Frédéric Chantraine

Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia

BACKGROUND The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear. METHODS We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks. RESULTS In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3). CONCLUSIONS An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).

Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia—a step forward but not the definitive answer

Preeclampsia (PE) is a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, which resolves on placental delivery. It is thought to be the consequence of impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries. In PE the maternal plasma concentration of free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) is decreased whereas the concentration of soluble fms-like tyrosine kinase-1 (sFlt-1) and of soluble endoglin (sEng) is increased. These soluble receptors may bind VEGF, PLGF and TGFbeta1 and TGFbeta3 in the maternal circulation, causing endothelial dysfunction in many maternal tissues. Hence there is a view that the pathogenesis is more or less clarified. According to the vascular theory, poor placentation leads to poor uteroplacental perfusion and hypoxia, which stimulates sFlt-1 and sEng production causing the maternal syndrome. This assumption has been recently challenged. The role of hypoxia as the main stimulus for release of sFlt-1 has been questioned and the role of inflammatory mechanisms has been emphasized. According to this inflammatory theory, poor placentation may predispose more to placental oxidative stress than hypoxia and endothelial dysfunction may be part of a broader disorder of systemic inflammation. Finally, the recent demonstration of activating auto-antibodies to the angiotensin 1 receptor that experimentally play a major pathogenic role in PE further suggests a pleiotropism of aetiologies for this condition. The purpose of this review is to critically evaluate the recent hypotheses and their possible insights on early diagnosis, prevention and treatment.

Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells.

Background Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines. Methodology and Principal Findings Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ∼60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines. Conclusions and Significance The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation.

A study of progress of labour using intrapartum translabial ultrasound, assessing head station, direction, and angle of descent.

Please cite this paper as: Tutschek B, Braun T, Chantraine F, Henrich W. A study of progress of labour using intrapartum translabial ultrasound, assessing head station, direction, and angle of descent. BJOG 2011;118:62–69.

Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice

Pre-eclampsia (PE) is a leading cause of maternal and fetal/neonatal morbidity and mortality worldwide. Clinical diagnosis and definition of PE is commonly based on the measurement of non-specific signs and symptoms, principally hypertension and proteinuria1–3. However, due to the recognition that measurement of proteinuria is prone to inaccuracies and the fact that PE complications often occur before proteinuria becomes significant, most recent guidelines also support the diagnosis of PE on the basis of hypertension and signs of maternal organ dysfunction other than proteinuria3–5. Furthermore, the clinical presentation and course of PE is variable, ranging from severe and rapidly progressing early-onset PE, necessitating preterm delivery, to late-onset PE at term. There may be associated intrauterine growth restriction (IUGR), further increasing neonatal morbidity and mortality. These features suggest that the classical standards for the diagnosis of PE are not sufficient to encompass the complexity of the syndrome. Undoubtedly, proper management of pregnant women at high risk for PE necessitates early and reliable detection and intensified monitoring, with referral to specialized perinatal care centers, to reduce substantially maternal, fetal and neonatal morbidity6,7. In the decade since Maynard et al.8 reported that excessive placental production of soluble fms-like tyrosine kinase receptor-1 (sFlt-1), an antagonist of vascular endothelial growth factor and placental growth factor (PlGF), contributes to the pathogenesis of PE, extensive research has been published demonstrating the usefulness of angiogenic markers in both diagnosis and the subsequent prediction and management of PE and placenta-related disorders. Various reports have demonstrated that disturbances in angiogenic and antiangiogenic factors are implicated in the pathogenesis of PE and have possible relevance in the diagnosis and prognosis of the disease. Increased serum levels of sFlt-1 and decreased levels of PlGF, thereby resulting in an increased sFlt-1/PlGF ratio, can be detected in the second half of pregnancy in women diagnosed to have not only PE but also IUGR or stillbirth, i.e. placenta-related disorders. These alterations are more pronounced in early-onset rather than late-onset disease and are associated with severity of the clinical disorder. Moreover, the disturbances in angiogenic factors are reported to be detectable prior to the onset of clinical symptoms (disease), thereby allowing discrimination of women with normal pregnancies from those at high risk for developing pregnancy complications, primarily PE9–30. Plasma concentrations of angiogenic/antiangiogenic factors are of prognostic value in obstetric triage: similar to the progressively worsening clinical course observed in women with early-onset PE, changes in the angiogenic profile leading to a more antiangiogenic state can be found. Current definitions of PE are poor in predicting PE-related adverse outcomes. A diagnosis of PE based on blood pressure and proteinuria has a positive predictive value of approximately 30% for predicting PE-related adverse outcomes31. Estimation of the sFlt-1/PlGF ratio allows identification of women at high risk for imminent delivery and adverse maternal and neonatal outcome23,30,32–35. Moreover, it has also been shown that the time-dependent slope of the sFlt-1/PlGF ratio between repeated measurements is predictive for pregnancy outcome and the risk of developing PE, and repeated measurements have been suggested36. However, the ‘optimal’ time interval for a follow-up test remains unclear. Finally, high values are closely related to the need to deliver immediately22,23,37. Additionally, in normal and complicated pregnancies, angiogenic factors are correlated with Doppler ultrasound parameters, mainly uterine artery (UtA) indices38–42. Combining the sFlt-1/PlGF ratio with UtA Doppler ultrasound, at the time of diagnosis of early-onset PE, has prognostic value mainly for perinatal complications, being limited for the prediction of maternal complications37,43. The additional measurement of the sFlt-1/PlGF ratio has been shown to improve the sensitivity and specificity of Doppler measurement in predicting PE44–48, supporting its implementation in screening algorithms. Whereas studies on the predictive efficacy of the sFlt-1/PlGF ratio in the first trimester have yielded contradictory results49, reports on the use of this marker as an aid in prediction from the mid trimester onwards have led to its suggested use as a screening tool, especially for identifying all women developing PE and requiring delivery within the subsequent 4 weeks50–52. This short review of the literature highlights that measurement of the sFlt-1/PlGF ratio has the potential to become an additional tool in the management of PE, particularly as automated tests that allow rapid and easy measurement of these markers are now widely available. Nevertheless, although these markers were incorporated recently into the German guidelines53, no formal recommendation regarding how to use sFlt-1, PlGF or the sFlt-1/PlGF ratio has been established in any official protocol. The purpose of this paper is to answer questions that are frequently asked around the use of the sFlt-1/PlGF ratio in the diagnosis and prediction of PE and regarding the implications for clinical practice, in particular, ‘When?’ and ‘In which women?’ should the sFlt-1/PlGF ratio be measured and, ‘What should be done with the results?’, and to provide guidance to educate physicians on the use of the sFlt-1/PlGF ratio in clinical practice. To achieve this, international experts in the use of angiogenic markers have strived to develop a consensus statement on the clinical use of the sFlt-1/PlGF ratio and the consequential management in pregnant women with suspected PE or at a high risk of developing PE.

Abnormal vascular architecture at the placental-maternal interface in placenta increta

OBJECTIVE The objective of the study was to characterize the vascular architecture at the placental-maternal interface in pregnancies complicated by placenta increta and normal pregnancies. STUDY DESIGN Vessel numbers and cross-section area density and spatial and area distributions in 13 placenta-increta placental beds were compared with 9 normal placental beds using computer-assisted image analysis of whole-slide CD31 immunolabeled sections. RESULTS The total areas occupied by vessels in normal and placenta-increta placental beds were comparable, but vessels were significantly sparser and larger in the latter. Moreover, placenta-increta-vessel distributions (area and distance from the placental-myometrial junction) were more heterogeneous. CONCLUSION Size and spatial organization of the placenta-increta vascular architecture at the placental-maternal interface differed from normal and might partially explain the severe hemorrhage observed during placenta-increta deliveries.

