REVIEW URRENT C OPINION
Cardiovascular disease in women: the significance of hypertension and gestational diabetes during pregnancy Joanne M. Lind, Annemarie Hennessy, and Mark McLean
Purpose of review Cardiovascular disease (CVD) remains the major killer of women around the globe. Complications during pregnancy, including hypertensive disorders of pregnancy and gestational diabetes mellitus, are now recognized as risk factors for future CVD. Recent findings Studies of diverse populations demonstrate the links between these complications of pregnancy and a woman’s future risk of CVD including atherosclerosis, hypertension, stroke, coronary artery disease, and heart failure. Markers that persist in these women following pregnancy continue to be identified and include microalbuminuria, proteinuria, elevated homocysteine levels, C-reactive protein, and salt sensitivity. Efforts are now being placed on establishing specialized clinics to monitor women beyond pregnancy to help reduce the burden of future disease. Summary Pregnancy offers a unique window through which women at risk of future CVD may be identified. Clinicians have an opportunity to implement health monitoring, lifestyle modifications, and other interventions during this period, and beyond, that will help reduce the burden of CVD. Research should continue to focus on identifying and understanding the mechanisms that lead to future CVD in these women; deciphering whether pregnancy unmasks an existing predisposition to disease, compounds the risk of future disease, or is the direct cause of future disease. Keywords cardiovascular disease, gestational diabetes mellitus, hypertensive disorders of pregnancy, pregnancy
INTRODUCTION More women die of cardiovascular disease (CVD) than any other cause [1,2] and mortality rates increase with increasing age (Fig. 1). Clinical researchers are interested in understanding the mechanisms that lead to disease and, ultimately, how disease can be prevented in at-risk women. Antenatal care is often the first time in a woman’s life when her blood pressure and blood glucose levels are closely monitored, offering a unique opportunity to identify young women who, it is now clear, are at risk of future CVD. Hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) are the two most common medical complications of pregnancy, both of which were once thought to resolve after delivery of the child. We now know that these conditions represent disturbed physiological adaptations to pregnancy and carry serious implications for a woman’s long-term health
including future hypertension, stroke, coronary artery disease, heart failure, type 2 diabetes mellitus (T2DM), and renal disease. Current research is focusing on how these complications of pregnancy result in future disease, and whether there are defining characteristics of some women who experience a HDP or GDM that make them more likely to develop future disease. Screening programs during pregnancy and subsequent implementation of prevention strategies for at-risk individuals would reduce the burden of disease and promote healthy ageing in women.
University of Western Sydney, School of Medicine, NSW, Australia Correspondence to Dr Joanne M. Lind, University of Western Sydney, School of Medicine, Campbelltown Campus, Locked Bag 1797, Penrith, NSW 2751, Australia. Tel: +61 2 4620 3803; e-mail: [email protected] Curr Opin Cardiol 2014, 29:447–453 DOI:10.1097/HCO.0000000000000094
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KEY POINTS
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Studies have shown that HDP and GDM increase a woman’s risk of future CVD.
40
Infectious and parasitic diseases
Markers of CVD, including microalbuminuria and proteinuria, elevated levels of homocysteine, elevated levels of C-reactive protein, and salt sensitivity have been shown to persist in women for many years after having a HDP and/or GDM.
Deaths (% of total)
Cancers
Clinics that monitor women after a complicated pregnancy are currently being introduced and evaluated to determine whether they can be successful in assisting women to modify their lifestyles in order to reduce the risk of future CVD. More research is required, including the study of women prior to, during, and beyond pregnancy to determine why women who experience a HDP and/or GDM have an increased risk of CVD.
HYPERTENSIVE DISORDERS OF PREGNANCY HDP, which include gestational hypertension, preeclampsia/eclampsia, and chronic hypertension with or without superimposed preeclampsia, occur in 5–10% of all pregnancies [3]. This is a complex set of disorders that are thought to result from a combination of maternal and fetal factors [4 ] in which inadequate placental cytotrophoblast invasion early in pregnancy can result in increasing placental hypoxia, as the pregnancy progresses, and elevated maternal blood pressure. Widespread maternal endothelial dysfunction [5 ] and increased systemic peripheral resistance [6 ] have also been associated with HDP. The clinical features range in severity from a mild increase in blood pressure to maternal death. Delivery of the placenta was originally thought to cure the disease but there is now an emerging body of literature that has identified long-term implications of these disorders for the cardiovascular health of the mother. &
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LONG-TERM CONSEQUENCES OF HYPERTENSIVE DISORDERS OF PREGNANCY Research linking HDP to long-term maternal CVD was first carried out more than a decade ago, and relied on observational data to identify an association of HDP with future hypertension, stroke, coronary artery disease, and ischemic heart disease [7–9]. Data continue to emerge demonstrating these initial associations in various populations around the world. Estimates of CVD later in life differ across studies depending on the length of time since 448
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Cardiovascular diseases
30 20 10 0 All ages
15–29
30–49
50–69
70+
Age category (years)
FIGURE 1. Worldwide estimates of the top three causes of death in females (2011). Cardiovascular disease is the leading cause of death in women 50 years of age and over. Data sourced from [2] and the ‘Infectious and parasitic diseases’ category includes respiratory infections.
pregnancy and the inclusion criteria for the study. All studies, however, show significant differences in the frequency of subsequent disease between those who experienced normotensive pregnancies and those who developed HDP (Fig. 2) [10 –14 ,15 , 16 ,17 ,18 ]. The most recent studies have been carried out in Australia, Taiwan, Finland, and Japan. A study of 71 819 women enroled in the 45 and Up Study, Australia, found that women who had reported having high blood pressure during pregnancy had increased odds of both hypertension and stroke later in life [13 ]. These women also had a younger age of onset of CVD compared with women who were normotensive during pregnancy. The odds ratio (OR) for future hypertension in this study was shown to be greater if women were overweight or obese, with an OR of up to 12.48 [99% confidence interval (CI) 10.63 to 14.66] for hypertension in women who were overweight or obese later in life, and who had been diagnosed with HDP [13 ]. A study of 240 048 Taiwanese women demonstrated that women with HDP had a higher incidence of coronary artery disease (P < 0.001), congestive heart failure (P < 0.001), hypertension (P < 0.001), and diabetes (P < 0.001) after a hypertensive pregnancy compared with women who had a normotensive pregnancy. These women also had a greater rate of chronic kidney disease [hazard ratio (HR): 9.38; 95% CI 7.09–12.40) and a greater rate of end-stage renal disease (HR: 12.4; 95% CI 8.54–18.00) compared with women who were normotensive during pregnancy [19 ]. The rates observed in this study were greater for women who had preeclampsia or &
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Cardiovascular disease in women Lind et al.
