gestational diabetes mellitus ( gdm ) is defined as any degree of glucose intolerance developing or first recognized during pregnancy that is not clearly overt diabetes . it affects from 5 - 6% to 1520% of pregnancies worldwide , depending on population demographics , screening methods , diagnostic criteria in use , and maternal lifestyle . the pathophysiological mechanisms behind the onset of gdm are still not well understood . in the second and third trimesters of pregnancy , there is a physiological increase of insulin resistance as a result of placental hormones such as estrogen , progesterone , human placental lactogen , human placenta growth hormone , and cortisol that antagonize the action of insulin . the gradual decline in insulin sensitivity is considered a physiological mechanism that helps to provide glucose to the fetus , and it coincides with a gradual increase in the secretion of insulin to maintain normal glucose tolerance [ 3 , 4 ] . pregnancy is per se a hyperinsulinemic condition and gdm may develop if insulin secretion by the beta cells is unable to compensate the pregnancy - associated insulin resistance . most women with gdm are overweight or obese and have all the features of metabolic syndrome , but lean women with none of the common risk factors can develop gdm too . women with gdm are at greater risk of metabolic syndrome ( characterized by central obesity , dyslipidemia , and insulin resistance ) and type 2 diabetes years after their pregnancy [ 6 , 7 ] . gdm progresses to type 2 diabetes in the years after pregnancy with a cumulative incidence in the range of 2.670% , from 6 weeks to 28 years postpartum . women who develop gdm are also at higher risk of overt cardiovascular disease ( cvd ) later in life . while a diagnosis of type 2 diabetes in these women markedly raises their cvd risk , some studies have demonstrated that a diagnosis of gdm alone contributes to this risk , with or without any subsequent type 2 diabetes . in a cross - sectional study , 332 women with a history of gdm had a higher prevalence of cvd 29.9 years after the index pregnancy ( adjusted or : 1.85 ; 95% ci : 1.212.82 ) , irrespective of any type 2 diabetes ( or : 1.56 ; 95% ci : 1.0022.43 ) . retnakaran and shah investigated the possible relationship between mild glucose tolerance in pregnancy and cvd risk in later life in a retrospective population - based cohort study . they studied 13,888 women who developed gdm , 71,831 women who had an abnormal 50  g glucose test result but no gdm , and 349,977 women who had a normal response to the 50  g glucose challenge , with a median follow - up of 12.3 years . compared with the women with normal glucose tolerance , the authors found an adjusted hazard ratio for cvd ( acute myocardial infarction , coronary bypass , coronary angioplasty , stroke , and carotid endarterectomy ) of 1.66 ( 95% ci : 1.302.13 ) for the gdm women and 1.19 ( 95% ci : 1.021.39 ) for the women with an abnormal glucose test result . adjusting for the subsequent onset of type 2 diabetes led to attenuation of the hazard ratios for cvd , which became 1.25 ( 95% ci : 0.961.62 ) for the gdm group and 1.16 ( 95% ci : 0.991.36 ) for the group with an abnormal glucose test result . the authors concluded that even women with mild hyperglycemia in pregnancy , but no gdm , are at higher risk of subsequent adverse cardiovascular outcomes . it should be emphasized , however , that a large proportion of the elevated cvd risk in the abovementioned study could relate to the subsequent onset of type 2 diabetes , as suggested by the hazard ratios adjusted for this diagnosis . be that as it may , the effect of gdm on the risk of cvd remains to be fully elucidated : it is still not clear whether the association existing between gdm and cvd is independent of the increased risk of cvd associated with type 2 diabetes . in this paper , we review the relationship between common cvd risk factors and a history of gdm and take a look at potential new markers of cvd in such women ( figure 1 ) . a review of the international literature was conducted as regards the cardiovascular risk for women with gdm or a history of gdm . the keywords used were as follows : gestational diabetes mellitus , cardiovascular disease , cardiovascular risk , vascular disease , pregnancy , and pregnancy complication . only data deriving from human studies and produced from 2005 onwards were considered in order to ensure that the evidence was topical . data regarding patients with prior diabetes ( type 1 or type 2 ) were not considered . in the literature , there is plenty of evidence of a greater risk of hypertension in women with a history of gdm . carr et al .   