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Anne Eskild - One of the best experts on this subject based on the ideXlab platform.
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angiogenic factors in maternal circulation and Preeclampsia with or without fetal growth restriction
Acta Obstetricia et Gynecologica Scandinavica, 2012Co-Authors: Lars J Vatten, Bjorn Olav Asvold, Anne EskildAbstract:Objective To study associations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in maternal circulation with the risk of Preeclampsia with and without fetal growth restriction. Design Nested case-control study. Setting A cohort of 29 948 pregnant women in Norway. Sample Cases were identified through linkage to the Medical Birth Registry of Norway. We selected 69 preterm and 36 term Preeclampsia cases with delivery of a small-for-gestational-age (SGA) infant, 83 preterm and 154 term Preeclampsia cases without SGA delivery, and 384 normotensive controls. Methods We measured PlGF and sFlt-1 in maternal serum samples from each trimester. Main outcome measures Odds ratios of Preeclampsia subtypes by tertile categories of PlGF and sFlt-1. Results Low (lowest third) PlGF and sFlt-1 levels in the first trimester, and low (lowest third) increase in PlGF and strong (highest third) increase in sFlt-1 from first to second trimester were associated with increased risk of preterm Preeclampsia, both with and without SGA offspring. For term Preeclampsia with SGA offspring, the associations were similar to the findings for preterm Preeclampsia. For term Preeclampsia without SGA offspring, low increase in PlGF from first to second trimester and high sFlt-1 in the third trimester were associated with increased risk. Conclusions Low PlGF and high sFlt-1 levels in maternal circulation are associated with subsequent development of Preeclampsia, regardless of whether fetal growth is affected or not. For term Preeclampsia without fetal growth restriction, the imbalance in angiogenic factors seems to appear later in pregnancy than for preterm Preeclampsia.
Roberto Romero - One of the best experts on this subject based on the ideXlab platform.
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should bilateral uterine artery notching be used in the risk assessment for Preeclampsia small for gestational age and gestational hypertension
Journal of Ultrasound in Medicine, 2010Co-Authors: Jimmy Espinoza, Roberto Romero, Juan Pedro Kusanovic, Ray O Bahadosingh, Maria Teresa Gervasi, Wesley Lee, Edi Vaisbuch, Shali MazakitoviAbstract:Objective. The purpose of this study was to determine the value of bilateral uterine artery notching in the second trimester in the risk assessment for Preeclampsia, gestational hypertension, and small-for-gestational-age (SGA) without Preeclampsia. Methods. This prospective cohort study included 4190 singleton pregnancies that underwent ultrasound examination between 23 and 25 weeks' gestation. The 95th percentiles of the mean pulsatility index (PI) and resistive index (RI) of both uterine arteries were calculated. Multivariable logistic regression analyses were performed to determine if bilateral uterine artery notching is an independent explanatory variable for the occurrence of Preeclampsia, early-onset Preeclampsia (≤34 weeks), late-onset Preeclampsia (>34 weeks), gestational hypertension, and delivery of an SGA neonate without Preeclampsia, while controlling for confounding factors. Results. (1) The prevalence of Preeclampsia, early-onset Preeclampsia, late-onset Preeclampsia, SGA, and gestational hypertension were 3.4%, 0.5%, 2.9%, 10%, and 7.9%, respectively; (2) 7.2% of the study population had bilateral uterine artery notching; and (3) bilateral uterine artery notching was an independent explanatory variable for the development of Preeclampsia (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.28-3.36), early-onset Preeclampsia (OR, 4.47; 95% CI, 1.50-13.35), and gestational hypertension (OR, 1.50; 95% CI, 1.02-2.26), but not for late-onset Preeclampsia or SGA. Conclusions. Bilateral uterine notching between 23 and 25 weeks' gestation is an independent risk factor for the development of early-onset Preeclampsia and gestational hypertension. Thus, bilateral uterine artery notching should be considered in the assessment of risk for the development of these pregnancy complications.
