Accepted Manuscript

Review

Hyperglycemia in Pregnancy and its Implications for a Woman’s Future Risk

of Cardiovascular Disease

Ravi Retnakaran

PII: S0168-8227(17)32053-3
DOI: https://doi.org/10.1016/j.diabres.2018.04.008
Reference: DIAB 7323

To appear in: Diabetes Research and Clinical Practice

Received Date: 31 December 2017

Accepted Date: 4 April 2018

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

Ravi Retnakaran MD FRCPC1-3

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

Correspondence: Dr. Ravi Retnakaran

Professor of Medicine, University of Toronto
Leadership Sinai Centre for Diabetes, Mount Sinai Hospital,
60 Murray Street, Suite L5-025, Mailbox-21,
Toronto, Ontario, Canada M5T 3L9
Phone: (416) 586-4800 ext. 3941 Fax: (416) 586-8853
E-mail: ravi.retnakaran@sinaihealthsystem.ca

Short title: GDM and Heart Disease

Tables: 1

Abstract words: 186 Total Words: 3071

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

of gestational dysglycemia identifying a proportionate gradient of future risk of T2DM.

Importantly, a growing body of evidence suggests that an analogous relationship exists between

hyperglycemia in pregnancy and a woman’s long-term risk of cardiovascular disease (CVD), as

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

review, we discuss the emerging concept of hyperglycemia in pregnancy as an indicator of the

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

developing T2DM later in life [4].

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

subsequent cardiovascular disease (CVD)[13-22]. As shown in Table 1, these studies have

generally demonstrated a higher incidence of major cardiovascular events in women with a

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

potential cardiovascular risk implications of milder degrees of hyperglycemia in pregnancy.

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

it does for T2DM.

Impact of T2DM on Cardiovascular Risk after GDM

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

microvascular complications of retinopathy (defined as vitrectomy or photocoagulation) and

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].

Accordingly, it follows that consideration of other contributing factors besides diabetes is

warranted.

Traditional Cardiovascular Risk Factors after Hyperglycemia in Pregnancy

The metabolic syndrome is a diagnostic construct that has been applied to describe the

clustering of specific cardiovascular risk factors (typically central obesity, dysglycemia,

hypertension, hypertriglyceridemia and low levels of high-density lipoprotein (HDL) cholesterol)

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,

which also predicts future risk of both conditions.

Not surprisingly, previous studies have consistently reported an increased prevalence of

metabolic syndrome in women with previous GDM [25-28]. In a meta-analysis of 17 studies

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

American Heart Association/National Heart Lung and Blood Institute (AHA/NHLBI)

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

associations seen with hypertension, hypertriglyceridemia, and low HDL [28].

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

implications of hypertriglyceridemia and low HDL remain controversial. In contrast, the

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

be a factor contributing to their lifetime risk of CVD.

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

the elevated lifetime risk of CVD in this patient population [22,30].

Emerging Cardiovascular Risk Factors after Hyperglycemia in Pregnancy

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

evidenced by increased serum concentrations of inflammatory proteins) and adipocyte

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

implications of these non-traditional risk factors in women with a history of hyperglycemia in

pregnancy are not known.

Hyperglycemia in Pregnancy and the Natural History of CVD in Women

The early postpartum presence of gradients of cardiovascular risk factors (dysglycemia,

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

regard, emerging perspectives on the etiology of GDM may be informative. Specifically,

although hyperglycemia in pregnancy is typically diagnosed at the time of GDM screening in

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.

Implications and Opportunities for Research and Clinical Practice

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).

From a clinical perspective, the long-term cardiovascular implications of hyperglycemia in

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

in women with and without a history of GDM is warranted in this regard.

Ultimately, a better understanding of the natural history of CVD in relation to a woman’s

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

pharmacologic measures such as metformin [62-65].

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

Disease paradigm)[66-68]. In this context, early intervention to reduce cardiovascular risk in

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,

Function and Regeneration at Mount Sinai Hospital.

Funding: This research did not receive any specific grant from funding agencies in the public,

commercial, or not-for-profit sectors.

Conflicts of Interest: None to disclose

14
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Table 1: Studies evaluating the risk of cardiovascular disease (CVD) after pregnancy with GDM

Years since Risk of CVD after Did adjustment for diabetes

First Author Year N Country Study Design Pregnancy Previous GDM fully attenuate association?
Carr13 2006 995 United States Cross-sectional 29.9 years Higher risk No

Shah14 2008 89,453 Canada Longitudinal 11.5 years Higher risk Yes

Retnakaran15 2009 435,696 Canada Longitudinal 12.3 years Higher risk Yes

Savitz16 2014 849,639 United States Longitudinal 1 year No higher risk --

Fadl17 2014 15,949 Sweden Longitudinal 9.1 years Higher risk --

Kaul18 2015 240,083 Canada Longitudinal 5.3 years Higher risk --

Goueslard19 2016 1,518,990 France Longitudinal 7 years Higher risk No

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

Retnakaran22 2017 1,515,079 Canada Longitudinal 10.0 years Higher risk No

22