Frequency of hypertension in later life (%)
100 90
Normotensive pregnancy Hypertensive disorder of pregnancy
80 70 60 50 40 30 20 10 0 Hermes et al. [10]
Hashemi et al. [11]
McDonald et al. [12]
Tooher et al. [13]
Kattah et al. [14]
White et al. [15]
Brown et al. [16]
Weissgerber et al. [17]
Collen et al. [18]
FIGURE 2. Summary of recent studies measuring the frequency of hypertension in women after pregnancy. All studies compared women with normotensive pregnancies with women with hypertensive disorders of pregnancy. Time since pregnancy varied from 2.5 years [10 ] to more than 35 years [18 ]. All differences were found to be significant (P < 0.05). &
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eclampsia (the more severe form of HDP) compared with gestational hypertension alone. The ‘Northern Finland Birth Cohort 1966’ studied 10 314 women and demonstrated an increased risk of CVD in women who had HDP compared with normotensive pregnancies [20 ]. This study, with an average follow-up of 39.4 years, showed an association between gestational hypertension and an increased risk of ischemic heart disease, myocardial infarction, death from myocardial infarction, heart failure, ischemic stroke, kidney disease, and diabetes mellitus. The association between HDP and future CVD was evident in women even without previous known risk factors for CVD. Similarly, the Japan Nurses’ Health Study demonstrated increased odds of hypertension (OR: 2.85; 95% CI 2.45–3.11), hypercholesterolemia (OR: 1.49; 95% CI 1.29–1.72), and diabetes mellitus (OR: 1.53; 95% CI 1.11–2.11) in a cohort of 10 456 parous women who had experienced HDP [21 ]. All these studies clearly demonstrate the longterm implications of HDP and GDP for the mother’s subsequent cardiovascular health. &&
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GESTATIONAL DIABETES MELLITUS GDM is characterized by elevated blood glucose levels (impaired glucose tolerance or overt diabetes), which appear for the first time during pregnancy, usually during the third trimester. The prevalence of GDM ranges from 2 to 10% [22]. GDM occurs as a
consequence of the action of pregnancy-related hormones and represents a failure of the mother’s insulin-secreting capacity to respond to a physiological increase in demand. Normal glucose metabolism usually returns after delivery; however, a woman who experiences GDM will go on to have a seven-fold increased risk of permanent T2DM later in life [23]. The incidence of T2DM approaches 50% in the 10 years following a GDM pregnancy. Although there has been considerable attention to the consequences of GDM for pregnancy outcomes and the future health of the child, there has been relatively less focus on the long-term implications for the mother’s cardiovascular health.
LONG-TERM CONSEQUENCES OF GESTATIONAL DIABETES MELLITUS It has been established that GDM increases the risk of future T2DM in the mother [24] and increases the risk of future CVD events [25]. Retnakaran and Shah [26] showed that women with either GDM or evidence of an abnormal glucose tolerance test had a higher risk of being hospitalized for a CVD event (defined as acute myocardial infarction, coronary artery bypass, coronary angioplasty, stroke, or carotid endarterectomy) than women with no evidence of glucose intolerance during pregnancy (GDM: HR 1.66; 95% CI 1.30–2.13; abnormal glucose tolerance test: HR 1.19; 95% CI 1.02–1.39). Similarly, in a study by Shah et al. [25], 8191 women with GDM and 81 262 matched controls showed a significant
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association between GDM and a later CVD event (HR 1.71; 95% CI 1.08–2.69). These women were still relatively young, aged between 20 and 49 years, with a median follow-up of 11.5 years postpregnancy. It is likely that the excess rate of CVD in women with previous GDM will worsen with increasing age. More recent investigations have found similar links between GDM and CVD. An analysis of women enroled in the Coronary Artery Risk Development in Young Adults Study showed that history of GDM is associated with early subclinical atherosclerosis, as measured by carotid artery intima-media thickness (ccIMT) (mean ccIMT GDM 0.785; 95% CI 0.767– 0.803 compared with non-GDM: mean ccIMT 0.762; 95% CI 0.755–0.769, P ¼ 0.02 adjusted for age, race, and parity) [27 ]. A study of the impact of ethnicity on GDM and subsequent hypertension has shown that both Hispanic and white women with GDM are at an increased risk of hypertension (Hispanic HR: 3.25; 95% CI 1.85–5.72; white HR: 1.68; 95% CI 1.10–2.57) with a median follow-up of 3.8 years postpregnancy [28 ]. A prospective case–control study by Barden et al. [29 ] followed women from 28 weeks’ gestation to 10 years after pregnancy. The aim of the study was to determine whether future CVD and T2DM risk could be estimated based on the identification of cardiometabolic risk factors during pregnancy. Among women with GDM, those who had a ‘high-risk’ profile during pregnancy, namely, higher BMI; elevated systolic blood pressure, fasting blood glucose, triglycerides, and insulin; and, significantly, lower HDL cholesterol, were at greater risk of future CVD and T2DM than the women with GDM who were classified as having a ‘low-risk’ profile during pregnancy. Clustering these cardiometabolic risk factors during pregnancy was a better predictor of T2DM 10 years following pregnancy (OR: 6.75, 95% CI 2.0–22.7, Bayesian Information Criterion 88.5) than fasting glucose at diagnosis of GDM (OR: 4.56, 95% CI 1.50–13.85, Bayesian Information Criterion 92.4). High BMI during pregnancy was shown not to predict T2DM at 10 years postpregnancy, whereas the highrisk profile of women did predict future T2DM. HDP and GDM are not mutually exclusive conditions of pregnancy. Women with GDM have a 1.5 times greater likelihood of also developing HDP compared with women without GDM [30]. Both HDP and GDM have long-term consequences for the cardiovascular health of women and may indicate which women are at risk of future CVD. Although informative, these studies have yet to demonstrate causation; an emerging body of literature is now addressing markers of disease in women who have had HDP or GDM, bringing researchers one step closer to &&
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understanding how these complications of pregnancy can lead to future CVD.
