Review
Ravi Retnakaran
PII: S0168-8227(17)32053-3
DOI: https://doi.org/10.1016/j.diabres.2018.04.008
Reference: DIAB 7323
Please cite this article as: R. Retnakaran, Hyperglycemia in Pregnancy and its Implications for a Woman’s Future
Risk of Cardiovascular Disease, Diabetes Research and Clinical Practice (2018), doi: https://doi.org/10.1016/
j.diabres.2018.04.008
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Hyperglycemia in Pregnancy and its Implications
for a Woman’s Future Risk of Cardiovascular Disease
1- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada
2- Division of Endocrinology, University of Toronto, Toronto, Canada
3- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
Tables: 1
1
ABSTRACT
It is well established that gestational diabetes mellitus (GDM) identifies a population of women
who are at risk of ultimately developing type 2 diabetes (T2DM) later in life. Moreover, this
relationship extends across the full spectrum of hyperglycemia in pregnancy, with lesser degrees
Importantly, a growing body of evidence suggests that an analogous relationship exists between
well. Indeed, as compared to their peers, woman who had GDM have a higher risk of major
cardiovascular events, which first manifests within the first decade after the index pregnancy.
Although the absolute incidence of such events remains low in young women of child-bearing
age, the identification of future risk of CVD at this early point in its natural history may provide
the unique opportunity for timely intervention and ideally disease prevention. Thus, in this
future risk of CVD in young women and its implications for research and clinical practice.
Keywords: gestational diabetes, cardiovascular disease, heart, risk factors, women’s health
2
Introduction
It has been known for over 50 years that the diagnosis of gestational diabetes mellitus (GDM)
identifies a population of women who are at risk of ultimately developing type 2 diabetes
(T2DM) in the years thereafter [1-3]. The mechanistic basis for this relationship is chronic
pancreatic beta-cell dysfunction that underlies the pathophysiology of both GDM and subsequent
T2DM [3]. Specifically, hyperglycemia in pregnancy (i.e. the severity of which defines GDM)
arises because of the inability of the beta-cells to fully compensate for the physiologic insulin
resistance that characterizes the latter half of gestation [4]. In the years after delivery, it is the
progressive worsening of this beta-cell defect that drives the development of T2DM in affected
women [5-9]. Moreover, it should be recognized that any degree of glucose intolerance in
pregnancy (i.e. GDM being the most severe example of which) is actually a reflection of
underlying beta-cell dysfunction and indeed similarly identifies a proportionate gradient of future
risk of T2DM [9-12]. In this way, pregnancy can thus be looked upon as a stress test for the beta-
cells, the response to which can provide insight into a women’s likelihood of ultimately
In contrast to this association with future diabetic risk, the cardiovascular implications of
hyperglycemia in pregnancy are less well understood. However, a growing body of evidence
suggests that gestational dysglycemia can indeed provide insight into a woman’s future risk of
cardiovascular disease, as it does for diabetes. In this report, we will review this emerging
concept, its supporting evidence, and the resultant implications for further research and clinical
practice.
3
Gestational Diabetes and Cardiovascular Disease
In the past decade, a series of studies has evaluated the relationship between GDM and
history of GDM, as compared to their peers. When considered collectively, these studies may
provide some insights into the long-term cardiovascular risk implications of hyperglycemia in
pregnancy.