Prenatal diagnosis of abnormally invasive placenta reduces maternal peripartum hemorrhage and morbidity

Abnormally invasive placenta (AIP) poses diagnostic and therapeutic challenges. We analyzed clinical cases with confirmed placenta increta or percreta.

Abnormally Invasive Placenta – AIP. Awareness and pro‐active management is necessary

This theme issue focuses a serious and important topic in obstetrics and feto-maternal medicine: abnormally invasive placenta (AIP). Abnormally invasive placenta (AIP) is a broad term that covers conditions where the placenta is a true accreta, increta or percreta. To draw a line between these entities in the clinical situation, where the invasiveness of the placenta is not always known in advance, is not easy. Even after delivery the diagnosis is a challenge, except when the uterus is removed and examined by the pathologist, which is considered as the gold standard examination to classify AIP cases. The reason why we introduce the broad term abnormally invasive placenta (AIP) is that “placenta accreta” has been used with different definitions in the literature. The term placenta accreta originates from histopathology and defines the direct attachment of placental villi to the myometrium without intervening decidua. Depending on the depth of trophoblast invasion into the myometrium, three subtypes are differentiated by the pathologist: placenta accreta vera, increta and percreta. In placenta accreta vera, chorionic villi attach directly to the myometrium in the absence of decidua. In placenta increta, placental villi invade deeper into the myometrium, but do not extend to the outermost layers of the uterus. In placenta percreta, chorionic villi penetrate through the myometrium up to the serosa. The neo-vascularization caused by the growing placenta percreta may soften the tissues of the adjacent organs (bladder, intestines, parametrium and other neigboring tissues) and simulate invasion. But the placental tissue usually respects the serosa, unless it, – in rare cases, tenderizes or softens up the serosa, which may lead to eventual symptomatic uterine rupture. The problem is that the term “accreta” is used to describe different specific grades of abnormal placental infiltration from accreta to percreta, and at the same time it is used as a general term. Therefore, we believe that another general term for these conditions will be helpful. We propose a clinical definition of “abnormally invasive placenta” (AIP): a placenta that cannot be removed spontaneously or manually, without causing severe bleeding. Most articles on AIP report a mixture of cases of placenta accreta, increta and percreta, which makes it difficult to assess the results with regard to management of each single entity. Placenta percreta is the most serious of the abnormally invasive placentas and associated with a significant risk of severe maternal morbidity and mortality. The main problem of severe AIP is the elevated maternal morbidity and even mortality due to live-threatening bleeding at (forced) placental delivery if the condition is not suspected beforehand. The strong association between a previous cesarean delivery and AIP means that with the rise in cesarean section rates, seen in a an almost world-wide context (1), we will experience more cases of AIP in the future (2, 3). Only few studies have documented this, mostly because of a lack of longitudinal studies and the variation in use of the diagnosis of AIP. Still the frequency of severe AIP seems to have risen maybe 10 times over the last 50 years and approximately 1/500 to 1/2500 deliveries is complicated by AIP (4, 5). AIP is caused by a disturbed dialog between the decidua and trophoblast at the moment of implantation and placental development. Some authors argue that the infiltrating trophoblast is too “aggressive”, but most experts presume that the etiology is an incompetent or absent decidua caused by endometrial damage or trauma, caused by surgery like cesarean section or curettage, hysteroscopic operations, infections or irradiation of the uterus. Fibrosis in scar tissue may also be involved. Fundamental research in this field is still needed to achieve a full understanding of the etiology of AIP and possibly prevention of the development of AIP. A key factor in AIP management is the prenatal diagnosis. Only by this could delivery be planned in ideal conditions at a referral centre with the necessary additional and back-up services, so that the maternal risks could be significantly reduced. Prenatal diagnosis of AIP is challenging but feasible, if the ultrasonographer is searching actively for the well-described ultrasonic signs.

