Pregnancy as the Prodrome to Vascular Dysfunction and Cardiovascular Risk

Moulinath Banerjee; John Kennedy Cruickshank 

Nat Clin Pract Cardiovasc Med.  2006;3(11):596-603.  ?2006 Nature Publishing Group
Posted 11/10/2006

Summary and Introduction

Summary

In previously apparently healthy women, glucose intolerance and high blood pressure during pregnancy are common and frequently occur together. This article reviews the role of these gestational disorders as markers of vascular dysfunction and its pathophysiology. Mechanisms include alterations to function of large arteries and resistance vessels and to capillary blood flow. Much of the vessel pathology is seen in both gestational diabetes and hypertension. In women who have had transient diabetes during pregnancy and later redeveloped overt diabetes, cardiovascular risk is already elevated nearly fourfold before diagnosis, which is almost as high as the average risk after a clinical diagnosis of diabetes is made. This key finding suggests that vascular risk in such women is at least partly independent of overt hyperglycemia.

Introduction

Cardiovascular disease (CVD) accounts for one-third of all deaths worldwide, more commonly in men (11.8%) than in women (10.5%).[1] The proportion of life lost through CVD, has been estimated to be 18% for people in developed countries and at least 10% for those in developing countries, where this value is thought to be rising. In addition to progression of risk factors from fetal life and childhood,[2] early signals of CVD become apparent during pregnancy.[3-7] How the CVD or vascular dysfunction progresses is not clearly known because of the lack of longitudinal studies addressing this question. This Review examines the evidence available from pregnancy and the postnatal period and discusses where emerging evidence could provide opportunities for identification and prevention of early CVD in women.

Natural History of Cardiovascular Disease in Women: Diabetes, Glucose Intolerance or Glycemia?

The development of arterial pathology in both sexes starts early in life, although overt CVD is not common among women of childbearing age and its progression is delayed by around 10 years in comparison with men.[8] Smoking, diabetes, pregnancy-induced hypertension, and the oral contraceptive pill predispose premenopausal women to CVD. In postmenopausal women the incidence of coronary heart disease (CHD) almost equals that in men,[9] but the related mortality is declining less in women despite advances in prevention and therapy.[10] Before the menopause, the risk of myocardial infarction is generally low but does vary in the different menstrual phases,[11] increasing in the early days of the menstrual cycle.[12]

CVD risk is raised in women with diabetes, more so than in men with diabetes, probably at any age. In obese, insulin-resistant women this difference is partly conferred by greater increases in total, LDL and non-HDL cholesterols than in comparable men. In a study of 117,629 women over 20 years of age, those who later developed diabetes had substantially elevated relative risk (RR) of CVD before (RR 3.75, 95% CI 3.1-4.5) as well as after (RR 4.57, 95% CI 3.9-5.4) clinical diagnosis of diabetes.[13] This key finding suggests that vascular risk is independent at least of overt hyperglycemia at diagnosis and that dysglycemia, crucially, is a continuous variable. Women with diabetes seem to lose the protection of their premenopausal years, as they have similar cardiovascular mortality whether they are older or younger than 50 years.[14] Mortality risk is also higher in women with diabetes than in men who have coronary artery disease.[15] Despite the relative protection from cardiovascular events in younger women without diabetes, after myocardial infarction such women have higher short-term and long-term mortality than men of the same age.[16] The mechanism for this difference between the sexes is not yet known.

In the UK, the prevalence of gestational diabetes mellitus (GDM), which affects fetomaternal outcomes, varies between 0.5% and 4.0%.[17] Interventions can improve outcomes at intermediary levels of glucose tolerance during pregnancy,[18] but whether risk develops at a certain glucose threshold or develops gradually and continuously across the glycemic or other metabolic spectrum is still unknown. The current international Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study[19] aims to answer these issues for neonates and mothers. Although women with isolated dysglycemia in pregnancy clearly have detectably altered vascular function, when these alterations develop remains unclear. Our hypothesis is that a woman's cardiovascular risk rises linearly with the degree of hyperglycemia, across its full range, as well as with rising blood pressure in pregnancy, as does risk for offspring after birth.

