Development of preeclampsia provides a window of opportunity for early cardiovascular risk screening and intervention

It is well established that women who have had a pregnancy complicated by preeclampsia (PE) are at an increased risk of hypertension (relative risk [RR]: 3.70; 95% CI: 2.70–5.05) [1], ischemic heart disease (RR: 2.16; 95% CI: 1.86–2.52) [1], major stroke (RR: 1.81; 95% CI: 1.45–2.27) [1] and premature cardiovascular death (RR: 1.49; 95% CI: 1.05–2.14) [1] compared with women with normotensive pregnancies; in women who developed severe and/or early-onset PE, the risks were greater, especially for premature cardiovascular death (RR: 8.12; 95% CI: 4.31–15.33) [1–4]. Numerous retrospective analyses comparing women who developed PE to healthy pregnancy controls have demonstrated differences in potential cardiovascular risk (CVR) factors, including increased blood pressure, lipids and BMI, along with evidence of insulin resistance, residual microalbuminuria and the metabolic syndrome at various time points in the postpartum period [5,6]. Our prospective cohort data have shown that many women who develop PE either already have underlying (typically undiagnosed) CVRs, or are at risk of developing them [7]. Specifically, by 1 year postpartum, we found that women who had developed PE had increased blood pressure, total cholesterol, higher low-density-lipoprotein cholesterol, triglycerides, increased BMI, fasting insulin, insulin resistance (i.e., the homeostasis model assessment–insulin resistance index) and microalbumin/creatinine ratio, and that incorporating these data and the markers of obesity, we also identified significantly more PE women with the metabolic syndrome [7]. Persistence or progression of these CVRs over years postpartum, probably leads to the subsequent development of cardiovascular disease (CVD) [1,2,4,8]. Based on our prospective cohort, mathematical modeling predicts a two-to-three-fold increased risk of significant cardiovascular events within 10 years of developing PE, and the risk is greatest with severe and/or early-onset PE. Already, we have seen women in the cohort who had developed PE subsequently require therapeutic intervention for CVRs (e.g., hypertension and hyperlipidemia) and/or present with CVD. The magnitude of this increased risk is in keeping with the published retrospective epidemiologic data, further validating our prospective cohort [1].

Progress in the last 20 years in our understanding of what causes PE has led to a realization that it is a multisystem syndrome characterized by microvascular dysfunction, metabolic disturbances (e.g., dyslipidemia and insulin resistance), endothelial dysfunction, activation of the coagulation cascade and increased inflammatory response [9]. A two-stage model for the development of PE has been proposed, in which impaired placental perfusion (first stage) is translated into the maternal disease (second stage) upon a background of maternal constitutional factors; these constitutional factors appear to be, in the large part, the factors that make up the metabolic syndrome (e.g., central adiposity/increased BMI, hypertension, Type II diabetes, dyslipidemia and insulin resistance) [10–12]. As such, there are striking similarities between the pathophysiology of PE and atherosclerosis.

It has been stated that pregnancy is a cardiovascular stress test and that ‘failure’ leads to the unmasking of physiologic susceptibility (i.e., gestational diabetes or gestational hypertension) and/or to the development of PE [13]. Large database studies have identified that while the development of PE at term (i.e., mild PE for the most part) is associated with a small but significant increased risk of future CVD, the development of severe PE, or PE in more than one pregnancy, is associated with a greater risk of premature CVD [4,14]. That is, the degree to which you ‘fail’ the pregnancy stress test and the number of times you ‘fail’ it reflect not only your risk for future CVD, but the time frame over which it develops; severe or recurrent PE is probably associated with premature CVD, whereas nonrecurrent, later onset or mild PE may be more associated with CVD and cardiovascular death only after menopause [4,15].

