Free DNA and Nucleosome Concentrations in Pathological Pregnancies

Comparative Study of Plasma Free DNA and Nucleosome Concentrations: Pathological Versus Normal Pregnancies

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).

Study Overview

• Status: Completed
• Conditions: Venous Thrombosis; Pregnancy; Eclampsia; Pre-Eclampsia; Hypertension, Pregnancy-Induced; Pulmonary Embolism; HELLP Syndrome; Fetal Death; Placental Insufficiency
• Intervention / Treatment: Biological: Bloodwork, baseline; Biological: Blood work, Months 1 & 2; Biological: Bloodwork, Months -1 to -6

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.

• Study Type: Observational
• Enrollment (Actual): 137

Contacts and Locations

Study Locations

• France
  • Nîmes Cedex 9, France, 30029
    • CHU de Nimes - Hopital Universitaire Caremeau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group P: pregnancy w/complications; 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). 100 patients will be included. Interventions to be administered: Bloodwork, baseline	Biological: Bloodwork, baseline; 36 ml of blood are drawn at baseline (last month of pregnancy for groups P and T2, inclusion for group T1) in order to quantify the following: plasma free DNA concentration, plasma nucleosome concentration, hemoglobin, platelets, leukocytes, polynuclear neutrophils, mean corpuscular volume, monocytes, mean corpuscular hemoglobin, lymphocytes, polynuclear eosinophils, polynuclear basophils, D-Dimers, Fibrin monomers, Trophoblast microparticles, Angiogenic marker CD146.
Group T1: Healthy volunteers; Healthy volunteers with no history of chronic or neoplastic disease. 30 healthy volunteers will be included. Interventions to be administered: Bloodwork, baseline	Biological: Bloodwork, baseline; 36 ml of blood are drawn at baseline (last month of pregnancy for groups P and T2, inclusion for group T1) in order to quantify the following: plasma free DNA concentration, plasma nucleosome concentration, hemoglobin, platelets, leukocytes, polynuclear neutrophils, mean corpuscular volume, monocytes, mean corpuscular hemoglobin, lymphocytes, polynuclear eosinophils, polynuclear basophils, D-Dimers, Fibrin monomers, Trophoblast microparticles, Angiogenic marker CD146.
Group T2: Pregnancy, no complications; Pregnant patients with no identifiable pregnancy complications, and no history of chronic or neoplastic disease. 50 pregnant volunteers will be included. Interventions to be administered: Bloodwork, baseline	Biological: Bloodwork, baseline; 36 ml of blood are drawn at baseline (last month of pregnancy for groups P and T2, inclusion for group T1) in order to quantify the following: plasma free DNA concentration, plasma nucleosome concentration, hemoglobin, platelets, leukocytes, polynuclear neutrophils, mean corpuscular volume, monocytes, mean corpuscular hemoglobin, lymphocytes, polynuclear eosinophils, polynuclear basophils, D-Dimers, Fibrin monomers, Trophoblast microparticles, Angiogenic marker CD146.
Group T1x: 15 Healthy volunteers; 15 Healthy volunteers selected from group T1 (the first 15). These patients will have 2 additional months of follow up. Interventions to be administered: Blood work, Months 1 & 2	Biological: Bloodwork, baseline; 36 ml of blood are drawn at baseline (last month of pregnancy for groups P and T2, inclusion for group T1) in order to quantify the following: plasma free DNA concentration, plasma nucleosome concentration, hemoglobin, platelets, leukocytes, polynuclear neutrophils, mean corpuscular volume, monocytes, mean corpuscular hemoglobin, lymphocytes, polynuclear eosinophils, polynuclear basophils, D-Dimers, Fibrin monomers, Trophoblast microparticles, Angiogenic marker CD146.; Biological: Blood work, Months 1 & 2; 36 ml of blood are drawn at 1 & 2 months after inclusion in order to quantify the following: plasma free DNA concentration, plasma nucleosome concentration, hemoglobin, platelets, leukocytes, polynuclear neutrophils, mean corpuscular volume, monocytes, mean corpuscular hemoglobin, lymphocytes, polynuclear eosinophils, polynuclear basophils, D-Dimers, Fibrin monomers, Trophoblast microparticles, Angiogenic marker CD146.