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first trimester maternal serum pp13 in the risk assessment for Preeclampsia
American Journal of Obstetrics and Gynecology, 2008Co-Authors: Roberto Romero, Jimmy Espinoza, Juan Pedro Kusanovic, Nandor Gabor Than, Offer Erez, Francesca GotschAbstract:Objective The objective of the study was to determine whether first-trimester maternal serum placental protein 13 (PP13) concentrations can be used in the risk assessment for Preeclampsia. Study Design This case-control study included 50 patients with Preeclampsia and 250 patients with normal pregnancies. Samples were collected between 8 and 13 weeks of gestation. Serum PP13 concentrations were measured by immunoassay and expressed as medians and multiples of the median (MoM) for gestational age. Sensitivity and specificity were derived from receiver-operating characteristic curve analysis. Results (1) Serum PP13 concentration in the first trimester was significantly lower in patients who developed preterm and early-onset Preeclampsia than in those with normal pregnancies; and (2) at 80% specificity, a cutoff of 0.39 MoM had a sensitivity of 100% for early-onset Preeclampsia and 85% for preterm Preeclampsia. Conclusion Maternal serum first-trimester PP13 appears to be a reasonable marker for risk assessment for preterm Preeclampsia but a weak marker for severe Preeclampsia at term, and ineffective for identifying mild Preeclampsia at term.
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distinct subsets of micrornas are expressed differentially in the human placentas of patients with Preeclampsia
American Journal of Obstetrics and Gynecology, 2007Co-Authors: Beth L Pineles, Roberto Romero, Daniel Montenegro, Adi L Tarca, Yu Mi Han, Yeon Mee Kim, Sorin DraghiciAbstract:Objective Preeclampsia and small-for-gestational age (SGA) neonates have partially overlapping clinicopathologic features. MicroRNAs (miRNAs) are critical posttranscriptional regulators of gene expression. This study was performed to determine whether Preeclampsia and SGA are associated with alterations in placental miRNA expression. Study design Placentas were obtained from patients with (1) Preeclampsia (n = 9); (2) SGA (n = 9); (3) Preeclampsia + SGA (n = 9); and (4) a control group with spontaneous preterm labor and delivery (PTL; n = 9). The expression of 157 miRNAs was assessed by real-time quantitative reverse transcription-polymerase chain reaction. Results Differential expression between Preeclampsia and the control group (miR-210, miR-182) and between Preeclampsia + SGA and the control group (miR-210, miR-182*, and others) was found. Gene Ontology analysis of the target genes revealed enrichment for specific biological process categories (antiapoptosis: miR-182; regulation of transcription: miR-210). Conclusion This study reports, for the first time, increased expression of specific placental miRNAs in Preeclampsia with and without SGA. The findings also provide novel targets for further investigation of the pathophysiology of Preeclampsia.
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soluble endoglin and other circulating antiangiogenic factors in Preeclampsia
Obstetrical & Gynecological Survey, 2007Co-Authors: Richard J Levine, Roberto Romero, Cong Qian, Kai F Yu, Sharon E Maynard, Benjamin P Sachs, Baha M Sibai, Franklin H Epstein, Ravi Thadhani, Ananth S KarumanchiAbstract:The circulating antiangiogenic protein soluble fms-like tyrosine kinase 1 (sFltl), also known as soluble vascular endothelial growth factor (VEGF) receptor 1, sequesters the proangiogenic proteins placental growth factor (PlGF) and VEGF. Its circulating level correlates with the severity of preclampsia and with the onset of hypertension or proteinuria. Increased expression of sFltl in pregnant rats creates a state resembling Preeclampsia. Soluble endoglin, a coreceptor for transforming growth factors, is another antiangiogenic protein that acts with sFltl to produce a severe Preeclampsia-like syndrome in pregnant rats. This nested case-control study, enrolling healthy nulliparous women taking part in the Calcium for Preeclampsia Prevention (CPEP) trial, was designed to show whether endoglin is associated with Preeclampsia in humans. Seventy-two women having Preeclampsia