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Abstract

Gestational diabetes mellitus (GDM) affects many women in pregnancy and is enhanced by epidemic conditions of obesity, increasing age at the time of the first pregnancy, stressful life conditions, a sedentary lifestyle with less physical activity and unhealthy nutrition with highly processed, high-calorie food intake. GDM does not affect the mother and offspring in pregnancy alone, as there is compelling evidence of the long-term effects of the hyperglycemic state in pregnancy postpartum. Type 2 diabetes mellitus, cardiovascular disease and metabolic syndrome are more common in GDM women, and even the offspring of GDM women are reported to have higher obesity rates and a higher risk for noncommunicable diseases. Early prevention of risk factors seems to be key to overcoming the vicious cycle of cardiometabolic disease onset.

Keywords

cardiovascular disease cardiovascular risk disease prevention gestational diabetes mellitus lifestyle intervention metabolic syndrome postpartum period pregnancy pregnancy complication Type 2 diabetes mellitus

According to WHO, cardiovascular diseases (CVDs) are the most common cause of death globally, representing 30% of all deaths [1]. A further increase in deaths from 17.3 million in 2008 to 23.3 million deriving from CVDs is expected by the year 2030, mainly due to an increase of the following risk factors: unhealthy diet, obesity or Type 2 diabetes mellitus (T2DM), hyperlipidemia and physical inactivity [1,2]. Compared with men, who are prone to suffer from CVDs approximately 10 years earlier, women face a similar or aggravated risk profile after menopause [3]. However, women face less risk during their reproductive age due to a protective effect of estrogens. In fact, recent studies show that female risk populations, such as women suffering from polycystic ovary syndrome, T2DM or gestational diabetes mellitus (GDM), have an increased risk for CVDs [4]. Prediabetes or T2DM increase the risk for women tremendously, and women with impaired glucose metabolism encounter cardiovascular mortality more frequently [3,4]. Moreover, an elevated risk of myocardial infarction and stroke was already seen many years prior to clinical diagnosis of T2DM [5]. GDM is most often reported to have a prevalence of 2–6% in Europe and is reported to be higher after switching to new International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria and in other ethnicities, with numbers ranging from 1.7 to 11.6% in advanced economies [6 –9]. Buckley et al. identified many barriers in terms of screening processes, different national or even local guidelines in use, diverse policies across Europe and poor clinician awareness, which attenuate the discovery of diabetes in pregnancy [6]. Diabetes mellitus was divided into four distinct categories in a recent American Diabetes Association (ADA) position statement, and GDM was considered to be one of these [10]. GDM describes a heterogeneous group of hyperglycemic disorders detected in pregnancy [201]. Most GDM women are overweight or obese, and often present with the full picture of a metabolic syndrome; therefore, GDM may be regarded as ‘pre-Type 2 diabetes’. However, lean women without any common risk factors also develop GDM, and GDM may also encompass women with genetic forms, such as maturity-onset diabetes of the young or the presence of β-cell antibodies (e.g., late-onset autoimmunity diabetes in adults). GDM progresses to T2DM in the years after the index pregnancy with a 2.6–70% range for cumulative incidence at 6 weeks to 28 years postpartum and is associated with metabolic disturbances and CVDs in mothers and their offspring [11]. Higher risk for the onset of T2DM was suggested by another study in relation to ethnic origin, with higher risk seen in black women [12]. Furthermore, Asian–Indian and African–Caribbean ethnicities were described to have impaired glucose tolerance more often compared with women of European origin and with different risk factor profiles [13]. These studies showed that, especially in non-European women, impaired glucose metabolism and the metabolic syndrome are more prominent, revealing an urgent demand for strategies for cardiometabolic disease prevention in different ethnicities [14]. Intervention and prevention methods in order to stop the onset of metabolic disease and CVD in pregnancy, or thereafter in women with GDM, are important approaches in disease prevention [15 –18]. Unfortunately, recommendations from guidelines are conflicting, compliance of women for follow-up visits after GDM is poor – often not exceeding 50% – and high-quality interventions are lacking [16,19 –21]. Further research is necessary in order to shed light on the intervention and motivational options for this special-risk population and to find evidence-based approaches to reduce the risk for cardiovascular and metabolic diseases after pregnancy for both the mother and child.

Methods

A critical review of the worldwide peer-reviewed literature was conducted relating to the cardiovascular risk of women with GDM or a history of GDM. Using Medical Subject Heading (MEsH) search terms in the MEDLINE and EMBASE databases gave a result of 157 relevant abstracts (Table 1 & Supplementary Material; see online at www.futuremedicine.com/doi/suppl/10.2217/whe.13.69). Only data derived from human studies were chosen as relevant. Material produced from 2005 onwards was sought in order to ensure that the evidence was current. Only in highly important cases was peer-reviewed literature from years prior to 2005 chosen. In addition, duplicates were removed. All abstracts were searched for relevant information regarding CVD after GDM. After careful examination of the relevant literature, a hand search was carried out in order to identify further relevant literature from the reference lists. Using the Scopus database, forward and backward literature searches were performed for highly important articles only and for literature regarding treatment and prevention methods. Forty seven relevant articles were identified. In addition, two independent literature searches were performed in order to identify literature regarding lifestyle or pharmacological interventions in women with GDM and previous GDM to prevent progression of CVD or T2DM, and to identify cytokines, adipokines, hormones and other metabolic parameters throughout pregnancy in normal glucose-tolerant and gestational diabetic women, as well as previously diabetic women and obese/diabetic subjects. Further information regarding additional searches can be found in the Supplementary Material. Because the sources of information varied widely, a narrative synthesis approach was judged to be the most appropriate method for this review, which is mainly descriptive and does not involve a systematic approach [202].

Table 1.

Search protocol using Medical Subject Heading search terms in the MEDLINE and EMBASE databases.

Search stage	Search protocol†	Number of results
1	Exp diabetes, gestational/	25,292
2	Exp postpartum period/	87,698
3	Exp cardiovascular diseases/	4,709,554
4	Stage 1, 2 and 3	194
5	Remove duplicates from stage 4	184
6	Limit stage 5 to human	175
7	Limit stage 6 to year (2005–current)	157

†

Slash symbol (/) indicates that all subheadings were selected. ‘Exp’ indicates that the term was exploded.

Results

Cardiometabolic risk factors

Increased glucose levels and diabetes mellitus are well-known cardiovascular risk factors, in addition to other modifiable and unmodifiable risk factors that are relevant for metabolic diseases and CVDs (Figure 1). Diabetic women in particular have a four- to six-fold increased risk of developing coronary artery disease [22]. Studies have shown a vast variety of modifiable risk factors in GDM women and women with mild hyperglycemia with impaired glucose tolerance, atherogenic lipid profiles, higher age, lower insulin sensitivity, impaired β-cell function, elevated highly sensitive CRP (hsCRP) and, in addition, increased carotid intima–media thickness (CIMT) at a few months postpartum (Table 2) [23 –28]. Possession of two risk factors has been found to result in higher risk compared with pregnancies with only one risk factor [23]. A cutoff of 88 cm for waist circumference was shown to have a significant effect on diabetes progression [23].

Table 2.

Risk factors for cardiovascular disease in women previously affected by gestational diabetes mellitus.

Study (year)	Study sample; follow-up time	Risk factors in GDM women	HR (95% CI)	Additional findings	Ref.
Göbl et al. (2011)	110 women; <10 years pp	IGTHDL <55 mg/dl/1.42 mmol/lAge>35 years	6.77 (2.96–15.45)2.88 (1.24–6.67)3.06 (1.32–7.12)	T2DM present in 23/110 after median of 3.0 yearsPredictors for T2DM: insulinization in pregnancy,2-h glucose:>140 mg/dl/7.8 mmol/l, fasting glucose: >100 mg/dl/5.6 mmol/l	[23]
Akinci et al. (2011)	195 GDM women, 71 controls; >1 year PP	IGT, IFG, IR↑ CIMT↑ Atherogenic lipid profile	–	T2DM and MetSy more prevalent in GDM Predictors for T2DM: insulinization in pregnancy and antepartum OGTT values	[24]
Kvehaugen et al. (2010)	Pre-eclampsia: 23,GDM: 12,T1DM: 11,control: 17;5–8 years pp	↑ RRsysWaist:hip ratio <0.85Obesity↑ Fasting glucose	–	Weight gain and RRsys significantly increase in pre-eclamptic and GDM women.Offspring of GDM women are more often overweight or obese (NS), and have higher waist circumference	[25]
Retnakaran et al. (2010)	482 women; 3 months pp	↑ Total cholesterol↑ LDL↑ Triglycerides↑ Cholesterol:HDL ratio↑ ApoB↑ ApoB:ApoA1 ratio	–	–	[26]
Ozuguz et al. (2011)	61 GDM, 40 controls; 1 year pp	↑ Fasting glucose↑ Insulin↑ HOMA IR↑ Triglycerides↑ hsCRP↑ CIMT	–	hsCRP levels are an independent risk factor for the development of dysglycemia	[28]

↑ Increased; CIMT: Carotid intima–media thickness; GDM: Gestational diabetes mellitus; HDL: High-density lipoprotein; HOMA: Homeostatic model assessment; HR: Hazard ratio; hsCRP: Highly sensitive CRP; IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance; IR: Insulin resistance; LDL: Low-density lipoprotein; MetSy: Metabolic syndrome; NS: Not significant; OGTT: Oral glucose tolerance test; pp: Postpartum; RRsys: Systolic blood pressure; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus.

Figure 1.

Modifiable and unmodifiable risk factors for cardiovascular disease in women with gestational diabetes mellitus and women affected by the metabolic syndrome.

