Clinical performance of non‐invasive prenatal testing for trisomies 21, 18 and 13 in twin pregnancies: A cohort study and a systematic meta‐analysis

Abstract

Introduction:The objective of this study was to report on the clinical performance of non-invasive prenatal testing (NIPT) for trisomies 21, 18 and 13 in twin pregnancies and to define the performance of NIPT by combining our cohort study results with published studies in a systematic meta-analysis. Material and methods:A cohort study was carried out in the First Affiliated Hospital of Sun Yat-sen University and Kanghua Hospital. Meanwhile, searches of PubMed, EMBASE, The Cochrane Library and Web of Science for all relevant peer-reviewed articles were performed with a restriction to English language publication before 15 June 2019. Quality assessments were conducted with the Quality Assessment Tool for Diagnostic Accuracy Studies-2 checklist. Data analysis, heterogeneity, subgroup analysis and publication bias were carried out using META-DISC 1.4 and STATA 12.0.Results: In all, 141 twin pregnancies included in our cohort study; confirmation revealed one true-positive case for trisomy 21 and 140 true-negative cases. The sensitivity and specificity for trisomy 21 by NIPT were both 100%. Twenty-two eligible studies were enrolled in this meta-analysis together with our study. There were 199 cases of trisomy 21, 58 cases of trisomy 18, 14 cases of trisomy 13 and 6347 cases of euploids in total. For trisomy 21, NIPT showed the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.99, 1.00, 145.81, 0.06 and 1714.09, respectively. For trisomy 18, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.88, 1.00, 200.98, 0.19 and 483.68, respectively. Conclusions:The performance of NIPT for trisomy 21 in twin pregnancy was excellent and it was similar to that reported in singleton pregnancy. However, due to publication bias (trisomy 18) and small number of cases (trisomy 13), accurate assessment of the predictive performance of NIPT for trisomies 18 and 13 could not be achieved.Our study was approved by the institutional review board of the First Affiliated Hospital, Sun Yat-sen University (no. 2016-03). | Systematic review and meta-analysis | Literature search and study selectionSearches of PubMed, EMBASE, The Cochrane Library and Web of Science for all relevant peer-reviewed articles were performed with K E Y W O R D S non-invasive prenatal testing, trisomy 13, trisomy 18, trisomy 21, twin pregnancies Key messageNon-invasive prenatal testing performs well in twin pregnancies with trisomy 21 and can be popularized for routine prenatal screening in twin pregnancies.

Cell‐free DNA testing of maternal blood in screening for trisomies in twin pregnancy: updated cohort study at 10–14 weeks and meta‐analysis

“…The literature search identified 381 potentially relevant citations, but 366 were excluded because they were not relevant, a conference abstract rather than a peer‐reviewed paper, a review article, an opinion, not confined to twins, a case–control study, a study on clinical implementation of cfDNA testing in screening for aneuploidy in which pregnancy outcome data were provided for fewer than 85% of the study population or a proof‐of‐principle study reporting laboratory techniques rather than clinical validation of a predefined method of maternal blood cfDNA analysis (Figure 2). In total, 15 relevant studies were identified 2,13–26 but three of these 2,13,14 were excluded from the meta‐analysis because their data are included in the updated FMF results presented above. The characteristics of our current study and the 12 studies identified by the literature search are summarized in Table 1.…”

“…The literature search identified 12 studies reporting on screening for trisomy in twin pregnancies by cfDNA testing of maternal blood, in addition to our previous studies, the data from which are included in the current FMF study. The main features of these 12 studies are, first, the method of cfDNA testing was by MPSS in 11 studies and by targeted testing in only one, second, none of the studies was confined to the first trimester and, in some cases, testing was carried out as late as 36 weeks' gestation 16,26 , and, third, in nine of the studies, the cfDNA test provided a result in > 99% of cases 15–18,20,22,23,25,26 and, in six of the studies, pregnancy outcome was apparently obtained in > 99% of cases 14,16,18,21,23,24 .…”

