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A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.

ABSTRACT: OBJECTIVE:Changes in the maternal plasma concentrations of angiogenic (placental growth factor (PlGF) and vascular endothelial growth factor (VEGF)) and anti-angiogenic factors (sEng and vascular endothelial growth factor receptor-1 (sVEGFR-1)) precede the clinical presentation of preeclampsia. This study was conducted to examine the role of maternal plasma PlGF, sEng, and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia. METHODS:This longitudinal cohort study included 1622 consecutive singleton pregnant women. Plasma samples were obtained in early pregnancy (6-15 weeks) and midtrimester (20-25 weeks). Maternal plasma PlGF, sEng, and sVEGFR-1 concentrations were determined using sensitive and specific immunoassays. The primary outcome was the development of preeclampsia. Secondary outcomes included term, preterm, and early-onset preeclampsia. Receiving operating characteristic curves, sensitivity, specificity, positive and negative likelihood ratios, and multivariable logistic regression were applied. A p-value of <0.05 was considered significant. RESULTS:(1) The prevalence of preeclampsia, term, preterm, (<37 weeks) and early-onset preeclampsia (<34 weeks) was 3.8 (62/1622), 2.5 (40/1622), 1.4 (22/1622) and 0.6% (9/1622), respectively; (2) Higher likelihood ratios were provided by ratios of midtrimester plasma concentrations of PlGF, sEng, and sVEGFR-1 than single analytes; (3) Individual angiogenic and anti-angiogenic factors did not perform well in the identification of preeclampsia as a whole; in particular, they perform poorly in the prediction of term preeclampsia; (4) In contrast, a combination of these analytes such as the PlGF/sEng ratio, its delta and slope had the best predictive performance with a sensitivity of 100%, a specificity of 98-99%, and likelihood ratios for a positive test of 57.6, 55.6 and 89.6, respectively, for predicting early-onset preeclampsia. CONCLUSIONS:(1) The PlGF/sEng ratio and its delta and slope had an excellent predictive performance for the prediction of early-onset preeclampsia, with very high likelihood ratios for a positive test result and very low likelihood ratios for a negative test result; and (2) Although the positive likelihood ratios are high and the positive predictive values low, the number of patients needed to be closely followed is 4:1 for the PlGF/sEng ratio and 3:1 for the slope of PlGF/sEng.

SUBMITTER: Kusanovic JP

PROVIDER: S-EPMC3427777 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.

Kusanovic Juan Pedro JP Romero Roberto R Chaiworapongsa Tinnakorn T Erez Offer O Mittal Pooja P Vaisbuch Edi E Mazaki-Tovi Shali S Gotsch Francesca F Edwin Samuel S SS Gomez Ricardo R Yeo Lami L Conde-Agudelo Agustin A Hassan Sonia S SS

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 20091101 11

<h4>Objective</h4>Changes in the maternal plasma concentrations of angiogenic (placental growth factor (PlGF) and vascular endothelial growth factor (VEGF)) and anti-angiogenic factors (sEng and vascular endothelial growth factor receptor-1 (sVEGFR-1)) precede the clinical presentation of preeclampsia. This study was conducted to examine the role of maternal plasma PlGF, sEng, and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop pr ...[more]

PMID: 19900040

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Project description:Early identification of patients at risk of developing preeclampsia (PE) would allow providers to tailor their prenatal management and adopt preventive strategies, such as low-dose aspirin. Nevertheless, no mid-trimester biomarkers have as yet been proven useful for prediction of PE. This study investigates the ability of metabolomic biomarkers in mid-trimester maternal plasma to predict PE. A case-control study was conducted including 33 pregnant women with mid-trimester maternal plasma (gestational age [GA], 16-24 weeks) who subsequently developed PE and 66 GA-matched controls with normal outcomes (mid-trimester cohort). Plasma samples were comprehensively profiled for primary metabolic and lipidomic signatures based on gas chromatography time-of-flight mass spectrometry (GC-TOF MS) and liquid chromatography Orbitrap mass spectrometry (LC-Orbitrap MS). A potential biomarker panel was computed based on binary logistic regression and evaluated using receiver operating characteristic (ROC) analysis. To evaluate whether this panel can be also used in late pregnancy, a retrospective cohort study was conducted using plasma collected from women who delivered in the late preterm period because of PE (n = 13) or other causes (n = 21) (at-delivery cohort). Metabolomic biomarkers were compared according to the indication for delivery. Performance of the metabolomic panel to identify patients with PE was compared also to a commonly used standard, the plasma soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio. In the mid-trimester cohort, a total of 329 metabolites were identified and semi-quantified in maternal plasma using GC-TOF MS and LC-Orbitrap-MS. Binary logistic regression analysis proposed a mid-trimester biomarker panel for the prediction of PE with five metabolites (SM C28:1, SM C30:1, LysoPC C19:0, LysoPE C20:0, propane-1,3-diol). This metabolomic model predicted PE better than PlGF (AUC [95% CI]: 0.868 [0.844-0.891] vs 0.604 [0.485-0.723]) and sFlt-1/PlGF ratio. Analysis of plasma from the at-delivery cohort confirmed the ability of this biomarker panel to distinguish PE from non-PE, with comparable discrimination power to that of the sFlt-1/PlGF ratio. In conclusion, an integrative metabolomic biomarker panel in mid-trimester maternal plasma can accurately predict the development of PE and showed good discriminatory power in patients with PE at delivery.

