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

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.

Multiplex ligation-dependent probe amplification (MLPA) as a stand-alone test for rapid aneuploidy detection in amniotic fluid cells.

OBJECTIVE: This study aimed to determine the diagnostic application of multiplex ligation-dependent probe amplification (MLPA) as a stand-alone test for targeted detection of common chromosomal aneuploidies (i.e. 13, 18, 21, X and Y) in amniotic fluid cells in routine prenatal clinical practice. METHODS: In this evaluation study, the MLPA test using kit P095 was performed on 1000 consecutive amniotic fluid samples and the results obtained were compared with traditional karyotyping (TK), the gold standard. RESULTS: The absolute specificity and sensitivity of the MLPA test were 100%. The test yielded a rapid reporting time: 94% within three working days and 5% within seven working days. The test failure rate was 0.8%. The percentage of abnormalities undetectable using this specific test was 2.4%: abnormal foetal ultrasound (N=9), increased risk first trimester screening (N=2), advanced maternal age (N=3) or other reason for referral (N=10). These abnormalities can be categorised in clinically significant (N=8), clinically uncertain (N=4) and clinically nonsignificant (N=12). CONCLUSIONS: MLPA P095 is suitable as a stand-alone test for the rapid and efficient detection of the most common chromosomal aneuploidies in routine prenatal clinical practice. A flow chart for integrating the MLPA test into the cytogenetic laboratory workflow is presented.

Fetal anomaly scan potentially will replace routine AFAFP assays for the detection of neural tube defects.

OBJECTIVES: Introduction of the second-trimester fetal anomaly scan and the decision to offer this scan to every woman in the 18th-22nd week of pregnancy necessitates a re-evaluation of the diagnostic value of the measurement of alpha-fetoprotein (AFP) concentrations in the amniotic fluid (AF) for the detection of neural tube defects (NTDs). METHODS: In this study of 6501 women who underwent amniocentesis, amniotic fluid AFP (AFAFP) concentrations were measured. The women were divided into three categories: group I, without any increased risk of fetal NTD (N = 6188); group II, with an increased risk of fetal NTD (N = 258); and group III, with a clinically diagnosed fetal NTD with known AFAFP concentrations (N = 55). RESULTS: In 27 women of group I (0.4%), the MoM (multiple of the median) level was > 2.5 times the median AFP concentration for the corresponding gestational age, and in two fetuses this was related to NTD. In two pregnancies of group II (0.8%), an increased AFAFP was related to NTD. In group III, 44 of the 55 (80%) samples had an increased AFAFP. CONCLUSION: In the near future, it is likely that imaging will replace AFAFP assays for the detection of fetal NTDs because high quality ultrasound imaging will detect NTDs accurately.