Accepted Manuscript Preeclampsia and Future Cardiovascular Risk among Women: A Review Raheel Ahmed, Joseph Dunford, Roxana Mehran, MD Stephen Robson, MBBS, MRCOG, MD Vijay Kunadian, MBBS, MD PII:
S0735-1097(14)01154-1
DOI:
10.1016/j.jacc.2014.02.529
Reference:
JAC 19910
To appear in:
Journal of the American College of Cardiology
Received Date: 14 December 2013 Revised Date:
31 January 2014
Accepted Date: 4 February 2014
Please cite this article as: Ahmed R, Dunford J, Mehran R, Robson S, Kunadian V, Preeclampsia and Future Cardiovascular Risk among Women: A Review, Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2014.02.529. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Preeclampsia and Future Cardiovascular Risk among Women: A Review Raheel Ahmed1, Joseph Dunford1, Roxana Mehran MD2, Stephen Robson MBBS, MRCOG, MD3, 4, Vijay Kunadian MBBS, MD4, 5
Faculty of Medical Sciences, Newcastle University Medical School, UK
2
Mount Sinai School of Medicine, New York, NY, USA
3
Uterine Cell Signaling Group, Newcastle University, UK
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1
4
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Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK 5
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Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
Running title: Preeclampsia and heart disease
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Address reprint requests to: Dr. Vijay Kunadian MBBS, MD, FRCP, FACC, FESC Institute of Cellular Medicine │Faculty of Medical Sciences │Newcastle University 3rd Floor William Leech Building Newcastle upon Tyne United Kingdom NE2 4HH Tel 0044 191 2225797 Fax 0044 191 242 4290 E-mail [email protected]
Funding: None
Conflicts of Interests: None of the authors have any conflict of interest to disclose in relation to this manuscript
1
ACCEPTED MANUSCRIPT
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ABSTRACT Cardiovascular disease (CVD) continues to be the leading cause of death in the western world. Due to advancements in diagnosis, prevention and treatment, cardiovascular mortality has fallen in recent years. Previous studies have evaluated the impact of traditional risk factors such as hypercholesterolemia and smoking. However, limited studies have been conducted to evaluate gender discrepancies among patients with cardiovascular disease. Preeclampsia is a multisystem placentally-mediated disease, which usually arises after 32 weeks of gestation and classically presents with hypertension and proteinuria. Preeclampsia affects 3-5% of all pregnancies worldwide and is often complicated by fetal growth restriction. Women with a history of preeclampsia are at increased risk of future cardiovascular complications. Therefore, this topic is of significance to the cardiovascular health of over 300 million women worldwide. The goal of this review is to determine the association of preeclampsia and future cardiovascular risk and to explore the potential management options for these high-risk women.
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KEYWORDS: Preeclampsia, coronary artery disease, myocardial infarction, angina, acute coronary syndrome, hypertension, endothelium, vascular function
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ACCEPTED MANUSCRIPT INTRODUCTION Preeclampsia is a multisystem placentally-mediated disease, which usually occurs after 32 weeks of gestation, with distinctive features of hypertension and proteinuria. Preeclampsia affects 2-8% of all pregnancies(1). Therefore, this topic is of significance to the
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cardiovascular health of over 300 million women worldwide(2). The goal of this review is to determine the association of preeclampsia and future cardiovascular risk and to explore the potential management options for these high-risk women.
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Burden of Cardiovascular Disease in Women Overview
In the USA, coronary artery disease (CAD- including Angina pectoris or myocardial
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infarction [MI]) affects 6.1% of all women over 20 years of age, and 20.8% of women over 75 years of age. From a wider perspective, CVD (including CAD, stroke and other manifestations) is the leading cause of death among women, accounting for 51.7% of all deaths, equating to 419,730 deaths in 2008. Hypertension (defined as either a systolic blood
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pressure of greater than 140mmHg, diastolic blood pressure greater than 90mmHg, or receiving or having been advised of the need for antihypertensive medication) affects 32.7% of women of all ages, with prevalence increasing throughout life, from 6.8% among women
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aged 20-34 years up to 78.5% of women aged over 75 years(3).
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Hypertension in Pregnancy and Preeclampsia Hypertension is the most common medical complication of pregnancy, and can occur as gestational hypertension, preeclampsia, chronic hypertension or preeclampsia superimposed upon chronic hypertension(4). Hypertension is defined as a systolic blood pressure over 140mmHg or diastolic blood pressure above 90mmHg. In chronic hypertension, this abnormality is present before and following pregnancy, whereas in gestational hypertension blood pressure elevation is only present during pregnancy.
3
ACCEPTED MANUSCRIPT Preeclampsia usually occurs after 20 weeks of gestation and resolves by 3 months post-partum, and is clinically diagnosed based on symptoms of preeclampsia, present concurrently with gestational hypertension. Preeclampsia is a multisystem disorder that may involve renal dysfunction (proteinuria more than 300mg/24 hours, creatinine of more than
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90µmol/l or glomeruloendotheliosis), hematological dysfunction (hemolysis, disseminated intravascular coagulation, thrombocytopenia), hepatic dysfunction (raised transaminases with or without right hypochondrium pain) and neurological dysfunction (hyperreflexia, visual
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disturbances and headache). Several different diagnostic definitions of preeclampsia exist, however the diagnosis is ultimately made based upon the presence of the aforementioned
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criteria. Differences in definitions used between organizations and countries can lead to variations in management strategy amongst these patients, and heterogeneity between various studies evaluating preeclampsia, but utilizing different definitions(4). Preeclampsia can lead on to more severe conditions such as eclampsia, HELLP syndrome (hemolysis, elevated liver
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enzymes and low platelets), pulmonary oedema, renal failure, disseminated intravascular coagulation, placental abruption and fetal growth restriction(5). Pathophysiology of Preeclampsia
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The pathological hallmark of preeclampsia is a failure in the vascular remodeling of
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the maternal spiral arteries, resulting in hypo-perfusion of the placenta. This results in the release of various factors, such as inflammatory cytokines and anti-angiogenic proteins (e.g. soluble Vascular Endothelial Growth Factor [VEGFR]-1, soluble endoglin)(6,7), which cause systemic endothelial dysfunction, creating an imbalance in the secretion of endothelin and thromboxane leading to vasoconstriction. This increases lumen pressure, resulting in systemic hypertension. Moreover, reduced perfusion to different organ systems gives rise to the classical symptoms and signs of preeclampsia- hypertension, proteinuria, oedema, headache, scotomata, reduced glomerular filtration rate and fetal growth restriction (4,8).
