Title

Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation

Authors

Pe'er Dar, Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY. Electronic address: peerdar@gmail.com.
Bo Jacobsson, Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Cora MacPherson, The Biostatistics Center, George Washington University, Washington, DC.
Melissa Egbert, Natera Inc, Austin, TX.
Fergal Malone, Department of Obstetrics and Gynecology, Rotunda Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland.
Ronald J. Wapner, Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY.
Ashley S. Roman, Department of Obstetrics and Gynecology, New York University Grossman School of Medicine, New York, NY.
Asma Khalil, Department of Obstetrics and Gynecology, St George's Hospital, University of London, London, United Kingdom.
Revital Faro, Department of Obstetrics and Gynecology, St. Peter's University Hospital, New Brunswick, NJ.
Rajeevi Madankumar, Department of Obstetrics and Gynecology, Long Island Jewish Medical Center, Hyde Park, NY.
Lance Edwards, Suffolk Obstetrics & Gynecology, Port Jefferson, NY.
Sina Haeri, Austin Maternal-Fetal Medicine, Austin, TX.
Robert Silver, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT.
Nidhi Vohra, Department of Obstetrics and Gynecology, North Shore University Hospital, Manhasset, NY.
Jon Hyett, Department of Obstetrics and Gynecology, Royal Prince Alfred Hospital, University of Sydney, Camperdown, Australia.
Garfield Clunie, Department of Obstetrics and Gynecology, Icahn School of Medicine at Mount Sinai, New York, NY.
Zachary Demko, Natera Inc, Austin, TX.
Kimberly Martin, Natera Inc, Austin, TX.
Matthew Rabinowitz, Natera Inc, Austin, TX.
Karen Flood, Department of Obstetrics and Gynecology, Rotunda Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland.
Ylva Carlsson, Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Georgios Doulaveris, Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
Ciara Malone, Department of Obstetrics and Gynecology, Rotunda Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland.
Maria Hallingstrom, Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Susan Klugman, Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
Rebecca Clifton, The Biostatistics Center, George Washington University, Washington, DC.
Charlly Kao, Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
Hakon Hakonarson, Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
Mary E. Norton, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA.

Document Type

Journal Article

Publication Date

1-25-2022

Journal

American journal of obstetrics and gynecology

DOI

10.1016/j.ajog.2022.01.019

Keywords

aneuploidy; cell-free DNA; prenatal screening; trisomy

Abstract

BACKGROUND: Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy. OBJECTIVE: To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries. Women who had single-nucleotide-polymorphism-based cell-free DNA screening for trisomies 21, 18, and 13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. The test performance and test failure (no-call) rates were assessed for the cohort, and women with low and high previous risks for aneuploidy were compared. An updated cell-free DNA algorithm blinded to the pregnancy outcome was also assessed. RESULTS: A total of 20,194 women were enrolled at a median gestational age of 12.6 weeks (interquartile range, 11.6-13.9). The genetic outcomes were confirmed in 17,851 cases (88.4%): 13,043 (73.1%) low-risk and 4808 (26.9%) high-risk cases for aneuploidy. Overall, 133 trisomies were diagnosed (100 trisomy 21; 18 trisomy 18; 15 trisomy 13). The cell-free DNA screen positive rate was lower in the low-risk vs the high-risk group (0.27% vs 2.2%; P<.0001). The sensitivity and specificity were similar between the groups. The positive predictive value for the low- and high-risk groups was 85.7% vs 97.5%; P=.058 for trisomy 21; 50.0% vs 81.3%; P=.283 for trisomy 18; and 62.5% vs 83.3; P=.58 for trisomy 13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. The trisomy rate was higher in the 287 cases with no-call results than patients with a result on a first draw (2.8% vs 0.7%; P=.001). The updated algorithm showed similar sensitivity and specificity to the study algorithm with a lower no-call rate. CONCLUSION: In women at a low risk for aneuploidy, single-nucleotide-polymorphism-based cell-free DNA has high sensitivity and specificity, positive predictive value of 85.7% for trisomy 21 and 74.3% for the 3 common trisomies. Patients who receive a no-call result are at an increased risk of aneuploidy and require additional investigation.

Department

Epidemiology

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