Health Economic Evaluation of Non-Invasive Prenatal Exclusion Diagnosis

NCT07469657 | Not Yet Recruiting

• 2 other identifiers: APHP240985IDRCB
• Study Type: observational
• Target: 300
• Locations: 1 country
• Sites: 1

Brief Summary

Since the discovery of a small fraction of circulating cell-free fetal DNA (ccffDNA) in the blood of the mother, non-invasive prenatal diagnosis (NIPD) techniques using a simple blood sample have been developed to 1) screen for chromosomal abnormalities, 2) diagnose fetal sex, and 3) detect variants not carried by the mother (exclusion NIPD by PCR). Exclusion NIPD by PCR is currently available for certain common variants, but developing it for each variant takes 3-6 weeks per center. The development process for PCR NIPD is lengthy and costly for each variant tested, thereby restricting access to this technique. In practice, this technique is not widely available to couples at risk of transmitting a severe monogenic disease in France, due to the large number of different genes and multiple variants of a given gene. Next-generation sequencing (NGS) is based on the simultaneous, parallel execution of millions of sequencing reactions, enabling the same nucleotide sequence to be sequenced hundreds of times. It provides qualitative information on the nature of the sequenced base, as well as quantitative information on the number of times the base has been sequenced (reads). Although it only allows for the analysis of around 2% of the entire genome, NGS sequencing of the exome corresponds to almost all the exons of the 22,000 or so genes in our genome. However, this generates a large amount of data, leading to additional costs. Since its widespread adoption by diagnostic laboratories, some teams have developed an NGS-based NIPD for the exclusion of a pathogenic variant. It allows the analysis of multiple pathogenic variants without requiring an additional development phase. They have demonstrated that NGS-based NIPD is a robust and reliable technology, but one that incurs additional reagent costs. In France, 1,700 to 1,800 prenatal diagnostic tests (PND) for monogenic diseases are performed each year due to family history. Between 35 and 40% of couples undergoing invasive PND could benefit from NIPD by NGS, as proposed in the PrenatSafe project. The increased availability of NIPD, whether by PCR or NGS, could also affect couples' demand in the long term. In France, the introduction of NIPD by NGS is likely to lead to an increase in requests for NIPD, as many couples with a low risk of recurrence (in the case of de novo mutations) will probably opt for it due to its lack of iatrogenicity. The rapid and widespread rise of NIPD by NGS, made possible by the use of a standardized, generalizable technique such as NGS, will transform our practices throughout the country. The PrenatSafe project therefore aims to evaluate the cost/benefit ratio of NIPD by NGS compared to the current standard procedure: NIPD by PCR when performed in clinical practice or PND by invasive sampling (trophoblast biopsy or amniocentesis), using an automated, standardized NGS technique involving exome sequencing, which covers almost all indications for exclusion NIPD. This project is the first cost-consequence analysis of prospective exome-based NIPD, using a single standardized technique. The aim is to translate this innovative technology into routine practice if it proves beneficial and economically viable. Exome-based NIPD for exclusion can be fully automated, from ccfDNA extraction to sequencing. This reduces the risk of human error and brings turnaround times in line with the requirements of prenatal diagnosis. If successful, exome-based NIPD would become an earlier alternative to invasive PND without increasing the risk of fetal loss. It would be available for a very large number of indications and could easily be transferred to other prenatal diagnosis centers in France.

Conditions

Monogenic Diseases; Genetic Diseases, Inborn

Keywords

Prenatal Diagnosis (PND); Non-Invasive Prenatal Diagnosis (NIPD); Circulating Cell-Free Fetal DNA (cffDNA); Next Generation Sequencing (NGS); Cost and Outcomes

Outcome Measures

Primary Outcomes (1)

• Cost-consequence analysis

  Total costs associated with non-invasive prenatal diagnosis (NIPD) based on circulating cell-free fetal DNA analyzed by next-generation exome sequencing, compared with current prenatal diagnostic procedures.

  From inclusion until 1 month after the expected date of delivery or the post-termination consultation, up to 8 months

Secondary Outcomes (8)

• Cost-effectiveness Analysis of NGS-based NIPD

  From inclusion until 1 month after the expected date of delivery or the post-termination consultation, up to 8 months

• Participation Rate in NGS-based NIPD

  From inclusion until 1 month after the expected date of delivery or the post-termination consultation, up to 8 months

• Acceptability of NGS-based NIPD

  From inclusion until 1 month after the expected date of delivery or the post-termination consultation, up to 8 months

• Rate of Non-Conclusive NIPD Results

  From inclusion until 1 month after the expected date of delivery or the post-termination consultation, up to 8 months

• Factors Associated with NGS-based NIPD Failure

  From inclusion until 1 month after the expected date of delivery or the post-termination consultation, up to 8 months

Study Arms (1)

NIPD by NGS

The study group includes pregnant couples at risk of transmitting a severe monogenic disorder, for whom prenatal diagnosis has been approved by a multidisciplinary prenatal committee. Eligible participants are over 18, have an ongoing pregnancy (≥7 weeks), and meet technical criteria for exclusion of NIPD by next-generation exome sequencing. Informed consent is required.

Diagnostic Test: NIPD by NGS

Interventions

NIPD by NGS DIAGNOSTIC_TEST

Two additional 10 ml blood samples (Streck tubes) will be collected from the pregnant woman during routine pregnancy monitoring, prior to any invasive prenatal diagnosis if indicated, in order to extract maternal circulating DNA. This circulating cell-free DNA comprises a small amount of fetal DNA, approximately 10%. Exome sequencing will be performed on circulating DNA in order to detect the exclusion pathogenic variant.

NIPD by NGS

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Couples undergoing prenatal diagnosis are at high risk of transmitting a severe incurable condition due to a monogenic defect.

You may qualify if:

• Couple aged over 18 years
• Ongoing pregnancy of at least 7 weeks gestational age
• Requesting, within clinical care, invasive prenatal diagnosis or PCR-based NIPD for a particularly severe monogenic disorder, with indication confirmed by a Multidisciplinary Prenatal Diagnosis Center (CPDPN)
• Causative gene covered by the Agilent V8 exome capture kit
• Affiliated with the national general social security system
• Informed consent obtained from the pregnant woman and her partner

You may not qualify if:

• Prenatal diagnosis request not approved by a Multidisciplinary Prenatal Diagnosis Center (CPDPN)
• Disorder not analyzable by next-generation sequencing (e.g., triplet repeat expansions, sequence homology)
• Woman carrying the pathogenic variant
• Woman or partner deprived of liberty, under guardianship or curatorship
• Index case other than the father, a child, or a fetus from a previous pregnancy within the couple.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• URC-CIC Paris Descartes Necker Cochin: collaborator
• Imagine: collaborator

Study Sites (1)

Hôpital Necker Enfants Malades

Paris, Île-de-France Region, 75015, France

Location

Biospecimen

Retention: SAMPLES WITH DNA

Two additional blood tubes (10 mL) from the pregnant woman

MeSH Terms

Conditions

Genetic Diseases, Inborn

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Julie STEFFANN, MD,PhD

  Hôpital Universitaire Necker - Enfants Malades

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Julie STEFFANN, MD, PhD

CONTACT

01 44 38 17 47; julie.steffann@aphp.fr

Sarah BOUCHARD, Project manager

CONTACT

01 42 19 28 79; sarah.bouchard@aphp.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 27, 2026
• First Posted: March 13, 2026
• Study Start: March 1, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029
• Last Updated: March 13, 2026

Record last verified: 2026-03

Locations

FR (1)