Review of gestational diabetes mellitus effects on vascular structure and function

Blood pressure

Blood pressure ranged from 103.7/66.6 ± 8.3/5.6 to 128/72 ± 5/3 mmHg in the control women and from 106.5/62.9 ± 11.1/8.5 to 136.78/73.8 ± 6/10.4 mmHg in women with previous GDM (Table 2).

Adiposity

All studies reported BMI, with previous GDM women consistently higher than the control women. Five studies^{7,10,11,14,17} reported waist-to-hip ratio, with previous GDM women having a higher ratio in three studies.^2,11,17 Of those reporting, waist circumference ranged from 71.7 ± 8.8 to 87 ± 0.6 cm in the controls and 73.6 ± 5.7 to 92 ± 13.19 cm in the previous GDM cases (Table 2).

Glycaemic status

In 13 studies,^{7–15,17,19–21} the control groups had lower fasting blood sugar (FBS) and OGTT levels than all previous GDM groups, while Fakhrzadeh et al. ¹⁶ reported no difference between groups (Table 3). Akinci et al. ¹⁸ noted that the prevalence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) was higher in the previous GDM group after adjusting for pre-pregnancy BMI, family history of T2DM and postpartum diabetes. Additionally, Fakhrzadeh et al., ¹⁶ Akinci et al. ¹⁸ and Gunderson et al. ²¹ reported basal insulin resistance with the homeostatic model assessment index (HOMA), noting that the HOMA index was higher in the previous GDM women versus the controls.

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Table 3.

Subject metabolic parameters.