MARKERS OF CARDIOVASCULAR DISEASE FOLLOWING HYPERTENSIVE DISORDERS OF PREGNANCY AND GESTATIONAL DIABETES MELLITUS The evidence now points to dysfunction of microvascular tone in women with prior HDP as an important pathogenic factor in the development of CVD. Endothelial dysfunction results from an imbalance between vasoconstrictive and vasodilatory processes and is a precursor of future CVD. This may induce a proinflammatory endothelial phenotype that promotes the development of CVD precursors such as hypertension and atherosclerosis. In recent years, a number of markers of cardiovascular and endothelial dysfunction have been studied in women within, and remote from, pregnancy to determine their utility as independent predictors of future CVD [6 ,31]. These have included measurements of microalbuminuria and proteinuria, homocysteine, C-reactive protein, and salt sensitivity. An examination of a large multiracial cohort of the Family Blood Pressure Program has recently demonstrated that women who had HDP were more likely to have hypertension, diabetes, and a higher BMI compared with women without HDP, as would be predicted based on previous research. In addition, these women had a significantly increased prevalence of microalbuminuria (19% in HDP women versus 12.8% in non-HDP women) and proteinuria (5.4% in HDP women versus 2.9% in nonHDP women). HDP women also had significant increased urine albumin–creatinine ratios compared with both nulliparous women and women with normotensive pregnancies [14 ]. Proteinuria and microalbuminuria are now widely accepted as important risk factors for CVD [32] in addition to their implications for the progression to chronic kidney disease [33]. Markers of inflammation may predict an increased risk of future CVD. High-sensitivity C-reactive protein (hs-CRP) is one such marker; hs-CRP is synthesized in the liver and has been associated with systemic inflammation and cardiovascular events [34]. Participants enroled in the Family Blood Pressure Program were examined to determine the association between a history of HDP and subsequent measures of hs-CRP. A history of HDP was associated with higher levels of hs-CRP, as well as significantly increased rates of hypertension and diabetes and higher BMI [16 ]. Hs-CRP has also been shown to be significantly altered in women following GDM, along with higher levels of HDL &
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cholesterol and triglycerides [35], compared with women who experienced a healthy pregnancy. Homocysteine concentrations have also been shown to be elevated in women, decades after experiencing HDP [16 ]. Homocysteine concentrations are elevated in women at the time of preeclampsia and associated with oxidative stress and endothelial dysfunction; elevated homocysteine concentrations are a known marker of CVD. Martillotti et al. [36 ] suggested that, following HDP, ‘salt sensitivity’, as measured by changes in blood pressure, may be altered; such salt sensitivity is a known independent risk factor for CVD. They found that women with a history of preeclampsia are salt sensitive before menopause and that the nocturnal fall in blood pressure in these women is significantly modified by salt intake. While these studies have demonstrated lasting markers of cardiovascular dysfunction following not uncommon complications of pregnancy, we have still to achieve an understanding of the pathogenesis of CVD after such pregnancy complications and determine methods to prevent its development. A number of risk factors are shared between HDP, GDM, and other CVDs, including obesity, insulin resistance, kidney disease, and chronic hypertension [16 ]. Women with existing stressors on the cardiovascular system are much more likely to develop HDP and/or GDM. Pregnancy is the ultimate stress test of a woman’s cardiovascular and metabolic systems! It has been proposed that any predisposition to CVD will be unmasked during pregnancy in the form of HDP and/or GDM. Markers that are altered in women following HDP and GDM may be present prior to pregnancy, and cohorts need to be established that recruit women preconception and follow them during pregnancy and beyond. The extent to which HDP causes future CVD cannot be clearly established until more work focuses on cohorts of women prior to their first pregnancy. &&
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HDP, which is to include the frequency of blood pressure monitoring and a medical review at 6–8 weeks after birth [38]. The American Congress of Obstetricians and Gynecologists have recently released a document recommending yearly assessment of blood pressure, lipids, fasting blood glucose, and BMI following a medical history of preeclampsia [39], as well as a call to action to promote health after GDM [40]. The benefits of establishing clinics to follow women postpartum are currently under investigation [41]. One such clinic was established at Kingston General Hospital, Queens University, Ontario, Canada, which is the first of its kind in North America. This ‘Maternal Health Clinic’ aims to see women who have had a complication of pregnancy related to cardiovascular health [42 ]. While it is too early to assess the long-term clinical benefit in these women, it has already been identified that women postpartum are at risk of future CVD. Similar programs have been implemented for women following GDM, namely, the Diabetes Prevention Program [43]. This program has been running for over a decade and has recently been translated to cater for low-income Latino mothers, who are at the highest risk of GDM in the USA [44 ]. &&
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SCREENING WOMEN FOR CARDIOVASCULAR DISEASE AFTER PREGNANCY Because of the growing evidence linking CVD to complications of pregnancy, recent research has examined the extent to which this information is incorporated into a woman’s future CVD risk profile and how these women are monitored after pregnancy. A survey of 212 obstetricians and gynecologists in Germany showed that the majority (86.6%) were aware of the association between preeclampsia and future risk of stroke, hypertension, and kidney disease [37 ]. In the United Kingdom, physicians are advised to write a care plan for women following &&
CONCLUSION Pregnancy complications may serve as one of the earliest clinical markers of future CVD in women. Advancing age can be expected to reveal an even greater toll of CVD in women who have experienced previous complications of pregnancy. It is, therefore, important that we identify the pathogenic mechanisms for CVD in this population. Identification of clinically applicable markers of CVD risk will then allow preventive interventions to be delivered to the women most at risk, prior to the occurrence of devastating cardiovascular events. Identifying and monitoring women at higher risk of future disease will presumably help to reduce the overall burden of CVD in the community. Women may be more likely to be motivated to change their lifestyle habits during pregnancy and the postpartum period in order to produce the best outcomes for their child’s health and their own health as a mother. Acknowledgements J.M.L. is the recipient of an Australian National Health and Medical Research Council Biomedical Fellowship. No funding was received for this work. Conflicts of interest There are no conflicts of interest.
