Preeclampsia and health risks later in life: an immunological link

Abstract

Pregnancy represents a period of physiological stress, and although this stress is experienced for a very modest portion of life, it is now recognized as a window to women's future health, often by unmasking predispositions to conditions that only become symptomatic later in life. In normal pregnancy, the mother experiences mild metabolic syndrome-like condition through week 20 of gestation. A pronounced phenotype of metabolic syndrome may program pregnancy complications such as preeclampsia. Preeclampsia is a serious complication with a myriad of manifestations for mother and offspring. This pregnancy syndrome is a polygenic disease and has been now linked to higher incidence of cardiovascular disease, diabetes, and several other disorders associated with vulnerable organs. Furthermore, the offspring born to preeclamptic mothers also exhibit an elevated risk of cardiovascular disease, stroke, and mental disorders during adulthood. This suggests that preeclampsia not only exposes the mother and the fetus to complications during pregnancy but also programs chronic diseases in later life. The etiology of preeclampsia is thought to be primarily associated with poor placentation and entails excessive maternal inflammation and endothelial dysfunction. It is well established now that the maternal immune system and the placenta are involved in a highly choreographed cross-talk that underlies adequate spiral artery remodeling required for uteroplacental perfusion and free flow of nutrients to the fetus. Since normal pregnancy is associated with a sequence of events represented by temporal events of inflammation (implantation), anti-inflammation (gestation), and inflammation (parturition), it is quite possible that unscheduled alterations in these regulatory responses may lead to pathologic consequences. Although it is not clear whether immunological alterations occur early in pregnancy, it is proposed that dysregulated systemic and placental immunity contribute to impaired angiogenesis and the onset of preeclampsia. This review will focus on important aspects of the immune system that coordinate with placental dysfunction to program preeclampsia and influence health in later life.

The impact of proteinuria on maternal and perinatal outcomes among women with pre‐eclampsia

“…Nonetheless, immunologic and inflammatory factors play important roles in the development of this disease, and the first contact between a women's immune systems and an abundance of nonself antigen that comes from the fetus could activate those factors. 12,13 The present study cohort had a high incidence of severe preeclampsia, which was diagnosed when clinical or laboratory findings suggested organ failure, imminent onset of eclampsia, or elevated blood pressure. The use of proteinuria as the selection criteria could, therefore, have led to bias as women with mild term pre-eclampsia often undergo delivery without assessment of a 24-hour urine sample.…”

“…The pathophysiologic mechanisms of pre‐eclampsia are unclear. Nonetheless, immunologic and inflammatory factors play important roles in the development of this disease, and the first contact between a women's immune systems and an abundance of non‐self antigen that comes from the fetus could activate those factors …”

Immune‑related pathophysiological causes relevant to a subset of patients with preeclampsia (Review)

“…To date, a substantial number of epidemiological studies have been published, indicating that preeclampsia is associated with an increased risk of hypertension, cardiovascular and metabolic diseases in later life (1)(2)(3)(4). Maternal preeclampsia is a major determinant of an offspring's risk of developing cardiovascular disease, stroke and mental disorders during later adult life (4). The adverse intrauterine environment factors, including immune responses, inflammation, or oxidative stress, play a key role in causing this disorder.…”

“…Preeclampsia is a pregnancy complication characterized by new-onset hypertension and proteinuria that may be accompanied by generalized maternal endothelial dysfunction and end organ dysfunction. This disease leads to maternal and perinatal morbidity and mortality, and it also confers an increased long-term risk of chronic illnesses, including preterm birth, babies with low birth weight, cardiovascular disease and stroke (1)(2)(3)(4). Emerging evidence suggests that the etiopathogenesis is multifactorial, resulting from a combined contribution of dietary and demographic factors, maternal genetic predisposition, epigenetic alterations and environmental insults (4-7).…”

“…Although the initial cause of preeclampsia remains unknown, abnormal EVT invasion appears to play an important role in the pathogenesis of preeclampsia. Furthermore, emerging evidence indicates that preeclampsia has stage-specific gene signatures: Immune escape from natural killer (NK) cell attack may enhance EVT invasion ('stop' preeclampsia development) and inflammation, oxidative stress and an imbalance in the angiogenic factors promote disease progression ('go' preeclampsia development) (4,7,13,14,(18)(19)(20). This model underscores a stage-dependent 'go or stop' dichotomy that exerts opposing influences, possibly through a better ability to flexibly adapt to a changing environment.…”