Several growth factors such as vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF) are involved in the placental vascular development. We investigated whether dysregulation in the VEGF family may explain the defective uteroplacental vascularization characterizing preeclampsia. We compared pregnancies complicated by early onset severe preeclampsia or intrauterine growth retardation to normal pregnancies. Maternal plasma, placentas, and placental bed biopsies were collected. The mRNA levels of VEGF-A, PlGF, and their receptors were quantified in placentas and placental beds. Levels of VEGF-A, PlGF, and soluble VEGF receptor (VEGFR) were assessed in maternal plasma. In compromised pregnancies, elevated levels of VEGF-A and VEGFR-1 mRNAs may reflect the hypoxic status of the placenta. On contrast, the membrane-bound VEGFR-1 was decreased in the placental bed of preeclamptic patients. Preeclampsia was associated with low levels of circulating PlGF and increased levels of total VEGF-A and soluble VEGFR-1. Free VEGF-A was undetectable in maternal blood. Immunohistochemical studies revealed that VEGF-A and PlGF were localized in trophoblastic cells. Altogether, our results suggest two different pathophysiological mechanisms associated with preeclampsia. The first one is related to an overproduction of competitive soluble VEGFR-1 that may lead to suppression of VEGF-A and PlGF effects. The second one is the down-regulation of its membrane bound form (VEGFR-1) in the placental bed, which may result in the defective uteroplacental development.
Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill-defined. This report by an international multidisciplinary (obstetricians, nephrologists, hematologists, intensivists, neonatologists and complement biologists) working group summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, co-existing symptoms, first-line laboratory work-up and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are to urgently rule in or out thrombotic thrombocytopenic purpura (TTP) with ADAMTS13 activity testing, to consider alternative disorders with features of TMA (preeclampsia/eclampsia, Hemolysis Elevated Liver enzymes Low Platelets (HELLP) syndrome, antiphospholipid syndrome (APS)) or ultimately to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS) as a diagnosis of exclusion. Even though rare, it is paramount to diagnose TTP and aHUS associated with pregnancy and postpartum, as both require urgent specific treatment.
Aspirin is currently the most widely prescribed treatment in the prevention of cardiovascular complications. The indications for the use of aspirin during pregnancy are, however, the subject of much controversy. Since the first evidence of the obstetric efficacy of aspirin in 1985, numerous studies have tried to determine the effect of low-dose aspirin on the incidence of preeclampsia, with very controversial results. Large meta-analyses including individual patient data have demonstrated that aspirin is effective in preventing preeclampsia in high-risk patients, mainly those with a history of preeclampsia. However, guidelines regarding the usage of aspirin to prevent preeclampsia differ considerably from one country to another. Screening modalities, target population, and aspirin dosage are still a matter of debate. In this review, we report the pharmacodynamics of aspirin, its main effects according to dosage and gestational age, and the evidence-based indications for primary and secondary prevention of preeclampsia.
A critical step in the establishment of human pregnancy is the invasion of the uterus wall by extravillous cytotrophoblasts (EVCTs) during the first trimester. It is well established that human chorionic gonadotropin hormone (hCG) is secreted by the endocrine syncytiotrophoblast (ST) into the maternal compartment. We recently reported that invasive EVCTs also produce hCG, suggesting an autocrine role in the modulation of trophoblast invasion. Here we analyzed the role of hCG secreted in vitro by primary cultures of invasive EVCT and noninvasive ST. We first demonstrated that LH/CG receptor was present in EVCTs in situ and in vitro as well as in an EVCT cell line (HIPEC65). We next showed that hCG secreted by EVCTs stimulated progesterone secretion by MA10 cells in a concentration-dependent manner. Incubation of HIPEC65 with EVCT supernatants induced a 10-fold increase in cell invasion, whereas ST supernatants had no effect. This stimulating effect was strongly decreased when hCG was depleted from EVCT supernatants containing a large amount of the hyperglycosylated form of hCG, which is almost undetectable in ST supernatants. Finally, we investigated the regulation of hCG expression by peroxisome proliferator-activated receptor (PPAR)-gamma, a nuclear receptor shown to inhibit trophoblast invasion. Activation of PPARgamma decreased alpha- and beta-subunit transcript levels and total hCG secretion in primary EVCTs. Our results offer the first evidence that hCG secreted by the invasive trophoblast, likely the hyperglycosylated form of hCG, but not by the syncytiotrophoblast, promotes trophoblast invasion and may be a PPARgamma target gene in trophoblast invasion process.
BackgroundThe first reports on the pandemic influenza 2009 A/H1N1v from the USA, Mexico, and Australia indicated that this disease was associated with a high mortality in pregnant women. The aim of this study was to describe and compare the characteristics of severe critically ill and non-severe pregnant women with 2009 A/H1N1v-related illness in France.Methodology/Principal FindingsA national registry was created to screen pregnant women with laboratory-confirmed 2009 A/H1N1v influenza. Three hundred and fifteen patients from 46 French hospitals were included: 40 patients were admitted to intensive care units (severe outcomes), 111 were hospitalized in obstetric or medical wards (moderate outcomes), and 164 were outpatients (mild outcomes). The 2009 A/H1N1v influenza illness occurred during all pregnancy trimesters, but most women (54%), notably the severe patients (70%), were in the third trimester. Among the severe patients, twenty (50%) underwent mechanical ventilation, and eleven (28%) were treated with extracorporeal membrane oxygenation. Three women died from A/H1N1v influenza. We found a strong association between the development of a severe outcome and both co-existing illnesses (adjusted odds ratio [OR], 5.1; 95% confidence interval [CI], 2.2–11.8) and a delay in oseltamivir treatment after the onset of symptoms (>3 or 5 days) (adjusted OR, 4.8; 95% CI, 1.9–12.1 and 61.2, 95% CI; 14.4–261.3, respectively). Among the 140 deliveries after 22 weeks of gestation known to date, 19 neonates (14%) were admitted to a neonatal intensive care unit, mainly for preterm delivery, and two neonates died. None of these neonates developed 2009 A/H1N1v infection.ConclusionsThis series confirms the high incidence of complications in pregnant women infected with pandemic A/H1N1v observed in other countries but depicts a lower overall maternal and neonatal mortality and morbidity than indicated in the USA or Australia. Moreover, our data demonstrate the benefit of early oseltamivir treatment in this specific population.
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Neonatal cancer is rare and comprises a heterogeneous group of neoplasms with substantial histological diversity. Almost all types of paediatric cancer can occur in fetuses and neonates; however, the presentation and behaviour of neonatal tumours often differs from that in older children, leading to differences in diagnosis and management. The causes of neonatal cancer are unclear, but genetic factors probably have a key role. Other congenital abnormalities are frequently present. Teratoma and neuroblastoma are the most common histological types of neonatal cancer, with soft-tissue sarcoma, leukaemia, renal tumours, and brain tumours also among the more frequent types. Prenatal detection, most often on routine ultrasound or in the context of a known predisposition syndrome, is becoming more common. Treatment options pose challenges because of the particular vulnerability of the population. Neonatal cancer raises diagnostic, therapeutic, and ethical issues, and management requires a multidisciplinary approach.
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