A new classification allowing assessment of instrumental vaginal-birth practices.

BACKGROUND: Instrumental vaginal birth, a very common intervention in obstetrics, concerns nearly one in eight women in France. Instrumentally assisted vaginal childbirth can be for maternal and/or fetal indications. Although it reduces recourse to caesarean section, it is subject to risks. Practices concerning instrumental birth are disparate, varying among different practitioners, maternity units and countries, and it is essential to be able to evaluate them. Our objective was to create a classification tool of women requiring instrumental birth to facilitate the analysis of practices within our maternity unit as well as to enable temporal and geographical comparisons. MATERIALS AND METHODS: We propose a simple and robust classification based on the same principles as Robson's classification. It is made up of seven totally inclusive and mutually exclusive groups. Our classification was refined and validated using the Delphi method by a panel of 14 experts from throughout France, and tested in our maternity unit using data from throughout 2021. RESULTS: The seven clinically relevant groups are based on five obstetric criteria (multiplicity, presentation, gestational age, previous type of birth, induction of labor). To classify each woman in a group, five successive questions are posed in a predefined order. The classification has been validated by the experts with highly satisfactory overall agreement. CONCLUSION: In order to improve the quality of care, we propose a tool to standardize the evaluation of instrumental vaginal birth practice (called the "Isère classification", after the county where we work in south-eastern France). It will also facilitate the comparison the practices among different maternity units in a network, a country or even among different countries.

Induction of labour: creation of a classification of Grenoble allowing an assessment of the evaluation of practices.

BACKGROUND: Induction of labour, a very common obstetric procedure, affects about one in five pregnant women in most developed countries. Induction of labour is medically indicated, is subject to risks and additional costs, and is often poorly experienced by patients. The practices concerning induction vary widely from centre to centre and therefore need to be evaluated. Our aim was to develop a tool for evaluating induction of labour which would facilitate geographical and temporal comparisons. METHODS: We have created a classification based on the principles of the internationally known Robson classification. It should be simple, robust, reproducible and require readily available data in each file. The groups are fully inclusive and mutually exclusive. This classification has been validated by a Delphi method. RESULTS: Our classification includes 8 clinically relevant groups according to 5 obstetrical criteria. In order to classify each patient into a group, a simple system based on a maximum of 7 successive questions (from 1 to 7 questions) is used. Our classification has been validated by 13 national experts with satisfactory overall approval. CONCLUSIONS: With a view to improving the quality of care, our Grenoble classification would allow a standardization of the evaluation of practices of the induction of labour over time in the same maternity hospital. It would also allow the comparison of practices within different maternity hospitals in a network, a country or even different countries.

Balloon catheter vs oxytocin alone for induction of labor in women with one previous cesarean section and an unfavorable cervix: a multicenter, retrospective study.

PURPOSE: To compare the rate of vaginal birth between double-balloon catheter and oxytocin alone for induction of labor in women with one previous cesarean section and an unfavorable cervix. MATERIALS AND METHODS: A retrospective and observational study was conducted from 2013 to 2017, at the Saint-Etienne University Hospital where women received induction with a double-balloon catheter for 12 h and at the Grenoble Alpes University Hospital where women received induction with a low-dose oxytocin infusion. Primary outcome was the rate of vaginal birth. RESULTS: Out of 1920 women eligible for attempting a vaginal birth after one previous cesarean section, 501 had a labor induction. Among women with an unfavorable cervix, 160 received a double-balloon catheter in Saint Etienne and 152 received oxytocin alone in Grenoble. The vaginal birth rate was higher in the double-balloon catheter group (61% versus 47% in the oxytocin group). An induction of labor with oxytocin alone reduced chances of vaginal birth (aOR 0.38 CI-95% [0.22-0.66]) compared to cervical ripening with double-balloon catheter. The perinatal morbidity was similar in the two groups. There was, however, 3.9% uterine rupture in the oxytocin group versus 0.6% in the double-balloon group (p = 0.11). CONCLUSION: For induction of labor in women with one previous cesarean section and with unfavorable cervix, cervical ripening with a double-balloon catheter increases the rate of vaginal birth without increased risk of uterine rupture.

Prokineticin 1 is a new biomarker of human oocyte competence: expression and hormonal regulation throughout late folliculogenesis.

