Olav Lapaire

Potential markers of preeclampsia – a review

Preeclampsia is a leading cause of maternal and fetal/neonatal mortality and morbidity worldwide. The early identification of patients with an increased risk for preeclampsia is therefore one of the most important goals in obstetrics. The availability of highly sensitive and specific physiologic and biochemical markers would allow not only the detection of patients at risk but also permit a close surveillance, an exact diagnosis, timely intervention (e.g. lung maturation), as well as simplified recruitment for future studies looking at therapeutic medications and additional prospective markers. Today, several markers may offer the potential to be used, most likely in a combinatory analysis, as predictors or diagnostic tools. We present here the current knowledge on the biology of preeclampsia and review several biochemical markers which may be used to monitor preeclampsia in a future, that, we hope, is not to distant from today.

MALDI-TOF Mass Array Analysis of RASSF1A and SERPINB5 Methylation Patterns in Human Placenta and Plasma

Differences in DNA methylation patterns between placenta and blood cells of pregnant women have been suggested as potential biomarkers for noninvasive prenatal diagnostic strategies, including for common obstetrical complications, such as preeclampsia. New findings in epigenetic origins of fetal or placental disorders may improve our ability for optimal management of these conditions. Using a novel high-throughput mass spectrometry on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array, we compared the quantitative methylation changes of RASSF1 and SERPINB5 (also known as MASPIN) genes in placenta and plasma samples. We analyzed the methylation status of a total of 3569 CpG dinucleotides on these two genes in 83 different samples: 50 plasma samples (20 from pregnant women and 30 from nonpregnant women) and 33 placenta tissue samples (25 from normal pregnancies and eight from preeclamptic pregnancies). The aim of this study was to assess the utility of epigenetic changes as biomarkers for noninvasive prenatal diagnostic procedures. Using a two-way hierarchical cluster analysis, significantly different methylation levels of the RASSF1 gene were found between placenta (normal and preeclamptic) and plasma samples of pregnant women. Although the SERPINB5 gene was hypomethylated in placenta DNA more than in plasma DNA, it did not demonstrate significant differences between studied groups. The MALDI-TOF mass spectrometry analysis of placenta and plasma DNA methylation patterns may serve as a tool for the study of gender-independent biomarkers in noninvasive prenatal diagnosis.

The special role of ultrasound for screening, staging and surveillance of malignant ovarian tumors: distinction from other methods of diagnostic imaging

AbstractnOvarian cancer is the most aggressive gynecologic malignancy, with a 5-year survival rate ranging around 40xa0%. A crucial factor influencing the prognosis is early detection of a suspicious mass and referral to a gynecologic oncology center for further diagnosis, staging and debulking surgery. Here, we present the different imaging methods ultrasound (US), magnetic resonance imaging, computer tomography (CT) and 18F-fluoro-deoxyglucose positron emission tomography (PET)/CT that are used for the characterization, diagnosis, staging and surveillance of ovarian cancer. In this review, we focus on US and discuss in detail the advantages and the limitations, as well as the appropriate indications for each of the individual imaging techniques.

Cell-free nucleic acids in (maternal) blood: any relevance to (reproductive) immunologists?

Cell-free foetal DNA recently hit the international headlines by facilitating the non-invasive prenatal testing (NIPT) of foetal chromosomal anomalies directly from maternal blood samples. Being largely of placental origin, cell-free foetal DNA may also, however, provide insight into underlying pathological changes in preeclampsia, or the influences of external stresses, such as hypoxia. This analysis may be enhanced by the simultaneous assessment of placenta-derived, cell-free mRNA species. The source of maternal cell-free DNA is not readily apparent, but may involve neutrophil extracellular traps (NETs). The rapid rise in this material following removal of the placenta, especially in preeclampsia, may indicate a rapid transient maternal inflammatory response to placenta-derived debris. Since NETs have recently been shown to promote coagulation, this may provide a link to pregnancy-associated thrombosis or placental infarction. The presence of cell-free, placenta-derived DNA may not be as innocuous as commonly assumed, as it is largely hypomethylated and could, like bacterial DNA, trigger the activation of maternal immune effector cells via interaction with toll-like receptor 9 (TLR9), thereby contributing to an excessive inflammatory response in preeclampsia or preterm labour. Possibly the most fascinating aspect concerning placenta-derived, cell-free nucleic acids is the recent report that placental exosomes loaded with placenta-specific C19MC miRNA species may modulate the antiviral response of maternal immune cells, thereby ensuring foetal well-being.

Water birth: is the water an additional reservoir for group B streptococcus?

Objective: Water birth became popular in the last years, despite the fact that many questions like the risk of infection for the newborn remain unanswered. Group B streptococcal (GBS) infections in the newborn remain a challenge in obstetrics and neonatology. Method: We conducted a prospective trial to study the impact of water birth on the colonization rate of the bath water and, more importantly, the GBS-colonization rate of the newborn. Result: After water birth the bath water was significantly more often colonized with GBS than after immersion followed by a delivery in bed. The newborns, however, showed no difference in GBS colonization and there was even a trend towards less GBS colonization of the newborn after a water delivery. Conclusion: Regarding GBS colonization of the newborn during water birth there might be a wash out effect, which protects the children during the delivery.

The risk of placental abruption when using prostaglandins for cervical ripening in women with preeclampsia: comparing misoprostol versus dinoprostone

Objective.u2003Recent data have raised concern about the safety of using misoprostol in women with preeclampsia. We wanted to evaluate the risk of placental abruption in women with preeclampsia undergoing cervical ripening with misoprostol compared to dinoprostone. Methods.u2003We evaluated data on 403 preeclamptic women receiving either misoprostol (Nu2009=u2009235) or dinoprostone (Nu2009=u2009168) at different regimens and delivering in two university hospitals in Switzerland (Geneva and Basel). The main outcome was the incidence of placental abruption in both groups using two definitions for placental abruption (“clinical” and “post hoc”). We performed univariable and multivariable analysis. Results.u2003The overall incidence of placental abruption was 1.5% (six cases); 1.3% (3) in the misoprostol group versus 1.8% (3) in the dinoprostone group; pu2009=u20090.69). When using the post-hoc definition the incidence was higher in the latter group (1.3 versus 5.4%; pu2009=u20090.03). In multivariable analyses, the risk of placental abruption using the “post hoc” definition was associated with the use of dinoprostone. Conclusions.u2003The use of misoprotol in preeclamptic women appears to be safe and is not associated with a higher risk of placental abruption when compared with other prostaglandins. Concerns about the use of misoprostol in the case of preeclampsia are not justified.

Gestational Diabetes Mellitus Is Associated with Altered Neutrophil Activity

Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance, in that it is transient and solely occurs in pregnancy. Pregnancies with GDM are at high risk of developing preeclampsia (PE), a leading cause of fetal and maternal morbidity or mortality. Since PE is associated with excessive activation of circulatory neutrophils and occurrence of neutrophil extracellular traps (NETs) in affected placentae, we examined these features in cases with GDM, as this could be a feature linking the two conditions. Our data indicate that neutrophil activity is indeed altered in GDM, exhibiting pronounced activation and spontaneous generation of NETs by isolated neutrophils in in vitro culture. In this manner, GDM may similarly affect neutrophil behavior and NET formation as witnessed in other forms of diabetes, with the addition of the physiological changes mediated by pregnancy. Since circulatory TNF-α levels are elevated in cases with GDM, a feature also observed in this study, we examined whether this pro-inflammatory cytokine contributed to neutrophil activation. By using infliximab, a clinically utilized TNF-α antagonist, we observed that the pro-NETotic effect of GDM sera was significantly reduced. We also detected pronounced neutrophil infiltrates in placentae from GDM cases. The occurrence of NETs in these tissues is suggested by the extracellular co-localization of citrullinated histones and myeloperoxidase. In addition, elevated neutrophil elastase (NE) mRNA and active enzymatic protein were also detected in such placentae. This latter finding could be important in the context of previous studies in cancer or diabetes model systems, which indicated that NE liberated from infiltrating neutrophils enters surrounding cells, altering cell signaling by the degradation of IRS1. These findings could potentiate the underlying inflammatory response process in GDM and possibly open an avenue for the therapeutic interventions in gestational hyperglycemia.