“…The second meta‐analysis examined 10 studies in twin pregnancies, including prospective or retrospective cohort and case–control studies with no criteria on the degree of follow‐up; in a combined total of 69 cases of trisomy 21, 13 cases of trisomy 18 and three cases of trisomy 13, the respective DRs were 99%, 85% and 100% and the combined FPR was 0.05% 30 . The third meta‐analysis examined 25 studies in twin pregnancies, including prospective or retrospective cohort and case–control studies with no criteria on the degree of follow‐up; in a combined total of 199 cases of trisomy 21, 58 cases of trisomy 18 and 14 cases of trisomy 13, the respective DRs were 99%, 88% and 85% and the combined FPR was 0% 25 . The fourth meta‐analysis 26 examined 12 studies in twin pregnancies and, although their stated inclusion criteria were identical to those of Gil et al 2 ,.…”

“…The FMF study is the only one examining the performance of cfDNA testing of maternal blood in first-trimester screening for trisomy in twin pregnancy. The study used targeted analysis of cfDNA, either by next-generation sequencing or by a custom microarray, and demonstrated that, first, a result is obtained, after first or second sampling, in about 95% of cases, second, in about 7% of cases undergoing first-trimester screening, it may not be possible to confirm the results with prenatal or postnatal karyotyping because such testing may not be undertaken if the pregnancy ends in termination, miscarriage or stillbirth or is lost to follow-up, and, third, even though our study population of 1442 cases is relatively large for studies on twin pregnancies, the Lau (2013) 15 1 1 (100; 2.5-100) 11 0 (0; 0-28.49) Huang (2014) 16 9 9 (100; 66.4-100) 180 0 (0; 0-2.03) Tan (2016) 17 4 4 (100; 39.8-100) 506 0 (0; 0-0.73) Du (2017) 18 2 2 (100; 15.8-100) 89 0 (0; 0-4.06) Le Conte (2018) 19 3 3 (100; 29.2-100) 415 1 (0.24; 0.01-1.34) Yang (2018) 20 4 4 (100; 39.8-100) 396 0 (0; 0-0.93) Norwitz (2019) 21 5 5 (100; 47.8-100) 102 0 (0; 0-3.55) Yin (2019) 22 7 7 (100; 59.0-100) 1997 1 (0.05; 0-0.28) Yu (2019) 23 16 16 (100; 79.4-100) 1141 0 (0; 0-0.32) Chibuk (2020) 24 52 51 (98.1; 89.7-100) 333 13 (3.9; 2.09-6.58) He (2020) 25 1 1 (100; 2.5-100) 140 0 (0; 0-2.60) Khalil (2021) 26 13 13 (100; 75. Huang (2014) 16 2 1 (50.0; 1.3-98.7) 187 0 (0; 0-1.95) Le Conte (2018) 19 1 1 (100; 2.5-100) 417 0 (0; 0-0.88) Yang (2018) 20 1 1 (100; 2.5-100) 399 0 (0; 0-0.92) Norwitz (2019) 21 5 5 (100; 47.8-100) 102 0 (0; 0-3.55) Yin (2019) 22 2 2 (100; 15.8-100) 2002 0 (0; 0-0.18) Yu (2019) 23 4 4 (100; 39.8-100) 1153 0 (0; 0-0.32) Chibuk (2020) 24 24 24 (100; 85.8-100) 361 4 (1.11; 0.30-2.81) Khalil (2021) 26 1 0 (0; 0-97.…”

Twins Living Apart: Behavioral Insights/Twin Study Reviews: Managing Monochorionic-Diamniotic Twin Pregnancies; Paternity Testing in Multiple Pregnancies; Twin Research on Resilience; Trisomies in Twin Pregnancies/Human Interest: Reunited Brazilian Twins; Website for Twins with Disabled Co-Twins; Twins Separated in Secret of the Nile Series; Mengele: Unmasking the Angel of Death; Twins Helping Others

“…A prospective study of the efficacy of noninvasive prenatal testing (NIPT) of twin pregnancies for trisomy 21 (Down syndrome), trisomy 18 (Edwards' syndrome) and trisomy 13 (Patau syndrome) is of interest. The work was conducted by He et al (2020), who represent a number of universities and hospitals in China. The researchers asserted that prenatal screening of multiple pregnancies is becoming increasingly important because such conceptions are rising due to advances in reproductive technology.…”