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Pre-Eclampsia

Clinical Signs and Symptoms

Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches

“Armaly, Z., Jadaon, J. E., Jabbour, A., & Abassi, Z. A. (2018). Preeclampsia: novel mechanisms and potential therapeutic approaches. Frontiers in physiology, 9, 973”

INTRODUCTION

· Preeclampsia is a serious complication of pregnancy affecting 3-8% of all pregnancies, increasing the risk of all-cause mortality for both mother and fetus [1]

· Preeclampsia can cause intra-uterine fetal growth restriction (IUGR), placental abruption, preterm delivery, and other complications

· Preeclampsia is associated with hypertension, kidney damage, liver injury/failure, CNS damage, stroke, and even death in pregnant women [2]

· Preeclampsia is responsible for more than 60,000 maternal deaths annually worldwide, making it the third cause of maternal mortality after bleeding and embolism [1]

· Key biomarkers of either placental or vascular origins, including placenta growth factor (PlGF) and antiangiogenic factors such as soluble fms-like tyrosine kinase-1 (sFLT1) or soluble endoglin (sENG), are being incorporated into the diagnosis and risk assessment of preeclampsia [3]

Pre-eclampsia is a serious disease diagnosed by sudden onset hypertension and at least one other complication such as proteinuria, organ dysfunction, or fetal growth restriction.

· Pre-eclampsia is classified based on gestational age at clinical presentation into preterm, term, and postpartum, with early-onset and late-onset also used for research purposes.

Epidemiology

Incidence and mortality

· Pre-eclampsia has a global prevalence of 4.6% of deliveries, with regional rates ranging from 1% to 5.6%.

· Preterm pre-eclampsia has a prevalence of less than 1%.

· Pre-eclampsia is generally reported as lower in low-income and middle-income countries (LMICs) than in high-income countries (HICs), but differences in classification, access to prenatal care, and under-reporting in LMICs affect prevalence data.

· Hypertensive disorders of pregnancy, including pre-eclampsia, are the second most common cause of maternal deaths worldwide, causing an estimated 62,000-77,000 deaths per year.

· Maternal mortality is higher in a pre-eclamptic pregnancy than in a non-pre-eclamptic pregnancy, with an adjusted odds ratio of 3.73.

· The risk of fetal death in pre-eclamptic pregnancies is higher than in non-pre-eclamptic pregnancies, with an adjusted odds ratio of 3.12.

Medically indicated preterm birth rates are high in pre-eclamptic pregnancies, resulting in an increase in neonatal deaths, which are 2.7 times higher than in pregnancies resulting in a term birth

RISK FACTORS FOR PREECLAMPSIA

· Preeclampsia is a disease with poorly understood mechanisms.

· Some predisposing factors that increase the risk of developing preeclampsia include antiphospholipid antibody syndrome (APLA-S), chronic kidney disease (CKD), lupus, former preeclampsia, first pregnancy, obesity, pregestational hypertension, older age, diabetes mellitus, and multifetal pregnancy [4]

· The mechanisms underlying the increased risk associated with these factors are largely unknown, but underlying diseases characterized by an imbalance of angiogenic factors and coagulation may explain why certain populations are at risk.

· Despite the association between these risk factors and preeclampsia, the disease is unpredictable in most cases.

PATHOGENESIS OF PREECLAMPSIA

· Preeclampsia is a systemic disease that can negatively affect multiple organs in women, including future cardiovascular and renal diseases.

· Preeclampsia, especially early-onset preeclampsia, is associated with a higher risk of morbidity and mortality, which can persist decades after disease occurrence.

· The pathogenesis of early-onset and late-onset preeclampsia is different.

· Early-onset preeclampsia is associated with reduced maternal spiral artery conversion, placental malperfusion, oxidative stress, and altered biomarker patterns [5].

· Late-onset preeclampsia is associated with genetic maternal pre-disposition to cardiovascular disease .

· The remodeling of the uterine spiral arteries plays a crucial role in the pathogenesis of early-onset preeclampsia [6].

· Spiral artery remodeling is essential for fetal nutrition, and this process involves the secretion of many molecules, including VEGF, sFlt1, PlGF, and endoglin [7].

Angiogenic Factors

Preeclampsia, a pregnancy complication, is caused by insufficient remodeling of spiral arteries in the placenta that results in ischemic placenta and oxidative stress.

This stimulates the release of prohypertensive and anti-angiogenic factors, such as sFlt-1, leading to generalized endothelial dysfunction and multisystem damage.

