from Heart wire -- a professional news service of WebMD

November 6, 2007 -- Two new papers published online November 1, 2007 in BMJ shed more light on the association between preeclampsia and cardiovascular disease, suggesting that the two might share common causes or mechanisms.

The first, a meta-analysis and systematic review by Leanne Bellamy (Imperial College School of Medicine, London, UK) and colleagues, finds that women who have preeclampsia in pregnancy have a more than twofold increased risk of vascular disease later in life [1]. Although a positive association between preeclampsia and cardiovascular disease has previously been demonstrated, individual studies have had too few events to estimate the risks with precision. Senior author Dr David Williams (University College, London, UK) told heart wire : "We looked at three million women altogether, with 200,000 cases of preeclampsia, and we've been able to strengthen the observations made in the smaller studies. We've got a fairly robust conclusion that if you have had a pregnancy complicated by preeclampsia, you do have an increased risk of heart disease in later life."

In an accompanying editorial, Drs LA Magee and P von Dadelszen (University of British Columbia, Vancouver), agree [2]. Bellamy et al have summarized "the consistency and strength of the association between preeclampsia and cardiovascular disease," they note.

In the second paper, Dr Elisabeth Balstad Magnussen (Trondheim University Hospital, Norway) et al show in their population-based cohort study that women with cardiovascular risk factors before pregnancy were at higher risk of developing preeclampsia during pregnancy [3]. This research, say Magee and von Dadelszen, provides "support for a shared pathogenesis between cardiovascular disease and preeclampsia."

Women with preeclampsia: Earlier primary prevention for CVD

Bellamy et al analyzed 25 studies involving over three million women to calculate the future health risks of women who have had a pregnancy affected by preeclampsia. There were 198,252 women affected by preeclampsia and 29,495 episodes of cardiovascular disease and cancer (study outcomes).

After a mean of 14.1 years of follow-up, women with a history of preeclampsia had an almost fourfold increased risk of hypertension (odds ratio 3.70), a twofold increased risk of ischemic heart disease (OR 2.16), and an almost twofold increased risk of stroke (OR 1.81) and venous thromboembolism (OR 1.79).

They found no increase in risk of any cancer, however, including breast cancer, suggesting a specific relationship between preeclampsia and cardiovascular disease, although the mechanism underlying this association remains to be defined, they note. They found a small increase in overall mortality among women who had had preeclampsia (OR 1.49 after 14.5 years).

The British researchers point out, however, that most of the women in this review would not have reached menopause by the time of follow-up, so their absolute risk of ischemic heart disease is likely to have been low.

But in the studies included in the review that did follow women for 35 to 30 years, "there was a similar doubling of risk to those studies that had shorter follow-up, suggesting that the risk persists," Williams told heart wire .

And one of the biggest studies they included looked at whether preeclampsia could be considered an independent risk factor for cardiovascular disease, he noted, and they concluded that it was. "If we suppose that preeclampsia is a novel independent risk factor, then you double the risk on top of all classical risk factors, and these women with preeclampsia might become eligible for primary prevention at an earlier age," he adds.

Early preeclampsia even more dangerous

The British team also demonstrated that early-onset preeclampsia (at <37 weeks of gestation) is associated with an even greater risk of future cardiovascular disease. This finding came from two large studies included in the review, Williams said. "Quite amazingly, if you had preeclampsia at <37 weeks you had a seven- to eightfold increased risk of future cardiovascular disease."

And preeclampsia in any pregnancy compared with preeclampsia in only the first pregnancy was also associated with a greater relative risk (RR) of future hypertension. "It is likely that women who have recurrent preeclampsia have an underlying pathological phenotype that puts them at risk of hypertension and cardiovascular disease," the researchers say.

This means that cardiologists and general practitioners evaluating a woman's risk of cardiovascular disease in middle age should be asking them if they had preeclampsia at all during pregnancy, if it occurred in more than one pregnancy, and at what point in the pregnancy it occurred, Williams says, adding: "Preeclampsia helps us to identify women who might not otherwise be picked up from just having a high cholesterol alone."

Women with high BP seven times more likely to develop preeclampsia

Magnussen et al linked a Norwegian population-based study of cardiovascular risk markers and Norway's medical birth registry. They studied 3494 women who gave birth after participating in the population-based study, of whom 133 (3.8%) had preeclampsia.

After adjustment for smoking, previous preeclampsia, parity, maternal age, education, socioeconomic position, and duration between baseline measurements and delivery, positive associations were found between prepregnancy serum levels of triglycerides, cholesterol, low-density-lipoprotein (LDL) cholesterol, blood pressure, and risk of preeclampsia.

The odds ratio of developing preeclampsia for women with baseline systolic blood pressures (SBP) >130 mm Hg (highest fifth) was 7.3 vs women with SBP <111 mm Hg (lowest fifth). Those with the highest triglycerides and highest cholesterol had twofold higher risks of preeclampsia than those in the lowest fifths (OR 2.3). Similar results were found for women who were having their first baby and women who had already had a baby.

"We found that cardiovascular risk factors that were present years before pregnancy are associated with a risk of preeclampsia," say Magnussen et al. This finding suggests that unfavorable cardiovascular and metabolic profiles may represent primary causes of preeclampsia and that these factors predispose both to preeclampsia and to subsequent cardiovascular disease, suggesting that the two may share a common origin, they note.

