Clinical trial NCT01736826: Free DNA and Nucleosome Concentrations in Pathological Pregnancies
Official title: Comparative Study of Plasma Free DNA and Nucleosome Concentrations: Pathological Versus Normal Pregnancies
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pregnancy
Venous Thrombosis
Pulmonary Embolism
Hypertension, Pregnancy-Induced
Eclampsia
HELLP Syndrome
Pre-Eclampsia
Fetal Death
Placental Insufficiency
Keywords: plasma nucleosome concentration
plasma free DNA concentration
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
First posted: 2012-11-29
Enrollment: 137
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population includes three groups:

Group P: 100 pregnant women with complications typical of placental vascular disease or venous thromboembolism.

Group T1: 30 non-pregnant, healthy volunteers

* The first 15 patients from group T1 will form group T1x. The latter group has two months of additional follow up.

Group T2: 50 pregnant, healthy volunteers

* The first 15 patients from group T2 will form group T2x. The latter group has 7 months of follow-up during pregnancy.

Brief summary: The primary objective of this study is to demonstrate that plasma concentrations of nucleosomes and free DNA differ between three groups:

1. pregnant patients with complications typical of placental insufficiency or venous thrombosis (group P),
2. healthy women (Group T1) and
3. healthy pregnant women (Group T2).

Detailed description: Our secondary objectives include the following:

1. To describe, in 15 healthy, non-pregnant women changes in plasma concentrations of nucleosomes and free DNA over 3 months.
2. To describe, in 15 pregnant women (without complications), changes in plasma concentrations of nucleosomes and free DNA over the last 7 months of pregnancy
3. To show that plasma concentrations of nucleosomes and free DNA, in patients with complicated pregnancies differ according to the nature of the complication
4. To show that a relationship exists between the concentrations of nucleosomes, free DNA, and total granulocyte microparticles (and trophoblast particles for pregnant women)
5. To evaluate the relationship between nucleosome concentrations, free DNA concentrations and circulating leukocyte populations
6. To evaluate the relationship between nucleosome concentrations, free DNA concentrations and hemostasis markers
7. To describe changes in hemostasis markers throughout pregnancy
8. To evaluate the relationship between nucleosome concentrations, free DNA concentrations and the angiogenic marker CD146
9. To add to the Nîmes University Hospital biological collections.

Eligibility criteria: Inclusion Criteria for all patients:

* The patient must have given her informed and signed consent
* The patient must be insured or beneficiary of a health insurance plan

Inclusion Criteria for patients in group P:

* The patient is pregnant and has complications typical of placental vascular disease (preeclampsia, eclampsia, HELLP syndrome, retro-placental hematoma, in utero fetal death) or venous thromboembolism (deep vein thrombosis, pulmonary embolism)

Inclusion Criteria for patients in group T1:

* The patient is available for 3 months of follow-up
* The patient is a non-pregnant healthy volunteer
* No identifiable chronic pathologies
* No history of neoplastic disease
* No history of chronic infectious disease
* No acute disease (such as benign infection), now or within the past two weeks

Inclusion Criteria for patients in group T2:

* The patient is available for 7 months of follow-up
* The patient is pregnant, with no identifiable pregnancy complications
* No identifiable chronic pathologies
* No history of neoplastic disease
* No history of chronic infectious disease
* No acute disease (such as benign infection), now or within the past two weeks

Exclusion Criteria for all patients:

* The patient is participating in another study (with the exception of the following studies: PAPILLO-PMA (2013-A00538-37), ElastoMAP (2013-A01148-37), ElastoDéclenche (2014-A00828-39), LXRs (2009-A00968-49), Bakri (2013-A00914-41), OASIS 2 (2013-A00022-43)).
* The patient is in an exclusion period determined by a previous study
* The patient is under judicial protection, under tutorship or curatorship
* The patient refuses to sign the consent
* It is impossible to correctly inform the patient
* The patient cannot read French
* The patient is receiving hormonal ovarian stimulation in the context of medically assisted procreation
* Impossible to perform venipuncture under good conditions
* New complication or pathology during the study (except for pregnancy complications in group P)

Exclusion Criteria for group P:

* Twin or multiple pregnancy
* The patient is participating in another study (with the exception of those mentioned in the exclusion criteria for all patients and the DG Postpartum study (2013-A00277-38)

Exclusion Criteria for group T1:

* The patient is pregnant
* The patient is breast feeding
* The patient has given birth within the last 3 months
* Known history of chronic disease
* History of treated neoplastic disease
* Acute disease within the past two weeks (includes benign disease)

Exclusion Criteria for group T2:

* Pregnancy with complications
* Known history of chronic disease
* History of treated neoplastic disease
* Acute disease within the past two weeks (includes benign disease)
* Twin or multiple pregnancy