In general, progression to T2DM is a very strong risk factor for future CVD, with a fourfold cardiovascular risk elevation even before diagnosis and a long list of equally modifiable risk factors [29,30]. An older cross-sectional study found no differences between self-reported GDM and normal glucose tolerance (NGT) groups in terms of most cardiovascular risk factors, except for greater levels of mean fasting glucose (94.0 mg/dl/5.2 mmol/l vs 106.8 mg/dl/5.9 mmol/l; p < 0.001) and mean fasting insulin (10.2 vs 14.0 IU/l; p < 0.001) [14]. After adjustment for demographic factors and waist circumference, a mitigating effect was observed. Fasting glucose and the ratio of urine microalbumin:creatinine remained significant. Increased body fat mass is often reported to be higher in GDM women compared with other groups, showing its important role in the pathogenesis of both T2DM and CVD; it is unknown whether T2DM and CVD are independent or dependently interacting with each other in this case [31,32]. Two large-scale population-based studies, together assessing more than 1.6 million participants, indicated that women with GDM have a higher risk for pre-eclampsia and pregnancy-induced hypertension (PIH), both of which are associated with CVD and hypertension in later life [33,34].

GDM & epigenetics

In addition to various environmental stressors triggering methylations, hydroxymethylations, histone modifications and RNA-based mechanisms, and causing quick adaption of cells, maternal hyperglycemia was reported to affect fetal development in utero [35]. A changing intrauterine environment at the stage when cells are developing fastest can cause improper imprinting of genes. This might result in the development of CVD, obesity, T2DM or the metabolic syndrome in later life. A two- to four-fold higher risk in the offspring of mothers with GDM and Type 1 diabetes mellitus (T1DM) for the development of obesity and the metabolic syndrome was reported by Clausen et al. [36]. This was corroborated by a study that also reported higher obesity rates in T1DM offspring 7 years after the pregnancy, as well as publications showing higher overweight prevalence and insulin resistance in GDM offspring throughout childhood, as well as higher prevalence rates of T2DM [37 –39]. By contrast, these findings were not supported in offspring of gestational diabetic or T1DM mothers in other studies [38,40,41]. Although these data are conflicting, a genetic background is indisputable and, to some extent, hyperglycemia – as one of many factors – might play an additional role in disease progression and result in a combined effect. Rijpert et al. showed that T1DM offspring with optimal glucose control (glycated hemoglobin aim: <6.0%/42.08 mmol/mol) in pregnancy had comparable results with the offspring of healthy mothers in the parameter of the metabolic syndrome at 6–8 years of age [40]. Thus, optimal glycemic control seems to be crucial in disease prevention, in addition to lifestyle factors in later life. Fetal dynamic processes of epigenetic mechanisms seem to play a role in disease development.

Figure 1 gives an overview of the ‘common soil’ risk factors in CVDs and T2DM, but primarily focuses on postpartum findings in women with GDM. GDM and/or the metabolic syndrome are influenced by genetic background, as well as epigenetics. Post-GDM women often show hypertension and endothelial dysfunction. Furthermore, pre-eclampsia and pregnancy-induced hypertension are more often detected in GDM women. Dyslipidemia (increased free fatty acids, higher triglycerides and lower high-density lipoprotein cholesterol) and ectopic lipids (increased intramyocellular and hepatocellular lipid storage), as well as impaired body fat distribution with central obesity, are commonly seen in GDM women postpartum. This results in unfavorable changes in adipokines or cytokines. Markers of inflammation are raised and often associated with a prothrombotic state. This is often associated with lifestyle factors, such as overnutrition and physical inactivity, which further increase the risk for CVD.

Cardiovascular risk: continuous effects of mild metabolic disturbances or induction through overt T2DM

In a cross-sectional study with 995 GDM and healthy participants, women with a history of GDM had a higher prevalence of CVD (adjusted odds ratio [OR]: 1.85; 95% CI: 1.21–2.82) independent of T2DM [42]. All of these women had a family history of T2DM. Not only higher CVD events at a younger age were reported, but CVD risk factors, such as T2DM and the metabolic syndrome, were also more common. Another study confirmed these results of a higher risk for CVD events in GDM women over the course of 11.5 years [43]. A study investigating the influence of mild glucose intolerance on cardiovascular risk was performed by Retnakaran and Shah [44]. A 50-g glucose challenge test (GCT) in order to screen for abnormal glucose tolerance was carried out in a sample of nearly 450,000 women aged between 20 and 49 years followed by an oral glucose tolerance test (OGTT) if the GCT was abnormal. In total, 71,831 of the participants had an abnormal GCT but NGT, 13,888 women had an abnormal GCT and GDM, and 349,977 women had a normal GCT. The median follow-up time was 12.3 years. Primary outcomes included admission to hospital for acute myocardial infarction, coronary bypass, coronary angioplasty, stroke or carotid endarterectomy. A higher risk was seen in women with GDM, and women with abnormal GCT only compared with control women. Cardiovascular event rates per 10,000 person-years were 4.2, 2.3 and 1.9 among women with GDM, an abnormal GCT but normal OGTT and NGT, respectively. The adjusted hazard ratio (HR) for women with GDM for CVD was 1.66 (95% CI: 1.30–2.13), while for those with an oral glucose test but no GDM, the adjusted HR was 1.19 (95% CI: 1.02–1.39) compared with women with NGT. After adjustment for consecutive progression to T2DM, the relationship between CVD, GDM and mild glucose intolerance was attenuated, which corroborated previous results in which the CVD risk was mitigated from a HR of 1.71 (95% CI: 1.08–2.69) to a HR of 1.13 (95% CI: 0.67–1.89) [43]. In this study, a great proportion of the elevated risk for CVDs could be reasoned with the subsequent progression to T2DM. Nevertheless, taking into account the relatively young study population with a low-risk potential and the long onset time of diabetes-induced CVD, the authors concluded that there was no relationship between T2DM and CVD in this sample [44]. A ‘common soil hypothesis’ was discussed as the underlying mechanism for CVD and T2DM [44,45]. This study concluded an increased incidence of subsequent CVD in women with mild hyperglycemia – not affected by GDM – and presented a continuous effect of hyperglycemia on adverse cardiovascular outcomes. To date, no clear segregation can be made between CVD risk coming from GDM or mild hyperglycemia, or through the development of T2DM. Further studies need to evaluate this aspect.

Clinical relevance of 1-h glucose values

Women who are not diagnosed with GDM but instead with isolated hyperglycemia using the 1-h postpartum OGTT had a higher cardiovascular risk than women with elevated 2- or 3-h glucose levels, suggesting the clinical importance of peak glucose values for risk assessment [46]. The clinical relevance of the 1-h OGTT for postpartum risk assessment was confirmed by another study showing that, at 3–6 months postpartum, the 1-h OGTT value was a stronger predictor of insulin sensitivity than fasting or 2-h glucose values [47], thus, peak glucose levels are of clear clinical importance for the further cardiometabolic risk stratification of women with GDM.

Vascular abnormalities & endothelial dysfunction in GDM & prior GDM

Studies show an influence of hyperglycemia on vascular function with conflicting results [32,48 –52]. In a 2-month postpartum follow-up study, arterial stiffness and endothelial function were assessed by Davenport et al. in 30 women stratified into three groups: NGT; GDM and normoglycemic postpartum (GDM-N group); and GDM and hyperglycemic postpartum (GDM-H group) [48]. Ten nulliparous controls were also measured. Carotid and brachial artery distensibility, pulse wave velocity and flow-mediated dilatation (FMD) were assessed, and a decreased distensibility of brachial and carotid arteries was found in the GDM-N group. Brachial artery distensibility returned to control levels only in NGT women. A decreased FMD in previously GDM women (GDM-N: 4.1 ± 2.3%; GDM-H: 4.4 ± 0.9) compared with NGT women (10.8 ± 1.3; p < 0.01) was described, suggesting the early derangement of endothelial function shortly after birth directly influenced by the hyperglycemic state in pregnancy and thereafter [48,53]. Insulin sensitivity, glucose area under the curve and triglycerides were shown to have a positive association with arterial stiffness [48,54]. After adjustment for insulin sensitivity or glucose area under the curve, no further evidence was given for brachial and carotid artery distensibility or differences in FMD [48]. Heitritter et al. found increased peripheral vascular resistance (1658 ± 290 vs 1462 ± 340 dyne/s/cm⁵), decreased stroke volume (65 ± 13 vs 75 ± 14 ml/beat) and decreased cardiac output (70 ± 12 vs 74 ± 13 ml/s) in the GDM cohort of a postpartum collective of women with GDM and NGT after at least 1 year postpartum [55]. In this study, insulin sensitivity and glycemic state seemed to play a key role in progression to CVD, but further investigation is required. A recent study showed an improvement in the ambulatory arterial stiffness index from 0.26 ± 0.10 to 0.17 ± 0.09 (p = 0.002) in women with dietary-treated GDM after delivery [50]. GDM women receiving insulin did not show significantly improved results compared with dietary or control groups at 3 months postpartum. Notably, mechanisms behind arterial stiffness in previously GDM women have not been well investigated. Conflicting results were presented by Brewster et al., showing no differences in FMD, FMD after 60 s, baseline arterial diameter, peak shear rate and reactive hyperemia at 6 years postpartum [49]. Cardiac autonomic function was impaired in approximately half of all examined GDM women in another study [56]. This was related to glycemic control, but not to insulin sensitivity. Advanced glycation end products might interact with macromolecules in the arterial wall, causing arterial stiffness. Significantly higher levels of serum amyloid A were detected in women with GDM compared with healthy pregnant controls, and this was correlated with CIMT [57]. These changes might progress subsequent to the onset of CVD and T2DM [58,59].

Changes in nitric oxide bioactivity

Impaired endothelial function was described in GDM in several studies and assessed by a decreased bioactivity of vascular nitric oxide (NO), at least in overweight women [60]. In this study, insulin resistance and increased ADMA – an endogenous NO synthase (NOS) inhibitor – contributed to endothelial dysfunction. In another study, elevated concentrations of ADMA were associated with deterioration of glucose tolerance in women with GDM after a median follow-up of 2.75 years [61]. Moreover, ADMA was described to be associated with obesity [53].