	Volpe et al.13,a	Akinci et al.17,a	Bo et al.9,a	Pleiner et al.12,a	Heitritter et al.20,a	Hannemann et al.10,b	Hu et al.11,b	Anastasiou et al.7,a
Fasting glucose (mmol/L)
Cases	4.68 ± 0.53	4.94 ± 0.09			4.77 ± 0.72	4.5 (4.0–5.0)	4.5 (3.8–5.7)
Cases – non-obese			5.1 ± 0.5	4.88 ± 0.11	4.66 ± 0.89			5.2
Cases – obese			5.3 ± 0.6	5.33 ± 0.285				5.3
Controls	4.41 ± 0.24	4.29 ± 0.10	4.8 ± 0.4	4.94 ± 0.17	4.27 ± 0.55	4.4 (3.9–5.0)	4.2 (1.8–6.4)	5.0
2-h glucose (mmol/L)
Cases	–	6.42 ± 0.25	–		8.10 ± 1.89	5.5	–
Cases – non-obese				5.55 ± 0.28	7.94 ± 2.16			5.2
Cases – obese				8.66 ± 0.50				5.6
Controls	–	4.34 ± 0.15	–	–	5.61 ± 1.44	5.0	–	4.8
Cholesterol (mmol/L)
Cases	–	4.84 ± 0.17	–		4.81 ± 0.96	4.4 (3.0–5.8)	5.1 (3.7–8.1)
Cases – non-obese				5.72 ± 0.34	4.68 ± 0.98			5.5 ± 0.8
Cases – obese				5.04 ± 0.28				5.8 ± 1.4
Controls	–	4.31 ± 0.15	–	4.58 ± 0.23	4.53 ± 0.62	4.8 (3.1–6.1)	5.0 (3.6–6.8)	4.8 ± 0.7
Triglycerides (mmol/L)
Cases	1.03 ± 0.76	1.57 ± 0.23			1.41 ± 0.07	0.92 (0.50–1.70)	1.1 (0.4–2.5)
Cases – non-obese			0.63 (0.41)	1.10 ± 0.37	1.20 ± 0.64			0.96 ± 0.35
Cases – obese			0.86 (0.53)	121 ± 0.20				1.62 ± 0.94
Controls	0.71 ± 0.24	0.94 ± 0.07	0.78 (0.53)	0.89 ± 0.11	0.67 ± 0.25	1.10 (0.40–1.75)	0.9 (0.4–4.3)	0.84 ± 0.47
LDL (mmol/L)
Cases	–	2.64 ± 0.12		–	2.97 ± 0.98	2.46 (1.43–3.60)	–
Cases – non-obese			2.7 ± 0.7		2.79 ± 0.91			2.69 ± 0.7
Cases – obese			3.0 ± 0.8					3.3 ± 1.7
Controls	–	2.29 ± 0.13	2.8 ± 0.6	–	2.84 ± 0.72	2.94 (1.29–4.30)	–	2.4 ± 0.6
HDL (mmol/L)
Cases	–	1.51 ± 0.06		–	1.22 ± 0.28	1.27 (0.93–3.03)	–
Cases – non-obese			1.6 ± 0.2		1.37 ± 0.26			1.9 ± 0.3
Cases – obese			1.3 ± 0.3					1.5 ± 0.5
Controls	–	1.70 ± 0.08	1.6 ± 0.3	–	1.34 ± 0.26	1.40 (1.08–2.29)	–	1.6 ± 0.4
	Fakhrzadeh et al.16,a		Akinci et al.18,a		Gunderson et al.21,a	Brewster et al.15,a		Freire et al.19,a
Fasting glucose (mmol/L)
Cases	5.12 ± 0.52		–		5.78 ± 1.63	4.8 ± 0.6		6.12 ± 0.33
Cases – non-obese
Cases – obese
Controls	4.86 ± 0.43		–		5.13 ± 1.04	4.6 ± 0.4		4.17 ± 0.06
2-h glucose (mmol/L)
Cases	–		–		–	8.3 ± 1.4		–
Cases – non-obese
Cases – obese
Controls	–		–		–	7.7 ± 1.6		–
Cholesterol (mmol/L)
Cases	4.61 ± 0.83		5.15 ± 1.13		4.80 ± 0.82	–		4.91 ± 0.13
Cases – non-obese
Cases – obese
Controls	4.43 ± 0.76		4.54 ± 0.81		4.78. ± 0.82	–		4.44 ± 1.20
Triglycerides (mmol/L)
Cases	1.23 ± 0.66		1.38 ± 0.76		1.13 ± 0.55	–		1.60 ± 0.17
Cases – non-obese
Cases – obese
Controls	1.20 ± 0.47		0.99 ± 0.61		1.01 ± 0.58	–		0.85 ± 0.04
LDL (mmol/L)
Cases	2.37 ± 0.55		3.2 ± 0.99		2.81 ± 0.76	–		2.95 ± 0.12
Cases – non-obese
Cases – obese
Controls	2.28 ± 0.45		2.49 ± 0.71		2.77 ± 0.74	–		2.46 ± 0.09
HDL (mmol/L)
Cases	1.34 ± 0.32		1.33 ± 0.36		1.46 ± 0.39	–		1.29 ± 0.05
Cases – non-obese
Cases – obese
Controls	1.31 ± 0.30		1.59 ± 0.44		1.53 ± 0.43	–		1.53 ± 0.05
	Banerjee et al.8,b							Davenport et al.14,a
Fasting glucose (mmol/L)					Fasting glucose (mmol/L)
Cases	5.5 (4.9–6.2)				Cases – GDM normal			~ 4.5
Cases – UQ	4.8 (4.5–5.0)				Cases – GDM hyperglycaemic			~ 5.5
Cases – obese					Control – normal pregnancy			~ 4.5
Controls	4.7 (4.6–4.8)				Control – not pregnant			–
2-h glucose (mmol/L)					2-h glucose (mmol/L)
Cases	–				Cases – GDM normal			~ 5.5
Cases – UQ	–				Cases – GDM hyperglycaemic			~ 10.0
Cases – obese					Control – normal pregnancy			~ 5.0
Controls	–				Control – not pregnant			–
Cholesterol (mmol/L)					Cholesterol (mmol/L)
Cases	4.5 (3.6–5.3)				Cases – GDM normal			5.2 ± 0.59
Cases – UQ	4.4 (4.0–4.8)				Cases – GDM hyperglycaemic			5.19 ± 0.84
Cases – obese					Control – normal pregnancy			4.59 ± 1.04
Controls	4.3 (3.9–4.8)				Control – not pregnant			–
Triglycerides (mmol/L)					Triglycerides (mmol/L)
Cases	1.1 (0.8–1.3)				Cases – GDM normal			1.51 ± 1.07
Cases – UQ	1.0 (0.9–1.2)				Cases – GDM hyperglycaemic			1.58 ± 0.96
Cases – obese					Control – normal pregnancy			0.73 ± 0.35
Controls	0.7 (0.5–0.9)				Control – not pregnant			–
LDL (mmol/L)					LDL (mmol/L)
Cases	–				Cases – GDM normal			3.22 ± 0.40
Cases – UQ	–				Cases – GDM hyperglycaemic			3.22 ± 0.72
Cases – obese					Control – normal pregnancy			2.91 ± 0.91
Controls	–				Control – not pregnant			–
HDL (mmol/L)					HDL (mmol/L)
Cases	1.2 (1.1–1.3)				Cases – GDM normal			1.34 ± 0.32
Cases – UQ	1.5 (1.4–1.7)				Cases – GDM hyperglycaemic			1.24 ± 0.17
Cases – obese					Control – normal pregnancy			1.34 ± 0.24
Controls	1.5 (1.0–1.9)				Control – not pregnant			–

LDL: low-density lipoprotein; HDL: high-density lipoprotein; GDM: gestational diabetes mellitus; UQ: upper quartile.

a

Values reported as mean ± standard deviation.

b

Values reported as median (range).

