadian Diabetes Association, the Heart and Stroke Foundation of Ontario, and the Ontario Ministry of Research and Innovation, this program has yielded many important findings regarding the early natural history of pre-diabetes and diabetes in women, as per its initial objective. Along the way, however, unanticipated findings pertaining to cardiovascular disease have opened new avenues of investigation.
It has been suggested that atherosclerosis and T2DM may arise from a “common soil,” since many individuals appear to be susceptible to both conditions.(5) Accordingly, we have been characterizing the cardiovascular risk factor profiles of the maternal cohort described above. This profile consists of both traditional cardiovascular risk factors (such as blood pressure and lipids) and emerging non-traditional risk factors (such as fat-derived hormones like adipokines and inflammatory proteins). Interestingly, in evaluating these profiles, we found that relationships existed between a woman’s glucose tolerance status in pregnancy and her cardiovascular risk factors as early as three months after delivery.(6-9) Indeed, these risk factors followed gradients that tracked with her glucose tolerance status in the recent pregnancy. In other words, at three months postpartum, women with gestational diabetes mellitus (the most severe dysglycemia in pregnancy) had higher levels of vascular risk factors than women with milder gestational impaired glucose tolerance, who in turn had higher levels than women with normal glucose tolerance in pregnancy.
While the absolute levels of such risk factors would not be at the level to attract clinical attention in practice, particularly since they are in young women of childbearing age who have a very low likelihood of having cardiovascular disease at the time, the clear gradients that emerged after stratifying women by their gestational glucose tolerance status were of interest. Indeed, these gradients raised the possibility that these women may be at different degrees of risk for ultimately developing cardiovascular disease in the future, in the same way as they are known to be at different levels of risk for T2DM.
To test this hypothesis, we looked at rates of clinical cardiovascular disease as tracked by administrative data for the province of Ontario in women with varying degrees of glucose intolerance in pregnancy.(10) As predicted, these data revealed, within 12 years of their index pregnancy, women with a history of gestational diabetes mellitus had an increased incidence of cardiovascular disease. Similarly, and akin to the analogous gradients of risk seen for T2DM, women with milder glucose intolerance in pregnancy also had an increased risk after 12 years, one that was lesser than that of women with gestational diabetes mellitus but higher than their peers.(10) The model emerging from these data is that long-term exposure to the cardiovascular risk factor gradients that we have documented in women with varying degrees of gestational dysglycemia ultimately contributes to the development of clinical cardiovascular disease. We are thus studying the changes over time in vascular risk factors and function in the maternal cohort described earlier in order to gain insight into the early natural history of cardiovascular disease.
The presence of gradients of vascular risk factors in the early postpartum raises the question of whether these differences were present prior to the pregnancy. To address this question, in collaboration with colleagues in Ottawa, Canada and Changsha, China, we are conducting a CIHR-funded study in China, where we have established a so-called “pre-conception cohort.” In this unique study, we are recruiting a cohort of women prior to pregnancy and performing cardio-metabolic characterization at that time, which is then repeated longitudinally during and after pregnancy.(11) This approach will provide insight into the pre-pregnancy status and determinants of the risk gradients that we have previously noted in pregnancy and in the postpartum.
Finally, in both of the maternal cohorts described so far (Toronto and China), the earliest underpinnings of cardio-metabolic disease may be in the offspring. Indeed, with current interest in the long-term programming implications of the first 2 000 days of life, the children of the women participating in these cohorts provide the unique opportunity to characterize early changes in cardio-metabolic risk factors in the setting of well-defined maternal exposures.(12-15) Taken together with maternal characterization before, during, and after pregnancy, these birth cohorts are enabling the application of a life-course approach towards elucidation of the early natural history and pathophysiologic determinants of T2DM and cardiovascular disease.
Ravi Retnakaran MD MSc FRCPC
Endocrinologist and Clinician-Scientist,
Leadership Sinai Centre for Diabetes,
Department of Medicine, University of Toronto
1. Retnakaran R. Glucose tolerance status in pregnancy: A window to the future risk of diabetes and cardiovascular disease in young women. Curr Diabetes Rev. 2009; 5(4):239-44.
2. Retnakaran R, Qi Y, Sermer M, et al. Glucose intolerance in pregnancy and future risk of pre-diabetes or diabetes. Diabetes Care. 2008; 31(10):2026-31.
3. Retnakaran R, Qi Y, Sermer M, et al. Beta-cell function declines within the first year postpartum in women with recent glucose intolerance in pregnancy. Diabetes Care. 2010; 33(8):1798-1804.
4. Retnakaran R, Qi Y, Connelly PW, et al. Risk of early progression to pre-diabetes or diabetes in women with recent gestational dysglycemia but normal glucose tolerance at 3-months postpartum. Clin Endocrinol. 2010; 73(4):476-83.
5. Stern MP. Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes. 1995; 44(4):369-74.
6. Retnakaran R, Qi Y, Connelly PW, et al. The graded relationship between glucose tolerance status in pregnancy and postpartum levels of LDL cholesterol and apolipoprotein B in young women: Implications for future cardiovascular risk. J Clin Endocrinol Metab. 2010; 95(9):4345-53.
7. Retnakaran R, Qi Y, Sermer M, et al. Glucose intolerance in pregnancy and postpartum risk of metabolic syndrome in young women. J Clin Endocrinol Metab. 2010; 95(2):670-7.
8. Retnakaran R, Qi Y, Connelly PW, et al. Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta-cell dysfunction and fasting glycaemia. Diabetologia. 2010; 53(2):268-76.
9. Retnakaran R, Qi Y, Sermer M, et al. The postpartum cardiovascular risk factor profile of women with isolated hyperglycemia at 1-hour on the oral glucose tolerance test in pregnancy. Nutr Metab Cardiovasc Dis. 2011; 21(9):706-12.
10. Retnakaran R, Shah BR. Mild glucose intolerance in pregnancy and risk of cardiovascular disease in young women: population-based cohort study. CMAJ. 2009; 181(6-7):371-76.
11. Wen SW, Xie RH, Tan H, Walker MC, et al. Preeclampsia and gestational diabetes mellitus: pre-conception origins? Med Hypotheses. 2012; 79(1): 120-25.
12. Retnakaran R, Ye C, Hanley AJ, et al. Effect of maternal weight, adipokines, glucose intolerance and lipids on infant birthweight in women without gestational diabetes mellitus. CMAJ. 2012; 184(12):1353-60.
13. Borgono C, Hamilton JK, Ye C, et al. Determinants of insulin resistance in infants at 1 year of age: impact of gestational diabetes mellitus. Diabetes Care. 2012; 35(8):1795-97.
14. Kew S, Hamilton JK, Ye C, et al. Vitamin D status and cardio-metabolic assessment in infancy. Pediatric Res. 2013; 74(2):217-22.
15. Retnakaran R, Ye C, Hanley AJ, et al. Effect of maternal gestational diabetes on the cardiovascular risk factor profile of infants at 1 year of age. Nutr Metab Cardiovasc Dis. 2013; 23(12):1175-81.