First-trimester placental protein 13, PAPP-A, uterine artery Doppler and maternal characteristics in the prediction of pre-eclampsia

Objective

To test the hypothesis that a combination of PP13, PAPP-A and first-trimester uterine artery Doppler would improve the prediction of pre-eclampsia.

Methods

This is a prospective cohort study of pregnant women followed from the first-trimester to delivery. PP13 and PAPP-A were determined by immunoassay of maternal serum at 11-14 weeks’, when uterine artery Doppler measurements were assessed. Cases identified with any form of pre-eclampsia were compared with a control group without pre-eclampsia. The sensitivity of each marker or their combinations in predicting pre-eclampsia for different fixed false positive rates was calculated from the ROC curves.

Results

Forty two women were diagnosed with pre-eclampsia and 410 women with pregnancies not complicated by pre-eclampsia were used as controls. For a fixed false positive rate (FPR) of 20%, PP13, PAPP-A and mean uterine artery pulsatility index identified 49%, 58% and 62% respectively, of women who developed any form of pre-eclampsia. PP13 was best in predicting early onset pre-eclampsia with a sensitivity of 79% at a 20% FPR. Combinations of the three first-trimester assessments did not improve the prediction of pre-eclampsia in later pregnancy.

Conclusion

First-trimester PP13, PAPP-A and uterine artery PI are reasonable, individual predictors of women at risk to develop pre-eclampsia. Combinations of these assessments do not further improve the prediction of pre-eclampsia.     

First trimester maternal serum vitamin D and markers of preeclampsia

Abstract

Objective: There is evidence that vitamin D deficiency is associated with preeclampsia. The aim of the study was to determine if maternal levels of vitamin D at 1st trimester were related to markers of preeclampsia.

Material: Serum levels of 25-hydroxy-vitamin D (25OHD), PAPP-A, PlGF, uterine artery pulsatility index and mean arterial pressure were measured in 280 pregnant women.

Results: Preeclampsia markers were not related to 25OHD concentration.

Conclusion: First trimester maternal serum concentration of vitamin D does not seem to be connected with markers of preeclampsia.     

Evaluation of maternal serum progranulin levels in normotensive pregnancies,and pregnancies with early- and late-onset preeclampsia

Aims: To investigate the possible pathophysiological associations between progranulin (PGRN) and preeclampsia (PE), early-onset PE (EOPE) and late-onset PE (LOPE).

Study design: A cross-sectional study was designed to include consecutive patients with uncomplicated pregnancy (n?=?28), EOPE (n?=?30) and LOPE (n?=?22). Maternal levels of serum PGRN were measured with the use of an enzyme-linked immunosorbent assay kit.

Results: The mean serum PGRN level was significantly higher in women with PE compared to the control group (54.17?±?4.20?pg/ml versus 42.37?±?5.64?pg/ml, p?<?0.001), in the LOPE group compared to the control group (51.63?±?4.61?pg/ml versus 42.37?±?5.64?pg/ml, p?<?0.001) and also in women with EOPE compared to women with LOPE (56.03?±?2.68?pg/ml versus 51.63?±?4.61?pg/ml, p?<?0.001). Serum PGRN was negatively correlated with gestational age at birth (r?= ?0.669, p?=?0.001) and birth weight (r?= ?0.653, p?=?0.001); and positively correlated with systolic (r?=?0.653, p?=?0.001) and diastolic blood pressure (r?=?0.601, p?=?0.001), C-reactive protein (r?=?0.519, p?=?0.001), uterine artery pulsatility (r?=?0.441, p?=?0.001) and resistance indices (r?=?0.441, p?=?0.001).

Conclusions: Serum PGRN levels increase significantly in women with PE as an indirect sign of placental dysfunction. This increase is even more prominent in women with EOPE. The serum PGRN in the third trimester is positively correlated with gestational age at birth and birth weight.     

Combined Doppler ultrasound and platelet indices for prediction of preeclampsia in high-risk pregnancies

Abstract

Objectives: To evaluate Doppler ultrasound and platelet indices for the prediction of preeclampsia (PE).

Design: Prospective observational study.

