Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation - 20/07/22
, Bo Jacobsson, MD, PhD b, c, Cora MacPherson, PhD d, Melissa Egbert, MS e, Fergal Malone, MD f, Ronald J. Wapner, MD g, Ashley S. Roman, MD h, Asma Khalil, MD i, Revital Faro, MD j, Rajeevi Madankumar, MD k, Lance Edwards, MD l, Sina Haeri, MD m, Robert Silver, MD n, Nidhi Vohra, MD o, Jon Hyett, MD p, Garfield Clunie, MD q, Zachary Demko, PhD e, Kimberly Martin, MD e, Matthew Rabinowitz, PhD e, Karen Flood, MD f, Ylva Carlsson, MD, PhD b, c, Georgios Doulaveris, MD a, Ciara Malone, MD f, Maria Hallingstrom, PhD b, Susan Klugman, MD a, Rebecca Clifton, PhD d, Charlly Kao, PhD r, Hakon Hakonarson, MD, PhD r, Mary E. Norton, MD sAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : aneuploidy, cell-free DNA, prenatal screening, trisomy
Plan
| All the site principal investigators (P.D., B.J., F.M., R.W., A.R., A.K., R.F., R.M., L.E., S.H., R.S., N.V., J.H., C.M., R.C., and M.N.) received institutional research support from the funding sponsor (Natera). M.E., Z.D., and M.R. are employed by the study’s funding sponsor (Natera) and hold stock or options to hold stock. K.M. is a consultant to the funding sponsor (Natera) and holds stock and options to hold stock. J.H. has an ongoing research collaboration that includes financial support for biochemical analytes from Perkin Elmer; has earned honoraria and/or given talks that were not compensated from Natera, Roche, and Canon; and has participated in Asian/Australasian expert consultancies for Natera and Roche. |
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| B.J. reports research clinical diagnostic trials with Ariosa (completed), Vanadis (completed), Natera (ongoing), and Hologic (completed), with institutional expenditures reimbursed per patient and no personal reimbursements. He also reports clinical probiotic studies with products provided by FukoPharma (ongoing, no funding) and BioGaia (ongoing; also provided a research grant for the specific study), coordination of scientific conferences and meetings with commercial partners as such as ESPBC 2016 and a Nordic educational meeting about noninvasive prenatal testing and preeclampsia screening. B.J. and Y.C. collaborated in the IMPACT study where Roche, Perkin Elmer, and Thermo Fisher provide reagents to placental growth factor analyses. R.J.W. receives research funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and receives support from Illumina for research reagents. M.N. is a consultant to Invitae. All the other authors report no conflict of interest. |
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| The study was funded by Natera, Inc, Austin, TX. The study was a collaboration between the clinical investigators and the funding sponsor. P.D., M.N., and R.C. designed the protocol with the sponsor (M.E., Z.D., K.M., and M.R.). There were no confidentiality agreements pertaining to study results between the authors, sites, or sponsor. |
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| The trial was registered on ClinicalTrials.gov with identifier NCT02381457, Single-nucleotide-polymorphism-based Microdeletion and Aneuploidy RegisTry (SMART). |
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| Data sharing: Data sharing requests should be submitted to the corresponding author (P.D.) for consideration. The requests will be considered by the study publication committee. The study protocol and statistical analysis plan will be available on request. Individual patient data will not be available. Access to deidentified data may be granted following submission of a written proposal and a signed data sharing agreement. Files will be shared using a secure file transfer protocol. |
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| Ethical approval: This study was designed in compliance with an investigational-review-board-approved protocol (Ethical and Independent Review Services Study ID, 17113; date of certification, August 28, 2017, date of renewal August 20, 2020). Written informed consent was obtained from all the study participants. |
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| Cite this article as: Dar P, Jacobson B, MacPherson C, et al. Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation. Am J Obstet Gynecol 2022;227:259.e1-14. |
Vol 227 - N° 2
P. 259.e1-259.e14 - août 2022 Retour au numéro
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