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Kochanek K, Xu J, Murphy S, et al. Deaths: final data for 2009. Nat Vital Stat Rep 2011; 60:1–117. 2. World Health Organization. WHO methods and data sources for global causes of death 2000-2011. Global Health Estimates Technical Paper WHO/HIS/HSI/GHE/2013.3. 2013. Available: http://www.who.int/health info/statistics/GlobalCOD_method.pdf. [Accessed 1 May 2014] 3. Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of preeclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 2011; 25:391–403. 4. Szpera-Gozdziewicz A, Breborowicz GH. Endothelial dysfunction in the & pathogenesis of preeclampsia. Front Biosci 2014; 19:734–746. Provides a recent review of the likely pathogenesis of preeclampsia. 5. Brandao AH, Felix LR, do Carmo Patricio E, et al. Difference of endothelial & function during pregnancies as a method to predict preeclampsia. Arch Gynecol Obstet 2014. [Epub ahead of print] This study measures endothelial function via ultrasound of the brachial artery and demonstrates that flow-mediated dilation can be used to predict preeclampsia. 6. Lupton SJ, Chiu CL, Hodgson LA, et al. Changes in retinal microvascular & caliber precede the clinical onset of preeclampsia. Hypertension 2013; 62:899–904. This is the first study to show that retinal microvasculature calibre is altered in women with preeclampsia. 7. Irgens HU, Reisaeter L, Irgens LM, et al. Long term mortality of mothers and fathers after preeclampsia: population based cohort study. BMJ 2001; 323:1213–1217. 8. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001; 357:2002–2006. 9. Jonsdottir LS, Arngrimsson R, Geirsson RT, et al. Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 1995; 74:772–776. 10. Hermes W, Tamsma JT, Grootendorst DC, et al. Cardiovascular risk & estimation in women with a history of hypertensive pregnancy disorders at term: a longitudinal follow-up study. BMC Pregnancy Childbirth 2013; 13:126. This study compared a number of CVD risk prediction scores and showed that women with HDP had an increased CVD risk in all risk prediction scoring methods. 11. Hashemi S, Ramezani Tehrani F, Mehrabi Y, et al. Hypertensive pregnancy & disorders as a risk factor for future cardiovascular and metabolic disorders (Tehran Lipid and Glucose Study). J Obstet Gynaecol Res 2013; 39:891– 897. Extends current knowledge on CVD following HDP to an Iranian population, using a population-based cohort, with an average of 10 years’ follow-up. 12. McDonald SD, Ray J, Teo K, et al. Measures of cardiovascular risk and & subclinical atherosclerosis in a cohort of women with a remote history of preeclampsia. Atherosclerosis 2013; 229:234–239. This article showed that, while women with preeclampsia have an increased risk of CVD 20 years after pregnancy, they do not have increases in dysglycemia, dislipidemia, renal dysfunction, or carotid intima-media thickness. 13. Tooher J, Chiu CL, Yeung K, et al. High blood pressure during pregnancy is & associated with future cardiovascular disease: an observational cohort study. BMJ Open 2013; 3:e002964. This is the first study to show that a combination of present-day high BMI and a history of HDP greatly increases risk of future high blood pressure and stroke. 14. Kattah AG, Asad R, Scantlebury DC, et al. Hypertension in pregnancy is a risk & factor for microalbuminuria later in life. J Clin Hypertens (Greenwich) 2013; 15:617–623. This study is the largest to date to show that women with a history of HDP have a significantly increased risk of microalbuminuria in later life. 15. White WM, Turner ST, Bailey KR, et al. Hypertension in pregnancy is && associated with elevated homocysteine levels later in life. Am J Obstet Gynecol 2013; 209:454; e1-7. First study to show that homocysteine concentration is elevated in women, decades after a hypertensive pregnancy. 16. Brown CM, Turner ST, Bailey KR, et al. Hypertension in pregnancy is && associated with elevated C-reactive protein levels later in life. J Hypertens 2013; 31:2213–2219. Largest study to date showing that C-reactive protein is elevated in women many years after pregnancy and that C-reactive protein concentrations may assist in predicting women at risk of CVD. 17. Weissgerber TL, Turner ST, Bailey KR, et al. Hypertension in pregnancy is a & risk factor for peripheral arterial disease decades after pregnancy. Atherosclerosis 2013; 229:212–216. This study is the first to use ankle–brachial index to show an association between HDP and peripheral arterial disease in later life.
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First study to show that there are racial differences in cardiovascular risk following a GDM pregnancy. Hispanic and white women have a greater risk of hypertension following GDM compared with women without GDM. 29. Barden A, Singh R, Walters B, et al. A simple scoring method using && cardiometabolic risk measurements in pregnancy to determine 10-year risk of type 2 diabetes in women with gestational diabetes. Nutr Diabetes 2013; 3:e72. First study to cluster women according to their cardiometabolic risk profile during pregnancy and show that this is a better predictor of subsequent T2DM than BMI. 30. Bryson CL, Ioannou GN, Rulyak SJ, et al. Association between gestational diabetes and pregnancy-induced hypertension. Am J Epidemiol 2003; 158:1148–1153. 31. Carty DM, Delles C, Dominiczak AF. Novel biomarkers for predicting preeclampsia. Trends Cardiovasc Med 2008; 18:186–194. 32. Currie G, Delles C. Proteinuria and its relation to cardiovascular disease. Int J Nephrol Renovasc Dis 2013; 7:13–24. 33. van der Velde M, Halbesma N, de Charro FT, et al. Screening for albuminuria identifies individuals at increased renal risk. J Am Soc Nephrol 2009; 20:852–862. 34. Kaptoge S, Di Angelantonio E, Pennells L, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012; 367:1310– 1320. 35. Rivero K, Portal VL, Vieira M, et al. Prevalence of the impaired glucose metabolism and its association with risk factors for coronary artery disease in women with gestational diabetes. Diabetes Res Clin Pract 2008; 79:433–437. 36. Martillotti G, Ditisheim A, Burnier M, et al. Increased salt sensitivity of && ambulatory blood pressure in women with a history of severe preeclampsia. Hypertension 2013; 62:802–808. First study to demonstrate that women with a history of preeclampsia are salt sensitive before the onset of menopause. Women with a history of preeclampsia had a significant rise in ambulatory blood pressure on a high salt diet compared with controls, even though their blood pressure remained within the normal range. 37. Heidrich MB, Wenzel D, von Kaisenberg CS, et al. Preeclampsia and long&& term risk of cardiovascular disease: what do obstetrician-gynecologists know? BMC Pregnancy Childbirth 2013; 13:61. The study shows that, although obstetricians–gynecologists are aware of a higher CVD risk in women following preeclampsia, there is limited follow-up care and counseling for these women. This study was carried out in Germany and has implications for management of women after pregnancy around the world. &
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Cardiovascular disease in women Lind et al. 38. National Collaborating Centre for Women’s and Children’s Health. Hypertension in pregnancy. The management of hypertensive disorders during pregnancy. London, UK: National Institute for Health and Clinical Excellence (NICE); 2010. 39. Task Force on Hypertension in Pregnancy. Hypertension in Pregnancy. Washington, DC: The American College of Obstetricians and Gynecologists; 2013. 40. Gabbe SG, Landon MB, Warren-Boulton E, et al. Promoting health after gestational diabetes: a National Diabetes Education Program call to action. Obstet Gynecol 2012; 119:171–176. 41. Spaan J, Peeters L, Spaanderman M, et al. Cardiovascular risk management after a hypertensive disorder of pregnancy. Hypertension 2012; 60:1368– 1373.
42. Cusimano MC, Pudwell J, Roddy M, et al. The maternal health clinic: an initiative for cardiovascular risk identification in women with pregnancy-related complications. Am J Obstet Gynecol 2013; 210:438; e1–9. This article reports on data from the first maternal health clinic established in North America. This clinic may prevent CVD in women by managing their care following a pregnancy complicated with disease. 43. The Diabetes Prevention Program Research Group. The Diabetes Prevention Program: design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999; 22:623–634. 44. Philis-Tsimikas A, Fortmann AL, Dharkar-Surber S, et al. Dulce Mothers: an & intervention to reduce diabetes and cardiovascular risk in Latinas after gestational diabetes. Transl Behav Med 2014; 4:18–25. This is the first article to demonstrate the effectiveness of translating the Diabetes Prevention Program for a Spanish-speaking population to implement lifestyle changes in women following a GDM pregnancy.