Methods: The study included 270 normal pregnancy primigravida <20?years at 20–24-week gestation. Doppler ultrasound was done to detect uterine artery diastolic notch and to measure the pulsation index (PI) and the resistance index (RI). The platelet count (PC), mean platelet volume (MPV), platelet distribution width (PDW) and platelet large cell ratio (Plcr) was measured by automated blood picture.

Outcome: Validity of combined tests in prediction of PE.

Results: Patients who developed PE had significant higher percentage of diastolic notch, higher mean PI, RI, and significant increase of MPV and PDW than normotensive women (p?<?.001). Patients with abnormal Doppler and abnormal platelet indices had significant higher incidence of severe PE (p?<?.001).

Conclusion: Abnormal platelet indices combined with abnormal Doppler is a predictor of severity rather than the rate of development of PE.     

The maternal plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated in SGA and the magnitude of the increase relates to Doppler abnormalities in the maternal and fetal circulation

Objectives. The soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1), an antagonist to vascular endothelial growth factor and placental growth factor, has been implicated in the pathophysiology of preeclampsia. Preeclampsia and pregnancy complicated with small for gestational age (SGA) fetuses share some pathophysiologic derangements, such as failure of physiologic transformation of the spiral arteries, endothelial cell dysfunction, and leukocyte activation. The objectives of this study were to: (1) determine whether plasma concentrations of sVEGFR-1 in mothers with SGA fetuses without preeclampsia at the time of diagnosis are different from those in patients with preeclampsia or normal pregnant women, and (2) examine the relationship between plasma concentrations of sVEGFR-1 and Doppler velocimetry in uterine and umbilical arteries in patients with preeclampsia and those with SGA.

Study design. A cross-sectional study was conducted to determine the concentrations of the soluble form of VEGFR-1 in plasma obtained from normal pregnant women (n = 135), women with SGA fetuses (n = 53), and patients with preeclampsia (n = 112). Patients with SGA fetuses and those with preeclampsia were sub-classified according to the results of uterine and umbilical artery Doppler velocimetry examinations. Plasma concentrations of sVEGFR-1 were determined by an ELISA. Since these concentrations change with gestational age, differences among various subgroups were statistically estimated with the delta value, defined as the difference between the observed and expected plasma sVEGFR-1 concentration. The expected values were derived from regression analysis of plasma sVEGFR-1 concentrations in normal pregnancy. Regression analysis and univariate and multivariate analysis were employed.

Results. (1) Mothers with SGA fetuses had a mean plasma concentration of sVEGFR-1 higher than normal pregnant women (p < 0.001), but lower than patients with preeclampsia (p < 0.001). (2) Among patients with SGA fetuses, only those with abnormal uterine artery Doppler velocimetry had a mean plasma sVEGFR-1 concentration significantly higher than normal pregnant women (p < 0.001). (3) Among mothers with SGA fetuses in whom Doppler velocimetry was performed (n = 41), those with abnormalities in both the uterine and umbilical artery velocimetry had the highest mean delta of sVEGFR-1 plasma concentration (mean ± standard deviation (SD): 0.69 ± 0.29). Conversely, patients who had normal Doppler velocimetry in both uterine and umbilical arteries had the lowest mean delta (mean ± SD: 0.09 ± 0.29) of sVEGFR-1 plasma concentrations (ANOVA; p < 0.001). (4) Among patients with preeclampsia in whom Doppler velocimetry was performed (n = 69), those with abnormalities in both the uterine and umbilical artery velocimetry had the highest mean delta sVEGFR-1 plasma concentration (mean ± SD: 1.01 ± 0.22) among all groups classified (ANOVA; p < 0.001). (5) Among patients with SGA and those with preeclampsia, there was a relationship (Chi-square for trend p < 0.001 for both) between the severity of Doppler velocimetry abnormalities and the proportion of patients who had high delta sVEGFR-1 plasma concentrations (defined as a concentration two standard deviations (2SD) above the mean delta of normal pregnant women). (6) Multiple regression analysis suggested that the diagnostic category (e.g., SGA or preeclampsia), Doppler abnormalities, and gestational age at blood sampling were associated with an increase in plasma sVEGFR-1 concentrations (p < 0.001).

