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      Circulating SPINT1 is a biomarker of pregnancies with poor placental function and fetal growth restriction

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          Abstract

          Placental insufficiency can cause fetal growth restriction and stillbirth. There are no reliable screening tests for placental insufficiency, especially near-term gestation when the risk of stillbirth rises. Here we show a strong association between low circulating plasma serine peptidase inhibitor Kunitz type-1 (SPINT1) concentrations at 36 weeks’ gestation and low birthweight, an indicator of placental insufficiency. We generate a 4-tier risk model based on SPINT1 concentrations, where the highest risk tier has approximately a 2-5 fold risk of birthing neonates with birthweights under the 3 rd, 5 th, 10 th and 20 th centiles, whereas the lowest risk tier has a 0-0.3 fold risk. Low SPINT1 is associated with antenatal ultrasound and neonatal anthropomorphic indicators of placental insufficiency. We validate the association between low circulating SPINT1 and placental insufficiency in two other cohorts. Low circulating SPINT1 is a marker of placental insufficiency and may identify pregnancies with an elevated risk of stillbirth.

          Abstract

          There are no reliable tests for placental insufficiency, which can lead to fetal growth restriction and stillbirth. Here the authors demonstrate that low levels of circulating SPINT1 are associated to low birthweight, and several ultrasound and neonatal anthropomorphic indicators of placental insufficiency.

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          Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.

          Alterations in circulating soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. Since soluble endoglin, another antiangiogenic protein, acts together with sFlt1 to induce a severe preeclampsia-like syndrome in pregnant rats, we examined whether it is associated with preeclampsia in women. We performed a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial. The study included all 72 women who had preterm preeclampsia ( or =37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age. Circulating soluble endoglin levels increased markedly beginning 2 to 3 months before the onset of preeclampsia. After the onset of clinical disease, the mean serum level in women with preterm preeclampsia was 46.4 ng per milliliter, as compared with 9.8 ng per milliliter in controls (P<0.001). The mean serum level in women with preeclampsia at term was 31.0 ng per milliliter, as compared with 13.3 ng per milliliter in controls (P<0.001). Beginning at 17 weeks through 20 weeks of gestation, soluble endoglin levels were significantly higher in women in whom preterm preeclampsia later developed than in controls (10.2 ng per milliliter vs. 5.8 ng per milliliter, P<0.001), and at 25 through 28 weeks of gestation, the levels were significantly higher in women in whom term preeclampsia developed than in controls (8.5 ng per milliliter vs. 5.9 ng per milliliter, P<0.001). An increased level of soluble endoglin was usually accompanied by an increased ratio of sFlt1:PlGF. The risk of preeclampsia was greatest among women in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone. Rising circulating levels of soluble endoglin and ratios of sFlt1:PlGF herald the onset of preeclampsia. Copyright 2006 Massachusetts Medical Society.
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            Maternal and fetal risk factors for stillbirth: population based study

            Objective To assess the main risk factors associated with stillbirth in a multiethnic English maternity population. Design Cohort study. Setting National Health Service region in England. Population 92 218 normally formed singletons including 389 stillbirths from 24 weeks of gestation, delivered during 2009-11. Main outcome measure Risk of stillbirth. Results Multivariable analysis identified a significant risk of stillbirth for parity (para 0 and para ≥3), ethnicity (African, African-Caribbean, Indian, and Pakistani), maternal obesity (body mass index ≥30), smoking, pre-existing diabetes, and history of mental health problems, antepartum haemorrhage, and fetal growth restriction (birth weight below 10th customised birthweight centile). As potentially modifiable risk factors, maternal obesity, smoking in pregnancy, and fetal growth restriction together accounted for 56.1% of the stillbirths. Presence of fetal growth restriction constituted the highest risk, and this applied to pregnancies where mothers did not smoke (adjusted relative risk 7.8, 95% confidence interval 6.6 to 10.9), did smoke (5.7, 3.6 to 10.9), and were exposed to passive smoke only (10.0, 6.6 to 15.8). Fetal growth restriction also had the largest population attributable risk for stillbirth and was fivefold greater if it was not detected antenatally than when it was (32.0% v 6.2%). In total, 195 of the 389 stillbirths in this cohort had fetal growth restriction, but in 160 (82%) it had not been detected antenatally. Antenatal recognition of fetal growth restriction resulted in delivery 10 days earlier than when it was not detected: median 270 (interquartile range 261-279) days v 280 (interquartile range 273-287) days. The overall stillbirth rate (per 1000 births) was 4.2, but only 2.4 in pregnancies without fetal growth restriction, increasing to 9.7 with antenatally detected fetal growth restriction and 19.8 when it was not detected. Conclusion Most normally formed singleton stillbirths are potentially avoidable. The single largest risk factor is unrecognised fetal growth restriction, and preventive strategies need to focus on improving antenatal detection.
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              Labor Induction versus Expectant Management in Low-Risk Nulliparous Women

              The perinatal and maternal consequences of induction of labor at 39 weeks among low-risk nulliparous women are uncertain.
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                Author and article information

                Contributors
                t.klino@unimelb.edu.au
                stong@unimelb.edu.au
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                15 May 2020
                15 May 2020
                2020
                : 11
                : 2411
                Affiliations
                [1 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, , University of Melbourne, ; Heidelberg 3084 Victoria, Australia
                [2 ]ISNI 0000 0004 0577 6561, GRID grid.415379.d, Mercy Perinatal, Mercy Hospital for Women, ; Heidelberg 3084 Victoria, Australia
                [3 ]Foresight Health, Adelaide, 169 Fullarton Rd., Dulwich, 5065 South Australia Australia
                [4 ]ISNI 0000000121662407, GRID grid.5379.8, University of Manchester, Manchester Academic Health Science Centre, St Mary’s Hospital, ; Manchester, M13 OJH UK
                [5 ]GRID grid.410678.c, Pathology Department, Austin Health, ; Heidelberg 3084 Victoria, Australia
                [6 ]ISNI 0000000121885934, GRID grid.5335.0, Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, , University of Cambridge, ; Cambridge, CB2 3EG UK
                Author information
                http://orcid.org/0000-0001-9099-7745
                http://orcid.org/0000-0001-8898-0434
                http://orcid.org/0000-0003-0913-2096
                http://orcid.org/0000-0002-4931-4233
                Article
                16346
                10.1038/s41467-020-16346-x
                7228948
                32415092
                79c81c06-85db-4024-860c-6f3031f7759d
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 27 July 2019
                : 24 April 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001104, RANZCOG Research Foundation (RANZCOG);
                Funded by: The Stillbirth Foundation
                Funded by: FundRef https://doi.org/10.13039/501100009324, Tommy's;
                Funded by: National Institute Health Research Manchester Academic Health Science Centre
                Funded by: FundRef https://doi.org/10.13039/501100000268, RCUK | Biotechnology and Biological Sciences Research Council (BBSRC);
                Funded by: Centre for Trophoblast Research
                Funded by: FundRef https://doi.org/10.13039/501100000925, Department of Health | National Health and Medical Research Council (NHMRC);
                Award ID: 1105603
                Award ID: 1065854
                Award ID: 1136418
                Award ID: 1183854
                Award Recipient :
                Categories
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                Custom metadata
                © The Author(s) 2020

                Uncategorized
                biomarkers,diseases
                Uncategorized
                biomarkers, diseases

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