Lipid status

The total cholesterol levels for previous GDM women were elevated in eight studies.^{7,8,12,16–20} In all but one of the studies ¹⁹ that assessed high-density lipoprotein (HDL) cholesterol, the controls had higher levels of HDL than previous GDM cases. However, the non-obese previous GDM groups had HDL levels similar to or higher than the controls, while the obese previous GDM groups had HDL levels lower than the controls.^7–9,14 The low-density lipoprotein (LDL) was higher in the previous GDM groups in 8 of 10 studies.^{7,9,14,16,17,19–21} The non-obese previous GDM women had LDL levels similar to or lower than the controls, while obese previous GDM women had higher LDL levels than the controls.^7,9,14 However, two studies^10,21 reported similar LDL levels between previous GDM and control groups, with statin use higher in the previous GDM women in one study. ²¹ In all but four studies,^9–11,16 triglycerides levels were significantly higher in previous GDM than control women (Table 3).

Inflammatory markers

The parameters measured in more than one study were high sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, adiponectin, plasminogen activator inhibitor (PAI)-1 and fibrinogen. Fibrinogen was higher in the previous GDM women,^12,17,18 while high adiponectin was negatively correlated with previous GDM.^13,16,20 In addition, women with previous GDM had higher levels of hsCRP and PAI-1 than the control women;^9,13,17,20 however, Fakhrzadeh et al. ¹⁶ reported hsCRP and PAI-1 levels to be lower in the previous GDM group. Heitritter et al. ²⁰ found that IL-6 was increased in previous GDM women, whereas Fakhrzadeh et al. ¹⁶ reported lower IL-6 for the previous GDM group, and Bo et al. ⁹ found that previous GDM women with a BMI ⩾25 kg/m² had higher IL-6 levels than the controls.

Circulating E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were measured only by Bo et al., ⁹ who found that E-selectin and ICAM-1 were highest in previous GDM women with a BMI ⩾25 kg/m² and lowest in control women. Interestingly, VCAM-1 was highest in previous GDM women with a BMI <25 kg/m². In addition, asymmetric NG, NG-dimethyl l-arginine (ADMA) and its isomer symmetric dimethyl-arginine (SDMA) were measured by Pleiner et al. ¹² Both ADMA and SDMA were highest in previous GDM women with a BMI ⩾25 kg/m². The previous GDM women with a BMI <25 kg/m² had similar ADMA and SDMA values to the male control group.

Macrovascular arterial structure and function

Eight studies used ultrasound as the primary method of choice when measuring macrovascular structure (Table 4). Bo et al., ⁹ Hu et al., ¹¹ Volpe et al., ¹³ Fakhrzadeh et al., ¹⁶ Akinci et al.,^17,18 Freire et al. ¹⁹ and Gunderson et al. ²¹ used high-resolution Doppler ultrasound to measure carotid intima medial thickness (CIMT). Bo et al. ⁹ found that previous GDM women, despite no metabolic abnormalities and independent of BMI, had higher CIMT, E-selectin and ICAM-1 values than control women 6 years postpartum. Hu et al. ¹¹ also found that women with previous GDM had increased common carotid artery wall stiffness and lower pulsatile diameter changes 2–4 years postpartum compared to control women. Interestingly, in the control group, age was associated with arterial stiffness in both the carotid artery and aorta; however, in the previous GDM group, this trend was not shown. Similarly, Volpe et al. ¹³ found increased CIMT in previous GDM women compared to controls 2 years postpartum, despite no difference in BMI between groups and only one woman meeting the criteria for metabolic syndrome. Akinci et al. ¹⁷ noted that serum osteoprotegerin (OPG) levels were elevated in previous GDM women and a significant predictor for elevated CIMT 3 years postpartum. Later, Akinci et al. ¹⁸ found that the development of postpartum diabetes and metabolic syndrome were associated with increased CIMT in previous GDM women compared to controls at 1 year. Freire et al. ¹⁹ were the first to show that previous GDM women and women with metabolic syndrome had similar increased CIMT; however, in the regression models used, previous GDM was associated with increased CIMT regardless of cardiometabolic status and parity at 32 months postpartum.

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Table 4.

Vascular function.

	Macrovascular		Microvascular
	Method of assessment	Results	Method of assessment	Results
Bo et al. 9	Carotid intima medial thickness (CIMT)	CIMT increased in previous GDM women with and without metabolic syndrome components versus controls	–
Hu et al. 11	CIMT	CIMT increased in previous GDM women versus controls	Doppler perfusion imaging of blood flow induced by ACh in hand and foot	Decreased vasodilatory response to ACh in previous GDM women versus controls
Volpe et al. 13	CIMT	CIMT increased in previous GDM women versus controls	–	–
Fakhrzadeh et al. 16	CIMT	CIMT not significantly different between previous GDM women and controls	–	–
	Flow-mediated dilation (FMD) of the right brachial artery	FMD reduced in previous GDM women versus controls
Akinci et al. 17	CIMT	CIMT increased in previous GDM women versus controls	–	–
Akinci et al. 18	CIMT	CIMT increased in previous GDM women versus controls	–	–
Freire et al. 19	CIMT	CIMT increased in previous GDM women versus controls independent of the presence of risk factors for metabolic syndrome	–	–
Gunderson et al. 21	CIMT	CIMT increased in previous GDM women versus controls	–	–
Anastasiou et al. 7	Brachial artery FMD	FMD response reduced in both obese and non-obese previous GDM women versus controls	–	–
Hannemann et al. 10	Brachial artery FMD	No difference in FMD response between previous GDM women and controls	Doppler flowmetry after 42°C brass heater to right dorsum of foot	Maximum microvascular vasodilatory capacity reduced in previous GDM women versus controls, but no difference in response to ACh
			Doppler perfusion imaging on local forearm skin blood flow after ACh and sodium nitroprusside
Pleiner et al. 12	Brachial artery FMD response to Ach, norepinephrine, glyceryltrinitrate, N(G)-monomethyl-l-arginine	Vasodilation impaired in overweight previous GDM women versus non-overweight previous GDM women	–	–
		Vasoconstriction less in overweight previous GDM women; non-overweight previous GDM women and controls similar response
Davenport et al. 14	Brachial artery FMD	FMD response reduced in previous GDM women versus controls	–	–
	Pulse wave velocity (brachial and carotid artery)	Increased arterial stiffness in previous GDM women versus controls
Brewster et al. 15	Brachial artery FMD	No difference in FMD response among women with previous glucose intolerance during pregnancy or previous GDM compared to women with normal glucose tolerance	–	–
Banerjee et al. 8	–	–	Subcutaneous arteries from gluteal fat biopsy examined using wire myography	Maximal endothelium-dependent dilation was reduced in previous GDM women
				Endothelium-independent dilation was similar across groups
Heitritter et al. 20	Haemodynamic studies	Higher central systolic pressure, mean arterial pressure, peripheral resistance, lower mean stroke volume and cardiac output in previous GDM women

GDM: gestational diabetes mellitus; ACh: acetylcholine.

Of the five studies^{7,10,12,14,16} that used flow-mediated dilation (FMD) to assess arterial function, four studies^7,12,14,16 found reduced FMD response in previous GDM women versus the controls. Fakhrzadeh et al. ¹⁶ evaluated vascular properties by both CIMT and FMD. After adjusting for age and blood pressure in the previous GDM group, they were the only study to conclude no difference in CIMT between groups; however, they noted an impairment of FMD in the previous GDM group compared with the control group that showed no correlation with biochemical or inflammatory markers 4 years postpartum. Anastasiou et al. ⁷ found that FMD was compromised in both the obese and non-obese previous GDM women 3–6 months postpartum as compared with the control subjects, even with normal glucose tolerance. In contrast, Hannemann et al. ¹⁰ found no difference in FMD of normoglycaemic previous GDM women compared to the control women matched on age, BMI and smoking. Pleiner et al. ¹² following the trend reported by others found that the arterial response in previous GDM women and in overweight women was significantly compromised compared to the control group of healthy men. Davenport et al. ¹⁴ assessed FMD of the right brachial artery and the carotid artery, finding distensibility in both control groups was higher than both previous GDM groups, and suggested this possibly a factor of clinical and/or subclinical hyperglycaemia and decreased insulin sensitivity in the postpartum period. Brewster et al. ¹⁵ compared brachial artery FMD measurements and noted no difference between previous GDM and control groups 6 years postpartum despite having long-term cardiovascular risks (Table 4).

Microvascular arterial function

Three studies measured microvascular function (Table 4). Hannemann et al. ¹⁰ and Hu et al. ¹¹ used laser Doppler flowmetry and acetylcholine on the skin of the dorsum of the foot and forearm. Hu et al. ¹¹ found that the microvascular response in women with previous GDM was lower than in the control women. Hannemann et al. ¹⁰ also observed that maximum microvascular vasodilatory capacity (MMVC) was significantly reduced in women with previous GDM compared to the control group. However, this difference was only observed in the dorsum of the foot, while the brachial artery dilation revealed no difference in flow between the control and previous GDM groups. Banerjee et al. ⁸ used a subcutaneous fat biopsy to isolate the small arteries which were then put through different chemical stimuli. They found that overweight women with either previous GDM or marginally raised glycaemia during pregnancy had impaired small artery endothelial function at 2 years postpartum.