Conclusions. These observations provide support for the participation of the soluble receptor of vascular endothelial growth factor in the pathophysiology of SGA with abnormal uterine artery Doppler velocimetry and preeclampsia. An excess of sVEGFR-1 is released into the maternal circulation of patients with preeclampsia and those with SGA fetuses, as abnormalities of impedance to blood flow involve uterine and umbilical circulation.     

Maternal,fetal and perinatal characteristics of preeclampsia cases with and without abnormalities in uterine artery Doppler indexes

Abstract

Objective: To compare the maternal and fetal characteristics and perinatal outcome in mild and severe preeclampsia cases with and without uterine artery Doppler abnormalities.

Methods: Two hundred and fifty-nine mild and severe preeclampsia cases were evaluated retrospectively. Doppler measurements were done in the section where uterine artery raised from the hypogastric artery. Pulsatility index above the 95th percentile of the corresponding gestational age was accepted as abnormal.

Results: In mild and severe preeclampsia cases with abnormal Doppler (AD), the rate of intrauterine growth restriction, preterm birth and low birth weight was higher than, but the neonatal intensive care unit stay was similar to the cases with normal Doppler. Base excess was higher in the AD group, in mild and severe preeclampsia. The rate of low Apgar score at 5?min and perinatal mortality was higher in the AD group, in the mild preeclampsia. The strongest independent predictor of the perinatal morbidity and mortality was the presence of prematurity and of the prematurity was the presence of abnormal uterine artery Doppler.

Conclusions: Maternal and perinatal morbidity and perinatal mortality increase in mild to severe preeclampsia cases with abnormal uterine artery Doppler. The abnormal uterine artery Doppler increases the morbidity and mortality by increasing the risk of prematurity.     

Screening for pre-eclampsia by using maternal serum inhibin A, activin A, human chorionic gonadotropin, unconjugated estriol, and alpha-fetoprotein levels and uterine artery Doppler in the second trimester of pregnancy

AIMS: To analyse the predictive power of maternal serum inhibin A, activin A, human chorionic gonadotropin (hCG), unconjugated estriol (uE(3)), alpha-fetoprotein (AFP) levels and uterine artery Doppler in the second trimester of pregnancy in screening for pre-eclampsia. METHODS: Maternal serum inhibin A, activin A, hCG, uE(3), and AFP levels and uterine artery Doppler were determined in 178 healthy, pregnant women in the second trimester of pregnancy. Serum samples were collected between the 16th and 18th weeks of gestation, and Doppler investigation was performed between the 24th and 26th weeks of gestation. Receiver operating characteristic curves were created to analyse the predictive powers of the above parameters in screening for pre-eclampsia. Different combinations also were analysed. RESULTS: The rate of pre-eclampsia was 7.9% (14/178). Maternal serum inhibin A, activin A, hCG, AFP levels, the rate of presence of the prediastolic notch and uterine artery resistance index (RI) values in pre-eclamptic pregnancies were significantly higher than those in healthy pregnancies. Presence of the prediastolic notch, uterine artery RI, maternal serum activin A and inhibin A levels had high predictive efficacy, and each had a sensitivity between 70 and 93% and a specificity between 87% and 98%. The addition of inhibin A or activin A measurement to the Doppler velocimetry improved the specificity to 99-100%. CONCLUSIONS: Maternal serum inhibin A and activin A levels and uterine artery Doppler appear to be useful screening tests during the second trimester for pre-eclampsia. However, addition of these hormonal markers to Doppler velocimetry only slightly improves the predictive efficacy, which appears clinically insignificant.     

Predicting small for gestational age in the first trimester of pregnancy using maternal ophthalmic artery Doppler indices

Objective: To assess the capacity of maternal ophthalmic Doppler indices for predicting small for gestational age (SGA) newborns in the first trimester of pregnancy.

Methods: We performed a prospective observational cohort study involving 499 singleton pregnancies during the first trimester scan (11–14 weeks). The following maternal ophthalmic Doppler indices were assessed: pulsatility index (PI), first diastolic peak velocity (PD1) and peak ratio (PR)?=?PD1/peak systolic velocity. We considered SGA all newborns with weight below 10th percentile. We used chi-square test (χ²) to compare the groups. We used area under receiver operating characteristics (ROC) curves with 95% confidence intervals (CI) and detection rate of 5% of false positive of each maternal ophthalmic Doppler index and the mean uterine artery PI for prediction SGA.