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ACCEPTED MANUSCRIPT Increased Cardiovascular Risk Factors Following Preeclampsia Following a pregnancy complicated by preeclampsia, the prevalence of cardiovascular risk factors further increases. It has been demonstrated that early onset preeclampsia leads to an increased risk of developing metabolic syndrome in later life compared to late onset
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preeclampsia(9). The Cardiovascular Health After Maternal Placental Syndromes
(CHAMPS) study demonstrated a 12-fold increased risk of CVD with a history of
preeclampsia and metabolic syndrome compared to women with neither (Hazard Ratio [HR]
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11·7; 95% confidence interval [CI] 4·9-28·3)(10). It is thus clear that metabolic syndrome, preeclampsia and future CVD are related, but a direct causative relationship has not yet been
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determined(11,12).
The Association of Preeclampsia and Future CV Risk
Several trials have demonstrated that patients with preeclampsia are at greater risk of developing CVD in later life. Data from studies is displayed in Table 1. The CHAMPS study
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cohort included 1.03 million women, none of whom had CVD before their first pregnancy. It was observed that CVD (defined as hospital admission or revascularisation for coronary artery, cerebrovascular, or peripheral artery disease at least 90 days after the delivery
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discharge date) was twice as common (HR 2.0; 95% CI 1.7-2.2) in women who had a
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placentally-mediated condition in pregnancy (gestational hypertension, preeclampsia, placental abruption or infarction). A Taiwanese Population based cohort study demonstrated an increased risk of major CV events (myocardial infarction [MI], cardiac shock, malignant dysrhythmia, cerebrovascular accident, or any other condition requiring percutaneous cardiac intervention, coronary artery bypass, an implantable cardiac defibrillator or thrombolysis) within 3 years of a preeclamptic pregnancy (HR 12.6; 95% CI 2.4-66.3)(13). Another study demonstrated increased rates of cardiovascular events (hospitalizations for acute MI, acute stroke or undergoing a coronary artery revascularisation procedure) amongst women with a
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ACCEPTED MANUSCRIPT history of preeclampsia (HR 2.2; 95% CI 1.3-3.6) and increased thromboembolic events amongst women with previous severe preeclampsia (HR 2.3; 95% CI 1.3-4.2) during a mean follow-up of 7.8 years(14). Other studies have followed these women long term to determine future risk of CVD
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and demonstrated increased rates of hospitalisation and death from ischemic heart disease (IHD) and MI (Risk Ratio 2.24; 95% CI 1.42-3.53 (15) and 2.0; 95% CI 1.5-2.5 (16)
respectively) during 15-19 years of follow-up. The Rochester Family Heart Study, with a
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mean follow up of 27 years, demonstrated that the coronary artery calcium score was higher among those with a history of preeclampsia (Odds Ratio [OR] 2.4; 95% CI 1.2-4.9) after
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adjustment for age, blood pressure and body mass index(17). Moreover, a population based cohort study in Norway demonstrated that following preeclampsia and preterm delivery, with a 25 year follow-up, there was elevated maternal death due to CVD defined as IHD, disease of the pulmonary circulation or disease affecting the heart (HR 8.12; 95% CI 4.31-15.33)(18).
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A Californian study, with a median follow up of 37 years, demonstrated increased CVD related death following preeclampsia (HR 2.14; 95% CI: 1.29-3.57) with a further significant
20.26)(19).
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increase in risk if preeclampsia occurred before 34 weeks gestation (HR 9.54; 95% CI: 4.5-
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A previous systematic review and meta-analysis demonstrated increased cardiovascular mortality (due to IHD, CAD, MI or congestive heart failure) with a history of preeclampsia (OR 2.29; 95% CI: 1.73-3.04)(20). Recently, a large meta-analysis of 43 studies demonstrated that women with a history of preeclampsia or eclampsia had an increased risk of CVD (leading to either a clinical diagnosis or a fatal outcome) (HR 2.28; 95 % CI: 1.872.78), cerebrovascular disease (HR 1.76; 95 % CI 1.43-2.21) and of developing hypertension (HR 3.13; 95 % CI 2.51-3.89) (21). Varying risk rates reported by different studies may be due to the fact that studies were conducted in different patient populations with different risk
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ACCEPTED MANUSCRIPT profiles, and at different time periods. Nevertheless, the risk of future cardiovascular events following a preeclamptic event remains consistently high across all studies. The Association of Preeclampsia and Future Risk of Chronic Hypertension Several studies have demonstrated the association of preeclampsia with future
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development of chronic hypertension. A prospective cohort study of 815 women, with an average 10 years follow up, observed that hypertension in later life was more common in those primigravid women who had preeclampsia or eclampsia than in the control group of
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women who were normotensive during pregnancy (Relative Risk 2.63; 95% CI 1.66-
4.17)(22). Additionally, recurrent preeclampsia or preeclampsia developing before 30 weeks
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of gestation has been observed to further augment the risk of future hypertension(23). A Danish registry based cohort, which followed up women with severe preeclampsia for a median follow up of 14.6 years after the affected pregnancy, observed an increased risk of developing hypertension (HR 6.73; 95% CI 6.04-7.49)(24). Similarly, the medical birth
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registry of Norway and Nord-Trondelag Health Study demonstrated an increase in the need for medication to manage hypertension (after a mean follow up of 16.5 years) in those with history of preeclampsia (OR 3.1; 95% CI 2.2-4.3)(25). Analysis of patient data from phase 2
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of the Family Blood Pressure Programme Study demonstrated an increased risk of suffering
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from chronic hypertension after the age of 40 for women who suffered from hypertension during pregnancy compared to those who remained normotensive during pregnancy (HR 1.88; 95% CI: 1.49-2.39)(26). The PREVFEM (Preeclampsia Risk EValuation in FEMales) study evaluated the prevalence of various cardiovascular risk factors in women with a history of early onset preeclampsia with a 10 year follow up, and observed that amongst these women there was an increased risk of hypertension (adjusted HR 3.59; 95% CI 2.48-5.20), and also a higher
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ACCEPTED MANUSCRIPT prevalence of obesity (26.8% vs. 20.2%, p=0.04) along with an increased waist circumference (86.5cm vs. 83.2cm, p=0.001) compared to the control group(27). A recent systematic review and meta-analysis demonstrated that 1885 out of 3658 (52%) of women with a history of preeclampsia had hypertension after an average follow up
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of 14.1 years (Relative Risk [RR] 3.70; 95% CI 2.70-5.05)(28). Lykke et al (24) sub-
classified preeclampsia into mild (hypertension and proteinuria) and severe (as with mild but with the addition of signs of HELLP syndrome). They demonstrated that the risk of chronic
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hypertension was greatest with severe preeclampsia (Relative Risk 6.07, as compared to 3.61 for mild preeclampsia, following adjustment for subsequent development of type 2 diabetes).
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The Association of Preeclampsia and Arterial Stiffness
Arterial stiffness can be determined by using ultrasound to calculate the pulse-wave velocity (PWV). Women with elevated PWVs have been observed to be at an increased risk of developing preeclampsia(29,30). Meta-analysis has demonstrated that increase in PWV
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(and thus increased vascular stiffness) is an important feature of preeclampsia(31). In a study that assessed women with a history of preeclampsia, at a mean of 16 months after delivery, a trend towards increased heart to brachial PWV was observed, with more central measures of
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PWV (heart to femoral and heart to carotid) not being significantly elevated; this suggests
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that there may be persistent vascular stiffness affecting mainly the smaller arteries following a preeclamptic pregnancy(32). This is supported by a study by Yinon et al, who also observed, through calculation of the radial augmentation index (a measure of arterial stiffness derived similarly to PWV), that women with a history of early onset preeclampsia, who at the time of the study were 6-24 months postpartum, had increased arterial stiffness (p=0.0105). Amongst women with late onset preeclampsia, the trend towards increased arterial stiffness was not statistically significant (p=0.08)(33).
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ACCEPTED MANUSCRIPT Pulse wave reflection, a measurement of arterial stiffness related to endothelial dysfunction, has also been observed to be elevated during preeclampsia, however amongst non-pregnant normotensive women with a previous history of preeclampsia who were also included in the study a similar increase was not noted(34). Another technique, velocity vector
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imaging, has also been used to demonstrate increased arterial stiffness in preeclamptic women(35); however it has not yet been used to evaluate arterial stiffness following preeclampsia.
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The Association of Preeclampsia and Gestational Hyperlipidaemia or Insulin Resistance Normal gestational hyperlipidaemia is known to involve approximately a 3-fold
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increase in triglyceride levels and 50% increase in total cholesterol, mainly low LDL and phospholipids, which typically return to normal levels by 6 to 10 weeks postpartum. In a study by Hubel and colleagues consisting of gestationally matched preeclamptic and normal pregnant women, the LDL-cholesterol:apo B ratio was decreased and triglyceride
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concentrations were increased in patients with preeclampsia. Serum soluble vascular cell adhesion molecule-1 (VCAM-1), concentrations were markedly increased in preeclampsia. Apo B, free fatty acids, total cholesterol, and LDL-cholesterol were also increased. This
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study concluded that the predominance of smaller, denser LDL, a potential contributor to
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endothelial cell dysfunction, is a feature of preeclampsia(36). These findings are also supported by those from a similar study conducted by Sattar et al(37). Abnormal lipid parameters might be a contributor to future cardiovascular risk in these women. In normal pregnancy, insulin sensitivity is decreased to allow better transfer of glucose to the fetus. However, in preeclampsia insulin resistance is exaggerated for up to three months postpartum. The risk of developing diabetes mellitus after a preeclamptic pregnancy has been observed to increase almost two-fold(38,39).
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ACCEPTED MANUSCRIPT The Association of Preeclampsia and Peripheral Vascular Disease (PVD) or Stroke There have been fewer studies examining the relationship between preeclampsia and subsequent risk of PVD or stroke. Initially, a report from the World Health Organization identified gestational hypertension as a risk factor for thromboembolic disease only in those
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women who were taking the oral contraceptive pill(40). The Stroke Prevention in Young Women Study suggested preeclampsia as a risk factor for stroke. This study observed that, as compared to normotensive pregnancies, women with history of preeclampsia had an
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increased risk for death from stroke (adjusted RR 3.59; 95% CI 1.04-12.4)(41,42). Similarly, the increased risk for stroke in women who reported hypertension in pregnancy remained
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significantly elevated, even after controlling for traditional risk factors in the Family Blood Pressure Programme study (HR 2.10; 95% CI 1.19-3.71)(43) and in the previously discussed Taiwanese population based cohort study (HR 14.5; 95% CI 1.3-165.1) with up to 6.8 years of follow-up(13).
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Risk of CVD in Children Born to Preeclamptic Women
Importantly, it has also been observed that preeclampsia has implications for the child’s cardiovascular health following birth that persist throughout life. Several studies, and
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meta-analysis thereof, have observed that blood pressure amongst such children is elevated
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by, on average, 2.39 mmHg systolic and 1.35mmHg diastolic, with most participants in these studies being under 20 years of age (range 4-30 years)(2). A further study demonstrated elevated pulmonary artery pressure (by approximately 30%) and reduced flow mediated dilation (again by 30%) amongst children aged 13 (±7 years) born after preeclamptic pregnancies(44). However, this study was conducted in a population living at high altitude (3600m above sea level) and so may not be entirely representative of more typical patient groups.
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ACCEPTED MANUSCRIPT In later life, the Helsinki Birth Cohort Study observed that children born following preeclamptic pregnancies had almost double the risk of stroke over its 75 years of observation (HR 1.9; 95% CI 1.2-3.0, p=0.01)(45). It is hypothesized that fetal metabolic adaptations may
Managing CVD Risk amongst Previously Preeclamptic Women
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manifest as CVD in later life(46).
Given the elevated risk of CVD following preeclampsia, the key question is whether interventions to reduce the risks are appropriate. Current systems for formally scoring
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cardiovascular risk, such as QRISK(47), do not take preeclampsia into account as an
independent risk factor. However, due to associated risks, such as increased prevalence of
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metabolic syndrome and/or its constituent features, women with prior preeclampsia have been observed to have elevated risk scores using systems such as the Framingham risk score, the SCORE score and the Reynolds risk score(48,49). Therefore, calculation of 10 year risk of CVD during post-partum follow up could provide a valuable opportunity to identify
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women at greatest risk of future CVD, and for whom intervention is likely to be most beneficial.
In their 2011 guidelines for the prevention of cardiovascular disease in women(50),
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the AHA considers a previous history of preeclampsia or gestational diabetes to be a “major
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risk factor” as part of its system of risk assessment, alongside conditions such as hypertension and hypercholesterolemia, and other features such as smoking, physical inactivity, obesity or family history. Presence of one, or more, of these factors fulfils the guidelines criteria for being “at risk” of CVD, with a 5.5% annual risk of MI, stroke or death due to cardiovascular causes. This compares to a 19% risk amongst patients in “high risk states” (with established CVD, a ≥10% CVD risk [determined by risk score], diabetes or renal failure) and a 2.2% annual risk amongst women in the absence of these risk factors. The most suitable treatment to prevent future CVD therefore varies according to risk category, and women with previous
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ACCEPTED MANUSCRIPT preeclampsia are at least “at risk” of CVD. This risk is potentially compounded by additional comorbidities and risk factors; however, only the presence of features of one or more “high risk states” is sufficient to increase the risk classification based on these guidelines. There is little evidence to guide risk stratification amongst women with prior preeclampsia, and it is
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therefore left largely to clinician discretion.
The National Institute of Clinical Excellence (NICE) guidelines in the United
Kingdom recommend that a post-natal review of the woman’s health be conducted at 6-8
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weeks following a preeclamptic pregnancy(51). This provides an excellent opportunity for cardiovascular risk assessment amongst these women, and a chance to consider the early
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implementation of interventional measures. At this time, women should be advised of the implications preeclampsia has for future pregnancies, and it is also be appropriate to educate them regarding the increased CVD risk that they face. When assessing cardiovascular risk amongst these women, transient features of preeclampsia (such as hypertension or renal
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dysfunction) may still persist and have not yet resolved(52). Risk scores should be calculated to account for traditional risk factors, and we would suggest that at this time women with an estimated annual risk above 5% (in line with the AHAs “at risk” group) should be followed
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up at 6-12 months postpartum, in order to reassess risk. In the meantime, lifestyle
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modification measures can be implemented to facilitate the resolution of the preeclamptic pathology and improve cardiovascular health, and during follow up other treatment options can be considered.
Pharmacological and Life Style Management of Previously Preeclamptic Women Amongst women whose blood pressure exceeds 140/90mmHg (130/80mmHg in patients with co-morbid chronic kidney disease or diabetes mellitus) pharmacological measures are appropriate (class 1, level A)(50). In the presence of cardiovascular risk factors and a high annual CVD risk (>20%), moderate risk (10-20%) or lower risk (3 years
Females Study- case control study 26
ACCEPTED MANUSCRIPT assessing CV risk factors Brown et al.
Systematic review
2013
and meta-analysis:
NA
NA
Cardiovascular
2.28 (1.87-2.78)
disease
1.76 (1.43-2.21)
Stroke
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3.13 (2.51-3.89)
43 studies
Hypertension
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NA- not available, IHD- Ischemic heart disease, CV- Cardiovascular, MI-myocardial
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infarction
27
ACCEPTED MANUSCRIPT
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ABBREVIATIONS ACE Angiotensin Converting Enzyme AHA American Heart Association CAD Coronary Artery Disease CHAMPS Cardiovascular Health After Maternal Placentation Syndrome study COMT Catechol-O-Methyl Transferase CRP C-Reactive Protein CVD Cardiovascular Disease EPC Endothelial Progenitor Cell HELLP Haemolysis, Elevated Liver enzymes, Low Platelets IHD Ischaemic Heart Disease LDL Low Density Lipoprotein NICE National Institute for Clinical Excellence PAPP-A Pregnancy Associated Plasma Protein A PFA-100 Platelet Function Analyser PlGF Placental Growth Factor PREDIMED Prevención con Dieta Mediterránea PREVFEM Preeclampsia Risk EValuation in FEMales PWV Pulse Wave Velocity Sflt1 Soluble form of the type 1 VEGF receptor STARTS Strategies To Avoid Returning To Smoking UAD Uterine Artery Doppler VCAM-1 Vascular Cell Adhesion Molecule 1 VEGF Vascular Endothelial Growth Factor 2-ME 2-Methoxy Estradiol
S0735-1097(14)01154-1
DOI:
10.1016/j.jacc.2014.02.529
Reference:
JAC 19910
To appear in:
Journal of the American College of Cardiology
Received Date: 14 December 2013 Revised Date:
31 January 2014
Accepted Date: 4 February 2014
Please cite this article as: Ahmed R, Dunford J, Mehran R, Robson S, Kunadian V, Preeclampsia and Future Cardiovascular Risk among Women: A Review, Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2014.02.529. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Preeclampsia and Future Cardiovascular Risk among Women: A Review Raheel Ahmed1, Joseph Dunford1, Roxana Mehran MD2, Stephen Robson MBBS, MRCOG, MD3, 4, Vijay Kunadian MBBS, MD4, 5
Faculty of Medical Sciences, Newcastle University Medical School, UK
2
Mount Sinai School of Medicine, New York, NY, USA
3
Uterine Cell Signaling Group, Newcastle University, UK
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1
4
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Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK 5
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Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
Running title: Preeclampsia and heart disease
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Address reprint requests to: Dr. Vijay Kunadian MBBS, MD, FRCP, FACC, FESC Institute of Cellular Medicine │Faculty of Medical Sciences │Newcastle University 3rd Floor William Leech Building Newcastle upon Tyne United Kingdom NE2 4HH Tel 0044 191 2225797 Fax 0044 191 242 4290 E-mail [email protected]
Funding: None
Conflicts of Interests: None of the authors have any conflict of interest to disclose in relation to this manuscript
1
ACCEPTED MANUSCRIPT
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ABSTRACT Cardiovascular disease (CVD) continues to be the leading cause of death in the western world. Due to advancements in diagnosis, prevention and treatment, cardiovascular mortality has fallen in recent years. Previous studies have evaluated the impact of traditional risk factors such as hypercholesterolemia and smoking. However, limited studies have been conducted to evaluate gender discrepancies among patients with cardiovascular disease. Preeclampsia is a multisystem placentally-mediated disease, which usually arises after 32 weeks of gestation and classically presents with hypertension and proteinuria. Preeclampsia affects 3-5% of all pregnancies worldwide and is often complicated by fetal growth restriction. Women with a history of preeclampsia are at increased risk of future cardiovascular complications. Therefore, this topic is of significance to the cardiovascular health of over 300 million women worldwide. The goal of this review is to determine the association of preeclampsia and future cardiovascular risk and to explore the potential management options for these high-risk women.
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KEYWORDS: Preeclampsia, coronary artery disease, myocardial infarction, angina, acute coronary syndrome, hypertension, endothelium, vascular function
2
ACCEPTED MANUSCRIPT INTRODUCTION Preeclampsia is a multisystem placentally-mediated disease, which usually occurs after 32 weeks of gestation, with distinctive features of hypertension and proteinuria. Preeclampsia affects 2-8% of all pregnancies(1). Therefore, this topic is of significance to the
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cardiovascular health of over 300 million women worldwide(2). The goal of this review is to determine the association of preeclampsia and future cardiovascular risk and to explore the potential management options for these high-risk women.
SC
Burden of Cardiovascular Disease in Women Overview
In the USA, coronary artery disease (CAD- including Angina pectoris or myocardial
M AN U
infarction [MI]) affects 6.1% of all women over 20 years of age, and 20.8% of women over 75 years of age. From a wider perspective, CVD (including CAD, stroke and other manifestations) is the leading cause of death among women, accounting for 51.7% of all deaths, equating to 419,730 deaths in 2008. Hypertension (defined as either a systolic blood
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pressure of greater than 140mmHg, diastolic blood pressure greater than 90mmHg, or receiving or having been advised of the need for antihypertensive medication) affects 32.7% of women of all ages, with prevalence increasing throughout life, from 6.8% among women
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aged 20-34 years up to 78.5% of women aged over 75 years(3).
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Hypertension in Pregnancy and Preeclampsia Hypertension is the most common medical complication of pregnancy, and can occur as gestational hypertension, preeclampsia, chronic hypertension or preeclampsia superimposed upon chronic hypertension(4). Hypertension is defined as a systolic blood pressure over 140mmHg or diastolic blood pressure above 90mmHg. In chronic hypertension, this abnormality is present before and following pregnancy, whereas in gestational hypertension blood pressure elevation is only present during pregnancy.
3
ACCEPTED MANUSCRIPT Preeclampsia usually occurs after 20 weeks of gestation and resolves by 3 months post-partum, and is clinically diagnosed based on symptoms of preeclampsia, present concurrently with gestational hypertension. Preeclampsia is a multisystem disorder that may involve renal dysfunction (proteinuria more than 300mg/24 hours, creatinine of more than
RI PT
90µmol/l or glomeruloendotheliosis), hematological dysfunction (hemolysis, disseminated intravascular coagulation, thrombocytopenia), hepatic dysfunction (raised transaminases with or without right hypochondrium pain) and neurological dysfunction (hyperreflexia, visual
SC
disturbances and headache). Several different diagnostic definitions of preeclampsia exist, however the diagnosis is ultimately made based upon the presence of the aforementioned
M AN U
criteria. Differences in definitions used between organizations and countries can lead to variations in management strategy amongst these patients, and heterogeneity between various studies evaluating preeclampsia, but utilizing different definitions(4). Preeclampsia can lead on to more severe conditions such as eclampsia, HELLP syndrome (hemolysis, elevated liver
TE D
enzymes and low platelets), pulmonary oedema, renal failure, disseminated intravascular coagulation, placental abruption and fetal growth restriction(5). Pathophysiology of Preeclampsia
EP
The pathological hallmark of preeclampsia is a failure in the vascular remodeling of
AC C
the maternal spiral arteries, resulting in hypo-perfusion of the placenta. This results in the release of various factors, such as inflammatory cytokines and anti-angiogenic proteins (e.g. soluble Vascular Endothelial Growth Factor [VEGFR]-1, soluble endoglin)(6,7), which cause systemic endothelial dysfunction, creating an imbalance in the secretion of endothelin and thromboxane leading to vasoconstriction. This increases lumen pressure, resulting in systemic hypertension. Moreover, reduced perfusion to different organ systems gives rise to the classical symptoms and signs of preeclampsia- hypertension, proteinuria, oedema, headache, scotomata, reduced glomerular filtration rate and fetal growth restriction (4,8).
4
ACCEPTED MANUSCRIPT Increased Cardiovascular Risk Factors Following Preeclampsia Following a pregnancy complicated by preeclampsia, the prevalence of cardiovascular risk factors further increases. It has been demonstrated that early onset preeclampsia leads to an increased risk of developing metabolic syndrome in later life compared to late onset
RI PT
preeclampsia(9). The Cardiovascular Health After Maternal Placental Syndromes
(CHAMPS) study demonstrated a 12-fold increased risk of CVD with a history of
preeclampsia and metabolic syndrome compared to women with neither (Hazard Ratio [HR]
SC
11·7; 95% confidence interval [CI] 4·9-28·3)(10). It is thus clear that metabolic syndrome, preeclampsia and future CVD are related, but a direct causative relationship has not yet been
M AN U
determined(11,12).
The Association of Preeclampsia and Future CV Risk
Several trials have demonstrated that patients with preeclampsia are at greater risk of developing CVD in later life. Data from studies is displayed in Table 1. The CHAMPS study
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cohort included 1.03 million women, none of whom had CVD before their first pregnancy. It was observed that CVD (defined as hospital admission or revascularisation for coronary artery, cerebrovascular, or peripheral artery disease at least 90 days after the delivery
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discharge date) was twice as common (HR 2.0; 95% CI 1.7-2.2) in women who had a
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placentally-mediated condition in pregnancy (gestational hypertension, preeclampsia, placental abruption or infarction). A Taiwanese Population based cohort study demonstrated an increased risk of major CV events (myocardial infarction [MI], cardiac shock, malignant dysrhythmia, cerebrovascular accident, or any other condition requiring percutaneous cardiac intervention, coronary artery bypass, an implantable cardiac defibrillator or thrombolysis) within 3 years of a preeclamptic pregnancy (HR 12.6; 95% CI 2.4-66.3)(13). Another study demonstrated increased rates of cardiovascular events (hospitalizations for acute MI, acute stroke or undergoing a coronary artery revascularisation procedure) amongst women with a
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ACCEPTED MANUSCRIPT history of preeclampsia (HR 2.2; 95% CI 1.3-3.6) and increased thromboembolic events amongst women with previous severe preeclampsia (HR 2.3; 95% CI 1.3-4.2) during a mean follow-up of 7.8 years(14). Other studies have followed these women long term to determine future risk of CVD
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and demonstrated increased rates of hospitalisation and death from ischemic heart disease (IHD) and MI (Risk Ratio 2.24; 95% CI 1.42-3.53 (15) and 2.0; 95% CI 1.5-2.5 (16)
respectively) during 15-19 years of follow-up. The Rochester Family Heart Study, with a
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mean follow up of 27 years, demonstrated that the coronary artery calcium score was higher among those with a history of preeclampsia (Odds Ratio [OR] 2.4; 95% CI 1.2-4.9) after
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adjustment for age, blood pressure and body mass index(17). Moreover, a population based cohort study in Norway demonstrated that following preeclampsia and preterm delivery, with a 25 year follow-up, there was elevated maternal death due to CVD defined as IHD, disease of the pulmonary circulation or disease affecting the heart (HR 8.12; 95% CI 4.31-15.33)(18).
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A Californian study, with a median follow up of 37 years, demonstrated increased CVD related death following preeclampsia (HR 2.14; 95% CI: 1.29-3.57) with a further significant
20.26)(19).
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increase in risk if preeclampsia occurred before 34 weeks gestation (HR 9.54; 95% CI: 4.5-
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A previous systematic review and meta-analysis demonstrated increased cardiovascular mortality (due to IHD, CAD, MI or congestive heart failure) with a history of preeclampsia (OR 2.29; 95% CI: 1.73-3.04)(20). Recently, a large meta-analysis of 43 studies demonstrated that women with a history of preeclampsia or eclampsia had an increased risk of CVD (leading to either a clinical diagnosis or a fatal outcome) (HR 2.28; 95 % CI: 1.872.78), cerebrovascular disease (HR 1.76; 95 % CI 1.43-2.21) and of developing hypertension (HR 3.13; 95 % CI 2.51-3.89) (21). Varying risk rates reported by different studies may be due to the fact that studies were conducted in different patient populations with different risk
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ACCEPTED MANUSCRIPT profiles, and at different time periods. Nevertheless, the risk of future cardiovascular events following a preeclamptic event remains consistently high across all studies. The Association of Preeclampsia and Future Risk of Chronic Hypertension Several studies have demonstrated the association of preeclampsia with future
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development of chronic hypertension. A prospective cohort study of 815 women, with an average 10 years follow up, observed that hypertension in later life was more common in those primigravid women who had preeclampsia or eclampsia than in the control group of
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women who were normotensive during pregnancy (Relative Risk 2.63; 95% CI 1.66-
4.17)(22). Additionally, recurrent preeclampsia or preeclampsia developing before 30 weeks
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of gestation has been observed to further augment the risk of future hypertension(23). A Danish registry based cohort, which followed up women with severe preeclampsia for a median follow up of 14.6 years after the affected pregnancy, observed an increased risk of developing hypertension (HR 6.73; 95% CI 6.04-7.49)(24). Similarly, the medical birth
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registry of Norway and Nord-Trondelag Health Study demonstrated an increase in the need for medication to manage hypertension (after a mean follow up of 16.5 years) in those with history of preeclampsia (OR 3.1; 95% CI 2.2-4.3)(25). Analysis of patient data from phase 2
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of the Family Blood Pressure Programme Study demonstrated an increased risk of suffering
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from chronic hypertension after the age of 40 for women who suffered from hypertension during pregnancy compared to those who remained normotensive during pregnancy (HR 1.88; 95% CI: 1.49-2.39)(26). The PREVFEM (Preeclampsia Risk EValuation in FEMales) study evaluated the prevalence of various cardiovascular risk factors in women with a history of early onset preeclampsia with a 10 year follow up, and observed that amongst these women there was an increased risk of hypertension (adjusted HR 3.59; 95% CI 2.48-5.20), and also a higher
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ACCEPTED MANUSCRIPT prevalence of obesity (26.8% vs. 20.2%, p=0.04) along with an increased waist circumference (86.5cm vs. 83.2cm, p=0.001) compared to the control group(27). A recent systematic review and meta-analysis demonstrated that 1885 out of 3658 (52%) of women with a history of preeclampsia had hypertension after an average follow up
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of 14.1 years (Relative Risk [RR] 3.70; 95% CI 2.70-5.05)(28). Lykke et al (24) sub-
classified preeclampsia into mild (hypertension and proteinuria) and severe (as with mild but with the addition of signs of HELLP syndrome). They demonstrated that the risk of chronic
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hypertension was greatest with severe preeclampsia (Relative Risk 6.07, as compared to 3.61 for mild preeclampsia, following adjustment for subsequent development of type 2 diabetes).
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The Association of Preeclampsia and Arterial Stiffness
Arterial stiffness can be determined by using ultrasound to calculate the pulse-wave velocity (PWV). Women with elevated PWVs have been observed to be at an increased risk of developing preeclampsia(29,30). Meta-analysis has demonstrated that increase in PWV
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(and thus increased vascular stiffness) is an important feature of preeclampsia(31). In a study that assessed women with a history of preeclampsia, at a mean of 16 months after delivery, a trend towards increased heart to brachial PWV was observed, with more central measures of
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PWV (heart to femoral and heart to carotid) not being significantly elevated; this suggests
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that there may be persistent vascular stiffness affecting mainly the smaller arteries following a preeclamptic pregnancy(32). This is supported by a study by Yinon et al, who also observed, through calculation of the radial augmentation index (a measure of arterial stiffness derived similarly to PWV), that women with a history of early onset preeclampsia, who at the time of the study were 6-24 months postpartum, had increased arterial stiffness (p=0.0105). Amongst women with late onset preeclampsia, the trend towards increased arterial stiffness was not statistically significant (p=0.08)(33).
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ACCEPTED MANUSCRIPT Pulse wave reflection, a measurement of arterial stiffness related to endothelial dysfunction, has also been observed to be elevated during preeclampsia, however amongst non-pregnant normotensive women with a previous history of preeclampsia who were also included in the study a similar increase was not noted(34). Another technique, velocity vector
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imaging, has also been used to demonstrate increased arterial stiffness in preeclamptic women(35); however it has not yet been used to evaluate arterial stiffness following preeclampsia.
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The Association of Preeclampsia and Gestational Hyperlipidaemia or Insulin Resistance Normal gestational hyperlipidaemia is known to involve approximately a 3-fold
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increase in triglyceride levels and 50% increase in total cholesterol, mainly low LDL and phospholipids, which typically return to normal levels by 6 to 10 weeks postpartum. In a study by Hubel and colleagues consisting of gestationally matched preeclamptic and normal pregnant women, the LDL-cholesterol:apo B ratio was decreased and triglyceride
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concentrations were increased in patients with preeclampsia. Serum soluble vascular cell adhesion molecule-1 (VCAM-1), concentrations were markedly increased in preeclampsia. Apo B, free fatty acids, total cholesterol, and LDL-cholesterol were also increased. This
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study concluded that the predominance of smaller, denser LDL, a potential contributor to
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endothelial cell dysfunction, is a feature of preeclampsia(36). These findings are also supported by those from a similar study conducted by Sattar et al(37). Abnormal lipid parameters might be a contributor to future cardiovascular risk in these women. In normal pregnancy, insulin sensitivity is decreased to allow better transfer of glucose to the fetus. However, in preeclampsia insulin resistance is exaggerated for up to three months postpartum. The risk of developing diabetes mellitus after a preeclamptic pregnancy has been observed to increase almost two-fold(38,39).
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ACCEPTED MANUSCRIPT The Association of Preeclampsia and Peripheral Vascular Disease (PVD) or Stroke There have been fewer studies examining the relationship between preeclampsia and subsequent risk of PVD or stroke. Initially, a report from the World Health Organization identified gestational hypertension as a risk factor for thromboembolic disease only in those
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women who were taking the oral contraceptive pill(40). The Stroke Prevention in Young Women Study suggested preeclampsia as a risk factor for stroke. This study observed that, as compared to normotensive pregnancies, women with history of preeclampsia had an
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increased risk for death from stroke (adjusted RR 3.59; 95% CI 1.04-12.4)(41,42). Similarly, the increased risk for stroke in women who reported hypertension in pregnancy remained
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significantly elevated, even after controlling for traditional risk factors in the Family Blood Pressure Programme study (HR 2.10; 95% CI 1.19-3.71)(43) and in the previously discussed Taiwanese population based cohort study (HR 14.5; 95% CI 1.3-165.1) with up to 6.8 years of follow-up(13).
