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Objective: The soluble fms-like tyrosine kinase (sFlt-1)/placental growth factor (PlGF) ratio is a reliable tool in the assessment of preeclampsia. We tested the hypothesis that the sFlt-1/PlGF ratio is able to identify women at risk for imminent delivery. We characterized the sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders., Study Design: We investigated 388 singleton pregnancies with normal pregnancy outcome, 164 with PE, 36 with gestational hypertension, and 42 with chronic hypertension. sFlt-1 and PlGF were measured in serum samples., Results: Patients with preeclampsia had a significantly increased sFlt-1/PlGF ratio as compared with controls and with patients with chronic and gestational hypertension in <34 weeks and ≥34 weeks (P < .001). Time to delivery was significantly reduced in women with preeclampsia in the highest quartile of the sFlt-1/PlGF ratio (P < .001)., Conclusion: The sFlt-1/PlGF ratio allows the identification of women at risk for imminent delivery and is a reliable tool to discriminate between different types of pregnancy-related hypertensive disorders., (Copyright © 2012 Mosby, Inc. All rights reserved.)

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.

Human pregnancy is a metabolic and immune challenge for the mother who has to accommodate in her womb a semi-allogeneic fetus whose energy needs increase tremendously with gestation. Recent compelling research has suggested that proper inflammatory changes and oxidative balance are a requisite for successful pregnancy. The placenta is an integral component of this inflammatory response as it actively produces a variety of cytokines and immunomodulatory hormones. In preeclampsia, a life-threatening disorder of pregnancy that is characterized by widespread damage and dysfunction of the maternal endothelium, placental oxidative stress and aberrant cytokine expression induces an exaggerated maternal systemic inflammatory response to pregnancy.

Recent studies have suggested that the innate immune system is involved in the pathogenesis of preeclampsia. Its pathogenesis involves neutrophil activation and increased levels of cell-free DNA in the maternal plasma. Activation of neutrophils has recently been shown to induce DNA containing neutrophil extracellular traps (NETs) which trap and kill bacteria. Massive NETs induction by the placentally derived factors (IL-8 and placental micro-debris) and their increased presence in preeclamptic placenta suggest that NETs might be involved in the pathogenesis of preeclampsia. Therefore, increased presence of NETs in preeclampsia may play a role in the deficient placental perfusion associated with this disorder.

Objective: To compare the efficacy of vaginal misoprostol versus dinoprostone for induction of labor (IOL) in patients with preeclampsia according to the WHO criteria., Study Design: Ninety-eight patients were retrospectively analyzed. A total of 47 patients received 3 mg dinoprostone suppositories every 6 h (max. 6 mg/24 h) whereas 51 patients in the misoprostol group received either 50 mug misoprostol vaginally every 12 h, or 25 mug every 6 h (max. 100 mug/24 h). Primary outcomes were vaginal delivery within 24 and 48 h, respectively., Results: The probability of delivering within 48 h was more than three-fold higher in the misoprostol than in the dinoprostone group: odds ratio (OR)=3.48; 95% confidence interval (CI) 1.24, 10.30, whereas no significant difference was observed within 24 h (P=0.34). No correlation was seen between a ripe cervix prior to IOL and delivery within 24/48 h (P=0.33 and P=1.0, respectively). More cesarean sections were performed in the dinoprostone group due to failed IOL (P=0.0009). No significant differences in adverse maternal outcome were observed between both study groups, whereas more neonates (12 vs. 6) of the dinoprostone group were admitted to the NICU (P=0.068)., Conclusion: This study suggests that misoprostol may have some advantages compared to dinoprostone, including improved efficacy and lower cost of the drug, even in cases of preeclampsia.