Results: 27 (5.4%) patients delivered SGA newborns, 12 (2.4%) patients developed preeclampsia (PE) and delivered SGA newborns, and 460 had uneventful pregnancies (controls). We observed significant difference of PI and PR between SGA (SGA and SGA+PE) and control groups, p?=?0.043 and p?=?0.014, respectively. To 5% of false positive, the detection rate of SGA (SGA and SGA+PE groups) using PI, PD1 and PR were 14.8, 3.7, 14.8, 16.7, 16.7 and 16.7%, respectively. Mean uterine PI was significantly higher in the SGA+PE group (p?=?0.003).

Conclusion: The isolated use of maternal ophthalmic Doppler indices or in combination with uterine artery Doppler, in the first trimester of pregnancy, was not efficient to predict SGA newborns.     

Comparison of interleukin-6 levels in maternal and umbilical cord blood in early- and late-onset preeclampsia

Purpose: Increased inflammatory response and cytokines are claimed to play a significant role in the etiology of preeclampsia. Interleukin-6 (IL-6) is a proinflammatory cytokine. Limited number of studies evaluating IL-6 levels in preeclamptic patients have produced conflicting results. Therefore, the present study sought to compare maternal and umbilical cord serum levels of IL-6 in early- and late-onset preeclamptic pregnancies as well as in normal pregnancies. Materials and methods: A total of 69 participants were enrolled in the study. The control group consisted of 24 participants with normal pregnancies. Preeclampsia group consisted of 45 participants. The preeclampsia group was further classified into the subgroups of early- and late-onset preeclampsia. Late-onset preeclampsia group consisted of 24 women whereas early-onset preeclampsia group consisted of 21 women. Serum and umbilical cord samples of IL-6 were compared. Results: There was no significant difference between maternal and umbilical cord serum IL-6 concentrations between the preeclampsia and control group. No significant difference was observed in maternal and umbilical cord serum IL-6 levels between early- and late-onset preeclampsia groups. Conclusion: Our results do not support an increase in IL-6 levels in patients with early- and late-onset preeclampsia. The clinical relevance of our findings needs to be further investigated.     

First trimester uterine artery Doppler for the prediction of preeclampsia and foetal growth restriction

Feasibility and reproducibility of uterine artery Doppler (UAD) at 11–14 gestational weeks was recently confirmed. Normal range values were established for resistance and pulsatility indexes. A body of evidence supports that the risk of developing preeclampsia or foetal growth restriction is highest when UAD impedance (evaluated by sus-mentioned indexes or uterine artery notch persistence) remains bilaterally high from first to second trimester, whereas the risk is lowest when UAD impedance is low from 11 to 14 gestational weeks. In unselected women, the sensitivity of 11–14 weeks-UAD is high but the positive predictive value is low, and data do not support its introduction as the sole predictive test. In models using maternal history and 11–14 weeks-UAD, the negative predictive value is high while abnormal UAD may identify a high proportion of women that will develop early-onset preeclampsia. Algorithms combining biochemical markers could still improve this prediction rate at higher cost and complexity.     

Metabolomics and first-trimester prediction of early-onset preeclampsia

Objective: To evaluate the use of metabolomics for the first-trimester detection of maternal metabolic dysfunction and prediction of subsequent development of early-onset preeclampsia (PE). Study design: This was a case-control study of maternal plasma samples collected at 11–13 weeks’ gestation from 30 women who had subsequently developed PE requiring delivery before 34 weeks and 60 unaffected controls. Nuclear magnetic Resonance (NMR) spectroscopy was used to identify and quantify metabolomic changes in cases versus controls. Both genetic computing and standard statistical analyses were performed to predict the development of PE from the metabolite concentrations alone as well as the combination of metabolite concentrations with maternal characteristics and first-trimester uterine artery Doppler pulsatility index (PI). Results: Significant differences between cases and controls were found for 20 metabolites. A combination of four of these metabolites (citrate, glycerol, hydroxyisovalerate, and methionine) appeared highly predictive of PE with an estimated detection rate of 75.9%, at a false-positive rate (FPR) of 4.9%. The predictive performance was improved by the addition of uterine artery Doppler PI and fetal crown-rump length (CRL) and with an estimated detection rate of 82.6%, at a FPR of 1.6%. Conclusion: A profound change in the first-trimester metabolite profile was noted in women who had subsequently developed early-onset PE. Preliminary algorithms appeared highly sensitive for first trimester prediction of early onset PE.     