Primary outcomes:
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: Base line (day 0)
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: Base line (day 0)
Secondary outcomes:
measure: Hemoglobin (g/l)
timeFrame: baseline (day 0)
measure: Platelets (g/l)
timeFrame: baseline (day 0)
measure: Leukocytes (g/l)
timeFrame: baseline (day 0)
measure: Polynuclear neutrophils(g/l)
timeFrame: baseline (day 0)
measure: Mean corpuscular volume (fL)
timeFrame: baseline (day 0)
measure: Monocytes (g/l)
timeFrame: baseline (day 0)
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: baseline (day 0)
measure: Lymphocytes (g/l)
timeFrame: baseline (day 0)
measure: Polynuclear eosinophils (g/l)
timeFrame: baseline (day 0)
measure: Polynuclear basophils (g/l)
timeFrame: baseline (day 0)
measure: D-dimers (ng/ml)
timeFrame: baseline (day 0)
measure: Fibrin monomers (ng/ml)
timeFrame: baseline (day 0)
measure: Trophoblast microparticles (%)
timeFrame: baseline (day 0)
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: baseline (day 0)
measure: Hemoglobin (g/l)
timeFrame: 1 month
measure: Platelets (g/l)
timeFrame: 1 month
measure: Leukocytes (g/l)
timeFrame: 1 month
measure: Polynuclear neutrophils(g/l)
timeFrame: 1 month
measure: Mean corpuscular volume (fL)
timeFrame: 1 month
measure: Monocytes (g/l)
timeFrame: 1 month
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: 1 month
measure: Lymphocytes (g/l)
timeFrame: 1 month
measure: Polynuclear eosinophils (g/l)
timeFrame: 1 month
measure: Polynuclear basophils (g/l)
timeFrame: 1 month
measure: D-dimers (ng/ml)
timeFrame: 1 month
measure: Fibrin monomers (ng/ml)
timeFrame: 1 month
measure: Trophoblast microparticles (%)
timeFrame: 1 month
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: 1 month
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: 1 month
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: 1 month
measure: Hemoglobin (g/l)
timeFrame: 2 months
measure: Platelets (g/l)
timeFrame: 2 months
measure: Leukocytes (g/l)
timeFrame: 2 months
measure: Polynuclear neutrophils(g/l)
timeFrame: 2 months
measure: Mean corpuscular volume (fL)
timeFrame: 2 months
measure: Monocytes (g/l)
timeFrame: 2 months
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: 2 months
measure: Lymphocytes (g/l)
timeFrame: 2 months
measure: Polynuclear eosinophils (g/l)
timeFrame: 2 months
measure: Polynuclear basophils (g/l)
timeFrame: 2 months
measure: D-dimers (ng/ml)
timeFrame: 2 months
measure: Fibrin monomers (ng/ml)
timeFrame: 2 months
measure: Trophoblast microparticles (%)
timeFrame: 2 months
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: 2 months
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: 2 months
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: 2 months
measure: Hemoglobin (g/l)
timeFrame: -1 months
measure: Hemoglobin (g/l)
timeFrame: -2 months
measure: Hemoglobin (g/l)
timeFrame: -3 months
measure: Hemoglobin (g/l)
timeFrame: -4 months
measure: Hemoglobin (g/l)
timeFrame: -5 months
measure: Hemoglobin (g/l)
timeFrame: -6 months
measure: Platelets (g/l)
timeFrame: -1 months
measure: Platelets (g/l)
timeFrame: -2 months
measure: Platelets (g/l)
timeFrame: -3 months
measure: Platelets (g/l)
timeFrame: -4 months
measure: Platelets (g/l)
timeFrame: -5 months
measure: Platelets (g/l)
timeFrame: -6 months
measure: Leukocytes (g/l)
timeFrame: -1 months
measure: Leukocytes (g/l)
timeFrame: -2 months
measure: Leukocytes (g/l)
timeFrame: -3 months
measure: Leukocytes (g/l)
timeFrame: -4 months
measure: Leukocytes (g/l)
timeFrame: -5 months
measure: Leukocytes (g/l)
timeFrame: -6 months
measure: Polynuclear neutrophils(g/l)
timeFrame: -1 months
measure: Polynuclear neutrophils(g/l)
timeFrame: -2 months
measure: Polynuclear neutrophils(g/l)
timeFrame: -3 months
measure: Polynuclear neutrophils(g/l)
timeFrame: -4 months
measure: Polynuclear neutrophils(g/l)
timeFrame: -5 months
measure: Polynuclear neutrophils(g/l)
timeFrame: -6 months
measure: Mean corpuscular volume (fL)
timeFrame: -1 months
measure: Mean corpuscular volume (fL)
timeFrame: -2 months
measure: Mean corpuscular volume (fL)
timeFrame: -3 months
measure: Mean corpuscular volume (fL)
timeFrame: -4 months
measure: Mean corpuscular volume (fL)
timeFrame: -5 months
measure: Mean corpuscular volume (fL)
timeFrame: -6 months
measure: Monocytes (g/l)
timeFrame: -1 months
measure: Monocytes (g/l)
timeFrame: -2 months
measure: Monocytes (g/l)
timeFrame: -3 months
measure: Monocytes (g/l)
timeFrame: -4 months
measure: Monocytes (g/l)
timeFrame: -5 months
measure: Monocytes (g/l)
timeFrame: -6 months
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: -1 months
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: -2 months
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: -3 months
