A history of pre-eclampsia increases the risk of future hypertension, ischaemic heart disease, stroke, venous thromboembolism, and death from any cause. The major contribution to all cause mortality seems to be cardiovascular disease, as there was no difference in the relative risk of death from breast cancer or any other cancers.
It is possible that much of the excess risk of future ischaemic heart disease and stroke is explained by the link between pre-eclampsia and blood pressure.19
Most studies (12 of 15) only made adjustment for age, but three adjusted for diabetes mellitus, features of the metabolic syndrome, smoking, and socioeconomic status.w9w17 w18
In one of these studies that included over a million women the association between pre-eclampsia and future cardiovascular disease seems to be independent of prepregnancy hypertension, diabetes mellitus, obesity, dyslipidaemia, the metabolic syndrome, and smoking.w18
We found a similar twofold increased risk of cardiovascular disease in those studies with incomplete adjustment for established cardiovascular risk factors.
Pre-eclampsia most commonly occurs during the first pregnancy. Women who had pre-eclampsia early (<37 weeks' gestation) in their first pregnancy were more likely to have recurrent pre-eclampsia compared with those who had pre-eclampsia late in their first pregnancy (>37 weeks' gestation). Recurrent pre-eclampsia compared with a single episode has been associated with a sevenfold increased risk of later hypertension.w3 We also found that pre-eclampsia in any pregnancy compared with pre-eclampsia in only the first pregnancy was associated with a greater relative risk of future hypertension. It is likely that women who have recurrent pre-eclampsia have an underlying pathological phenotype that puts them at risk of hypertension and cardiovascular disease.
We also observed in the sensitivity analysis that women who had early pre-eclampsia had the greatest risk of future cardiovascular disease and this was higher than those who had “severe” pre-eclampsia. This observation was supported by tests of heterogeneity. It follows that the timing of onset of pre-eclampsia more accurately reflects the severity of the maternal cardiovascular phenotype than the severity to which pre-eclampsia may evolve, which more probably reflects the timeliness of antenatal observations.
Most women in the studies in our review will not have reached the menopause by the time of follow-up, so their absolute risk of ischaemic heart disease is likely to have been low. A woman living in the United Kingdom aged 40-49 years and with an average level of risk factors for cardiovascular disease has an almost 4% risk of a cardiovascular event within 10 years (J Moon, personal communication, 2007). If the increased risk of cardiovascular disease after pre-eclampsia is independent of these risk factors this risk would increase to around 8% for an otherwise similar woman with a history of pre-eclampsia. Two reports included in our review followed up women for more than 20 years after pre-eclampsia and the data indicated that the twofold risk of later cardiovascular disease persists long term.w13w17
Since the risk of a cardiovascular event increases with age, absolute risk at age 50-59 years would be 8.3% and 17.8% for a woman without and with a history of pre-eclampsia and at 60-69 years would be 14.2% and 30.7%, suggesting that a woman with pre-eclampsia might become eligible for primary prevention at an earlier age.20
The matter of the independence of the effect of pre-eclampsia on cardiovascular risk could be dealt with by an analysis of data at participant level from studies that measured risk factors.
Most populations included in the systematic review were of European origin, such as women from North America, Canada, and western Europe. It is possible that other ethnic groups will have different risk ratios for future cardiovascular disease. Women of Afro-Caribbean origin have an increased risk of pre-eclampsia,21
which may translate into a higher risk of future cardiovascular disease.
The null association with cancer, a common cause of morbidity and mortality in later life, suggests the associations are specific to cardiovascular disease. This observation may indicate a common cause for pre-eclampsia and cardiovascular disease or a deleterious effect of pre-eclampsia on the maternal vascular system, or both.