before 37 weeks' gestation were compared with four groups, each comprising 120 women, who had Preeclampsia at term; had gestational hypertension; were normotensive but had an small-for-gestational-age infant; or were normotensive and delivered a normal-sized infant. Severe Preeclampsia developed in 61% of women with preterm Preeclampsia and 25% of those with Preeclampsia at term (after 37 weeks' gestation). Symptomatic women with preterm Preeclampsia had significantly higher serum levels of soluble endoglin than control women. Term Preeclampsia also was associated with elevated circulating levels of endoglin. At 17-20 weeks' gestation, endoglin levels were significantly higher in women who later developed preterm Preeclampsia than in control women. The same was the case at gestational weeks 25 through 28 for women who developed term Preeclampsia. Elevated endoglin levels usually were accompanied by an increased sFltl:P1GF ratio. The risk of Preeclampsia was greatest for women in the highest quartile of the control distributions for both biomarkers but not for either one alone. On multivariable analysis, large increases in the risk of Preeclampsia with a small-for-gestational-age infant were associated with the highest quartile of soluble endoglin or sFltl:P1GF ratio. These findings, combined with those of experimental rodent studies, suggest that circulating soluble endoglin and spil-which cause endothelial dysfunction by different mechanisms-may contribute to the development of Preeclampsia. Whether levels of these biomarkers will be useful in predicting the onset of clinical Preeclampsia remains to be determined by longitudinal prospective studies.
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an elevated maternal plasma but not amniotic fluid soluble fms like tyrosine kinase 1 sflt 1 at the time of mid trimester genetic amniocentesis is a risk factor for Preeclampsia
American Journal of Obstetrics and Gynecology, 2005Co-Authors: Chanwook Park, Joong Shin Park, Soonsup Shim, Jong Kwan Jun, Bo Hyun Yoon, Roberto RomeroAbstract:Objective The purpose of this study was to determine if an elevated concentration of soluble fms-like tyrosine kinase-1(sFlt-1) in maternal plasma and amniotic fluid is a risk factor for the subsequent development of Preeclampsia. Study design A case-control study was conducted to compare mid-trimester concentrations of maternal plasma and amniotic fluid sFlt-1 in patients who developed Preeclampsia with those who did not. The study included 32 cases with Preeclampsia (18 cases: severe Preeclampsia) and 128 matched controls with normal outcomes. Patients with an abnormal fetal karyotype or major anomaly, multiple pregnancies, chronic hypertension, diabetes, and renal disease were excluded. Soluble Flt-1 concentration was measured by specific immunoassay. Nonparametric techniques were used for statistical analysis. Results 1) The median maternal plasma, but not amniotic fluid, sFlt-1 concentration in patients who developed Preeclampsia was significantly higher than in the control cases (maternal plasma: median 730 pg/mL, range 60-3375 pg/mL vs median 441 pg/mL, range 58-1959 pg/mL, P P =.65). 2) The median plasma concentration of sFlt-1 was higher in cases of severe Preeclampsia than in those with mild Preeclampsia without reaching statistical significance (median 762 pg/mL, range 261-3309 pg/mL vs median 334 pg/mL, range 60-3375 pg/mL; P =.07). However, there was no significant difference in the median amniotic fluid sFlt-1 concentrations between patients with severe Preeclampsia and those with mild Preeclampsia ( P =.45). 3) An elevated maternal plasma sFlt-1 concentration (higher than 700 pg/mL) is a risk factor for the development of Preeclampsia (OR 3.9, 95% CI 1.7-8.6) and severe Preeclampsia (OR 7.4, 95% CI 2.5-22.1) after genetic amniocentesis. 4) The median interval from amniocentesis to the diagnosis of Preeclampsia in patients with maternal plasma sFlt-1 concentrations higher than 700 pg/mL was 117 days (range 19-154 days). Conclusion An elevated concentration of sFlt-1 in maternal plasma at the time of mid-trimester amniocentesis is a risk factor for the subsequent development of Preeclampsia.
K H Nicolaides - One of the best experts on this subject based on the ideXlab platform.