First, as the risk of major clinical cardiovascular events (such as myocardial infarction, stroke,
and cardiovascular death) is low in women of child-bearing age, it is not surprising that the only
study that did not find an association between GDM and CVD followed patients to just 1 year
postpartum (when any propensity for vascular disease likely would not yet have had time to
manifest clinically in young women)[16]. Indeed, in this context, it is instead noteworthy that
even studies with follow-up between 5.3 and 10 years postpartum have revealed a higher
incidence of CVD in women who had GDM, compared to their peers [17-19,22]. Second, this
elevated vascular risk is modest in its overall magnitude, in keeping with the low likelihood of
clinical CVD in young women. Nevertheless, this risk has been consistently apparent across
study populations ranging in size from 995 to >1.5 million women, with follow-up varying
between 5.3 years to >25 years postpartum (Table 1). When one considers the lack of consensus
in GDM diagnostic criteria and screening protocols across jurisdictions (which can result in
varying degrees of dysglycemia in the women so diagnosed across studies), the possibility
emerges that gestational hyperglycemia may identify a gradient of risk for future CVD, as it does
for T2DM. In support of this possibility, it is notable that a study of 435,696 women [15] found
that those with mild glucose intolerance in pregnancy had an elevated risk of CVD events over
4
median 12.3 years after delivery as compared to their normoglycemic peers (adjusted hazard
ratio (HR) 1.19, 95%CI 1.02–1.39), which was lower than that of women who had GDM
(adjusted HR 1.66, 95%CI 1.30–2.13). Thus, while it is clear that GDM (i.e. the most severe
gestational hyperglycemia) predicts future CVD, further studies are warranted to evaluate the
Confirmation that this risk extends to milder gestational dysglycemia would mean that
her glycemic response to pregnancy could provide insight into a woman’s future risk of CVD, as
The possibility that gestational hyperglycemia may identify analogous risk gradients for both
T2DM and CVD leads to the natural question of whether intercurrent diabetes may mediate the
observed association between GDM and subsequent cardiovascular events. In this regard,
evaluation of the impact of diabetes on this association has yielded conflicting findings in the
studies to date (Table 1). Specifically, adjustment for diabetes fully attenuated the higher risk of
CVD in women with previous GDM in some studies [14,15,21] but not in others [13,19,22].
Nevertheless, for evaluation of the impact of diabetes in this setting, two key points warrant
consideration.
First, it is important to recognize that, since atherosclerosis develops over decades, the
emergence of differential risks of CVD between women with GDM and their peers within 5.3 to
10 years after pregnancy likely reflects insufficient time for postpartum progression to T2DM to
be solely responsible. Second, as T2DM is likely both a mediator and confounder in the
association between GDM and CVD [23], adjustment for its presence may not be the ideal
5
approach to its handling. Of potential interest in this regard is a recent study [22] in which
1,515,079 women were followed for median 10.0 years postpartum with stratification into the
following 4 groups: those with GDM who subsequently developed T2DM after pregnancy
(n=15,585); women with GDM who did not develop T2DM (n=41,299); women who did not
have GDM but nevertheless developed T2DM (n=49,397); and those who had neither GDM nor
T2DM (n=1,408,798). With this analytic approach, it was shown that, amongst women with
GDM, only those who subsequently progressed to T2DM had increased risks of the advanced
nephropathy (as defined by need for dialysis). In contrast, however, women with GDM had an
elevated risk of incident CVD whether or not they progressed to T2DM in the years after
pregnancy. While those who developed T2DM had greater risk (HR 2.82, 95%CI 2.41-3.30), it is
nevertheless notable that women with GDM who did not progress to T2DM still had a higher
risk of CVD than women who had neither GDM nor T2DM (HR 1.30, 95%CI 1.07-1.59). These
data thus suggest that, unlike microvascular risk potential, the risk of macrovascular disease is an
inherent feature of GDM, with subsequent diabetes serving to amplify this risk [22].
warranted.
The metabolic syndrome is a diagnostic construct that has been applied to describe the
within individuals who are at risk of developing both T2DM and CVD [24]. Although the
6
diagnostic criteria, underlying pathophysiology, and clinical value of the metabolic syndrome
have all been vigorously debated, its associations with incident diabetes and vascular disease are
undeniable. In this way, there exist clear similarities between the metabolic syndrome and GDM,
involving 5832 women [27], those with a history of GDM were shown to have a markedly
elevated risk of metabolic syndrome (odds ratio 3.96, 95%CI 2.99 to 5.26). There are two key
points to recognize in this regard. First, this risk is readily apparent as early as 3 months after
delivery, at which time there is already a high prevalence of metabolic syndrome in women who
had GDM (prevalence of 20% by International Diabetes Federation (IDF) criteria and 16.8% by
criteria)[28]. Second, the relationship between GDM and metabolic syndrome extends across the
spectrum of hyperglycemia in pregnancy [28]. Indeed, women who had gestational impaired
glucose tolerance (GIGT) also have an increased prevalence of metabolic syndrome at 3 months
postpartum, albeit at lesser rates than those who had GDM (prevalence of 17.6% by IDF criteria
and 15.4% by AHA/NHLBI criteria)[28]. Moreover, both GDM and GIGT independently predict
early postpartum metabolic syndrome after adjustment for covariates [28]. Thus, as it does for
future risk of T2DM, the spectrum of hyperglycemia in pregnancy similarly identifies a gradient
of risk for metabolic syndrome that is apparent within 3 months after delivery. In addition, this
stepwise relationship extends to component disorders of the metabolic syndrome, with analogous
Since hypertriglyceridemia and low HDL are typical features of the dyslipidemia that arises
7
in patients with T2DM, their presence in women who had hyperglycemia in pregnancy (which
predicts future diabetes risk) may not be surprising. Moreover, the cardiovascular risk
cardiovascular significance of low-density lipoprotein (LDL) cholesterol and its main lipoprotein
(apolipoprotein B (apoB)) is very well established. As such, it is notable that previous studies
have reported that women with a history of GDM have elevated serum concentrations of LDL
[25,29,30]. Most importantly, as seen with the metabolic syndrome, this relationship is present in
the early postpartum and extends across the range of hyperglycemia in pregnancy [30]. Indeed,
compared to their peers, women with GDM and GIGT have a more atherogenic lipid profile by 3
months postpartum, as characterized by increased serum concentrations of LDL and apoB [30].
