Non Invasive Prenatal Testing of Down Syndrome (SAFE 21)

Non Invasive Prenatal Testing of Down Syndrome From Maternal Blood Sample

This is a randomized controlled trial in women at risk following combined prenatal screening for Down Syndrome. Women will be asked about their preferences between NIPT and routine prenatal diagnosis based on a dedicated questionnaire. Women will then be randomized between NIPT and standard invasive prenatal diagnosis.

Study Overview

• Status: Completed
• Conditions: Down Syndrome
• Intervention / Treatment: Procedure: Non Invasive Prenatal Testing; Procedure: Invasive Prenatal Testing

Detailed Description

This is a randomized controlled trial in women at risk following combined prenatal screening for Down Syndrome. Women will be asked about their preferences between NIPT and routine prenatal diagnosis based on a dedicated questionnaire. Women will then be randomized between NIPT and standard invasive prenatal diagnosis.

The general objectives are :

• Promote the rapid and large implementation of Non Invasive Prenatal Testing (NIPT) for Down syndrome.
• Improve the management of women at risk after combined first trimester screening and reduce the number of invasive procedures and induced miscarriages .
• Evaluate NIPT medically (in reducing the rate of invasive sampling and related complications, diagnostic performance and feasibility and acceptability in routine practice) and based on cost-analysis in comparison with standard invasive prenatal diagnosis currently proposed .
• Clarify the conditions of implementation and dissemination of NIPT in the overall organization of prenatal screening for trisomy 21 (and provide data to later adjust or not the combination of tests and thresholds).

Promote the organization as networks of professionals involved in prenatal screening for trisomy 21 in order to allow the emergence of a national system of collection of outcomes to improve the quality of practices

The main judgement criteria are:

• Main:

  - Percentage of fetal loss in each group

• Secondary:

  • Percentage of invasive tests in each group (amniocentesis or chorionic villus sampling )
  • Diagnostic performance of NIPT , in particular false positive and negative
  • Percentage of results within 3 weeks and average time interval for results of NIPT
  • Percentage of inconclusive results of DPANI
  • Percentage of other anomalies discovered at invasive sampling
  • Percentage of invasive samples taken despite normal NIPT (either because of later ultrasound anomaly or for maternal reinsurance)
  • Association between maternal characteristics ( weight, height, parity , previous history , serum markers ... ) and the results of NIPT
  • Cost analysis of NIPT in routine clinical practice

The study will include 2450 high risk women in order to be powered enough to detect a 1% reduction of miscarriages in the group undergoing NIPT instead of routine invasive prenatal diagnosis.

• Study Type: Interventional
• Enrollment (Actual): 2111
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Hôpital Necker- Enfants Malades

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• pregnant women over 18
• at risk for Down syndrome> 1/250 based on combined screening using ultrasound together with maternal serum markers and prior to fetal karyotyping
• singleton pregnancy
• pregnancy between 11SA et 18SA
• willing a fetal karyotype

Exclusion Criteria:

• risk for Down syndrome< 1/250 or >1/5
• NT> 3 mm, PAPP-A or beta HCG <0.3 MoM or >5 MoM
• multiple pregnancy , vanishing twin
• morphological abnormalities at US
• Kown chromosomal anomaly in parents
• Patients not willing a fetal karyotype

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Non Invasive Prenatal Testing; Blood sample	Procedure: Non Invasive Prenatal Testing
Active Comparator: Invasive Prenatal Testing; CVS or amniocentesis	Procedure: Invasive Prenatal Testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number or miscarriages	at birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number or invasive tests		at birth
false positive and negative rates of NIPT		At birth
Dedicated questionnaire for patients		day 5
Cost of invasive tests and NIPT in euros	measure in euros	at birth

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Principal Investigator: Laurent J Salomon, MD, PhD, Assistance Publique - Hopitaux de Paris; Study Director: Michel VEKEMANS, MD, PhD, Assistance Publique - Hopitaux de Paris

Publications and helpful links

General Publications

• Le Bras A, Salomon LJ, Bussieres L, Malan V, Elie C, Mahallati H, Ville Y, Vekemans M, Durand-Zaleski I. Cost-effectiveness of five prenatal screening strategies for trisomies and other unbalanced chromosomal abnormalities: model-based analysis. Ultrasound Obstet Gynecol. 2019 Nov;54(5):596-603. doi: 10.1002/uog.20301.
• Seror V, L'Haridon O, Bussieres L, Malan V, Fries N, Vekemans M, Salomon LJ, Ville Y; SAFE 21 Study Group. Women's Attitudes Toward Invasive and Noninvasive Testing When Facing a High Risk of Fetal Down Syndrome. JAMA Netw Open. 2019 Mar 1;2(3):e191062. doi: 10.1001/jamanetworkopen.2019.1062.
• Malan V, Bussieres L, Winer N, Jais JP, Baptiste A, Le Lorc'h M, Elie C, O'Gorman N, Fries N, Houfflin-Debarge V, Sentilhes L, Vekemans M, Ville Y, Salomon LJ; SAFE 21 Study Group. Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21: A Randomized Clinical Trial. JAMA. 2018 Aug 14;320(6):557-565. doi: 10.1001/jama.2018.9396.

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2014
• Primary Completion (Actual): November 7, 2016
• Study Completion (Actual): November 7, 2016

Study Registration Dates

• First Submitted: April 2, 2014
• First Submitted That Met QC Criteria: April 28, 2014
• First Posted (Estimated): April 30, 2014

Study Record Updates

• Last Update Posted (Estimated): September 19, 2025
• Last Update Submitted That Met QC Criteria: September 15, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: prenatal; miscarriage; Amniocentesis; invasive; NIPT; Down, trisomy 21; screening.
• Additional Relevant MeSH Terms: Urogenital Diseases; Neurologic Manifestations; Nervous System Diseases; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Pregnancy Complications; Neurobehavioral Manifestations; Congenital Abnormalities; Abnormalities, Multiple; Intellectual Disability; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Abortion, Spontaneous; Down Syndrome
• Other Study ID Numbers: P130601; 2013-A00998-37 (Other Identifier: ANSM)