Preeclampsia—an immune disease? An epidemiologic narrative

The maternal syndrome preeclampsia is triggered by syncytiotrophoblast (STB) stress; the heterogeneity of the syndrome is caused by the different pathways leading to this STB stress. Inflammation plays a pivotal role in the pathogenesis of preeclampsia. While, the immune system at large is therefore intimately involved in the causation of this heterogeneous syndrome, the role of the adaptive immune system is more controversial. The classic paradigm placed preeclampsia as the disease of the nulliparous pregnant women. Up to the later part of the 20th century, human reproduction, particularly in Western societies, was characterised by a low rate of pre-marital sex, and the great majority of children being born within one stable sexual relationship. More prolonged periods of regular sexual intercourse within a stable relationship have been demonstrated to reduce the risk of preeclampsia and fetal growth restriction. Primarily animal studies have indeed shown that repetitive sperm exposure leads to partner specific mucosal tolerance. Societal changes made partner change over the reproductive period of individual women extremely common. For the adaptive immune system of multiparous women, being pregnant in a new sexual relationship (primipaternity) would represent being faced with a new “hemi-allograft”. In these pregnancies, potential couple-specific immune “maladaptation” could lead to the superficial cytotrophoblast invasion of the spiral arteries, known to be associated with early-onset preeclampsia. Having a new pregnancy in a different relationship does indeed increase the risk for this type of preeclampsia. Large epidemiologic population studies identified prolonged birth interval but not “primipaternity” as a risk factor for preeclampsia in multiparous women. This apparent contradiction is explained by the fact that the great majority of preeclampsia cases in these population studies involve term preeclampsia. In late-onset preeclampsia, the far more common phenotype of the syndrome, STB stress is not caused by lack of proper spiral artery modification, but involves maternal genetic predisposition to cardiovascular and metabolic disease, with in particular obesity/metabolic syndrome representing major players. Partner or couple specific issues are not detectable in this disease phenotype.