Objectives: We examined the concentration of activin A in a prospective manner before the clinical manifestation of preeclampsia and compared the data with those of cell-free fetal DNA in the maternal plasma., Methods: The levels of activin A were analysed by enzyme-linked immunosorbent assay (ELISA) for pregnant women: (1) with preeclampsia (n = 34) in the third-trimester and normal controls (n = 44); and (2) at-risk of preeclampsia in the second-trimester (n = 15) as indicated by uterine artery Doppler and normal controls (n = 68). Correlation between activin A level and cell-free fetal DNA level was examined using the Spearman rank test., Results: The level of plasma activin A was significantly higher in the preeclamptic samples (12.056 vs 7.068 ng/mL, p = 0.000). The increase in the activin A concentration was observed prior to the onset of preeclampsia (3.483 vs 1.324 ng/mL, p = 0.000). This increase in activin A correlated significantly with the increased level of cell-free fetal DNA, in the maternal circulation prior to the onset of preeclampsia (r = 0.977, p = 0.000)., Conclusion: Our data suggest that circulatory activin A could be an independent biomarker for the early identification and monitoring of preeclampsia., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Manifest pre-eclampsia is associated with activation of peripheral neutrophils as well as elevations in maternal cell-free DNA. For this reason, we were very intrigued by recent reports indicating that activated circulatory neutrophils secrete nuclear DNA to generate extracellular DNA lattices, termed NETs (neutrophil extracellular traps). Our preliminary data indicate that placental syncytiotrophoblast microparticles, which are released in elevated amounts in pre-eclampsia, can induce NETs in isolated neutrophils. Furthermore, we found evidence for the increased presence of NETs directly in the intervillous space of pre-eclamptic placentae. Therefore, these newly discovered entities may be implicated in the underlying etiology of this disorder.

Recent studies have provided new insight into aberrations in the immunological interplay between mother and fetus and their potential role in the development of recurrent fetal loss and preeclampsia. The action of anti-phospholipid antibodies in recurrent fetal loss is now proposed to involve the complement system, neutrophil activation and the production of TNFalpha by immune bystander cells. A clear involvement of the immune system is emerging in preeclampsia, involving mainly the innate arm, especially neutrophils. The activation of peripheral neutrophils by placentally released inflammatory debris triggers the induction of neutrophil extracellular traps (NETs), which may lead to an occlusion of the intervillous space, thereby further promoting a condition of placental hypoxia. It has, hence, been suggested that new therapeutic strategies be developed, including the possible use of TNFalpha antagonists in cases of recurrent miscarriage. These strategies need to be addressed with caution due to the possible induction of fetal congenital abnormalities.

Background: Maternal serum concentrations of macrophage migration inhibitory factor (MIF) have recently been reported to be elevated in cases with preeclampsia. These findings may be important in increasing our understanding of the underlying events leading to the development of preeclampsia, as this cytokine is also expressed in the placenta, where it has been shown to possess immunemodulatory activities. For this reason we attempted to independently verify this report., Methods: Plasma levels of MIF were assessed by ELISA in plasma samples collected from normal healthy male and female blood donors (n=20 per group), as well as healthy normal pregnant women in all three trimesters of pregnancy (n=60). In addition, MIF levels were examined from cases with mild and severe preeclampsia (n=20 per study cohort) and matched normotensive pregnancies (n=20)., Results: MIF levels were found to be elevated in pregnancy (median=10.1 ng/ml) when compared to non-pregnant controls (median=1.7 ng/ml). A moderate, but not significant, elevation was found to occur from the first to the third trimester of pregnancy. No significant difference was found to occur between the two preeclampsia study groups when compared to the normotensive control group., Conclusions: Our data suggest that circulatory MIF concentrations are elevated throughout pregnancy, but are not further increased in preeclampsia.

Objectives: Preeclampsia has been shown to be associated with an increased number of fetal and maternal erythroblasts in the maternal circulation, suggesting that preeclampsia involves increased leakage of fetal cells across the placental barrier, as well as increased erythropoiesis. We examined the relationship between circulatory erythroblast levels with maternal plasma concentrations of erythropoietin and activin A., Methods: In a case-control study, we examined 15 pregnancies affected by preeclampsia and 10 matched controls. Erythroblasts were enriched from maternal blood samples by magnetic cell sorting, enumerated and correlated with corresponding plasma activin A and erythropoietin concentrations., Results: The proportion of erythroblast was elevated in preeclampsia (0.8 vs. 0.1%, p = 0.023). Erythropoietin and activin A concentrations were significantly elevated in preeclampsia (100.4 vs. 44.5 pg/ml, p = 0.023, and 7.4 vs. 1.85 ng/ml, p = 0.029, respectively). Circulatory erythroblast numbers were found to correlate with plasma activin A concentrations (r = 0.76, p = 0.01) in cases with preeclampsia. No such relationship existed for erythropoietin., Conclusions: Our data suggest that increased concentrations of activin A promote enhanced levels of erythropoiesis in preeclampsia. As the placenta is one of the major sources of activin A in pregnancy, this increase in activin A-dependent erythropoiesis in preeclampsia may be a reflection of an underlying placental hypoxic condition., ((c) 2006 S. Karger AG, Basel)

Objectives: We have recently observed that fetal DNA and fetal corticotropin-releasing hormone (CRH) mRNA are associated with in vitro generated syncytiotrophoblast-derived microparticles, and that the ratio of fetal DNA to mRNA (CRH) varied according to whether the particles were derived by predominantly apoptotic, apo-necrotic or necrotic pathways. Hence, we examined whether these ratios varied in maternal plasma samples taken from normotensive and preeclamptic pregnancies in vivo., Methods: Maternal plasma samples were collected from 18 cases with preeclampsia and 29 normotensive term controls. Circulatory fetal CRH mRNA and DNA levels were quantified by real-time PCR and RT-PCR., Results: Circulatory fetal mRNA and fetal DNA levels were significantly elevated in the preeclampsia study group when compared to normotensive controls. Alterations in the fetal mRNA to DNA ratio between the study and control groups were minimal, even when stratified into early (<34 weeks of gestation) and late (>34 weeks of gestation) onset preeclampsia., Conclusions: Our data suggest that although circulatory fetal DNA and mRNA levels are significantly elevated in preeclampsia, the ratios in maternal plasma are not dramatically altered., (Copyright 2006 S. Karger AG, Basel.)

Background: Circulatory neutrophils have been reported to be activated in preeclampsia. It has been suggested that maternal plasma levels of elastase may serve as a possible cell-free marker to quantify such activation. Although plasma elastase levels have been found to be elevated in cases with manifest preeclampsia and eclampsia, this has not yet been examined in cases with early and late onset preeclampsia. We have now examined this aspect., Methods: In this retrospective study, maternal plasma samples were examined from eight cases with early onset preeclampsia (<34 weeks of gestation), eight cases with late onset preeclampsia (>34 weeks of gestation) and an equal number of gestational age matched normotensive term controls. Plasma concentrations of elastase were measured by ELISA using a commercially available assay., Results: Plasma elastase concentrations were significantly elevated the preeclampsia study group when compared to the normotensive control group (median=139.2 ng/ml versus median=72.1 ng/ml; P=0.0025). These elevations remained significant when the preeclampsia study group was stratified into case with early onset preeclampsia (median=118.8 ng/ml versus median=62.2 ng/ml; P=0.03), but jailed failed to attain significance for those cases with late onset preeclampsia (median=181.3 ng/ml versus median=86.3 ng/ml; P=0.061)., Conclusions: Our data indicate that elastase levels are elevated in both early and late onset forms of preeclampsia, and imply that the activation of neutrophils may be more acute in the former than in the latter (238 words).

Recent studies have suggested that pre-eclampsia may result from endothelial cell damage and overt immune activity triggered by the elevated release of syncytiotrophoblast-derived micro-particles (STBM). In this context, STBM have been reported to inhibit lymphocyte proliferation and induce Jurkat T cell apoptosis. In this study, STBM were prepared by three different in vitro methods (mechanical dissection, villous explant culture, and placental perfusion) and their functional properties were tested on T lymphocytes enriched from peripheral blood samples. Mechanically- and villous explant-derived STBM significantly inhibited activation, proliferation and cytokine release by T lymphocytes, while placental perfusion-derived STBM significantly induced T cell proliferation and a slight increase in IFNgamma release. None of the STBM preparations caused T cell apoptosis. Therefore, STBM prepared by different methods in vitro exhibit different effects on circulating T cells, a feature that will have to be taken into account when considering their potential role in normal pregnancy and pre-eclampsia.

Preeclampsia, a severe pregnancy-related disorder, involves an overt activation of the maternal innate immune system, proposed to result from the elevated release of inflammatory syncytiotrophoblast microparticles (STBM) and cytokines from underlying placental anomaly involving abnormal trophoblast differentiation. Activation of circulating neutrophils has recently been shown to lead to the generation of fibrous extracellular lattices containing DNA, termed NETs (neutrophil extracellular traps). Therefore, we examined whether placentally derived factors activated peripheral neutrophils to generate NETs, and whether NETs formation was increased in preeclamptic placenta. Activation of isolated circulatory neutrophils on treatment with placentally derived factors (interleukin-8 and STBM) was assessed by measuring CD11b expression using Flow cytometry. Furthermore, NETs generation by these activated neutrophils in vitro and in vivo in the placental tissue sections were examined using electron microscopy and fluorescence microscopy. We report that placentally-derived interleukin-8 and STBM efficiently activated neutrophils and triggered NETs formation. Large numbers of NETs were present directly in the intervillous space of preeclamptic placentae. NETs, therefore, appear to be an integral part of neutrophil activation, and their increased presence in preeclampsia suggests that NETs may play a role in the underlying pathology.

Introduction: Elevations in circulatory DNA, as measured by real-time PCR, have been observed in pregnancies with manifest preeclampsia. Recent reports have indicated that circulatory nucleosome levels are elevated in the periphery of cancer patients. We have now examined whether circulatory nucleosome levels are similarly elevated in cases with preeclampsia., Methods: Maternal plasma samples were prepared from 17 cases with early onset preeclampsia (<34 weeks gestation) with 14 matched normotensive controls, as well as 15 cases late-onset preeclampsia (>34 weeks gestation) with 10 matched normotensive controls. Levels of circulatory nucleosomes were quantified by commercial ELISA (enzyme-linked immunosorbant assay)., Results: The level of circulatory nucleosomes was significantly elevated in both study preeclampsia groups, compared to the matched normotensive control group (p = 0.000 and p = 0.001, respectively)., Conclusions: Our data suggests that preeclampsia is associated with the elevated presence of circulatory nucleosomes, and that this phenomenon occurs in both early- and late-onset forms of the disorder., (Copyright 2005 John Wiley & Sons, Ltd.)

Objectives: We have previously shown that the levels of circulatory fetal DNA are elevated in preeclampsia and that these increases correspond to disease severity. Several reports have indicated that increased levels of antiphospholipid (anti-PL) and anti-DNA antibodies may be associated with preeclampsia, in particular with the severe forms of the disorder. Since the release of cell-free DNA by the placenta is attributed to some form of cell death or damage and as anti-PL and anti-double-stranded DNA (dsDNA) antibodies have been proposed to lead to placental damage, we have studied the relationship between these parameters in preeclampsia., Methods: Circulating fetal DNA levels in samples taken from pregnant women with mild (n = 12) or severe (n = 12) preeclampsia and from normal pregnant controls (n = 35) were quantified using a Taqman real-time Polymerase Chain Reaction (PCR) assay. The Anti-PL antibodies (IgG and IgM) were assayed by anticardiolipin ELISA and by commercial anti-beta2-Glycoprotein I (GPI) ELISA kits. Anti-dsDNA antibodies (IgG and IgM) were analyzed by a commercially available anti-dsDNA ELISA kit., Results: No correlation could be drawn with the quantity of circulatory fetal DNA in the samples analyzed and corresponding anti-PL or anti-dsDNA antibody levels. Furthermore, no significant difference existed between the levels of these antibodies in the two study groups and the control cohort., Conclusion: Our data suggest that the mechanism leading to the increased release of cell-free circulatory DNA from the placenta does not involve trophoblast damage mediated by these agents. Our analysis also questions the reported involvement of anti-PL and anti-DNA antibodies in preeclampsia.

The examination of fetal cells, specifically erythroblasts, and cell-free fetal DNA from the blood of pregnant women is currently the subject of intense research with the aim of developing new risk-free methods for prenatal diagnosis. An unexpected finding made during these studies was that the traffic of fetal erythroblasts into the maternal peripheral circulation was enhanced in pre-eclampsia. Independent prospective studies examining samples collected in the second trimester indicated that this perturbation in fetal cell trafficking occurs early in pregnancy, well before the onset of pre-eclampsia symptoms. The quantitative analysis of cell-free fetal and maternal DNA levels indicated that these concentrations were elevated in a co-ordinate manner in manifest pre-eclampsia, and that these elevations corresponded to disease severity. On the other hand, analysis of prospectively collected samples indicated that only cell-free fetal but not maternal DNA levels were elevated before onset of symptoms in pregnancies which subsequently developed pre-eclampsia. These data support hypotheses suggesting that pre-eclampsia is a multi-step disorder, initiated by a placental lesion that occurs early in pregnancy and which subsequently leads to a systemic maternal inflammatory response and associated endothelial cell damage.

Fetal cells, specifically fetal erythroblasts, as well as cell-free fetal DNA are present in the maternal circulation. Both are currently being investigated as a means for the non-invasive risk-free analysis of fetal genetic traits. The origin of this cell-free fetal DNA in the maternal circulation is currently unclear. Since numerous fetal erythroblasts have been demonstrated to exhibit an apoptotic phenotype in the form of fragmented nuclear DNA, it has been proposed that such trafficking fetal cells may be a possible source. This hypothesis is supported by reports of elevated numbers of fetal erythroblast and cell-free fetal DNA concentrations in pregnancies affected by pre-eclampsia or polyhydramnios. To address this question, we have examined fetal erythroblast numbers and cell-free DNA concentrations in the same maternal blood samples. Our study, performed on both normal and pathologically-affected pregnancies, indicates that no correlation exists between these two fetal cellular and molecular species. This is most evident in pregnancies affected by onset of preterm labour, where significant elevations in cell-free fetal DNA concentrations were detected without any concomitant elevation in fetal erythroblast numbers. Our data therefore suggest that an alternative cell type is the source of cell-free fetal DNA. Furthermore, it appears that the release of cell-free fetal DNA from this cell type is affected by pathological placental conditions which are not associated with an increase in fetal cell trafficking.

Objective: Elevations in cell free fetal DNA has previously been determined in pregnancies affected by preeclampsia. A recent report has indicated that cell free fetal DNA concentrations are elevated early in pregnancy before disease onset. As we have recently performed a prospective study to examine fetal cell traffic in pregnancies at risk for developing preeclampsia, we now quantify cell free fetal DNA concentrations in these samples., Methods: Blood samples were collected in the second trimester of pregnancy from pregnancies at risk for preeclampsia. Cell free fetal DNA amounts were quantified by real-time PCR. These results were then correlated with subsequent pregnancy outcome., Results: Free fetal DNA levels were significantly higher (median of 422.9 vs. 128.5 copies/mL maternal plasma; p=0.005) in plasma samples from women who developed preeclampsia ( n=10) when compared to those who had unremarkable pregnancies ( n=40)., Conclusions: Our data independently confirm the finding that maternal plasma cell free fetal DNA levels are elevated early in pregnancies, which later develop preeclampsia.