CONTEXT: Prokineticin 1 (PROK1) quantification in global follicular fluid (FF) has been recently reported as a predictive biomarker of in vitro fertilization (IVF) outcome. It is now necessary to evaluate its clinical usefulness in individual follicles. OBJECTIVES: To evaluate the clinical value of PROK1 secretion in individual FF to predict oocyte competence. To determine the impact of follicular size, oocyte maturity, and gonadotropin treatments on PROK1 secretion. DESIGN AND SETTING: Prospective cohort study from May 2015 to May 2017 at the University Hospital of Grenoble. PATIENTS: A total of 69 infertile couples underwent IVF. INTERVENTION(S): Collection of 298 individual FF from 44 women undergoing IVF; 52 individual cumulus cell (CC) samples and 15 CC primary cultures from 25 women undergoing IVF-intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Oocyte competence was defined as the ability to sustain embryo development to the blastocyst stage. Follicular size was measured by 2D-sonography. PROK1 concentration was quantified by ELISA assay. RESULTS: PROK1 concentration was correlated to follicular size (r = 0.85, P = 2.2 × 10-16). Normalized PROK1 concentration in FF was predictive of subsequent oocyte competence (AUROC curve = 0.76 [95% CI, 0.69-0.83]; P = 1.7 × 10-9), irrespectively of day-2 embryo morphokinetic parameters. The expression and secretion of PROK1 were increased in FF and CC of mature oocytes (P < 0.01). Follicle Stimulating Hormone and hCG up-regulated PROK1 secretion in CC primary cultures (P < 0.01; P < 0.05), probably through the cAMP pathway (P < 0.01). CONCLUSIONS: PROK1 quantification in individual FF could constitute a new predictive biomarker of oocyte competence in addition with embryo morphokinetic parameters. TRIAL REGISTRATION NUMBER: none.

PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development.

PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants (n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ(+/-) and PPARγ(-/-) mice. Major processes of placental development that are known to be controlled by PPARγ, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ(-/-) mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion.

[Prokineticins: new regulatory peptides in human reproduction]. / Prokinéticines - De nouveaux peptides régulateurs de la reproduction humaine.

During the last decade, there has been growing evidence for the involvement of prokineticins and their receptors (PROK/PROKR) in human reproduction, with multiple roles in the female and male reproductive systems. The PROK/PROKR signalling complex has been reported as a new actor in ovary, uterus, placenta, and testis physiology, with marked dysfunction in various pathological conditions such as polycystic ovary syndrome, recurrent pregnancy loss, preeclampsia, and ectopic pregnancy. Altogether, the results strongly suggest the involvement of prokineticins in spermatogenesis, oocyte competence, embryo implantation, pregnancy, and delivery, and argue for the clinical relevance of these cytokines and their receptors as diagnostic markers for several reproductive diseases.

["Red code" C-sections: A new tool developed with Delphi method is enabling analysis of practices]. / Césariennes « code rouge ¼ : création d'une grille de pertinence par méthode Delphi permettant l'analyse de pratique.

OBJECTIVE: In France, C-sections are classified through a color code according to their degree of urgency. A red-classified C-section is triggered when life of mother or fetus is immediately threatened These cases happen very rarely and represent less than 1% of total deliveries. Many French maternity hospitals are above this rate. This risky procedure should remain an exception. The main purpose of this study is to develop a new tool enabling to determine the relevance of red C-sections in order to improve obstetrical practices. METHODS: Eleven national obstetrical experts were submitted with relevant-estimated indications of red C-sections. A two-round Delphi methodology was then used to reach a consensus on a new table of relevance. RESULTS: Five different groups of indications were proposed to the panel of experts. After two rounds, four groups achieved a consensus by being qualified "very relevant" or "relevant" by more than 80% of the 11 experts. CONCLUSION: The aim of this new consensual table of relevance is to improve quality of care. It allows to evaluate the relevance of red C-sections and determine when red C-sections are non-relevant but it particularly helps teams to identify ways of improvements. Finally, this tool enables a reproductible analysis that can be further intra- or inter-hospitals developed towards harmonization of practices.

EG-VEGF maternal levels predict spontaneous preterm birth in the second and third trimesters in pregnant women with risk factors for placenta-mediated complications.