Identification of patients at risk for preeclampsia with the use of uterine artery Doppler velocimetry and copeptin

Purpose: To investigate the relationship between maternal copeptin levels and uterine artery Doppler examination and progress of preeclampsia.

Materials and methods: A cross-sectional study was designed with women those were screened at 20?+?0 – 24+ 6 weeks’ gestation between May 2014 and August 2014. The obstetric records of all normotensive women were examined. Uterine artery Doppler velocimetry results and serum copeptin levels were measured. The patients were divided into two groups according to normal (n?=?67) and abnormal uterine artery Doppler (n?=?21) findings.

Results: Maternal age was significantly lower in group 1 (n?=?21, 23.9%) than in group 2 (n=?67, 76.1%) (p?p?=?0.002).

Conclusions: Copeptin levels are significantly higher in patients who develop preeclampsia.     

Comparison of indications of pregnancy termination and prognosis of mothers and neonates in early- and late-onset preeclampsia

Objective: To compare the indications of pregnancy termination and prognosis between early-onset preeclampsia (EOP) and late-onset preeclampsia (LOP). Methods: In total, 100 patients diagnosed early-onset preeclampsia in our hospital from January 1, 2012, to June 30, 2014, were recruited for this retrospective cohort study. At the same time, we randomly chose another 100 late-onset preeclampsia as the contrast group. Criterion distinguishing early versus late was set at week 34 of gestation. Indications for pregnancy termination and prognosis of mothers and neonates were compared between the groups. Results: Significant differences were observed between the groups regarding indications for terminating pregnancy. The EOP indications to terminate the pregnancy were mainly fetal-related, while LOP were mainly maternal-related. Postpartum neonatal morbidity and mortality were significantly higher, mean gestational age onset and delivery were significantly earlier, latent period for delivery and postpartum hospitalization time were significantly longer, admission 24 h proteinuria was significantly higher in EOP than in LOP group (P < 0.05). Conclusion: EOP is a distinct and more severe clinical entity with earlier gestational age onset and delivery. EOP might be a fetal-related disease complicated by severe placental and perinatal injuries; LOP might be a maternal-related derived disease condition.     

Correlation between maternal serum-amniotic fluid anti-angiogenic factors and uterine artery Doppler indices

Purpose: Elevated sFlt-1 and sEng is usually a clue for impending preeclampsia and intrauterine growth restriction. Likewise, uterine artery Doppler ultrasound is being investigated for prediction of similar conditions. In this study, we aimed to explore the possible relations of these two proteins in different body compartments with uterine artery Doppler indices (UtAD) in a healthy second trimester obstetric population.

Methods: Levels of sFlt-1 and sEng were measured in serum and amniotic fluid samples of 43 patients. UtAD were measured on the days of sample collections. Findings were then analyzed for possible correlation.

Results: There was a positive correlation between the levels of maternal serum sFlt-1 (MSsFlt-1) and sEng levels (MSsEng) (r=?0.516, pr=??0.371, p=?0.016). No correlation was found between UtAD and studied protein levels in amniotic fluid. Mean MSsFlt-1 level was 305.2?±?220.1?pg/ml and mean AFsFlt-1 was 48.9?±?11.8?ng/ml. Mean MSsEng level was 4.5?±?1.3?ng/ml, mean AFsEng level was found 0.7?±?0.3?ng/ml. Mean values for UtAD were 1.3?±?0.4, 0.6?±?0.1 and 3.5?±?1.3 for PI, RI, and S/D, respectively.

Conclusion: In normal second trimester pregnancies, there is a positive correlation between serum levels of sFlt-1 and sEng levels. Amniotic fluid levels of sEng and sFlt-1 are not correlated with UtAD in uncomplicated pregnancies.