demonstrated that women with prior gdm were more likely to develop hypertension than women with no history of gdm ( 46.8% versus 37% ; p < 0.001 ) and that any hypertension would be diagnosed at an earlier age in the former than in the latter ( 40  1.0 versus 47.8  0.9 years ; p < 0.001 ) . studied a large cohort of 240,083 women giving birth over a 10-year period . during this time , 14.9% of the nonobese women with a history of gdm developed hypertension ; the hazard ratio , adjusted for maternal age , preeclampsia , parity , smoking status , ethnicity , and socioeconomic status , was 2.0 ( 1.82.2 ) ; and in the obese women with a history of gdm , the rate of hypertension rose to 26.8% and the hazard ratio to 3.7 ( 3.24.3 ) . .   recently reported on a large nationwide population - based retrospective study conducted in france , with a follow - up of 7 years . the results of logistic regression analysis adjusted for age showed that gdm was associated with a significantly higher risk of hypertension , with an adjusted or of 2.92 ( 2.773.08 ) . like the situation seen for hypertension , carr et al . showed that women who developed gdm were more likely to report a history of acquired dyslipidemia ( 33.9% versus 26.3% ; p < 0.05 ) , to take medication for dyslipidemia ( 18.4% versus 13.7% ; p < 0.05 ) , and to be diagnosed with dyslipidemia at a younger age ( 47.6  1.3 versus 51.9  1.0 years ; p = 0.01 ) than women with no history of gdm . in another study , women with singleton pregnancies who had gdm or normal glucose tolerance were examined from 2 to 24 months after their pregnancy : those with a history of gdm had higher total cholesterol ( 5.06 versus 4.56  mmol / l ; p = 0.001 ) , ldl - cholesterol ( 3.17 versus 2.57  mmol / l ; p = 0.001 ) , and triglyceride levels ( 1.02 versus 0.86  mmol / l ; p = 0.01 ) and lower hdl - cholesterol levels ( 1.53 versus 1.73  mmol / l ; p = 0.001 ) . in a similar study population , retnakaran et al . found gdm to be an independent predictor of total cholesterol , ldl - cholesterol , and triglyceride levels measured 3 months after delivery . these authors also demonstrated a stronger correlation between the area under the curve on the antepartum oral glucose tolerance test and postpartum levels of ldl - cholesterol and triglycerides , total cholesterol to hdl ratio , apob , and apob to apoa1 ratio ( all r > 0.21 ; p < 0.0001 ) and an inverse relationship with hdl - cholesterol ( r = 0.21 ; p < 0.0001 ) , after adjusting for age , ethnicity , and family history of diabetes . metabolic syndrome is characterized by abdominal obesity , hypertension , dyslipidemia , and abnormal glucose tolerance . the condition carries a six- to eightfold higher risk of cvd and a two- to threefold higher cvd - related mortality rate by comparison with healthy controls . women who have had gdm are at high risk of developing metabolic syndrome . in a cohort of caucasian women , for instance , the prevalence of metabolic syndrome 16 months after delivery was 9% among the women with a history of gdm and only 1% among controls ( p < 0.01 ) , when ncep , atp iii criteria were applied . this prevalence rose from 9% to 14.5% for the former and from 1% to 2% for the latter when idf criteria were adopted ( p < 0.001 ) . other studies on cohorts of caucasian women with a follow - up ranging from 5 to 11 years after delivery found that the prevalence of metabolic syndrome among the women with a history of gdm ranged from 11.1% to 43% , as opposed to 4.66.1% in a control population [ 1012 ] . a recent hospital - based cohort study found that the risk of metabolic syndrome 26 years after delivery was 2.4 times higher in women with a history of gdm than in those with normal glucose tolerance in pregnancy . multivariate analysis indicated that a history of gdm predicted the onset of metabolic syndrome with an or of 2.83 . recently examined the prevalence of metabolic syndrome in women with a history of gdm according to the new criteria for the diagnosis of this condition . their sample consisted of 265 women with a history of gdm at a mean of 2.6 years after the index pregnancy and 378 women with normal glucose tolerance in pregnancy at a mean of 3.3 years after pregnancy . according to the atp iii criteria , 25.3% of the gdm women had metabolic syndrome as opposed to 6.6% of the controls . the authors also found that obesity confers a significant excess risk of metabolic syndrome in women who have had gdm , with an or of 3.9 ( 95% ci : 2.07.9 ) for obese women with as opposed to without a history of gdm . even women with a history of gdm who have no common cv risk factors are at greater risk of cvd than those with normal glucose tolerance in pregnancy . gdm seems to have a significant impact on endothelial function and structure , triggering the first step towards the development of atherosclerosis . carotid artery intima - media thickness ( cimt ) is a subclinical measure of early atherosclerosis that strongly predicts heart disease and stroke , particularly in women . in recent years bo et al . measured cimt six and a half years after delivery in 82 women with and 113 without a history of gdm . they found cimt to be significantly higher in the former than in the latter , even among women with no components of metabolic syndrome , and irrespective of