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Risk of CVD in Children Born to Preeclamptic Women
Importantly, it has also been observed that preeclampsia has implications for the child’s cardiovascular health following birth that persist throughout life. Several studies, and
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meta-analysis thereof, have observed that blood pressure amongst such children is elevated
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by, on average, 2.39 mmHg systolic and 1.35mmHg diastolic, with most participants in these studies being under 20 years of age (range 4-30 years)(2). A further study demonstrated elevated pulmonary artery pressure (by approximately 30%) and reduced flow mediated dilation (again by 30%) amongst children aged 13 (±7 years) born after preeclamptic pregnancies(44). However, this study was conducted in a population living at high altitude (3600m above sea level) and so may not be entirely representative of more typical patient groups.
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ACCEPTED MANUSCRIPT In later life, the Helsinki Birth Cohort Study observed that children born following preeclamptic pregnancies had almost double the risk of stroke over its 75 years of observation (HR 1.9; 95% CI 1.2-3.0, p=0.01)(45). It is hypothesized that fetal metabolic adaptations may
Managing CVD Risk amongst Previously Preeclamptic Women
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manifest as CVD in later life(46).
Given the elevated risk of CVD following preeclampsia, the key question is whether interventions to reduce the risks are appropriate. Current systems for formally scoring
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cardiovascular risk, such as QRISK(47), do not take preeclampsia into account as an
independent risk factor. However, due to associated risks, such as increased prevalence of
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metabolic syndrome and/or its constituent features, women with prior preeclampsia have been observed to have elevated risk scores using systems such as the Framingham risk score, the SCORE score and the Reynolds risk score(48,49). Therefore, calculation of 10 year risk of CVD during post-partum follow up could provide a valuable opportunity to identify
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women at greatest risk of future CVD, and for whom intervention is likely to be most beneficial.
In their 2011 guidelines for the prevention of cardiovascular disease in women(50),
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the AHA considers a previous history of preeclampsia or gestational diabetes to be a “major
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risk factor” as part of its system of risk assessment, alongside conditions such as hypertension and hypercholesterolemia, and other features such as smoking, physical inactivity, obesity or family history. Presence of one, or more, of these factors fulfils the guidelines criteria for being “at risk” of CVD, with a 5.5% annual risk of MI, stroke or death due to cardiovascular causes. This compares to a 19% risk amongst patients in “high risk states” (with established CVD, a ≥10% CVD risk [determined by risk score], diabetes or renal failure) and a 2.2% annual risk amongst women in the absence of these risk factors. The most suitable treatment to prevent future CVD therefore varies according to risk category, and women with previous
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ACCEPTED MANUSCRIPT preeclampsia are at least “at risk” of CVD. This risk is potentially compounded by additional comorbidities and risk factors; however, only the presence of features of one or more “high risk states” is sufficient to increase the risk classification based on these guidelines. There is little evidence to guide risk stratification amongst women with prior preeclampsia, and it is
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therefore left largely to clinician discretion.
The National Institute of Clinical Excellence (NICE) guidelines in the United
Kingdom recommend that a post-natal review of the woman’s health be conducted at 6-8
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weeks following a preeclamptic pregnancy(51). This provides an excellent opportunity for cardiovascular risk assessment amongst these women, and a chance to consider the early
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implementation of interventional measures. At this time, women should be advised of the implications preeclampsia has for future pregnancies, and it is also be appropriate to educate them regarding the increased CVD risk that they face. When assessing cardiovascular risk amongst these women, transient features of preeclampsia (such as hypertension or renal
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dysfunction) may still persist and have not yet resolved(52). Risk scores should be calculated to account for traditional risk factors, and we would suggest that at this time women with an estimated annual risk above 5% (in line with the AHAs “at risk” group) should be followed
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up at 6-12 months postpartum, in order to reassess risk. In the meantime, lifestyle
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modification measures can be implemented to facilitate the resolution of the preeclamptic pathology and improve cardiovascular health, and during follow up other treatment options can be considered.
Pharmacological and Life Style Management of Previously Preeclamptic Women Amongst women whose blood pressure exceeds 140/90mmHg (130/80mmHg in patients with co-morbid chronic kidney disease or diabetes mellitus) pharmacological measures are appropriate (class 1, level A)(50). In the presence of cardiovascular risk factors and a high annual CVD risk (>20%), moderate risk (10-20%) or lower risk (3 years
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ACCEPTED MANUSCRIPT assessing CV risk factors Brown et al.
Systematic review
2013
and meta-analysis:
NA
NA
Cardiovascular
2.28 (1.87-2.78)
disease
1.76 (1.43-2.21)
Stroke
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3.13 (2.51-3.89)
43 studies
Hypertension
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NA- not available, IHD- Ischemic heart disease, CV- Cardiovascular, MI-myocardial
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infarction
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ABBREVIATIONS ACE Angiotensin Converting Enzyme AHA American Heart Association CAD Coronary Artery Disease CHAMPS Cardiovascular Health After Maternal Placentation Syndrome study COMT Catechol-O-Methyl Transferase CRP C-Reactive Protein CVD Cardiovascular Disease EPC Endothelial Progenitor Cell HELLP Haemolysis, Elevated Liver enzymes, Low Platelets IHD Ischaemic Heart Disease LDL Low Density Lipoprotein NICE National Institute for Clinical Excellence PAPP-A Pregnancy Associated Plasma Protein A PFA-100 Platelet Function Analyser PlGF Placental Growth Factor PREDIMED Prevención con Dieta Mediterránea PREVFEM Preeclampsia Risk EValuation in FEMales PWV Pulse Wave Velocity Sflt1 Soluble form of the type 1 VEGF receptor STARTS Strategies To Avoid Returning To Smoking UAD Uterine Artery Doppler VCAM-1 Vascular Cell Adhesion Molecule 1 VEGF Vascular Endothelial Growth Factor 2-ME 2-Methoxy Estradiol