Cardiovascular Function in Relation to Gestational Dysglycemia

Vascular alterations in GDM have been widely reported. Changes in placental vessels include impaired relaxation,[20] decreased nitric oxide synthesis leading to reduced blood flow and increased placental vascular resistance,[21] reduced matrix metalloproteinase-9 activity,[22] increased oxidative stress,[23] reduced junctional adhesion molecules between endothelial cells,[24] higher thromboxane concentrations, and reduced prostacyclin-to-thromboxane ratios.[25] The relationship between the degree of glycemic disorder and vascular dysfunction is less clear. Despite a notable volume of in vitro data on the placental vasculature, few nonplacental vascular studies seem to have been published. Work from the six studies we found is described below.

Endothelial Function

Knock et al.[26] investigated function of small subcutaneous arteries harvested during cesarean section for ex vivo examination. The participants were 14 normotensive pregnant women with GDM and 14 nondiabetic pregnant women. Endothelial dysfunction and impaired prostaglandin-dependent relaxation were seen in the GDM group vessels compared with controls. In another study, vascular function was assessed by brachial artery flow-mediated and nitrate-induced dilatation during the third trimester in 23 pregnant women with glucose intolerance and in 15 pregnant women with normal glucose tolerance.[27] Flow-mediated dilatation was impaired in the pregnant women, whereas endothelium-independent dilation was similar in the two groups. These indices correlated well with fasting glucose and area under the curve during the oral glucose tolerance testing (r = 0.6)

Postpartum Small and Large Vessel Function

Aortic function assessed by ultrasonography and small vessel performance assessed by iontophoresis and laser Doppler flowmetry were impaired in 17 women with a history of GDM compared with 20 controls, despite apparently normal glucose tolerance at the time of assessment.[28] Hannemann et al.[29] reported on 17 women with a history of GDM and 17 controls matched for BMI, menstrual phase, smoking status, age, blood pressure, and lipid profiles. Glucose tolerance was normal in both groups. An impaired response of the microcirculation to hyperemia was found in the GDM group but no difference was seen in any other large or small arterial index. Anastasiaou et al.[30] studied a similar population and found impaired brachial artery flow-mediated dilatation in women with GDM. Although BMI did not affect this result, overweight women had impaired nitroglycerine-induced vasodilator responses (endothelium independent) compared with normal weight women, irrespective of history of glucose tolerance ( Table 1 ).

Echocardiographic Changes

Heittritter et al.[31] investigated echocardiographic parameters and inflammatory markers in 25 women with histories of GDM and in 23 controls. They found decreased stroke volume, cardiac output and serum adiponectin, and increased peripheral resistance, C-reactive protein, interleukin-6, and plasminogen activation inhibitor-1 activity in the GDM group.

Cardiovascular Function After Gestational Hypertension

Hypertension is seen in about 6% of all pregnancies, and is categorized in the following ways: chronic hypertension, pre-eclampsia/eclampsia, pre-eclampsia superimposed on chronic hypertension, and gestational hypertension.[32] As both gestational hypertension and pre-eclampsia/eclampsia generally resolve after delivery, we refer to these conditions together in this article as GHPE.

The basic pathology of hypertension in pregnancy remains unclear, despite the disorder having been recognized and studied for more than 50 years. The placental defect most commonly observed is failure of cytotrophoblastic cells to invade the spiral arterioles, leading to decreased uteroplacental perfusion.[33] Other placental vascular changes include imbalance between increased synthesis of thromboxane and decreased production of prostaglandin I2,[34] increased oxidative stress,[35] metalloproteinase expression,[36] and vascular endothelial concentrations,[37] but reduced levels of placental growth factor,[38] and endothelial dysfunction.[39] Many of these changes are also reported in GDM.

Risk of Postpartum Hypertension and Metabolic Changes

Women who develop GHPE have a raised risk of subsequent hypertension. After 7 years' follow-up of 223 women who had eclampsia, the risk was highest among those who developed hypertension before rather than after 30 weeks of gestation.[40] At 14 years after the index pregnancy, hypertension was five times more common in 273 women with a history of pre-eclampsia than in 86 women with normotensive pregnancies.[41] The prevalence of hypertension was greater among women with gestational hypertension than among those who had pre-eclampsia/eclampsia or normotensive pregnancies. The prevalence of hypercholesterolemia or diabetes did not differ between the two groups. Similar results were reported in follow-up of 15 years in 46 cases of pre-eclampsia and 47 controls with normal pregnancy.[42] The risk of subsequent hypertension was highest if the hypertensive disorder recurred in subsequent pregnancies.

