Biomarkers of Cytomegalovirus Fetal Infection and Disease (BIO-CCMV)

Biomarkers of Fetal Infection and Disease Following Maternal HCMV Infection

The purposes of this study are to determine 1) if the diagnosis of CMV fetal infection could be done directly in the maternal blood instead of requesting an amniocentesis and 2) if innovative technologies such as proteomic, transcriptomic, methylomic and lipidomic applied in fetal samples could allow the discovery of new biomarkers of fetal infection.

Study Overview

• Status: Recruiting
• Conditions: Cytomegalovirus Congenital
• Intervention / Treatment: Biological: Bio-specimen collected

Detailed Description

Human cytomegalovirus (HCMV) is the most common cause of congenital infection worldwide. The diagnosis of CMV fetal infection relies on the detection of viral DNA in amniotic fluid by polymerase chain reaction after amniocentesis. Non-invasive diagnosis of fetal infection directly in maternal blood is not available. Symptoms develop in about 10% of HCMV-infected fetuses. Despite important advance in medical imaging, establishing the prognosis of an infected fetus remains challenging. Thrombocytopenia, blood HCMV DNA, anti-HCMV immunoglobulin M and β2-microglobulin are recognized biomarkers of symptomatic fetal infections. However, the predictive value of these individual markers is not. Omics technologies could help to establish multimarker signatures of symptomatic infections.

The objective of the study is to:

• validate fetal blood HCMV DNA, anti-HCMV immunoglobulin M , β2-microglobulin and platelet count as biomarkers of fetal disease;
• identify new biomarkers of severe fetal disease using transcriptomic, methylomic and lipidomic analyses of fetal blood and of amniotic fluid.
• validate a non-invasive CMV fetal infection diagnosis tool based on deep-sequencing of targeted CMV genes in maternal blood

• Study Type: Observational
• Enrollment (Anticipated): 265

Contacts and Locations

• Study Contact: Name: Marianne LERUEZ, MD, PhD; Phone Number: +33 (0) 1 44 49 49 49 62; Email: marianne.leruez@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Recruiting
    • Hopital Necker Enfants-malades
    • Contact: Marianne LERUEZ, MD, PhD; Phone Number: +33 (0) 1 44 49 49 49 62; Email: marianne.leruez@aphp.fr

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

• 320 pregnant women with CMV primary infection or carrying a fetus with compatible ultrasound features to obtained 65 infected fetuses and 15 fetuses diagnosed with severely symptomatic infection
• 200 controls pregnant women carrying a fetus with aneuploidy-dysgonosomy

Description

Inclusion Criteria:

CMV cases:

• Informed consent obtained from the mother;
• Pregnant women either with a history of primary CMV infection in pregnancy or carrying a fetus with ultrasound features compatible with CMV infection and willing to have amniocentesis for fetal diagnosis of CMV infection

Control cases :

- Pregnant women carrying a fetus with aneuploidy-dysgonosomy

Exclusion Criteria:

CMV cases:

• Fetuses older than the 26 weeks of gestation at the time of diagnosis of HCMV infection or impossibility to collect foetal samples by the end of the 26th week of gestation
• Mother unable to understand the protocol
• Absence of informed consent
• Any clinical rationale not to perform cordocentesis
• Mother <18 years age
• Administration of immunoglobulins or anti-viral therapy to the mother before the collection of fetal samples or before the diagnosis of symptomatic fetal infection
• Administration of anti-HCMV drugs to the foetus before the collection of fetal samples or before the diagnosis of symptomatic fetal infection
• Administration of immunosuppressive drugs to the mother during pregnancy
• Maternal auto immune disorders
• Multiple pregnancies.

Control cases :

• Mother unable to understand the protocol
• Absence of informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CMV cases; bio-specimen collected for pregnant women with CMV infection	Biological: Bio-specimen collected
Control cases; bio-specimen collected for pregnant women carrying a fetus with aneuploidy-dysgonosomy	Biological: Bio-specimen collected

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Abnormal Laboratory Values in fetal blood	Fetal platelet in mm3/ml, β2 microglobulinein mg/L, proteins concentration in mg/L , Metabolites concentration in mmoles/l , Lipids concentration in mmoles/l , RNA messagers concentration in µg/ml profil	At 23 weeks gestation +/- 3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Abnormal Laboratory Values in amniotic fluid	CMV DNA quantification in UI/mL , protein concentration in mg/L, Metabolites concentration in mmoles/l , Lipids concentration in mmoles/l, RNAm concentration in µg/ml profil ,	At 23 weeks gestation +/- 3 weeks
Non invasive diagnosis of fetal CMV infection in maternal blood in UI/mL.	CMV fetal DNA measurement in maternal blood	At 23 weeks gestation +/- 5 weeks

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Bourgon N, Fitzgerald W, Aschard H, Magny JF, Guilleminot T, Stirnemann J, Romero R, Ville Y, Margolis L, Leruez-Ville M. Cytokine Profiling of Amniotic Fluid from Congenital Cytomegalovirus Infection. Viruses. 2022 Sep 28;14(10):2145. doi: 10.3390/v14102145.
• Benoist G, Salomon LJ, Jacquemard F, Daffos F, Ville Y. The prognostic value of ultrasound abnormalities and biological parameters in blood of fetuses infected with cytomegalovirus. BJOG. 2008 Jun;115(7):823-9. doi: 10.1111/j.1471-0528.2008.01714.x.
• Fabbri E, Revello MG, Furione M, Zavattoni M, Lilleri D, Tassis B, Quarenghi A, Rustico M, Nicolini U, Ferrazzi E, Gerna G. Prognostic markers of symptomatic congenital human cytomegalovirus infection in fetal blood. BJOG. 2011 Mar;118(4):448-56. doi: 10.1111/j.1471-0528.2010.02822.x. Epub 2010 Dec 24.
• Desveaux C, Klein J, Leruez-Ville M, Ramirez-Torres A, Lacroix C, Breuil B, Froment C, Bascands JL, Schanstra JP, Ville Y. Identification of Symptomatic Fetuses Infected with Cytomegalovirus Using Amniotic Fluid Peptide Biomarkers. PLoS Pathog. 2016 Jan 25;12(1):e1005395. doi: 10.1371/journal.ppat.1005395. eCollection 2016 Jan.

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (ANTICIPATED): December 1, 2022
• Study Completion (ANTICIPATED): June 1, 2023

Study Registration Dates

• First Submitted: January 3, 2017
• First Submitted That Met QC Criteria: March 21, 2017
• First Posted (ACTUAL): March 27, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Non-invasive diagnosis; Biomarkers; Cytomegalovirus Congenital; Omics
• Other Study ID Numbers: 14024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO