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Biochemical markers and physiological parameters as indices for identifying patients at risk of developing pre-eclampsia

Packer, C Subah

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Pre-eclampsia is a frequent cause of maternal death, prematurity and perinatal morbidity and mortality [1]. Pre-eclampsia is characterized by hypertension, proteinuria and oedema. Without intervention, pre-eclampsia progresses to eclampsia, which is characterized by malignant hypertension and epileptiform convulsions requiring emergency Caesarian section. To prevent the high risk of mortality and morbidity such as maternal renal scarring that occurs with eclampsia and emergency C-section, the prudent approach to managing pre-eclampsia is to schedule a C-section delivery before progression to full-blown eclampsia. However, diagnosing pre-eclampsia is not simple and the criteria used in the diagnosis (i.e. hypertension, proteinuria and oedema) do not usually clearly manifest until relatively late in the pregnancy. Therefore, hypertension is used as a first sign and C-sections are often scheduled for moderately hypertensive patients when there is suspicion of pre-eclampsia. What proportion of these patients with gestational hypertension are really suffering from pre-eclampsia and is there a way of determining who will be pre-eclamptic early rather than late in the pregnancy? Pre-eclampsia is a disorder of which the cause and the predictors are elusive. Blood pressure tends to rise in pregnancy. Incidences of transient gestational hypertension have been reported to be as high as 30% [2]. Is this an era of epidemic of pre-eclampsia or is the rise in incidence of gestational hypertension reflective of the epidemics of metabolic syndrome, obesity and essential hypertension?

Determination of the aetiology and development of specific diagnostic tools of pre-eclampsia are not trivial undertakings. There are numerous circulating factors that are potential candidates to play a causative role in the mechanism and/or to serve as a marker of pre-eclampsia. These include, but are not limited to, various reactive oxygen species, co-factors such as vitamin B6 (pyridoxine) and prothrombins. The complexity of the problem lies in the fact that most of the candidates are altered with changes in female sex steroid balance, such as occurs in pregnancy, menopause and with oral contraceptives. For example, most pregnancies are accompanied by rises in superoxide dismutase activity, decreases in placental lipid peroxides, increased NO release (from umbilical vessels), increased nitrate concentrations, a deficiency in active vitamin B6 leading to a decrease in GABA and a rise in sympathetic outflow, and a rise in Factor II (prothrombin). Oral contraceptives are known to produce similar effects. Many of the circulating factors that are altered with changes in sex steroid status are altered to greater degree in pre-eclampsia and are also affected by other disorders such as obesity, essential hypertension and type II diabetes. Furthermore, the risk of developing pre-eclampsia appears to be greater in women who have family histories of essential hypertension, and there may also be a relationship between the risk of pre-eclampsia and the metabolic syndrome. In the placentas of pre-eclamptic patients, increased levels of lipid peroxides are observed [3]. Lee et al. [4] reported enhanced neutrophil NADPH oxidase-mediated reactive oxygen species production in pre-eclampsia. Various reports have indicated a relationship between pyridoxine status and hypertension in pregnant women and in women taking anovulatory steroids [5–7], and there is also evidence of a direct causative relationship between pyridoxine deficiency and high blood pressure [8,9]. Changes in pyridoxal phosphate levels and in Factor II levels may be responsible for increased blood pressure and increased risk of clot formation, respectively. Accordingly, alterations in a wide variety of circulating factors are not specific to pre-eclamptic patients but are just more pronounced in pre-eclampsia compared to normal pregnancy. Thus, the task at hand may be to determine the critical levels, or critical changes in levels, of circulating factors that would be indicative of pre-eclampsia rather than to find a specific marker that is uniquely altered in pre-eclampsia.

Both early events and late events of pre-eclampsia involve increased vascular resistance with consequent hypertension, ischaemia of vital organs and culminate in stroke if unchecked. Most of the circulating factors that are up-regulated in pre-eclampsia have the common feature of causing increased vasoconstriction. Although studies of just one factor or even of one class of factors have not provided reliable early biochemical markers of pre-eclampsia, in this issue of the journal, D'Aniello et al. [10] make a very convincing case for using a combination of two markers. Specifically, the authors show that combined maternal serum Factor-II : C and uterine arterial resistance index at mid-trimester provide a diagnostic tool of high reliability in identifying patients who will develop pre-eclampsia, as well as those who will not develop pre-eclampsia, in an Italian population. If the high reliability reported in this study holds true in a more extensive study in a larger sample pool, then this new method of the early prediction of pre-eclampsia will prove invaluable in not only improving intervention and outcomes of those at highest risk, but also in minimizing unnecessary treatments such as C-sections for those who are identified as not at risk. Expansion of the study to span multiple nationalities and to incorporate additional parameters such as diabetes before essential hypertension or family history of hypertension would provide further insight into the aetiology. A universal diagnostic tool to predict pre-eclampsia would prove most valuable.


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