Another study anaylzed subcutaneous arterial biopsies at 2 years after pregnancy, including eight control women, 13 mild hyperglycemic women and eight women in a GDM group [32]. GDM and mild hyperglycemic women had normal vascular structure and stiffness, but also had clearly detectable impaired endothelium-dependent function. Response to carbachol in terms of maximal endothelium dilation was impaired in arteries from mild hyperglycemic women (51.7%; p = 0.04) and GDM women (43.3%; p = 0.01). Impairment in NOS activity was detected in GDM and mild hyperglycemic women after inhibition of NOS with decreased maximum endothelium-dependent dilation. Moreover, endothelial impairment was associated with BMI at biopsy in multiple regression models, but not with current glycemia. The authors concluded that vasocrine signals from adipose tissue affect glycemia and influence small vessel function [32,62]. In particular, perivascular fat seems to have a vital function in vascular integrity and local inflammation, causing anticontractile effects and mediators [63]. Whether the mechanisms behind vascular impairment are caused primarily by plasma glucose or are related to inflammatory processes in adipose tissue remains unclear.

Endothelial adhesion molecules & dysfibrinolysis

Endothelial adhesion molecules have a major role in the pathogenesis of CVD and were shown to be significantly increased in GDM and NGT women in pregnancy [52]. After delivery, circulating E-selectin and circulating VCAM-1 remained increased only in GDM women. Moreover, correlations between E-selectin and glycated hemoglobin were described before and after delivery. In a more recent study, E-selectin levels were shown to correlate with triglycerides, PAI-1 antigen and soluble ICAM-1 [51]. These findings indicate an association of GDM with atherogenic biomarkers and ICAM-1 independently of BMI and fasting glucose. Furthermore, a study of 74 GDM and 20 NGT women during and after pregnancy showed significantly elevated mean PAI-1, tissue plasminogen activator, fasting and stimulated plasma concentrations of proinsulin, C-peptide and insulin in GDM women, as well as a lower disposition index and no changes in plasma levels of fibrinogen and von Willebrand factor [31]. In prediction models for PAI-1 elevation, only fasting proinsulin and the waist:hip ratio remained significant in women with GDM with impaired insulin sensitivity, indicating a dependence of PAI-1 on plasma proinsulin and abdominal obesity.

After 6.5 years of follow-up, higher levels of E-selectin and ICAM-1, and higher intima–media thickness were observed [64]. Intima–media thickness was significantly associated with E-selectin, ICAM-1, IL-6 and hsCRP.

Inflammatory parameters

Several studies examined women with GDM aiming to measure cytokines and adipokines postpartum [55,65 –80]. Glucose tolerance and insulin sensitivity are strongly influenced by inflammatory mediators, such as CRP, IL-6, PAI-1 and TNF-α, as well as mediators produced in adipose tissue – so-called adipokines (e.g., adiponectin, leptin, RBP-4, resistin, visfatin, omentin, nesfatin and chemerin) or other peptides influencing glucose homeostasis, which seem to play an important role in the subsequent pathogenesis of T2DM or subsequent CVD in women with previous GDM (Table 3).

Table 3.

Cytokines, adipokines, hormones and other metabolic parameters throughout pregnancy in normal glucose-tolerant and gestational diabetic women, previously gestational diabetic women and obese/diabetic subjects.

Parameter	NGT†	GDM†	Previous GDM†	Obesity/ diabetes†	Ref.
CRP	↑	↑	↑	↑	[67]
IL-6	↑	↑	↑	↑	[67]
TNF-α	↑	↑	↑	↑	[67]
PAI-1	↑	↑	↑	↑	[67]
Adiponectin	↓/=	↓	↓	↓	[67]
Leptin	↑	↑/↓/=	↑/=	↑	[67]
RBP-4	↑/↓	↓/=	↑	↑/↓	[67]
Resistin	↑	↓/=	↑	↑	[67]
Visfatin	↑	↑	?	↑	[67]
Omentin	↑/=	↓/=	?	↓	[70,71,121 –124]
Nesfatin-1	?	↓	↓	↑/↓	[74,75,125,126]
Apelin	↓	↑/=	↓	↑/↓	[74–76,127,128]
Chemerin	=	=	?	↑	[77,129,130]
Vaspin	↓	=	↓	↑/↓/=	[72,73,124,131]
proBNP	↑	↓	=	↓	[78,79,132,133]
Lp(a)	↑	=	?	=/↑	[134 –136]
DPP4	↑	?	?	=	[137,138]
GLP-1	?	↓	↓	↓/=	[80,139,140]

NGT women are compared with healthy nonpregnant women, GDM with NGT women, post-GDM with healthy women, obese and diabetic subjects (note: male and female) with healthy controls.

†

More than one symbol indicates results from different studies

↑: Elevated levels; ↓: Decreased levels; ?: Unknown; =: Similar levels; GDM: Gestational diabetes mellitus; Lp(a): Lipoprotein A; NGT: Normal glucose tolerance. Adapted from [67].

Ectopic lipid content

Kautzky-Willer et al. determined the lipid content of soleus and tibialis anterior muscles with magnetic resonance spectroscopy and related it to insulin sensitivity and body fat mass in a study with women with previous GDM and NGT at 4–6 months after delivery [81]. In a more recent study of this group, ¹H/³¹P magnetic resonance spectroscopy was carried out at 4–5 years postpartum in glucose-tolerant GDM women who were not obese and NGT controls in order to measure intrahepatic fat mass and muscular ATPase activity [82]. As ectopic lipids are elevated in GDM women, deteriorated energy metabolism might influence these abnormalities [81]. In conclusion, minimal changes were found in energy metabolism and muscle glucose, further to increased body and muscle fat mass, and lower insulin sensitivity. At 4–5 years after the index pregnancy, liver fat is already increased, indicating pathologic mechanisms in hepatic metabolism, which may be able to progress cardiometabolic disorders in glucose-tolerant nonobese women. The latter corroborates the results of an earlier study in obese nondiabetic women affected by GDM in pregnancy, which showed that GDM women with high liver fat content had increased insulin resistance and higher fasting serum triglyceride and insulin concentrations compared with those with low liver fat content [83]. In addition to this, excess hepatic lipid storage, as found in nonalcoholic fatty liver disease without prior diagnosis of hyperglycemia is strongly associated with progression to T2DM and CVD [84]. Detailed study findings are documented in Table 4.

Table 4.

Studies examining ectopic lipid content in gestational diabetic women.

Study (year)	Study results	Ref.
Kautzky-Willer et al. (2003)	GDM vs NGT:45% higher body fat mass35% lower insulin sensitivity index (p < 0.05)IMCL: S: 31% higher; T: 61% higherIR subgroup of GDM women:IMCL-S: 66%; IMCL-T: 86% higher than in NGT, 28% higher than in GDM women with normal insulin sensitivity Insulinization resulted in significantly higher IMCL-S and IMCL-T than dietary-treated womenAdjusted analysis:IMCL-T reflects insulin sensitivityIMCL-S is related to obesity	[81]
Prikoszovich et al. (2011)	GDM vs NGT:36% higher fat mass12% lower insulin sensitivityDecreased log transformed ATPase levels (10.6 ± 3.8 vs 12.1 ± 1.4 umol/ml/muscle-1/min-1; p < 0.03); after adjustment for body fat mass, there was a relationship with adiponectin61 and 69% increased IMCL in GDM-IR vs GDM-IS women and IR vs IS womenIHCL twice as high in GDM and IR women; correlation: positive with body fat, inverse with IS	[82]
Tiikkainen et al. (2002)	High IHCL vs low IHCL: Increased prevalence of IRIncreased fasting serum triglycerides (1.93 ± 0.21 vs 1.11 ± 0.09 mM; p < 0.01)Increased insulin concentrations (14 ± 3 vs 10 ± 1 mU/l; p < 0.05)Higher 24-h blood pressureLower whole-body IS		[83]

GDM: Gestational diabetes mellitus; IHCL: Intrahepatocellular lipid content; IMCL: Intramyocellular lipid content; IR: Insulin resistant; IS: Insulin sensitive; NGT: Normal glucose tolerance; S: Soleus muscle; T: Tibialis anterior muscle.

A different approach for predicting future cardiometabolic disturbances of prior GDM was derived from the calculation of a fatty liver index (FLI), as assessed by ¹H-magnetic resonance spectroscopy at 3–6 months postpartum [85]. Strong positive associations with insulin resistance were shown with increasing FLI in GDM women. The high-FLI group also had elevated IL-6, PAI-1, tissue plasminogen activator, fibrinogen and hsCRP in comparison with the low-FLI group. Furthermore, the degradation of free fatty acids measured during the course of the OGTT was less pronounced in the high-FLI group. In another study, free fatty acids were higher in women with GDM, which was hypothesized to result from impairment of lipolysis inhibition caused by insulin [86]. Hyperlipidemia and ectopic lipid storage may therefore increase the risk of T2DM and CVD. Notably, the incidence of prediabetes or diabetes increased with FLI levels, and the calculation of risk for diabetes onset over 10 years in Cox proportional hazard models showed an association of FLI levels with diabetes risk [85]. Women in the high-FLI group had the highest risk compared with the low-FLI group (HR: 7.85; 95% CI: 2.02–30.5), suggesting that high liver fat content is a relevant risk factor in addition to insulin resistance or prediabetes for progression to T2DM and subsequent CVD in the near future.

Prevention factors

Many modifiable risk factors in women with previous GDM progressing to T2DM and subsequent CVD have been reported above. Disease prevention seems to be a very appropriate way to break the vicious cycle of cardiometabolic disease pathogenesis with a ‘common soil’ of risk factors. Different approaches, with impressive and promising results, have been reported throughout literature [15 –18,87 –105].

Lactation

A recent German study investigated long-term protective effects of breastfeeding on the development of T2DM in 304 GDM women [89]. The follow-up time was up to 19 years postpartum. The development of T2DM was dependent on treatment during pregnancy (dietary vs insulin), BMI and the detection of islet autoantibodies.

The median duration of breastfeeding was 9 weeks and was shorter in insulin-treated GDM and obese women. Breastfeeding was associated with a median onset time of T2DM of 12.2 years (95% CI: 7.7–16.8) only in autoantibody-negative GDM women, whereas in women who never breastfed, it was only 2.2 years (95% CI: 0.0–6.1; p = 0.012). A duration of more than 3 months was associated with lowest risk, with a 15-year risk of 42% (95% CI: 28.9–55.1) compared with 72% (95% CI: 60.5–84.7; p = 0.0002). This study demonstrates an easy and cost-effective method of cardiometabolic disease prevention in women affected by GDM, which was confirmed by another study examining data of 139,681 postmenopausal women and their risk for CVD in relation to lactation [90]. Women with more than 12 months of lactation in their lives reported less hypertension (OR: 0.88), diabetes (OR: 0.80), hyperlipidemia (OR: 0.81) or CVD (OR: 0.91) than never-breastfeeding women. Obesity was not affected by breastfeeding. This study clearly showed – for most risk factors – an inverse association of prevalence of hypertension, T2DM, hyperlipidemia and CVD with duration of lactation. Primiparas, who were breastfeeding for between 7 and 12 months, were significantly less affected by CVD (HR: 0.72; 95% CI: 0.53–0.97) than women who were not. In addition, a longer duration of lactation was associated with a risk reduction in incidence of the metabolic syndrome over a timespan of 20 years in women both with and without GDM [91]. Decreasing incidence rates were seen in GDM women (49.4 [95% CI: 25.8–84.7] to 8.5 [95% CI: 1.8–24.8]) and NGT women (15.8 [95% CI: 11.3–21.5] to 9.2 [95% CI: 5.3–14.6]). Despite demonstrating the effectiveness of breastfeeding in white women, black women seemed to have no or limited benefit from lactation. Lactation clearly shows benefits in pregnant women of up to an adjusted risk reduction of nearly 90% in GDM women (HR: 0.14; 95% CI: 0.04–0.55) and 60% in NGT women (HR: 0.44; 95% CI: 0.23–0.84) after 9 months or more of breastfeeding, which was intensified by physical activity in the GDM group [91]. The evidence favors a strong positive association of breastfeeding duration with a reduction of cardiometabolic disorders, starting at a duration of 1 month breastfeeding and with an increasing risk reduction with increasing duration of lactation.

Lifestyle intervention

With respect to lifestyle intervention programs, there are two possibilities: either to prevent the onset of GDM in pregnancy or to prevent the onset of T2DM after a diagnosis of GDM. Indisputably, both approaches together provide the best efficacy.

Lifestyle intervention in pregnancy

Some studies examined or will examine the effectiveness of lifestyle interventions in pregnancy [15,17,18,88,93,102]. Table 5 presents recent lifestyle intervention studies in pregnancy.

Table 5.

Lifestyle intervention strategies in gestational diabetic women in pregnancy.

Study (year)	Design	Population	Intervention	Study results (intervention vs control)	Additional information	Ref.
Oostdam et al. (2012)	RCT	121 overweight/obese women, <20 weeks gestation	Supervised, individual aerobic and strength training, 2×/week for 60 min vs routine care	GDM: 14.6 vs 24.6% (p = 0.37) No differences in fasting glucose and insulin, HOMA-IS, glycated hemoglobin, weight gain or physical activity No differences in birth outcomes in gestational age, birth weight, LGA or cesarean section	Compliance low: only 16.3% in lifestyle group attended ≥half of the training sessions	[93]
Luoto et al. (2011)	Cluster-randomized trial	399 euglycemic pregnant women with ≥1 risk factor, 8–12 weeks gestation	Individual intensified counseling on physical activity, diet and weight gain, five antenatal visits vs routine care	GDM: 12.4 vs 15.8% (p = 0.36) No differences in fasting, 1-h or 2-h glucose and insulin, HOMA-IR, weight gain and pre-eclampsiaBehavior: less saccharose; more dietary fiber; less saturated fatty acids; more polyunsaturated fatty acidsBirth outcomes: birth weight: 3532 ± 514 vs 3659 ± 455 g (p = 0.035); LGA: 12.1 vs 19.7% (p = 0.043)	No differences in adverse events, except for less headache in weeks 32–34 in the intervention group	[15]
Oostdam et al. (2011)	Systematic review 19 studies	–	Metformin vs no metformin (n = 369); low glycemic index diet advice vs high glycemic index/low fat diet advice (n = 127); any dietary counseling vs usual care (n = 836); probiotics with dietary counseling vs dietary counseling alone (n = 256); self-monitoring weight gain vs standard care (n = 257); exercise vs usual care (n = 238)	Dietary advice significantly reduced GDM incidenceNo intervention lowered fasting glucose effectivelyLow glycemic index diet and exercise program significantly reduced macrosomia risk	Quality of evidence: low, more studies required	[102]
Tobias et al. (2011)	Systematic review 12 studies,(seven prepregnancy, five early pregnancy)	Prepregnancy: n = 34,929; early pregnancy: n = 4401	Physical activity only	Exercise prepregnancy: OR: 0.45 (95% CI: 0.28–0.75) Exercise in early pregnancy: OR: 0.76 (95% CI: 0.70–0.83)	2813 GDM women of 34,929 participants 361 GDM women of 4401 participants	[88]

GDM: Gestational diabetes mellitus; HOMA: Homeostatic model assessment; IR: Insulin resistance; IS: Insulin sensitivity; LGA: Large for gestational age; OR: Odds ratio; RCT: Randomized controlled trial.

Unfortunately, no effect of lifestyle intervention was found in the ambitious FitFor2 study [93]. Analysis based on the intention to treat showed no differences between groups. One reason for the lack of observed effects in this study was low compliance. Similar results were reported in other studies, suggesting that commencing intervention programs in the second semester might be too late, whereas physical activity before pregnancy and in the first trimester of pregnancy was significantly associated with lower GDM risk [88,102]. A Finnish lifestyle intervention study demonstrated fewer numbers of large-for-gestational-age newborns at birth and changes in dietary behavior in GDM women during pregnancy, and revealed a decreased risk of developing GDM in the lifestyle cohort [15].

On the other hand, in another study, dietary interventions effectively reduced the risk of GDM by 60%, as well as gestational hypertension and preterm birth [103]. The Vitamin D and Lifestyle Intervention for Gestational Diabetes Mellitus Prevention project is going to examine whether dietary intervention, physical activity or vitamin D in different combinations will be effective in the prevention of the development of GDM in overweight and obese women [106]. The Vitamin D and Lifestyle Intervention for Gestational Diabetes Mellitus Prevention study is currently being performed in 880 obese pregnant women.

Lifestyle intervention after pregnancy A lifestyle intervention pilot study delivered by telephone for 12 months in previously GDM women reported a nonsignificant but higher postpartum weight control in diet and physical activity groups compared with controls (37.5 vs 21.4%; p = 0.07) [98]. In the intervention group, a significantly decreased dietary fat intake compared with usual care was observed, in addition to not significantly increased breastfeeding. The feasibility of lifestyle interventions starting at the diagnosis of GDM in pregnancy and throughout the postpartum period was proven in this study, with retention at over 85%. Furthermore, women meeting the Institute of Medicine recommendations for weight gain in pregnancy more often met the study aims of regaining prepregnancy weight [98,107].

Several large-scale lifestyle intervention studies in order to prevent the onset of T2DM also included GDM women (~16%) and showed effectiveness (Table 6) [99 –101]. In all three studies (SLIM, DPP and DPS studies), diabetes incidence was reduced significantly. Only the DPP study provided a subanalysis for women with a history of GDM [96]. Prior GDM women had a crude incidence rate of diabetes that was 71% higher than those who were unaffected during pregnancy. Lifestyle intervention reduced diabetes incidence by approximately 50%. A small Malaysian study in women with previous GDM showed that a low glycemic index diet compared with conventional dietary recommendations over 6 months was associated with significant weight reduction and improved metabolic parameters [95]. In conclusion, lifestyle intervention in GDM women postpartum is an effective approach to delaying T2DM onset and subsequent diabetic angiopathy.

Table 6.

Overview of lifestyle and pharmacological intervention studies.

Author (year); study	Design	Population	Intervention	Participation of GDM women	Main study results	Ref.
Tuomilehto et al. (2001); Finnish DPS	RCT;FU: 4 years	n = 522; 66% female	Lifestyle intervention (diet and exercise) vs control	GDM included via FINDRISC as ‘previously high blood glucose’	Cumulative diabetes incidence: 11% in intervention group (95% CI: 6–15) vs 23% in control group (95% CI: 17–29) 58% diabetes risk reduction (p < 0.001) in intervention group	[100]
Roumen et al. (2008); SLIM	RCT;<FU: 3 years	n = 147; 49% female	Lifestyle intervention (diet and exercise) vs control	GDM not excluded	Cumulative diabetes incidence: 18% in intervention group vs 32% in control group (p = 0.07) Relative risk: 0.52 (95% CI: 0.25–1.10)	[101]
Shyam et al. (2013)	RCT;FU: 6 months	n = 77; 100% female	Conventional healthy dietary recommendation vs low glycemic index groups	100%	Significant improvements in glucose tolerance and bodyweight reduction in low glycemic index groups	[95]
Ratner et al.(2008)Knowler et al. (2002); DPP	RCT;FU: 2.8 years	n = 3234; 68% female	Metformin vs placebo vs lifestyle intervention (diet and exercise) Subanalysis of 2190 women of DPP with 350 GDM women	16.1%	Diabetes incidence: 11.0, 7.8 and 4.8 cases/100 person-years in placebo, metformin and lifestyle groups, respectivelyIncidence reduction: 58% lifestyle (95% CI: 48–66); 31% metformin (95% CI: 17–43)GDM: diabetes incidence reduction of 50% in lifestyle and metformin groups NGT: diabetes incidence reduction of 49 and 14% in lifestyle and metformin groups, respectively	[96,99]
DeFronzo et al. (2011); ACT NOW	RCT;FU: 2.4 years	n = 602; 58% female	Pioglitazone vs placebo	17.5%	T2DM conversion hazard ratio in pioglitazone group: 0.28 (95% CI: 0.16–0.49)Annual T2DM incidence rates: 2.1% in pioglitazone group and 7.6% in placebo group	[104]
Gerstein et al. (2006); DREAM	RCT;FU: 3 years	n = 5269; 59% female	Rosiglitazone vs placebo	GDM not excluded	T2DM progression: 11.6% in rosiglitazone group and 26.0% in placebo group; hazard ratio: 0.40 (95% CI: 0.35–0.46)	[108]
Zinman et al. (2010); CANOE	RCT;FU: 3.9 years	n = 207; 67% female	Metformin and rosiglitazone vs placebo	Inclusion of GDM	Relative diabetes risk reduction: 66% (95% CI: 41–80)	[87]

FINDRISC: Finnish Diabetes Risk Score; FU: Follow-up time; GDM: Gestational diabetes mellitus; NGT: Normal glucose tolerance; RCT: Randomized controlled trial; T2DM: Type 2 diabetes mellitus.

Table 6 gives an overview of lifestyle and pharmacological studies, which included or were carried out in women with a history of GDM. Figure 2 shows the treatment options for women with previous GDM.

Figure 2.

Prevention options in women with gestational diabetes mellitus.

Pharmacological intervention studies

Several studies investigated pharmaceutical treatment options and included GDM women at postpartum (Table 1) [87,96,97,104,108]. An approximately 50% reduction in diabetes incidence was observed in the GDM group treated with metformin in the DPP study [96]. Higher effectiveness of metformin in women with a history of GDM compared with those without was also reported. In the ACT NoW study, the risk of progression to T2DM was significantly reduced, but a higher prevalence of side effects, such as weight gain and edema, was also observed [104]. The PIPOD study determined the progression of CIMT in premenopausal Hispanic women with previous GDM [97]. The CIMT rate in women receiving pioglitazone was 69% lower after 3 years of therapy. Furthermore, other diabetes prevention studies, such as DREAM or CANOE, using pharmacological interventions showed high effectiveness in the total study groups, but did not report effectiveness in subgroups, such as GDM women (Table 6).

Figure 2 presents the prevention options for stopping the subsequent progression of CVD. Different approaches have been shown to be effective (e.g., increased physical activity or a healthy diet in order to maintain normal weight or reduce weight [5–10%] if overweight or perfroming a randomized controlled trial showing a positive effect of pioglitazone or metformin) [15,17,18,87,88,93,95 –97,99 –102,104,108]. The data currently available indicates that incretin-based therapies might be of relevance in CVD prevention in the future [109], but further studies need to prove this. Other lifestyle factors, as well as other ameliorating factors, are also of importance. Regular follow-up visits are recommended in order to control for metabolic or other risk factors in patients who are at high risk.

Subsequent pregnancy & contraception

The influence of a subsequent pregnancy was examined in a Canadian sample of women with a 4.5-year follow-up time [110]. The hypothesis that physiological insulin resistance of a subsequent pregnancy accelerates the pathogenesis of T2DM was discussed. In this sample, 16.2% of participants developed GDM. After adjustment, an association between reduced diabetes risk and subsequent pregnancy was found (adjusted HR: 0.68; 95% CI: 0.60–0.76). Above all, a modestly increased risk of T2DM was seen in subsequent GDM pregnancies (adjusted HR: 1.16; 95% CI: 1.01–1.34), as well as a decrease in risk with each nondiabetic pregnancy (adjusted HR: 0.34; 95% CI: 0.27–0.41). In subsequent pregnancies with recurrent GDM, we could not find any association with either impairment of glucose metabolism or cardiovascular risk [111].

There is a lack of information in terms of choice of best contraceptive method after GDM, with there only being a few published studies. No significant changes in carbohydrate metabolism were described with hormonal contraception [112]. If obesity, hypertension or dyslipidemia are present, either a hormonal contraceptive with no vascular effects or a mechanical method is recommended [112]. In addition, the use of gestagen-only contraceptives was described to lead to an increased risk for T2DM in Hispanic populations [113].

Conclusion & future perspective

As GDM, obesity, T2DM and CVD prevalence is growing, further randomized controlled trials focusing on intervention methods in pregnancy and thereafter – or, even better, involving both periods – are needed in order to shed light on the pathogenesis of these diseases. We need evidence of specific treatment strategies that are able to reduce obesity and the metabolic syndrome postpartum, and subsequent CVD.

Health economies all around the world are called to invest in primary preventative approaches, as the costs of cardiometabolic diseases are rapidly increasing and are more expensive if diseases have fully progressed. Cost–effectiveness analyses revealed that new International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria are effective when postpartum monitoring is able to prevent diabetes progression [114]. International consensus on GDM diagnosis, as recently presented by WHO [115], screening methods, treatment options and treatment after delivery is urgently needed, as this disease affects not just the mother, but also the child. Furthermore, screening rates are reported to be far from optimal, with only approximately half of all women attending a postpartum retest [116].

Lifelong monitoring is recommended for all diagnosed abnormalities of glucose metabolism, starting at the detection of prediabetes. Moreover, screening for glycemic abnormalities after GDM in pregnancy helps to identify women who are at high risk for T2DM and CVD, and might help to reduce complications in following pregnancies, as well as discovering women who might benefit from lifestyle and pharmacological interventions. With regards to the prevention of the development of GDM, many studies suggest a major role of hyperglycemia in pregnancy on outcomes, cardiometabolic parameters and disease progression in the offspring. Intrahepatocellular lipid content at 1–3 weeks of age measured by magnetic resonance spectroscopy was 68% higher in children born to obese or GDM mothers compared with normal-weight mothers, suggesting a fetal origin of nonalcoholic fatty liver disease [117]. In 587 Caucasian offspring of mothers with a diabetic pregnancy, the effects of intrauterine hyperglycemia were examined at 18–27 years after their delivery [118]. This study showed a higher risk for glucose intolerance in the offspring of diabetic mothers, as insulin sensitivity and β-cell functions were impaired. Placental dysfunction is triggered by hyperglycemia, which causes vascular impairment, misbalance of vasoactive molecules and enhanced oxidative stress, and affects both the mother and fetus [119]. Substrates playing key roles in angiogenesis are proven to be impaired due to hyperglycemia triggered by the growth factors insulin and IGF-II [120].

Future studies should extend our current knowledge of GDM-related cardiometabolic risk to include new biomarkers that are able to predict increased risk of cardiovascular events and diabetes in the mother and offspring. Important research topics will include studies of GDM offspring and fetal programming in order to increase our understanding of the impact of the intrauterine environment on future health and enable primary prevention of cardiometabolic disease. When looking through the literature, no clear distinction could be made between CVD and T2DM, as both diseases have the same underlying risk factors, suggesting a ‘common soil’ of disease progression. A continuous effect of hyperglycemia on adverse cardiovascular outcomes is speculated and was reported in one study [44], but more studies would be needed focusing specifically on this aspect.

As at least two generations are affected by GDM (the mother and offspring), future preventative programs should either focus on finding the best modalities to prevent the onset of GDM or on finding treatment possibilities as soon as possible. Lifestyle intervention programs for the mother and child affected by GDM, or ideally for the whole family, are needed, as nearly all family members face similar risk factors. Mostly, women at high risk suffer from GDM by the first trimester and experience untreated hyperglycemia for several weeks until GDM screening at 24–28 weeks of pregnancy. Thus, screening for women who are at high risk should take place as early as possible, ideally using a WHO 75-g OGTT, or at least an assessment of fasting glucose or glycated hemoglobin. With an epidemic of obesity, T2DM and CVD in mind, disease prevention programs are key to stopping disease progression in patients who are at risk, and these may be able to save enormous costs for economic systems, as disease onset is stopped or delayed. Taking into account the idea that, for all noncommunicable diseases, the predicted future numbers will rapidly increase, actions to stop the onset of disease will have to start now, not in future.

Executive summary

Risk factors

Women with polycystic ovary syndrome, Type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM) have an increased risk for cardiovascular diseases (CVDs). Women with impaired glucose metabolism encounter cardiovascular mortality more frequently.

Progression to T2DM based from previous GDM is a very strong risk factor for future CVD, with a fourfold cardiovascular and coronary artery disease risk elevation.

Women with previous GDM are at higher risk for CVD at a younger age compared with their healthy peers.

GDM & CVD

GDM progresses to T2DM in 2.6–70% of cases after 6 weeks to 28 years postpartum.

An association between metabolic disturbances and CVDs in the mother and offspring has been reported.

A higher risk of T2DM onset was found in black women. Furthermore, Asian–Indian and African-Caribbean ethnicities were described to have impaired glucose tolerance more often.

Insulin sensitivity and glycemic state seem to play key roles in progression to CVD.

Screening of women who are at high risk for T2DM should take place as early as possible after a GDM pregnancy, or at least a measurement of fasting glucose and glycated hemoglobin should be taken.

A continuous effect of hyperglycemia on adverse cardiovascular outcome has been speculated.

Endothelial dysfunction

Early derangement of endothelial function is directly influenced by hyperglycemia in pregnancy and thereafter.

In GDM, endothelial function is impaired, as determined by a decreased bioavailability of nitric oxide and nitric oxide synthase activity.

Perivascular fat seems to have a vital function in vascular integrity and local inflammation.

Endothelial adhesion molecules play a major role in the pathogenesis of CVD.

Fat distribution/lipids

GDM women have higher body fat mass and lower insulin sensitivity.

Mean intramyocellular lipid contents in soleus and tibialis anterior muscles are higher in GDM women. Intramyocellular lipid content of the tibialis reflects insulin sensitivity, whereas intramyocellular lipid content of the soleus is related to obesity.

Women treated with insulin shows significantly higher intramyocellular lipid contents in soleus and tibialis anterior muscles than dietary-treated women.

Intrahepatocellular lipids are twice as high in previously GDM and insulin-resistant women.

GDM women with high liver fat content have increased insulin resistance and higher fasting serum triglyceride and insulin concentrations compared with low liver fat content women.

Hyperlipidemia and ectopic lipid storage might increase the risk of T2DM and CVD.

Pharmacological treatment options

An approximately 50% reduction of diabetes incidence was observed in a GDM group with metformin treatment.

Pioglitazone reduces the risk of progression to T2DM by 72%.