It is possible that transient but severe endothelial dysfunction, observed in pre-eclampsia,1
potentiates a cascade of events that progresses to atherosclerosis. Endothelial dysfunction has been observed as early as 23 weeks' gestation in women who develop pre-eclampsia later, during pre-eclampsia itself, and at least three months after pre-eclampsia has resolved.1 22 23
In support of a common causal link, obesity, hyperlipidaemia, hypertension, and other disorders associated with pre-existing endothelial dysfunction, such as diabetes mellitus and polycystic ovarian syndrome, are risk factors shared by women at risk of both pre-eclampsia and cardiovascular disease.12
Moreover, women with inherited thrombophilias are at increased risk of pre-eclampsia and venous thromboembolic disease.24 25
A potential role for angiogenic peptides and their endogenous inhibitors in the physiology of pre-eclampsia is in keeping with this hypothesis as these pathways have been implicated in the development of cardiovascular disease.26
It is possible therefore that pre-eclampsia is the initial point of expression of an inherent adverse phenotype associated with the early development of cardiovascular disease. One exception is the notable discordance between the protective effect of smoking on risk of pre-eclampsia and its deleterious effect on risk of cardiovascular disease.27 28
It is unlikely that our observations are the result of chance because of the large number of women included (>3.4 million) and the large number of incident cases. Furthermore, there was a strong consistency of the association between pre-eclampsia and future cardiovascular disease in different studies for most end points. The only outcome for which there was evidence of small study bias was incident hypertension (see bmj.com).29
Clear concordance was, however, found between the effect estimates of the largest studies included in the meta-analyses and the overall relative risks that we produced for each outcome. The effect estimate for incident hypertension after pre-eclampsia (relative risk 3.7, 2.7 to 5.05) could be an overestimation, and a relative risk less prone to bias would be the one obtained from pooling the largest studies—that is 2.37, 2.11 to 2.66.
Assessing the quality of included studies is controversial. The application of a quantitative score of study quality as part of study selection in meta-analysis is a process that has not been validated and can itself introduce bias. To overcome this problem we evaluated relevant study characteristics that may introduce bias to the meta-analysis, and we used these characteristics in a sensitivity analysis (fig 4). This approach indicated that the findings were robust. Most of the studied cohorts were retrospective, which limited our ability to assess adequately the effect of potential confounders on observed associations.
Some women in older studies with pregnancy induced hypertension may have been misclassified as having pre-eclampsia, but when analyses were restricted to women with a clear phenotype such as severe pre-eclampsia, similar results were obtained. Furthermore, we showed that women who had pregnancy induced hypertension have a similar, but lower, risk of future hypertension and cardiovascular disease as those who had rigorously defined pre-eclampsia (see bmj.com).
The WHO criteria for international classification of diseases were universally adopted for the diagnoses of all outcomes except hypertension. A minimum diastolic blood pressure of 90 mm Hg or the use of antihypertensives after the pregnancy with pre-eclampsia were used to diagnose hypertension. As included studies spanned more than 40 years, alterations in diagnostic criteria occurred, with reclassification (eight, ninth, and 10th revisions). This may not have affected the numbers of future events but may have increased the likelihood of misclassification. Since the overall relative risks were consistently increased for all cardiovascular outcomes, this possibility is unlikely.
Women who have had pre-eclampsia have an increased risk of cardiovascular disease, including an almost fourfold increased risk of hypertension and an approximately twofold increased risk of fatal and non-fatal ischaemic heart disease, stroke, and venous thromboembolism in later life. This may explain the small increase in risk of death. The lack of association between pre-eclampsia and future cancer, in particular breast cancer, suggests a specific relation between pre-eclampsia and cardiovascular disease.
The mechanism underlying this association remains to be defined, but whatever its nature a history of pre-eclampsia should be considered in the evaluation of women's risk of cardiovascular disease. If the risk proves independent of established risk factors for cardiovascular disease, affected women would be eligible for preventive therapies at an earlier age than usual.
What is already known on this topic
- A positive association has been found between pre-eclampsia and future cardiovascular disease but individual studies have had too few incident events to estimate the risks with precision
- It is uncertain whether the association is specific to cardiovascular diseases or extends to other common life threatening disorders such as cancer
What this study adds
- After pre-eclampsia, women have an increased risk of hypertension, fatal and non-fatal ischaemic heart disease, stroke, and venous thromboembolism in later life
- Early onset pre-eclampsia (<37 weeks' gestation) is associated with an even greater risk of future cardiovascular disease
- No association was found between pre-eclampsia and future breast cancer