Review J Vasc Res 2014;51:290–304 DOI: 10.1159/000367627
Received: February 14, 2014 Accepted after revision: August 13, 2014 Published online: October 8, 2014
Preeclampsia and Maternal Cardiovascular Disease: Consequence or Predisposition? George Osol Ira Bernstein Department of Obstetrics and Gynecology, University of Vermont College of Medicine, Burlington, Vt., USA
Abstract Formerly preeclamptic women stand a higher chance of developing cardiovascular disease (CVD) later in life and may experience a shortened life span. This review updates the pathophysiology and definition of this complex disease and highlights the protective role of pregnancy by considering the relationship between pregnancy interval and likelihood of disease recurrence. The evidence for persistent maternal cardiovascular impairment following preeclampsia (PE) is considered, e.g. postpartum changes in CVD occurrence, blood pressure elevation and changes in the renin-angiotensin-aldosterone system). Since maternal endothelial dysfunction is a hallmark of PE, we summarize the evidence for reduced flow-mediated dilation in women with previous PE, and consider the utility and shortcomings of this clinical measure. In addition to viewing postpartum changes as a consequence of this disease, we consider the alternative view that PE might be the manifestation of a maternal phenotype that already has some predisposition to or is in the earlier stages of CVD; in this case, some of the postpartum residual deficits (or their antecedents) may have already been present prior to pregnancy. Finally, we consider the use
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of novel biomarkers for predicting or detecting PE prior to the appearance of clinical symptoms. © 2014 S. Karger AG, Basel
Introduction
Although the ‘Barker hypothesis’ (named for the late David Barker) was initially greeted with skepticism, a plethora of subsequent studies have substantiated its validity [1, 2]. The burgeoning field of fetal programming attests to the fact that maternal nutritional or endocrine stresses during gestation can have long-lasting postnatal effects on the offspring. Compared to fetal programming, however, relatively little attention has been paid to the parallel idea that pregnancy may, in effect, reprogram/permanently alter the maternal organism. Pregnancy has been called a ‘stress test for life’ [3], and the fact that fetal cells and DNA normally enter into the mother’s bloodstream during pregnancy and persist in her circulation (fetal microchimerism) only broadens the argument for lasting, perhaps even permanent, consequences of pregnancy for the mother’s cardiovascular system [4]. Even a healthy pregnancy challenges the adaptive limits of the maternal organism. Primarily driven by placental signals (e.g. hormones and growth factors), gestationDr. George Osol Department of Obstetrics and Gynecology University of Vermont College of Medicine Burlington, VT 05405 (USA) E-Mail George.Osol @ uvm.edu
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Key Words Pregnancy · Preeclampsia · Cardiovascular disease · Gestational interval · Endothelial damage · Aging
Preeclampsia, the ‘Disease of Theories’
PE occurs in 3–8% of pregnancies and is a leading cause of maternal and perinatal morbidity and mortality worldwide [13, 14]. Primarily diagnosed by new-onset hypertension, commonly combined with proteinuria and other end-organ injury during pregnancy, PE usually develops in the second half of gestation and may be associated with headache, edema, abdominal pain, disseminated intravascular coagulation, hepatic or renal problems and visual disturbances. If unchecked, it may progress to eclampsia, and PE or eclampsia may lead to the death of the mother and fetus. PE accounts for 17–24% of all maternal intrapartum deaths worldwide [15], and it has been estimated that 50,000 mothers and 500,000 babies die every year from its complications [15, 16]. There is currently no treatment and no cure except for delivery of the placenta. The etiology of this relatively common condition has proved to be surprisingly difficult to resolve despite the fact that PE occurs worldwide, is readily diagnosed and is clearly associated with gestation. PE requires a placenta but not a fetus, as women with molar pregnancy may develop the disease [17]. Severe PE, or an imitation thereof [18], may occur during the postpartum period, but this is relatively uncommon [18–20], as is a variant in which the woman remains normotensive but develops other symptoms of the disease [16]. Preeclampsia and Maternal CVD
Complicating factors are that PE may develop at different times during gestation (early vs. late) and manifest with varying levels of severity. Acknowledged to be multifactorial in etiology, PE is better viewed as a syndrome rather than as one disease. For example, 20–25% of preeclamptic women develop a life-threatening variant syndrome characterized by hemolysis, elevated lipids and low platelets, i.e. the HELLP syndrome, and in a very small proportion, symptoms do not develop until after parturition [21, 22]. Another impediment to understanding its etiology is that the disease only occurs spontaneously in humans. Even among primates, the spontaneous appearance of PE/ eclampsia has been reported only rarely in great apes, including chimpanzees and gorillas [23–25]. There is one report on the patas monkey [26] and a case of edema, proteinuria and hypertension in a pregnant baboon, i.e. a presentation that suggested PE, which was ultimately attributed to glomerulonephritis [27]. Thus, animal models may mimic some symptoms of PE like placental underperfusion, e.g. the reduced uterine perfusion pressure model [28], hypertension, e.g. systemic nitric oxide synthase (NOS) inhibition [29, 30] and proteinuria, e.g. the angiotensinogen/renin overexpression transgenic rat model [31]; these, however, likely do not recapitulate its true etiology [32, 33]. For example, while overactivation of the renin-angiotensin-aldosterone system (RAAS) leads to PElike symptoms in rodents, the degree of RAAS activation is thought to be less pronounced in preeclamptic women even though pressor sensitivity to angiotensin II infusion is augmented both intrapartum and postpartum [34]. Moreover, PE is not simply the manifestation of hypertension and proteinuria during pregnancy. The most recent definition compiled by an American College of Obstetrics and Gynecology panel reflects this fact (table 1) and is consistent with updated definitions by Australian and Canadian societies that have described PE using a broader set of criteria including renal insufficiency, hepatocellular dysfunction or fetal growth restriction [35, 36].
