The Two Stage Model of preeclampsia proposes that a poorly perfused placenta (Stage 1) produces factor(s) leading to the clinical manifestations of preeclampsia (Stage2). Stage 1 is not sufficient to cause the maternal syndrome but interacts with maternal constitutional factors (genetic, behavioral or environmental) to result in Stage 2. Recent information indicates the necessity for modifications of this model. It is apparent that changes relevant to preeclampsia and other implantation disorders can be detected in the first trimester, long before the failed vascular remodeling necessary to reduce placental perfusion. In addition, although the factor(s) released from the placenta has usually been considered a toxin, we suggest that what is released may also be an appropriate signal from the fetal/ placental unit to overcome reduced nutrient availability that cannot by tolerated by some women who develop preeclampsia. Further, it is evident that linkage is not likely to be by one factor but several, different for different women. Also although the initial model limited the role of maternal constitutional factors to the genesis of Stage 2, this does not appear to be the case. It is evident that the factors increasing risk for preeclampsia are also associated with abnormal implantation. These several modifications have important implications. An earlier origin for Stage 1, which appears to be recognizable by altered concentrations of placental products, could allow earlier intervention. The possibility of a fetal placental factor increasing nutrient availability could provide novel therapeutic options. Different linkages and preeclampsia subtypes could direct specific preventive treatments for different women while the role of maternal constitutional factors to affect placentation provides targets for prepregnancy therapy. The modified Two Stage Model provides a useful guide towards investigating pathophysiology and guiding therapy.

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The etiology and pathogenesis of the pregnancy syndrome preeclampsia remain poorly understood. There is substantial evidence to suggest that the diverse manifestations of preeclampsia, including altered vascular reactivity, vasospasm, and discrete pathology in many organ systems, are derived from pathologic changes within the maternal vascular endothelium. With the theme of endothelial cell dysfunction emphasized, this review focuses on the role of oxidative stress (an imbalance favoring oxidant over antioxidant forces) in the pathogenesis of preeclampsia. Data are summarized regarding 1) the role of the placenta in preeclampsia; 2) evidence and mechanisms of oxidative stress in the preeclampsia placenta; 3) markers of oxidative stress in the maternal circulation; and 4) the potential role of maternal dyslipidemia in generation of oxidative stress. A recurrent theme is that free radical reactions, promoted by "cross-talk" between the diseased placenta and maternal dyslipidemia, promote a vicious cycle of events that make cause and effect difficult to distinguish but likely contribute to the progression of preeclampsia.

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The largest gene cluster of human microRNAs (miRNAs), the chromosome 19 miRNA cluster (C19MC), is exclusively expressed in the placenta and in undifferentiated cells. The precise expression pattern and function of C19MC members are unknown. We sought to profile the relative expression of C19MC miRNAs in primary human trophoblast (PHT) cells and exosomes. Using high-throughput profiling, confirmed by PCR, we found that C19MC miRNAs are among the most abundant miRNAs in term human trophoblasts. Hypoxic stress selectively reduced miR-520c-3p expression at certain time-points with no effect on other C19MC miRNAs. Similarly, differentiation in vitro had a negligible effect on C19MC miRNAs. We found that C19MC miRNAs are the predominant miRNA species expressed in exosomes released from PHT, resembling the profile of trophoblastic cellular miRNA. Predictably, we detected the similar levels of circulating C19MC miRNAs in the serum of healthy pregnant women at term and in women with pregnancies complicated by fetal growth restriction. Our data define the relative expression levels of C19MC miRNAs in trophoblasts and exosomes, and suggest that C19MC miRNAs function in placental-maternal signaling.

