TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands

Abstract

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), 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 because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.

Strategy for Use of Genome-Wide Non-Invasive Prenatal Testing for Rare Autosomal Aneuploidies and Unbalanced Structural Chromosomal Anomalies

“…One of the main study limitations was that this was a selected set of pregnancy samples and thus may not be truly representative of a larger general pregnancy population. Other recent publications have looked at genome-wide NIPT in patient populations of at least 10,000 patients [5,6,34,43], with a few publications reporting results from populations of over 50,000 patients [28,44,45]. However, the observed assay failure rate and FF distribution in our study population were consistent with those observed in the referral population, suggesting the data is representative.…”

“…In our cohort, even if the number is too small to draw definitive conclusions, this strategy is particularly interesting in the low-risk population (first-tier screening) because four of the five anomalies belonged to Groups 2 and 3. If we reanalyze the cohort presented in the recent study of the Dutch NIPT Consortium [28], only 47 women would have received a positive NIPT call for RAAs instead of 101, and all cases with fetal RAAs would have been diagnosed. In our study, targeting SUAs and trisomies 8, 9, 12, 14, 15, 16, and 22 only would generate a positive NIPT call rate of 0.57% (17/3007).…”

“…In recent years, test menu options have expanded to include sex chromosome aneuploidies [24,25], select microdeletions/duplications [26,27], and ACAs [5,6,28]. Although ACAs are rarer, NIPT studies have shown a screen-positive rate of 0.1% for SUAs and 0.34% for RAAs [29].…”

Genome‐wide cfDNA testing of maternal blood

“…The results from the first year of GW-cfDNA testing in The Netherlands (TRIDENT-2 study) included 56 818 women who underwent GW-cfDNA testing, from an initial cohort of 73 239 women who had a cfDNA test; in 207 (0.4%) of these women, the test was positive for RATs (n = 101), SIs (n = 95) or complex abnormal profiles (n = 11) 3 . Among the 101 RATs, six were confirmed but only one of these was associated with an abnormal phenotype.…”

Noninvasive prenatal testing as compared to chorionic villus sampling is more sensitive for the detection of confined placental mosaicism involving the cytotrophoblast

“…Genome-wide NIPT was performed as part of the Dutch Trident 2 study (Trident = Trial by Dutch laboratories for Evaluation of NIPT), using shallow massively parallel sequencing and WISECONDOR for analysis. 5 The four cases presented here involved one case of trisomy 5 and trisomy 7 and three cases of trisomy 8. According to our local protocol, a CVS was recommended, which was performed transabdominally in all cases.…”