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predictive performance of the competing risk model in screening for Preeclampsia
American Journal of Obstetrics and Gynecology, 2019Co-Authors: David Wright, M Y Tan, Neil Ogorman, Liona C Poon, Argyro Syngelaki, Alan Wright, K H NicolaidesAbstract:Background The established method of screening for Preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors the patient is classified as high risk and in their absence as low risk. However, the performance of such an approach is poor. We developed a competing risks model, which allows combination of maternal factors (age, weight, height, race, parity, personal and family history of Preeclampsia, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, method of conception and interpregnancy interval), with biomarkers to estimate the individual patient-specific risks of Preeclampsia requiring delivery before any specified gestation. The performance of this approach is by far superior to that of the risk scoring systems. Objective The objective of the study was to examine the predictive performance of the competing risks model in screening for Preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, referred to as the triple test, in a training data set for the development of the model and 2 validation studies. Study Design The data for this study were derived from 3 previously reported prospective, nonintervention, multicenter screening studies for Preeclampsia in singleton pregnancies at 11+0 to 13+6 weeks’ gestation. In all 3 studies, there was recording of maternal factors and biomarkers and ascertainment of outcome by appropriately trained personnel. The first study of 35,948 women, which was carried out between February 2010 and July 2014, was used to develop the competing risks model for prediction of Preeclampsia and is therefore considered to be the training set. The 2 validation studies were comprised of 8775 and 16,451 women, respectively, and they were carried out between February and September 2015 and between April and December 2016, respectively. Patient-specific risks of delivery with Preeclampsia at Results The detection rate at the screen-positive rate of 10% of early-Preeclampsia, preterm-Preeclampsia, and all-Preeclampsia was about 90%, 75%, and 50%, respectively, and the results were consistent between the training and 2 validation data sets. The area under the receiver operating characteristic curve was >0.95, >0.90, and >0.80, respectively, demonstrating a very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slopes were very close to 1.0, demonstrating a good agreement between the predicted risks and observed incidence of Preeclampsia. In the prediction of early-Preeclampsia and preterm-Preeclampsia, the observed incidence in the training set and 1 of the validation data sets was consistent with the predicted one. In the other validation data set, which was specifically designed for evaluation of the model, the incidence was higher than predicted, presumably because of better ascertainment of outcome. The incidence of all-Preeclampsia was lower than predicted in all 3 data sets because at term many pregnancies deliver for reasons other than Preeclampsia, and therefore, pregnancies considered to be at high risk for Preeclampsia that deliver for other reasons before they develop Preeclampsia can be wrongly considered to be false positives. Conclusion The competing risks model provides an effective and reproducible method for first-trimester prediction of early Preeclampsia and preterm Preeclampsia as long as the various components of screening are carried out by appropriately trained and audited practitioners. Early prediction of preterm Preeclampsia is beneficial because treatment of the high-risk group with aspirin is highly effective in the prevention of the disease.
