Pregnancy involves an interplay between maternal and fetal factors affecting changes to maternal anatomy and physiology to support the developing fetus and ensure the well-being of both the mother and offspring. A century of research has provided evidence of the imperative role of the placenta in the development of
preeclampsia. Recently, a growing body of evidence has supported the adaptations of the maternal cardiovascular system during normal pregnancy and its maladaptation in
preeclampsia. Debate surrounds the roles of the placenta vs the maternal cardiovascular system in the pathophysiology of
preeclampsia. We proposed an integrated model of the maternal cardiac-placental-fetal array and the development of
preeclampsia, which reconciles the disease phenotypes and their proposed origins, whether placenta-dominant or maternal cardiovascular system-dominant. These phenotypes are sufficiently diverse to define 2 distinct types:
preeclampsia Type I and Type II. Type I
preeclampsia may present earlier, characterized by placental dysfunction or malperfusion, shallow trophoblast invasion, inadequate spiral artery conversion, profound syncytiotrophoblast stress, elevated soluble fms-like
tyrosine kinase-1 levels, reduced placental
growth factor levels, high peripheral vascular resistance, and
low cardiac output. Type I is more often accompanied by
fetal growth restriction, and low placental
growth factor levels have a measurable impact on maternal cardiac remodeling and function. Type II
preeclampsia typically occurs in the later stages of pregnancy and entails an evolving maternal cardiovascular intolerance to the demands of pregnancy, with a moderately dysfunctional placenta and inadequate blood supply. The soluble fms-like
tyrosine kinase-1-placental
growth factor ratio may be normal or slightly disturbed, peripheral vascular resistance is low, and cardiac output is high, but these adaptations still fail to meet demand. Emergent placental dysfunction, coupled with an increasing inability to meet demand, more often appears with
fetal macrosomia, multiple pregnancies, or
prolonged pregnancy. Support for the notion of 2 types of
preeclampsia observable on the molecular level is provided by single-cell transcriptomic survey of gene expression patterns across different cell classes. This revealed widespread dysregulation of gene expression across all cell types, and significant imbalance in fms-like
tyrosine kinase-1 (FLT1) and placental
growth factor, particularly marked in the syncytium of early
preeclampsia cases. Classification of
preeclampsia into Type I and Type II can inform future research to develop targeted screening, prevention, and treatment approaches.