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Pre-Eclampsia

Pathophysiology

Establishment of a healthy pregnancy The placenta is central to pre-eclampsia: pre-eclampsia is found only when a placenta is or was recently present.

The placenta is formed from extra-embryonic lineages in the blastocyst: trophectoderm cells differentiate into villus progenitor cytotrophoblasts, which fuse to form the syncytiotrophoblast or differentiate into invasive extravillous trophoblasts[120], and extra-embryonic mesoderm differentiates into villus core stromal tissue and blood vessels[120].

EVTs and uterine-resident immune cells, including uterine natural killer cells and regulatory T (Treg) cells, actively remodel the maternal spiral arteries into wide-bore, low-flow uterine arteries by removing vascular smooth muscle cells that surround the artery.

Remodelling is initiated by uterine-resident innate immune cells, including uterine NK cells and T regulatory (Treg) cells, which cause the loss of vascular smooth muscle cells surrounding the spiral arteries and regulate extravillous trophoblast invasion through the decidua via the secretion of angiogenic growth factors and cytokines[125].

At around 10–12 weeks of gestation, the trophoblast endovascular plugs dislodge[126,127], enabling increasing volumes of maternal blood to perfuse the intervillous space and increasing fetoplacental oxygenation

Placental Development: Fertilization to Full Term

The timeline covers the development of the fetus and placenta over 40 weeks of pregnancy

Weeks 0-13 mark the start of fetal and placental development after the fertilized blastocyst implants in the uterine wall

The placenta at this time is a relatively low-oxygen environment

Placental villi are lined with cytotrophoblasts and syncytiotrophoblasts

Cytotrophoblasts breach the uterine wall and remodel blood vessels to become a source of maternal blood for the placenta

The placenta develops to provide oxygen and nutrients to the fetus and to remove waste and nutrients

Over time, the villi become increasingly branched to accommodate the growing demands of the developing fetus.

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Spiral Artery Remodeling

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Vascular adaptations during pregnancy

Maternal cardiovascular system undergoes significant expansion during healthy pregnancy

Increased plasma volume and cardiac output from early gestation driven by placental-released factors

Prevents increases in blood pressure by decreased systemic vascular resistance, increased arterial compliance, and peripheral vasodilation

Endothelial release of vasodilatory factors and activation of the renal renin-angiotensin-aldosterone system also contribute to preventing blood pressure increases

Little evidence for autonomic regulation driving cardiovascular changes during pregnancy; adaptations are primarily endothelial and myogenic

Endothelium is highly responsive to humoral factors and physical forces as the interface between blood and vascular smooth muscle.

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The maternal cardiovascular system undergoes significant expansion, including increased plasma volume and increased cardiac output from as early as 3–4 weeks of gestation, primarily driven by placental-released factors[128].

Syncytiotrophoblast stress in preterm pre-eclampsia is thought to arise from abnormal placentation during early pregnancy, characterized by inadequate extravillous trophoblast invasion and spiral artery remodelling[145,146] (Fig. 2b).

This reduces blood flow to the placenta, resulting in placental hypoxia and placental ischaemia and reperfusion injury, causing syncytiotrophoblast stress.

It is hypothesized that syncytiotrophoblast stress is not present early in gestation of a pregnancy that is later complicated by term pre-eclampsia[149], explaining why early pregnancy predictive models for pre-eclampsia, which often include risk factors and biomarkers of abnormal placentation, demonstrate high accuracy in the prediction of preterm pre-eclampsia but underperform in the prediction of term pre-eclampsia[150].

These hypotheses have been difficult to test experimentally due to the inherent problem of obtaining early pregnancy placenta from ongoing pregnancies

Immune system dysfunction Maternal immunological problems are associated with abnormalities at the fetal–maternal interface.

Immunological tolerance to the fetus and placenta, whose genes are half-paternal, is facilitated, in part, by reduced placental expression of MHC and the human leukocyte antigen (HLA) system; this mechanism endeavours to avoid innate rejection of semi-allogeneic fetal cells[151].