Accordingly, the possibility emerges that chronic exposure to an atherogenic dyslipidemia may
Interestingly, LDL particle characteristics may offer further support for this possibility.
Small dense LDL particles are susceptible to oxidation, resulting in oxidized LDL species that
contribute to the atherosclerotic process. In this context, it is notable that the lipid profile of
women has been characterized as exhibiting a preponderance of small dense LDL particles, with
an increased proportion of the very small LDL IVA and LDL IVB subclasses [31,32]. Moreover,
it has been reported that women with GDM have an increased susceptibility to LDL oxidation
across pregnancy [33]. Taken together, these data raise the possibility that long-term exposure to
higher LDL concentrations, coupled with enhanced oxidative susceptibility, may contribute to
8
Emerging non-traditional cardiovascular risk factors may also be relevant in women with a
history of gestational hyperglycemia. In the past 2 decades, chronic sub-clinical inflammation (as
dysfunction (as reflected in the dysregulation of circulating adipokines) have been recognized as
pathologic effects of obesity that can be tracked by changes in their circulating biomarkers,
which in turn have emerged as novel risk factors for T2DM and CVD in the general population
[34-39]. Accordingly, given their risk of developing both of these conditions, there has been
interest in the evaluation of inflammatory proteins and adipokines in women with previous
GDM.
Several studies have reported that women with a history of GDM have elevated serum levels
of inflammatory biomarkers such as sialic acid, C-reactive protein (CRP), and plasminogen
activator inhibitor-1 [40-43]. Amongst adipokines, the most studied in this patient population is
adiponectin, low circulating levels of which have been documented before, during and after
pregnancy in women who developed GDM [43-48]. Moreover, at 3-months postpartum, women
who had GDM or GIGT both exhibit lower adiponectin concentrations, as compared to women
who maintained normal glucose tolerance in pregnancy [48]. Conversely, however, it should be
noted that the potential relationships of inflammatory biomarkers and adipokines with future risk
of CVD in this patient population have not been studied to date. As such, the cardiovascular
9
metabolic syndrome, LDL, apoB etc)[10,28,30] in relation to the severity of preceding
hyperglycemia in pregnancy raises the question of when these gradients may first arise. In this
late 2nd trimester (i.e. when the physiologic insulin resistance of gestation has advanced to the
point of posing its stress test for the beta-cells), a growing body of evidence suggests that women
who develop antepartum dysglycemia differ from their peers long before this diagnosis [49].
Indeed, when measured in the 1 st trimester (i.e. prior to the insulin resistance of the latter half of
gestation), several circulating markers have been shown to predict the subsequent development
of GDM later in pregnancy [49]. These markers have included glycemic measures, fasting
insulin, triglycerides, HDL, adiponectin, CRP, tissue plasminogen activator antigen, and insulin-
like growth factor binding protein-2 [45,46,49-53]. Moreover, even prior to pregnancy, women
who go on to develop GDM appear to differ from those who do not do so. Pre-gravid
measurements of fasting glucose, fasting insulin, triglycerides, HDL, adiponectin and the hepatic
enzyme gamma glutamyl transferase (GGT) have all been reported to predict the subsequent
development of GDM in pregnancy [44,49,54-58). It thus appears that (i) women who develop
hyperglycemia in pregnancy differ from their peers before, during, and after pregnancy, and that
(ii) these differences extend beyond the beta-cell/glucoregulatory physiology that underlies their
clinical presentation. The concept emerging from these data is that the strata of gestational
dysglycemia (such as GDM and GIGT) may be identifying women with chronic subclinical
metabolic dysfunction who are only detected clinically because of antepartum glucose tolerance
testing in the setting of the aforementioned physiologic stress test posed by the insulin resistance
of late gestation. This model would suggest then that the cardiovascular risk factor gradients
10
observed at 3 months postpartum likely long preceded the pregnancy itself. Accordingly, it is
possible that differential long-term exposure to cardiovascular risk factors may underlie the
emerging associations between hyperglycemia in pregnancy and a woman’s risk of CVD later in
life. While this possibility remains conjecture at this time, it is suggestive of opportunities for
further research and clinical intervention, towards the goal of ultimately reducing cardiovascular
risk in women.
