Hamutal Meiri

A novel approach to first‐trimester screening for early pre‐eclampsia combining serum PP‐13 and Doppler ultrasound

To investigate the value of maternal serum placental protein 13 (PP‐13) measurement and uterine artery Doppler during first‐trimester screening in the prediction of early pre‐eclampsia.

First-trimester maternal serum PP-13, PAPP-A and second-trimester uterine artery Doppler pulsatility index as markers of pre-eclampsia.

To evaluate whether measurement of maternal serum placental protein‐13 (PP‐13) and pregnancy‐associated plasma protein‐A (PAPP‐A) at 11 + 0 to 13 + 6 weeks of gestation alone or in combination with second‐trimester uterine artery pulsitility measured by Doppler velocimetry is useful in predicting those women who will develop pre‐eclampsia

Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

Background Preterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low‐dose aspirin during pregnancy reduces the risk of preterm preeclampsia. Methods In this multicenter, double‐blind, placebo‐controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention‐to‐treat principle. Results A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow‐up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between‐group differences in the incidence of neonatal adverse outcomes or other adverse events. Conclusions Treatment with low‐dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo. (Funded by the European Union Seventh Framework Program and the Fetal Medicine Foundation; EudraCT number, 2013‐003778‐29; Current Controlled Trials number, ISRCTN13633058.)

First-trimester maternal serum PP13 in the risk assessment for preeclampsia

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.

Longitudinal determination of serum placental protein 13 during development of preeclampsia

Objective: To determine maternal serum placental protein 13 (PP13) in normal pregnancy and preeclampsia. Methods: A prospective, longitudinal study with 41 normal pregnant women, 18 cases with preterm delivery or cervix insufficiency and 4 with developing late-onset preeclampsia. Six hundred and sixty-six maternal blood samples were obtained every 2–4 weeks starting at 5–8 weeks gestation (10–12 samples/patient) and tested for serum PP13 by ELISA. Results: In normal pregnant women delivering at term, median maternal serum PP13 levels were growing from 166 to 202 pg/ml and 382 pg/ml in the first, second and third trimester, respectively. Preeclamptic women had significantly reduced PP13 levels in the first trimester (multiples of median of 0.14 at 7–8 weeks; p = 0.005 compared to normal). PP13 in the third trimester was significantly higher compared to normal at 35–36 weeks with PP13 multiples of median of 1.79. Conclusion: This preliminary study indicates that low levels of PP13 in early pregnancy identify at-risk pregnancies, whereas high levels precede the syndrome in late pregnancy and suggest syncytiotrophoblast necrosis.

First-trimester markers for the prediction of pre-eclampsia in women with a-priori high risk

To investigate the predictive value of the combination of first‐trimester serum placental protein 13 (PP13), uterine artery Doppler pulsatility index (PI) and pulse wave analysis (augmentation index at a heart rate of 75 beats per min (AIx‐75)), and to evaluate concurrent and contingent strategies using this combination for assessing the risk of pre‐eclampsia in high‐risk women.

The choriocarcinoma cell line BeWo: syncytial fusion and expression of syncytium-specific proteins

Fusion of the trophoblast-derived choriocarcinoma cell line BeWo can be triggered by forskolin. BeWo cells are regularly used as a cell culture model to mimic in vivo syncytialisation of placental villous trophoblast. The β subunit of human chorionic gonadotropin (CGB), placental alkaline phosphatase as well as placental protein 13 (PP13, LGALS13) are exclusively expressed in the syncytiotrophoblast of the human placenta, and CGB is commonly used as a marker of syncytial differentiation. Here we tested the hypothesis that syncytial fusion precedes CGB and LGALS13 expression in trophoblast-derived BeWo cells. BeWo cells were cultured for 48 h in the presence or absence of forskolin and varying concentrations of H-89, a protein kinase A inhibitor that interferes with the forskolin-mediated pathway of syncytial fusion. LGALS13 and CGB expression were quantified by DELFIA and real-time PCR. Cell fusion was determined by morphological analysis and cell counting after immunofluorescence staining. In forskolin-stimulated BeWo cells that were hindered to fuse by treatment with H-89, levels of CGB protein expression were not altered, while LGALS13 protein and mRNA expression decreased significantly to control levels without forskolin. The LGALS13 protein expression data coincided with a significant decrease in syncytial fusion, while CGB protein expression was unaffected by rates of cell fusion and proliferation. We postulate that CGB protein expression is not necessarily linked to syncytial fusion, and thus CGB should be used with great caution as a marker of BeWo cell fusion.

Placental and trophoblastic in vitro models to study preventive and therapeutic agents for preeclampsia

In the field of preeclampsia, enormous efforts are ongoing to identify biomarkers predicting the syndrome already in the first trimester of pregnancy. At the same time, there is the need for in vitro models to test such biomarkers prior to their use in clinical trials. In addition, in vitro models may accelerate the development and evaluation of the benefit of any putative therapeutics. Therefore, in vitro systems have been established to evaluate the release of biomarkers and measure the effect of putative therapeutics using placental villous explants as well as the choriocarcinoma cell line BeWo. For explants, a cryogenic method to freeze, transport and thaw villous explants was developed to use such tissues for a multi-site tissue culture evaluation. Here we focus on three out of many in vitro models that have been established for human placental trophoblast. (1) Choriocarcinoma cell lines such as BeWo, Jeg-3 and Jar cells (2) isolated primary trophoblast cells, and (2) villous explants from normal placentas delivered at term. Cell lines were used to assess the effect of differentiation and fusion on the expression and release of a preeclampsia marker (placental protein 13; PP13) and beta-hCG. Moreover, cell lines were used to study the effect of putative preeclampsia therapeutics such as vitamins C and E, heparin and aspirin on marker release and viability. Cryopreservation of villous explants enabled shipment to a remote laboratory and testing of parameters in different countries using explants from one and the same placenta. Recently published data make it tempting to speculate that the choriocarcinoma cell line BeWo as well as fresh and cryogenically stored placental villous explants may well serve as in vitro models to study preventive and therapeutic agents in the field of preeclampsia.

Pregenesys pre-eclampsia markers consensus meeting: What do we require from markers, risk assessment and model systems to tailor preventive strategies?

The Pregenesys Consensus Meeting held in Cambridge on 13 July 2009 was organized by the Pregenesys Consortium to review and critically discuss current knowledge regarding early markers of preeclampsia, to identify priorities and opportunities for future research, to consider issues that may need to be addressed in future recommendations and to highlight key issues in cost effectiveness and national policies concerning prediction and early screening for the risk of developing preeclampsia. This report summarizes the outcome of the Consensus Meeting and draws attention to issues for further investigation with specific regard to single versus multiple markers, early versus late risk identification, and the long-term effects on both maternal and perinatal health and the need to include these in any future cost-benefit assessment.

First trimester maternal serum placental protein 13 for the prediction of pre-eclampsia in women with a priori high risk.

To evaluate whether first trimester maternal serum PP13 can predict pre‐eclampsia among women with a priori high risk.