WHAT MATTERS IN PRE-ECLAMPSIA: A DIAGNOSIS OR THE OUTCOMES ASSOCIATED WITH THAT DIAGNOSIS?

Pre-eclampsia is a clinical syndrome defined by the maternal signs of hypertension and proteinuria. That pre-eclampsia is so-defined could be said to be an historical accident - it might just as usefully be hyperuricaemic gestational hypertension, for example, in terms of predicting adverse perinatal outcomes. Unlike the disease process of type I diabetes, there is no defined causal relationship between a single pathological entity (eg islet cell destruction) and the clinical entity. In addition, there is also said to be a fetal syndrome of pre-eclampsia - that of IUGR and fetal acidosis. However, at term, when the bulk of pre-eclampsia occurs, the maternal syndrome is more commonly associated with macrosomia than with IUGR. This underlies the belief that the route to the maternal syndrome is not solely through imperfect placentation during the first trimester (reflected in fetal IUGR and early-onset pre-eclampsia), but to an imbalance between feto-placental demands and maternal vascular supply (even with normal uteroplacental arterial adaptation).

It appears that pre-eclampsia is a uniquely human condition. In evolutionary terms, why would a condition have been selected for that mainly affects primigravidae and their fetuses, if it were uniformly deleterious? Increasing evidence suggests that pre-eclampsia may be generally adaptive in the face of relative placental imbalance (uteroplacental mismatch), leading to improved survival, quality of that survival, and neurodevelopmental outcomes for infants delivered of pregnancies with uteroplacental mismatch - this would be reflected in the mild, evanescent pre-eclampsia that arises at term. What would seem to matter is those cases of biological overshoot, whereby the maternal response to mismatch is exaggerated and potentially dangerous for both mother and fetus. This biological overshoot appears to be more prevalent in early-onset pre-eclampsia, where the maternal and perinatal risks are greatest.

Therefore, in trials of 'pre-eclampsia prophylaxis' what is it that we should try to prevent? Is it (i) the occurrence of a BP >140/90 and 0.3g/24h proteinuria or (ii) the adverse maternal and perinatal outcomes that cluster around the maternal syndrome? It is my belief that it is the latter. In any study design to prevent 'pre-eclampsia' I feel that, with our current state of knowledge, the investigators must design and power their study to examine the effect of the proposed intervention on the adverse consequences of pre-eclampsia, not just the diagnosis itself. If a proposed intervention actually works in preventing 'pre-eclampsia' (and we're still waiting for one), then it may be possible that that intervention may actually remove perinatal advantages and adversely influence perinatal outcomes.

An example of this might be the use of antihypertensives to prevent pre-eclampsia. It is possible that the use of antihypertensives would reduce the frequency of achieving a BP >140/90, thereby reducing the incidence of hypertension, even if hyperuricaemic proteinuria supervenes. Lowering BP over weeks of pregnancy may confer adverse perinatal risks in terms of reduced fetal growth velocity and a cluster of other adverse perinatal events. Therefore, the avoidance of a maternal diagnosis of 'pre-eclampsia' might actually be associated with increased perinatal risks.

Similarly, in defining the severity of pre-eclampsia, it becomes important to assess the ability of severity criteria to predict adverse maternal and perinatal outcomes. This needs to be done in a prospective fashion using admission diagnoses, not ultimate diagnoses. Clinicians need to have an effective diagnostic framework that will advise them, and the families for whom they care, of the risks for adverse outcomes derived from evidence-based severity criteria that effectively predicts adverse outcomes and that are pertinent to the initial assessment of these women and ongoing surveillance as the clinical syndrome evolves.

In summary, pre-eclampsia appears to a biological double-edged sword: (i) any maternal advantages are hard to discern, however, perinatal advantages may occur in a significant proportion of cases; (ii) the mild, late-onset syndrome may be largely adaptive, while the early-onset syndrome clearly is not for either mother or fetus. As our knowledge of the complexity of the pre-eclampsia process grows, so should the sophistication of our clinical and scientific definitions, our understanding of the pathophysiology, and the design of our studi