Placenta Growth Factor (PlGF) is a proangiogenic factor expressed by the placenta and endothelium and is important for the development of placental vascular system. Reduced levels of PlGF have been found in preeclampsia, and the infusion of recombinant PlGF abolishes hypertension development in experimental preeclampsia [8].

Soluble fms-Like Tyrosine Kinase-1 (sFlt-1) acts as a potent scavenger of VEGF and PlGF, thus inducing endothelial dysfunction. sFlt-1 is overexpressed due to placental hypoxia and is a potential biomarker for the diagnosis of preeclampsia. Elevated sFlt-1 leads to the manifestation of preeclampsia symptoms such as hypertension and proteinuria [1].

Diagnosis of Preeclampsia

· Preeclampsia is defined as de novo hypertension and new onset of proteinuria after mid pregnancy.

· Early clinical signs of preeclampsia may be absent or unremarkable, and the reliability of hypertension and proteinuria as gold standards is compromised, especially in the presence of chronic hypertension and CKD [9].

· Angiogenic imbalance is a link between preeclampsia and malperfused placenta and maternal genetic predisposition.

· sFlt- 1, sEng, and PlGF are mounting biomarkers for the diagnosis of preeclampsia and possess prognostic features [10].

· A ratio of sFlt-1 to PlGF of 38 or lower drawn at 24–37 weeks of gestation can reliably predict the absence of preeclampsia and fetal adverse outcomes within one week [11].

· sEng could be a useful biomarker for early prediction of preeclampsia .

Kidney Placenta Crosstalk

· In preeclampsia, kidney damage contributes to the increased risk of later hypertension, chronic kidney disease (CKD), ischemic heart disease, stroke, persistent proteinuria, and end-stage renal disease (ESRD) [12].

· Superficial placental implantation due to abnormal angiogenesis is the early driving event for the development of preeclampsia.

· Excessive production of antiangiogenic sFlt-1 and sEng reduces the bioavailability of free pro-angiogenic PlGF and VEGF, thus leading to systemic endothelial dysfunction, including in the kidney [13].

· Glomerular endotheliosis is the hallmark characteristic renal pathologic lesion of preeclampsia.

Novel Mechanisms Based Therapeutics

· Preeclampsia is a life-threatening complication during pregnancy for both mother and fetus. The available treatment options are limited and do not work for most cases.

· However, new therapies have been developed that target implicated circulating angiogenic factors.

· Specifically, these strategies rely on correcting the angiogenic balance, either by promoting proangiogenic factors or by blocking those of antiangiogenic properties.

· Replenishing the circulatory levels of vascular endothelial growth factor (VEGF) or placental growth factor (PlGF) exerts beneficial effects in experimental preeclampsia [14].

· Elimination or reduction of the circulating levels of soluble Fms-like tyrosine kinase-1 (sFlt-1) has been shown to ameliorate the angiogenic imbalance.

· Proton pump inhibitors (PPIs) decrease sFlt-1 and sEng secretion, attenuate endothelial dysfunction, dilate blood vessels, decrease blood pressure, and exert antioxidant and anti-inflammatory effects [15].

· Pregnant women taking PPIs have been associated with a decrease in sFlt-1. However, prospective trials are still warranted.

Summary

· Preeclampsia is a clinical state that affects multiple organs of pregnant women.

· Research in the last decade has led to the discovery of novel biomarkers that allow for early diagnosis and prediction of outcomes for preeclampsia.

· In early-onset preeclampsia, deficient trophoblast invasion and arterial remodeling lead to aberrant maternal-fetal interactions during early pregnancy and placental malperfusion, causing oxidative stress and biomarker patterns.

· In late-onset preeclampsia, there is a genetic maternal pre-disposition to cardiovascular disease that manifests as preeclampsia in response to pregnancy-induced stress.

· sFlt-1 and sEng are not solely biomarkers but responsible for the angiogenic imbalance and generalized endothelial dysfunction in preeclampsia.

· Elimination of serum sFlt-1 through apheresis has yielded promising results in pipeline clinical trials for preeclampsia treatment.

References

1. Jim, B. and S.A. Karumanchi, Preeclampsia: Pathogenesis, Prevention, and Long-Term Complications. Semin Nephrol, 2017. 37(4): p. 386-397.

2. Armaly, Z., et al., Preeclampsia: novel mechanisms and potential therapeutic approaches. Frontiers in physiology, 2018. 9: p. 973.

3. Baltajian, K., et al., Sequential plasma angiogenic factors levels in women with suspected preeclampsia. Am J Obstet Gynecol, 2016. 215(1): p. 89.e1-89.e10.