OP17.05: Diagnostic accuracy of different sFlt-1 and PlGF cut-off values in the assessment of preterm and term pre-eclampsia

in the first trimester. We aimed to explore pregnancy outcomes in women with a positive PE screening test using the Fetal Medicine Foundation (FMF) algorithm. Methods: We conducted a prospective cohort study of Canadian pregnant women with singleton fetus recruited at 11-14 weeks. Lethal anomalies and medical termination of pregnancies were excluded. Maternal age, body mass index, methods of conception, personal history of PE, ethnicity, mean arterial blood pressure, PAPP-A, PlGF and mean uterine artery pulsatility index were submitted into the online FMF algorithm. Simple imputation was used for the treatment of missing values. Pregnancy outcomes, including PE, small for gestational age (SGA) <3rd centile and fetal death, were reported for women with a positive preterm PE screening test (≥1/70) and compared to women with a negative (<1/70) screening test. Results: We included 6067 participants, including 672 (11%) with a positive FMF screening test. The latter were at greater risk of PE (13.4% vs. 3.4%), preterm PE (3.7% vs. 0.3%), PE<34 weeks (1.3% vs. 0.09%), SGA<3rd centile (4.1% vs. 1.4%), preterm SGA<3rd centile (0.7% vs. 0.04%), fetal death (1.2% vs. 0.4%; p=0.004), miscarriage at 14-20 weeks (0.6% vs. 0.2%; p=0.04), or any of the above complications (16.8% vs. 5.0%) than women with negative screening test (all with p<0.0001, except if otherwise specified). Thirty (4.5%) women with a positive test developed one of the severe complications (preterm PE, preterm SGA, fetal death) compared to 31 (0.6%) women with a negative screening test (p<0.0001) after exclusion of miscarriages. Conclusions: Women with a first-trimester positive FMF preterm PE screening test are at high-risk of severe pregnancy complications that are preventable with low-dose aspirin in early pregnancy.

Replacement of oxytocin bolus administration by infusion: influences on postpartum outcome.

PurposePostpartum haemorrhage (PPH) represents a leading cause of maternal morbidity and mortality. Giving oxytocin after birth reduces the risk for PPH. It has never been tested whether different methods of oxytocin administration affect the maternal outcome. This study aims to compare the infusion versus the bolus application of oxytocin after singleton vaginal delivery.MethodsThis retrospective monocentre study compares the incidence of clinically relevant postpartum complications in women receiving 5xa0IE of oxytocin as a bolus or as a 100xa0ml-infusion over 5xa0min, given immediately after birth. Included were women delivering singletons vaginally at term. We used propensity score weighting to compare outcomes between women receiving bolus and infusion and to minimize the selection bias in this retrospective cohort.Results1765 patients were included. Patient characteristics were balanced. We found no significant differences for the combined overall postpartum adverse outcome (the incidence of PPH, manual removal of the placenta and/or curettage). For the single outcomes, we observed a significantly higher frequency of manual removal of the placenta (Odds ratio 1.47, 95xa0% CI 1.02–2.13) and a slightly higher but clinically not relevant estimated blood loss (Relative effect 1.05, 95xa0% CI 1.01–1.10) in the infusion group.ConclusionThe data show a tendency towards more complications in the infusion group. It is related to a more frequent need for manual removal of the placenta.