Group T2x: 15 Pregnancy, no complications; 15 patients selected from group T2 (the first 15); these patients will have 7 months of follow up during pregnancy. Interventions to be administered: Bloodwork, Months -1 to -6	Biological: Bloodwork, baseline; 36 ml of blood are drawn at baseline (last month of pregnancy for groups P and T2, inclusion for group T1) in order to quantify the following: plasma free DNA concentration, plasma nucleosome concentration, hemoglobin, platelets, leukocytes, polynuclear neutrophils, mean corpuscular volume, monocytes, mean corpuscular hemoglobin, lymphocytes, polynuclear eosinophils, polynuclear basophils, D-Dimers, Fibrin monomers, Trophoblast microparticles, Angiogenic marker CD146.; Biological: Bloodwork, Months -1 to -6; 36 ml of blood are drawn at the third, fourth, fifth, sixth, seventh and eight months of normal pregnancy (corresponding to months -1 to -6 before comparative baseline; this group is included in the study early during pregnancy)in order to quantify the following: plasma free DNA concentration, plasma nucleosome concentration, hemoglobin, platelets, leukocytes, polynuclear neutrophils, mean corpuscular volume, monocytes, mean corpuscular hemoglobin, lymphocytes, polynuclear eosinophils, polynuclear basophils, D-Dimers, Fibrin monomers, Trophoblast microparticles, Angiogenic marker CD146.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total plasma concentration of free DNA (ng/ml)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	Base line (day 0)
Total plasma concentration of nucleosomes (AU)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth	Base line (day 0)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin (g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Platelets (g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Leukocytes (g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Polynuclear neutrophils(g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Mean corpuscular volume (fL)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Monocytes (g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Mean corpuscular hemoglobin (pg/GR)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Lymphocytes (g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Polynuclear eosinophils (g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Polynuclear basophils (g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
D-dimers (ng/ml)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Fibrin monomers (ng/ml)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Trophoblast microparticles (%)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Angiogenic marker CD146 (ng/ml)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	baseline (day 0)
Hemoglobin (g/l)	For group T1x only	1 month
Platelets (g/l)	For group T1x only	1 month
Leukocytes (g/l)	For group T1x only	1 month
Polynuclear neutrophils(g/l)	For group T1x only	1 month
Mean corpuscular volume (fL)	For group T1x only	1 month
Monocytes (g/l)	For group T1x only	1 month
Mean corpuscular hemoglobin (pg/GR)	For group T1x only	1 month
Lymphocytes (g/l)	For group T1x only	1 month
Polynuclear eosinophils (g/l)	For group T1x only	1 month
Polynuclear basophils (g/l)	For group T1x only	1 month
D-dimers (ng/ml)	For group T1x only	1 month
Fibrin monomers (ng/ml)	For group T1x only	1 month
Trophoblast microparticles (%)	For group T1x only	1 month
Angiogenic marker CD146 (ng/ml)	For group T1x only	1 month
Total plasma concentration of free DNA (ng/ml)	For group T1x only	1 month
Total plasma concentration of nucleosomes (AU)	For group T1x only	1 month
Hemoglobin (g/l)	For group T1x only	2 months
Platelets (g/l)	For group T1x only	2 months