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competing risks model in screening for Preeclampsia by maternal characteristics and medical history
American Journal of Obstetrics and Gynecology, 2015Co-Authors: David Wright, Argyro Syngelaki, Ranjit Akolekar, Leona Poon, K H NicolaidesAbstract:OBJECTIVE: The purpose of this study was to develop a model for Preeclampsia based on maternal demographic characteristics and medical history. STUDY DESIGN: This was a screening study of 120,492 singleton pregnancies at 11-13 weeks’ gestation, including 2704 pregnancies (2.2%) that experienced Preeclampsia. A survival-time model for the gestational age at delivery with Preeclampsia was developed from variables of maternal characteristics and history. This approach assumes that, if the pregnancy was to continue indefinitely, all women would experience Preeclampsia and that whether they do so or not before a specified gestational age depends on competition between delivery before or after development of Preeclampsia. A 5-fold cross validation studywasconductedtocomparetheperformanceofthenewmodelwith theNationalInstituteforHealthandClinicalExcellence(NICE)guidelines. RESULTS: In the new model, increased risk for Preeclampsia, with a consequent shift in the Gaussian distribution of the gestational age at delivery with Preeclampsia to the left, is provided by advancing maternal age, increasing weight, Afro-Caribbean and South Asian racialorigin, medicalhistoryofchronichypertension, diabetesmellitus and systemic lupus erythematosus or antiphospholipid syndrome, family history and personal history of Preeclampsia, and conception by in vitro fertilization. The risk for Preeclampsia decreases with increasing maternal height and in parous women with no previous Preeclampsia; in the latter, the protective effect, which is related inversely to the interpregnancy interval, persists beyond 15 years. At a screen-positive rate of 11%, as defined by NICE, the new model predicted 40%, 48%, and 54% of cases of total Preeclampsia and Preeclampsia requiring delivery at <37 and <34 weeks’ gestation, respectively,whichweresignificantlyhigherthantherespectivevalues of 35%, 40%, and 44% achieved by application of NICE guidelines. CONCLUSION: A new model that is based on maternal characteristics and medical history has been developed for the estimation of patientspecific risks for Preeclampsia. Such estimation of the a priori risk for Preeclampsia is an essential first step in the use of Bayes theorem to combine maternal factors with biomarkers for the continuing development of more effective methods of screening for the disease.
Eduard Gratacos - One of the best experts on this subject based on the ideXlab platform.
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placental angiogenic growth factors and uterine artery doppler findings for characterization of different subsets in Preeclampsia and in isolated intrauterine growth restriction
American Journal of Obstetrics and Gynecology, 2006Co-Authors: F Crispi, Carmen Dominguez, Elisa Llurba, Pilar Martingallan, L Cabero, Eduard GratacosAbstract:Objective The purpose of this study was to evaluate possible relationships between placental markers and endothelial dysfunction in Preeclampsia and intrauterine growth restriction. Study design A prospective study was conducted in 76 patients with Preeclampsia and 37 patients with intrauterine growth restriction that were classified as early onset ( Results In early-onset Preeclampsia and intrauterine growth restriction, placental growth factor was lower and soluble fms-like tyrosine kinase–1 and vascular cell adhesion molecule–1 higher than in control subjects, although all changes were more pronounced in Preeclampsia. In late-onset Preeclampsia, those patients with abnormal uterine artery Doppler indices had higher soluble fms-like tyrosine kinase–1 and vascular cell adhesion molecule–1 levels. Conclusion Biochemical changes in early-onset Preeclampsia and intrauterine growth restriction point to a common placental disorder and a state of endothelial dysfunction, which may require interaction with other factors to explain the maternal disease in Preeclampsia. Data in late-onset Preeclampsia suggest that a proportion of them may occur with minimal placental involvement.
David Wright - One of the best experts on this subject based on the ideXlab platform.
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predictive performance of the competing risk model in screening for Preeclampsia
American Journal of Obstetrics and Gynecology, 2019Co-Authors: David Wright, M Y Tan, Neil Ogorman, Liona C Poon, Argyro Syngelaki, Alan Wright, K H NicolaidesAbstract:Background The established method of screening for Preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors the patient is classified as high risk and in their absence as low risk. However, the performance of such an approach is poor. We developed a competing risks model, which allows combination of maternal factors (age, weight, height, race, parity, personal and family history of Preeclampsia, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, method of conception and interpregnancy interval), with biomarkers to estimate the individual patient-specific risks of Preeclampsia requiring delivery before any specified gestation. The performance of this approach is by far superior to that of the risk scoring systems. Objective The objective