Essay: Preeclampsia

Preeclampsia (PE) is a multisystem disorder complicating 5-7% of all pregnancies that manifests with a variety of maternal clinical symptoms (e.g. hypertension) and remains a major cause of maternal and perinatal morbidity and mortality worldwide. The traditional definition of preeclampsia according to the ACOG (American Congress of Obstetricians and Gynecologists) criteria refers to the onset of high blood pressure (140/90 or higher) after 20 weeks of gestation in a previously normotensive woman [62], [63]. The most severe cases are characterized by a variety of other clinical disturbances including proteinurea (≥0.3 gr/day), edema, neurologic involvement, epigastric pain, impaired liver function, thrombocytopenia and are often associated with fetal growth restriction [62]. Preeclampsia may progress to eclampsia (i.e. convulsions and cerebral edema) which can rapidly kill. Complications most often arise before anticipated delivery (at 23-36 wks) and require premature delivery. The insufficient perfusion of the placenta in PE often impairs fetal development, and premature birth due to PE is related with cerebral palsy, blindness, epilepsy, deafness, lung conditions, and seizures [62]. The precise pathogenic mechanisms of preeclampsia are unknown; therefore, effective preventive strategies remain indefinable, and delivery remains the main approach to avoiding maternal morbidity and mortality [64]. The lack of effective therapeutic approaches, especially in early PE, is a serious health concern in clinical practice. The American Heart Association in recent times identified a history of preeclampsia as a risk factor for cardiovascular diseases (CVD). Infect women with preeclampsia have increased risk of hypertension, stroke, and other cardiovascular morbidity and mortality later in life [65], [66]. Common mechanisms such as inflammation, oxidative stress and endothelial dysfunction are crucial for the initiation and progression of both CVD and preeclampsia [67], [68]. Statins are notorious for their cardio protective effects by decreasing circulating cholesterol levels [69] as well as anti-inflammatory and antioxidant effects [70]. In the past few years, ex vivo human and animal studies have investigated the potential use of statins in preventing pregnancy complications like preeclampsia (Table 1). It is thought that a discrepancy between angiogenic (vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and anti-angiogenic (soluble Fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) factors characterize the preeclampsia (Figure 3).  High circulating levels of both sEng and sFlt-1/PlGF are usually detected before the onset of preterm preeclampsia [71], [72].  sFlt1 and soluble endoglin antagonize VEGF and transforming growth factor-β1 (TGFβ1) signaling. The physiological levels of VEGF and TGFβ1 signaling in the vasculature preserve vascular homeostasis during normal pregnancy [73]. On the other hand, in preeclampsia, excess placental secretion of sFlt1 and sEng inhibits VEGF and TGFβ1 signaling [73]. Recently, studies using endothelial cells or placental explants have shown that simvastatin increases Hemoxygenase-1 (HO-1) expression, an anti-inflammatory enzyme that inhibits placental sFlt-1 and sEng release, suggesting that statins could protect against pregnancy-induced oxidative stress and serious inflammation characteristic of peeclampsia [74]. Rat model induced with HO-1 developed many features of PE positively affected blood pressure, angiogenic balance, superoxide, and endothelin-1 production in the ischemic placenta [75]. In another study, Costantine and colleagues [76] showed that pravastatin improved the vascular reactivity in a mouse model of preeclampsia induced by overexpression of sFlt-1. Furthermore, Ahmed et al. [77] showed that pravastatin increased circulating levels of VEGF in an immunological model of murine preeclampsia (CBA×DBA/2 mice). In this model, pravastatin restored VEGF levels, placental perfusion and development by: 1) inhibition of sFlt-1 release from macrophages and 2) stimulation of VEGF release from trophoblasts. This glomerular injury decreased vascular hypersensitivity to angiotensin II and established overall prognosis of gestation in this immunological model.  Kumasawa et al. [78] evaluated the effects of pravastatin by transfecting mouse with the human sFlt1 (hsFlt1) gene in vitro and then placing the treated murine blastocysts in pseudo pregnant foster mothers. In this model circulating levels of hsFlt1 in the maternal blood increased after 16.5 days of gestation. Hypertension and pathological proteinuria developed and then disappeared postpartum [78]. The induction of PIGF release that antagonizes the effects of hsFLT1 prevented the miscarriages in this model. Interestingly, the descendants of preeclamptic mice treated with pravastatin didn’t show teratogenicity or developmental abnormalities [78]. To determine the effects of pravastatin on the angiogenic and placental hypoxic imbalance, Saad et al. [79] unsystematically allocated pregnant CD1 mice to injection with adenovirus-carrying sFlt-1.  The authors observed that at day 18 pravastatin treatment reduced sFlt-1 and sEng concentrations and an up-regulation of placental PlGF and VEGF expression and down-regulation of TGFβ3, and hypoxia markers as HIF-1α, and HIF-2α [79]. Taken together, these animal studies suggest that statins may be a good therapeutic option for preventing symptoms of PE although the mechanistic action remains unknown (Figure. 4). Although the mouse is the most frequently used animal model for placenta and pregnancy research there are limitations in its use as a model because of the multiparous nature of mice, the markedly different developmental trajectories in terms of pre- and postnatal organ development, differences in placental structure [80] and presence of human-specific genetic features including micro-RNAs in the human placenta [81]. So it is imperative to perform clinical trials to translate the animal findings to humans. The world’s first randomized placebo-controlled clinical trial, StAMP trial (Statins to Ameliorate early onset Preeclampsia) is presently recruiting patients in the United Kingdom and will notify us about the probable positive effects of statins in PE (http://www.controlled-trials.com/ISRCTN23410175.). This study evaluates pravastatin as therapy for severe early-onset PE, particularly taking in consideration anti-angiogenic factors. Moreover, it will reveal the valuable or undesirable effects connected to exposure to pravastatin during gestation. In addition, a NIH-sponsored placebo-controlled Phase I study is currently going in the USA, aiming to establish the pharmacokinetic parameters and to accumulate preliminary safety data when pravastatin is used as a prophylactic daily treatment in pregnant women at high risk of PE (http:// clinicaltrials.gov/show/NCT01717586). This study will be used to set up dosage and response information that will be utilized in clinical trials to assess pravastatin’s effectiveness in preventing PE in high-risk women [82].