Maternal placental syndromes: pathological mechanisms and long-term consequences

Abstract

Preeclampsia, intra uterine growth restriction (IUGR) and placental abruption are major contributors to maternal and perinatal morbidity and mortality. In these disorders the placenta is a key aetiological factor and therefore preeclampsia, IUGR and placental abruption are also referred to as maternal placental syndromes (MPS).It is now widely accepted that impaired spiral artery remodelling in the placental bed is a key factor in the development of MPS. Extravillous trophoblasts fail to remodel maternal spiral arteries, into high capacity and low resistance vessels, in complicated pregnancies. Failure of this process results in “shallow” placentation and, in some cases, the preeclamptic syndrome, which is clinically defined as a multisystem syndrome by its key signs hypertension and concomitant proteinuria after 20 weeks of gestation. Interestingly, the risk of cardiovascular disease is increased after a hypertensive pregnancy and common risk factors suggest a shared pathogenesis. Given that pregnancy is considered as a stress test for future cardiovascular health, it has been proposed that women with MPS fail this stress test and are at higher risk for developing cardiovascular disease later in life. We found that the immune cell involvement was significantly different in women with preeclampsia. Of special interest is the higher level of T-cells in the placental bed. Specific lesions of spiral arteries, acute atherosis, which show a striking resemblance to atherosclerosis, were shown to correlate with higher levels of triglycerides and LDL cholesterol. The biobank of placental bed biopsies we collected is unique and our methods have been published in a comprehensive review. Further we have shown that endoplasmic reticulum (ER) stress may play an important role in the failure of spiral artery remodelling, in research conducted at the University of Cambridge. ER stressed trophoblast cells display a diminished invasive capacity, most likely due to reduced MMP activity. This suggests that ER stress may negatively impact trophoblast invasiveness in vivo and, thus, may be implicated in the pathophysiology of MPS. We propose that a pro-inflammatory phenotype might cause this ER stress. Interestingly we also showed that higher levels of pro-inflammatory markers CRP and fibrinogen correlate with a recurrence of preeclampsia. CRP and fibrinogen are also independent risk factors for cardiovascular disease. We show that levels of risk factors for cardiovascular disease are significantly higher in women with a history of preeclampsia, but also in women with placental abruption. The differences in prevalence of postpartum hypertension between early onset preeclampsia, late onset preeclampsia, and pregnancy-induced hypertension (PIH) are interesting. In early-onset preeclampsia, the prevalence is the highest, followed by PIH and late-onset preeclampsia. Furthermore, women with previous early-onset preeclampsia have the most deviant risk profile, compared to late-onset preeclampsia and PIH, in terms of glucose levels and lipid profile. Collectively, this suggests that likelihood of developing cardiovascular disease later in life may be reflected in post-partum (biochemical) risk factors. Our results support development of early prevention programmes for high-risk women but also indicate that physicians should stratify for the different hypertensive pregnancy complications in order to further personalize preventive strategies.