PE as a Two-Stage Disease
Current thinking about the genesis of PE favors the 2-phase concept pioneered by Roberts and Hubel [37], in which placental underperfusion secondary to shallow spiral artery trophoblast invasion triggers the release of soluble antiangiogenic molecules such as soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng), as well as placental debris (microparticles) into the maternal cirJ Vasc Res 2014;51:290–304 DOI: 10.1159/000367627
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al cardiovascular adaptations include plasma volume expansion, peripheral vasodilation, increased cardiac output, cardiac and vascular remodeling and altered hemodynamics [5–8]. Many of the gestational changes in the heart and blood vessels return to prepregnancy values after parturition, although some hysteresis may be present. Animal studies have shown that multiparity leads to increased vascular stiffness, venous tone and endothelial dysfunction, and that these changes may be related to increased formation of reactive oxygen species and decreased availability of nitric oxide (NO) [9–11]. From a clinical standpoint, understanding how a mother’s cardiovascular health is affected by a pregnancy complicated by a serious disease such as preeclampsia (PE) may be even more important in view of the evidence (reviewed below) of postpartum cardiovascular impairment in women who have been preeclamptic; this includes a shortened life span along with an increased risk of chronic hypertension, diabetes mellitus, ischemic heart disease, thromboembolism, hypothyroidism and kidney disease [12].
lege of Obstetrics and Gynecology in 20131 Hypertension: blood pressure ≥140/90 mm Hg on two occasions at least 4 h apart after 20 weeks of gestation in a woman with previously normal blood pressure and Proteinuria ≥300 mg/24 h or protein/creatinine ratio ≥0.3 or dipstick reading of 1+ In the absence of proteinuria, new-onset hypertension with any of the following: – Thrombocytopenia (platelet count 1.1 mg/dl, or a doubling of the serum creatinine in the absence of other renal diseases) – Impaired liver function (blood concentrations of transaminases elevated >2×) – Pulmonary edema – Cerebral or visual symptoms 1
http://www.acog.org/resources http://www.acog.org/resources and publications/task force and work group reports/hypertension in pregnancy.
culation. By preventing vasodilatory and angiogenic signals from interacting with receptors on the endothelium, the soluble receptors create a growth factor/cytokine imbalance that favors vasoconstriction and diminishes angiogenesis [38]. Specifically, sFlt-1 binds vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) while increased levels of circulating sEng inhibit TNF-β signaling, and increase vascular tone by blocking the activation of endothelial eNOS (NOS-3). Placentally derived compounds may also damage the maternal cardiovascular system in their own right [39], in keeping with the older definition of the disease as a toxemia. Spiral artery atherosis has also been observed [40], usually later in pregnancy, and is characterized by fibrinoid necrosis, perivascular lymphatic infiltration and subendothelial accumulation of foam cells (lipid-filled CD68-positive macrophages). The combination of shallow trophoblast invasion, reduced remodeling and atherosis (which occurs in some but not all preeclamptic women) predisposes to placental infarction and underperfusion as well as the release of placental substances that damage the maternal cardiovascular system (phase 1), and leads to the maternal syndrome which is characterized by generalized endothelial dysfunction, hypertension and organ damage (phase 2). Immune factors may also play a role. For example, Bonney [41] posited that PE stems from a maternal im292
J Vasc Res 2014;51:290–304 DOI: 10.1159/000367627
mune response to stress or abnormal cell death at the fetomaternal interface (placenta and decidua), rather than the more traditional view of gestational immunology being driven by discrimination between ‘self’ and ‘non-self’. Her study specifically addressed the pathophysiology of PE by modifying Matzinger’s original ‘danger model’ [42–44], hypothesizing that PE may develop secondary to defective trophoblast signaling, spiral artery remodeling and early placentation. Other factors such as oxidative stress and/or endothelial dysfunction may also contribute to the generation of ‘danger’ signals that trigger antifetal immunity and contribute to the development of the PE syndrome. A variation of this concept is a 3-phase model proposed by Redman and Sargent [45, 46] that adds an initial immune phase attributed to incomplete tolerization to the allogenic fetus, followed by placental underperfusion and the maternal syndrome. Augmented systemic inflammation, dyslipidemia and acute atherosis are also commonly cited as contributing to the maternal syndrome, especially in pregnancies complicated by restriction of fetal growth [16]. Some preeclamptic women also overexpress agonizing antibodies to the angiotensin 1 (AT1) receptor that induce vasoconstriction, hypertension and an increased oxidative state [8, 46].
Relationship between Gestational Interval and Likelihood of PE Recurrence
Compared to women who have experienced a normal pregnancy, former preeclamptics have a 7-fold greater risk of disease recurrence [47–49]. At the same time, studies that have examined the relationship between gestational interval and likelihood of recurrence agree that a woman who has been pregnant (even if she was preeclamptic) is afforded some protection against disease recurrence. Hence, the risk of redeveloping PE in a second pregnancy is initially relatively low, but then increases 10–12% per year, returning to a baseline risk after 5–8 years [47, 50]. Thus, paradoxically, even a preeclamptic pregnancy offers temporary protection against disease recurrence for reasons that are not known. Other factors such as a change in partner may also increase risk [51], suggesting a paternal component that has often been attributed to immunologic mechanisms. The aforementioned danger model [41] is congruent with this thinking, as it predicts that disease severity would increase after a long interval or with changed paternity. Thus, a subsequent pregnancy with the same partner and/ Osol/Bernstein
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Table 1. Diagnostic criteria for PE as revised by the American Col-
1.00
Survival distribution function
0.95
0.90
0.85
0.80
No PE PE after 34 weeks of gestation PE by 34 weeks of gestation
0.75 0
Persistent Maternal Cardiovascular Impairment following Pregnancy with PE
Although the early studies by Chesley [57] and Fisher et al. [58] did not find any increased mortality in white women who had eclampsia during their first pregnancy. Since then, considerable evidence has accumulated to suggest that previously preeclamptic women are indeed more likely to develop systemic hypertension and to die at an earlier age from CVD [12, 59–63]. In a prospective study with a long follow-up of 37 years [64], the mutually adjusted hazard ratio of subsequent cardiovascular death was 2.14, with a 95% confidence interval (CI) of 1.29–3.57. For more severe preeclamptics (early-onset, 50%; an increase of 13.6 vs. 8.9 mm Hg in response to a single dose) in women who had had PE relative to those who had had a normal pregnancy or had never been pregnant [63]. Interestingly, this was primarily due to an increase in diastolic rather than systolic pressure, and was detected 6–18 months postpartum. There was a modest (r2 = 0.29) correlation between the change in mean arterial pressure and the ratio of AT1/ AT2 receptors measured in skin, but only in previously preeclamptic women. The immune system may provide a link between angiotensin and PE, as preeclamptic women may have increased levels of autoantibodies that bind to and activate the AT1 receptor [78] on vascular smooth muscle, leading to vasoconstriction and hypertension. These antibodies, which are present in 95% of preeclamptic women [79], may also sensitize the AT1 receptor by increasing its affinity for endogenous angiotensin II through a mechanism that induces cross-linking and maintenance of an activated conformation [80]. Osol/Bernstein
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ratios were also determined, and sympathetic activity was evaluated by tilt-table testing while measuring venous renin and aldosterone concentrations before and during the test. Blood pressure and cardiac responses to the cold pressor test were also recorded. This study is noteworthy for its prospective design, the inclusion of nonpreeclamptic women with GH and the use of 24-hour ambulatory blood pressure monitoring. Their findings indicated that BMI and insulin resistance were significantly elevated in both women with PE and women with GH 3–4 years postpartum, on average. Twenty-four hour blood pressure was increased by 6–8 mm Hg, but there were no measurable differences between groups in renin or aldosterone responses to tilt testing, the cardiac response to the cold pressor test, glomerular filtration rate or sympathetic activity. There were also no differences in FMD, which contrasts with several other studies (described below). Metabolic changes that may affect cardiovascular risk have also been noted. One case-control study examined a small cohort of women who experienced PE in their first pregnancy, and age-matched women with uncomplicated first pregnancies (13 in each group). Analysis of fasting blood samples obtained during the luteal phase (days 19– 22) of the menstrual cycle showed that women with previous PE had significantly elevated serum triglycerides, insulin and glucose, and there was a higher fasting insulin resistance index, i.e. metabolic changes that may predispose to subsequent CVD [68]. Some degree of blood pressure elevation in former preeclamptics has been noted in a number of studies (32 were cited in the most recent meta-analysis by Brown et al. [59]). While the elevation in blood pressure is often in the prehypertensive range (35 and 1.96 (1.34–2.87) for a maternal age of >40 years. Their examination of blood pressure was cursory, however, with only the effect of having a diastolic pressure >80 mm Hg being evaluated and, predictably, only a modest effect being noted, i.e. 1.38 (1.01–1.87). Conversely, in the HUNT2 study in Norway, in which 66,140 adults participated, the RR for PE development was considerably elevated in women with a systolic blood pressure >130 mm Hg at 7.3 (3.1–17.2) [118]. Many published studies did not stratify disease severity, so these values likely underestimate the RR in the severe (early-onset) disease variant. Influences on the likelihood of developing PE may extend back months or even years before pregnancy. The most extreme example, perhaps, is the influence of events that occurred prior to the mother’s birth, with several studies having shown that the weight of the mother at her birth may also play a role. One Norwegian study found Osol/Bernstein
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to the rise in blood pressure within pregnancies between the first and third trimesters. The observation of a time-limited effect of pregnancy on blood pressure in subsequent pregnancies was confirmed by Mikolajczyk et al. [110] in a much larger cohort (n = 533). Both studies suggest that pregnancy has an effect on the maternal vascular tree (presumably through the substantial structural remodeling during pregnancy) and that this effect wanes over time. This finding is consistent with the epidemiologic observations that longer intervals between pregnancies are associated with an increased risk of PE and that this effect accounts for some of the previous risk attributed to new paternity. In recently completed analyses published in abstract form only [111], we expand on this observation of persistent vascular remodeling following pregnancy by demonstrating that several of the prepregnancy cardiovascular risk factors that are elevated prior to pregnancy in women who subsequently develop PE are reduced as a result of normal pregnancy, with these changes lasting for at least 1 year postpartum. These indices include pulse wave velocity as well as mean arterial pressure which were significantly elevated prior to pregnancy in women who subsequently developed PE [97] and diminished significantly when reexamined 1 year after delivery at term. Additional recent epidemiologic evidence supports the likelihood that the major contributor to long-term cardiovascular risk in women who have had PE is present prior to a first pregnancy. Romundstad et al. [112] examined biomarkers for the development of CVD measured before and after both hypertensive and uncomplicated pregnancies. They concluded that the positive association of PE and GH with postpregnancy cardiovascular risk may be due largely to shared prepregnancy risk factors rather than a direct influence of the hypertensive disorder in pregnancy, and concluded that the ‘maternal constitution’ was key to both the likelihood of developing PE, and of a later risk of CVD. In addition, a family history of hypertension is known to be an important risk factor for the development of severe PE [113], and there are specific physiologic characteristics linked to a family history of CVD that are elements of the PE phenotype [104].
Strategies for Predicting PE and the Use of Novel Biomarkers as a Means of Early Detection
From a medical standpoint, a more practical approach for predicting PE might be through the detection of circulating factors that predate the development of symptoms later in gestation, since the current standard of care is such that PE is usually diagnosed after gestational week 20. In the past decade, numerous studies have documented altered concentrations of circulating factors (the AT1 activating antibody has already been considered), particularly those derived from the PE placenta. The current knowledge on this topic was recently reviewed [121–123] by the authors who pioneered the sFlt-1 theory a decade ago [121, 124]. Commonly viewed as a state of ‘angiogenic imbalance’, plasma concentrations of antiangiogenic molecules such as sFlt-1 (which binds VEGF and PlGF) and sEng (which binds TGF-β) are elevated in the circulation of women with PE, while free concentrations of PlGF and VEGF are reduced [8]. Increased circulating levels of proinflammatory cytokine markers such as TNF-α and IL-6 have also been reported [125]; some of these are released from placental microparticles which also display elevated concentrations in women with PE [126, 127]. The use of circulating epigenetically modified cell-free nucleic acids [128] or microRNA profiles [129] as novel biomarkers has also received recent attention. However, in spite of intensive study, to date, there are no definitive, reliably predictive tests for PE. The WHO reviewed the usefulness of predictive tests and concluded that there is no cost-effective or reliable screening test for PE [130], though this review was published as long ago as 2004. Multicenter trials that propose using a combination of proprietary metabolomic and proteomic markers are Preeclampsia and Maternal CVD
ongoing [e.g. 15], and more than 200 candidate biomarkers have been proposed, e.g. placental hormones, angiogenic factors and lipids. However, to date, none of these markers, alone or in combination, has proved to be sufficiently specific and sensitive for clinical use [15]. While exercise is often viewed as a panacea for CVD, a prospective population-based cohort study from Norway did not find any reduction in PE risk in women who were physically active prior to conception [131]. The effects of nutritional interventions are also limited [132], although some beneficial effects of antiplatelet agents, primarily low-dose aspirin and calcium supplementation have been noted [133]. Some beneficial effects of exercise in previously preeclamptic women have also been noted, with the results of some studies suggesting that exercise may be potentially helpful for disease prevention [134–136]. A recent review of the research strategies for prediction of PE, including maternal risk factors, mean arterial pressure, ultrasound parameters and biomarkers, concluded that the most promising strategies involve a variety of individual parameters in combination. The main categories of interest are: angiogenic/antiangiogenic factors, placental proteins, free fetal hemoglobin, markers of renal function, ultrasound evaluation of uteroplacental blood flow and evaluation of maternal risk factors [137]. A discussion on how specific markers can be used to predict PE can be found in several recent papers [138–140]. Consistent with this thinking, the improved pregnancy outcomes via early detection (IMPROvED) trial, launched in 2013 [15], involves a consortium of eight academic institutions and four small and medium enterprises in five countries: Germany, Ireland, the Netherlands, the UK and Sweden. It seeks to recruit 5,000 lowrisk nulliparous women early in pregnancy for blood analysis, using proprietary metabolomic and proteomic platforms in an effort to detect PE. Although many studies have attempted to predict or screen for PE using one or two markers, we are technologically at a point where more complex algorithms allow the interpretation of changes in a number of different markers and better use can be made of targeted provocation tests. Perhaps the most promising approach is one that characterizes the individual’s genotype/phenotype and then uses this information to inform the appropriate algorithm for disease prediction and detection. By using personalized medicine that takes family history, ethnicity, genotype and phenotype into consideration, we may be able to finally target the PE syndrome in a way that yields true clinical benefit and ameliorates the significant morbidity and mortality associated with this gestational disease. J Vasc Res 2014;51:290–304 DOI: 10.1159/000367627
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that women who were born small (below the 5th birth weight percentile) were 2–3 times more likely to develop GH (this study did not distinguish PE). This was not the case for women who were born large (above the 90th percentile) and there was no association with the father’s birth weight [119]. The strengths of this particular study were its prospective design and size (nearly 200,000 women were selected from a registry of >2 million stratified by birth weight). An earlier case-control study from the USA was smaller in size (2,180 women with GH and almost 23,000 without GH) but they also found a strong, inverse relationship between maternal birth weight and the likelihood of developing GH, with an odds ratio of 2.1 [120].
Finally, one must consider how to factor-in the increased risk of CVD among women with previous PE into clinical management. In 2011, the American Heart Association formally recognized the hypertensive complications of pregnancy as a major risk factor for the subsequent development of CVD [133]. Their guideline also
outlined the evidence-based interventions that could be applied to those at risk with the goal of primary prevention. These recommendations can be used to guide the clinical management of those recognized as being at a high risk for future cardiovascular events.
References
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112 Romundstad PR, et al: Hypertension in pregnancy and later cardiovascular risk: common antecedents? Circulation 2010; 122:579–584. 113 Bezerra PC, et al: Family history of hypertension as an important risk factor for the development of severe preeclampsia. Acta Obstet Gynecol Scand 2010;89:612–617. 114 Sibai B, Dekker G, Kupferminc M: Pre-eclampsia. Lancet 2005;365:785–799. 115 Poon LC, et al: Maternal risk factors for hypertensive disorders in pregnancy: a multivariate approach. J Hum Hypertens 2010;24: 104–110. 116 van Dijk M, Oudejans C: (Epi)genetics of pregnancy-associated diseases. Front Genet 2013;4:180. 117 Duckitt K, Harrington D: Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330:565. 118 Magnussen EB, et al: Prepregnancy cardiovascular risk factors as predictors of preeclampsia: population-based cohort study. BMJ 2007;335:978. 119 Rasmussen S, Irgens LM: Pregnancy-induced hypertension in women who were born small. Hypertension 2007;49:806–812. 120 Innes KE, et al: Association of a woman’s own birth weight with her subsequent risk for pregnancy-induced hypertension. Am J Epidemiol 2003;158:861–870. 121 Naljayan MV, Karumanchi SA: New developments in the pathogenesis of preeclampsia. Adv Chronic Kidney Dis 2013;20:265–270. 122 Hagmann H, et al: The promise of angiogenic markers for the early diagnosis and prediction of preeclampsia. Clin Chem 2012;58: 837–845. 123 Wang A, Rana S, Karumanchi SA: Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology (Bethesda) 2009;24:147–158. 124 Maynard SE, et al: Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649–658. 125 LaMarca BD, et al: Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr Hypertens Rep 2007; 9:480–485. 126 Redman CW, et al: Review: Does size matter? Placental debris and the pathophysiology of pre-eclampsia. Placenta 2012; 33(suppl):S48–S54.
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127 van der Post JA, et al: The functions of microparticles in pre-eclampsia. Semin Thromb Hemost 2011;37:146–152. 128 Kim YJ: Pathogenesis and promising noninvasive markers for preeclampsia. Obstet Gynecol Sci 2013;56:2–7. 129 Stubert J, et al: miRNA expression profiles determined in maternal sera of patients with HELLP syndrome. Hypertens Pregnancy 2014;33:215–235. 130 Conde-Agudelo A, Villar J, Lindheimer M: World Health Organization systematic review of screening tests for preeclampsia. Obstet Gynecol 2004;104:1367–1391. 131 Tyldum EV, Romundstad PR, Slordahl SA: Pre-pregnancy physical activity and preeclampsia risk: a prospective populationbased cohort study. Acta Obstet Gynecol Scand 2010;89:315–320. 132 Thorne-Lyman A, Fawzi WW: Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 2012;26(suppl 1):75–90. 133 Thangaratinam S, et al: Prediction and primary prevention of pre-eclampsia. Best Pract Res Clin Obstet Gynaecol 2011; 25: 419–433. 134 Scholten RR, et al: Cardiovascular effects of aerobic exercise training in formerly preeclamptic women and healthy parous control subjects. Am J Obstet Gynecol 2014. 135 Genest DS, et al: Impact of exercise training on preeclampsia: potential preventive mechanisms. Hypertension 2012;60:1104–1109. 136 Kasawara KT, et al: Exercise and physical activity in the prevention of pre-eclampsia: systematic review. Acta Obstet Gynecol Scand 2012;91:1147–1157. 137 Anderson UD, et al: Review: Biochemical markers to predict preeclampsia. Placenta 2012;33(suppl):S42–S47. 138 Masoura S, et al: Biomarkers in pre-eclampsia: a novel approach to early detection of the disease. J Obstet Gynaecol 2012;32:609– 616. 139 Sanchez-Ramos L, et al: The protein-to-creatinine ratio for the prediction of significant proteinuria in patients at risk for preeclampsia: a meta-analysis. Ann Clin Lab Sci 2013; 43:211–220. 140 Forest JC, et al: Candidate biochemical markers for screening of pre-eclampsia in early pregnancy. Clin Chem Lab Med 2012; 50:973–984.
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99 Bernstein IM, et al: Intolerance to volume expansion: a theorized mechanism for the development of preeclampsia. Obstet Gynecol 1998;92:306–308. 100 Bernstein IM, et al: Relationship of plasma volume to sympathetic tone in nulliparous women. Am J Obstet Gynecol 2003; 188: 938–942. 101 Damron DP, et al: Platelet activation, sympathetic tone, and plasma volume in nulligravid women of reproductive age. Obstet Gynecol 2004;103:931–936. 102 Bernstein IM, et al: The relationship of plasma volume, sympathetic tone, and proinflammatory cytokines in young healthy nonpregnant women. Reprod Sci 2009; 16: 980– 985. 103 Damron DP, et al: Uterine blood flow response to alpha-adrenergic blockade in nulligravid women of reproductive age. J Soc Gynecol Investig 2004;11:388–392. 104 McBride CA, et al: The relationship of a family history for hypertension, myocardial infarction, or stroke with cardiovascular physiology in young women. Reprod Sci 2014;21: 509–516. 105 Hale S, et al: Pulse pressure and arterial compliance prior to pregnancy and the development of complicated hypertension during pregnancy. Reprod Sci 2010;17:871–877. 106 Hale SA, et al: Prepregnancy vascular dysfunction in women who subsequently develop hypertension during pregnancy. Pregnancy Hypertens 2013;3:140–145. 107 Aardenburg R, et al: Low plasma volume following pregnancy complicated by pre-eclampsia predisposes for hypertensive disease in a next pregnancy. BJOG 2003; 110: 1001– 1006. 108 Aardenburg R, et al: A low plasma volume in formerly preeclamptic women predisposes to the recurrence of hypertensive complications in the next pregnancy. J Soc Gynecol Investig 2006;13:598–603. 109 Bernstein IM, et al: The influence of pregnancy on arterial compliance. Obstet Gynecol 2005;105:621–625. 110 Mikolajczyk RT, et al: Effects of interpregnancy interval on blood pressure in consecutive pregnancies. Am J Epidemiol 2008;168: 422–426. 111 Bernstein IM, Hale S, Badger G: Evidence for persistent vascular remodeling following pregnancy. Am J Obstetr Gynecol 2014; 210:S400.
Received: February 14, 2014 Accepted after revision: August 13, 2014 Published online: October 8, 2014
Preeclampsia and Maternal Cardiovascular Disease: Consequence or Predisposition? George Osol Ira Bernstein Department of Obstetrics and Gynecology, University of Vermont College of Medicine, Burlington, Vt., USA
Abstract Formerly preeclamptic women stand a higher chance of developing cardiovascular disease (CVD) later in life and may experience a shortened life span. This review updates the pathophysiology and definition of this complex disease and highlights the protective role of pregnancy by considering the relationship between pregnancy interval and likelihood of disease recurrence. The evidence for persistent maternal cardiovascular impairment following preeclampsia (PE) is considered, e.g. postpartum changes in CVD occurrence, blood pressure elevation and changes in the renin-angiotensin-aldosterone system). Since maternal endothelial dysfunction is a hallmark of PE, we summarize the evidence for reduced flow-mediated dilation in women with previous PE, and consider the utility and shortcomings of this clinical measure. In addition to viewing postpartum changes as a consequence of this disease, we consider the alternative view that PE might be the manifestation of a maternal phenotype that already has some predisposition to or is in the earlier stages of CVD; in this case, some of the postpartum residual deficits (or their antecedents) may have already been present prior to pregnancy. Finally, we consider the use
© 2014 S. Karger AG, Basel 1018–1172/14/0514–0290$39.50/0 E-Mail [email protected] www.karger.com/jvr
of novel biomarkers for predicting or detecting PE prior to the appearance of clinical symptoms. © 2014 S. Karger AG, Basel
Introduction
Although the ‘Barker hypothesis’ (named for the late David Barker) was initially greeted with skepticism, a plethora of subsequent studies have substantiated its validity [1, 2]. The burgeoning field of fetal programming attests to the fact that maternal nutritional or endocrine stresses during gestation can have long-lasting postnatal effects on the offspring. Compared to fetal programming, however, relatively little attention has been paid to the parallel idea that pregnancy may, in effect, reprogram/permanently alter the maternal organism. Pregnancy has been called a ‘stress test for life’ [3], and the fact that fetal cells and DNA normally enter into the mother’s bloodstream during pregnancy and persist in her circulation (fetal microchimerism) only broadens the argument for lasting, perhaps even permanent, consequences of pregnancy for the mother’s cardiovascular system [4]. Even a healthy pregnancy challenges the adaptive limits of the maternal organism. Primarily driven by placental signals (e.g. hormones and growth factors), gestationDr. George Osol Department of Obstetrics and Gynecology University of Vermont College of Medicine Burlington, VT 05405 (USA) E-Mail George.Osol @ uvm.edu
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Key Words Pregnancy · Preeclampsia · Cardiovascular disease · Gestational interval · Endothelial damage · Aging
Preeclampsia, the ‘Disease of Theories’
PE occurs in 3–8% of pregnancies and is a leading cause of maternal and perinatal morbidity and mortality worldwide [13, 14]. Primarily diagnosed by new-onset hypertension, commonly combined with proteinuria and other end-organ injury during pregnancy, PE usually develops in the second half of gestation and may be associated with headache, edema, abdominal pain, disseminated intravascular coagulation, hepatic or renal problems and visual disturbances. If unchecked, it may progress to eclampsia, and PE or eclampsia may lead to the death of the mother and fetus. PE accounts for 17–24% of all maternal intrapartum deaths worldwide [15], and it has been estimated that 50,000 mothers and 500,000 babies die every year from its complications [15, 16]. There is currently no treatment and no cure except for delivery of the placenta. The etiology of this relatively common condition has proved to be surprisingly difficult to resolve despite the fact that PE occurs worldwide, is readily diagnosed and is clearly associated with gestation. PE requires a placenta but not a fetus, as women with molar pregnancy may develop the disease [17]. Severe PE, or an imitation thereof [18], may occur during the postpartum period, but this is relatively uncommon [18–20], as is a variant in which the woman remains normotensive but develops other symptoms of the disease [16]. Preeclampsia and Maternal CVD
