Definition of pre-eclampsia
Pre-eclampsia (hereafter referred to as PE) is a syndrome that affects 3-5% of pregnancies and is the cause of serious complications for a mother and her foetus. PE is the second leading cause of maternal mortality after sepsis (a serious medical condition caused by an immune response). Because of this we should always take into consideration biomarkers of pre-eclampsia, which we will discuss later.
The clinical diagnosis and definition of PE is based on the identification of non-specific signs and symptoms, such as hypertension and urinary protein excretion (“proteinuria”). PE is defined by the occurrence of hypertension and proteinuria after 20 weeks of gestation. Recently, because of the acceptance that the measurement of proteinuria is prone to variation and the fact that complications of PE may occur before the onset of proteinuria, the diagnosis is broadened and defined as the presence of hypertension in conjunction with signs of maternal organ dysfunction independent of proteinuria.
The cause of PE is multifactorial. Many risk factors related to maternal characteristics, placental characteristics or maternal pathology have been defined. Among the most important maternal risk factors are African ethnicity, obesity, age of the pregnant woman under 20 years or over 35 years and smoking. Primiparity, multiple gestation, previous pre-eclampsia and abnormal placentation have been described as immunogenic risk factors. Maternal pathological risk factors include chronic hypertension, diabetes mellitus, renal failure and thrombophilias.
PE is a gestation-specific disease with multisystemic involvement. Clinical manifestations are the consequence of endothelial dysfunction with a wide spectrum of manifestations such as epigastric pain, nausea and vomiting, weight gain, facial oedema, pleural or ascitic fluid, renal failure, liver failure, HELLP syndrome (haemolysis, increased plasma liver enzyme concentrations and thrombocytopenia).
The presentation and course of EP is variable and ranges from early-onset severe EP with rapid progression requiring early termination of gestation to a late-onset syndrome with a term part. In addition, EP may be associated with intrauterine growth restriction (IUGR), which further increases neonatal morbidity and mortality. The above features suggest that the classical standards for diagnosis are not sufficient to cater for the full complexity of the syndrome. Adequate management of women at high risk of EP requires early detection and referral to specialised perinatal centers to reduce maternal, foetal and neonatal morbidity.
Pathophysiology of pre-eclampsia
Although PE is a systemic disease, its origin seems to be in the placenta. Two very specific phases in the pathophysiology of PE have been described.
- A first phase, in the first half of pregnancy, consists of a deficient placentation due to a shallow invasion of the maternal spiral arteries by foetal trophoblastic tissue, resulting in a state of placental hypoxia. This placental ischaemia causes the release from the maternal circulation of a whole series of placental factors that will be responsible for maternal endothelial dysfunction.
- In a second phase, in the second half of pregnancy, the maternal systemic response to this endothelial cell dysfunction in the maternal blood vessels appears and is responsible for vasoconstriction, increased capillary permeability and platelet aggregation.
Biomarkers of pre-eclampsia
As far as biochemical markers are concerned, different markers related to PE have been described and can be classified according to whether they are markers of placental dysfunction, markers of abnormal uterine artery remodelling, released placental meters or markers of systemic maternal endothelial dysfunction.
Within markers of placental dysfunction, the two most studied markers are pregnancy-associated plasma protein A (PAPP-A), a placental protein of the metalloproteinase family, which promotes implantation and trophoblast invasion, and placental protein 13 (PP13), a placental protein of the galectin family, which influences vascular dilatation changes during uterine artery remodelling.
Among the group of placental markers released are growth factors involved in uterine angiogenesis, such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β) and placental growth factor (PIGF), which interact with their receptors to allow vasodilation, capillary formation and thus angiogenesis at the endothelial cell level. Of these markers, the most studied growth factor as a biomarker of PE is PIGF, a member of the VEGF family, which interacts with the VEGF receptor also named fms tyrosine kinase 1 (Flt-1) to stimulate angiogenesis. There is a soluble truncated variant of this receptor (sFlt-1) that maintains the binding capacity of its ligands, both VEGF and PIGF, but binding in its soluble form prevents its binding to the blocked receptor, thus preventing angiogenesis. During pregnancy, PIGF plasma concentration values increase until the middle of the third trimester and then decrease until delivery, while sFlt-1 values increase until the end of pregnancy to prevent the formation of blood vessels before delivery.
Role of angiogenic factors in the pathophysiology of PE
PE is characterised by an imbalance between angiogenic and anti-angiogenic factors. The study of these factors is useful in the diagnosis and monitoring of patients with a clinical suspicion of having the disease, i.e. in those pregnant women with clinical signs or symptoms of PE, and have an important prognostic value in discriminating patients at risk of developing maternal or foetal complications.
In PE, plasma PIGF concentration values are lower throughout pregnancy, while sFlt-1 values are higher and increase earlier. Decreased PIGF values, elevated sFlt-1 values and an increased sFlt-1 / PIGF ratio have been reported in both women with PE and women before the development of PE. Several studies indicate that the sFlt-1 / PIGF ratio is the most useful marker for the diagnosis of PE and the best predictor to determine those patients at increased risk of adverse maternal or fetal outcomes due to placental insufficiency, including not only PE, but also IUGR or stillbirth.
Current evidence on the usefulness of the sFlt1 / PlGF ratio in clinical practice
So far, observational studies have shown that:
– In patients with clinically suspected disease, a discriminated value (cut-off point) of sFlt1 /PIGF ratio of 38 (irrespective of gestational age) distinguishes those patients with an increased risk of developing PE or perinatal complications in the following week with a negative predictive value of 99.3%. In contrast, a ratio above 38 had a positive predictive value of developing PE in the next 4 weeks of 36.7% or any adverse maternal or fetal outcome of 66%.
-Flt-1 /PIGF ratio values > 85 between 20 and 33+6 weeks gestation or > 110 above 34 weeks are highly diagnostic of PE and adverse outcomes; 85% of patients with elevated ratios required termination of pregnancy in less than 15 days.
– Patients with PE and sFlt-1 / PIGF ratio >655 are at high risk of imminent termination of pregnancy due to maternal or fetal complications.
Theoretical cost-effectiveness studies suggest that the use of the sFlt-1 / PIGF ratio as a criterion for PE is cost beneficial. In addition, its determination may change the decision to perform other measurements, ultrasound scans, administration of corticosteroids or antihypertensive measurement and inductions of labour to allow resources to be directed to patients at higher risk of complications.
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