Leukocytes (g/l)	For group T1x only	2 months
Polynuclear neutrophils(g/l)	For group T1x only	2 months
Mean corpuscular volume (fL)	For group T1x only	2 months
Monocytes (g/l)	For group T1x only	2 months
Mean corpuscular hemoglobin (pg/GR)	For group T1x only	2 months
Lymphocytes (g/l)	For group T1x only	2 months
Polynuclear eosinophils (g/l)	For group T1x only	2 months
Polynuclear basophils (g/l)	For group T1x only	2 months
D-dimers (ng/ml)	For group T1x only	2 months
Fibrin monomers (ng/ml)	For group T1x only	2 months
Trophoblast microparticles (%)	For group T1x only	2 months
Angiogenic marker CD146 (ng/ml)	For group T1x only	2 months
Total plasma concentration of free DNA (ng/ml)	For group T1x only	2 months
Total plasma concentration of nucleosomes (AU)	For group T1x only	2 months
Hemoglobin (g/l)	For group T2x only	-1 months
Hemoglobin (g/l)	For group T2x only	-2 months
Hemoglobin (g/l)	For group T2x only	-3 months
Hemoglobin (g/l)	For group T2x only	-4 months
Hemoglobin (g/l)	For group T2x only	-5 months
Hemoglobin (g/l)	For group T2x only	-6 months
Platelets (g/l)	For group T2x only	-1 months
Platelets (g/l)	For group T2x only	-2 months
Platelets (g/l)	For group T2x only	-3 months
Platelets (g/l)	For group T2x only	-4 months
Platelets (g/l)	For group T2x only	-5 months
Platelets (g/l)	For group T2x only	-6 months
Leukocytes (g/l)	For group T2x only	-1 months
Leukocytes (g/l)	For group T2x only	-2 months
Leukocytes (g/l)	For group T2x only	-3 months
Leukocytes (g/l)	For group T2x only	-4 months
Leukocytes (g/l)	For group T2x only	-5 months
Leukocytes (g/l)	For group T2x only	-6 months
Polynuclear neutrophils(g/l)	For group T2x only	-1 months
Polynuclear neutrophils(g/l)	For group T2x only	-2 months
Polynuclear neutrophils(g/l)	For group T2x only	-3 months
Polynuclear neutrophils(g/l)	For group T2x only	-4 months
Polynuclear neutrophils(g/l)	For group T2x only	-5 months
Polynuclear neutrophils(g/l)	For group T2x only	-6 months
Mean corpuscular volume (fL)	For group T2x only	-1 months
Mean corpuscular volume (fL)	For group T2x only	-2 months
Mean corpuscular volume (fL)	For group T2x only	-3 months
Mean corpuscular volume (fL)	For group T2x only	-4 months
Mean corpuscular volume (fL)	For group T2x only	-5 months
Mean corpuscular volume (fL)	For group T2x only	-6 months
Monocytes (g/l)	For group T2x only.	-1 months
Monocytes (g/l)	For group T2x only.	-2 months
Monocytes (g/l)	For group T2x only.	-3 months
Monocytes (g/l)	For group T2x only.	-4 months
Monocytes (g/l)	For group T2x only.	-5 months
Monocytes (g/l)	For group T2x only.	-6 months
Mean corpuscular hemoglobin (pg/GR)	For group T2x only.	-1 months
Mean corpuscular hemoglobin (pg/GR)	For group T2x only.	-2 months
Mean corpuscular hemoglobin (pg/GR)	For group T2x only.	-3 months
Mean corpuscular hemoglobin (pg/GR)	For group T2x only.	-4 months
Mean corpuscular hemoglobin (pg/GR)	For group T2x only.	-5 months
Mean corpuscular hemoglobin (pg/GR)	For group T2x only.	-6 months
Lymphocytes (g/l)	For group T2x only.	-1 months
Lymphocytes (g/l)	For group T2x only.	-2 months
Lymphocytes (g/l)	For group T2x only.	-3 months
Lymphocytes (g/l)	For group T2x only.	-4 months
Lymphocytes (g/l)	For group T2x only.	-5 months
Lymphocytes (g/l)	For group T2x only.	-6 months
Polynuclear eosinophils (g/l)	For group T2x only.	-1 months
Polynuclear eosinophils (g/l)	For group T2x only.	-2 months
Polynuclear eosinophils (g/l)	For group T2x only.	-3 months
Polynuclear eosinophils (g/l)	For group T2x only.	-4 months
Polynuclear eosinophils (g/l)	For group T2x only.	-5 months
Polynuclear eosinophils (g/l)	For group T2x only.	-6 months
Polynuclear basophils (g/l)	For group T2x only.	-1 months
Polynuclear basophils (g/l)	For group T2x only.	-2 months
Polynuclear basophils (g/l)	For group T2x only.	-3 months
Polynuclear basophils (g/l)	For group T2x only.	-4 months
Polynuclear basophils (g/l)	For group T2x only.	-5 months