Uterine NK cells and T lymphocytes are located in the decidua and have a critical role in promoting maternal immune tolerance to the fetus.

Treg cells exert immune tolerance functions by mechanisms including antigen presentation, secretion of inhibitory cytokines and cytolysis of target cells[152,153].

Abnormal release of Treg cell factors, including cytokines and microRNA, is found in pre-eclampsia[154].

Angiotensin II receptor type 1 auto-antibodies (AT1-AAs) are elevated in the serum of women with pre-eclampsia[158].

AT1-AAs have a sustained effect on vasoconstriction and can cause endothelial cell damage[158]

Maternal metabolic and cardiovascular health Accumulating evidence suggests that pre-eclampsia is associated with impaired maternal metabolic and cardiovascular function, leading to inadequate adaptation to the demands of pregnancy[159,160,161,162,163].

Altered metabolic and cardiovascular function is proposed to contribute to pre-eclampsia by causing reduced spiral artery remodelling in preterm pre-eclampsia and altered placental metabolic function in both preterm and term pre-eclampsia[163].

Metabolomic studies undertaken in serum of women at 11–13 weeks of gestation who later developed late-onset pre-eclampsia identified that insulin resistance and metabolic syndrome, mitochondrial dysfunction, disturbance of energy metabolism, oxidative stress, and lipid dysfunction are present in late-onset pre-eclampsia[164], suggesting that disturbances can be identified early in the disease process

Dysregulated placental gene expression Two small studies using chorionic villus samples (CVS) collected from pregnancies that subsequently developed early-onset (<34 weeks of gestation) pre-eclampsia identified dysregulated placental and decidual gene expression at the end of the first trimester[165,166,167].

The placental tissue exhibited dysregulated expression of genes associated with angiogenesis and oxidative stress[165] and, in decidual tissue, genes associated with inflammation/immunoregulation, cell motility, decidualization and NK cell function were altered[166,167]

Many of these factors have since been validated in preterm pre-eclampsia, including complement factor H and prothrombin[35,36,37,168].

Smaller studies that distinguished between early-onset and late-onset pre-eclampsia identified that early-onset placenta samples had increased gene expression for genes involved in metabolic processes, and late-onset placenta samples had increased expression of genes involved in immune processes[170,171].

These findings further suggest that the mechanisms involved in the three forms of pre-eclampsia are different

Dysregulated placental release of factors Alterations in placental secreted factors, including angiogenic proteins, pro-inflammatory cytokines and small extracellular vesicles, before the development of pre-eclampsia have been demonstrated in maternal blood[139,172,173,174,175,176].

The ratio of sFLT1 to PGF is used as a helpful tool when diagnosing placental dysfunction in pre-eclampsia, with higher sensitivity and specificity being achieved for early-onset pre-eclampsia[177,178]

Soluble endoglin is another notable anti-angiogenic factor released by the pre-eclamptic placenta with a similar pattern in serum as sFLT1.

Increased syncytiotrophoblast release of extracellular vesicles (Fig. 2b) into the maternal circulation is found in pre-eclampsia[191,192,193].

Emerging evidence suggests that syncytiotrophoblast-released extracellular vesicles are internalized by endothelial cells, into which they release these factors and drive the maternal endothelial dysfunction and inflammation observed in pre-eclampsia[176,194,195,196]

Vascular involvement The maternal endothelium is thought to be an important target of the placental-released factors hypothesized to drive pre-eclampsia[197].

Endothelial dysfunction can lead to reduced blood flow to organs such as the heart and kidney[133] and reduced venous blood drainage and associated venous congestion.

This contributes to organ dysfunction and can induce reflex constriction of arteries[199].

It is hypothesized that the endothelial dysfunction driven by placental-released factors initiates and drives hypertension in pre-eclampsia.

Machine learning approaches using biochemical data retrieved from electronic medical records from 11,006 women at 14–17 to 34 weeks of gestation have been documented to predict late-onset pre-eclampsia early in the second trimester[92], suggesting that early pregnancy placental vascular impairment occurs in late-onset pre-eclampsia

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