The six stages of pre-eclampsia

For many years pre eclampsia has been considered to be a two-stage disease. The first stage comprises poor placentation. The second stage is the clinical expression of the disease namely new hypertension and new proteinuria. The first stage is preclinical and symptomless, which evolves between weeks 8 and 18 of pregnancy, when the uteroplacental circulation is established by spiral artery remodelling. Its consequence is dysfunctional perfusion of the intervillous space of the placenta with oxidative and haemodynamic stress. The damaged placenta releases excessive pro-inflammatory and antiangiogenic factors into the maternal circulation. With increasing knowledge, this model has become inadequate. First the antecedents of poor placentation have become clearer and are immunological in origin, reflecting the mother’s ability to accommodate to the genetic foreignness of her unborn child. They begin, as discussed already in this meeting, with preconceptual tolerisation of the mother to the semen of the prospective father of her child. A lack of tolerisation, arising from a short interval between first coitus and conception increases the likelihood of poor placentation and pre-eclampsia (Stage 1). This is presumed to affect the health and growth of the embryo immediately after implantation but there is little evidence of this at the moment (Stage 2). Placentation begins after week 8 when the uteroplacental circulation, which previously has been closed by trophoblast plugs in the spiral arteries, begins to open. Defective placentation may arise from premature opening, and perfusion of the intervillous space by oxygenised arterial blood before the placenta is equipped to cope with the stress. Placentation extends over about 10 weeks and, when it is defective, constitutes stage 3 of pre-eclampsia. Stages 4–6 all occur in the second half of pregnancy. Stage 4 is associated with excessive or deficient placental derived factors in the mother’s blood, secondary to placental damage, before the appearance of clinical signs. When the diagnosis of pre-eclampsia can be made stage 5 has begun. Stage 6 affects less than half of women with pre-eclampsia. It is the superimposition of a second and later spiral artery lesion called acute atherosis, which has some resemblance to atherosclerosis, which is suffered by middle and old-aged, non-pregnant adults. Its importance is that it further reduces uteroplacental perfusion and predisposes to spiral artery thrombosis, which underlies the occurrence of placental infarcts. The evidence for and the mechanisms of these multiple stages will be briefly presented.