**3. Key elements of the pathophysiology**

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

Severe features of preeclampsia (any of these findings):

higher on two occasions at least 4 h apart

**F.** New-onset cerebral or visual disturbances

**B.** Thrombocytopenia

**E.** Pulmonary edema

**D.** Progressive renal insufficiency

**A.** Systolic blood pressure of 160 mmHg or higher or diastolic blood pressure of 110 mmHg or

**C.** Impaired liver function as indicated by abnormally elevated liver enzymes

**60**

**2. Definition of preeclampsia**

*Classification of hypertensive disorders in pregnancy.*

**Figure 1.**

indicative of target organ injury [3, 4].

Preeclampsia/eclampsia is described as a pregnancy-specific systemic disorder of unknown etiology and is a potentially serious disease with symptoms related to a generalized vascular endothelial activation. The placenta seems to be a crucial component in the pathophysiology of the disease. Preeclampsia is a multisystemic disease characterized by the development of hypertension after 20 weeks of gestation, with the presence of proteinuria or, in its absence, of signs or symptoms

Preeclampsia can be defined as a new onset of hypertension (>140/90 mmHg) after gestational week 20 together with significant proteinuria (300 mg/24 h) [5, 6]. Hypertension is considered mild until diastolic or systolic levels reach or exceed 110 and 160 mmHg, respectively. It is recommended that a diagnosis of hypertension requires at least two determinations at least 4 h apart. Proteinuria is diagnosed when 24-h excretion equals or exceeds 300 mg in 24 h or the ratio of measured protein to creatinine in a single-voided urine measures or exceeds 0.3 (each measured as mg/dL), termed the urinary protein/creatinine ratio [1]. The definitive treatment of preeclampsia is delivery to prevent development of

Precise causes of preeclampsia are still unknown, but contributors are impaired angiogenesis [7], systemic endothelial dysfunction [8], and decreased vascular compliance resulting in impaired accommodation of the volume expansion required for healthy gestation [9].

During normal pregnancy, the villous cytotrophoblast invades into the inner third of the myometrium, and spiral arteries are remodeled. The remodeling contains four steps: decidua-associated remodeling, the intraluminal appearance of migratory endovascular trophoblasts, their intramural incorporation and trophoblast-associated remodeling, and maternal reendothelialization.

Preeclampsia has a complex pathophysiology, the primary cause likely being abnormal placentation. Defective invasion of the spiral arteries by cytotrophoblast cells is observed during preeclampsia. Recent studies have shown that cytotrophoblast invasion of the uterus is actually a unique differentiation pathway in which the fetal cells adopt certain attributes of the maternal endothelium they normally replace. In preeclampsia, this differentiation process is defective [10].

In normal pregnancy the uterine arteries are resilient and elastic, and they lose their sensitivity to vasoconstrictors. In a preeclamptic pregnancy there is increased uterine arterial resistance and higher sensitivity to vasoconstrictors and thus chronic placental ischemia and oxidative stress. This chronic placental ischemia causes fetal complications, including fetal growth restriction (FGR) and intrauterine death. In parallel, oxidative stress induces release into the maternal circulation of substances such as free radicals, oxidized lipids, cytokines, and serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1/sFlt-1). These abnormalities are responsible for endothelial dysfunction [8] with vascular hyperpermeability, thrombophilia, and hypertension, so as to compensate for the decreased blood flow in the uterine arteries due to peripheral vasoconstriction. Endothelial dysfunction is responsible for the clinical signs observed in the mother, i.e., impairment of the hepatic endothelium contributing to onset of the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, impairment of the cerebral endothelium inducing cerebral edema or posterior

**Figure 2.** *Pathogenesis of preeclampsia.*

reversible encephalopathy syndrome (PRES), refractory neurological disorders, or even eclampsia. In kidney, the depletion of vascular endothelial growth factor (VEGF) in the podocytes leads to endotheliosis, and these block the slit diaphragms in the basement membrane, exacerbating the already decreased glomerular filtration and causing proteinuria. Finally, endothelial dysfunction promotes microangiopathic hemolytic anemia, and vascular hyperpermeability associated with low serum albumin causes edema, particularly in the lower limbs or lungs. The crucial issue to understand is that the prime mover of preeclampsia is abnormal placentation [11] [**Figure 2**].