Subclinical atherosclerosis progression is decelerated by pioglitazone.

Lifestyle intervention treatment options

More than 3 months of breastfeeding is associated with a lower risk of T2DM progression.

More than 12 months of lactation in life results in less hypertension, diabetes, hyperlipidemia or CVD. Obesity is not affected by breastfeeding.

Lifestyle intervention reduces diabetes incidence by approximately 50%.

Dietary interventions reduces the risk of GDM by 60%, as well as bringing about a significant reduction of gestational hypertension and preterm birth.

Physical activity before and in early pregnancy is significantly associated with lower GDM risk.

Future perspective

Lifelong monitoring is recommended for all with diagnosed abnormalities of glucose metabolism, starting at the detection of prediabetes.

Early prevention of risk factors seems to be key to breaking the vicious cycle of cardiometabolic disease onset.

Recommendations from guidelines are conflicting, compliance for follow-up visits among women after GDM is poor and high-quality interventions are lacking. Therefore, it is necessary to establish standard guidelines for the prevention, diagnosis and correct treatment of both GDM and CVDs.

Acknowledgements

The authors would like to thank A Thomas for graphical design and support.

Financial & competing interests disclosure

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

of considerable interest

WHO. Global Status Report on Noncommunicable Diseases 2010. WHO Press, Geneva, Switzerland (2011).

Mathers

Loncar

. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 3(11), e442 (2006).

Kautzky-Willer

Dorner

Jensby

Rieder

. Women show a closer association between educational level and hypertension or diabetes mellitus than males: a secondary analysis from the Austrian HIS. BMC Public Health 12, 392 (2012).

Kautzky-Willer

Handisurya

. Metabolic diseases and associated complications: sex and gender matter! Eur. J. Clin. Invest. 39(8), 631–648 (2009).

Stampfer

Haffner

Solomon

Willett

Manson

. Elevated risk of cardiovascular disease prior to clinical diagnosis of Type 2 diabetes. Diabetes Care 25(7), 1129–1134 (2002).

Study showing elevated risk for cardiovascular disease in women prior to a diagnosis of Type 2 diabetes mellitus.

10.

Buckley

Harreiter

Damm

Gestational diabetes mellitus in Europe: prevalence, current screening practice and barriers to screening. A review. Diabet. Med. 29(7), 844–854 (2012).

11.

Metzger

Gabbe

Persson

International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33(3), 676–682 (2010).

12.

Hedderson

Ehrlich

Sridhar

Darbinian

Moore

Ferrara

. Racial/ethnic disparities in the prevalence of gestational diabetes mellitus by BMI. Diabetes Care 35(7), 1492–1498 (2012).

13.

Schneider

Bock

Wetzel

Maul

Loerbroks

. The prevalence of gestational diabetes in advanced economies. J. Perinat. Med. 40(5), 511–520 (2012).

14.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 36(Suppl. 1), S67–S74 (2013).

15.

Position statement of the American Diabetes Association.

16.

Kim

Newton

Knopp

. Gestational diabetes and the incidence of Type 2 diabetes: a systematic review. Diabetes Care 25(10), 1862–1868 (2002).

17.

Xiang

Black

Racial and ethnic disparities in diabetes risk after gestational diabetes mellitus. Diabetologia 54(12), 3016–3021 (2011).

18.

Kousta

Efstathiadou

Lawrence

The impact of ethnicity on glucose regulation and the metabolic syndrome following gestational diabetes. Diabetologia 49(1), 36–40 (2006).

19.

Kim

Cheng

Beckles

. Cardiovascular disease risk profiles in women with histories of gestational diabetes but without current diabetes. Obstet. Gynecol. 112(4), 875–883 (2008).

20.

Luoto

Kinnunen

Aittasalo

Primary prevention of gestational diabetes mellitus and large-for-gestational-age newborns by lifestyle counseling: a cluster-randomized controlled trial. PLoS Med. 8(5), e1001036 (2011).

21.

England

Dietz

Njoroge

Preventing Type 2 diabetes: public health implications for women with a history of gestational diabetes mellitus. Am. J. Obstet. Gynecol. 200(4), 365.e1–365.e8 (2009).

22.

Gilinsky

Hughes

McInnes

. More Active Mums in Stirling (MAMMiS): a physical activity intervention for postnatal women. Study protocol for a randomized controlled trial. Trials 13, 112 (2012).

23.

Jelsma

van Poppel

Galjaard

DALI: vitamin D and lifestyle intervention for gestational diabetes mellitus (GDM) prevention: an European multicentre, randomised trial – study protocol. BMC Pregnancy Childbirth 13(1), 142 (2013).

24.

Currie

Sinclair

Murphy

Madden

Dunwoody

Liddle

. Reducing the decline in physical activity during pregnancy a systematic review of behaviour change interventions. PLoS ONE 8(6), e66385 (2013).

25.

Kwong

Mitchell

Senior

Chik

. Postpartum diabetes screening: adherence rate and the performance of fasting plasma glucose versus oral glucose tolerance test. Diabetes Care 32(12), 2242–2244 (2009).

26.

Ferrara

Peng

Kim

. Trends in postpartum diabetes screening and subsequent diabetes and impaired fasting glucose among women with histories of gestational diabetes mellitus: a report from the Translating Research Into Action for Diabetes (TRIAD) study. Diabetes Care 32(2), 269–274 (2009).

27.

Legato

Gelzer

Goland

Gender-specific care of the patient with diabetes: review and recommendations. Gend. Med. 3(2), 131–158 (2006).

28.

Göbl

Bozkurt

Prikoszovich

Winzer

Pacini

Kautzky-Willer

. Early possible risk factors for overt diabetes after gestational diabetes mellitus. Obstet. Gynecol. 118(1), 71–78 (2011).

29.

Akinci

Celtik

Genc

Evaluation of postpartum carbohydrate intolerance and cardiovascular risk factors in women with gestational diabetes. Gynecol. Endocrinol. 27(5), 361–367 (2011).

30.

Kvehaugen

Andersen

Staff

. Anthropometry and cardiovascular risk factors in women and offspring after pregnancies complicated by preeclampsia or diabetes mellitus. Acta Obstet. Gynecol. Scand. 89(11), 1478–1485 (2010).

31.

Retnakaran

Connelly

Sermer

Hanley

Zinman

. The graded relationship between glucose tolerance status in pregnancy and postpartum levels of low-density-lipoprotein cholesterol and apolipoprotein B in young women: implications for future cardiovascular risk. J. Clin. Endocrinol. Metab. 95(9), 4345–4353 (2010).

32.

Tura

Mari

Prikoszovich

Pacini

Kautzky-Willer

. Value of the intravenous and oral glucose tolerance tests for detecting subtle impairments in insulin sensitivity and beta-cell function in former gestational diabetes. Clin. Endocrinol. (Oxf.) 69(2), 237–243 (2008).

33.

Ozuguz

Isik

Berker

Gestational diabetes and subclinical inflammation: evaluation of first year postpartum outcomes. Diabetes Res. Clin. Pract. 94(3), 426–433 (2011).

34.

Banerjee

Cruickshank

. Pregnancy as the prodrome to vascular dysfunction and cardiovascular risk. Nat. Clin. Pract. Cardiovasc. Med. 3(11), 596–603 (2006).

35.

Sullivan

Umans

Ratner

. Gestational diabetes: implications for cardiovascular health. Curr. Diab. Rep. 12(1), 43–52 (2012).

36.

Farhan

Winzer

Tura

Fibrinolytic dysfunction in insulin-resistant women with previous gestational diabetes. Eur. J. Clin. Invest. 36(5), 345–352 (2006).

37.

Banerjee

Anderson

Malik

Austin

Cruickshank

. Small artery function 2 years postpartum in women with altered glycaemic distributions in their preceding pregnancy. Clin. Sci. (Lond.) 122(2), 53–61 (2012).

38.

Fadl

Ostlund

Magnuson

Hanson

. Maternal and neonatal outcomes and time trends of gestational diabetes mellitus in Sweden from 1991 to 2003. Diabet. Med. 27(4), 436–441 (2010).

39.

Shand

Bell

McElduff

Morris

Roberts

. Outcomes of pregnancies in women with pre-gestational diabetes mellitus and gestational diabetes mellitus; a population-based study in New South Wales, Australia, 1998–2002. Diabet. Med. 25(6), 708–715 (2008).

40.

Ruchat

Houde

Voisin

Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases. Epigenetics 8(9), 935–943 (2013).

41.

Clausen

Mathiesen

Hansen

Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or Type 1 diabetes. J. Clin. Endocrinol. Metab. 94(7), 2464–2470 (2009).

42.

Lindsay

Nelson

Walker

Programming of adiposity in offspring of mothers with Type 1 diabetes at age 7 years. Diabetes Care 33(5), 1080–1085 (2010).

43.

Boerschmann

Pfluger

Henneberger

Ziegler

Hummel

. Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus. Diabetes Care 33(8), 1845–1849 (2010).

44.

Clausen

Mathiesen

Hansen

High prevalence of Type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or Type 1 diabetes: the role of intrauterine hyperglycemia. Diabetes Care 31(2), 340–346 (2008).

45.

Rijpert

Evers

de Valk

Cardiovascular and metabolic outcome in 6–8 year old offspring of women with Type 1 diabetes with near-optimal glycaemic control during pregnancy. Early Hum. Dev. 87(1), 49–54 (2011).

46.

Stuart

Amer-Wahlin

Persson

Kallen

. Long-term cardiovascular risk in relation to birth weight and exposure to maternal diabetes mellitus. Int. J. Cardiol. 168(3), 2653–2657 (2013).

47.

Carr

Utzschneider

Hull

Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history of Type 2 diabetes. Diabetes Care 29(9), 2078–2083 (2006).

48.

Shah

Retnakaran

Booth

. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes Care 31(8), 1668–1669 (2008).

49.

Retnakaran

Shah

. Mild glucose intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. CMAJ 181(6–7), 371–376 (2009).

50.

Demonstrates that even mild glucose intolerance is associated with a higher cardiovascular risk.

51.

Stern

. Diabetes and cardiovascular disease. The ‘common soil’ hypothesis. Diabetes 44(4), 369–374 (1995).

52.

Retnakaran

Sermer

Connelly

Hanley

Zinman

. 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. 21(9), 706–712 (2011).

53.

Göbl

Bozkurt

Prikoszovich

Tura

Pacini

Kautzky-Willer

. Estimating the risk after gestational diabetes mellitus: can we improve the information from the postpartum OGTT? Am. J. Physiol. Endocrinol. Metab. 304(5), E524–E530 (2013).

54.

Davenport

Goswami

Shoemaker

Mottola

. Influence of hyperglycemia during and after pregnancy on postpartum vascular function. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302(6), R768–R775 (2012).

55.

Brewster

Floras

Zinman

Retnakaran

. Endothelial function in women with and without a history of glucose intolerance in pregnancy. J. Diabetes Res. 2013, 382670 (2013).

56.

Karkkainen

Laitinen

Heiskanen

Need for insulin to control gestational diabetes is reflected in the ambulatory arterial stiffness index. BMC Pregnancy Childbirth 13, 9 (2013).

57.

Sokup

Ruszkowska

Goralczyk

Elevation of sE-selectin levels 2–24 months following gestational diabetes is associated with early cardiometabolic risk in nondiabetic women. Int. J. Endocrinol. 2012, 278050 (2012).

58.

Kautzky-Willer

Fasching

Jilma

Waldhausl

Wagner

. Persistent elevation and metabolic dependence of circulating E-selectin after delivery in women with gestational diabetes mellitus. J. Clin. Endocrinol. Metab. 82(12), 4117–4121 (1997).

59.

One of the first studies identifying postpartum gestational diabetes mellitus (GDM) as a risk factor for vascular integrity impairment.

60.

Pleiner

Mittermayer

Langenberger

Impaired vascular nitric oxide bioactivity in women with previous gestational diabetes. Wien. Klin. Wochenschr. 119(15–16), 483–489 (2007).

61.

Cecelja

Chowienczyk

. Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review. Hypertension 54, 1328–1336 (2009).

62.

Heitritter

Solomon

Mitchell

Skali-Ounis

Seely

. Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J. Clin. Endocrinol. Metab. 90(7), 3983–3988 (2005).

63.

Gasic

Winzer

Bayerle-Eder

Roden

Pacini

Kautzky-Willer

. Impaired cardiac autonomic function in women with prior gestational diabetes mellitus. Eur. J. Clin. Invest. 37(1), 42–47 (2007).

64.

Eren

Vural

Cece

Association of serum amyloid A with subclinical atherosclerosis in women with gestational diabetes. Gynecol. Endocrinol. 28(12), 1010–1013 (2012).

65.

Bierhaus

Hofmann

Ziegler

Nawroth

. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc. Res. 37, 586–600 (1998).

66.

Eckel

Wassef

Chait

Prevention Conference VI: diabetes and cardiovascular disease. Writing Group II: pathogenesis of atherosclerosis in diabetes. Circulation 105, e138–e143 (2002).

67.

Chiang

Sung

Homocysteine induces smooth muscle cell proliferation through differential regulation of cyclins A and D1 expression. J. Cell. Physiol. 226, 1017–1026 (2010).

68.

Paradisi

Biaggi

Ferrazzani

De Carolis

Caruso

. Abnormal carbohydrate metabolism during pregnancy: association with endothelial dysfunction. Diabetes Care 25, 560–564 (2002).

69.

Yudkin

Eringa

Stehouwer

. ‘Vasocrine’ signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet 365, 1817–1820 (2005).

70.

Study linking cytokines of perivascular fat inflammation with vascular disorders.

71.

Greenstein

Khavandi

Withers

Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119, 1661–1670 (2009).

72.

Valpreda

Menato

Should we consider gestational diabetes a vascular risk factor?

Atherosclerosis 194, 72–79 (2007).

73.

Winzer

Wagner

Festa

Plasma adiponectin, insulin sensitivity, and subclinical inflammation in women with prior gestational diabetes mellitus. Diabetes Care 27(7), 1721–1727 (2004).

74.

Vrachnis

Augoulea

Iliodromiti

Lambrinoudaki

Sifakis

Creatsas

. Previous gestational diabetes mellitus and markers of cardiovascular risk. Int. J. Endocrinol. 2012, 458610 (2012).

75.

Vrachnis

Belitsos

Sifakis

Role of adipokines and other inflammatory mediators in gestational diabetes mellitus and previous gestational diabetes mellitus. Int. J. Endocrinol. 2012, 549748 (2012).

76.

Xiang

Kawakubo

Trigo

Kjos

Buchanan

. Declining beta-cell compensation for insulin resistance in Hispanic women with recent gestational diabetes mellitus: association with changes in weight, adiponectin, and C-reactive protein. Diabetes Care 33(2), 396–401 (2010).

77.

Costacou

Bosnyak

Harger

Markovic

Silvers

Orchard

. Postpartum adiponectin concentration, insulin resistance and metabolic abnormalities among women with pregnancy-induced disturbances. Prev. Cardiol. 11(2), 106–115 (2008).

78.

Lewandowski

Nadel

Lewinski

Positive correlation between serum omentin and thrombospondin-1 in gestational diabetes despite lack of correlation with insulin resistance indices. Ginekol. Pol. 81(12), 907–912 (2010).

79.

Barker

Lim

Georgiou

Lappas

. Omentin-1 is decreased in maternal plasma, placenta and adipose tissue of women with pre-existing obesity. PLoS ONE 7(8), e42943 (2012).

80.

Stepan

Kralisch

Klostermann

Preliminary report: circulating levels of the adipokine vaspin in gestational diabetes mellitus and preeclampsia. Metabolism 59(7), 1054–1056 (2010).

81.

Giomisi

Kourtis

Toulis

Serum vaspin levels in normal pregnancy in comparison with non-pregnant women. Eur. J. Endocrinol. 164(4), 579–583 (2011).

82.

Aydin

. The presence of the peptides apelin, ghrelin and nesfatin-1 in the human breast milk, and the lowering of their levels in patients with gestational diabetes mellitus. Peptides 31(12), 2236–2240 (2010).

83.

Aslan

Celik

Cord blood nesfatin-1 and apelin-36 levels in gestational diabetes mellitus. Endocrine 41(3), 424–429 (2012).

84.

Telejko

Kuzmicki

Wawrusiewicz-Kurylonek

Plasma apelin levels and apelin/APJ mRNA expression in patients with gestational diabetes mellitus. Diabetes Res. Clin. Pract. 87(2), 176–183 (2010).

85.

Pfau

Stepan

Kratzsch

Circulating levels of the adipokine chemerin in gestational diabetes mellitus. Horm. Res. Paediatr. 74(1), 56–61 (2010).

86.

Andreas

Zeisler

Handisurya

N-terminal-pro-brain natriuretic peptide is decreased in insulin dependent gestational diabetes mellitus: a prospective cohort trial. Cardiovasc. Diabetol. 10, 28 (2011).

87.

Yamada

Koyama

Furuta

Effects of caesarean section on serum levels of NT-proBNP. Clin. Endocrinol. (Oxf.) 78(3), 460–465 (2013).

88.

Bonde

Vilsboll

Nielsen

Reduced postprandial GLP-1 responses in women with gestational diabetes mellitus. Diabetes Obes. Metab. 15(8), 713–720 (2013).

89.

Kautzky-Willer

Krssak

Winzer

Increased intramyocellular lipid concentration identifies impaired glucose metabolism in women with previous gestational diabetes. Diabetes 52(2), 244–251 (2003).

90.

Demonstrates ectopic lipid storage in women with previous GDM, suggesting GDM has an effect on Type 2 diabetes mellitus, nonalcoholic fatty liver disease and cardiovascular disease progression.

91.

Prikoszovich

Winzer

Schmid

Body and liver fat mass rather than muscle mitochondrial function determine glucose metabolism in women with a history of gestational diabetes mellitus. Diabetes Care 34(2), 430–436 (2011).

92.

Tiikkainen

Tamminen

Hakkinen

Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes. Res. 10(9), 859–867 (2002).

93.

Bhatia

Curzen

Calder

Byrne

. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur. Heart J. 33(10), 1190–1200 (2012).

94.

Bozkurt

Göbl

Tura

Fatty liver index predicts further metabolic deteriorations in women with previous gestational diabetes. PLoS ONE 7(2), e32710 (2012).

95.

Tura

Pacini

Winhofer

Non-esterified fatty acid dynamics during oral glucose tolerance test in women with former gestational diabetes. Diabet. Med. 29(3), 351–358 (2012).

96.

Zinman

Harris

Neuman

Low-dose combination therapy with rosiglitazone and metformin to prevent Type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 376(9735), 103–111 (2010).

97.

Tobias

Zhang

van Dam

Bowers

. Physical activity before and during pregnancy and risk of gestational diabetes mellitus: a meta-analysis. Diabetes Care 34(1), 223–229 (2011).

98.

Ziegler

Wallner

Kaiser

Long-term protective effect of lactation on the development of Type 2 diabetes in women with recent gestational diabetes mellitus. Diabetes 61(12), 3167–3171 (2012).

99.

Schwarz

Ray

Stuebe

Duration of lactation and risk factors for maternal cardiovascular disease. Obstet. Gynecol. 113(5), 974–982 (2009).

100.

Gunderson

Jacobs

Jr Chiang

Duration of lactation and incidence of the metabolic syndrome in women of reproductive age according to gestational diabetes mellitus status: a 20-year prospective study in CARDIA (Coronary Artery Risk Development in Young Adults). Diabetes 59(2), 495–504 (2010).

101.

Hoedjes

Berks

Vogel

Preferences for postpartum lifestyle counseling among women sharing an increased cardiovascular and metabolic risk: a focus group study. Hypertens. Pregnancy 30(1), 83–92 (2011).

102.

Oostdam

van Poppel

Wouters

No effect of the FitFor2 exercise programme on blood glucose, insulin sensitivity, and birthweight in pregnant women who were overweight and at risk for gestational diabetes: results of a randomised controlled trial. BJOG 119(9), 1098–1107 (2012).

103.

Mudd

Owe

Mottola

Pivarnik

. Health benefits of physical activity during pregnancy: an international perspective. Med. Sci. Sports Exerc. 45(2), 268–277 (2013).

104.

Shyam

Arshad

Ghani

Abdul R

Low glycaemic index diets improve glucose tolerance and body weight in women with previous history of gestational diabetes: a six months randomized trial. Nutr. J. 12, 68 (2013).

105.

Ratner

Christophi

Metzger

Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J. Clin. Endocrinol. Metab. 93(12), 4774–4779 (2008).

106.

Xiang

Hodis

Kawakubo

Effect of pioglitazone on progression of subclinical atherosclerosis in non-diabetic premenopausal Hispanic women with prior gestational diabetes. Atherosclerosis 199(1), 207–214 (2008).

107.

Ferrara

Hedderson

Albright

A pregnancy and postpartum lifestyle intervention in women with gestational diabetes mellitus reduces diabetes risk factors: a feasibility randomized control trial. Diabetes Care 34(7), 1519–1525 (2011).

108.

Knowler

Barrett-Connor

Fowler

Reduction in the incidence of Type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346(6), 393–403 (2002).

109.

Tuomilehto

Lindstrom

Eriksson

Prevention of Type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344(18), 1343–1350 (2001).

110.

Roumen

Corpeleijn

Feskens

Mensink

Saris

Blaak

. Impact of 3-year lifestyle intervention on postprandial glucose metabolism: the SLIM study. Diabet. Med. 25(5), 597–605 (2008).

111.

Oostdam

van Poppel

Wouters

van Mechelen

. Interventions for preventing gestational diabetes mellitus: a systematic review and meta-analysis. J. Womens Health (Larchmt) 20(10), 1551–1563 (2011).

112.

Thangaratinam

Rogozinska

Jolly

Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence. BMJ 344, e2088 (2012).

113.

DeFronzo

Tripathy

Schwenke

Pioglitazone for diabetes prevention in impaired glucose tolerance. N. Engl. J. Med. 364(12), 1104–1115 (2011).

114.

Gerstein

Santaguida

Raina

Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies. Diabetes Res. Clin. Pract. 78(3), 305–312 (2007).

115.

Leandro

Fidalgo

Bento-Santos

Maternal moderate physical training during pregnancy attenuates the effects of a low-protein diet on the impaired secretion of insulin in rats: potential role for compensation of insulin resistance and preventing gestational diabetes mellitus. J. Biomed. Biotechnol. 2012, 805418 (2012).

116.

American College of Obstetricians and Gynecologists. ACOG Committee opinion no. 548: weight gain during pregnancy. Obstet. Gynecol. 121(1), 210–212 (2013).

117.

Gerstein

Yusuf

Bosch

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368(9541), 1096–1105 (2006).

118.

Nauck

. A critical analysis of the clinical use of incretin-based therapies – the benefits by far outweigh the potential risks. Diabetes Care 36(7), 2126–2132 (2013).

119.

Retnakaran

Austin

Shah

. Effect of subsequent pregnancies on the risk of developing diabetes following a first pregnancy complicated by gestational diabetes: a population-based study. Diabet. Med. 28(3), 287–292 (2011).

120.

Winhofer

Tura

Prikoszovich

The impact of recurrent gestational diabetes on maternal metabolic and cardiovascular risk factors. Eur. J. Clin. Invest. 43(2), 190–197 (2013).

121.

Kerlan

. Postpartum and contraception in women after gestational diabetes. Diabetes Metab. 36(6 Pt 2), 566–574 (2010).

122.

Xiang

Kjos

Takayanagi

Trigo

Buchanan

. Detailed physiological characterization of the development of Type 2 diabetes in Hispanic women with prior gestational diabetes mellitus. Diabetes 59(10), 2625–2630 (2010).

123.

Werner

Pettker

Zuckerwise

Screening for gestational diabetes mellitus: are the criteria proposed by the international association of the diabetes and pregnancy study groups cost-effective?

Diabetes Care 35(3), 529–535 (2012).

124.

WHO. Diagnostic Criteria and Classification of Hyperglycaemia First Detected in Pregnancy. (WHO/NMH/MND/13.2). WHO Press, Geneva, Switzerland (2013).

125.

Bhake

Dayan

. The management of gestational diabetes mellitus after pregnancy. Pract. Diabet. Int. 27(8), 364–367a (2010).

126.

Brumbaugh

Tearse

Cree-Green

Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. J. Pediatr. 162(5), 930–936.e1 (2013).

127.

Kelstrup

Damm

Mathiesen

Insulin resistance and impaired pancreatic beta-cell function in adult offspring of women with diabetes in pregnancy. J. Clin. Endocrinol. Metab. 98(9), 3793–3801 (2013).

128.

Gauster

Desoye

Totsch

Hiden

. The placenta and gestational diabetes mellitus. Curr. Diab. Rep. 12(1), 16–23 (2012).

129.

Hiden

Lassance

Tabrizi

Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM)-associated upregulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto–placental endothelium. J. Clin. Endocrinol. Metab. 97(10), 3613–3621 (2012).

130.

Tan

Adya

Farhatullah

Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 57(4), 801–808 (2008).

131.

Tan

Pua

Syed

Lewandowski

O'Hare

Randeva

. Decreased plasma omentin-1 levels in Type 1 diabetes mellitus. Diabet. Med. 25(10), 1254–1255 (2008).

132.

de Souza Batista

Yang

Lee

Omentin plasma levels and gene expression are decreased in obesity. Diabetes 56(6), 1655–1661 (2007).

133.

Auguet

Quintero

Riesco

New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women. BMC Med. Genet. 12, 60 (2011).

134.

Wang

Chen

Guan

Jiang

. Fasting plasma levels of nesfatin-1 in patients with Type 1 and Type 2 diabetes mellitus and the nutrient-related fluctuation of nesfatin-1 level in normal humans. Regul. Pept. 159(1–3), 72–77 (2010).

135.

Zhang

Yang

Liu

Boden

Yang

. Increased plasma levels of nesfatin-1 in patients with newly diagnosed Type 2 diabetes mellitus. Exp. Clin. Endocrinol. Diabetes 120(2), 91–95 (2012).

136.

Kourtis

Gkiomisi

Mouzaki

Apelin levels in normal pregnancy. Clin. Endocrinol. (Oxf.) 75(3), 367–371 (2011).

137.

Soriguer

Garrido-Sanchez

Garcia-Serrano

Apelin levels are increased in morbidly obese subjects with Type 2 diabetes mellitus. Obes. Surg. 19(11), 1574–1580 (2009).

138.

Garces

Sanchez

Ruiz-Parra

Serum chemerin levels during normal human pregnancy. Peptides 42, 138–143 (2013).

139.

Wang

Wei

Zhang

Jia

. [Relationship of serum Chemerin to obesity and Type 2 diabetes mellitus]. Zhonghua Yi Xue Za Zhi 89(4), 235–238 (2009).

140.

Youn

Kloting

Kratzsch

Serum vaspin concentrations in human obesity and Type 2 diabetes. Diabetes 57(2), 372–377 (2008).

141.

Franz

Andreas

Schiessl

NT-proBNP is increased in healthy pregnancies compared to non-pregnant controls. Acta Obstet. Gynecol. Scand. 88(2), 234–237 (2009).

142.

Wang

Larson

Levy

Impact of obesity on plasma natriuretic peptide levels. Circulation 109(5), 594–600 (2004).

143.

Neary

Kilby

Kumpatula

Fetal and maternal lipoprotein metabolism in human pregnancy. Clin. Sci. (Lond.) 88(3), 311–318 (1995).

144.

Donatelli

Verga

Vaccaro

Russo

Bucalo

Scarpinato

. Serum lipoprotein Lp(a) in obesity. Diabetes Res. 20(4), 127–131 (1992).

145.

Todoric

Handisurya

Leitner

Harreiter

Hoermann

Kautzky-Willer

. Lipoprotein(a) is not related to markers of insulin resistance in pregnancy. Cardiovasc. Diabetol. 12(1), 138 (2013).

146.

Zhao

Song

Fan

Elevation of plasma soluble CD26 levels during pregnancy. J. Obstet. Gynaecol. Res. 38(1), 272–279 (2012).

147.

Firneisz

Varga

Lengyel

Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker. PLoS ONE 5(8), e12226 (2010).

148.

Nauck

Stockmann

Ebert

Creutzfeldt

. Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes. Diabetologia 29(1), 46–52 (1986).

149.

Demonstrates the incretin effect. This is essential for understanding modern diabetes therapy and it may positively influence cardiovascular risk.

150.

Calanna

Christensen

Holst

Secretion of glucagon-like peptide-1 in patients with Type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia 56(5), 965–972 (2013).

151.

Kautzky-Willer

. Pathogenesis of gestational DM (2013). www.diapedia.org/other-types-of-diabetes-mellitus/41040851394/pathogenesis-of-gestational-dm (Accessed 24 September 2013)

152.

Centre for Reviews and Dissemination. Systematic Reviews: CRD's guidance for undertaking reviews in health care (2008). www.york.ac.uk/inst/crd/pdf/Systematic_Reviews.pdf (Accessed 24 September 2013)

Gestational Diabetes Mellitus and Cardiovascular Risk after Pregnancy

Abstract

Keywords

Methods

Results

Cardiometabolic risk factors

GDM & epigenetics

Cardiovascular risk: continuous effects of mild metabolic disturbances or induction through overt T2DM

Clinical relevance of 1-h glucose values

Vascular abnormalities & endothelial dysfunction in GDM & prior GDM

Changes in nitric oxide bioactivity

Endothelial adhesion molecules & dysfibrinolysis

Inflammatory parameters

Ectopic lipid content

Prevention factors

Lactation

Lifestyle intervention

Lifestyle intervention in pregnancy

Pharmacological intervention studies

Subsequent pregnancy & contraception

Conclusion & future perspective

Acknowledgements

Financial & competing interests disclosure

References