4. Al-Jameil, N., et al., A brief overview of preeclampsia. J Clin Med Res, 2014. 6(1): p. 1-7.

5. Lisonkova, S., et al., Maternal morbidity associated with early-onset and late-onset preeclampsia. Obstet Gynecol, 2014. 124(4): p. 771-781.

6. Pijnenborg, R., L. Vercruysse, and M. Hanssens, The uterine spiral arteries in human pregnancy: facts and controversies. Placenta, 2006. 27(9-10): p. 939-58.

7. Zhou, C.C., et al., Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med, 2008. 14(8): p. 855-62.

8. Kar, M., Role of biomarkers in early detection of preeclampsia. J Clin Diagn Res, 2014. 8(4): p. Be01-4.

9. Sibai, B.M. and C.L. Stella, Diagnosis and management of atypical preeclampsia-eclampsia. Am J Obstet Gynecol, 2009. 200(5): p. 481.e1-7.

10. Santner-Nanan, B., et al., Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J Immunol, 2009. 183(11): p. 7023-30.

11. Sovio, U., et al., Prediction of Preeclampsia Using the Soluble fms-Like Tyrosine Kinase 1 to Placental Growth Factor Ratio: A Prospective Cohort Study of Unselected Nulliparous Women. Hypertension, 2017. 69(4): p. 731-738.

12. Wang, I.K., et al., Association between hypertensive disorders during pregnancy and end-stage renal disease: a population-based study. Cmaj, 2013. 185(3): p. 207-13.

13. Romero, R., et al., A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med, 2008. 21(1): p. 9-23.

14. Spradley, F.T., et al., Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension. Hypertension, 2016. 67(4): p. 740-7.

15. Onda, K., et al., Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction. Hypertension, 2017. 69(3): p. 457-468.

Pre-eclampsia

Evdokia Dimitriadis; Daniel L. Rolnik; Wei Zhou; Guadalupe Estrada-Gutierrez; Kaori Koga; Rossana P. V. Francisco; Clare Whitehead; Jon Hyett; Fabricio da Silva Costa; Kypros Nicolaides; Ellen Menkhorst

2023

Synopsis

Pre-eclampsia is the most common complication of pregnancy and is the leading cause of maternal and neonatal morbidity and mortality, according to the The Health Organization.

Time of pre-eclampsia onset is thought to reflect an underlying difference in the aetiology. Early pregnancy pre- eclampia prediction tests and preventive aspirin prophylaxis show utility for preterm but not term pre-ECLampsia. Remodelling is initiated by uterine-resident innate immune cells. Hypertensive disorders of pregnancy are the second most common cause of maternal deaths worldwide. Pre-eclampsia is a complex multisystem disease, diagnosed by sudden-onset hypertension and at least one associated complication. Treatment of even mild chronic hypertension with antihypertensive medication from before or in early pregnancy reduces the risk of developing pre-e Clampsia by 18%. The researchers reviewed 94 studies. The results appear to offer an alternative view to prior research in this area: “There has been data to suggest a link between SARS-CoV-2 infection in pregnancy and an increased risk of developing pre-eclampsia. Some systematic reviews found an increase in risk when collating data from different cohorts. Other studies have reported that COVID-19 infection during pregnancy does not increase the risk,” Dimitriadis argued. The authors recommend that further studies are required to determine whether the incidence of pre-eclampsia itself and the long-term, poor outcomes for mother and baby are improved by routine induction.

Summary

Introduction Pre-eclampsia is a complex multisystem disease, diagnosed by sudden-onset hypertension (>20 weeks of gestation) and at least one other associated complication, including proteinuria, maternal organ dysfunction or uteroplacental dysfunction (for example, fetal growth restriction (FGR) or angiogenic imbalance).

Pre-eclampsia is associated with complications such as eclampsia, haemorrhagic stroke, haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome, placental abruption, renal failure, and pulmonary oedema[10,11] (Fig. 1).

In this Primer, the authors summarize current knowledge of the epidemiology, risk factors, pathophysiology, clinical presentation, diagnosis, prediction, management and outcomes of pre-eclampsia.

The authors discuss patient quality of life and the outstanding research questions aimed at improving clinical practice and understanding the aetiology of pre-eclampsia

Incidence and mortality The global prevalence of all pre-eclampsia in the years 2002–2010 was estimated at 4.6% of deliveries but reported regional rates varied between 1% and 5.6%14.

