TRIDENT-2: National implementation of genome-wide non-invasive prenatal testing as a first-tier screening test in the Netherlands

Diane Van Opstal ⁶ Karuna van der Meij ¹ Erik Sistermans ¹ Merryn Macville ² Servi Stevens ² Caroline Bax ³ Mireille Bekker ⁴ Caterina Bilardo ⁵ Elles Boon ¹ Marjan Boter ⁶ Karin Diderich ⁶ Christine de Die-Smulders ² Leonie Duin ⁷ Brigitte Faas ⁸ Ilse Feenstra ⁸ Monique Haak ⁹ Mariëtte Hoffer ¹⁰ Nicolette den Hollander ¹⁰ Iris Hollink ⁶ Fernanda Jehee ⁶ Maarten Knapen ¹¹ Angelique Kooper ¹² Irene van Langen ¹³ Klaske Lichtenbelt ¹⁴ Ingeborg Linskens ¹⁵ Merel van Maarle ¹² Dick Oepkes ⁹ Mijntje Pieters ¹⁵ Heleen Schuring-Blom ¹⁴ Esther Sikkel ¹⁶ Birgit Sikkema-Raddatz ¹³ Dominique Smeets ⁸ Malgorzata Srebniak ⁶ Ron Suijkerbuijk ¹³ Gita Tan-Sindhunata ¹ Jeanine van der Ven ¹⁷ Shama van Zelderen-Bhola ¹ Lidewij Henneman ¹ Robert-Jan Galjaard ⁶ Marjan Weiss ¹ the Dutch NIPT Consortium ¹

¹Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
²Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, University Medical Center, Maastricht, Maastricht, Netherlands
³Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
⁴Department of Obstetrics and Gynaecology, Utrecht University Medical Center, Utrecht, Netherlands
⁵Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
⁶Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
⁷Department of Obstetry and Gynaecology, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
⁸Department of Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical Center, Nijmegen, Netherlands
⁹Department of Obstetrics, Leiden University Medical Center, Leiden, Netherlands
¹⁰Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
¹¹Department of Obstetrics and Fetal medicine, Erasmus Medical Center, Rotterdam, Netherlands
¹²Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
¹³Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
¹⁴Department of Genetics, Utrecht University Medical Center, Utrecht, Netherlands
¹⁵Department of Obstetrics and Gynecology, Maastricht University Medical Center, Maastricht, Netherlands
¹⁶Department of Obstetrics and Gynecology, Radboud university medical center, Nijmegen, Netherlands
¹⁷Verloskundigenpraktijk Velp, Verloskundigenpraktijk Velp, Velp, Netherlands

The Netherlands is the first country to perform a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started April 1st 2017 as the so-called TRIDENT-2 study, licensed by the Dutch Ministry of Health. Women who choose for prenatal screening can opt to have NIPT or the first-trimester combined test (FCT). Women who elect NIPT can choose for reporting on the chromosomes 21, 18 and 13 with or without chromosomal aberrations on the other autosomes (size resolution of 10-20Mb). Sex chromosomes are not analyzed. Analysis was performed with WISECONDOR . In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7239 (4%) chose FTC, and 54% did not participate in 1^st trimester prenatal screening. Seventy-eight percent of women that chose for NIPT, chose for the reporting of other chromosome aberrations as well. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%) and 13 (55, 0.08%) is in line with earlier studies. The Positive Predictive Values (PPV), 96% for trisomy 21, 98% for trisomy 18 and 53% for trisomy 13, were higher than expected. The number of other chromosome aberrations was 207 (0.36%). This involved other trisomies (101, 0.18%, PPV 6%), structural chromosomal aberrations (95, 0.16%, PPV 32%) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate, as the benefits of detecting other fetal chromosomal aberrations need to be balanced against the risks of false positives, parental anxiety and a potential increase in diagnostic procedures. The first year data provided here including clinical and laboratory follow-up will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded in a national screening program, with a single chain for prenatal care including counseling, testing and follow-up.