This does not rule out the possibility that the preeclamptic process itself may also contribute to subsequent cardiovascular risk, they conclude.

What can doctors do for women with preeclampsia?

In their editorial, Magee and von Dadelszen point out that despite the important attributable risk of cardiovascular disease associated with preeclampsia, "the absolute risk over the short term is low."

But the question still remains as to what clinicians should do for women with preeclampsia, they state. Several possible routes of action exist, they note. The most appropriate initial intervention for such women is to encourage a heart-healthy diet and lifestyle changes to decrease the risk of cardiovascular disease, they say.

"Unfortunately, simply advising people to undertake a healthier lifestyle is not enough to change their behavior. However, women might be more receptive if they have had a complicated pregnancy," they suggest.

Second, they agree with the British researchers that doctors should ask women about their pregnancy experiences. Women with a history of preeclampsia or gestational hypertension should have their risk of cardiovascular disease actively assessed three to six months postpartum, they should be advised on a healthy diet and lifestyle, they "should probably be screened early for traditional risk markers of cardiovascular disease, and they should be treated, at a minimum, according to published guidelines.

"Future research must investigate whether targeting women with previous preeclampsia identifies a population that is more receptive to lifestyle changes or one that should have their traditional cardiovascular risk markers treated earlier and more aggressively (or both)," they conclude.

Drs. Magee and von Dadelszen have acted as expert witnesses in cases related to hypertensive disorders of pregnancy. Dr. von Dadelszen has received an unrestricted grant from Lilly Canada.

Sources

1. Bellamy L, Casas, J-P, Hingorani AD, et al. Preeclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ November 2, 2007 online first doi: 10.1136/bmj.39335.385301.BE.
2. Magnussen EB, Salvesen KA, Vatten LJ, et al. Prepregnancy cardiovascular risk factors as predictors of preeclampsia: population-based cohort study. BMJ November 2, 2007 online first doi: 10.1136/bmj.39366.416817.BE.
3. Magee LA and von Dadelszen. Preeclampsia and increased cardiovascular risk. BMJ November 2, 2007 online first doi: 10.1136/bmj.39337.425500.80.

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Clinical Context

Study Highlights

• Magnussen and colleagues
  • Adults in 1 county in Norway were invited to participate in this population-based study. Subjects were evaluated at baseline with a thorough history and assessment of plasma glucose and lipid levels.
  • The authors found 3494 women who had delivered an infant with a gestational age of more than 22 weeks or birth weight of more than 500 g between 1995 and 2005. 3.8% of these women were noted to have preeclampsia.
  • The main study outcome was the relationship between cardiovascular risk factors at baseline and the risk for preeclampsia. This result was adjusted for age, parity, history of preeclampsia, educational level, and whether the woman received Social Security benefits.
  • Smoking and a higher educational level were associated with a reduced risk for preeclampsia, and women who used oral contraceptives at baseline experienced nearly half the risk for preeclampsia vs never or previous users.
  • Women in the highest quintile for SBP (> 130 mm Hg) had an OR of 7.3 for developing preeclampsia vs women in the lowest quintile (< 111 mm Hg). A similarly increased risk was found in comparing women with diastolic blood pressure in the highest quintile (> 78 mm Hg) vs the lowest quintile (< 64 mm Hg).
  • Increasing body mass index and waist circumference were positively associated with the risk for preeclampsia, as were higher levels of total, non–high-density lipoprotein, and LDL cholesterol. Elevated triglyceride and glucose levels were less robust in predicting an increased risk for preeclampsia.
• Bellamy and colleagues
  • The authors conducted a systematic review and meta-analysis of studies that followed long-term events after the diagnosis of preeclampsia. Preeclampsia was defined by a blood pressure exceeding 140/90 mm Hg with proteinuria greater than 0.3 g/day after 20 weeks of gestation.
  • Specific long-term outcomes of interest were cardiovascular events, cancer, and mortality.
  • Of 117 articles identified, 25 met criteria for the meta-analysis. Overall, the studies compared 198,252 women with preeclampsia with 3,488,160 women who did not have preeclampsia.
  • The RR for hypertension was 3.70 in comparing women with and without a history of preeclampsia. The mean weighted follow-up time for this outcome was 14.1 years. Pregnancy-induced hypertension also increased the risk for future hypertension (RR, 3.39).
  • The mean weighted follow-up time for ischemic heart disease outcomes was 11.7 years, and preeclampsia was associated with a RR of 2.16 for this outcome. Subgroup analysis based on parity did not significantly alter this finding, but preeclampsia before 37 weeks of gestation seemed particularly strong as a risk factor for future ischemic heart disease.
  • The RR for stroke in comparing women with and without a history of preeclampsia was 1.81, and the RR for venous thromboembolism was 1.79.
  • Preeclampsia did not affect the risk for incident cancer, including breast cancer.
  • The mean weighted follow-up time for the outcome of overall mortality was 14.5 years, and the RR for death associated with preeclampsia was 1.49. Again, preeclampsia at less than 37 weeks of gestation was a particularly potent risk factor for this outcome.

Pearls for Practice

• In the current study by Magnussen and colleagues, traditional cardiovascular risk factors predicted an increased risk of developing preeclampsia, but the use of oral contraceptives reduced this risk.
• The current meta-analysis by Bellamy and colleagues suggests that a history of preeclampsia increases the risk for different types of future cardiovascular events as well as overall mortality. However, preeclampsia does not affect the risk for incident cancer.

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