Keywords::
Gestational diabetes mellitus (GDM), or glucose intolerance first recognized during pregnancy Citation[1], is associated with future cardiovascular disease (CVD) risk in the mother Citation[2,3]. GDM affects 4–14% of pregnancies every year, and the prevalence of glucose intolerance during pregnancy has been increasing Citation[4,5]. The increasing prevalence of risk factors for GDM and diabetes suggest that glucose intolerance during pregnancy will continue to rise. These risk factors include advancing maternal age and racial–ethnic shifts in childbearing demographics Citation[6], along with obesity preceding pregnancy and excessive weight gain during pregnancy Citation[7].
The recognition of GDM may provide a ‘teachable moment’ during which women might implement lifestyle or pharmacotherapy to reduce their CVD risk. The young age at which women with GDM are diagnosed (typically in their fourth decade), their more extensive contact with healthcare providers for prenatal care, and their willingness to address behaviors such as tobacco abuse for the sake of the fetus could enable CVD prevention Citation[8]. However, pregnant women also face significant obstacles to behavior change, and evidence is currently limited regarding the effectiveness of targeting women with GDM. It is also unclear which women are at highest risk, because not all women with GDM have adverse CVD risk factor profiles. Similarly, it is unknown how CVD evolves in these women and which mediators should be targeted.
GDM & CVD outcomes
Epidemiologic studies of the link between GDM and CVD events are difficult to conduct owing to the lag time between pregnancy, in the third and fourth decades of life, and CVD events, typically two to three decades later. Studies are also limited by the ascertainment of GDM, which historically has been irregular: screening criteria vary between institutions and medical organizations. Currently, no large prospective cohort studies of GDM and non-GDM women exist that ascertain CVD events in a systematic fashion.
Therefore, association between GDM and actual CVD events rests primarily upon two studies Citation[2,3]. In a cross-sectional study, Carr et al. found that women with a GDM history had a higher risk of CVD events than women without a GDM history Citation[2]. However, women in this study were highly selected in that all had at least two first-degree relatives with Type 2 diabetes and were participants in the Genetics of Non-Insulin Dependent Diabetes (GENNID) study. Therefore, women with GDM in this cohort were probably at higher risk for future glucose intolerance and CVD events than women with GDM in less selected populations; this is suggested by the fact that 93% of women with histories of GDM and 63% of women without histories of GDM developed Type 2 diabetes in GENNID. While women with histories of GDM had events at a younger age than women without such histories (45 vs 53 years; p < 0.05), much of the risk seemed to be mediated through the greater Type 2 diabetes risk in the women with histories of GDM (adjusted odds ratio: 1.58; 95% CI: 1.00–2.49). GDM and CVD were ascertained by self-report, peripheral vascular disease was not ascertained, and GDM screening was not practiced as commonly as it is today, making these estimates susceptible to recall and survivor bias. Using administrative data, Shah and colleagues conducted a retrospective study that also found that a history of GDM was associated with a greater risk of coronary disease events Citation[3]. As in the study by Carr et al., much of this risk seemed to be mediated through the elevated Type 2 diabetes risk of women with histories of GDM (adjusted hazard ratio: 1.13; 95% CI: 0.67–1.89).
These outcome studies raise several questions: is the risk of CVD events elevated among women with histories of GDM who do not develop diabetes? How can we identify these women? Can CVD event risk be reduced among women with histories of GDM? Do other risk factors, particularly blood pressure and lipid levels, cross the diagnostic thresholds for ‘abnormal’ and therefore ‘treatable’ before glucose levels are consistent with diabetes? We do not have answers to the first three questions. However, smaller studies have addressed abnormalities in other CVD risk factors and indicators of CVD function in the GDM population.
