Metatranscriptomic Next Generation Sequencing in First Trimester Trophoblast With Increased Fetal Nuchal Translucency (METAHCN) (METAHCN)

Pathogen Detection by Metatranscriptomic Next Generation Sequencing in the Trophoblast Collected in Women Carrying a Fetus With Increasing Nuchal Translucency in the First Trimester of Pregnancy

The study is based on the hypothesis that increased nuchal translucency may be associated with a materno fetal infection and that the pathogen responsible for this infection could be identify with metatranscriptomic next-generation sequencing in the trophoblast tissue.

Study Overview

• Status: Recruiting
• Conditions: Increased Nuchal Translucency in the First Trimester of Pregnancy
• Intervention / Treatment: Biological: Metatranscriptomic; Diagnostic test: Specific microbiologic diagnosis

Detailed Description

Nuchal translucency > 3.5 mm in the first trimester of pregnancy is due to fluid accumulation in the subcutaneous tissue in the nuchal area. This is seen in around 1% of all pregnancies. Increased nuchal translucency is explained by a chromosomic abnormality (mainly Down syndrome) in 30 to 40% of cases. Therefore, the state of the art is to perform an array CGH on chorionic villi sampling. Cases of nuchal translucency that are not explained by a chromosomic abnormality may be associated: with fetal defect (heart, congenital diaphragmatic hernia) in 10% of cases, with genetic disease in 4% of cases or with miscarriage or fetal death of unknown etiology in 18% of cases.

The etiology of increased nuchal translucency remains unknown in more than 50% of the cases. It could be linked to inflammation or reflect an infection but this latter association has been rarely studied. This association was suggested in a study reporting serology of CMV, toxoplasmosis or B19 parvovirus primary infections in pregnant women carrying a fetus with increased nuchal translucency. In those rare cases, the microorganism was not searched directly in the trophoblast tissue. In the investigators' center, the investigators describe in a context of maternal primary infection, one case of increased nuchal translucency with a positive CMV PCR in the trophoblast tissue collected at 12 weeks. Other pathogens yet not identified might be associated with increased nuchal translucency.

Metatranscriptomic next generation sequencing (mNGS) allows to search for any pathogens without a priori. It is therefore a powerful technic to study this potential association between increased nuchal translucency and infection.

• Study Type: Observational
• Enrollment (Anticipated): 110

Contacts and Locations

• Study Contact: Name: Jacques FOURGEAUD, PharmD; Phone Number: 01 44 49 56 11; Email: jacques.fourgeaud@aphp.fr
• Study Contact Backup: Name: Aminata TRAORE; Phone Number: 01 48 19 27 34; Email: aminata.traore6@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Recruiting
    • Hôpital Necker - Enfants Malades
    • Contact: Laurence BUISSIERES, PhD; Phone Number: 01 44 49 43 26; Email: laurence.buissieres@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

Pregnant women consulting in the prenatal diagnosis Unit of the University Hospital Necker-Enfants-malades

Description

Inclusion Criteria:

• Pregnant women
• Singleton pregnancy
• First trimester (11 GA+0D to 13 GA+6D)
• Carrying a fetus with a nuchal translucency > 3.5 mm for which a chorionic villi sampling is performed OR a suspicion of genetic abnormalities for which a chorionic villi sampling is performed
• Delivery planned at Necker hospital
• Not opposed to participation

Exclusion Criteria

• Age <18 years
• no health insurance
• difficulties in understanding the French language
• chronic infection (HIV, HBV, HVC and HTLV-1)

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Nuchal translucency with no genetic abnormalities; Pregnant women between 11 and 14 weeks with a fetus showing a nuchal translucency > 3.5 mm and no genetic abnormalities with array CGH.	Biological: Metatranscriptomic; Analysis with metatranscriptomic next generation sequencing of trophoblast obtained by chorionic villi sampling; Diagnostic test: Specific microbiologic diagnosis; If a microorganism is detected by metatranscriptomic NGS, specific diagnosis (PCR and serology) will be done in maternal and neonatal samples (blood, urine, saliva)
Nuchal translucency with genetic abnormalities; Pregnant women between 11 and 14 weeks with a fetus showing a nuchal translucency > 3.5 mm and a genetic abnormalities at array CGH.	Biological: Metatranscriptomic; Analysis with metatranscriptomic next generation sequencing of trophoblast obtained by chorionic villi sampling; Diagnostic test: Specific microbiologic diagnosis; If a microorganism is detected by metatranscriptomic NGS, specific diagnosis (PCR and serology) will be done in maternal and neonatal samples (blood, urine, saliva)
Genetic abnormalities; Pregnant women between 11 and 14 weeks with a fetus showing a nuchal translucency < 3.5 mm and a suspicion of genetic abnormalities	Biological: Metatranscriptomic; Analysis with metatranscriptomic next generation sequencing of trophoblast obtained by chorionic villi sampling; Diagnostic test: Specific microbiologic diagnosis; If a microorganism is detected by metatranscriptomic NGS, specific diagnosis (PCR and serology) will be done in maternal and neonatal samples (blood, urine, saliva)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
microorganisms (viruses, bacteria, or parasites) in trophoblast samples	Identification by metatranscriptomic NGS, from women carrying a fetus with nuchal translucency (group 1) and in controls (group 2 and 3)	At inclusion, 11-14 weeks of pregnancy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Miscarriage	Comparison in group 1 of the proportion of miscarriageaccording to the presence or not of a microorganism in the trophoblast.	at termination of pregnancy (assessed up to 7 months)
intrauterine death	Comparison in group 1 of the proportion of intrauterine death according to the presence or not of a microorganism in the trophoblast.	at termination of pregnancy (assessed up to 7 months)
fetal abnormalities	Comparison in group 1 of the proportion of fetal abnormalities, according to the presence or not of a microorganism in the trophoblast.	at delivery
Gestational age	Comparison in group 1 of gestational age at birth, according to the presence or not of a microorganism in the trophoblast.	at delivery
birth weight	Comparison in group 1 of birth weight, according to the presence or not of a microorganism in the trophoblast.	at delivery
Detection of the microorganism identified by metatranscriptomic NGS by conventional diagnostic method in maternal samples	Amplification by real time PCR of the microorganism identified by metatranscriptomic NGS in maternal blood, urine, saliva and amniotic fluid if available	at inclusion
Detection of the microorganism identified by metatranscriptomic NGS by conventional diagnostic method in maternal samples	specific serology to identify a maternal primary infection with the microorganism detected by metatranscriptomic NGS	at inclusion
Detection of the microorganism identified by metatranscriptomic NGS by conventional diagnostic method in neonatal samples	Amplification by real time PCR of the microorganism identified by metatranscriptomic NGS in neonatal blood, urine, saliva	3 days after birth
Detection of the microorganism identified by metatranscriptomic NGS by conventional diagnostic method in neonatal samples	specific serology to identify a maternal primary infection with the microorganism detected by metatranscriptomic NGS	3 days after birth

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Institut Pasteur; Pathogen Discovery Laboratory
• Investigators: Study Director: Marianne LERUEZ-VILLE, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Sebire NJ, Bianco D, Snijders RJ, Zuckerman M, Nicolaides KH. Increased fetal nuchal translucency thickness at 10-14 weeks: is screening for maternal-fetal infection necessary? Br J Obstet Gynaecol. 1997 Feb;104(2):212-5. doi: 10.1111/j.1471-0528.1997.tb11047.x.
• Faure-Bardon V, Fourgeaud J, Guilleminot T, Magny JF, Salomon LJ, Bernard JP, Leruez-Ville M, Ville Y. First-trimester diagnosis of congenital cytomegalovirus infection after maternal primary infection in early pregnancy: feasibility study of viral genome amplification by PCR on chorionic villi obtained by CVS. Ultrasound Obstet Gynecol. 2021 Apr;57(4):568-572. doi: 10.1002/uog.23608. Epub 2021 Mar 9.
• Regnault B, Bigot T, Ma L, Perot P, Temmam S, Eloit M. Deep Impact of Random Amplification and Library Construction Methods on Viral Metagenomics Results. Viruses. 2021 Feb 7;13(2):253. doi: 10.3390/v13020253.
• Bilardo CM, Timmerman E, Pajkrt E, van Maarle M. Increased nuchal translucency in euploid fetuses--what should we be telling the parents? Prenat Diagn. 2010 Feb;30(2):93-102. doi: 10.1002/pd.2396.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 7, 2022
• Primary Completion (ANTICIPATED): May 1, 2024
• Study Completion (ANTICIPATED): November 1, 2024

Study Registration Dates

• First Submitted: May 2, 2022
• First Submitted That Met QC Criteria: May 20, 2022
• First Posted (ACTUAL): May 24, 2022

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2023
• Last Update Submitted That Met QC Criteria: February 10, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: high throughput sequencing; next generation sequencing; metagenomic; nuchal translucency; metatranscriptomic; trophoblast
• Other Study ID Numbers: APHP211328

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No