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      Effect of Low-Dose Aspirin on Soluble FMS-Like Tyrosine Kinase 1/Placental Growth Factor (sFlt-1/PlGF Ratio) in Pregnancies at High Risk for the Development of Preeclampsia

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          Abstract

          Background: Soluble FMS-like Tyrosine Kinase 1 (sFlt-1) and placental growth factor (PlGF) have been reported to be highly predictive several weeks before the onset of preeclampsia. Objective: To investigate longitudinal changes of serum levels sFlt-1 and PlGF in pregnant women at high risk for the development of preeclampsia and to reveal an impact of aspirin on maternal serum concentrations of sFlt-1 and PlGF. Methods: This was a prospective longitudinal study in 394 women with various risk factors for the development of preeclampsia (chronic hypertension, antiphospholipid syndrome/APS or systemic lupus erythematosus/SLE, thrombophilia, women with a history of preeclampsia, pathologic first trimester screening for preeclampsia) and 68 healthy women. Serum levels of sFlt-1 and PlGF were measured prospectively at 4-week intervals (from gestational weeks 12 until postpartum). Results: The sFlt-1/PlGF ratio was significantly higher in women with an adverse obstetric outcome compared to women with a normal pregnancy, starting between 20 and 24 weeks of gestation. There was no effect of aspirin on sFlt-1/PlGF ratio in women with chronic hypertension, APS/SLE, thrombophilia and controls. The use of aspirin showed a trend towards an improvement of the sFlt-1/PlGF ratio in women with preeclampsia in a previous pregnancy and a significant effect on the sFlt-1/PlGF ratio in women with a pathologic first trimester screening for preeclampsia. Conclusions: Our findings reveal an impact of aspirin on sFlt-1/PlGF ratio in women with a pathologic first trimester screening for preeclampsia, strongly supporting its prophylactic use.

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          Circulating angiogenic factors and the risk of preeclampsia.

          The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. Copyright 2004 Massachusetts Medical Society
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            ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002.

            (2002)
            Hypertensive disease occurs in approximately 12-22% of pregnancies, and it is directly responsible for 17.6% of maternal deaths in the United States (1,2). However, there is confusion about the terminology and classification of these disorders. This bulletin will provide guidelines for the diagnosis and management of hypertensive disorders unique to pregnancy (ie, preeclampsia and eclampsia), as well as the various associated complications. Chronic hypertension has been discussed elsewhere (3).
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              The two stage model of preeclampsia: variations on the theme.

              The Two Stage Model of preeclampsia proposes that a poorly perfused placenta (Stage 1) produces factor(s) leading to the clinical manifestations of preeclampsia (Stage 2). 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 is completed. 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 be tolerated by some women who develop preeclampsia. Further, it is evident that linkage is not likely to be 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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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                10 September 2019
                September 2019
                : 8
                : 9
                : 1429
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Division of Obstetrics, Medical University of Graz, A-8036 Graz, Austria
                [2 ]Department of Internal Medicine, Div. of Endocrinology and Diabetology, Endocrinology Lab Platform, Medical University of Graz, A-8036 Graz, Austria
                [3 ]Department for Core Facility Computational Bioanalytics, Center for Medical Research (ZMF), Medical University of Graz, A-8036 Graz, Austria
                Author notes
                [†]

                Both authors equally contributed.

                Author information
                https://orcid.org/0000-0002-3077-108X
                https://orcid.org/0000-0003-2940-4255
                https://orcid.org/0000-0002-7196-454X
                Article
                jcm-08-01429
                10.3390/jcm8091429
                6780316
                31510056
                04669450-2793-45aa-b4c5-58747483deee
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 08 August 2019
                : 03 September 2019
                Categories
                Article

                adverse pregnancy outcome,aspirin,first trimester screening for preeclampsia,high-risk pregnancies,preeclampsia,sflt1/plgf ratio

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