Preeclampsia (PE) is a hypertensive pregnancy disorder complicating up to 1–5% of pregnancies, and a major cause of maternal and fetal morbidity and mortality. In recent years, observational studies have consistently shown that PE carries an increased risk for the mother to develop cardiovascular and renal disease later in life. Women with a history of PE experience a 2-fold increased risk of long-term cardiovascular disease (CVD) and an approximate 5–12-fold increased risk of end-stage renal disease (ESRD). Recognition of PE as a risk factor for renal disease and CVD allows identification of a young population of women at high risk of developing of cardiovascular and renal disease. For this reason, current guidelines recommend cardiovascular screening and treatment for formerly preeclamptic women. However, these recommendations are based on low levels of evidence due to a lack of studies on screening and prevention in formerly preeclamptic women. This review lists the incidence of premature CVD and ESRD observed after PE and outlines observed abnormalities that might contribute to the increased CVD risk with a focus on kidney-related disturbances. We discuss gaps in current knowledge to guide optimal screening and prevention strategies. We emphasize the need for research on mechanisms of late disease manifestations, and on effective screening and therapeutic strategies aimed at reducing the late disease burden in formerly preeclamptic women.

CLINICAL PERSPECTIVES

Recognition of the hypertensive pregnancy disorder preeclampsia as a risk factor for cardiovascular and renal disease allows identification of a young population of women at risk. Additional research into mechanisms and effective screening and prevention approaches is required to establish evidence based guidelines to decrease the long-term burden of cardiovascular and renal disease in formerly preeclamptic patients.

INTRODUCTION

Population-based studies have shown consistently that women with a history of the hypertensive pregnancy disorder preeclampsia (PE) experience a 2-fold increased risk of long-term cardiovascular disease (CVD) [1]. This increased risk of CVD is accompanied by disturbances in renal function [2,3]. In the past 5–10 years, it has also been shown that women with a history of PE have an approximate 5–12-fold increased risk of developing end-stage renal disease (ESRD) in later life [46].

Recognition of PE as a risk factor for cardiovascular and renal disease allows identification of a young population of women at high risk. Recently, the American Heart Association (AHA), as well as the American Stroke Association (ASA), acknowledged PE as a woman-specific risk factor for CVD. Both organizations recommend follow-up and treatment of formerly preeclamptic women in their guidelines [7,8]. In addition, the Netherlands was the first country in Europe to implement a guideline on cardiovascular risk management after reproductive disorders in women [9]. However, specific recommendations on screening and prevention in the established guidelines are based on low levels of evidence. Currently there are no studies available to evaluate the effectiveness and efficacy of these different policies.

In order to identify effective screening and prevention strategies, additional insights into the mechanisms underlying the late disease manifestations in women with a history of PE are required. This review outlines kidney-related disturbances that might contribute to the increased risk of CVD and kidney disease. We emphasize the need for research into mechanisms, screening and prevention to establish evidence-based guidelines for a customized approach of formerly PE patients. Ultimately, such guidelines may help to decrease the burden of CVD and renal disease as late manifestations of PE.

PREECLAMPSIA

PE is a major cause of maternal and fetal morbidity and mortality worldwide, complicating up to 1–5% of pregnancies [10,11]. Traditionally, PE is characterized by de-novo development of hypertension (≥140/90 mmHg) and proteinuria during the second half of pregnancy [12]. However, other findings associated with PE, such as new-onset thrombocytopenia, renal insufficiency, neurological complications, liver involvement and fetal growth restriction, may substitute for new-onset proteinuria according to the latest definitions [13]. The disease can be classified as either early-onset PE (onset before 34 weeks of gestation) or late-onset PE (onset at or after 34 weeks of gestation). The presenting features overlap, but early- and late-onset PE are associated with different maternal and fetal outcomes, and are thought to have a different etiological background [14]. The exact etiology behind PE is still unknown, but there seems to be an interaction between immunological, genetic and environmental factors. Redman and Sargent [15] proposed a three-stage model for the development of PE. According to this model, PE originates very early in pregnancy from incomplete toleration of the allogeneic fetus (first stage) resulting in reduced immune-regulated remodelling of the spiral arteries in the decidua (second stage). In response to the incomplete process of placentation, diverse placental factors, such as the anti-angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), are released into the maternal circulation. These and other placental factors induce generalized maternal endothelial dysfunction, and lead to the clinical manifestations of hypertension and proteinuria (third stage). In addition to the model of early placental dysfunction, more recent models suggest that restricted size of the uterus and the placental bed, and depletion of cytotrophoblast progenitors to replenish the syncytiotrophoblast layer can limit placental health and result in clinical PE [16]. Discontinuation of the production of placental factors by delivery of the placenta is, at present, the only therapeutic solution, often resulting in preterm birth. After delivery quick normalization of the maternal blood pressure and proteinuria are observed in most of the patients.

