Pregnancy Complications, Pre-Eclampsia, Growth Retardation, Intrauterine
Conditions
Keywords
trophoblasts, autophagy, apoptosis, placenta, pregnancy
Brief summary
Pregnancy increases the risk of thrombosis. Placenta-mediated diseases are a risk factor for cardiovascular pathologies and can lead to maternal-fetal morbidity and mortality. It is essential to understand the cellular and molecular mechanisms of dysfunctions at the vascular-placental interface so that systemic vascular risk can be characterized and, ultimately, screened for, on the basis of new markers (targeted preventive management). Deregulated autophagy could be the starting point for cell death by apoptosis or necrosis leading to complications. The pathophysiological mechanisms involved in trophoblast apoptosis are incompletely described. This project follows on from the GrossAuTop-1 study, which investigated the intra- and inter-individual variability of autophagy and apoptosis activities in women during pregnancy. The aim of this project is to study autophagy and apoptosis activities specifically in women developing a placental vascular complication during pregnancy.
Detailed description
Pregnancy increases the risk of thrombosis. Diseases mediated by the placenta are a risk factor for cardiovascular pathologies. They are responsible for significant maternal-fetal morbidity and mortality. Understanding and exploring the cellular and molecular mechanisms of dysfunctions at the vascular-placental interface could provide arguments for understanding systemic vascular risk, characterizing it and ultimately screening for it on the basis of new markers, thus paving the way for targeted preventive management, feeding into the general principle of precision medicine. Autophagy enables cell development, differentiation and survival, but if deregulated, it could be the starting point for cell death by apoptosis or necrosis, and promote the development of complications. The pathophysiological mechanisms involved in trophoblast apoptosis are incompletely described. A deregulation of the trophoblast proliferation/cell death balance could be at the origin of placental pathologies. The regulation of autophagy and autophagy-dependent events during pregnancy have not been fully identified. We hypothesize that there is an intratrophoblastic dialogue between autophagy and apoptosis mechanisms, with the promotion of one partially inhibiting the other. The increase in trophoblastic autophagy during pregnancy could thus constitute an anti-apoptosis defense phenomenon, whose depletion would lead to cellular apoptosis and pathogenic consequences when it devastates the syncytiotrophoblast. This project follows on from the GrossAuTop-1 study, which investigated the intra- and inter-individual variability of autophagy and apoptosis activities in women during pregnancy: the inclusions corresponded to all-pregnant women, the majority of whom developed a normal pregnancy. The aim of this project is to study autophagy and apoptosis activities specifically in women developing a placental vascular complication during pregnancy.
Interventions
DIAGNOSTIC_TESTBlood test
16 blood samples (16 tubes, i.e. 55.3 ml) will be taken at inclusion. Pregnant women will be seen every month as part of their pregnancy follow-up, and blood (11 tubes, i.e. 35.5 ml) and urine samples will be taken at each follow-up visit. At delivery, a systematic blood sample will be taken as part of the usual care, and an additional 11 tubes of blood (35.5 ml) will be taken.
DIAGNOSTIC_TESTUrine test
Urine samples will be taken at the inclusion visit and at each follow-up visit.
Sponsors
Centre Hospitalier Universitaire de Nīmes
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pregnant women developing a placental vascular complication (preeclampsia and/or intrauterine growth retardation), hospitalized and delivering at Nimes University Hospital. * Pregnant woman with free and informed consent. * Pregnant woman affiliated with and/or benefiting from a health insurance scheme.