Abstract-Gestational hypertension is differentiated into higher and lower risk by the presence or absence of proteinuria.We asked if hyperuricemia, a common finding in pregnancy hypertension, might also be an indicator of increased risk. We examined fetal outcome data from 972 pregnancies collected from 1997 to 2002 in a nested case-control study. Participants were nulliparous with no known medical complications. The frequency of preterm birth, the duration of pregnancy, frequency of small-for-gestational-age infants, and birth weight centile were determined for pregnancies assigned to 8 categories by the presence or absence of combinations of hypertension, hyperuricemia, and proteinuria. In women with gestational hypertension, hyperuricemia was associated with shorter gestations and smaller birth weight centiles and increased risk of preterm birth and small-for-gestational-age infants. Hyperuricemia increased the risk of these outcomes in the presence or absence of proteinuria. Risk was also increased in a small group of women with hyperuricemia and proteinuria without hypertension. Women with only hypertension and hyperuricemia have similar or greater risk as women with only hypertension and proteinuria. Those with hypertension, proteinuria, and hyperuricemia have greater risk than those with hypertension and proteinuria alone. The risk of these outcomes increased with increasing uric acid. Hyperuricemia is at least as effective as proteinuria at identifying gestational hypertensive pregnancies at increased risk. Uric acid should be reexamined for clinical and research utility. Key Words: gestational hypertension Ⅲ preeclampsia Ⅲ pregnancy Ⅲ uric acid Ⅲ intrauterine growth restriction Ⅲ preterm birth Ⅲ risk assessment H ypertensive disorders during pregnancy increase maternal and infant risk. The greatest impact is associated with the pregnancy-specific syndrome, preeclampsia. 1 Preeclampsia, conventionally diagnosed by the gestational onset of hypertension and proteinuria, increases perinatal mortality 5-fold 1 and kills 50,000 women yearly worldwide. 2 Its management, delivery to halt the progression of the pathophysiology, is responsible for 15% of preterm births in developed countries. 3 Gestational hypertension without proteinuria has much less of an adverse effect on maternal or fetal outcome, whereas the major risk from hypertension that antedates pregnancy is the superimposition of preeclampsia. 4 The importance of differentiating these conditions is reflected in several classification schemes in which gestational hypertension with proteinuria is separated from gestational hypertension without proteinuria and hypertension that antedates pregnancy. 4 -6 These diagnostic criteria currently used to discriminate high-risk from lower risk women with gestational hypertension are arbitrary. The term "preeclampsia" was coined in the early 20th century when it was recognized that hypertension and proteinuria could be precursors to a pregnancy-specific seizure disorder, eclampsia, which had been recognized for...

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In preeclampsia, poor placental perfusion may result in maternal endothelial dysfunction, but the pathways involved are largely unknown. Candidate placental mediators include products of oxidative stress released into the maternal circulation. Xanthine oxidase has been implicated in postischemic-reperfusion injury via the generation of superoxide anion radicals (superoxide; O 2 .؊ ) and hydrogen peroxide. We examined placentas and placental bed curettings and/or biopsies from preeclamptic control pregnant women to test the hypothesis that xanthine oxidase is a mediator of oxidative stress in placentas from women with preeclampsia. The expression of xanthine dehydrogenase/xanthine oxidase holoenzyme and the activity of xanthine oxidase, the isoform known to generate reactive oxygen species, were increased in a subpopulation of cytotrophoblasts of preeclamptic women. Additionally, the expression of superoxide dismutase, which would scavenge superoxide produced by xanthine oxidase, was reduced in the same cells. Preeclampsia, a pregnancy-specific disorder, is the leading cause of maternal mortality in the Western world and increases perinatal mortality fivefold. The clinical diagnosis is based on the new onset of hypertension and the appearance of proteinuria and edema during pregnancy. It is evident, however, that these findings are a small component of a multisystemic disease that reduces perfusion to virtually all of the organs in the body. 1 The hypothesis has been advanced that much of the disease could be explained by alterations in the function of vascular endothelium. Increasing data support this hypothesis. 2 The more complete hypothesis posits that the placenta, likely in response to reduced perfusion, produces a circulating factor(s) that alters endothelial cell function. 2 Among the candidate molecules are products resulting from oxidative stress. 3 Oxidative stress, the result of freeradical generation in excess of protective mechanisms, is suggested as an important component of other disorders that affect endothelial function, including diabetes and atherosclerosis. 4,5 Evidence for oxidative stress in preeclampsia includes elevated lipid hydroperoxides or their metabolites and reduced plasma antioxidant activity. 3,6 -8 Xanthine oxidase, which metabolizes xanthine and hypoxanthine to uric acid with production of superoxide and hydrogen peroxide, is an integral mediator of reactive oxygen species generation in many settings. Usually, this enzyme is present as the holoenzyme xanthine dehydrogenase/xanthine oxidase (XDH/XO). The dehydrogenase isoform (XDH) converts purines to uric acid with reducton of nicotinamide-adenine dinucleotide (NAD) to reduced NAD (NADH). With hypoxia and in response to several cytokines, XDH/XO synthesis increases, and the conversion of the enzyme to the XO form is enhanced. 9 Reduced organ perfusion and subsequent reperfusion are proposed to result in increased XO during reduced flow and in subsequent formation of reactive oxygen species with reperfusion. The inadequate pla...