Placental-related diseases of pregnancy: Involvement of oxidative stress and implications in human evolution

Abstract

Miscarriage and pre-eclampsia are the most common disorders of human pregnancy. Both are placental-related and exceptional in other mammalian species. Ultrasound imaging has enabled events during early pregnancy to be visualized in vivo for the first time. As a result, a new understanding of the early materno-fetal relationship has emerged and, with it, new insight into the pathogenesis of these disorders. Unifying the two is the concept of placental oxidative stress, with associated necrosis and apoptosis of the trophoblastic epithelium of the placental villous tree. In normal pregnancies, the earliest stages of development take place in a low oxygen (O2) environment. This physiological hypoxia of the early gestational sac protects the developing fetus against the deleterious and teratogenic effects of O2 free radicals (OFRs). In miscarriage, development of the placento-decidual interface is severely impaired leading to early and widespread onset of maternal blood flow and major oxidative degeneration. This mechanism is common to all miscarriages, with the time at which it occurs in the first trimester depending on the aetiology. In contrast, in pre-eclampsia the trophoblastic invasion is sufficient to allow early pregnancy phases of placentation but too shallow for complete transformation of the arterial utero-placental circulation, predisposing to a repetitive ischaemia-reperfusion (I/R) phenomenon. We suggest that pre-eclampsia is a three-stage disorder with the primary pathology being an excessive or atypical maternal immune response. This would impair the placentation process leading to chronic oxidative stress in the placenta and finally to diffuse maternal endothelial cell dysfunction.

Figure 1

Diagram showing the oxygen (O₂) delivery system in the adult body (left) to ensure that cells are not exposed to the full atmospheric concentration and excessive oxidative stress; plugging of the maternal spiral arteries and the presence of the large exocoelomic cavity (right), devoid of an O₂ carrier, could serve as a similar protective mechanism for embryonic tissues during the first trimester.

Figure 2

Diagram of a gestational sac at the end of the 2nd month showing the myometrium (M), the decidua (D), the placenta (P), the exo-coelomic cavity (ECC), the amniotic cavity (AC) and the secondary yolk sac (SYS).

Figure 3

Diagram of the utero–placental interface in the first trimester and later in pregnancy showing the reduced cytotrophoblastic plugging and incomplete transformation of the spiral arteries in pregnancies complicated by pre-eclampsia.