Exclusion criteria
* Multiple pregnancy. * Presence of hypertension and/or proteinuria prior to pregnancy. * Participant in an interventional drug study. * Persons in a period of exclusion determined by another study. * Persons under court protection, guardianship or curatorship. * Persons unable to give consent. * Persons for whom it is impossible to give informed information.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of cells expressing LC3 (microtubule-associated protein light chain 3) protein | Baseline | Level of autophagy in trophoblastic test cells quantified by the percentage of cells expressing LC3 (microtubule-associated protein light chain 3) protein |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apoptosis activity | Baseline | Percentage of cells expressing annexin-V in pregnant women developing placental vascular pathology |
| A. Apoptosis activity | Month 1 | Percentage of cells expressing annexin-V in pregnant women developing placental vascular pathology |
| B. Autophagy/apoptosis balance | Baseline | Ratio between percentage of cells expressing LC3 protein and percentage of cells expressing annexin-V |
| C.Kinetics of different biological activities (autophagy, apoptosis, autophagy/apoptosis balance) during pregnancy follow-up: LC3 protein | Baseline | LC3 protein will be measured as a % |
| C.Kinetics of different biological activities (autophagy, apoptosis, autophagy/apoptosis balance) during pregnancy follow-up: cells expressing annexin-V | Baseline | Cells expressing annexin-V will be measured as a % |
| D. Concentration of circulating Placental Growth Factor | Baseline | Circulating Placental Growth Factor measured on blood samples in pg/mL |
| D. Concentration of circulating soluble fms-like tyrosine kinase receptor-1 | Baseline | Circulating soluble fms-like tyrosine kinase receptor-1 measured on blood samples in pg/mL |
| E. Correlation between autophagy/apoptosis balance and markers of renal function: proteinuria | Baseline | Proteinuria will be measured in mg/L |
| E. Correlation between autophagy/apoptosis balance and markers of renal function: creatinuria | Baseline | Creatinuria will be measured in mmol/L |
| E. Correlation between autophagy/apoptosis balance and markers of renal function: C-reactive protein | Baseline | C-reactive protein will be measured in mg/L |
| E. Correlation between autophagy/apoptosis balance and markers of renal function: Fibrinogen | Baseline | Fibrinogen will be measured in g/L |
| E. Coagulation parameters : activated partial thromboplastin time | Baseline | Activated partial thromboplastin time will be measured in seconds |
| E. Coagulation parameters : Prothrombin time | Baseline | Prothrombin time will be measured in seconds |
| E. Coagulation parameters : Fibrinogen | Baseline | Fibrinogen will be measured in g/L |
| E. Coagulation parameters : D-dimers | Baseline | D-dimers will be measured in ng/mL |
| E. Coagulation parameters : Thrombin generation time | Baseline | Thrombin generation time will be measured in seconds |
| Complete Blood Count : White blood cells, Lymphocytes, Neutrophils, Monocytes, Eosinophils and Basophils | Baseline | White blood cells, Lymphocytes, Neutrophils, Monocytes, Eosinophils and Basophils will be measured in 10\^9/L |
| Complete Blood Count : Red blood cells | Baseline | Red blood cells will be measured in 10\^12/L |
| Complete Blood Count : Hemoglobin | Baseline | Hemoglobin will be measured in g/L |
| Complete Blood Count : Platelets | Baseline | Platelets will be measured in % |
| Complete Blood Count : Hematocrit | Baseline | Hematocrit will be measured in % |
| Complete Blood Count : Mean Corpuscular Volume | Baseline | Mean Corpuscular Volume will be measured in f/L |
| Complete Blood Count : Mean Corpuscular Hemoglobin | Baseline | Mean Corpuscular Hemoglobin will be measured in pg |
| Complete Blood Count : Mean Corpuscular Hemoglobin Concentration | Baseline | Mean Corpuscular Hemoglobin Concentration will be measured in g/L |
| Ferritin | Baseline | Ferritin will be measured in ng/mL |
| F. Association between autophagy/apoptosis balance and the presence of constitutive thrombophilia | Baseline | Constitutive thrombophilia: presence of prothrombin or factor V Leiden gene mutation, protein S, C, antithrombin deficiency will be sought: YES/NO |
| F. Association between autophagy/apoptosis balance and the presence of acquired thrombophilia | Baseline | Acquired thrombophilia: presence of anti-phospholipid antibodies (lupus anticoagulant and/or anti-b2-glycoprotein 1 and/or anti-cardiolipid) will be sought: YES/NO |
| Comparison of results on trophoblastic cell autophagy induction potential, apoptosis and autophagy/apoptosis balance | Baseline | The results on trophoblastic cell autophagy induction potential, apoptosis and autophagy/apoptosis balance) will be compared with data obtained from the first GrossAuTop-1 study (normal pregnancy). |
| H.Association between autophagy/apoptosis balance and HbF levels in maternal blood during pregnancy. | Baseline | Determination of fetal hemoglobin (HbF) in maternal blood, measured in % |
| E. Coagulation parameters : Fibrin monomers | Baseline | Fibrin monomers will be measured in mg/mL |
Other
| Measure | Time frame | Description |
|---|---|---|
| I. Constitution of a Biobank | Baseline | A biobank (plasmabank, serum bank, mononuclear cells) will be set up for ancillary studies on other markers of placental vascular pathologies and venous thromboembolic disease. |
Countries
France
Contacts
Primary ContactSylvie BOUVIER, Dr.
Backup ContactAnissa MEGZARI
Outcome results
None listed