Pre-Eclamptic Pregnancies: An Opportunity to Identify Women at Risk for Future Cardiovascular Disease

Abstract

Evaluation of: Bellamy L, Casas JP, Hingorani AD, Williams DJ: Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. Br. Med. J. 335(7627), 974 (2007). Evidence has emerged over the years suggesting that women who develop hypertensive pregnancy disorders, most notably pre-eclampsia, are at an increased risk for cardiovascular disease later in life. In this study, a systematic review and meta-analysis were performed, assessing the future risks of cardiovascular disease, cancer and all-cause mortality in women with a history of pre-eclampsia and eclampsia. Women with a history of pre-eclampsia or eclampsia, compared with women without such a history, had an increased risk for cardiovascular disease, including a fourfold increased risk for hypertension, a twofold increased risk for ischemic heart disease, stroke and deep venous thrombosis, and a 1.5-times higher all-cause mortality. The study suggests that affected women may be eligible for preventive therapies at an earlier age, especially if future studies establish the role of pre-eclampsia as an independent cardiovascular risk factor.

Increasing evidence suggests that women with a history of pre-eclamptic pregnancies are at an increased risk for future cardiovascular disease (CVD) [1]. An association between pre-eclampsia and the risk for developing hypertension later in life was recognized as early as the first part of the 19th Century [2], and was further supported by studies published between 1960 and 1970 [3,4]. This position was questioned in the 1970s by the results published by Chesley that showed no increased risk for future CVD for primiparous eclamptic women compared wth controls [5,6]. Despite the serious limitations of this study related to small sample size and the use of historical controls rather than a specific normotensive control group, its results led to the conclusion that hypertensive disease of pregnancy is limited to the affected pregnancy and has few, if any, future healthcare implications. Renewed interest in gender-specific risk factors occurred as a result of the CVD pandemic in women, which has emerged as the leading cause of death for women over 50 years of age. On the practice side, population-based strategies aimed at optimizing cardiovascular health in women have focused on overcoming the gender-based disparities in the delivery of cardiovascular care since women, compared with men, tend to be both undere-valuated and undertreated for modifiable CVD risk factors [7,8]. On the research side, efforts have focused on studying gender-specific CVD risk factors, and have indicated that the same CVD risk factors affect both men and women, but that the relative significance of these risk factors may be gender specific [9,10]. in addition, it has increasingly been recognized that conditions unique to women, such as pregnancy and its complications, hormone use and menopause, may affect clinical course and outcomes. As a result, studies conducted over the last decade have extended their focus from just studying the association of pre-eclampsia and hypertension later in life, to include future CVD, encompassing coronary, cerebrovascular and peripheral vascular disease [11]. The results of these studies have consistently supported the association of pre-eclampsia with increased risks for CVD, CVD-related death and all-cause death. For the most part, these studies have been population/registry based, have not controlled for conventional risk factors, and have reported a limited number of cardiovascular outcomes. The paper from Bellamy et al. comes as a timely and thorough review of the available literature, while further quantifying the magnitude of the association between pre-eclampsia and future incident disease (CVD and cancer) and mortality.

Results

In the current paper, Bellamy and colleagues performed a systematic review and meta-analysis assessing the future risks for CVD, cancer and all-cause mortality in women with a history of pre-eclampsia and eclampsia [1]. They conducted a search of Medline and Embase between 1960 and December 2006. The inclusion criteria required that a cohort study identify pre-eclampsia as a risk factor under investigation, aiming to identify incident disease as the outcome. Retrospective and prospective cohort studies were included; case–control studies were excluded. In total, 117 papers were identified, of which 25 were selected for analysis. These studies included 3,488,160 women, of whom 198,252 had pre-eclampsia. Subsequent CVD was identified in 29,495 women.

A total of 13 studies involving 21,030 women examined the future risk of hypertension. The weighted mean follow up was 14.1 years. The authors found that 1885 of 3658 women with pre-eclampsia developed hypertension later in life, providing a relative risk (RR) of 3.7. There was significant heterogeneity among the studies, with the smaller studies finding a higher relative risk for future hypertension. Analysis limited to the two largest studies with more than 200 cases of hypertension provided a RR of 2.37.