Differential expression of Vegfr-2 and its soluble form in preeclampsia.

Background Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably, soluble sVEGFR-1 (also known as sFlt-1) and soluble endoglin (sEng), as well as to decreased PlGF. Recently, soluble VEGF type 2 receptor (sVEGFR-2) has emerged as a crucial regulator of lymphangiogenesis. To date, however, there is a paucity of information on the changes of VEGFR-2 that occur during the clinical onset of PE. Therefore, the aim of our study was to characterize the plasma levels of VEGFR-2 in PE patients and to perform VEGFR-2 immunolocalization in placenta. Methodology/Principal findings By ELISA, we observed that the VEGFR-2 plasma levels were reduced during PE compared with normal gestational age matched pregnancies, whereas the VEGFR-1 and Eng plasma levels were increased. The dramatic drop in the VEGFR-1 levels shortly after delivery confirmed its placental origin. In contrast, the plasma levels of Eng and VEGFR-2 decreased only moderately during the early postpartum period. An RT-PCR analysis showed that the relative levels of VEGFR-1, sVEGFR-1 and Eng mRNA were increased in the placentas of women with severe PE. The relative levels of VEGFR-2 mRNA as well as expressing cells, were similar in both groups. We also made the novel finding that a recently described alternatively spliced VEGFR-2 mRNA variant was present at lower relative levels in the preeclamptic placentas. Conclusions/Significance Our results indicate that the plasma levels of anti-angiogenic factors, particularly VEGFR-1 and VEGFR-2, behave in different ways after delivery. The rapid decrease in plasma VEGFR-1 levels appears to be a consequence of the delivery of the placenta. The persistent circulating levels of VEGFR-2 suggest a maternal endothelial origin of this peptide. The decreased VEGFR-2 plasma levels in preeclamptic women may serve as a marker of endothelial dysfunction.

Soluble fms-Like Tyrosine Kinase-1-to-Placental Growth Factor Ratio and Time to Delivery in Women With Suspected Preeclampsia.

OBJECTIVE: To assess the association of a serum soluble fms-like tyrosine kinase 1-to-placental growth factor (sFlt-1-to-PlGF) ratio of greater than 38 with time to delivery and preterm birth. METHODS: Secondary analysis of an observational cohort study that included women 18 years of age or older from 24 to 36 6/7 weeks of gestation at their first study visit with suspected (not confirmed) preeclampsia. Participants were recruited from December 2010 to January 2014 at 30 sites in 14 countries. A total of 1,041 women were included in time-to-delivery analysis and 848 in preterm birth analysis. RESULTS: Women with an sFlt-1-to-PlGF ratio greater than 38 (n=250) had a 2.9-fold greater likelihood of imminent delivery (ie, delivery on the day of the test) (Cox regression hazard ratio 2.9; P<.001) and shorter remaining time to delivery (median 17 [interquartile range 10–26] compared with 51 [interquartile range 30–75] days, respectively; Weibull regression factor 0.62; P<.001) than women with an sFlt-1-to-PlGF ratio of 38 or less, whether or not they developed preeclampsia. For women who did not (n=842) and did develop preeclampsia (n=199), significant correlations were seen between an sFlt-1-to-PlGF ratio greater than 38 and preterm birth (r=0.44 and r=0.46; both P<.001). Among women who did not develop preeclampsia, those who underwent iatrogenic preterm delivery had higher median sFlt-1-to-PlGF ratios at their first visit (35.3, interquartile range 6.8–104.0) than those who did not (8.4, interquartile range 3.4–30.6) or who delivered at term (4.3, interquartile range 2.4–10.9). CONCLUSIONS: In women undergoing evaluation for suspected preeclampsia, a serum sFlt-1-to-PlGF ratio greater than 38 is associated with a shorter remaining pregnancy duration and a higher risk of preterm delivery.