Women with GHPE have also frequently been noted to have concomitant insulin resistance. In a longitudinal study of 5,889 women, 94 had gestational hypertension and pre-eclampsia.[43] At age 31 years, these women had a higher blood pressure, although not to hypertensive levels, than those who had had normal pregnancies. Increased waist circumferences, waist-to-hip ratios, BMI, and increased serum insulin levels, and lower glucose-to-insulin ratios were also noted among women with GHPE. Similar findings of increased insulin resistance were reported in a group of 29 normotensive women with a history of pre-eclampsia and 32 controls examined 18 months postpartum ( Table 2 ).[44]

Indices of Vascular Dysfunction in Gestational Hypertensive Disorders

Endothelial Function. In patients with GHPE impaired endothelial function occurs in the uteroplacental circulation and in the systemic blood vessels.[45] Stress-induced forearm blood flow was impaired in 16 women with pre-eclampsia 6-12 months postpartum, when compared with 34 controls.[46] Chambers et al.[47] had reported impaired flow-mediated dilatation in 113 women with a history of pre-eclampsia compared with 48 normotensive women; flow mediated dilatation improved after administration of vitamin C in women with previous pre-eclampsia. Endothelial function of subcutaneous resistance arteries harvested during cesarean section was impaired in 12 patients with GHPE when compared with 12 nonhypertensive pregnant women.[48] Loss of endothelium-mediated dilatation but preservation of constrictor responses in resistance arterioles was noted in patients with prior pre-eclampsia.[49] Impaired bradykinin-mediated, endothelium-dependent vasodilation of resistance arterioles had been reported in 6 women with GHPE compared with 24 women with normotensive pregnancies.[50] The underlying mechanism seems to be reduced sensitivity to cyclic GMP in the endothelium of patients with GHPE.[51] The defect is found before development of pre-eclampsia, as shown by reduced flow-mediated dilatation at 23-25 weeks of gestation.[52]

Large Vessel Function. The only report of large vessel dysfunction, with high values for aortic pulse wave velocity, BMI, and blood pressure, as well as increased joint and skin stiffness, was from a study of 44 women with previous pre-eclampsia and 46 with normal pregnancies.[53] These data suggest widespread pathology beyond just large or resistance vessels, since the increase in joint and skin stiffness could be due to poor capillary supply or related to expression of profibrotic factors.

Echocardiography. Novelli et al.[54] investigated 39 patients with current GHPE, 40 nonpregnant women with essential hypertension, and 38 normotensive, nonpregnant women. These investigators found similar early diastolic dysfunction in the GHPE and essential hypertension groups, whereas late diastolic dysfunction was evident only in the essential hypertension group. Altered left ventricular geometry as concentric hypertrophy was more pronounced in the GHPE group than in the other two groups. The presence of concentric hypertrophy was also associated with proteinuria but not with poor fetal outcomes, although the infants' vascular status was not measured.

Microcirculatory Function. Very few studies on microcirculatory function have been reported in antenatal or postnatal states. Laser Doppler flowmetry responses following iontophoresis with acetylcholine were excessive in women during and after pre-eclampsia,[55-57] but those before and after local thermal stimulation were impaired in women with, rather than without, pre-eclampsia.[58] Different mechanisms underlie this apparent discrepancy in response. While iontophoresis with acetylcholine uses mostly endothelium-dependent nitric oxide release for the ensuing vasodilatation and sodium nitroprusside works directly as a nitrate donor irrespective of the endothelium, the response to heat has a complex mechanism mediated through a local neural reflex, calcitonin gene-related peptide, substance P, neurokinin A, and heat sensitive vanilloid receptors. The fact that endothelium-generated nitric oxide is still required for these responses to heat, however, is shown by abolition of the response after administration of the nitric-oxide-synthase inhibitor l-NAME.[59] How nitric oxide generation is modulated by heat stimuli in women with pre-eclampsia is not yet known ( Table 3 ).