While the development of PE may contribute to the risk of developing CVD, it is unlikely to be the cause of it. Women with PE more frequently have a family history of CVD and prepregnancy CVRs, such as obesity, chronic hypertension, diabetes and dyslipidemia [16–19]. Therefore, women with underlying, perhaps undiagnosed, CVRs that make up the metabolic syndrome or are predisposed to developing the metabolic syndrome because of family history (i.e., genetics) are at an increased risk of developing PE and are more likely to be diagnosed with hypertension, obesity, atherosclerosis and Type 2 diabetes at some point after delivery, which eventually results in CVD [20]. The actual contribution of PE to the development of premature CVD is unknown. The development of PE may cause the microalbuminuria [21,22] and, perhaps, contribute to the impairment of endothelial function that persists postpartum [23,24], both of which are markers of increased risk for CVD, but it is unknown if PE results in worsening of the other CVRs. We are currently carrying out a large, longitudinal, preconception cohort study of first-time pregnant women to specifically address this question.

According to the 2007 Heart and Stroke Foundation Annual Report on Canadians Health [101], Canadian women are now as likely as men to die from CVD (approximately 37,000 Canadian women die of heart disease and stroke every year). The report highlights that, compared to men, a woman’s risk of dying following a cardiovascular event is higher. It had previously been assumed that differences in care occurred because women tended to be older and sicker at the point that they were hospitalized. However, when accounting for confounding variables, a woman’s risk of dying following a heart attack or stroke is 16 and 11% greater, respectively, than men. While the reasons are unclear, systemic, social and biologic factors are all thought to play a role [25]. Commonly used CVD preventive interventions are based on studies conducted primarily in men and it is uncertain whether the results can be generalized to include women.

A recent Ontario (Canada) population-based cohort study using linked administrative data reported that the prevalence of hypertension in women of child-bearing age (20–49 years old) in 2005 was 7.75%, which has progressively increased since 1995 [26]. In another study, a random sample of visible minority adults in Ontario in 2006 found the prevalence of hypertension in women to be 2.7% (20–39 years of age) and 20.5% (40–59 years of age) [27]. Interestingly, these numbers for women of reproductive age are very similar to the incidence of PE (approximately 5%). Unfortunately, neither authors, in keeping with the lack of recognition of PE and/or new onset hypertension in pregnancy as a marker of future CVD [28], asked subjects regarding their pregnancy history [Leenen F, Pers. Comm.]. They concluded that “public health strategies to prevent and manage hypertension and its sequelae are urgently needed”; this should include early risk identification in women who developed PE.

In 2000, the Heart and Stroke Foundation of Canada led the development of the Victoria Declaration on Women, Heart Disease and Stroke international recommendations on how to ensure equity in heart health status between women and men [102]. Unfortunately, the statistics demonstrating that more women than men die from CVD around the world has, for the most part, remained unknown by physicians and the public [25,29]. Two of the key recommendations in the Victoria Declaration that have not been adequately acted upon are: that more effort is required to provide primary prevention, screening, diagnosis and treatment; prevention of recurrence; rehabilitation and support programs and services that are tailored to women’s needs; and that Canadian women and their physicians need to be aware of their risk for, and the signs and symptoms of, CVD.

Pregnancy and adverse pregnancy outcomes provide a tremendous early opportunity where women can change their future health. It is estimated that over 80% of all Canadian women attain pregnancy at least once, and the average age of first pregnancy is 30 years. Since pregnancy is a time when women access the healthcare system on a regular basis, often for the first time, all forms of health screening, including CVR identification, intervention postpartum could be efficiently carried out for health preservation and disease prevention. Unfortunately, the development of adverse pregnancy outcomes is not recognized by most clinicians as a risk factor for CVD [28]. Early diagnosis and management of CVRs can prevent up to 80% of all CVDs, which is significant considering that CVD has an annual cost in Canada of more than CAD$22 billion [103]. Better informing and counseling the women prior to discharge from hospital following their affected pregnancy will allow them to be more proactive in managing their own health.

Rarely can a group at high risk for a disease – in this case, CVD – be identified early enough to target follow-up and intervention for prevention. The early identification of CVRs and subsequent implementation of innovative intervention strategies has the real potential to prevent long-term cardiovascular morbidity and mortality in these women.

Financial & competing interests disclosure

Graeme N Smith holds grants from the Canadian Institutes of Health Research (CIHR) related to this subject area. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.