Hypertensive disorders of pregnancy are the second most common cause of maternal deaths worldwide (14% of deaths, 95% CI 11.4–17.4), causing an estimated 62,000–77,000 deaths per year[22,23].

Maternal mortality is higher in a pre-eclamptic pregnancy than in a non-pre-eclamptic pregnancy (adjusted odds ratio 3.73, 95% CI 2.15–6.47)[20].

The risk of fetal death in pre-eclamptic pregnancies is higher than that in non-pre-eclamptic pregnancies[20] as a result of FGR and placental abruption.

High rates of medically indicated preterm birth result in an increase in neonatal deaths, which are 2.7 times higher than in pregnancies resulting in a term birth[20]

Risk factors There are many risk factors identified as associated with pre-eclampsia (Table 1); individually, none of these has strong power to predict pre-eclampsia risk and, even in combination, their predictive power is weak[24].

A recent comparison of clinical practice guidelines and evidence supporting these risk factors found that many guidelines had a lack of close alignment between the risk factors and the evidence supporting them[24].

These guidelines are mostly produced in HICs; they do not include factors important to LMICs such as access to health-care providers/clinical instrumentation to perform tests and risk-factors particular to LMICs including adolescence, malaria or anaemia[24,27].

Few models are validated in low-resource settings[24,27]

Genetic risk factors Recognition that eclampsia was commonly reported in mothers, sisters and daughters suggests genetic involvment[28]; yet, to date, no single high-risk gene has been identified.

There are multiple maternal and fetal gene alleles and mutations associated with pre-eclampsia[33,34,35,36,37,38,39], possibly reflecting the syndromic nature of this disease.

Many of these identified genes are associated with thrombophilic factors[34,35,36,37], angiogenic factors[33,40] or immune responses[38,39].

The causality of these associations and the clinical utility of identifying such changes are yet to be examined in larger studies

Racial disparities Caution is required when interpreting studies that investigate pre-eclampsia risk associated with racial background as many do not correctly account for possible mediators and confounding factors, including health-care disparities and differing cardiovascular profiles.

In a large cohort study involving >168,000 women with singleton pregnancies in the UK, Black women had twice the risk of developing pre-eclampsia at any stage of gestation than white women[52].

This association was strongest for early-onset (3.5-fold) and preterm (2.5-fold) pre-eclampsia[52].

First-trimester screening following the Fetal Medicine Foundation algorithm improves perinatal outcomes in the non-white population by 60%53, suggesting that health disparity is avoidable with personalized risk assessment and correct care pathway allocation

Maternal age The relationship between pre-eclampsia risk and maternal age follows a J-shaped curve, with increased risk in adolescents and in women older than 35 years of age[54,55,56].

Advanced maternal age (≥35 years) is associated with an increased risk of pre-existing cardiometabolic dysfunction and medical disorders, multiple pregnancies, and use of artificial reproductive technologies, all of which increase the risk of pre-eclampsia.

Pre-existing medical conditions may increase the risk of developing hypertensive disease in pregnancy, including pre-eclampsia.

Treatment of even mild chronic hypertension with antihypertensive medication from before or in early pregnancy reduces the risk of developing pre-eclampsia by 18%[59].

The severity of kidney disease and degree of proteinuria are important predictors of the risk of developing pre-eclampsia, even in the absence of associated pathologies, including chronic hypertension.

A disrupted gut microbiota has been linked to other diseases that are risk factors for pre-eclampsia, including obesity and metabolic disorders[84]

Obstetric history Primiparity is associated with a threefold increase in the likelihood of developing pre-eclampsia[30].

Epidemiological studies have shown an increase in the risk of pre-eclampsia with increasing inter-pregnancy interval, equivalent to that of primiparity, when the interval is >10 years[58,88]

This hypothesis is consistent with the finding that women who conceived by in vitro fertilization (IVF) or intrauterine insemination using donor gametes are at significantly higher risk than those who undergo IVF with autologous egg or partner sperm[89,90].

Conception by IVF, intracytoplasmic sperm injection or egg donation increases the risk of pre-eclampsia compared with pregnancies conceived naturally or via intrauterine insemination; the risk is even higher with frozen-thawed embryo transfer cycles than with fresh cycles[101]

This may be because of impaired vascular health and maternal adaptation to pregnancy in women who lack a corpus luteum at conception[102,103,104].

Given that there seems to be a dose–response relationship and similarity in the activation of many of the same molecular pathways such as angiogenesis and endothelial dysfunction, this finding warrants further investigation

Environmental factors Residence at high altitudes (>2,700 m) is associated with increased risk of pre-eclampsia[14,112,113,114].