GDM, CVD risk factors & indicators of CVD function
Among women with a GDM history, blood pressure, HDL and triglyceride levels are elevated and associated with diabetes and milder glucose intolerance Citation[9–12]. While levels of blood pressure and lipids were elevated compared with controls, these were still usually within normal range and related to glucose continuously, without a threshold effect. In a cross-sectional analysis, we found that women with a GDM history who do not have diabetes may not have increased risk of other CVD risk factor abnormalities, and it is possible that the subset of women who cross the thresholds for ‘abnormal’ for glucose are more likely to cross thresholds for lipid and blood pressure abnormalities as well Citation[12]. I am unaware of any prospective studies that have examined the sequence of CVD risk factor evolution among women with a GDM history.
Markers of endothelial and cardiac function are also impaired in women with histories of GDM compared with controls and this appears to occur in a continuous fashion. Heitritter et al. found that women with a GDM history had greater vascular resistance, lower stroke volume and lower cardiac output than women without a GDM history Citation[13]. Postpartum GDM women also appear to have greater diastolic dysfunction upon echocardiography Citation[14], increased carotid intimal medial thickness Citation[15] and poorer brachial artery flow-mediated dilation compared with controls Citation[16], all of which are markers for vascular dysfunction. Similarly, biochemical markers of endothelial function, particularly vascular adhesion molecule-1 Citation[17], E-selectin Citation[17], and inflammatory markers including C-reactive protein Citation[13], fibrinogen Citation[18] and plasminogen activator inhibitor-1 Citation[13], have been found to be elevated in the GDM population compared with controls. We found that elevations in C-reactive protein and fibrinogen were not marked after consideration for other recognized CVD risk factors, particularly central obesity, but reports conflict Citation[19].
In summary, studies of intermediate markers, particularly CVD risk factors, endothelial and cardiac function studies, and biochemical markers strongly suggest that women with GDM have unfavorable profiles compared with unaffected women. However, the significance of the degree of impairment is not clear. This is particularly true for risk factors, which appear to be related in a continuous fashion and therefore may be less useful for risk stratification for intervention.
Recommendations & five-year view
We recommend that women with GDM undergo glucose screening for postpartum diabetes; engage in weight reduction to reduce future diabetes risk and risk to additional pregnancies; and engage in physical activity to assist in weight reduction, increase functionality, and reduce CVD risk and mortality. We make these recommendations while recognizing that little evidence exists to support them.
Cohort studies examining the risk factor evolution of GDM women using standardized criteria for risk factor and event ascertainment are needed. Such prospective studies could answer the following questions: which risk factors are most important for risk of CVD events? Which subset of the GDM population is most vulnerable to CVD events, and how early can these women be identified? Do biochemical markers offer prognostic value beyond recognized CVD risk factors?
While mechanisms of action and mediators of CVD risk remain unclear with women with GDM, this does not preclude intervention studies. Women with even remote histories of GDM can reduce their diabetes risk through implementation of weight loss and physical activity programs. Studies examining the effectiveness of interventions in women closer to their pregnancy might determine whether earlier intervention could avert more diabetes cases and reduce the incidence of other CVD risk factor abnormalities and diabetes complications. Such interventions also need to be evaluated for their long-term effects on offspring. Successful interventions would leverage the tight inter-relationship between maternal and child health during the unique condition of pregnancy, and in doing so, avert disease in an efficient and cost-effective manner.
Key issues
• Gestational diabetes mellitus (GDM) is a risk factor for future cardiovascular disease events in the mother.
• GDM is increasing in prevalence, driven by greater maternal obesity and weight gain during pregnancy.
• It is not known why many women with GDM do not develop diabetes or cardiovascular disease.
• The value of risk stratification and intervention during or soon after delivery has not been demonstrated.
• Outcome studies are few and limited to cross-sectional or retrospective reports.
• Numerous smaller studies demonstrate a continuous relationship between markers of cardiovascular function and GDM.
• Additional work is needed to determine the value of intervention and the evolution of cardiovascular disease in women with GDM.
Financial & competing interests disclosure
This work was supported by grant K23-DK-071552 from the National Institute of Diabetes and Digestive and Kidney Diseases. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Related Research Data
References
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