of the study was to examine the predictive performance of the competing risks model in screening for Preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, referred to as the triple test, in a training data set for the development of the model and 2 validation studies. Study Design The data for this study were derived from 3 previously reported prospective, nonintervention, multicenter screening studies for Preeclampsia in singleton pregnancies at 11+0 to 13+6 weeks’ gestation. In all 3 studies, there was recording of maternal factors and biomarkers and ascertainment of outcome by appropriately trained personnel. The first study of 35,948 women, which was carried out between February 2010 and July 2014, was used to develop the competing risks model for prediction of Preeclampsia and is therefore considered to be the training set. The 2 validation studies were comprised of 8775 and 16,451 women, respectively, and they were carried out between February and September 2015 and between April and December 2016, respectively. Patient-specific risks of delivery with Preeclampsia at Results The detection rate at the screen-positive rate of 10% of early-Preeclampsia, preterm-Preeclampsia, and all-Preeclampsia was about 90%, 75%, and 50%, respectively, and the results were consistent between the training and 2 validation data sets. The area under the receiver operating characteristic curve was >0.95, >0.90, and >0.80, respectively, demonstrating a very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slopes were very close to 1.0, demonstrating a good agreement between the predicted risks and observed incidence of Preeclampsia. In the prediction of early-Preeclampsia and preterm-Preeclampsia, the observed incidence in the training set and 1 of the validation data sets was consistent with the predicted one. In the other validation data set, which was specifically designed for evaluation of the model, the incidence was higher than predicted, presumably because of better ascertainment of outcome. The incidence of all-Preeclampsia was lower than predicted in all 3 data sets because at term many pregnancies deliver for reasons other than Preeclampsia, and therefore, pregnancies considered to be at high risk for Preeclampsia that deliver for other reasons before they develop Preeclampsia can be wrongly considered to be false positives. Conclusion The competing risks model provides an effective and reproducible method for first-trimester prediction of early Preeclampsia and preterm Preeclampsia as long as the various components of screening are carried out by appropriately trained and audited practitioners. Early prediction of preterm Preeclampsia is beneficial because treatment of the high-risk group with aspirin is highly effective in the prevention of the disease.
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competing risks model in screening for Preeclampsia by maternal characteristics and medical history
American Journal of Obstetrics and Gynecology, 2015Co-Authors: David Wright, Argyro Syngelaki, Ranjit Akolekar, Leona Poon, K H NicolaidesAbstract:OBJECTIVE: The purpose of this study was to develop a model for Preeclampsia based on maternal demographic characteristics and medical history. STUDY DESIGN: This was a screening study of 120,492 singleton pregnancies at 11-13 weeks’ gestation, including 2704 pregnancies (2.2%) that experienced Preeclampsia. A survival-time model for the gestational age at delivery with Preeclampsia was developed from variables of maternal characteristics and history. This approach assumes that, if the pregnancy was to continue indefinitely, all women would experience Preeclampsia and that whether they do so or not before a specified gestational age depends on competition between delivery before or after development of Preeclampsia. A 5-fold cross validation studywasconductedtocomparetheperformanceofthenewmodelwith theNationalInstituteforHealthandClinicalExcellence(NICE)guidelines. RESULTS: In the new model, increased risk for Preeclampsia, with a consequent shift in the Gaussian distribution of the gestational age at delivery with Preeclampsia to the left, is provided by advancing maternal age, increasing weight, Afro-Caribbean and South Asian racialorigin, medicalhistoryofchronichypertension, diabetesmellitus and systemic lupus erythematosus or antiphospholipid syndrome, family history and personal history of Preeclampsia, and conception by in vitro fertilization. The risk for Preeclampsia decreases with increasing maternal height and in parous women with no previous Preeclampsia; in the latter, the protective effect, which is related inversely to the interpregnancy interval, persists beyond 15 years. At a screen-positive rate of 11%, as defined by NICE, the new model predicted 40%, 48%, and 54% of cases of total Preeclampsia and Preeclampsia requiring delivery at <37 and <34 weeks’ gestation, respectively,whichweresignificantlyhigherthantherespectivevalues of 35%, 40%, and 44% achieved by application of NICE guidelines. CONCLUSION: A new model that is based on maternal characteristics and medical history has been developed for the estimation of patientspecific risks for Preeclampsia. Such estimation of the a priori risk for Preeclampsia is an essential first step in the use of Bayes theorem to combine maternal factors with biomarkers for the continuing development of more effective methods of screening for the disease.