PREMATURE CVD AND ESRD AFTER PREECLAMPSIA

Despite normalization of the maternal preeclamptic phenotype after birth, studies consistently show that formerly preeclamptic women experience an approximately doubled risk of cardiovascular events occurring primarily in the fifth and sixth decade of life [17]. Formerly preeclamptic women develop chronic hypertension and CVD 6–8 years earlier compared with women with a history of normotensive pregnancy [18,19]. In the years between the index pregnancy and manifestation of CVD, formerly preeclamptic women already present increased levels of several cardiovascular risk factors such as high BMI, insulin resistance and high cholesterol and triglycerides [20,21]. In addition, mildly increased systolic and diastolic blood pressures are often found in the first years postpartum [22,23]. A recent meta-analysis shows that women with a history of PE have a relative risk (RR) of 3.13 of hypertension and an odds ratio (OR) of 2.28 for future CVD [1]. Both severity (blood pressure systolic >160 mmHg or diastolic >110 mmHg) and early onset of PE (<34 weeks) increase this risk even further [24]. Women with a history of more than one hypertensive pregnancy have a higher risk to develop high blood pressure compared with women with only one hypertensive pregnancy [21].

Current literature reports that risk of developing CVD is not only increased in formerly preeclamptic women, but also in women who experienced other pregnancy complications such as gestational hypertension and intrauterine growth restriction. Compared with PE, the risk of developing hypertension and CVD after gestational hypertension is slightly lower [25]. The risk of CVD after intrauterine growth restriction has been less well investigated. In a recently published Dutch Guideline for cardiovascular risk management after reproductive disorders, based on a meta-analysis of four studies [2629], women with a previous pregnancy complicated by intrauterine growth restriction were found to have a RR of 1.71 for developing CVD [9]. Additional studies suggest that this risk is higher after more than one IUGR pregnancy [27] and increases with the severity of the IUGR [30].

In addition to increased cardiovascular risk, population-based studies showed that PE affects renal health later in life. Vikse et al. [31] demonstrated that formerly preeclamptic women have a RR of 4.7 for developing ESRD after correction for traditional risk factors. This risk triples when women had PE during more than one pregnancy or a pregnancy complicated by low-birth-weight or preterm delivery [31]. Two Taiwanese cohort studies (with overlap) found hazard ratio (HR) of between 10.6 and 14.0 for developing ESRD after PE [4,5]. Although RRs are high, the absolute risk for ESRD in formerly preeclamptic patients remains quite low with an incidence of only 14.5/100.000 person years [31]. The prevalence of chronic kidney disease (CKD) in the general population is much higher and is associated with high rates of morbidity and mortality. However, the exact risk of CKD in formerly preeclamptic women is unknown. For now, only two studies have reported on CKD risk after hypertensive disorders of pregnancy. The study by Männistö et al. [32] reports HRs for development of CKD after pregnancy-induced hypertension (PIH) (HR 1.91) and PE (HR 0.75). These HRs are however difficult to interpret since they are based on very low incidences of CKD within the groups. The study by Wang et al. [4] in a Taiwanese cohort suggests that there is an increased risk of CKD after hypertensive pregnancy disorders. This study reports a HR of 9.4 after hypertensive pregnancy disorders in general, which might even be an underestimation of the real risk since the study classified CKD based on ICD-code registration and not on CKD stages derived from the estimated glomerular filtration rate (eGFR).