The ability to identify future risk of CVD early in its natural history in young women can
present a unique opportunity that has implications for both research and practice. Current
understanding of this natural history holds that chronic exposure to cardiovascular risk factors
eventually leads to deleterious effects on vessel function (e.g. endothelial dysfunction) and
structure (e.g. atherosclerosis) prior to the clinical presentation of CVD. From a research
perspective, the early identification of women at future risk of CVD can enable detailed
characterization of the pathophysiologic changes that arise over time as part of this process. In
this way, longitudinal study of women with varying degrees of hyperglycemia in pregnancy may
provide a model for studying the early pathophysiology of vascular disease (as it does for
T2DM).
pregnancy could provide an opportunity to identify high-risk women and intervene early in the
pathologic process. Ideally, such intervention would occur prior to the development of abnormal
vessel function and structure. In this regard, it is potentially encouraging that studies to date have
yielded conflicting findings on whether women with a history of GDM have impaired
11
endothelial function in the early postpartum years [59,60]. Similarly, although a meta-analysis
has suggested that carotid intima-media thickness (cIMT) is already slightly increased in women
with GDM during the index pregnancy, it remains unclear whether this association is largely
mediated by obesity [61]. Further longitudinal study over time of endothelial function and cIMT
history of gestational dysglycemia may enable targeted intervention towards the goal of risk
reduction and ideally disease prevention. While an evidence base for such therapy remains to be
established, it would seem prudent at this time to consider those interventions that can reduce the
risk of progression to T2DM in this setting. These interventions may include the promotion of
breastfeeding, healthy lifestyle practices (diet, physical activity) targeting weight control, and
Conclusion
The growing body of evidence reviewed herein suggests that hyperglycemia in pregnancy
may provide unique insight into a women’s risk of developing CVD later in life, in a manner
analogous to its implications for her future risk of diabetes. While much work remains to be done
to elucidate the pathophysiology underlying this association, the potential societal benefits of
such an understanding are enormous. Indeed, there is growing recognition of the importance of
maternal physiology on intrauterine programming of fetal pathways which may have resultant
effects on the long-term health of the offspring (as per the Developmental Origins of Health and
12
young women may ultimately offer the opportunity for transgenerational benefit for both mother
and child.
13
Acknowledgements: RR is supported by a Heart and Stroke Foundation of Ontario Mid-Career
Investigator Award and holds the Boehringer Ingelheim Chair in Beta-cell Preservation,
Funding: This research did not receive any specific grant from funding agencies in the public,
14
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67. Retnakaran R, Wen SW, Tan H, Zhou S, Ye C, Shen M, et al. Maternal pre-gravid
cardiometabolic health and infant birthweight: A prospective pre-conception cohort study.
Nutr Metab Cardiovasc Dis 2017; 27(8):723-30.
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68. Tam WH, Ma RCW, Ozaki R, Li AM, Chan MHM, Yuen LY, et al. In utero exposure to
maternal hyperglycemia increases childhood cardiometabolic risk in offspring. Diabetes
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Table 1: Studies evaluating the risk of cardiovascular disease (CVD) after pregnancy with GDM
Shah14 2008 89,453 Canada Longitudinal 11.5 years Higher risk Yes
Retnakaran15 2009 435,696 Canada Longitudinal 12.3 years Higher risk Yes
Shostrom20 2017 8,217 United States Cross-sectional 22.9 years Higher risk --
Tobias21 2017 89,479 United States Longitudinal 25.7 years Higher risk Yes
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