their bmi . cimt was also significantly associated with a history of gdm in a multiple regression analysis , after adjusting for waist circumference , bmi , blood pressure , and blood glucose levels . investigated cimt two years after delivery in 28 women with and 24 without a history of gdm . there were no differences between the two groups in terms of bmi , but the cimt values were higher in the gdm women , though they were still within the upper limit of normal ( 0.57  0.058 versus 0.51  0.051  mm , p < 0.01 ) . it is important to mention , however , that these groups also differed in terms of the principal components of metabolic syndrome ( waist circumference , blood pressure , fasting plasma glucose , and triglycerides ) , which were all significantly higher in the gdm women than in the controls . in a population - based , multicenter , longitudinal , and observational study conducted by gunderson et al . , 898 women with no diabetes or heart disease at the baseline subsequently had > 1 delivery and then reported their gdm history and underwent cimt measurement 20 years later . among the women who developed no type 2 diabetes or metabolic syndrome during the 20-year follow - up , the mean cimt was 0.023  mm greater for the women with a history of gdm in a model adjusted for age , race , parity , and prepregnancy bmi . on the other hand , the mean cimt did not differ by gdm history among the women who developed type 2 diabetes or metabolic syndrome during the follow - up . the authors concluded that a history of gdm can be considered a risk factor for atherosclerosis even before the onset of diabetes or metabolic syndrome . another proposed surrogate marker for the early detection of atherosclerosis is the flow - mediated dilation ( fmd ) of the brachial artery , which is an indicator of endothelial dysfunction measured fmd 36 months after delivery in nonobese and obese women with a history of gdm . they found fmd to be significantly lower in both nonobese and obese gdm women than in control women . they also showed that fmd correlated inversely with bmi , serum total cholesterol , and basal insulin resistance ( assessed with a homeostasis model ) . found fmd to be impaired in gdm women already 79 weeks after delivery . in this particular study , a sample of women was divided into 4 groups : those with a history of gdm who had become normoglycemic ; those with a history of gdm who remained hyperglycemic ; those with no history of gdm ; and those who had never been pregnant . interestingly , fmd no longer differed significantly between the four groups after controlling for glucose auc , which goes to show the importance of postpartum hyperglycemia in determining endothelial dysfunction after pregnancy . after adjusting for age and blood pressure levels , fakhrzadeh et al . reported a significant reduction in fmd 4 years after delivery in women with a history of gdm   by comparison with control women ( 26  0.11% versus 19.32  0.05% ; p = 0.003 ) . they also reported finding no correlation between fmd and inflammatory parameters , lipid profile , or insulin resistance indices ; they did not consider glucose auc . on the other hand , found no differences in fmd between women who had experienced gdm five years earlier and control women matched for age , bmi , and smoking habits . brewster et al . likewise found no differences in fmd between women with a history of gdm and control women 6 years after delivery ( mean 8.5% versus 9.3% , p = 0.61 ) . there is therefore no way of saying for sure that fmd is impaired in later years in women who have had gdm . it is worth noting that most of the studies that did find a worse fmd were conducted soon after delivery , so it may be that this impairment is an early vascular function abnormality that may return to normal with time if glucose tolerance returns to normal ; that is , fmd could be influenced mainly by hyperglycemia . supporting this hypothesis , found fmd to be significantly lower in gdm women than in controls ( 4.1  0.9% versus 10.9  1.1% ; p < 0.0001 ) in the third trimester of pregnancy . they found too that glucose auc independently influenced fmd ( p < 0.0001 ) . in another cross - sectional study on pregnant women with gdm ( n. 19 ) or preeclampsia ( n. 42 ) and controls with normal glucose tolerance and blood pressure ( n. 19 ) , guimares et al . also demonstrated a significantly reduced fmd in the women with gdm or preeclampsia by comparison with the controls , and they suggested the possibility of endothelial injury in such patients . in this recently studied the coronary flow velocity reserve ( cfvr ) , which reflects coronary microvascular function , in women with a history of gdm 6 months after delivery . they found this parameter to be significantly reduced in the gdm women by comparison with controls whose glucose tolerance remained normal in pregnancy ( 2.34  0.39 versus 2.83  0.21 ; p < 0.001 ) and also that insulin resistance , hyperglycemia , and oxidative stress markers were