Prediction of spontaneous preterm birth in asymptomatic women remains a great challenge for the public health system. The aim of the study was to determine the informational value of EG-VEGF circulating levels for prediction of spontaneous preterm birth in the second and third trimesters in pregnant women at high risk for placenta-mediated complications. A prospective multicenter cohort study including 200 pregnant patients with five-serum sampling per patient. Women with spontaneous preterm birth have higher concentrations of serum EG-VEGF than uncomplicated patients at 24 weeks, 28 weeks and 32 weeks (p = 0.03, 0.02 and < 0.001). The areas under the curve reached 0.9 with 100% sensitivity at 32 weeks for the prediction of spontaneous preterm birth. Serum EG-VEGF concentrations could be considered as a reliable biomarker of spontaneous preterm birth in high-risk for placenta-mediated complications pregnant women.

Protocadherin-12 cleavage is a regulated process mediated by ADAM10 protein: evidence of shedding up-regulation in pre-eclampsia.

Protocadherins are a group of transmembrane proteins with homophilic binding activity, members of the cadherin superfamily. Apart from their role in adhesion, the cellular functions of protocadherins are essentially unknown. Protocadherin (PCDH)12 was previously identified in invasive trophoblasts and endothelial and mesangial cells in the mouse. Invalidation studies revealed that the protein was required for optimal placental development. In this article, we show that its human homolog is abundantly expressed in various trophoblast subtypes of the human placenta and at lower levels in endothelial cells. We demonstrate that PCDH12 is shed at high rates in vitro. The shedding mechanism depends on ADAM10 and results in reduced cellular adhesion in a cell migration assay. PCDH12 is subsequently cleaved by the γ-secretase complex, and its cytoplasmic domain is rapidly degraded by the proteasome. PCDH12 shedding is regulated by interlinked intracellular pathways, including those involving protein kinase C, PI3K, and cAMP, that either increase or inhibit cleavage. In endothelial cells, VEGF, prostaglandin E(2), or histamine regulates PCDH12 shedding. The extracellular domain of PCDH12 was also detected in human serum and urine, thus providing evidence of PCDH12 shedding in vivo. Importantly, we observed an increase in circulating PCDH12 in pregnant women who later developed a pre-eclampsia, a frequent pregnancy syndrome and a major cause of maternal and fetal morbidity and mortality. In conclusion, we speculate that, like in mice, PCDH12 may play an important role in human placental development and that proteolytic cleavage in response to external factors, such as cytokines and pathological settings, regulates its activity.

In Underweight Women, Insufficient Gestational Weight Gain Is Associated with Adverse Obstetric Outcomes.

The pre-pregnancy BMI and the gestational weight gain are two important determinants of pregnancy outcomes. The aim of this study was to determine obstetric outcomes associated with insufficient gestational weight gain in women with a pre-pregnancy BMI < 18.5 kg/m2. This study was based on observational routinely collected data from University Hospital Maternity. The participants were allocated to the group sufficient or insufficient gestational weight gain: ≥12.5 kg and <12.5 kg respectively. Primary outcomes were the adjusted birth weight in percentiles (%) and the proportion of SGA newborns. Secondary outcomes were obstetric and perinatal outcomes. A total of 132 participants with a median age of 28 ± 8 years were included. The adjusted birth weight in percentiles was significantly lower in the insufficient gestational weight gain group (27.3 ± 45.0 vs. 46.3 ± 46.2%; p < 0.001). Moreover, the insufficient gestational weight gain is associated with a higher risk of SGA (27.0% vs. 11.6%; p = 0.03). Our study also showed increased risks of premature rupture of membranes, anaemia, and intrauterine growth restriction in women with an insufficient weight gain. Future studies should explore the risk factors associated with insufficient weight gain, in order to develop specific care for underweight pregnant women.

Role of NLRP7 in Normal and Malignant Trophoblast Cells.

Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, ßCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.

How to agree on what is fundamental to optimal teamwork performance in a situation of postpartum hemorrhage? A multidisciplinary Delphi French study to develop the Obstetric Team Performance Assessment Scale (OTPA Scale).

