**2.2 Etiology and pathophysiology of preeclampsia**

PE is considered a multisystem disorder, affecting several organs and maternal systems, including the vascular system, liver, kidney and brain. Despite the intensive research in this area, the etiology of PE remains unknown. PE seems to have a multifactorial cause and is also known as the "disease of theories". In fact, there are several hypotheses raised to explain its etiology. Some those theories propose modifications in the trophoblastic invasion, immunologic intolerance between maternal and fetoplacental tissue, inflammatory changes in pregnancy and genetic modifications, underlying PE development. multisystem

Although its unknown cause, it is consensual that there are modifications occurring at different levels, like changes in placental perfusion, increased inflammatory response with changes in leukocyte activation, activation of the coagulation system, endothelial dysfunction and changes in lipid metabolism. The most accepted theory describes two stages for PE (Roberts & Gammil, 2005; Steegers et al., 2010): stage 1 - reduced placental perfusion; stage 2 - multisystem maternal syndrome.

According to this theory, the first pathological change in PE occurs in the uteroplacental circulation, resulting in an inadequate vascular remodelling and/or placental ischemia. In the second phase, the damaged placenta (ischemic placenta) secretes factors that cause endothelial dysfunction, followed by the appearance of maternal clinical symptoms.

The event(s) that trigger(s) the change in the trophoblastic invasion remains unknown; however, genetic, immunological and environmental factors (nutritional deficiencies and hypoxia environment) seem to have some contribution.

The remodelling of spiral arteries takes place at the end of the 1st trimester of pregnancy, and is very important, because it allows an increasing blood flow, in response to higher fetomaternal exchanges. A failure in this process may result in reduced placental blood flow, causing the formation of a hypoxic environment that may trigger PE, which might be associated or not with IUGR. In this case, the spiral arteries have a reduction in its lumen and may be linked to inadequate placentation and acute atherosis, or both.

There are studies revealing that children of PEc women present in adolescence, higher blood pressure levels with increased risk of developing hypertension, compared to children of normotensive pregnant women (Vatten et al., 2003; Tenhola et al., 2006, Kajantie et al., 2009). In another study, adolescents with low birth weight also presented blood pressure values higher than adolescents who were born with adequate weight

Low birth weight appears to be associated with an increased risk of developing type 2 Diabetes mellitus(Whincup et al., 2008), cardiovascular disease (Barker & Bagby, 2005) and hypertension (Lenfant, 2008) in adult life. This risk appears to be even greater if, in addition to low birth weight, further develop a marked increase in BMI (Eriksson et al., 2007; Barker et al., 2009). In a recent study, Raghupathy et al. (2010) mentioned that individuals who were underweight at birth and during infancy, followed by a sharp increase in BMI during adolescence, were associated with a reduction in glucose tolerance

PE is considered a multisystem disorder, affecting several organs and maternal systems, including the vascular system, liver, kidney and brain. Despite the intensive research in this area, the etiology of PE remains unknown. PE seems to have a multifactorial cause and is also known as the "disease of theories". In fact, there are several hypotheses raised to explain its etiology. Some those theories propose modifications in the trophoblastic invasion, immunologic intolerance between maternal and fetoplacental tissue, inflammatory changes

Although its unknown cause, it is consensual that there are modifications occurring at different levels, like changes in placental perfusion, increased inflammatory response with changes in leukocyte activation, activation of the coagulation system, endothelial dysfunction and changes in lipid metabolism. The most accepted theory describes two stages for PE (Roberts & Gammil, 2005; Steegers et al., 2010): stage 1 - reduced placental

According to this theory, the first pathological change in PE occurs in the uteroplacental circulation, resulting in an inadequate vascular remodelling and/or placental ischemia. In the second phase, the damaged placenta (ischemic placenta) secretes factors that cause endothelial dysfunction, followed by the appearance of maternal clinical

The event(s) that trigger(s) the change in the trophoblastic invasion remains unknown; however, genetic, immunological and environmental factors (nutritional deficiencies and

The remodelling of spiral arteries takes place at the end of the 1st trimester of pregnancy, and is very important, because it allows an increasing blood flow, in response to higher fetomaternal exchanges. A failure in this process may result in reduced placental blood flow, causing the formation of a hypoxic environment that may trigger PE, which might be associated or not with IUGR. In this case, the spiral arteries have a reduction in its lumen

and may be linked to inadequate placentation and acute atherosis, or both.

(Covelli et al., 2007).

symptoms.

and development of type 2 Diabetes mellitus.

**2.2 Etiology and pathophysiology of preeclampsia** 

perfusion; stage 2 - multisystem maternal syndrome.

hypoxia environment) seem to have some contribution.

in pregnancy and genetic modifications, underlying PE development.

The placenta seems to play a key role in the pathogenesis of PE, since the clinical symptoms disappear only after placental expulsion. PE seems to develop after a partial failure in the process of placentation, a process that occurs between 6-18 weeks of gestation. In this condition, only some of the spiral arteries of the placental circulation are invaded by trophoblasts. In the myometrial spiral arteries the muscular-elastic layer is not replaced; therefore, vascular resistance is higher and uteroplacental flow is reduced, as compared to what occurs in a normal pregnancy. This decrease in placental perfusion may significantly affect oxygenation, nutrition and fetal development. The reduction in placental perfusion in PE is usually accompanied by a reduction in fetal weight for gestational age (Catarino et al., 2008a).

The first observations on this phenomenon have been published for over three decades (Brosens et al., 1972), but several authors have confirmed these observations and attempted to clarify the mechanisms involved (Chaddha et al., 2004; Burton et al., 2009). Doppler fluxometry applied to the uterine arteries allowed the confirmation of the hemodynamic disturbances underlying placental insufficiency, and demonstrated that in PE occurs an increased (circulatory) resistance of placental vascular territory (Papageorghiou & Leslie, 2007; Boukerrou et al., 2009). As changes in placental blood flow are observed in PE before the onset of symptoms (Papageorghiou & Leslie, 2007), uterine artery Doppler, is performed early in the second trimester of pregnancy, in order to predict PE.

In PE an acute atherosis in the myometrial spiral arteries may also develop. The acute atherosis is an injury similar to the atherosclerotic lesion, characterized by the presence of fibrin deposits, accumulation of foam cells and infiltration of mononuclear leukocytes. This type of injury leads to a reduction of the arteries lumen, and, thus, to a decrease in placental perfusion, even in the absence of an inadequate placentation (Pijnenborg et al., 2006). The atherosis may progress to acute vascular obstruction of the spiral arteries, reducing blood flow to the placenta and causing placental infarction. In a study involving 400 placentas from PEc women, the vascular lesions in the placenta correlated with the severity of this pathology (Ghidini et al., 1997).