Polynuclear basophils (g/l)	For group T2x only.	-6 months
D-dimers (ng/ml)	For group T2x only.	-1 months
D-dimers (ng/ml)	For group T2x only.	-2 months
D-dimers (ng/ml)	For group T2x only.	-3 months
D-dimers (ng/ml)	For group T2x only.	-4 months
D-dimers (ng/ml)	For group T2x only.	-5 months
D-dimers (ng/ml)	For group T2x only.	-6 months
Fibrin monomers (ng/ml)	For group T2x only.	-1 months
Fibrin monomers (ng/ml)	For group T2x only.	-2 months
Fibrin monomers (ng/ml)	For group T2x only.	-3 months
Fibrin monomers (ng/ml)	For group T2x only.	-4 months
Fibrin monomers (ng/ml)	For group T2x only.	-5 months
Fibrin monomers (ng/ml)	For group T2x only.	-6 months
Trophoblast microparticles (%)	For group T2x only.	-1 months
Trophoblast microparticles (%)	For group T2x only.	-2 months
Trophoblast microparticles (%)	For group T2x only.	-3 months
Trophoblast microparticles (%)	For group T2x only.	-4 months
Trophoblast microparticles (%)	For group T2x only.	-5 months
Trophoblast microparticles (%)	For group T2x only.	-6 months
Angiogenic marker CD146 (ng/ml)	For group T2x only.	-1 months
Angiogenic marker CD146 (ng/ml)	For group T2x only.	-2 months
Angiogenic marker CD146 (ng/ml)	For group T2x only.	-3 months
Angiogenic marker CD146 (ng/ml)	For group T2x only.	-4 months
Angiogenic marker CD146 (ng/ml)	For group T2x only.	-5 months
Angiogenic marker CD146 (ng/ml)	For group T2x only.	-6 months
Total plasma concentration of nucleosomes (AU)	For group T2x only.	-1 months
Total plasma concentration of nucleosomes (AU)	For group T2x only.	-2 months
Total plasma concentration of nucleosomes (AU)	For group T2x only.	-3 months
Total plasma concentration of nucleosomes (AU)	For group T2x only.	-4 months
Total plasma concentration of nucleosomes (AU)	For group T2x only.	-5 months
Total plasma concentration of nucleosomes (AU)	For group T2x only.	-6 months
Total plasma concentration of free DNA (ng/ml)	For group T2x only.	-1 months
Total plasma concentration of free DNA (ng/ml)	For group T2x only.	-2 months
Total plasma concentration of free DNA (ng/ml)	For group T2x only.	-3 months
Total plasma concentration of free DNA (ng/ml)	For group T2x only.	-4 months
Total plasma concentration of free DNA (ng/ml)	For group T2x only.	-5 months
Total plasma concentration of free DNA (ng/ml)	For group T2x only.	-6 months
Fibrinogen (g/l)	For group P, baseline occurs within the 30 days preceding birth. For group T1, baseline = time of inclusion. For group T2, baseline occurs within the 30 days preceding birth.	Base line (day 0)
Fibrinogen (g/l)	For group T2x only.	-1 months
Fibrinogen (g/l)	For group T2x only.	-2 months
Fibrinogen (g/l)	For group T2x only.	-3 months
Fibrinogen (g/l)	For group T2x only.	-4 months
Fibrinogen (g/l)	For group T2x only.	-5 months
Fibrinogen (g/l)	For group T2x only.	-6 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Investigators: Study Director: Sylvie Bouvier, MD, Centre Hospitalier Universitaire de Nîmes; Principal Investigator: Eve Mousty, MD, Centre Hospitalier Universitaire de Nîmes

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): December 17, 2018
• Study Completion (Actual): December 17, 2018

Study Registration Dates

• First Submitted: November 27, 2012
• First Submitted That Met QC Criteria: November 27, 2012
• First Posted (Estimate): November 29, 2012

Study Record Updates

• Last Update Posted (Actual): January 11, 2019
• Last Update Submitted That Met QC Criteria: January 10, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: plasma nucleosome concentration; plasma free DNA concentration
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Pregnancy Complications; Placenta Diseases; Death; Hypertension; Embolism; Thrombosis; Venous Thrombosis; Eclampsia; Pre-Eclampsia; Pulmonary Embolism; Hypertension, Pregnancy-Induced; HELLP Syndrome; Fetal Death; Placental Insufficiency
• Other Study ID Numbers: LOCAL/2012/SB-01; 2014-A01120-47 (Other Identifier: RCB number)