Maternal hypoxia affecting multiple physiological systems, including placenta/decidual vasculature, is thought to drive this increased rate of pre-eclampsia[112], and it has been reported that multigenerational residents at high altitudes may be protected against pre-eclampsia compared with immigrants[113].

Air quality and exposure to ambient pollutants are risk factors for pre-eclampsia.

Associations between exposure to ambient particulate matter with diameter <2.5 µm (PM2.5)[115,116,117] and nitrogen dioxide[116] during pregnancy and increased pre-eclampsia have been reported; for PM2.5 exposure, this association may be more pronounced in pre-eclampsia with FGR115

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

Vascular adaptations during pregnancy 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

Pulmonary oedema Characterized by excessive fluid accumulation in the lungs, pulmonary oedema is a rare, acute, life-threatening condition, primarily associated with severe pre-eclampsia[201,202].

Pulmonary oedema is the second most common cause of death in pregnancies complicated by hypertension[203].

There are multiple causes of pulmonary oedema, including decreased oncotic pressure, increased capillary permeability, increased hydrostatic pressure and diastolic dysfunction.

Antihypertensive medications and excessive fluid administration are risk factors for pulmonary oedema[204].

Pulmonary oedema is most common (39%) postpartum[204], when fluid sequestered in the extravascular space is mobilized into the vascular space, increasing central venous and pulmonary capillary wedge pressure

Renal involvement The kidney is the organ most likely to be affected by endothelial injury in pre-eclampsia[198].

Renal biopsies of women with pre-eclampsia show glomerular endotheliosis that seems to be responsible for the decreased glomerular filtration rate noted in pre-eclampsia[205].

The characteristic proteinuria in pre-eclampsia is caused by high concentrations of sFLT1 inhibiting the expression of proteins of the podocyte slit diaphragm, such as synaptopodin and nephrin[206], which increases inter-podocyte separation.

The lack of vascular endothelial growth factor (VEGF) and PGF availability in the glomerular endothelium stimulates endothelin 1 expression that promotes podocyte detachment[207]

Liver involvement Liver damage in pre-eclampsia is characterized by periportal inflammation and hepatocellular damage, subcapsular haematoma and, in rare cases, hepatic failure or rupture[208].

Widespread microangiopathy causes vasospasm of hepatic sinusoids and promotes fibrin deposition in the microcirculation[209], leading to ischaemia.

Hepatic endothelial cells are highly dependent on VEGF, and its antagonism with sFLT1 significantly alters their function given the decreased availability of nitric oxide[210].

The resulting ischaemia causes oxidative stress and inflammation that affect hepatic acini, elevating the concentration of liver enzymes in blood and contributing to the onset of HELLP syndrome.

HELLP syndrome encompasses microangiopathic haemolysis, elevation of liver enzymes and thrombocytopenia.

The most common symptoms in affected patients are right-upper quadrant pain, epigastralgia, nausea and vomiting, headache and visual changes.

In severe cases, to disseminated intravascular coagulation corroborates the worsening of the case and is diagnosed by decreased levels of fibrinogen, antithrombin, and increased prothrombin time and fibrin[212]

Neurological involvement Neurological symptoms have been recognized as high-risk features of eclampsia for thousands of years[213].

Neurological complications are the direct cause of many maternal deaths due to pre-eclampsia, in LMICs, and include eclampsia, visual scotomata, cortical blindness, arterial ischaemic stroke, cerebral venous sinus thrombosis, subarachnoid and intracerebral haemorrhage, reversible cerebral vasoconstriction syndrome, and posterior reversible encephalopathy syndrome[213,214].

Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome occur most commonly in the postpartum period and often with little warning[215].

The mechanisms leading to neurological complications are being uncovered; the maternal cerebral vasculature is highly sensitive to pre-eclampsia[215].

Neurovascular dysfunction is clear in pre-eclampsia, with studies showing increased sympathetic activity of the autonomic nervous system[213,216], impaired cerebral autoregulation, increased blood–brain barrier permeability[132], and vasogenic oedema, with cerebral markers, including neurofilament light chain, being dysregulated in pre-eclamptic cerebrospinal fluid, serum and plasma[218]

Fetal growth restriction FGR occurs mainly due to placental dysfunction and is highly associated with preterm pre-eclampsia[219,220,221,222].

The ISSHP guidelines[2,13] specify that pre-eclampsia can be diagnosed after 20 weeks of gestation by new-onset hypertension in a patient previously with normotension plus one other pre-eclampsia-related symptom or sign

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