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Cardiovascular disease in women: the significance of hypertension and gestational diabetes during pregnancy Joanne M. Lind, Annemarie Hennessy, and Mark McLean
Purpose of review Cardiovascular disease (CVD) remains the major killer of women around the globe. Complications during pregnancy, including hypertensive disorders of pregnancy and gestational diabetes mellitus, are now recognized as risk factors for future CVD. Recent findings Studies of diverse populations demonstrate the links between these complications of pregnancy and a woman’s future risk of CVD including atherosclerosis, hypertension, stroke, coronary artery disease, and heart failure. Markers that persist in these women following pregnancy continue to be identified and include microalbuminuria, proteinuria, elevated homocysteine levels, C-reactive protein, and salt sensitivity. Efforts are now being placed on establishing specialized clinics to monitor women beyond pregnancy to help reduce the burden of future disease. Summary Pregnancy offers a unique window through which women at risk of future CVD may be identified. Clinicians have an opportunity to implement health monitoring, lifestyle modifications, and other interventions during this period, and beyond, that will help reduce the burden of CVD. Research should continue to focus on identifying and understanding the mechanisms that lead to future CVD in these women; deciphering whether pregnancy unmasks an existing predisposition to disease, compounds the risk of future disease, or is the direct cause of future disease. Keywords cardiovascular disease, gestational diabetes mellitus, hypertensive disorders of pregnancy, pregnancy
INTRODUCTION More women die of cardiovascular disease (CVD) than any other cause [1,2] and mortality rates increase with increasing age (Fig. 1). Clinical researchers are interested in understanding the mechanisms that lead to disease and, ultimately, how disease can be prevented in at-risk women. Antenatal care is often the first time in a woman’s life when her blood pressure and blood glucose levels are closely monitored, offering a unique opportunity to identify young women who, it is now clear, are at risk of future CVD. Hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) are the two most common medical complications of pregnancy, both of which were once thought to resolve after delivery of the child. We now know that these conditions represent disturbed physiological adaptations to pregnancy and carry serious implications for a woman’s long-term health
including future hypertension, stroke, coronary artery disease, heart failure, type 2 diabetes mellitus (T2DM), and renal disease. Current research is focusing on how these complications of pregnancy result in future disease, and whether there are defining characteristics of some women who experience a HDP or GDM that make them more likely to develop future disease. Screening programs during pregnancy and subsequent implementation of prevention strategies for at-risk individuals would reduce the burden of disease and promote healthy ageing in women.
University of Western Sydney, School of Medicine, NSW, Australia Correspondence to Dr Joanne M. Lind, University of Western Sydney, School of Medicine, Campbelltown Campus, Locked Bag 1797, Penrith, NSW 2751, Australia. Tel: +61 2 4620 3803; e-mail: [email protected] Curr Opin Cardiol 2014, 29:447–453 DOI:10.1097/HCO.0000000000000094
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KEY POINTS
50
Studies have shown that HDP and GDM increase a woman’s risk of future CVD.
40
Infectious and parasitic diseases
Markers of CVD, including microalbuminuria and proteinuria, elevated levels of homocysteine, elevated levels of C-reactive protein, and salt sensitivity have been shown to persist in women for many years after having a HDP and/or GDM.
Deaths (% of total)
Cancers
Clinics that monitor women after a complicated pregnancy are currently being introduced and evaluated to determine whether they can be successful in assisting women to modify their lifestyles in order to reduce the risk of future CVD. More research is required, including the study of women prior to, during, and beyond pregnancy to determine why women who experience a HDP and/or GDM have an increased risk of CVD.
HYPERTENSIVE DISORDERS OF PREGNANCY HDP, which include gestational hypertension, preeclampsia/eclampsia, and chronic hypertension with or without superimposed preeclampsia, occur in 5–10% of all pregnancies [3]. This is a complex set of disorders that are thought to result from a combination of maternal and fetal factors [4 ] in which inadequate placental cytotrophoblast invasion early in pregnancy can result in increasing placental hypoxia, as the pregnancy progresses, and elevated maternal blood pressure. Widespread maternal endothelial dysfunction [5 ] and increased systemic peripheral resistance [6 ] have also been associated with HDP. The clinical features range in severity from a mild increase in blood pressure to maternal death. Delivery of the placenta was originally thought to cure the disease but there is now an emerging body of literature that has identified long-term implications of these disorders for the cardiovascular health of the mother. &
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LONG-TERM CONSEQUENCES OF HYPERTENSIVE DISORDERS OF PREGNANCY Research linking HDP to long-term maternal CVD was first carried out more than a decade ago, and relied on observational data to identify an association of HDP with future hypertension, stroke, coronary artery disease, and ischemic heart disease [7–9]. Data continue to emerge demonstrating these initial associations in various populations around the world. Estimates of CVD later in life differ across studies depending on the length of time since 448
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Cardiovascular diseases
30 20 10 0 All ages
15–29
30–49
50–69
70+
Age category (years)
FIGURE 1. Worldwide estimates of the top three causes of death in females (2011). Cardiovascular disease is the leading cause of death in women 50 years of age and over. Data sourced from [2] and the ‘Infectious and parasitic diseases’ category includes respiratory infections.
pregnancy and the inclusion criteria for the study. All studies, however, show significant differences in the frequency of subsequent disease between those who experienced normotensive pregnancies and those who developed HDP (Fig. 2) [10 –14 ,15 , 16 ,17 ,18 ]. The most recent studies have been carried out in Australia, Taiwan, Finland, and Japan. A study of 71 819 women enroled in the 45 and Up Study, Australia, found that women who had reported having high blood pressure during pregnancy had increased odds of both hypertension and stroke later in life [13 ]. These women also had a younger age of onset of CVD compared with women who were normotensive during pregnancy. The odds ratio (OR) for future hypertension in this study was shown to be greater if women were overweight or obese, with an OR of up to 12.48 [99% confidence interval (CI) 10.63 to 14.66] for hypertension in women who were overweight or obese later in life, and who had been diagnosed with HDP [13 ]. A study of 240 048 Taiwanese women demonstrated that women with HDP had a higher incidence of coronary artery disease (P < 0.001), congestive heart failure (P < 0.001), hypertension (P < 0.001), and diabetes (P < 0.001) after a hypertensive pregnancy compared with women who had a normotensive pregnancy. These women also had a greater rate of chronic kidney disease [hazard ratio (HR): 9.38; 95% CI 7.09–12.40) and a greater rate of end-stage renal disease (HR: 12.4; 95% CI 8.54–18.00) compared with women who were normotensive during pregnancy [19 ]. The rates observed in this study were greater for women who had preeclampsia or &
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Cardiovascular disease in women Lind et al.