MECHANISTIC INSIGHTS

Adaptation to pregnancy demands increased cardiovascular and renal effort and it has been proposed that pregnancy is a stress test for the cardiovascular system by temporally unmasking limited cardiovascular reserves [33]. The increased cardiovascular and renal risk might be caused by common risk factors that PE shares with CVD and CKD (e.g. oxidative stress and metabolic alterations). Most of the metabolic alterations observed in formerly preeclamptic women such as insulin resistance and unfavourable lipid spectrum profiles are thought to be pre-existing. The increased insulin resistance is reflected in the higher rates of diabetes mellitus in formerly preeclamptic women. Formerly preeclamptic women have a RR of 1.71–3.63 to develop diabetes mellitus which might contribute to the risk of CVD and ESRD [3438]. However, the increased cardiovascular and renal risk may also result from disturbances caused by PE itself. A Norwegian study found that approximately 50% of the increased risk after PE can be explained by common risk factors [39]. Vikse et al. [40] suggested that PE itself is an independent risk factor for the development of ESRD and Chambers et al. [41] reported that the endothelial dysfunction observed in former preeclamptic women could not be explained by established maternal risk factors.

The exact nature of PE-specific molecular links between late cardiovascular and renal disease in formerly preeclamptic patients remain to be elucidated [42,43]. The predisposition might be caused by a combination of mildly disrupted pathways that are induced by PE that persist after pregnancy. Normal pregnancy is accompanied by elevation of angiotensin II (ang II), renin and aldosterone levels although the vascular responsiveness to ang II is decreased [44]. During PE, circulating components of the renin–angiotensin–aldosterone system (RAAS) are decreased, whereas sensitivity of ang II is significantly increased [45]. The disturbances in circulating RAAS components during PE pregnancy return to normal levels within 3 months after delivery but the sensitivity of the system remains disturbed postpartum. Four studies report mildly increased ang II sensitivity of the blood pressure in formerly preeclamptic women [4649]. In addition, a higher sodium sensitivity index and significant salt-induced increases in blood pressure were found in women with a history of PE [50]. The nocturnal fall of blood pressure in formerly preeclamptic patients was also affected by sodium intake although this was not the case in controls [50]. Increased sensitivity to ang II as well as to sodium might predispose to cardiovascular and renal disease.

Other persistent disturbances that might lead to the increased cardiovascular and renal risk in formerly preeclamptic women were described in detail in our previous paper [3]. In short, the angiogenic imbalance with elevated sFlt-1 causing persistent endothelial cell dysfunction [5153] and disturbances in the immune system with increased inflammatory markers [53,54] may predispose formerly PE women to cardiovascular and renal disease. Furthermore, formerly preeclamptic women have a higher sympathetic activity in blood pressure regulation causing lower baroreflex sensitivity and alterations in extracellular volume [55].

RENAL DISTURBANCES AFTER PREECLAMPSIA

The kidneys play an important role in the physiological adaptations of pregnancy. During pregnancy, effective renal plasma flow (ERPF) increases and renal hyperfiltration occurs with a 40–60% increase in glomerular filtration rate (GFR) in the second half of pregnancy. During preeclamptic pregnancy, the kidneys are strongly affected by systemic endothelial dysfunction leading to proteinuria and glomerular endotheliosis [56] and a lower GFR is observed [57]. After termination of a preeclamptic pregnancy, these renal disturbances normalize but do not resolve completely. In the direct postpartum period as well as years after pregnancy termination, mild but persistent disturbances in albuminuria and renal function are observed which may contribute to the increased risk of cardiovascular and renal disease.

