Study of the Efficacy of New Non-invasive Prenatal Tests for Screening for Fetal Trisomies Using Maternal Blood

Study Overview
=================
Brief Summary
-----------------
Each year, 450,000 Canadian women become pregnant and, as a result of their participation in prenatal screening for Down syndrome, approximately 10,000 of them will have an amniocentesis (i.e. sampling of liquid surrounding the fetus) and of those, 315 will be found to carry a baby with Down syndrome and 70 normal pregnancies will be lost from complications of the procedure. It has been discovered recently that, during pregnancy, there is fetal DNA in maternal blood in sufficient quantities to be analysed and methods have been proposed to detect the presence or not of a fetus with Down syndrome using maternal blood. The introduction of genomic blood testing as proposed in the context of this project could lead to increased detection of Down syndrome, less invasive screening with 9700 amniocentesis avoided each year in Canada, improving the peace of mind of pregnant women, and preventing the accidental loss of 70 normal fetuses, at a lower overall cost than current practice. However, these methods still need to be validated before being appropriately introduced in routine care. The study hypothesis is that new genomics-based non-invasive methods using fetal-DNA in maternal blood during pregnancy can be more effective than current prenatal screening methods for fetal aneuploidy. This project will carry out an independent study that will validate the performance and utility of different new genomic technologies for screening in pregnant women using maternal blood. The team of researchers will compare the real-life performance of different non-invasive assays and strategies to screen for fetal aneuploidy, and identify an evidence-based cost-effective approach for implementation of this new technology in the Canadian health care system. The deliverables of this project will enable decision makers, pregnant women and their partner to make informed choices pertaining to prenatal genetic screening and diagnosis, such as screening for Down syndrome, and reduce the risk to pregnancies associated with amniocentesis.

Detailed Description
-----------------
The present study is a real life comparative effectiveness study that will compare the performances and costs of several prenatal screening modalities for fetal aneuploidy (see interventions).

Official Title
-----------------
PEGASUS: PErsonalized Genomics for Prenatal Aneuploidy Screening USing Maternal Blood

Conditions
-----------------
Trisomy 21, Trisomy 18, Trisomy 13

Intervention / Treatment
-----------------
* Other: Integrated prenatal screening for Down's syndrome
* Other: Serum QUAD Assay for aneuploidy screening
* Other: Semiconductor MPSS NIPT assay using ccfDNA in maternal blood
* Other: Optical-based MPSS NIPT assay using ccfDNA in maternal blood
* Other: Harmony™ Test (Ariosa Diagnostics)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (High risk arm): women 19 years or older between 10 weeks and 23 weeks 6 days gestation undergoing amniocentesis or CVS for: positive prenatal screen; abnormal ultrasound previous pregnancy with trisomy patient or partner carrier of Robertsonian translocation involving chr 21 positive NIPT result Maternal age 40 or more Inclusion Criteria (Low risk arm): women 19 years and older who are 10 and 13 weeks 6 days gestation based on dating ultrasound (CRL) and are undergoing screening for Down syndrome (first trimester combined, SIPS or IPS) Exclusion Criteria: women with multiple gestations women with twin demise (spontaneous or elective) at any gestational age women with active or history of malignancy

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Screening
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Risk of aneuploidy<br>Integrated prenatal screening for Down's syndrome (with follow-up fetal karyotype if positive); Serum QUAD Assay for aneuploidy screening; Semiconductor MPSS NIPT assay using ccfDNA in maternal blood; Optical-based MPSS NIPT assay using ccfDNA in maternal blood; Harmony™ Test (Ariosa Diagnostics) | Other: Integrated prenatal screening for Down's syndrome<br>* Analysis of several serum biochemical markers, and fetal nuchal translucency by ultrasound, with computation of an individual risk of fetal aneuploidy.<br>* Other names: Downs' syndrome screening;Other: Serum QUAD Assay for aneuploidy screening<br>* Series of biochemical markers with results integrated into a computational estimate of risk of fetal aneuploidy<br>* Other names: First trimester QUAD prenatal screening assay;Other: Semiconductor MPSS NIPT assay using ccfDNA in maternal blood<br>* Analysis by next-generation sequencing of ccfDNA (circulating cell-free DNA) from maternal blood, using a targeted NIPT assay.<br>* Other names: Non-invasive prenatal diagnosis;Other: Optical-based MPSS NIPT assay using ccfDNA in maternal blood<br>* Analysis by next-generation sequencing of ccfDNA (circulating cell-free DNA) from maternal blood, using an un-targeted NIPT assay.<br>* Other names: Non-invasive prenatal diagnosis;Other: Harmony™ Test (Ariosa Diagnostics)<br>* Test that is commercially available (Ariosa Diagnostics). (will be used for benchmarking purposes in a subset of each arm)<br>* Other names: DANSR Assay;|
| Experimental: High risk of aneuploidy<br>Integrated prenatal screening for Down's syndrome (with follow-up fetal karyotype if positive); Serum QUAD Assay for aneuploidy screening; Semiconductor MPSS NIPT assay using ccfDNA in maternal blood; Optical-based MPSS NIPT assay using ccfDNA in maternal blood; Harmony™ Test (Ariosa Diagnostics) (subset) | Other: Integrated prenatal screening for Down's syndrome<br>* Analysis of several serum biochemical markers, and fetal nuchal translucency by ultrasound, with computation of an individual risk of fetal aneuploidy.<br>* Other names: Downs' syndrome screening;Other: Serum QUAD Assay for aneuploidy screening<br>* Series of biochemical markers with results integrated into a computational estimate of risk of fetal aneuploidy<br>* Other names: First trimester QUAD prenatal screening assay;Other: Semiconductor MPSS NIPT assay using ccfDNA in maternal blood<br>* Analysis by next-generation sequencing of ccfDNA (circulating cell-free DNA) from maternal blood, using a targeted NIPT assay.<br>* Other names: Non-invasive prenatal diagnosis;Other: Optical-based MPSS NIPT assay using ccfDNA in maternal blood<br>* Analysis by next-generation sequencing of ccfDNA (circulating cell-free DNA) from maternal blood, using an un-targeted NIPT assay.<br>* Other names: Non-invasive prenatal diagnosis;Other: Harmony™ Test (Ariosa Diagnostics)<br>* Test that is commercially available (Ariosa Diagnostics). (will be used for benchmarking purposes in a subset of each arm)<br>* Other names: DANSR Assay;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of cases with Fetal trisomy 21, 18 or 13 | Only pregnant women will be recruited, fetal outcome will be assessed by fetal karyotype or at or after delivery. | 6 weeks after the delivery date | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of women with assay failure |  | At end of pregnancy. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Fetal aneuploidy