Cardiovascular Outcomes. Studies with cardiovascular endpoints (CHD and stroke) have only been reported in women who had pre-eclampsia in the past. Smith et al.[3] reported excess CHD risk in a large cohort of Scottish women who had given birth preterm(relative risk 1.8, 95% CI 1.3-2.5), in those with previous small-for-birth date babies (relative risk 1.9, 95% CI 1.5-2.4) and those with previous pre-eclampsia (relative risk 2.0, 95% CI 1.5-2.5). The risk was highest in women in whom all three features had coexisted (relative risk 7.0, 95% CI 3.3-14.5). Wilson et al.[7] reported a relative risk for stroke in later life of 1.53 (95% CI 0.72-3.27) for gestational hypertension and 2.10 (95% CI 1.02-4.32) for pre-eclampsia/eclampsia compared with women with normal pregnancies.

Are Gestational Diabetes and Gestational Hypertension Linked?

Although common events occur together, from individual incidence, the frequency of GDM, and GHPE occurring in the same patient would only be expected to be about 0.24%. The incidence of GDM has, however, been 3.8% in all hypertensive disorders in pregnancy,[60] whereas gestational hypertension is present in 28% of patients with GDM.[61] The reason for this association is not well understood. Similar placental vascular changes are reported in both conditions. While placental nitric oxide synthesis is decreased in GDM,[21] it seems to be unaltered in patients with GHPE[62] and placental growth factor is reduced in GHPE[38] but not in patients with GDM.[63]

Several risk factors predispose to both conditions and many confounders might account for the association. Ostlund et al.[64] reported GDM to be a significant independent risk factor for GHPE; obesity, although an important association, did not fully account for the elevated risk. In a cohort of 184 women with GDM, presence of high blood pressure (115/65 mmHg versus 106/61 mmHg), BMI (33.7 kg/m2 versus 29.8 kg/m2), fasting glucose, insulin, uric acid, and C-reactive protein predicted pre-eclampsia.[65] In a retrospective analysis of 1,664 women with GDM, raised BMI, raised blood pressure during the first and second trimesters of pregnancy, pregnancy weight gain, parity, and fasting plasma glucose, and reduced maternal age all predicted development of pre-eclampsia.[66] Similar results have been reported from the DIAGEST[67] and Calcium for Preeclampsia Prevention[68] study groups.

Adipocytokines and Vascular Function

Adipocytokines are secreted from adipocytes and have both paracrine and endocrine actions on organs, probably including direct effects on arteries. Animal data suggest that leptin has the most prominent but bidirectional vascular action, promoting endothelial function and vasorelaxation yet also being associated with increased wall thickness, and a procoagulant state. Adiponectin downregulates cell adhesion molecules and thereby monocyte migration and endothelial cell activation in the inflammatory response of atherosclerotic plaques.[69] Women with pre-eclampsia have higher circulating adiponectin and leptin concentrations than women with normotensive pregnancies,[70-72] yet women with GDM have consistently lower circulating adiponectin; one study has also reported raised tumor necrosis factor levels.[73-75] These data all suggest that the role of adipocytokines in influencing vascular function in pregnancy is a promising avenue for further research.

Conclusion

Both glycemic and hypertensive disorders during pregnancy have prognostic implications for later cardiovascular health, although the underlying mechanisms have yet to be established. Insulin resistance has been suggested but might merely be a bystander effect. The placental vasculature could, therefore, be a direct target for therapy in pregnancy, but few data are as yet available. Aortic distensibility is a known indicator of prognosis in older adults[76-78] and could also become a target for intervention. Thus more-appropriate treatment directed at the vasculature itself, rather than or as well as at the traditional targets of higher blood pressure or hyperglycemia, might help to prevent cardiovascular outcomes in these at-risk women, and possibly also in their children.


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Table 1. Summary of Vascular Function Studies After Gestational Diabetes


Study Number of participants Large artery function Microcirculation
Cases Controls Method of assessment Result Method of assessment Result
Knock et al. (1997)26 15 15 ND ND Subcutaneous arteries harvested during cesarean section Impaired
Hu et al. (1998)28 17 20 Echo tracking of aorta Impaired Laser Doppler flowmetry Impaired
Anastasiou et al. (1998)30 33 19 Flow-mediated dilatation Impaired ND ND
Hannemann et al. (2002)29 17 17 Flow-mediated dilatation Normal Laser Doppler flowmetry Impaired
Paradisi et al. (2002)27 23 15 Flow-mediated dilatation Impaired ND ND
Heitritter et al. (2005)31 25 23 Echo tracking of aorta ↓SV, ↑TPR ND ND

Abbreviations: ND = Not Done; SV = Stroke Volume; TPR = Total Peripheral Resistance.