Frequency of hypertension in later life (%)
100 90
Normotensive pregnancy Hypertensive disorder of pregnancy
80 70 60 50 40 30 20 10 0 Hermes et al. [10]
Hashemi et al. [11]
McDonald et al. [12]
Tooher et al. [13]
Kattah et al. [14]
White et al. [15]
Brown et al. [16]
Weissgerber et al. [17]
Collen et al. [18]
FIGURE 2. Summary of recent studies measuring the frequency of hypertension in women after pregnancy. All studies compared women with normotensive pregnancies with women with hypertensive disorders of pregnancy. Time since pregnancy varied from 2.5 years [10 ] to more than 35 years [18 ]. All differences were found to be significant (P < 0.05). &
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eclampsia (the more severe form of HDP) compared with gestational hypertension alone. The ‘Northern Finland Birth Cohort 1966’ studied 10 314 women and demonstrated an increased risk of CVD in women who had HDP compared with normotensive pregnancies [20 ]. This study, with an average follow-up of 39.4 years, showed an association between gestational hypertension and an increased risk of ischemic heart disease, myocardial infarction, death from myocardial infarction, heart failure, ischemic stroke, kidney disease, and diabetes mellitus. The association between HDP and future CVD was evident in women even without previous known risk factors for CVD. Similarly, the Japan Nurses’ Health Study demonstrated increased odds of hypertension (OR: 2.85; 95% CI 2.45–3.11), hypercholesterolemia (OR: 1.49; 95% CI 1.29–1.72), and diabetes mellitus (OR: 1.53; 95% CI 1.11–2.11) in a cohort of 10 456 parous women who had experienced HDP [21 ]. All these studies clearly demonstrate the longterm implications of HDP and GDP for the mother’s subsequent cardiovascular health. &&
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GESTATIONAL DIABETES MELLITUS GDM is characterized by elevated blood glucose levels (impaired glucose tolerance or overt diabetes), which appear for the first time during pregnancy, usually during the third trimester. The prevalence of GDM ranges from 2 to 10% [22]. GDM occurs as a
consequence of the action of pregnancy-related hormones and represents a failure of the mother’s insulin-secreting capacity to respond to a physiological increase in demand. Normal glucose metabolism usually returns after delivery; however, a woman who experiences GDM will go on to have a seven-fold increased risk of permanent T2DM later in life [23]. The incidence of T2DM approaches 50% in the 10 years following a GDM pregnancy. Although there has been considerable attention to the consequences of GDM for pregnancy outcomes and the future health of the child, there has been relatively less focus on the long-term implications for the mother’s cardiovascular health.
LONG-TERM CONSEQUENCES OF GESTATIONAL DIABETES MELLITUS It has been established that GDM increases the risk of future T2DM in the mother [24] and increases the risk of future CVD events [25]. Retnakaran and Shah [26] showed that women with either GDM or evidence of an abnormal glucose tolerance test had a higher risk of being hospitalized for a CVD event (defined as acute myocardial infarction, coronary artery bypass, coronary angioplasty, stroke, or carotid endarterectomy) than women with no evidence of glucose intolerance during pregnancy (GDM: HR 1.66; 95% CI 1.30–2.13; abnormal glucose tolerance test: HR 1.19; 95% CI 1.02–1.39). Similarly, in a study by Shah et al. [25], 8191 women with GDM and 81 262 matched controls showed a significant
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association between GDM and a later CVD event (HR 1.71; 95% CI 1.08–2.69). These women were still relatively young, aged between 20 and 49 years, with a median follow-up of 11.5 years postpregnancy. It is likely that the excess rate of CVD in women with previous GDM will worsen with increasing age. More recent investigations have found similar links between GDM and CVD. An analysis of women enroled in the Coronary Artery Risk Development in Young Adults Study showed that history of GDM is associated with early subclinical atherosclerosis, as measured by carotid artery intima-media thickness (ccIMT) (mean ccIMT GDM 0.785; 95% CI 0.767– 0.803 compared with non-GDM: mean ccIMT 0.762; 95% CI 0.755–0.769, P ¼ 0.02 adjusted for age, race, and parity) [27 ]. A study of the impact of ethnicity on GDM and subsequent hypertension has shown that both Hispanic and white women with GDM are at an increased risk of hypertension (Hispanic HR: 3.25; 95% CI 1.85–5.72; white HR: 1.68; 95% CI 1.10–2.57) with a median follow-up of 3.8 years postpregnancy [28 ]. A prospective case–control study by Barden et al. [29 ] followed women from 28 weeks’ gestation to 10 years after pregnancy. The aim of the study was to determine whether future CVD and T2DM risk could be estimated based on the identification of cardiometabolic risk factors during pregnancy. Among women with GDM, those who had a ‘high-risk’ profile during pregnancy, namely, higher BMI; elevated systolic blood pressure, fasting blood glucose, triglycerides, and insulin; and, significantly, lower HDL cholesterol, were at greater risk of future CVD and T2DM than the women with GDM who were classified as having a ‘low-risk’ profile during pregnancy. Clustering these cardiometabolic risk factors during pregnancy was a better predictor of T2DM 10 years following pregnancy (OR: 6.75, 95% CI 2.0–22.7, Bayesian Information Criterion 88.5) than fasting glucose at diagnosis of GDM (OR: 4.56, 95% CI 1.50–13.85, Bayesian Information Criterion 92.4). High BMI during pregnancy was shown not to predict T2DM at 10 years postpregnancy, whereas the highrisk profile of women did predict future T2DM. HDP and GDM are not mutually exclusive conditions of pregnancy. Women with GDM have a 1.5 times greater likelihood of also developing HDP compared with women without GDM [30]. Both HDP and GDM have long-term consequences for the cardiovascular health of women and may indicate which women are at risk of future CVD. Although informative, these studies have yet to demonstrate causation; an emerging body of literature is now addressing markers of disease in women who have had HDP or GDM, bringing researchers one step closer to &&
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understanding how these complications of pregnancy can lead to future CVD.
