TY - JOUR
T1 - Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing
T2 - Follow-up results of the TRIDENT-2 study
AU - van Prooyen Schuurman, Lisanne
AU - Sistermans, Erik A.
AU - van Opstal, Diane
AU - Henneman, Lidewij
AU - Bekker, Mireille N.
AU - Bax, Caroline J.
AU - Pieters, Mijntje J.
AU - Bouman, Katelijne
AU - de Munnik, Sonja
AU - den Hollander, Nicolette S.
AU - Diderich, Karin E. M.
AU - Faas, Brigitte H. W.
AU - Feenstra, Ilse
AU - Go, Attie T. J. I.
AU - Hoffer, Mariëtte J. V.
AU - Joosten, Marieke
AU - Komdeur, Fenne L.
AU - Lichtenbelt, Klaske D.
AU - Lombardi, Maria P.
AU - Polak, Marike G.
AU - Jehee, Fernanda S.
AU - Schuring-Blom, Heleen
AU - The Dutch NIPT Consortium
AU - Stevens, Servi J. C.
AU - Srebniak, Malgorzata I.
AU - Suijkerbuijk, Ron F.
AU - Tan-Sindhunata, Gita M.
AU - van der Meij, Karuna R. M.
AU - van Maarle, Merel C.
AU - Vernimmen, Vivian
AU - van Zelderen-Bhola, Shama L.
AU - van Ravesteyn, Nicolien T.
AU - Knapen, Maarten F. C. M.
AU - Macville, Merryn V. E.
AU - Galjaard, Robert-Jan H.
AU - Dutch NIPT Consortium
N1 - Funding Information: The authors would like to thank all participating women for their contribution to the TRIDENT-2 study. We also thank all who have contributed to the organization and execution of the study, including health professionals, laboratory staff, and other supporting staff. Staff members of RIVM/CvB, the Regional Centers for Prenatal Screening, Peridos the online national digital registration system for prenatal screening, and EUROCAT are acknowledged for their collaboration. Beau van Hulst and Maurits van Prooyen Schuurman are acknowledged for their contribution to the data collection for this study, and Sandra van ‘t Padje is acknowledged for her work as functional manager of the NIPT Consortium. This work was supported by a grant from the Netherlands Organisation for Health Research and Development (ZonMw, No. 543002001). E.A.S. was one of the applicants of the ZonMW grant and is a member of the GenQA advisory board (unpaid) and the associate editor of Extracellular Vesicles and Circulating Nucleic Acids. D.V.O. is a member of the project group NIPT additional findings and Project group NIPT Laboratories of the National Institute for Public Health & Environment (RIVM) – Center for Population Screening (CvB). L.H. was one of the applicants of the ZonMW grant. M.N.B. is a member of the project group NIPT additional findings, of the RIVM-CvB (unpaid). C.J.B. is a member of the project group NIPT additional findings, of the RIVM-CvB (unpaid). M.J.P. is a member of the Project group NIPT Quality, and Project group NIPT additional findings, all of the RIVM-CvB (unpaid). M.V.E.M. is a member of the Program Committee Prenatal Screening, Project group NIPT Quality, and Project group NIPT Laboratories, all of the RIVM-CvB (unpaid). Part of the ZonMW grant was paid to his institution for TRIDENT-2 bio-informatic research. R.-J.H.G. was one of the applicants of the ZonMW grant, and he is a member of the Program Committee Prenatal Screening, Project group NIPT Quality, and Project group NIPT additional findings, all of the RIVM-CvB (unpaid). Funding Information: The authors would like to thank all participating women for their contribution to the TRIDENT-2 study. We also thank all who have contributed to the organization and execution of the study, including health professionals, laboratory staff, and other supporting staff. Staff members of RIVM/CvB, the Regional Centers for Prenatal Screening, Peridos the online national digital registration system for prenatal screening, and EUROCAT are acknowledged for their collaboration. Beau van Hulst and Maurits van Prooyen Schuurman are acknowledged for their contribution to the data collection for this study, and Sandra van ‘t Padje is acknowledged for her work as functional manager of the NIPT Consortium. This work was supported by a grant from the Netherlands Organisation for Health Research and Development (ZonMw, No. 543002001 ). Publisher Copyright: © 2022 The Authors
PY - 2022/6/2
Y1 - 2022/6/2
N2 - In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weight <2.3rd percentile (13.6% [24/177] vs 2.5% [3,892/155,491]; RR 5.5) were significantly increased compared to the general obstetric population. Of the 90 maternal findings, 12 (13.3%) were malignancies and 32 (35.6%) (mosaic) pathogenic copy number variants, mostly associated with mild or no clinical phenotypes. Data from this large cohort study provide crucial information for deciding if and how to implement GW-NIPT in screening programs. Additionally, these data can inform the challenging interpretation, counseling, and follow-up of additional findings.
AB - In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weight <2.3rd percentile (13.6% [24/177] vs 2.5% [3,892/155,491]; RR 5.5) were significantly increased compared to the general obstetric population. Of the 90 maternal findings, 12 (13.3%) were malignancies and 32 (35.6%) (mosaic) pathogenic copy number variants, mostly associated with mild or no clinical phenotypes. Data from this large cohort study provide crucial information for deciding if and how to implement GW-NIPT in screening programs. Additionally, these data can inform the challenging interpretation, counseling, and follow-up of additional findings.
KW - NIPS
KW - NIPT
KW - cfDNA
KW - common trisomies
KW - confined placental mosaicism
KW - fetal trisomy
KW - first tier test
KW - genome-wide
KW - prenatal screening
KW - rare autosomal trisomies
UR - http://www.scopus.com/inward/record.url?scp=85131101786&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2022.04.018
DO - https://doi.org/10.1016/j.ajhg.2022.04.018
M3 - Article
C2 - 35659929
SN - 0002-9297
VL - 109
SP - 1140
EP - 1152
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -