Pre-eclampsia: A complex and variable disease.

We would like to know the cause of pre-eclampsia. We would also like to be able to diagnose and treat it quickly and effectively, to be able to predict it accurately with one simple test and prevent it with safe and simple medication. But we cannot, nor on present evidence, will we ever be able to do so. Why is this? There are several reasons, which I will attempt to summarise: the heart of the problem is the complexity and variability of the disorder, which is so daunting that every specific statement about preeclampsia seems to have exceptions - it is truly a disease of exceptions. The cause of pre-eclampsia appears to be the placenta - in that the disorder can occur without a fetus as in hydatidiform mole, without a uterus as in abdominal pregnancy and is resolved by delivery (of the placenta). On the other hand some of the worst presentations are of women who are normal until delivery and then get a major crisis, eclampsia or the HELLP syndrome, immediately afterwards, when the placenta has gone. The placental problem is poor uteroplacental circulation secondary to inadequate remodelling of the spiral arteries that occurs between weeks 8 and week 18 (poor placentation). The maternal symptoms and signs arise from maternal endothelial dysfunction and an associated vascular inflammation. But the placental pathology can occur without features of pre-eclampsia and endothelial dysfunction can arise in mothers without placental disease (maternal pre-eclampsia). This apparent confusion can be resolved in part by recognising that pre-eclampsia is not a disease but a syndrome - encompassed by its defining features of new hypertension and proteinuria that remit after delivery. A syndrome is simply an empirical definition of a clinical presentation that demands action. It tells you nothing about pathogenesis. One syndrome usually encompasses several conditions and this is likely to be true of pre-eclampsia. The key here is to acknowledge that there are many routes to pre-eclampsia; that the final disorder arises from different mixes of environmental and genetic factors, with different contributions from the mother and the placenta. In terms of disease, the unique feature of the latter is that two individuals are involved, mother and baby, each with their different genetic make-ups. This can explain the heterogeneity of pre-eclampsia: for example the difference between early-onset disease with its high preponderance of fetuses that are growth restricted and prominent placental pathology in contrast to the late onset disease, which may be associated with large for gestational age fetuses and routinely reveals little placental pathology. Finally, many very mild features of pre-eclampsia arise towards term in normal healthy women. It is possible that all women are destined to get the disorder. Timing is the key feature, such that late gestation is a race against time: will spontaneous delivery occur before pre-eclampsia or vice versa?