Proteinuria

Micro-albuminuria is an indicator for the development of kidney disease and mediator of further renal diseade and CVD [58]. A meta-analysis showed that the occurrence of micro-albuminuria is as high as 31% in women with previous PE compared with 7% in controls at a weighted mean of 7.1 years postpartum [2]. In addition, this study showed a graded relationship between micro-albuminuria and the severity of PE, with a 4-fold increase after mild PE and a 8-fold increased after severe PE. A limitation of this meta-analysis is that most of the included studies did not correct for confounders (race, obesity, smoking and case history) and took place in heterogeneous clinical settings [including patients with haemolysis elevated liver enzymes and low platelets (HELLP) syndrome and diabetes mellitus]. Retrospective studies, which were not included in the meta-analysis, report lower incidences of proteinuria in formerly preeclamptic women. The study by Mangos et al. [23] reported no differences in albumin-to-creatinine ratio 4–5 years after pregnancy and a recent population-based study in Norway reports micro-albuminuria in only 1.1% of the formerly PE patients 10 years postpartum [59]. These studies indicate that a history of PE is not associated with a long-term increased risk of persisting micro-albuminuria. Berks et al. [60] reported proteinuria persisting in a considerable number of women (21%) shortly postpartum, but observed a decline over time to 14% of the women having proteinuria at 3 months postpartum and to only 2% at 2 years postpartum. This study shows that micro-albuminuria can slowly resolve over years after preeclamptic pregnancy. The authors speculate that this slow recovery of albuminuria might reflect a slow ongoing recovery process of the glomerular endothelium in the kidney.

Kidney function and renal haemodynamics

Current literature only reports on kidney function and renal haemodynamics early after PE. In the meta-analysis of McDonald et al. there were no significant differences in serum creatinine values, creatinine clearance and eGFR in formerly preeclamptic women compared with healthy parous controls [2] and Mangos et al. [23] did not report eGFR changes 4–5 years postpartum. Only recently, subtle changes in renal function and renal haemodynamics in formerly preeclamptic women were reported. Sandvik et al. [59] showed a high normal eGFR in previous early-onset preeclamptic women 10 years postpartum, which might indicate an early stage of hyperfiltration. Consistently, an increased filtration fraction (FF) was found in women with formerly early onset PE [61]. Of interest is that the increased FF in this study was observed as in the absence of co-morbidity and that the findings could not be explained by differences in mean arterial pressure (MAP), sodium and protein intake or RAAS activity. Hyperfiltration might be the first sign for future kidney problems in formerly preeclamptic women; an increased FF can contribute to progressive renal damage and a subsequent decline in GFR during long-term exposure [62,63].

Other renal haemodynamic parameters including ERPF and renal vascular resistance (RVR) were only evaluated in formerly preeclamptic patients in a few small studies. However, these studies included patients with co-morbidities such as hypertension which might well explain the renal haemodynamic findings [64,65].

TOWARDS SCREENING AND PREVENTION

PE as a risk factor for renal disease and CVD allows identification of a young population of women who are at high risk for the development of future disease (Figure 1). Since formerly preeclamptic patients are easily identifiable, some authors already suggested that women with a history of PE should undergo periodic renal and cardiovascular follow-up in order to detect subclinical damage and to take preventive measures [66]. The lack of studies on efficacy and effectiveness of screening and prevention in formerly preeclamptic women impedes the development of evidence-based guidelines. Nevertheless, some national guidelines recently implemented screening and treatment recommendations for formerly preeclamptic patients to reduce the risk of CVD. The ASA recommends considering evaluation of all women with a history of PE and eclampsia 6 months to 1 year postpartum, and to treat abnormal cardiovascular risk factors including hypertension, obesity, smoking and dyslipidaemia [8]. The current AHA guideline `prevention of CVD in women' marks women with a history of PE as at risk and recommends careful monitoring of risk factors following PE, without mentioning when monitoring and preventive measurements should be started. The AHA advises medical treatment with thiazide diuretics at a blood pressure ≥140/90 mm Hg. The multidisciplinary Dutch guideline for cardiovascular risk management after reproductive disorders recommends screening of risk factors at the age of 50 years after a pregnancy complicated by PE.

Window for screening and prevention after preeclampsia

Figure 1
Window for screening and prevention after preeclampsia

The presence of classical CVD risk factors, mechanistic disturbances and clinical manifestations before the onset of CVD and ESRD in women with a history of PE offer the opportunity for screening and prevention to reduce the risk of long-term events.