MARKERS OF CARDIOVASCULAR DISEASE FOLLOWING HYPERTENSIVE DISORDERS OF PREGNANCY AND GESTATIONAL DIABETES MELLITUS The evidence now points to dysfunction of microvascular tone in women with prior HDP as an important pathogenic factor in the development of CVD. Endothelial dysfunction results from an imbalance between vasoconstrictive and vasodilatory processes and is a precursor of future CVD. This may induce a proinflammatory endothelial phenotype that promotes the development of CVD precursors such as hypertension and atherosclerosis. In recent years, a number of markers of cardiovascular and endothelial dysfunction have been studied in women within, and remote from, pregnancy to determine their utility as independent predictors of future CVD [6 ,31]. These have included measurements of microalbuminuria and proteinuria, homocysteine, C-reactive protein, and salt sensitivity. An examination of a large multiracial cohort of the Family Blood Pressure Program has recently demonstrated that women who had HDP were more likely to have hypertension, diabetes, and a higher BMI compared with women without HDP, as would be predicted based on previous research. In addition, these women had a significantly increased prevalence of microalbuminuria (19% in HDP women versus 12.8% in non-HDP women) and proteinuria (5.4% in HDP women versus 2.9% in nonHDP women). HDP women also had significant increased urine albumin–creatinine ratios compared with both nulliparous women and women with normotensive pregnancies [14 ]. Proteinuria and microalbuminuria are now widely accepted as important risk factors for CVD [32] in addition to their implications for the progression to chronic kidney disease [33]. Markers of inflammation may predict an increased risk of future CVD. High-sensitivity C-reactive protein (hs-CRP) is one such marker; hs-CRP is synthesized in the liver and has been associated with systemic inflammation and cardiovascular events [34]. Participants enroled in the Family Blood Pressure Program were examined to determine the association between a history of HDP and subsequent measures of hs-CRP. A history of HDP was associated with higher levels of hs-CRP, as well as significantly increased rates of hypertension and diabetes and higher BMI [16 ]. Hs-CRP has also been shown to be significantly altered in women following GDM, along with higher levels of HDL &
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cholesterol and triglycerides [35], compared with women who experienced a healthy pregnancy. Homocysteine concentrations have also been shown to be elevated in women, decades after experiencing HDP [16 ]. Homocysteine concentrations are elevated in women at the time of preeclampsia and associated with oxidative stress and endothelial dysfunction; elevated homocysteine concentrations are a known marker of CVD. Martillotti et al. [36 ] suggested that, following HDP, ‘salt sensitivity’, as measured by changes in blood pressure, may be altered; such salt sensitivity is a known independent risk factor for CVD. They found that women with a history of preeclampsia are salt sensitive before menopause and that the nocturnal fall in blood pressure in these women is significantly modified by salt intake. While these studies have demonstrated lasting markers of cardiovascular dysfunction following not uncommon complications of pregnancy, we have still to achieve an understanding of the pathogenesis of CVD after such pregnancy complications and determine methods to prevent its development. A number of risk factors are shared between HDP, GDM, and other CVDs, including obesity, insulin resistance, kidney disease, and chronic hypertension [16 ]. Women with existing stressors on the cardiovascular system are much more likely to develop HDP and/or GDM. Pregnancy is the ultimate stress test of a woman’s cardiovascular and metabolic systems! It has been proposed that any predisposition to CVD will be unmasked during pregnancy in the form of HDP and/or GDM. Markers that are altered in women following HDP and GDM may be present prior to pregnancy, and cohorts need to be established that recruit women preconception and follow them during pregnancy and beyond. The extent to which HDP causes future CVD cannot be clearly established until more work focuses on cohorts of women prior to their first pregnancy. &&
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HDP, which is to include the frequency of blood pressure monitoring and a medical review at 6–8 weeks after birth [38]. The American Congress of Obstetricians and Gynecologists have recently released a document recommending yearly assessment of blood pressure, lipids, fasting blood glucose, and BMI following a medical history of preeclampsia [39], as well as a call to action to promote health after GDM [40]. The benefits of establishing clinics to follow women postpartum are currently under investigation [41]. One such clinic was established at Kingston General Hospital, Queens University, Ontario, Canada, which is the first of its kind in North America. This ‘Maternal Health Clinic’ aims to see women who have had a complication of pregnancy related to cardiovascular health [42 ]. While it is too early to assess the long-term clinical benefit in these women, it has already been identified that women postpartum are at risk of future CVD. Similar programs have been implemented for women following GDM, namely, the Diabetes Prevention Program [43]. This program has been running for over a decade and has recently been translated to cater for low-income Latino mothers, who are at the highest risk of GDM in the USA [44 ]. &&
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SCREENING WOMEN FOR CARDIOVASCULAR DISEASE AFTER PREGNANCY Because of the growing evidence linking CVD to complications of pregnancy, recent research has examined the extent to which this information is incorporated into a woman’s future CVD risk profile and how these women are monitored after pregnancy. A survey of 212 obstetricians and gynecologists in Germany showed that the majority (86.6%) were aware of the association between preeclampsia and future risk of stroke, hypertension, and kidney disease [37 ]. In the United Kingdom, physicians are advised to write a care plan for women following &&
CONCLUSION Pregnancy complications may serve as one of the earliest clinical markers of future CVD in women. Advancing age can be expected to reveal an even greater toll of CVD in women who have experienced previous complications of pregnancy. It is, therefore, important that we identify the pathogenic mechanisms for CVD in this population. Identification of clinically applicable markers of CVD risk will then allow preventive interventions to be delivered to the women most at risk, prior to the occurrence of devastating cardiovascular events. Identifying and monitoring women at higher risk of future disease will presumably help to reduce the overall burden of CVD in the community. Women may be more likely to be motivated to change their lifestyle habits during pregnancy and the postpartum period in order to produce the best outcomes for their child’s health and their own health as a mother. Acknowledgements J.M.L. is the recipient of an Australian National Health and Medical Research Council Biomedical Fellowship. No funding was received for this work. Conflicts of interest There are no conflicts of interest.
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Kochanek K, Xu J, Murphy S, et al. Deaths: final data for 2009. Nat Vital Stat Rep 2011; 60:1–117. 2. World Health Organization. WHO methods and data sources for global causes of death 2000-2011. Global Health Estimates Technical Paper WHO/HIS/HSI/GHE/2013.3. 2013. Available: http://www.who.int/health info/statistics/GlobalCOD_method.pdf. [Accessed 1 May 2014] 3. Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of preeclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 2011; 25:391–403. 4. Szpera-Gozdziewicz A, Breborowicz GH. Endothelial dysfunction in the & pathogenesis of preeclampsia. Front Biosci 2014; 19:734–746. Provides a recent review of the likely pathogenesis of preeclampsia. 5. Brandao AH, Felix LR, do Carmo Patricio E, et al. Difference of endothelial & function during pregnancies as a method to predict preeclampsia. Arch Gynecol Obstet 2014. [Epub ahead of print] This study measures endothelial function via ultrasound of the brachial artery and demonstrates that flow-mediated dilation can be used to predict preeclampsia. 6. Lupton SJ, Chiu CL, Hodgson LA, et al. Changes in retinal microvascular & caliber precede the clinical onset of preeclampsia. Hypertension 2013; 62:899–904. This is the first study to show that retinal microvasculature calibre is altered in women with preeclampsia. 7. Irgens HU, Reisaeter L, Irgens LM, et al. Long term mortality of mothers and fathers after preeclampsia: population based cohort study. BMJ 2001; 323:1213–1217. 8. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001; 357:2002–2006. 9. Jonsdottir LS, Arngrimsson R, Geirsson RT, et al. Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 1995; 74:772–776. 10. Hermes W, Tamsma JT, Grootendorst DC, et al. Cardiovascular risk & estimation in women with a history of hypertensive pregnancy disorders at term: a longitudinal follow-up study. BMC Pregnancy Childbirth 2013; 13:126. This study compared a number of CVD risk prediction scores and showed that women with HDP had an increased CVD risk in all risk prediction scoring methods. 11. Hashemi S, Ramezani Tehrani F, Mehrabi Y, et al. Hypertensive pregnancy & disorders as a risk factor for future cardiovascular and metabolic disorders (Tehran Lipid and Glucose Study). J Obstet Gynaecol Res 2013; 39:891– 897. Extends current knowledge on CVD following HDP to an Iranian population, using a population-based cohort, with an average of 10 years’ follow-up. 12. McDonald SD, Ray J, Teo K, et al. Measures of cardiovascular risk and & subclinical atherosclerosis in a cohort of women with a remote history of preeclampsia. Atherosclerosis 2013; 229:234–239. This article showed that, while women with preeclampsia have an increased risk of CVD 20 years after pregnancy, they do not have increases in dysglycemia, dislipidemia, renal dysfunction, or carotid intima-media thickness. 13. Tooher J, Chiu CL, Yeung K, et al. High blood pressure during pregnancy is & associated with future cardiovascular disease: an observational cohort study. BMJ Open 2013; 3:e002964. This is the first study to show that a combination of present-day high BMI and a history of HDP greatly increases risk of future high blood pressure and stroke. 14. Kattah AG, Asad R, Scantlebury DC, et al. Hypertension in pregnancy is a risk & factor for microalbuminuria later in life. J Clin Hypertens (Greenwich) 2013; 15:617–623. This study is the largest to date to show that women with a history of HDP have a significantly increased risk of microalbuminuria in later life. 15. White WM, Turner ST, Bailey KR, et al. Hypertension in pregnancy is && associated with elevated homocysteine levels later in life. Am J Obstet Gynecol 2013; 209:454; e1-7. First study to show that homocysteine concentration is elevated in women, decades after a hypertensive pregnancy. 16. Brown CM, Turner ST, Bailey KR, et al. Hypertension in pregnancy is && associated with elevated C-reactive protein levels later in life. J Hypertens 2013; 31:2213–2219. Largest study to date showing that C-reactive protein is elevated in women many years after pregnancy and that C-reactive protein concentrations may assist in predicting women at risk of CVD. 17. Weissgerber TL, Turner ST, Bailey KR, et al. Hypertension in pregnancy is a & risk factor for peripheral arterial disease decades after pregnancy. Atherosclerosis 2013; 229:212–216. This study is the first to use ankle–brachial index to show an association between HDP and peripheral arterial disease in later life.
