Possible mechanisms of association between preeclampsia and later disease

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Pre-eclampsia shares common features with some determinants of disease in later life. A candidate mechanism linking the two is insulin resistance. It has been suggested that pre-eclampsia is a manifestation of the insulin resistance syndrome and the evidence supporting this is reviewed elsewhere (Solomon and Seely, 2001). Although insulin resistance in pregnancy is associated with an increased risk of pre-eclampsia, the relative risk is modest, at approximately 2. This would not be considered a strong association and is consistent with the clinical impression that the majority of women with gestational diabetes do not experience severe adverse outcomes in pregnancy. One of the problems in the clinical investigation of the causes of pre-eclampsia is the multiorgan involvement in the affected individual. Literally dozens of circulating factors have been shown to be altered among women with pre-eclampsia, but it is unclear whether these are causal or epiphenomena. It has been shown that the risk of pre-eclampsia is associated with first trimester circulating maternal concentrations of pregnancy-associated plasma protein-A (PAPP-A), a trophoblast-derived regulator of the insulin-like growth factor system (Smith et al., 2002). This observation suggests the factors determining later pre-eclampsia may be evident in the very earliest weeks post-conception. The relatively weak link between factors such as insulin resistance in late pregnancy and the risk of pre-eclampsia may reflect the importance of conditions in very early pregnancy in determining the risk of disease.

Clearly, insulin resistance is just one of many possible mechanisms linking pre-eclampsia and cardiovascular disease in later life. Another is thrombophilia. There are reports that women with inherited thrombophilias are at increased risk of pregnancy complications (Gharavi et al.,

2001) and of IHD (Rosendaal et al., 1997a, b). However, genetic epidemiology is plagued by small-scale studies and a systematic tendency of journals to publish positive results. This results in a characteristic pattern of a flurry of interest in a given mutation followed by a series of negative results (Bonnici et al., 2002). Consistent with this, recent large-scale studies of inherited thrombophilias and pre-eclampsia have been negative (Morrison et al., 2002). Nevertheless, both pre-eclampsia and diseases such as IHD show strong familial associations (Morgan and Ward, 1999; Slack and Evans, 1966). It is plausible, given the common features of the pathophysiology of these conditions, that there may be common genetic determinants of IHD and pregnancy complications. Consistent with this, a recent study has shown that a family history of early onset IHD is associated with an increased risk of delivering a low birthweight baby (Pell et al., 2003). It is currently well recognized that development of gesta-tional diabetes during pregnancy identifies women who are insulin resistant and at increased risk of developing type 2 diabetes in later life (Linne et al.,

2002). In this case pregnancy could be seen as a test of the body's predisposition toward diabetes. It is possible that the failure of the mother to adapt to placentation and fetal growth leading to obstetric complications such as pre-eclampsia, intra-uterine growth restriction or preterm birth reflects occult cardiovascular, microvascular or hemostatic dysfunction. Since these will also make her susceptible to hypertension, atherosclerosis and throm-botic disorders, a woman's reproductive history may, therefore, also become informative in assessing her future risk of cardiovascular disease. The true nature and mechanism of these associations will only be resolved by large-scale prospective studies.

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