negatively associated with cvfr . on multivariate analysis , the authors also found an independent association between cfvr and gdm ( p = 0.02 ) . endothelial dysfunction is believed to be an important initiating factor in the development of atherosclerosis . like circulating levels of systemic inflammatory markers , the levels of some adipokines apelin , a recently discovered adipocytokine , is an endogenous ligand of the g protein - coupled receptor apj   that is produced by adipose tissue and expressed in various tissues ( brain , lung , heart , pancreas , kidney , and endothelial cells ) and believed to have a role in the cardiovascular system . in a recent study , 141 women with a history of gdm and 49 age- and bmi - matched healthy control women were tested for circulating apelin , il-6 , and plasminogen activator inhibitor levels and imt and took an oral glucose tolerance challenge . the results showed that plasma apelin levels were lower in women with a history of gdm and , in multiple regression analysis , they were negatively associated with fasting and postload glucose , il-6 , and carotid imt . suppressed apelin levels are therefore associated with a higher cardiovascular risk in women with a history of gdm . subclinical inflammation is another major risk factor for future cvd in the general population , and the higher risk of cvd later in life for women with a history of gdm is potentially at least partly due to inflammatory mechanisms . although several studies have demonstrated higher levels of markers reflecting vascular inflammation in women who have had gdm , the mechanisms behind vascular injury and cvd are not well understood . osteoprotegerin ( opg ) is a soluble member of the tumor necrosis factor ( tnf ) receptor superfamily that inhibits osteoclast maturation and protects bone from normal osteoclast remodeling . opg has an important role in lymphocyte development and apoptosis too , and its levels have been associated with cvd . in a cross - sectional case - control study , 128 women with a history of gdm and 67 age - matched controls were considered for a diagnosis of metabolic syndrome according to the criteria of the american heart association ( aha ) , and their glucose and insulin levels , serum lipids , opg , and cimt were also measured . the women who were confirmed to have metabolic syndrome had higher opg levels than those who were not , or healthy controls ; and serum opg levels were found to be associated with obesity , insulin resistance , and cimt . pentraxin 3 ( ptx3 ) is an essential component of innate immunity induced by various inflammatory stimuli . it is produced by endothelial cell macrophages and granulocytes at sites of inflammation   and may have a cardioprotective role : higher levels in patients with cvd reflect a beneficial response in terms of reduced immune activation . considered oral glucose tolerance test findings , lipid profiles , ptx3 levels , and arterial stiffness in 300 women during pregnancy and 5 years afterwards . early in pregnancy and 5 years later , ptx3 levels were lower in the women who developed gdm , and they were associated with bmi . low ptx3 levels in early pregnancy were inversely correlated with metabolic risk factors for cvd ( such as body composition , arterial stiffness , dyslipidemia , and a history of gdm ) 5 years after delivery . low plasma concentrations of ptx3 in early pregnancy are therefore associated with the subsequent onset of gdm and a higher risk of cvd later on . in conclusion , numerous studies have demonstrated an increased risk of type 2 diabetes , metabolic syndrome , and cvd after pregnancy in women who develop gdm , but the mechanisms contributing to the vascular dysfunction seen in gdm women remain uncertain . for the time being , no validated markers of this vascular risk are identifiable before the onset of diabetes , metabolic syndrome , or cardiovascular morbidity . novel potential early markers have recently been proposed , but further investigations on larger samples and longitudinal studies are needed to confirm their value . given the rising prevalence of gdm , future studies should aim to identify strong early markers of cvd in women who develop this condition , and specific strategies are warranted to prevent or reduce obesity , diabetes , metabolic syndrome , and consequent cvd , in this particular population .
the prevalence of gestational diabetes mellitus is increasing in parallel with the rising prevalence of type 2 diabetes and obesity around the world . 
 current evidence strongly suggests that women who have had gestational diabetes mellitus are at greater risk of cardiovascular disease later in life . 
 given the growing prevalence of gestational diabetes mellitus , it is important to identify appropriate reliable markers of cardiovascular disease and specific treatment strategies capable of containing obesity , diabetes , and metabolic syndrome in order to reduce the burden of cardiovascular disease in the women affected .