Figure 1
Window for screening and prevention after preeclampsia

The presence of classical CVD risk factors, mechanistic disturbances and clinical manifestations before the onset of CVD and ESRD in women with a history of PE offer the opportunity for screening and prevention to reduce the risk of long-term events.

The development of these guidelines is a good first step towards decreasing CVD burden in a specific group of women at high risk of developing premature CVD. Specific recommendations for screening and prevention strategies within these guidelines are, however, inconsistent and somewhat premature due to low levels of evidence. The choices for the proposed time points and parameters for screening are questionable because of a lack of knowledge on the exact time course of important different cardiovascular risk parameters after pregnancy complicated by PE to determine the optimal starting time and time interval for screening. In addition, it is not known which kind of treatment regimens are most effective to prevent CVD and renal disease due to a lack of randomized controlled trials (RCTs) in women in general, as well as in this specific population of women. Research is warranted to develop optimal evidence-based and cost-effective strategies for screening and prevention in formerly preeclamptic patients (Table 1).

Table 1
Recommendations for future research: towards screening and prevention of renal and cardiovascular disease after preeclampsia
Best screening strategies: 
Prospective cohorts with sequential follow-up of cardiovascular and renal risk parameters: 
- Determination of parameters to identify patients at high risk (glucose, lipids, blood pressure) 
- Determination of optimal start point of screening 
- Determination of optimal screening intervals 
Best prevention strategies: 
RCTs: 
- Optimal blood pressure lowering agents (e.g. RAAS inhibitors, diuretics, β-blockers) 
- Effects of life style interventions 
- Effects of correction of metabolic disturbances (e.g. statins) 
- Cost-effectiveness studies 
Best screening strategies: 
Prospective cohorts with sequential follow-up of cardiovascular and renal risk parameters: 
- Determination of parameters to identify patients at high risk (glucose, lipids, blood pressure) 
- Determination of optimal start point of screening 
- Determination of optimal screening intervals 
Best prevention strategies: 
RCTs: 
- Optimal blood pressure lowering agents (e.g. RAAS inhibitors, diuretics, β-blockers) 
- Effects of life style interventions 
- Effects of correction of metabolic disturbances (e.g. statins) 
- Cost-effectiveness studies 

RECOMMENDATIONS FOR FUTURE RESEARCH

Screening strategies

At this moment there are no studies that have published longitudinal follow-up of cardiovascular and renal risk parameters in women with a history of PE. Currently available data are often limited to only one measurement in the postpartum period. As a result, the time course of cardiovascular and renal disturbances after preeclamptic pregnancy is not mapped; e.g. it is not known which parameters improve (as was shown for micro-albuminuria by Berks et al. [60]) and/or may worsen in the years after pregnancy, and it is unclear at which time point after pregnancy we expect to find the first signs of an adverse cardiovascular profile. In addition, pre-pregnancy longitudinal cohorts are missing although it would be preferable to have pre-pregnancy data to better discriminate between pre-pregnancy and pregnancy effects on risks for CVD and renal disease.

Prospective cohorts with sequential follow-up of cardiovascular and renal risk parameters will be helpful to determine good screening markers, and to assess the optimal starting point and frequency of screening. A long-term design of such studies is of importance to establish the link between the different subtle and subclinical changes observed in formerly preeclamptic women and long-term risk of cardiovascular and renal disease. Women suffering from PE are relatively young and partly protected for rapid progression of renal disease and CVD by cardioprotective hormones such as estrogens. In addition, subclinical damage may be masked for several years at this young age by compensatory mechanisms such as renal hyperfiltration [62].

Prevention strategies

Recommendations for screening and treatment strategies in current guidelines follow from data extrapolated from cardiovascular preventive trials largely performed in older male subjects. This might not be the optimal strategy since underlying risk factors leading to cardiovascular risk in women differ from those in men [67]. PE is a female specific cardiovascular risk factor and in the years after PE, increased RAAS sensitivity, metabolic alterations (including lipid profiles and insulin sensitivity), endothelial dysfunction, sympathic overactivity, sodium sensitivity of blood pressure are present. These disturbances are most probably interrelated to the development of cardiovascular and renal disease. Targeted treatment can be aimed at either of these pathways by lifestyle modification and/or target drug therapy. Premenopausal estrogen is assumed to be a protective hormone. However, postmenopausal administration of estrogen therapy should not generally be considered as an option in these women as this has not shown to be beneficial in CVD prevention [68]. Additional insights into mechanistic disturbances in formerly preeclamptic women will be helpful to identify targetable pathways to reduce the renal and cardiovascular burden in these patients.

