First Trimester Risk Assessment Based on Ultrasound and Cell-free DNA vs Combined Screening

First Trimester Risk Assessment Based on Ultrasound and Cell-free DNA vs Combined Screening: Women's Experience

There is an ongoing debate regarding how cell-free DNA (cfDNA) screening can best be incorporated into current prenatal screening algorithms for chromosomal abnormalities.

Test performance of cfDNA has been shown to be better that first-trimester combined screening (FTCS). However, the cost of the cfDNA testing is considered too high to adopt as first line screening. Moreover, FTCS includes a detailed ultrasound examination of the fetus with nuchal translucency (NT) measurement that allows for early detection of fetal abnormalities.

An approach in which every woman are offered an early anatomy scan along with cfDNA may also be a reasonable option. Recently a randomized controlled trial, including 1,518 women with singleton pregnancy undergoing first-trimester screening, compared the screening performance of FTCS with an approach that uses the combination of a detailed ultrasound examination and cfDNA analysis. The trial showed that first-trimester risk assessment for trisomy 21 that includes a detailed ultrasound examination along cfDNA was associated with a significant reduction in the false-positive rate compared with FTCS. This approach obviates the need for maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A in screening for fetal aneuploidy.

Despite robust evidence on the very high detection rate of cfDNA in detecting trisomy 21, literature is lacking on data regarding women's experience and emotional well-being and satisfaction after test-results of women offered cfDNA compared to those offered FTCS.

Study Overview

• Status: Completed
• Conditions: Aneuploidy
• Intervention / Treatment: Diagnostic test: NIPT; Diagnostic test: combined screening

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Napoli, Italy, 80129
    • Gabriele Saccone

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Pregnant women with singleton gestations
• ≤12 6/7 weeks of gestation
• Normal ultrasound examination at the time of randomization
• >18 <45 years
• Crown-rump length (CRL) <84 mm at the time of randomization

Exclusion Criteria:

• Multiple gestations, including vanishing twins
• >12 6/7 weeks of gestation
• Ectopic pregnancy
• Abnormal ultrasound examination at the time of first prenatal visit
• Women who are unconscious, severly ill, mentally handicapped, or under the age of 18 years.
• Women who have already planned for invasive prenatal testing, e.g. for a history of prior child or pregnancy with chromosomal or genetic abnormalities
• CRL >84mm at the time of randomization

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NIPT; Women randomized in the intervention group will be offered cfDNA screening, along with an early detailed anatomy scan, including nuchal measurement, at 11-13 weeks of gestation. cfDNA analysis will include a simultaneous microarray-based assay of non-polymorphic (chromosomes 13, 18, 21, X and Y) and polymorphic loci to estimate chromosome proportion and fetal fraction. NIPT will be performed at the time of randomization or after if gestational age at randomization < 9 6/7 weeks of gestation.	Diagnostic test: NIPT; Women randomized in the intervention group will be offered cfDNA screening, along with an early detailed anatomy scan, including nuchal measurement, at 11-13 weeks of gestation. cfDNA analysis will include a simultaneous microarray-based assay of non-polymorphic (chromosomes 13, 18, 21, X and Y) and polymorphic loci to estimate chromosome proportion and fetal fraction. NIPT will be performed at the time of randomization or after if gestational age at randomization < 9 6/7 weeks of gestation. Women in both groups will be given oral counseling by obstetricians and will be counseled about test procedures, reporting time, test sensitivity and specificity, and the necessity to confirm abnormal screening results with invasive testing.
Other: Combined screening; Control group includes the standard of care. In our department, first-trimester risk assessment is performed routinely at 11-13 weeks of gestation by FTCS as per standard of care. FTCS includes crown-rump length, NT measurements, and a detailed ultrasound examination based on ISUOG guidelines. All operators who perform this examination are certified by the UK Fetal Medicine Foundation (FMF). A specific risk for aneuploidy is not calculated if NT measurement is >3.5 mm or if fetal anomaly is identified. These cases are deemed to be at a very high risk for chromosomal abnormalities and are offered invasive testing.	Diagnostic test: combined screening; Control group includes the standard of care. In our department, first-trimester risk assessment is performed routinely at 11-13 weeks of gestation by FTCS as per standard of care. FTCS includes crown-rump length, NT measurements, and a detailed ultrasound examination based on ISUOG guidelines. All operators who perform this examination are certified by the UK Fetal Medicine Foundation (FMF). A specific risk for aneuploidy is not calculated if NT measurement is >3.5 mm or if fetal anomaly is identified. These cases are deemed to be at a very high risk for chromosomal abnormalities and are offered invasive testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
reassurance	women will be asked about three questions, with up to 35 point for each question. 1) are you reassured about the test? 2) are you sure the test is correct? 3) test give me certain reassurance about the syndrome of my child	at the time of screening test
Anxiety	anxiety test assessed by State-Trait Anxiety Inventory (STAI)	at the time of screening test
Satisfaction of the pregnant women	women will be asked if retrospectively they are happy with the assigned screening test as post-test satisfaction questionnaire: Not all applicable (5 points); Hardly applicable (10 points); Somewhat applicable (20 points); Very much applicable (35 points)	11-13 weeks of gestation
False positive rate	False positive rate for any trosomy and for trisomy 21	1 week after test
Anxiety	anxiety test assessed by The Pregnancy-Related Anxiety Questionnaire (PRAQ-R)	at the time of screening test

Collaborators and Investigators

• Sponsor: Federico II University

Publications and helpful links

General Publications

• Migliorini S, Saccone G, Silvestro F, Massaro G, Arduino B, D'Alessandro P, Petti MT, Paino JAC, Guida M, Locci M, Zullo F. First-trimester screening based on cell-free DNA vs combined screening: A randomized clinical trial on women's experience. Prenat Diagn. 2020 Oct;40(11):1482-1488. doi: 10.1002/pd.5800. Epub 2020 Aug 13.

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2019
• Primary Completion (Actual): January 15, 2020
• Study Completion (Actual): February 15, 2020

Study Registration Dates

• First Submitted: August 26, 2019
• First Submitted That Met QC Criteria: August 30, 2019
• First Posted (Actual): September 4, 2019

Study Record Updates

• Last Update Posted (Actual): February 24, 2020
• Last Update Submitted That Met QC Criteria: February 20, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Chromosome Aberrations; Aneuploidy
• Other Study ID Numbers: 209/19

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