Complicating factors are that PE may develop at different times during gestation (early vs. late) and manifest with varying levels of severity. Acknowledged to be multifactorial in etiology, PE is better viewed as a syndrome rather than as one disease. For example, 20–25% of preeclamptic women develop a life-threatening variant syndrome characterized by hemolysis, elevated lipids and low platelets, i.e. the HELLP syndrome, and in a very small proportion, symptoms do not develop until after parturition [21, 22]. Another impediment to understanding its etiology is that the disease only occurs spontaneously in humans. Even among primates, the spontaneous appearance of PE/ eclampsia has been reported only rarely in great apes, including chimpanzees and gorillas [23–25]. There is one report on the patas monkey [26] and a case of edema, proteinuria and hypertension in a pregnant baboon, i.e. a presentation that suggested PE, which was ultimately attributed to glomerulonephritis [27]. Thus, animal models may mimic some symptoms of PE like placental underperfusion, e.g. the reduced uterine perfusion pressure model [28], hypertension, e.g. systemic nitric oxide synthase (NOS) inhibition [29, 30] and proteinuria, e.g. the angiotensinogen/renin overexpression transgenic rat model [31]; these, however, likely do not recapitulate its true etiology [32, 33]. For example, while overactivation of the renin-angiotensin-aldosterone system (RAAS) leads to PElike symptoms in rodents, the degree of RAAS activation is thought to be less pronounced in preeclamptic women even though pressor sensitivity to angiotensin II infusion is augmented both intrapartum and postpartum [34]. Moreover, PE is not simply the manifestation of hypertension and proteinuria during pregnancy. The most recent definition compiled by an American College of Obstetrics and Gynecology panel reflects this fact (table 1) and is consistent with updated definitions by Australian and Canadian societies that have described PE using a broader set of criteria including renal insufficiency, hepatocellular dysfunction or fetal growth restriction [35, 36].
PE as a Two-Stage Disease
Current thinking about the genesis of PE favors the 2-phase concept pioneered by Roberts and Hubel [37], in which placental underperfusion secondary to shallow spiral artery trophoblast invasion triggers the release of soluble antiangiogenic molecules such as soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng), as well as placental debris (microparticles) into the maternal cirJ Vasc Res 2014;51:290–304 DOI: 10.1159/000367627
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al cardiovascular adaptations include plasma volume expansion, peripheral vasodilation, increased cardiac output, cardiac and vascular remodeling and altered hemodynamics [5–8]. Many of the gestational changes in the heart and blood vessels return to prepregnancy values after parturition, although some hysteresis may be present. Animal studies have shown that multiparity leads to increased vascular stiffness, venous tone and endothelial dysfunction, and that these changes may be related to increased formation of reactive oxygen species and decreased availability of nitric oxide (NO) [9–11]. From a clinical standpoint, understanding how a mother’s cardiovascular health is affected by a pregnancy complicated by a serious disease such as preeclampsia (PE) may be even more important in view of the evidence (reviewed below) of postpartum cardiovascular impairment in women who have been preeclamptic; this includes a shortened life span along with an increased risk of chronic hypertension, diabetes mellitus, ischemic heart disease, thromboembolism, hypothyroidism and kidney disease [12].
lege of Obstetrics and Gynecology in 20131 Hypertension: blood pressure ≥140/90 mm Hg on two occasions at least 4 h apart after 20 weeks of gestation in a woman with previously normal blood pressure and Proteinuria ≥300 mg/24 h or protein/creatinine ratio ≥0.3 or dipstick reading of 1+ In the absence of proteinuria, new-onset hypertension with any of the following: – Thrombocytopenia (platelet count 1.1 mg/dl, or a doubling of the serum creatinine in the absence of other renal diseases) – Impaired liver function (blood concentrations of transaminases elevated >2×) – Pulmonary edema – Cerebral or visual symptoms 1
http://www.acog.org/resources http://www.acog.org/resources and publications/task force and work group reports/hypertension in pregnancy.
culation. By preventing vasodilatory and angiogenic signals from interacting with receptors on the endothelium, the soluble receptors create a growth factor/cytokine imbalance that favors vasoconstriction and diminishes angiogenesis [38]. Specifically, sFlt-1 binds vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) while increased levels of circulating sEng inhibit TNF-β signaling, and increase vascular tone by blocking the activation of endothelial eNOS (NOS-3). Placentally derived compounds may also damage the maternal cardiovascular system in their own right [39], in keeping with the older definition of the disease as a toxemia. Spiral artery atherosis has also been observed [40], usually later in pregnancy, and is characterized by fibrinoid necrosis, perivascular lymphatic infiltration and subendothelial accumulation of foam cells (lipid-filled CD68-positive macrophages). The combination of shallow trophoblast invasion, reduced remodeling and atherosis (which occurs in some but not all preeclamptic women) predisposes to placental infarction and underperfusion as well as the release of placental substances that damage the maternal cardiovascular system (phase 1), and leads to the maternal syndrome which is characterized by generalized endothelial dysfunction, hypertension and organ damage (phase 2). Immune factors may also play a role. For example, Bonney [41] posited that PE stems from a maternal im292
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mune response to stress or abnormal cell death at the fetomaternal interface (placenta and decidua), rather than the more traditional view of gestational immunology being driven by discrimination between ‘self’ and ‘non-self’. Her study specifically addressed the pathophysiology of PE by modifying Matzinger’s original ‘danger model’ [42–44], hypothesizing that PE may develop secondary to defective trophoblast signaling, spiral artery remodeling and early placentation. Other factors such as oxidative stress and/or endothelial dysfunction may also contribute to the generation of ‘danger’ signals that trigger antifetal immunity and contribute to the development of the PE syndrome. A variation of this concept is a 3-phase model proposed by Redman and Sargent [45, 46] that adds an initial immune phase attributed to incomplete tolerization to the allogenic fetus, followed by placental underperfusion and the maternal syndrome. Augmented systemic inflammation, dyslipidemia and acute atherosis are also commonly cited as contributing to the maternal syndrome, especially in pregnancies complicated by restriction of fetal growth [16]. Some preeclamptic women also overexpress agonizing antibodies to the angiotensin 1 (AT1) receptor that induce vasoconstriction, hypertension and an increased oxidative state [8, 46].
Relationship between Gestational Interval and Likelihood of PE Recurrence
Compared to women who have experienced a normal pregnancy, former preeclamptics have a 7-fold greater risk of disease recurrence [47–49]. At the same time, studies that have examined the relationship between gestational interval and likelihood of recurrence agree that a woman who has been pregnant (even if she was preeclamptic) is afforded some protection against disease recurrence. Hence, the risk of redeveloping PE in a second pregnancy is initially relatively low, but then increases 10–12% per year, returning to a baseline risk after 5–8 years [47, 50]. Thus, paradoxically, even a preeclamptic pregnancy offers temporary protection against disease recurrence for reasons that are not known. Other factors such as a change in partner may also increase risk [51], suggesting a paternal component that has often been attributed to immunologic mechanisms. The aforementioned danger model [41] is congruent with this thinking, as it predicts that disease severity would increase after a long interval or with changed paternity. Thus, a subsequent pregnancy with the same partner and/ Osol/Bernstein
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Table 1. Diagnostic criteria for PE as revised by the American Col-
1.00
Survival distribution function
0.95
0.90
0.85
0.80
No PE PE after 34 weeks of gestation PE by 34 weeks of gestation
0.75 0
Persistent Maternal Cardiovascular Impairment following Pregnancy with PE
Although the early studies by Chesley [57] and Fisher et al. [58] did not find any increased mortality in white women who had eclampsia during their first pregnancy. Since then, considerable evidence has accumulated to suggest that previously preeclamptic women are indeed more likely to develop systemic hypertension and to die at an earlier age from CVD [12, 59–63]. In a prospective study with a long follow-up of 37 years [64], the mutually adjusted hazard ratio of subsequent cardiovascular death was 2.14, with a 95% confidence interval (CI) of 1.29–3.57. For more severe preeclamptics (early-onset, 50%; an increase of 13.6 vs. 8.9 mm Hg in response to a single dose) in women who had had PE relative to those who had had a normal pregnancy or had never been pregnant [63]. Interestingly, this was primarily due to an increase in diastolic rather than systolic pressure, and was detected 6–18 months postpartum. There was a modest (r2 = 0.29) correlation between the change in mean arterial pressure and the ratio of AT1/ AT2 receptors measured in skin, but only in previously preeclamptic women. The immune system may provide a link between angiotensin and PE, as preeclamptic women may have increased levels of autoantibodies that bind to and activate the AT1 receptor [78] on vascular smooth muscle, leading to vasoconstriction and hypertension. These antibodies, which are present in 95% of preeclamptic women [79], may also sensitize the AT1 receptor by increasing its affinity for endogenous angiotensin II through a mechanism that induces cross-linking and maintenance of an activated conformation [80]. Osol/Bernstein
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ratios were also determined, and sympathetic activity was evaluated by tilt-table testing while measuring venous renin and aldosterone concentrations before and during the test. Blood pressure and cardiac responses to the cold pressor test were also recorded. This study is noteworthy for its prospective design, the inclusion of nonpreeclamptic women with GH and the use of 24-hour ambulatory blood pressure monitoring. Their findings indicated that BMI and insulin resistance were significantly elevated in both women with PE and women with GH 3–4 years postpartum, on average. Twenty-four hour blood pressure was increased by 6–8 mm Hg, but there were no measurable differences between groups in renin or aldosterone responses to tilt testing, the cardiac response to the cold pressor test, glomerular filtration rate or sympathetic activity. There were also no differences in FMD, which contrasts with several other studies (described below). Metabolic changes that may affect cardiovascular risk have also been noted. One case-control study examined a small cohort of women who experienced PE in their first pregnancy, and age-matched women with uncomplicated first pregnancies (13 in each group). Analysis of fasting blood samples obtained during the luteal phase (days 19– 22) of the menstrual cycle showed that women with previous PE had significantly elevated serum triglycerides, insulin and glucose, and there was a higher fasting insulin resistance index, i.e. metabolic changes that may predispose to subsequent CVD [68]. Some degree of blood pressure elevation in former preeclamptics has been noted in a number of studies (32 were cited in the most recent meta-analysis by Brown et al. [59]). While the elevation in blood pressure is often in the prehypertensive range (35 and 1.96 (1.34–2.87) for a maternal age of >40 years. Their examination of blood pressure was cursory, however, with only the effect of having a diastolic pressure >80 mm Hg being evaluated and, predictably, only a modest effect being noted, i.e. 1.38 (1.01–1.87). Conversely, in the HUNT2 study in Norway, in which 66,140 adults participated, the RR for PE development was considerably elevated in women with a systolic blood pressure >130 mm Hg at 7.3 (3.1–17.2) [118]. Many published studies did not stratify disease severity, so these values likely underestimate the RR in the severe (early-onset) disease variant. Influences on the likelihood of developing PE may extend back months or even years before pregnancy. The most extreme example, perhaps, is the influence of events that occurred prior to the mother’s birth, with several studies having shown that the weight of the mother at her birth may also play a role. One Norwegian study found Osol/Bernstein
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to the rise in blood pressure within pregnancies between the first and third trimesters. The observation of a time-limited effect of pregnancy on blood pressure in subsequent pregnancies was confirmed by Mikolajczyk et al. [110] in a much larger cohort (n = 533). Both studies suggest that pregnancy has an effect on the maternal vascular tree (presumably through the substantial structural remodeling during pregnancy) and that this effect wanes over time. This finding is consistent with the epidemiologic observations that longer intervals between pregnancies are associated with an increased risk of PE and that this effect accounts for some of the previous risk attributed to new paternity. In recently completed analyses published in abstract form only [111], we expand on this observation of persistent vascular remodeling following pregnancy by demonstrating that several of the prepregnancy cardiovascular risk factors that are elevated prior to pregnancy in women who subsequently develop PE are reduced as a result of normal pregnancy, with these changes lasting for at least 1 year postpartum. These indices include pulse wave velocity as well as mean arterial pressure which were significantly elevated prior to pregnancy in women who subsequently developed PE [97] and diminished significantly when reexamined 1 year after delivery at term. Additional recent epidemiologic evidence supports the likelihood that the major contributor to long-term cardiovascular risk in women who have had PE is present prior to a first pregnancy. Romundstad et al. [112] examined biomarkers for the development of CVD measured before and after both hypertensive and uncomplicated pregnancies. They concluded that the positive association of PE and GH with postpregnancy cardiovascular risk may be due largely to shared prepregnancy risk factors rather than a direct influence of the hypertensive disorder in pregnancy, and concluded that the ‘maternal constitution’ was key to both the likelihood of developing PE, and of a later risk of CVD. In addition, a family history of hypertension is known to be an important risk factor for the development of severe PE [113], and there are specific physiologic characteristics linked to a family history of CVD that are elements of the PE phenotype [104].
Strategies for Predicting PE and the Use of Novel Biomarkers as a Means of Early Detection
From a medical standpoint, a more practical approach for predicting PE might be through the detection of circulating factors that predate the development of symptoms later in gestation, since the current standard of care is such that PE is usually diagnosed after gestational week 20. In the past decade, numerous studies have documented altered concentrations of circulating factors (the AT1 activating antibody has already been considered), particularly those derived from the PE placenta. The current knowledge on this topic was recently reviewed [121–123] by the authors who pioneered the sFlt-1 theory a decade ago [121, 124]. Commonly viewed as a state of ‘angiogenic imbalance’, plasma concentrations of antiangiogenic molecules such as sFlt-1 (which binds VEGF and PlGF) and sEng (which binds TGF-β) are elevated in the circulation of women with PE, while free concentrations of PlGF and VEGF are reduced [8]. Increased circulating levels of proinflammatory cytokine markers such as TNF-α and IL-6 have also been reported [125]; some of these are released from placental microparticles which also display elevated concentrations in women with PE [126, 127]. The use of circulating epigenetically modified cell-free nucleic acids [128] or microRNA profiles [129] as novel biomarkers has also received recent attention. However, in spite of intensive study, to date, there are no definitive, reliably predictive tests for PE. The WHO reviewed the usefulness of predictive tests and concluded that there is no cost-effective or reliable screening test for PE [130], though this review was published as long ago as 2004. Multicenter trials that propose using a combination of proprietary metabolomic and proteomic markers are Preeclampsia and Maternal CVD
ongoing [e.g. 15], and more than 200 candidate biomarkers have been proposed, e.g. placental hormones, angiogenic factors and lipids. However, to date, none of these markers, alone or in combination, has proved to be sufficiently specific and sensitive for clinical use [15]. While exercise is often viewed as a panacea for CVD, a prospective population-based cohort study from Norway did not find any reduction in PE risk in women who were physically active prior to conception [131]. The effects of nutritional interventions are also limited [132], although some beneficial effects of antiplatelet agents, primarily low-dose aspirin and calcium supplementation have been noted [133]. Some beneficial effects of exercise in previously preeclamptic women have also been noted, with the results of some studies suggesting that exercise may be potentially helpful for disease prevention [134–136]. A recent review of the research strategies for prediction of PE, including maternal risk factors, mean arterial pressure, ultrasound parameters and biomarkers, concluded that the most promising strategies involve a variety of individual parameters in combination. The main categories of interest are: angiogenic/antiangiogenic factors, placental proteins, free fetal hemoglobin, markers of renal function, ultrasound evaluation of uteroplacental blood flow and evaluation of maternal risk factors [137]. A discussion on how specific markers can be used to predict PE can be found in several recent papers [138–140]. Consistent with this thinking, the improved pregnancy outcomes via early detection (IMPROvED) trial, launched in 2013 [15], involves a consortium of eight academic institutions and four small and medium enterprises in five countries: Germany, Ireland, the Netherlands, the UK and Sweden. It seeks to recruit 5,000 lowrisk nulliparous women early in pregnancy for blood analysis, using proprietary metabolomic and proteomic platforms in an effort to detect PE. Although many studies have attempted to predict or screen for PE using one or two markers, we are technologically at a point where more complex algorithms allow the interpretation of changes in a number of different markers and better use can be made of targeted provocation tests. Perhaps the most promising approach is one that characterizes the individual’s genotype/phenotype and then uses this information to inform the appropriate algorithm for disease prediction and detection. By using personalized medicine that takes family history, ethnicity, genotype and phenotype into consideration, we may be able to finally target the PE syndrome in a way that yields true clinical benefit and ameliorates the significant morbidity and mortality associated with this gestational disease. J Vasc Res 2014;51:290–304 DOI: 10.1159/000367627
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that women who were born small (below the 5th birth weight percentile) were 2–3 times more likely to develop GH (this study did not distinguish PE). This was not the case for women who were born large (above the 90th percentile) and there was no association with the father’s birth weight [119]. The strengths of this particular study were its prospective design and size (nearly 200,000 women were selected from a registry of >2 million stratified by birth weight). An earlier case-control study from the USA was smaller in size (2,180 women with GH and almost 23,000 without GH) but they also found a strong, inverse relationship between maternal birth weight and the likelihood of developing GH, with an odds ratio of 2.1 [120].
Finally, one must consider how to factor-in the increased risk of CVD among women with previous PE into clinical management. In 2011, the American Heart Association formally recognized the hypertensive complications of pregnancy as a major risk factor for the subsequent development of CVD [133]. Their guideline also
outlined the evidence-based interventions that could be applied to those at risk with the goal of primary prevention. These recommendations can be used to guide the clinical management of those recognized as being at a high risk for future cardiovascular events.
References
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