 

Table 2. High Blood Pressure and Other Cardiovascular Risk Factors After Gestational Hypertension or Pre-eclampsia/Eclampsia


Study Number of participants Mean duration of follow-up (years) Risk factors present among cases at follow-up
Cases Controls Hypertension (%) Raised cholesterol (%) Diabetes mellitus (%) BMI (kg/m2) Waist:hip ratio Fasting insulin (mU/l)
Sibai et al. (1992)40 223 NA 7.2 9.5 NA NA NA NA NA
Marin et al. (2000)41 273 86 13.6 55 24 3 30.3 NA NA
Norden et al. (2000)42 20 40 15.5 95 >5 >5 24.4 0.8 10.4
Pouta et al. (2004)43 94 63 Follow-up done at age 31 years NA NA NA 24.5 0.8 8.2
Wolf et al. (2004)44 29 32 1.5 0 NA NA 29.2 NA 14.0

Abbreviation: NA = Not Applicable.

 

Table 3. Summary of Studies on Cardiovascular Function in Gestational Hypertension and Pre-eclampsia


Study Number of participants Cardiovascular function Large vessels
Cases Controls Method of assessment Result Method of assessment Result
McCarthy et al. (1993)48 12 12Subcutaneous arteries harvested during cesarean section ↓EDV NDNA
Knock and Poston (1996)50 6 24Subcutaneous arteries harvested during cesarean section ↓EDV NDNA
Eneroth-Grimfors et al. (1993)56 10 20Laser Doppler flowmetry and iontophoresis ↑response to EDV No change No change
Davis et al. (2001)57 13 16Laser Doppler flowmetry and iontophoresis ↑response to EDV No change No change
Chambers et al. (2001) 47 113 48NA NAFlow-mediated dilatation ↓EDV
Beinder and Schlembach (2001)58 14 20Laser Doppler thermal augmentation ↓response to heat NDNA
Novelli et al. (2003)54 39 38Echocardiography ↓early diastolic function No change No change
Agatisa et al. (2004)46 16 34NA NAFlow-mediated dilatation ↓EDV
Blaauw et al. (2005)55 25 23Laser Doppler flowmetry and iontophoresis ↑response to EDV NDNA
Elvan-Taspinar et al. (2005)53 44 46Aortic pulse-wave velocity ↑velocity aPWV ↑aPWV
Wimalasundera et al. (2005)49 11 14Subcutaneous arteries harvested during cesarean section ↓EDV NDNA

Abbreviations: aPWV = Arterial Pulse Wave Velocity; EDV = Endothelium-dependent Vasodilatation; NA = Not Applicable; ND = Not Done.

 



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Sidebar: Key Points

  • Gestational diabetes and gestational hypertensive disorders might have common underlying pathophysiological mechanisms.

  • Gestational diabetes and gestational hypertensive disorders are associated with vascular dysfunction demonstrable in small and large vessels.

  • Long-term follow-up studies seem not to have been done in women with gestational diabetes, although studies in women with gestational hypertensive disorders have demonstrated raised cardiovascular risk.

  • Early intervention in women with gestational diabetes or hypertension, as well as better definition of their risk, could help to prevent future cardiovascular disease.

Acknowledgements

We thank Ms J Stewart and Miss K Molloy for help in preparation of the manuscript.

Reprint Address

Moulinath Banerjee, Division of Cardiovascular & Endocrine Sciences, Core Technology Facility (3rd Floor), University of Manchester, Manchester M13 9NT, UK. Email: moulinath.banerjee@manchester.ac.uk


Moulinath Banerjee is a British Heart Foundation Fellow.

John Kennedy Cruickshank is Professor of Cardiovascular Medicine and Clinical Epidemiology at Manchester Royal Infirmary, UK.

Competing Interests: The authors declared no competing interests.