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: -4 months
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: -5 months
measure: Mean corpuscular hemoglobin (pg/GR)
timeFrame: -6 months
measure: Lymphocytes (g/l)
timeFrame: -1 months
measure: Lymphocytes (g/l)
timeFrame: -2 months
measure: Lymphocytes (g/l)
timeFrame: -3 months
measure: Lymphocytes (g/l)
timeFrame: -4 months
measure: Lymphocytes (g/l)
timeFrame: -5 months
measure: Lymphocytes (g/l)
timeFrame: -6 months
measure: Polynuclear eosinophils (g/l)
timeFrame: -1 months
measure: Polynuclear eosinophils (g/l)
timeFrame: -2 months
measure: Polynuclear eosinophils (g/l)
timeFrame: -3 months
measure: Polynuclear eosinophils (g/l)
timeFrame: -4 months
measure: Polynuclear eosinophils (g/l)
timeFrame: -5 months
measure: Polynuclear eosinophils (g/l)
timeFrame: -6 months
measure: Polynuclear basophils (g/l)
timeFrame: -1 months
measure: Polynuclear basophils (g/l)
timeFrame: -2 months
measure: Polynuclear basophils (g/l)
timeFrame: -3 months
measure: Polynuclear basophils (g/l)
timeFrame: -4 months
measure: Polynuclear basophils (g/l)
timeFrame: -5 months
measure: Polynuclear basophils (g/l)
timeFrame: -6 months
measure: D-dimers (ng/ml)
timeFrame: -1 months
measure: D-dimers (ng/ml)
timeFrame: -2 months
measure: D-dimers (ng/ml)
timeFrame: -3 months
measure: D-dimers (ng/ml)
timeFrame: -4 months
measure: D-dimers (ng/ml)
timeFrame: -5 months
measure: D-dimers (ng/ml)
timeFrame: -6 months
measure: Fibrin monomers (ng/ml)
timeFrame: -1 months
measure: Fibrin monomers (ng/ml)
timeFrame: -2 months
measure: Fibrin monomers (ng/ml)
timeFrame: -3 months
measure: Fibrin monomers (ng/ml)
timeFrame: -4 months
measure: Fibrin monomers (ng/ml)
timeFrame: -5 months
measure: Fibrin monomers (ng/ml)
timeFrame: -6 months
measure: Trophoblast microparticles (%)
timeFrame: -1 months
measure: Trophoblast microparticles (%)
timeFrame: -2 months
measure: Trophoblast microparticles (%)
timeFrame: -3 months
measure: Trophoblast microparticles (%)
timeFrame: -4 months
measure: Trophoblast microparticles (%)
timeFrame: -5 months
measure: Trophoblast microparticles (%)
timeFrame: -6 months
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: -1 months
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: -2 months
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: -3 months
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: -4 months
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: -5 months
measure: Angiogenic marker CD146 (ng/ml)
timeFrame: -6 months
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: -1 months
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: -2 months
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: -3 months
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: -4 months
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: -5 months
measure: Total plasma concentration of nucleosomes (AU)
timeFrame: -6 months
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: -1 months
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: -2 months
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: -3 months
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: -4 months
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: -5 months
measure: Total plasma concentration of free DNA (ng/ml)
timeFrame: -6 months
measure: Fibrinogen (g/l)
timeFrame: Base line (day 0)
measure: Fibrinogen (g/l)
timeFrame: -1 months
measure: Fibrinogen (g/l)
timeFrame: -2 months
measure: Fibrinogen (g/l)
timeFrame: -3 months
measure: Fibrinogen (g/l)
timeFrame: -4 months
measure: Fibrinogen (g/l)
timeFrame: -5 months
measure: Fibrinogen (g/l)
timeFrame: -6 months
Other outcomes:
Locations:
city: Nîmes Cedex 9
country: France
facility: CHU de Nîmes - Hôpital Universitaire Carémeau
Study officials:
affiliation: Centre Hospitalier Universitaire de Nîmes
name: Sylvie Bouvier, MD
role: STUDY_DIRECTOR
affiliation: Centre Hospitalier Universitaire de Nîmes
name: Eve Mousty, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bouvier S, Traboulsi W, Blois SM, Demattei C, Joshkon A, Mousty E, Nollet M, Paulmyer-Lacroix O, Foucault-Bertaud A, Fortier M, Leroyer AS, Bachelier R, Letouzey V, Alfaidy N, Dignat-George F, Blot-Chabaud M, Gris JC, Bardin N. Soluble CD146 is increased in preeclampsia and interacts with galectin-1 to regulate trophoblast migration through VEGFR2 receptor. F S Sci. 2022 Feb;3(1):84-94. doi: 10.1016/j.xfss.2021.11.002. Epub 2021 Nov 19.
citation: Bouvier S, Mousty E, Fortier M, Demattei C, Mercier E, Nouvellon E, Chea M, Grosjean F, Letouzey V, Gris JC. Placenta-mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes. J Thromb Haemost. 2020 Dec;18(12):3371-3380. doi: 10.1111/jth.15105. Epub 2020 Oct 18.