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18. Collen AC, Hellgren M, Gustafsson H, et al. Cardiovascular and metabolic characteristics 40 years after hypertensive pregnancies: a long-term follow-up study of mothers. J Hypertens 2013; 31:758–765. Women with a history of HDP are shown to have higher pulse wave velocity and an overall impairment of vascular function compared with women who had a normotensive pregnancy. 19. Wang IK, Muo CH, Chang YC, et al. Association between hypertensive & disorders during pregnancy and end-stage renal disease: a population-based study. CMAJ 2013; 185:207–213. This article extends current knowledge by showing that Taiwanese women also have an increased risk of end-stage renal disease following HDP. 20. Mannisto T, Mendola P, Vaarasmaki M, et al. Elevated blood pressure in && pregnancy and subsequent chronic disease risk. Circulation 2013; 127:681–690. Large prospective cohort study in Northern Finland showing that HDP is an important risk factor for ischemic cardiovascular and cerebrovascular diseases. 21. Kurabayashi T, Mizunuma H, Kubota T, et al. Pregnancy-induced hypertension & is associated with maternal history and a risk of cardiovascular disease in later life: Japanese cross-sectional study. Maturitas 2013; 75:227–231. This study shows an association between HDP and hypertension, hypercholesterolemia, and diabetes mellitus in a Japanese cohort. 22. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National estimates and general information on diabetes and prediabetes in the United States; 2011. 23. Bellamy L, Casas JP, Hingorani AD, et al. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 2009; 373:1773–1779. 24. Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: risks and management during and after pregnancy. 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First study to show that there are racial differences in cardiovascular risk following a GDM pregnancy. Hispanic and white women have a greater risk of hypertension following GDM compared with women without GDM. 29. Barden A, Singh R, Walters B, et al. A simple scoring method using && cardiometabolic risk measurements in pregnancy to determine 10-year risk of type 2 diabetes in women with gestational diabetes. Nutr Diabetes 2013; 3:e72. First study to cluster women according to their cardiometabolic risk profile during pregnancy and show that this is a better predictor of subsequent T2DM than BMI. 30. Bryson CL, Ioannou GN, Rulyak SJ, et al. Association between gestational diabetes and pregnancy-induced hypertension. Am J Epidemiol 2003; 158:1148–1153. 31. Carty DM, Delles C, Dominiczak AF. Novel biomarkers for predicting preeclampsia. Trends Cardiovasc Med 2008; 18:186–194. 32. Currie G, Delles C. Proteinuria and its relation to cardiovascular disease. Int J Nephrol Renovasc Dis 2013; 7:13–24. 33. van der Velde M, Halbesma N, de Charro FT, et al. Screening for albuminuria identifies individuals at increased renal risk. J Am Soc Nephrol 2009; 20:852–862. 34. Kaptoge S, Di Angelantonio E, Pennells L, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012; 367:1310– 1320. 35. Rivero K, Portal VL, Vieira M, et al. Prevalence of the impaired glucose metabolism and its association with risk factors for coronary artery disease in women with gestational diabetes. Diabetes Res Clin Pract 2008; 79:433–437. 36. Martillotti G, Ditisheim A, Burnier M, et al. Increased salt sensitivity of && ambulatory blood pressure in women with a history of severe preeclampsia. Hypertension 2013; 62:802–808. First study to demonstrate that women with a history of preeclampsia are salt sensitive before the onset of menopause. Women with a history of preeclampsia had a significant rise in ambulatory blood pressure on a high salt diet compared with controls, even though their blood pressure remained within the normal range. 37. Heidrich MB, Wenzel D, von Kaisenberg CS, et al. Preeclampsia and long&& term risk of cardiovascular disease: what do obstetrician-gynecologists know? BMC Pregnancy Childbirth 2013; 13:61. The study shows that, although obstetricians–gynecologists are aware of a higher CVD risk in women following preeclampsia, there is limited follow-up care and counseling for these women. This study was carried out in Germany and has implications for management of women after pregnancy around the world. &
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Cardiovascular disease in women Lind et al. 38. National Collaborating Centre for Women’s and Children’s Health. Hypertension in pregnancy. The management of hypertensive disorders during pregnancy. London, UK: National Institute for Health and Clinical Excellence (NICE); 2010. 39. Task Force on Hypertension in Pregnancy. Hypertension in Pregnancy. Washington, DC: The American College of Obstetricians and Gynecologists; 2013. 40. Gabbe SG, Landon MB, Warren-Boulton E, et al. Promoting health after gestational diabetes: a National Diabetes Education Program call to action. Obstet Gynecol 2012; 119:171–176. 41. Spaan J, Peeters L, Spaanderman M, et al. Cardiovascular risk management after a hypertensive disorder of pregnancy. Hypertension 2012; 60:1368– 1373.
42. Cusimano MC, Pudwell J, Roddy M, et al. The maternal health clinic: an initiative for cardiovascular risk identification in women with pregnancy-related complications. Am J Obstet Gynecol 2013; 210:438; e1–9. This article reports on data from the first maternal health clinic established in North America. This clinic may prevent CVD in women by managing their care following a pregnancy complicated with disease. 43. The Diabetes Prevention Program Research Group. The Diabetes Prevention Program: design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999; 22:623–634. 44. Philis-Tsimikas A, Fortmann AL, Dharkar-Surber S, et al. Dulce Mothers: an & intervention to reduce diabetes and cardiovascular risk in Latinas after gestational diabetes. Transl Behav Med 2014; 4:18–25. This is the first article to demonstrate the effectiveness of translating the Diabetes Prevention Program for a Spanish-speaking population to implement lifestyle changes in women following a GDM pregnancy.
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