Eight studies examined pre-eclampsia and the subsequent risk of fatal and nonfatal ischemic heart disease. These studies involved 2,346,997 women, including 121,487 with pre-eclampsia, with a weighted mean follow-up of 11.7 years. There were 5097 ischemic heart disease events, with an RR of 2.16 for women with a history of pre-eclampsia. Unlike with hypertension, no significant heterogeneity was detected among the eight studies. Two studies specifically examined women with pre-eclampsia prior to 37 weeks of gestation and found a RR of 7.71, compared with normotensive women who delivered after 37 weeks' gestation. Two studies examined the impact of severe pre-eclampsia on future risk of ischemic heart disease and found a greatly increased RR of2.86 compared with those with mild pre-eclampsia with an RR of 1.92.

Four studies examined a total of 907 women with subsequent strokes in a cohort of 1,671,578 women, including 64,551 with pre-eclampsia. The RR for fatal and nonfatal stroke after pre-eclampsia, and during a weighted mean follow-up of 10.4 years, was 1.81; no significant heterogeneity was observed among the studies. A history of pre-eclampsia was associated with a greater RR for fatal stroke than nonfatal stroke (2.98 vs 1.76). Early pre-eclampsia, in other words, before 37 weeks' gestation, conferred a higher future risk of stroke (RR = 5.08) than pre-eclampsia diagnosed after 37 weeks' gestation (RR = 0.98).

Venous thromboembolism was identified during a weighted mean follow-up of 4.7 years in 470 of 427,693 women. The RR was 1.79 in 35,772 pre-eclamptic versus normal pregnancies. Only one study examined the effects of severe pre-eclampsia, and found a RR of 2.3, compared with 1.4 in women with mild pre-eclampsia.

The authors also studied the effects of pre-eclampsia on the future risk of breast cancer. After a weighted mean follow-up of 17 years, the RR of breast cancer was only 1.04, compared with women without a history of pre-eclampsia. Therefore, it suggests that pre-eclampsia is not a risk factor for the future development of breast cancer.

A significant increase in all-cause mortality was detected. Four studies examined 794,462 women, 49,049 of whom had a history of pre-eclampsia. During 14.5 years of weighted-mean years of follow-up, 7537 deaths were recorded. Given that breast cancer, a leading cause of death in women, did not provide an increased risk, the authors concluded that most of the all-cause mortality might be caused by cardiovascular events.

Significance

In the form of a well-conducted meta-analysis, this study has confirmed the association between pre-eclampsia/eclampsia and future CVD and all-cause mortality. In addition, it has provided strong evidence that the risks may be particularly high in patients who develop either early-onset or severe forms of pre-eclampsia. While these observations have been previously reported, these studies were unable to estimate the risks with precision as a result of small sample sizes and too few incident events.

Future perspective

The pathogenetic mechanisms that underlie the association between pre-eclampsia and future CVD are not well understood. One possibility is that these two conditions share common risk factors (such as obesity, hyperlipidemia and insulin resistance) that cause endothelial dysfunction, which can lead to pre-eclampsia and CVD at different times during a woman's life. Alternatively, pre-eclampsia itself may induce vascular and metabolic changes that may increase the risk for CVD later in life. Distinguishing between these two mechanisms is critically dependent on future studies that will compare risk factors and cardiovascular events between women who remain normotensive and those who develop pre-eclampsia in a longitudinal manner, in effect, before, during and after pregnancy. These studies may also establish whether pre-eclampsia is a dependent or independent risk factor; the latter may be proved by demonstrating that the association remains significant after controlling for established risk factors. If pre-eclampsia proves to be an independent CVD risk factor, improved screening, preventive and treatment strategies of this disorder may not only optimize pregnancy outcomes, but impact a woman's cardiovascular health in the long term. In the absence of these studies, it may be prudent to consider pre-eclampsia and eclampsia as markers of future CVD. A history of hypertensive disorders of pregnancy could be included as part of the assessment of a woman's overall risk profile. Women with a history of pre-eclampsia or eclampsia should be counseled not only for the risk of recurrence in future pregnancies, but also regarding future cardiovascular sequelae. Primary prevention in these women should consist of lifestyle modification, early detection of CVD risk factors and treatment according to current guidelines.

Executive summary

• Women with a history of pre-eclampsia, compared with those without such a history, are at increased risk for cardiovascular disease (CVD) later in life.

• The risk for CVD appears to be particularly high in subsets of patients with either early onset or severe forms of pre-eclampsia.

• The underlying mechanism of this association may be related to several common risk factors that may lead to pre-eclampsia and CVD at different times in a woman's life.

• Alternatively, pre-eclampsia may cause irreversible vascular and metabolic changes and, thus, modify the future risk for CVD.

• Regardless of the underlying mechanism, a history of pre-eclampsia may identify women at risk for CVD who may benefit from close monitoring and timely implementation of primary prevention measures.