INTRODUCTION: The objective of this study was to develop a new interdisciplinary teamwork scale, the Obstetric Team Performance Assessment (OTPA), for the management of the post-partum hemorrhage, through consensus agreement of obstetric caregivers. The goal is to provide a reliable tool for teaching and evaluating teams in high-fidelity simulation. METHODS: This prospective study is based on an expert consensus, using a Delphi method. The authors developed the "OTPA¼ specifically related to the management of post-partum hemorrhage, using existing recommendations. For the Delphi survey, the scale was distributed to a selected group of experts. After each round of Delphi, authors quantitatively analyzed each element of the scale, based on the percentages of agreement received, and reviewed each comment. This blind examination then led to the modification of the scale. The rounds were continued until 80-100 % agreement with a median overall response score equal to or greater than 8 was obtained for at least 60 % of items. Repeated 3 times, the process led to consensus and to a final version of the OTPA scale. RESULTS: From February to October 2018, 16 of the 33 invited experts participated in four Delphi cycles. Of the 37 items selected in the first round, only 19 (51.3 %) had an agreement of 80-100% with a median overall response score equal to or greater than 8 in the second round, and a third round was conducted. During this third round, 24 of the 37 items were validated (64.9 %) and 82 of the 88 sub-items obtained 80 %-100 % agreement (93.2 %). The fourth round consisted of proposing a weighting of the different items. CONCLUSION: Using a structured Delphi method, we provided a new interdisciplinary teamwork scale (OTPA), for the management of the post-partum hemorrhage. Thus, this scale will be able to be used during high-fidelity scenarii to assess performances of various teams facing a scenari of PPH. Moreover, this scale, focusing some crucial aspects of interdisciplinary teamwork will be useful for teaching purpose.

Skull fracture during instrumental delivery using spatulas: A case report with CT-scan imaging.

Neonatal skull fracture is rare and instrumental delivery is one of the risk factors. We present a case of parietal bone fracture in a term newborn with Thierry's spatulas who benefited from a 3D brain scan. If many cases have been reported with the use of forceps whatever their type, our case is to our knowledge the first one described with spatulas.

Surgical management of diaphragmatic and thoracic endometriosis': A French multicentric descriptive study.

INTRODUCTION: Surgical management of Diaphragmatic and thoracic endometriosis (DTE) is still controversial, a thoracic or an abdominal approach can be proposed. METHODS: We conducted a multicentric retrospective study in 8 thoracic, gynecology or digestive surgery units in 5 French university hospitals. The main objective was to review the current management of DTE. RESULTS: 50 patients operated for DTE from 2010 to 2017 were included: 26 with a thoracic approach and 24 with an abdominal approach. Preoperative pelvic endometriosis (PE) concerned 25 patients. In 38 patients, DTE diagnosis was made on clinical symptoms (pneumothorax (n = 19), chronic or catamenial chest pain (n = 18) or hemopneumothorax (n = 1)). Median time from onset of symptoms to diagnosis was 47 months (0-212). PE surgery concurrently occurred in 22 patients. We report diaphragmatic nodules, pleuropulmonary nodules and diaphragmatic perforations in 42, 5 and 22 women respectively. Lesions were right-sided in 45 patients. Nodules were destructed in 12 cases and resected in 38 cases. When a diaphragmatic reconstruction was needed (n = 31), a simple suture was performed in 26 patients, while 5 patients needed a mesh repair. Pleural symphysis was performed for all patients who received a thoracic approach. DTE resection was considered complete in 46 patients. Three patients had severe 30-days complications of DTE surgery. Median follow-up was 20 months (range 1-69). Recurrence occurred in 10 patients. CONCLUSION: The results emphasize the importance of systematically looking for chest pain in patients suffering from PE and underline the lack of a standardized procedure and treatment in DTE.

Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy.

Endocrine gland derived vascular endothelial growth factor (EG-VEGF) is a canonical member of the prokineticin (PROKs) family. It acts via the two G-protein coupled receptors, namely PROKR1 and PROKR2. We have recently demonstrated that EG-VEGF is highly expressed in the human placenta; contributes to placental vascularization and growth and that its aberrant expression is associated with pregnancy pathologies including preeclampsia and fetal growth restriction. These findings strongly suggested that antagonization of its receptors may constitute a potential therapy for the pregnancy pathologies. Two specific antagonists of PROKR1 (PC7) and for PROKR2 (PKRA) were reported to reverse PROKs adverse effects in other systems. In the view of using these antagonists to treat pregnancy pathologies, a proof of concept study was designed to determine the biological significances of PC7 and PKRA in normal pregnancy outcome. PC7 and PKRA were tested independently or in combination in trophoblast cells and during early gestation in the gravid mouse. Both independent and combined treatments uncovered endogenous functions of EG-VEGF. The independent use of antagonists distinctively identified PROKR1 and PROKR2-mediated EG-VEGF signaling on trophoblast differentiation and invasion; thereby enhancing feto-placental growth and pregnancy outcome. Thus, our study provides evidence for the potential safe use of PC7 or PKRA to improve pregnancy outcome.

NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment.

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

[Perinatal asphyxia and cerebral palsy: medicolegal implications]. / Asphyxie périnatale et paralysie cérébrale: implications médico-légales.

Over the last 30 years, improvements in obstetric practice (systematic fetal perpartum monitoring, Caesarean section, etc.) have markedly reduced the incidence of perinatal asphyxia, especially in the perpartum period. Yet the incidence of cerebral palsy has remained stable, at around 2 per 1000 live births, owing to the fact that this disorder is generally due to antenatal factors. Population-based studies have further demonstrated that acute perpartum asphyxia is a rare cause of cerebral palsy. Obstetrics is a discipline particularly subject to insurance claims, often because of late use or non use of Cesarean section. Perinatal judicial expertise is too often based on obsolete notions. Reform is necessary, focusing on upstream structural problems. The American model initiated by neurologists and adopted by many other disciplines should be widely adopted, including by lawyers and magistrates. It involves verifying the ethical character of the expertise challenged by the injured party, and drawing conclusions for professional practice?

The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects.

Vasculogenesis and angiogenesis are key processes of placental development, which occur throughout pregnancy. Placental vasculogenesis occurs during the first trimester of pregnancy culminating in the formation of hemangioblasts from intra-villous stem cells. Placental angiogenesis occurs subsequently, forming new blood vessels from existing ones. Angiogenesis also takes place at the fetomaternal interface, allowing essential spiral arteriole remodeling to establish the fetomaternal circulation. Vasculogenesis and angiogenesis in animal models and in humans have been studied in a wide variety of in vitro, physiological and pathological conditions, with a focus on the pro- and anti-angiogenic factors that control these processes. Recent studies revealed roles for new families of proteins, including direct participants such as the prokineticin family, and regulators of these processes such as the homeobox genes. This review summarizes recent advances in understanding the molecular mechanisms of actions of these families of proteins. Over the past decade, evidence suggests increased production of placental anti-angiogenic factors, as well as angiogenic factors are associated with fetal growth restriction (FGR) and preeclampsia (PE): the most threatening pathologies of human pregnancy with systemic vascular dysfunction. This review also reports novel clinical strategies targeting members of these family of proteins to treat PE and its consequent effects on the maternal vascular system.

Role of EG-VEGF in human placentation: Physiological and pathological implications.

Pre-eclampsia (PE), the major cause of maternal morbidity and mortality, is thought to be caused by shallow invasion of the maternal decidua by extravillous trophoblasts (EVT). Data suggest that a fine balance between the expressions of pro- and anti-invasive factors might regulate EVT invasiveness. Recently, we showed that the expression of the new growth factor endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is high in early pregnancy but falls after 11 weeks, suggesting an essential role for this factor in early pregnancy. Using human villous explants and HTR-8/SVneo, a first trimester extravillous trophoblast cell line, we showed differential expression of EG-VEGF receptors, PKR1 and PKR2, in the placenta and demonstrated that EG-VEGF inhibits EVT migration, invasion and tube-like organisation. EG-VEGF inhibitory effect on invasion was supported by a decrease in matrix metalloproteinase (MMP)-2 and MMP-9 production. Interference with PKR2 expression, using specific siRNAs, reversed the EG-VEGF-induced inhibitory effects. Furthermore, we determined EG-VEGF circulating levels in normal and PE patients. Our results showed that EG-VEGF levels were highest during the first trimester of pregnancy and decreased thereafter to non-pregnant levels. More important, EG-VEGF levels were significantly elevated in PE patients compared with age-matched controls. These findings identify EG-VEGF as a novel paracrine regulator of trophoblast invasion. We speculate that a failure to correctly down-regulate placental expression of EG-VEGF at the end of the first trimester of pregnancy might lead to PE.