Noninvasive prenatal screening in twin pregnancies with cell-free DNA using the IONA test: a prospective multicenter study

• Published in: American journal of obstetrics and gynecology 2021-07, Vol.225 (1), p.79.e1-79.e13
• Main Authors: Khalil, Asma, Archer, Rosalyn, Hutchinson, Victoria, Mousa, Hatem A., Johnstone, Edward D., Cameron, Martin J., Cohen, Kelly E., Ioannou, Christos, Kelly, Brenda, Reed, Keith, Hulme, Rachel, Papageorghiou, Aris T.
• Format: Article
• Language: English
• Subjects: aneuploidy; cell-free fetal DNA; detection rate; diagnostic accuracy; Down syndrome; false-positive rate; NIPT; noninvasive; screening; sensitivity; specificity; trisomy; twin
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2021.01.005

In singleton pregnancies, studies investigating cell-free DNA in maternal blood have consistently reported high detection rate and low false-positive rate for the 3 common fetal trisomies (trisomies 21, 18, and 13). The potential advantages of noninvasive prenatal testing in twin pregnancies are even greater than in singletons, in particular lower need for invasive testing and consequent fetal loss rate. However, several organizations do not recommend cell-free DNA in twin pregnancies and call for larger prospective studies. In response to this, we undertook a large prospective multicenter study to establish the screening performance of cell-free DNA for the 3 common trisomies in twin pregnancies. Moreover, we combined our data with that reported in published studies to obtain the best estimate of screening performance. This was a prospective multicenter blinded study evaluating the screening performance of cell-free DNA in maternal plasma for the detection of fetal trisomies in twin pregnancies. The study took place in 6 fetal medicine centers in England, United Kingdom. The primary outcome was the screening performance and test failure rate of cell-free DNA using next generation sequencing (the IONA test). Maternal blood was taken at the time of (or after) a conventional screening test. Data were collected at enrolment, at any relevant invasive testing throughout pregnancy, and after delivery until the time of hospital discharge. Prospective detailed outcome ascertainment was undertaken on all newborns. The study was undertaken and reported according to the Standards for Reporting of Diagnostic Accuracy Studies. A pooled analysis was also undertaken using our data and those in the studies identified by a literature search (MEDLINE, Embase, CENTRAL, Cochrane Library, and ClinicalTrials.gov) on June 6, 2020. A total of 1003 women with twin pregnancies were recruited, and complete data with follow-up and reference data were available for 961 (95.8%); 276 were monochorionic and 685 were dichorionic. The failure rate was 0.31%. The mean fetal fraction was 12.2% (range, 3%–36%); all 9 samples with a 3% fetal fraction provided a valid result. There were no false-positive or false-negative results for trisomy 21 or trisomy 13, whereas there was 1 false-negative and 1 false-positive result for trisomy 18. The IONA test had a detection rate of 100% for trisomy 21 (n=13; 95% confidence interval, 75–100), 0% for trisomy 18 (n=1; 95% confidence interval, 0–98), and 1