Project description:BackgroundPreeclampsia is a pregnancy-specific disorder that remains a leading cause of maternal, fetal and neonatal morbidity and mortality, and is associated with risk for future cardiovascular disease. There are no reliable predictors, specific preventative measures or treatments other than delivery. A widely held view is that the antecedents of preeclampsia lie with impaired placentation in early pregnancy. Accordingly, we hypothesized dysregulation of global gene expression in first trimester placentas of women who later manifested preeclampsia.MethodsSurplus chorionic villus sampling (CVS) tissues were collected at 10-12 weeks gestation in 160 patients with singleton fetuses. Four patients developed preeclampsia, and their banked CVS specimens were matched to 8 control samples from patients with unaffected pregnancies. Affymetrix HG-U133 Plus 2.0 GeneChips were utilized for microarray analysis. Naïve Bayes prediction modeling and pathway analysis were conducted. qRT-PCR examined three of the dysregulated genes.ResultsThirty-six differentially expressed genes were identified in the preeclampsia placentas. qRT-PCR verified the microarray analysis. Thirty-one genes were down-regulated. Many were related to inflammation/immunoregulation and cell motility. Decidual gene dysregulation was prominent. No evidence was found for alterations in hypoxia and oxidative stress regulated genes.ConclusionsTo our knowledge, this is the first study to show dysregulation of gene expression in the early placentas of women approximately 6 months before developing preeclampsia, thereby reinforcing a placental origin of the disorder. We hypothesize that placentation in preeclampsia is compromised in the first trimester by maternal and fetal immune dysregulation, abnormal decidualization, or both, thereby impairing trophoblast invasion. Several of the genes provide potential targets for the development of clinical biomarkers in maternal blood during the first trimester. Supplementary materials are available for this article via the publisher's online edition.

Project description:BACKGROUND:Little is known about racial-ethnic differences in the distribution of maternal serum levels of angiogenic and antiangiogenic factors and their associations with early-onset preeclampsia. OBJECTIVE:We sought to investigate the distribution of midtrimester maternal serum levels of placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor 1 and their associations with early-onset preeclampsia in whites, Hispanics, and blacks. STUDY DESIGN:A population-based nested case-control design was used to identify cases and controls of white, Hispanic, and black origin from a 2000 through 2007 live-birth cohort in 5 southern California counties. Cases included 197 women (90 whites, 67 Hispanics, and 40 blacks) with early-onset preeclampsia defined as hypertension and proteinuria with onset <32 weeks according to hospital records. Controls included a random sample of 2363 women without early-onset preeclampsia. Maternal serum specimens collected at 15-20 weeks' gestation as part of routine prenatal screening were tested for placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor 1. Serum levels of the 3 factors were log-normally distributed. Adjusted natural logarithmic means were compared between cases and controls and between racial-ethnic groups. Odds ratios and 95% confidence intervals derived from logistic regression models were calculated to measure the magnitude of the associations. RESULTS:Cases showed lower adjusted logarithmic means of placental growth factor but higher adjusted logarithmic means of soluble endoglin than controls across all 3 groups (P < .05). Cases also had higher adjusted means of soluble vascular endothelial growth factor receptor 1 than controls in whites (7.75 vs 7.52 log pg/mL, P < .05) and Hispanics (7.73 vs 7.40 log pg/mL, P < .05) but not in blacks (7.85 vs 7.69 log pg/mL, P = .47). Blacks were found to have higher levels of placental growth factor in both cases and controls when compared to whites and Hispanics (adjusted means: 4.69 and 5.20 log pg/mL in blacks, 4.08 and 4.78 log pg/mL in whites, and 3.89 and 4.70 log pg/mL in Hispanics, respectively, P < .05). Hispanic cases had the highest adjusted mean of soluble endoglin compared to white and black cases (9.24, 9.05, and 8.93 log pg/mL, respectively, P < .05). The weakest association of early-onset preeclampsia with placental growth factor and soluble endoglin was observed in blacks. The adjusted odds ratio per log pg/mL increase of the 2 analytes were 0.219 (95% confidence interval, 0.124-0.385) and 5.02 (95% confidence interval, 2.56-9.86) in blacks in comparison to 0.048 (95% confidence interval, 0.026-0.088) and 36.87 (95% confidence interval, 17.00-79.96) in whites (P < .05) and 0.028 (95% confidence interval, 0.013-0.060) and 86.68 (95% confidence interval, 31.46-238.81) in Hispanics (P < .05), respectively. As for soluble vascular endothelial growth factor receptor 1, the association was not significantly different among the racial-ethnic groups. CONCLUSION:Racial-ethnic differences were observed in the distribution of midtrimester maternal levels of placental growth factor and soluble endoglin and in the associations with early-onset preeclampsia. These differences should be considered in future studies to improve etiologic and prognostic understanding of early-onset preeclampsia.