At this moment, there are no large studies on the benefit of early lifestyle and/or therapeutic interventions in young women at risk and no RCTs for therapeutic options have been performed in this specific group of patients. It should be taken into account that preventive therapy is started at a very young age, which favours the choice of lifestyle changes. Lifestyle intervention on exercise, dietary habits and smoking cessation have been estimated to reduce cardiovascular risk in this patient group with an odds ratio of 0.91 [69]. The first study on postpartum lifestyle intervention after complicated pregnancy showed promising effects on body constitution and fat intake in a non-randomized cohort [70]. However, lifestyle modification is known to be difficult to achieve. Other strategies such as drug therapy with RAAS inhibition and/or statins might be more potent to reduce the cardiovascular and renal risk.

RCTs are required to determine the most effective treatment in this young female subcategory. Since the monitoring of hard outcomes (cardiovascular event and ESRD) is not feasible due to low incidences at this young age, the design of these RCTs should include monitoring of intermediate classical cardiovascular and renal parameters over a period of 5–10 years. The intermediate measurements will enable the performance of cardiovascular risk prediction to evaluate the effectiveness of the different treatment strategies. After the determination of the most effective treatment strategy in the formerly PE women, the challenge remains to identify the optimal starting point for intervention to cost-effectively reduce cardiovascular and renal manifestations. On an individual level, the start of preventive measures before the onset of symptoms might be superior to starting therapy after the onset of the first clinical manifestations (hypertension, fist stages of CKD). Adequate individualized cardiovascular risk prediction might help to identify women who will benefit from early preventive measures in a cost-effective way.

In conclusion, a history of PE serves as a risk marker for future premature cardiovascular and renal disease and thus provides a potential indicator for early identification of women at increased risk. A history of PE should be in included in screening for cardiovascular risk factors and prevention strategies should be developed for this specific young population. We emphasize the need for insights into the time course of risk factor development and mechanistic pathways in order to identify optimal screening and treatment options. Until we find effective therapies specific for post-preeclamptic women, these women should be screened and managed as well as possible with the general CVD preventive measures (blood pressure control and life style advice). Ultimately, a multidisciplinary approach will lead to the establishment of evidence-based guidelines with a customized and structured approach to formerly preeclamptic patients which may help to decrease the burden of CVD and renal disease in this population.

AUTHOR CONTRIBUTION

Nina Paauw collected relevant literature and drafted the manuscript. Kim Luijken collected relevant literature. Arie Franx en Marianne Verhaar provided intellectual content on the obstetric en nephrologic aspects. Titia Lely conceptualized and revised the manuscript. All authors approved the final manuscript as submitted.

Kim Luijken is a medical student participating in the Honours program of the Faculty of Medicine, UMC Utrecht.

FUNDING

Clinical fellowship, ZonMW – Project number 40-000703-97-12463 to A.T.L. and Junior Post-Doc Kolff Grant, Dutch Kidney Foundation – KJPB 11.026 to A.T.L.

Abbreviations

     
  • AHA

    American Heart Association

  •  
  • ang II

    angiotensin II

  •  
  • ASA

    American Stroke Association

  •  
  • CKD

    chronic kidney disease

  •  
  • CVD

    cardiovascular disease

  •  
  • eGFR

    estimated glomerular filtration rate

  •  
  • ERPF

    effective renal plasma flow

  •  
  • ESRD

    end-stage renal disease

  •  
  • FF

    filtration fraction

  •  
  • HR

    hazard ratio

  •  
  • PE

    preeclampsia

  •  
  • RAAS

    renin–angiotensin–aldosterone system

  •  
  • RCT

    randomized controlled trial

  •  
  • RR

    relative risk

  •  
  • sFlt-1

    soluble fms-like tyrosine kinase-1

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