Project description:INTRODUCTION:Accumulating evidence suggests that an imbalance between pro-angiogenic (i.e., vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) and anti-angiogenic factors (i.e., soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1)) is involved in the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic effects of transforming growth factor beta, and its soluble form has recently been implicated in the pathophysiology of PE. The objective of this study was to determine if changes in maternal plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development of disease among patients with normal pregnancies and those destined to develop PE (preterm and term) or to deliver a small for gestational age (SGA) neonate. METHODS:This longitudinal nested case-control study included 144 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n = 46); (2) patients who delivered an SGA neonate but did not develop PE (n = 56); and (3) patients who developed PE (n = 42). Longitudinal samples were collected at each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1, and PlGF were determined by specific and sensitive ELISA. RESULTS:(1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng throughout gestation than those with normal pregnancies; (2) patients destined to develop preterm PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies at 23 and 30 weeks, respectively (for preterm PE: p < 0.036 and for term PE: p = 0.002); (3) patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentrations of PlGF than those with a normal pregnancy throughout gestation, and the maternal plasma concentration of this analyte became detectable later among patients with pregnancy complications, compared to normal pregnant women; (4) there were no significant differences in the plasma concentrations of sVEGFR-1 between patients destined to deliver an SGA neonate and those with normal pregnancies; (5) patients destined to develop preterm and term PE had a significantly higher plasma concentration of sVEGFR-1 at 26 and 29 weeks of gestation than controls (p = 0.009 and p = 0.0199, respectively); and (6) there was no significant difference in the increment of sVEGFR-1 between control patients and those who delivered an SGA neonate (p = 0.147 at 25 weeks and p = 0.8285 at 40 weeks). CONCLUSIONS:(1) Changes in the maternal plasma concentration of s-Eng, sVEGFR-1, and PlGF precede the clinical presentation of PE, but only changes in s-Eng and PlGF precede the delivery of an SGA neonate; and (2) differences in the profile of angiogenic and anti-angiogenic response to intrauterine insults may determine whether a patient will deliver an SGA neonate, develop PE, or both.

Project description:BackgroundMaternal polyunsaturated fatty acid (PUFA) concentrations during pregnancy may have persistent effects on growth and adiposity in the offspring. A suboptimal maternal diet during pregnancy might lead to fetal cardiometabolic adaptations with persistent consequences in the offspring.ObjectiveWe examined the associations of maternal PUFA concentrations during pregnancy with childhood general and abdominal fat-distribution measures.DesignIn a population-based, prospective cohort study of 4830 mothers and their children, we measured maternal second-trimester plasma n-3 (ω-3) and n-6 (ω-6) PUFA concentrations. At the median age of 6.0 y (95% range: 5.6, 7.9 y), we measured childhood body mass index (BMI), the fat mass percentage, and the android:gynoid fat ratio with the use of dual-energy X-ray absorptiometry and measured the preperitoneal abdominal fat area with the use of ultrasound. Analyses were adjusted for maternal and childhood sociodemographic- and lifestyle-related characteristics.ResultsWe observed that higher maternal total n-3 PUFA concentrations, and specifically those of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid, were associated with a lower childhood total-body fat percentage and a lower android:gynoid fat mass ratio (P< 0.05) but not with childhood BMI and the abdominal preperitoneal fat mass area. Higher maternal total n-6 PUFA concentrations, and specifically those of dihomo-γ-linolenic acid, were associated with a higher childhood total-body fat percentage, android:gynoid fat mass ratio, and abdominal preperitoneal fat mass area (P< 0.05) but not with childhood BMI. In line with these findings, a higher maternal n-6:n-3 PUFA ratio was associated with higher childhood total-body and abdominal fat mass.ConclusionsLower maternal n-3 PUFA concentrations and higher n-6 PUFA concentrations during pregnancy are associated with higher body fat and abdominal fat in childhood. Additional studies are needed to replicate these observations and to explore the causality, the underlying pathways, and the long-term cardiometabolic consequences.

Dataset Information

A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.

Publications

A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.

Similar Datasets

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